EA040620B1 - PIPERIDINE CXCR7 RECEPTOR MODULATORS - Google Patents

Description

The invention relates to novel piperidine derivatives of formula (I) which are useful as drugs that are modulators of the CXCL11/CXCL12 CXCR7 receptor, and to related aspects, including methods for preparing compounds of formula (I), pharmaceutical compositions containing one or several compounds of formula (I) and to the use of compounds of formula (I) as modulators of the CXCL11/CXCL12 CXCR7 receptor. The invention also relates to compounds of formula (I) and their use as drugs in combination with one or more therapeutic agents and/or radiotherapy and/or targeted therapy for the treatment of malignant neoplasms (especially brain tumors, including malignant gliomas, multiforme glioblastoma, neuroblastoma, pancreatic cancer, including pancreatic adenocarcinoma/pancreatic ductal adenocarcinoma, gastrointestinal cancer, including colon carcinoma, hepatocellular carcinoma, Kaposi's sarcoma, leukemias, including adult T-cell leukemia; lymphomas; lung cancer; breast cancer; rhabdomyosarcoma; prostate cancer; esophageal squamous cell carcinoma; oral squamous cell carcinoma; endometrial cancer; thyroid carcinoma, including papillary thyroid carcinoma; metastatic cancers; pulmonary metastases; skin cancer, including number of melanomas and metastats ic melanoma; bladder cancer; multiple myelomas; osteosarcoma; cancers of the head and neck; and kidney cancer, including clear cell kidney cancer, metastatic clear cell kidney cancer).

Chemokine receptors are a group of G protein coupled receptors (GPCRs) that bind peptide chemokine ligands with high affinity. The main function of chemokine receptors is to direct the migration of leukocytes to lymphoid organs and tissues at rest and during inflammation, and the role of certain chemokine receptors in relation to non-hematopoietic cells and their progenitors has also been recognized.

CXCR7 (also known as ACKR3, also known as RDC1, also known as CMKOR1, also known as GPR159) contains two known chemokine ligands: CXCL12 (also known as stromal cell factor 1, SDF1; also known as pre-B cell growth, PBSF) and CXCL11 (also known as 1-TAC, also known as INF-y inducible T cell, chemoattractant).

The stromal chemoattractant CXCL12 is involved in the immunological control and regulation of inflammatory responses. CXCL12 is secreted by bone marrow stromal cells, endothelial cells, heart, skeletal muscle, liver, brain, kidney, and parenchyma cells and plays an essential role in stem cell proliferation, survival, and homing of hematopoietic progenitor cells into the bone marrow (Rankin SM et al.; Chemokine and adult bone marrow stem cells Immunol. let. 2012, 145(1-2):47-54). CXCL12 also recruits bone marrow-derived progenitor cells to sites of vasculature formation. In addition, it plays an important role in carcinogenesis. CXCL12 promotes recruitment of endothelial progenitors and suppressor cells of myeloid origin to tumor sites, as well as to other bone marrow cells. In addition, CXCL12 regulates angiogenesis/vasculogenesis associated with tumor progression and plays a key role in seeding circulating tumor cells to metastatic sites. In addition to chemotactic functions, CXCL12 has been shown to regulate tumor cell proliferation, motility, and survival (Kryczek I. et al.; CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers; Cancer Res. 2005, 65(2): 465-72; Teicher B. A. et al.; CXCL12 (SDF-1)/CXCR4 pathway in cancer; Clin. Can. Res. 2010, 16(11):2927-31; Domanska U. M. et al.; A review on CXCR4/ CXCL12 axis in oncology: no place to hide European J of cancer 2013, 49(l):219-30).

In addition to CXCR7, CXCL12 binds and activates CXCR4 (also known as fusin, also known as the seven-span membrane leukocyte receptor; LESTR, also known as D2S201E, also known as the 7-segment transmembrane receptor, also known as HM89, also known as lipopolysaccharide-associated protein 3; 1ap3, also known as LPS-associated protein 3), while CXCL11 binds and activates CXCR3 (also known as GPR9, also known as CD 183).

Thus, the interaction of CXCR7 and its ligands CXCL12 and CXCL11 (hereinafter referred to as the CXCR7 axis) is involved in targeting receptor-bearing cells to specific sites in the body, in particular to sites of inflammation, immune damage and immune dysfunction, and is also associated with tissue damage, induction apoptosis, cell growth and angiostasis. CXCR7 and its ligands are upregulated and expressed at high levels in a variety of pathological situations, including cancer, autoimmune disorders, inflammation, infection, transplant rejection, fibrosis, and neurodegeneration.

Malignant neoplasms are among the leading causes of death worldwide. Tumors are composed of abnormally proliferating malignant cancer cells as well as a functionally supportive microenvironment. This tumor microenvironment is composed of a complex array of cells, extracellular matrix components, and signaling molecules, and is mediated by altered communication between stromal and tumor cells. As tumors grow in size, they cause the production of a variety of factors that can help the tumor grow, such as angiogenic factors (promoting ingrowth of blood vessels) or that can help avoid attack by the host's immune response. CXCL12 is such an angiogenic and immunomodulatory factor produced in tumors.

The CXCR7 modulators of the present invention may be useful alone or in combination in cancers where CXCL11/CXCL12 expression of the CXCR7 receptor correlates with disease progression in cancers (particularly pancreatic cancer, pancreatic adenocarcinoma, breast cancer, hormone resistant prostate cancer, renal cell carcinoma, cervical cancer, intraepithelial neoplasia of the cervix, papillary thyroid carcinoma, bladder cancer, Ewing's sarcoma, colon cancer, malignant neoplasms of the colon, lung cancer, lung adenocarcinoma, non-small cell lung cancer, meningiomas , MALT lymphoma, skin squamous cell carcinoma, neuroendocrine tumors, nasopharyngeal cancer, glioblastoma multiforme, astrocytomas, gliomas, hepatocellular carcinoma, estrogen receptor-positive breast cancer, osteosarcoma, gallbladder cancer, tumors kidney and renal cell carcinoma). CXCR7 is also expressed in leukemias, adenocarcinomas, brain metastases, multiple myelomas, head and neck cancers, primary skin melanoma, melanoma, metastatic melanoma, rhabdomyosarcoma, pituitary adenoma, oral squamous cell carcinoma, oral tumors, lymphoplasmacytic lymphoma, T-cell adult leukemia, brain tumors, esophageal squamous cell carcinoma, esophageal cancer, ovarian carcinoma, lymphoma, virus-induced tumors, otorhinolaryngological neoplasm, Burkitt's lymphoma, Hodgkin's cancer, thyroid cancer, cervical squamous cell carcinoma, endometrial cancer, neuroblastoma, gastrointestinal cancer intestinal tract, lymphoproliferative disease, acute myeloid leukemia, acute lymphocytic leukemia, gastrointestinal cancer, nerve sheath tumors and choriocarcinoma, malignant pleural mesothelioma, neurilemnoma, meningioma, diffuse large B-cell lymphoma, oral leukoplakia, Kaposi's sarcoma and alveolar polar rhabdomyosarcoma (for reference, see Sun et al.; CXCL12/CXCR4/CXCR7 Chemokine Axis and Cancer Progression; Cancer Metastasis Rev. 2010, 29(4), 709-722).

These CXCR7 modulators may be useful, alone or in combination, in diseases where modulation of CXCR7 using siRNA, hairpin RNA, miRNA, overexpression, CXCR7 knockout animals, CXCR7 agonists, antagonists, antibodies, or nanobodies has been shown to alter tumor growth in experimental disease models either alone or in combination with cytotoxic treatments, including but not limited to hepatocellular carcinoma (Xue T.C. et al.; Down-regulation of CXCR7 inhibits the growth and lung metastasis of human hepatocellular carcinoma cells with highly metastatic potential; Exp. Ther. Med. 2012, 3(1): 117-123; Zheng et al.; Chemokine receptor CXCR7 regulates the invasion, angiogenesis and tumor growth of human hepatocellular carcinoma cells; Journal of Experimental and Clinical Cancer Research. 2010, 11;29:31), Kaposi's sarcoma (Raggo C. et al.; Novel cellular genes essential for transformation of endothelial cells by Kaposi's sarcoma associated herpesvirus; Cancer Res. 2005, 65(12):5084-95), T-cell leukemia (Jin Z. et al.; CXCR7 is inducible by HTLV-1 Tax and promotes growth and survival of HTLV-1-infected T cells; Int. J. Cancer. 2009, 125(9):2229-35), lymphomas (Burns J.M. et al.; A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development; J. Exp. Med. 2006, 203(9):2201-13), lung carcinoma, breast cancer (Miao Z. et al.; CXCR7 (RDC1) CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor- associated vasculature, PNAS 2007, 104(40): 15735-40), rhabdomyosarcomas (Grymula K. et al.; Overlapping and distinct role of CXCR7-SDF-1/ITAC and CXCR4-SDF-1 axes in regulating metastatic behavior of human rhabdomyosarcomas; Int. J. cancer. 2010, 127(11):2554-68), prostate cancer (Wang J. et al.; The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF1 in prostate cancer; J. biol. Chem. 2008, 283(7):4283-94), pancreatic cancer (Shakir M. et al.; T he chemokine receptors CXCR4/CXCR7 and their primary heterodimeric ligands CXCL12 and CXCL12/high mobility group box 1 in pancreatic cancer growth and development: finding flow; pancreas. 2015, 44(4):528-34), esophageal squamous cell carcinoma (Zhou S.M. et al.; miR-100 suppresses the proliferation and tumor growth of esophageal squamous cancer cells via targeting CXCR7; Oncol Rep. 2016, 35(6): 3453-9), endometrial cancer (Long P. et al.; Inhibition of CXCR4 and CXCR7 for reduction of cell proliferation and invasion in human endometrial cancer; Tumor boil. 2016, 37(6):7473-80), papillary thyroid carcinoma glands (Zhang H. et al.; The chemokine receptor CXCR7 is a critical regulator for the tumorigenesis and development of papillary thyroid carcinoma by inducing angiogenesis in vitro and in vivo; Tumor boil. 2016, 37(2):2415-23), oral squamous cell carcinoma (Chen N. et al.; CXCL12-CXCR4/CXCR7 axis contributes to cell motilities of oral squamous cell carcinoma; Tumor boil. 2016, 37(l):567-75), lung metastases (GoguetSurmenian et al. ; CXCR7-mediated progression of osteosarcoma in the lungs.; Br J Cancer. 2013, 109(6):157985), melanomas (McConnell A.T. et al.; Th e prognostic significance and impact of the CXCR4/CXCR7/CXCL12 axis in primary cutaneous melanoma; Br. J. Dermatol. 2016, doi: 10.1111/bjd. 14720), bladder cancer (Liu L. et al.; Decreased expression of miR-430 promotes the development of bladder cancer via the upregulation of CXCR7; Mol. Med. Rep. 2013, 8(1): 140 -6), plasmacytomas (Azab A.K. et al.; CXCR7-dependent angiogenic mononuclear cell trafficking regulates tumor progression in multiple myeloma; Blood. 2014, 124(12): 1905-14), osteosarcomas (Zhang Y. et al.; Knockdown of CXCR7 inhibits proliferation and invasion of osteosarcoma cells through inhibition of the PI3K/Akt and β-arrestin pathways; Oncol. Rep. 2014, 32(3):965-72), colon cancer (Wang H.X. et al.; Role of CXC chemokine receptor type 7 in carcinogenesis and lymph node metastasis of colon cancer; Mol. Clin. Oncol. 2015, 3(6):1229-1232), grade 4 astrocytomas (Walters M.J. et al.; Inhibition of CXCR7 extends survival following irradiation of brain tumors in mice and rats; Br. J. Cancer. 2014, 110(5): 1179-88), head and neck cancers (Maussang D. et al.; Llama-derived single var iable domains (nanobodies) directed against chemokine receptor CXCR7 reduce head and neck cancer cell growth in vivo; J biol. Chem. 2013, 288(41):29562-72), neuroblastoma (Liberman J. et al.; Involvement of the CXCR7/CXCR4/CXCL12 axis in the malignant progression of human neuroblastoma; Plos One. 2012, 7(8):e43665) and glioblastomas (Liu Y.; Targeting chemokine receptor CXCR7 inhibits glioma cell proliferation and mobility; Anticancer Res. 2015, 35(1):53-64; Walters M.J. et al.; Inhibition of CXCR7 extends survival following irradiation of brain tumours in mice and rats; Br. J. Cancer. 2014, 110(5): 1179-88; Ebsworth K. et al.; The effect of the CXCR7 inhibitor CCX662 on survival in the ENU rat model of glioblastoma; J. Clin. Oncol. 2012, 30(15) e13580); to transform tumor-associated blood vessels (Miao Z. et al.; CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. PNAS. 2007, 104(40): 15735-40); reduce tumor cell seeding (Grymula K. et al.; Overlapping and distinct role of CXCR7-SDF-1/ITAC and CXCR4-SDF-1 axes in regulating metastatic behavior of human rhabdomyosarcomas; Int. J. cancer. 2010, 127(11 ):2554-68); regulate leukocyte migration (Berahovich R.D. et al.; Endothelial expression of CXCR7 and the regulation of systemic CXCL12 levels; Immunology. 2014, 141(1):111-22); reduce the clinical rates of rheumatoid arthritis in collagen-induced arthritis mice (Watanabe K. et al.; Pathogenic role of CXCR7 in rheumatoid arthritis; Arthritis Rheum. 2010, 62(11):3211-20); reduce the clinical severity of experimental autoimmune encephalomyelitis affecting leukocyte infiltration and microglial chemotaxis :170; Bao J. et al.; CXCR7 suppression modulates microglial chemotaxis to ameliorate experimentally-induced autoimmune encephalomyelitis; Biochem. Biophys. Res. Commun. 2016 Jan 1; 469(1): 1-7); reduce disease activity of experimental autoimmune neuritis (Brunn A. et al.; Differential effects of CXCR4-CXCL12- and CXCR7-CXCL12-mediated immune reactions on murine P0106-125 -induced experimental autoimmune neuritis; Neuropathol. Appl. Neurobiol. 2013, 39( 7):772-87); promote remyelination in the cuprizone model by promoting oligodendroglial cell maturation (Williams J.L. et al.; Targeting CXCR7/ACKR3 as a therapeutic strategy to promote remyelination in the adult central nervous system; J. Exp. Med. 2014, 5; 211(5): 791-9, Gottle P. et al., Activation of CXCR7 receptor promotes oligodendroglial cell maturation, Ann Neurol 2010, 68(6):915-24); attenuate hypoxia-induced chronic pulmonary hypertension (Sartina E. et al.; Antagonism of CXCR7 attenuates chronic hypoxia-induced pulmonary hypertension; Pediatr. Res. 2012, 71(6):682-8); induce anxiolytic behavior (Ikeda Y. et al.; Modulation of circadian glucocorticoid oscillation via adrenal opioid-CXCR7 signaling alters emotional behavior; Cell. 2013, 5; 155(6): 1323-36); trigger an angiocrinal response to initiate liver regeneration and eliminate fibrosis to promote alveolar bone healing and reduce pulmonary fibrosis (Cao Z. et al.; Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis; Nat. Med. 2016, ;22(2): 154-62); limit atherosclerosis by reducing macrophage migration (Zhao D. et al.; Pioglitazone Suppresses CXCR7 Expression To Inhibit Human Macrophage Chemotaxis through Peroxisome Proliferator-Activated Receptor y; Biochemistry. 2015, 17; 54(45):6806-14; Ma W. et al., Atorvastatin inhibits CXCR7 induction to reduce macrophage migration Biochem Pharmacol 2014, 1;89(1):99-108); and improve the beneficial effects of mesenchymal stem cells for the treatment of renal ischemia/reperfusion injury (Liu H. et al.; The role of SDF-1CXCR4/CXCR7 axis in the therapeutic effects of hypoxia-preconditioned mesenchymal stem cells for renal ischemia/reperfusion injury; Plos One. 2012, 7(4):e34608).

In addition, CXCR7 has been suggested to be involved in cardiac stem cell migration (Chen D. et al.; Crosstalk between SDF-1/CXCR4 and SDF-1/CXCR7 in cardiac stem cell migration; Sci Rep. 2015, 5:16813) , chronic allograft vasculopathy (Thomas M.N. et al.; SDF-1/CXCR4/CXCR7 is pivotal for vascular smooth muscle cell proliferation and chronic allograft vasculopathy; Transpl. Int. 2015, 28(12): 1426-35), inflammatory bowel disease (Werner L. et al.; Involvement of CXCR4/CXCR7/CXCL12 Interactions in Inflammatory bowel disease; Theranostics. 2013, 3(1):40-6), chronic rhinosinusitis (Patadia M. et al.; Evaluation of the presence of B-cell attractant chemokines in chronic rhinosinusitis; Am. J. Rhinol. Allergy, 2010, 24(1): 11-6), human lung vascular disease (Rafii S. et al.; Platelet-derived SDF-1 primes the pulmonary capillary vascular niche to drive lung alveolar regeneration; Nat. Cell Biol. 2015, 17(2): 123-36) and the development of severe preeclampsia (Lu J. et a l.; CXCR4, CXCR7, and CXCL12 are associated with trophoblastic cells apoptosis and linked to pathophysiology of severe preeclampsia.; Exp. Mol. Pathol. 2016, 100(1): 184-91). In addition to the aforementioned diseases, modulators

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CXCR7 may be useful in the treatment of renal allograft rejection, systemic lupus erythematosus, osteoarthritis, pulmonary vascular disease, acute renal failure, ischemia, chronic allograft rejection, acute coronary syndrome, central nervous system injury; hyperlipidemia, hematopoietic stem cell transplantation, cerebral ischemia, hypertension, pulmonary hypertension, Shiga toxin-associated hemolytic uremic syndrome, HIV/AIDS; acute lung injury, asthma, cirrhosis, stress-related disorders, proliferative diabetic retinopathy, West Nile viral encephalitis, vascular injury, and pulmonary fibrosis.

Mechanistically, recent studies have provided increasing evidence that activation of the CXCL12 pathway is a potential mechanism for tumor resistance to both conventional therapies and biological agents through multiple complementary actions: (i) by directly promoting cancer cell survival, invasion, and cancer stem cell phenotype and/or tumor-initiating cells; (ii) by recruiting the distal stroma (ie cells derived from myeloid bone marrow) to facilitate immunosuppression, tumor recurrence and metastasis; and (iii) by direct or paracrine stimulation of angiogenesis (Duda DG et al. CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies?; Clin. Cancer Res; 2011, 17(8); 2074-80 ) have recently discussed preclinical and clinical data that support the potential use of anti-CXCL12 agents, including CXCR7 modulators, as sensitizers to currently available cancer therapies. In addition, upregulation of CXCR7 expression on the endothelium appears to be critical for inflammatory infiltration in autoimmune diseases. CXCL12 and CXCL11 are key ligands in the immune-inflammatory response: (i) by influencing cell migration, cell adhesion and cell survival (Kumar R. et al.; CXCR7 mediated Gia independent activation of ERK and Akt promotes cell survival and chemotaxis in T cells; Cell Immunol 2012, 272(2):230-41); (ii) by controlling cell differentiation and polarization, i.e. macrophages (Ma W. et al.; Atorvastatin inhibits CXCR7 induction to reduce macrophage migration. Biochem. Pharmacol. 2014, 1; 89(1):99-108), CD4+ T cells/Zohar Y. et al.; CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis; J.Clin. Invest. 2014, 124(5):2009-22), progenitor oligodendrocytes (Gottle P. et al.; Activation of CXCR7 receptor promotes oligodendroglial cell maturation; Ann. Neurol. 2010, 68(6):915-24); (iii) participating in homing processes (Lewellis S.W. et al.; Precise SDF1-mediated cell guidance is achieved through ligand clearance and microRNA-mediated decay. J. Cell Biol. 2013, 4; 200(3):337-55). Therefore, the targeting of CXCR7 and thus the regulation of its ligand content will play a critical role in the pathogenesis of a wide range of autoimmune and inflammatory diseases. Sanchez-Martin et al (Sanchez-Martin et al.; CXCR7 impact on CXCL12 biology and disease; Trends Mol. Med. 2013, 19(1): 12-22) recently discussed CXCR7 dysregulation in disease and highlighted the fact that this receptor is an attractive therapeutic target for the treatment of autoimmune diseases and inflammation.

Thus, these CXCR7 antagonists may be useful alone or in combination with one or more therapeutic agents and/or chemotherapy and/or radiotherapy and/or immunotherapy; in particular in combination with chemotherapy, radiotherapy, EGFR inhibitors, aromatase inhibitors, immunotherapy, such as, in particular, blockade of PD1 and/or PDL1 and/or blockade of CTLA4, or other targeted therapies; for the prevention/prevention or treatment of cancers such as carcinomas; adenocarcinomas; neuroendocrine tumors; skin cancer, including melanoma and metastatic melanoma; lung cancer, including non-small cell lung cancer; metastatic cancer; lung metastases; bladder cancer, including a tumor marker for bladder cancer; urothelial cancer; kidney cancer, including renal cell carcinoma; metastatic renal cell carcinoma, metastatic clear cell carcinoma of the kidney; gastrointestinal cancer, including colon carcinoma, colorectal adenoma, colorectal adenocarcinoma, colorectal cancer, metastatic colorectal cancer, familial adenomatous polyposis (FAP), esophageal cancer, oral squamous cell carcinoma; stomach cancer, gallbladder cancer, cholangiocarcinoma, hepatocellular carcinoma; pancreatic cancer, in particular pancreatic adenocarcinoma or ductal (adeno)carcinoma of the pancreas; endometrial cancer; ovarian cancer; cervical cancer; neuroblastoma; prostate cancer, including castration-resistant prostate cancer; brain tumors, including brain metastases, malignant gliomas, glioblastoma multiforme, medulloblastoma, meningiomas; breast cancer, including triple-negative breast cancer; oral tumors; tumors of the nasopharynx; thoracic cancer; cancers of the head and neck; leukemias, including acute myeloid leukemia, acute myeloid thyroid carcinoma, adult T-cell leukemia; thyroid carcinoma, including papillary thyroid carcinoma; choriocarcinoma; Ewing's sarcoma; osteosarcoma; rhabdomyosarcoma; Kaposi's sarcoma; lymphomas including Burkitt's lymphoma, Hodgkin's lymphoma, MALT-type lymphoma; primary intraocular B-cell lymphoma, multiple myeloma and virus-induced tumors; and diseases including CXCR7 and/or CXCL12 and/or CXCL11 mediated metastasis, chemotaxis, cell adhesion, transendothelial migration, cell proliferation and/or

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In particular, the potential role of CXCR7 in brain tumors, malignant glioma and glioblastoma multiforme is known from the literature. CXCL12 pathway modulators, including CXCR7 modulators, have been mentioned as potential therapeutic agents for the treatment of brain cancer in combination with chemotherapy or radiotherapy. For example, Hattermann et al. (Hattermann et al.; The chemokine receptor CXCR7 is highly expressed in human glioma cells and mediates antiapoptotic effects; Cancer research 2010, 70 (8):3299-3308) indicate that CXCL12 stimulation prevents apoptosis induced by camptothecin and temozolomide, and that CXCR7 antagonist reduces the anti-apoptotic effect of CXCL12. The authors concluded that CXCR7 is a functional receptor for CXCL12 in astrocytomas/glioblastomas and mediates resistance to drug-induced apoptosis. In addition, Hattermann et al. (Hattermann et al.; CXCL12 mediates apoptosis resistance in rat C6 glioma cells; Oncol. Rep. 2012, 27: 1348-1352) indicate that CXCL12 suppresses the antiproliferative effect of temozolomide. The authors also indicate that this effect can be almost completely eliminated by a specific antagonist of CXCR7, indicating that the anti-apoptotic effect of CXCL12 is mainly mediated through CXCR7. Ebsworth et al (Ebsworth et al.; Neuro Oncol (2013) 15 (suppl 3):iii37-iii61. ET-023) indicate that a CXCR7 antagonist significantly prolongs survival when administered in combination with radiation therapy in a rat model of glioblastoma. This observation is supported by other studies (e.g. Ebsworth K et al.; The effect of the CXCR7 inhibitor CCX662 on survival in the ENU rat model of glioblastoma; J Clin Oncol. 2012, 30(15) el3580; Walters MJ et al.; Inhibition of CXCR7 extends survival following irradiation of brain tumors in mice and rats, Br J Cancer 2014, 110(5): 1179-88, describing that inhibition of CXCR7 in vivo in combination with radiotherapy leads to a significant increase in survival time in another model of glioblastoma in rats. In addition, Liu S.C. et al (Liu S.C. et al.; Neuro-Oncology 2014; 16(1):21-28) indicate that inhibition of CXCL12 after irradiation inhibits tumor recurrence in autochthonous brain tumors in rats. Liu S.C. et al. (Liu S.C. et al.; Blockade of SDF-1 after irradiation inhibits tumor recurrences of autochthonous brain tumors in rats; Neuro Oncol. 2013, 16(1):21-8) also indicate that inhibition of CXCL12 in a model of brain metastases after irradiation leads to a marked inhibition of tumor growth and prolongation of life compared with irradiation alone. Calatozzolo C. et al (Calatozzolo C. et al.; Expression of the new CXCL12 receptor, CXCR7, in gliomas; Cancer Biol Ther. 2011, 11(2), 1-12) describe in in vitro experiments that CXCR7 antagonists showed complete inhibition of glioma proliferation.

In particular, the role of CXCR7 in pancreatic tumors has been described in the literature. Shakir et al. (Shakir M. et al.; The chemokine receptors CXCR4/CXCR7 and their primary heterodimeric ligands CXCL12 and CXCL12/high mobility group box 1 in pancreatic cancer growth and development: finding flow; Pancreas. 2015, 44(4):528-34 ) found that CXCR4 and CXCR7, when interacting with CXCL12, activated downstream protein kinases that provoked more aggressive behavior. Moreover, expression of CXCR7 and CXC112 correlates with histological parameters of tumors (Liu Z. et al.; Expression of stromal cell-derived factor 1 and CXCR7 ligand receptor system in pancreatic adenocarcinoma. World J. Surg. Oncol. 2014, 12:348) . These results were confirmed by Heinrich E.L. et al. (Heinrich E.L. et al.; Chemokine CXCL12 activates dual CXCR4 and CXCR7-mediated signaling pathways in pancreatic cancer cells; J. Transl. Med. 2012, 10:68). Therefore, CXCR7 modulators may be useful in the treatment of pancreatic cancer.

CXCR7 modulators may also be useful in the treatment of papillary thyroid carcinoma. Liu Z. et al. (Liu Z. et al.; The involvement of CXCR7 in modulating the progression of papillary thyroid carcinoma; J. Surg. Res. 2014, 191(2):379-88) described that CXCR7 messenger RNA and protein were markedly increased in papillary thyroid carcinoma and correlated with tumor progression. CXCR7 can regulate proliferation, cell cycle, apoptosis, invasion, and expression of cell cycle regulatory proteins involved in the S-G2 phase transition. Knockdown of CXCR7 in papillary thyroid carcinoma cells suppressed cell proliferation and invasion, caused S-phase arrest, and promoted apoptosis. Zhang H. et al. also demonstrated that CXCR7 affects the growth of papillary thyroid carcinoma cells and is involved in papillary thyroid carcinoma oncogenesis, probably through regulation of angiogenesis by pro-angiogenic VEGF or IL-8. (Zhang H. et al.; The chemokine receptor CXCR7 is a critical regulator for the tumorigenesis and development of papillary thyroid carcinoma by inducing angiogenesis in vitro and in vivo; Tumor Biol. 2016, 37(2):2415-23). The expression and function of the CXCR7 axis in thyroid cancer was confirmed by Zhu X et al. (by Zhu X et al.; Expression and function of CXCL12/CXCR4/CXCR7 in thyroid cancer; Int J Oncol. 2016, 48(6):2321-9).

CXCR7 modulators may also be useful in the treatment of lung cancer: Using a combination of overexpression and RNAi, Miao Z. et al (Miao Z. et al.; CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor- associated vasculature PNAS 2007, 104(40): 15735-40) found that CXCR7 promotes the growth of tumors derived from breast and lung cancer cells and increases experimental lung metastases. Iwakiri S. et al. (Iwakiri S. et al.; Higher ex- 5 040620 pression of chemokine receptor CXCR7 is linked to early and metastatic recurrence in pathological stage I nonsmall cell lung cancer; Cancer. 2009, 115(11):2580-93) found that higher expression

CXCR7 is associated with early and metastatic recurrence in pathological stage I non-small cell lung cancer.

CXCR7 modulators may also be useful in the treatment of hepatocellular carcinoma: according to the data obtained, CXCR7 expression is increased in hepatocellular carcinoma tissues. Knockdown of CXCR7 expression significantly inhibited hepatocellular carcinoma cell invasion, adhesion, and angiogenesis. In addition, suppression of CXCR7 expression leads to a decrease in tumor growth in a xenograft model of hepatocellular carcinoma (Zheng K. et al.; Chemokine receptor CXCR7 regulates the invasion, angiogenesis and tumor growth of human hepatocellular carcinoma cells; J. Exp. Clin. Cancer Res. 2010, 29:31). Monnier J. et al. also found that in a cohort of 408 human hepatocellular carcinomas, CXCR7 was significantly higher in tumors compared to normal liver controls (Monnier J. et al.; CXCR7 is up-regulated in human and murine hepatocellular carcinoma and is specifically expressed by endothelial cells, Eur J Cancer 2012, 48(1): 138-48). Immunohistochemical staining on human hepatocellular carcinoma sections confirmed that CXCR7 expression was significantly higher in cancer tissues. Using CXCR7 RNA interference in a hepatocellular carcinoma cell line, Xue T.C. et al. found that downregulating CXCR7 reduced tumor growth and lung metastases in nude mice. In addition, matrix multitissue block showed that HCCs with high expression of CXCR7 were prone to lung metastasis. Down-regulation of CXCR7 inhibits the growth and lung metastasis of human hepatocellular carcinoma cells with highly metastatic potential; Exp. Ther. Med 2012, 3(1):117-123).

CXCR7 modulators may also be useful in the treatment of metastatic colon cancer: Guillemot et al. (Guillemot et al.; CXCR7 receptors facilitate the progression of colon carcinoma within lung not within liver; Br. J. Cancer. 2012, 107(12): 1944-9) found that after injection of colorectal cancer cells in mice treated with antagonists CXCR7, there was a significant reduction in lung metastases. Wang HX et al studied CXCR7 expression in a colon cancer sample and found that CXCR7 content was significantly higher in colon tumors compared to normal colon tissue. In addition, in metastatic tumors of the lymph nodes of the colon, a significantly higher expression of CXCR7 was observed compared to non-metastatic tumors (Wang H.X. et al.; Role of CXC chemokine receptor type 7 in carcinogenesis and lymph node metastasis of colon cancer; Mol. Clin. Oncol 2015, 3(6):1229-1232).

CXCR7 modulators may also be useful in the treatment of head and neck cancers: A nanobody directed against CXCR7 reduced the growth of head and neck cancers in vivo (Maussang D. et al.; Llama-derived single variable domains (nanobodies) directed against chemokine receptor CxCR7 reduce head and neck cancer cell growth in vivo J biol Chem 2013, 288(41):29562-72). In addition, the same authors analyzed a wide range of tumor biopsies and found high expression of CXCR7 in head and neck cancers.

It is also noted that CXCR7 is expressed in brain metastases (Salmaggi et al.; CXCL12, CXCR4 and CXCR7 expression in brain metastases. Cancer Biol. Ther. 2009, 8:17, 1-7). The authors concluded that the CXCL12/CXCR4/CXCR7 pathway may be an interesting target for further research into the role of these molecules in the invasion and proliferation of metastatic cells.

Moreover, the effect of CXCR7 on inflammatory demyelinating diseases is known from the literature. CXCR7 is expressed in various regions of the adult mouse brain and is upregulated in a mouse model of multiple sclerosis (Banisadr G. et al.; Pattern of CXCR7 Gene Expression in Mouse Brain Under Normal and Inflammatory Conditions; J. Neuroimmune Pharmacol. 2016 Mar; 1 1 (1):2635). Altered expression patterns of CXCL12 at the blood-brain barrier (BBB) are implicated in multiple sclerosis and correlate with disease severity (McCandless E.E. et al.; Pathological expression of CXCL12 at the blood-brain barrier correlates with severity of multiple sclerosis; Am. J. Pathol 2008, 172(3):799-808). CXCR7 antagonism has been shown to be effective in experimental autoimmune encephalomyelitis in mice. These recent studies strongly suggest that CXCR7 is a disease-modifying molecule in multiple sclerosis through additional mechanisms: (i) by facilitating leukocyte entry into the perivascular space via redistribution of CXCL12 to the BBB (Cruz-Orengo L. et al.; CXCR7 antagonism CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity ; J Exp Med. 2011, 14; 208(2):32739) and regulation of CXCR4-mediated integrin activation (Hartmann T.N. et al.; A crosstalk between intracellular CXCR7 and CXCR4 involved in rapid CXCL12-triggered integrin activation but not in chemokinetriggered motility of human T lymphocytes and CD34+ cells, J Leukoc Biol 2008 84(4): 1130-40 (ii) by directly affecting chemotax is microglia (Bao. J. et al.; CXCR7 suppression modulates microglial

- 6 040620 chemotaxis to ameliorate experimentally-induced autoimmune encephalomyelitis; Biochem. Biophys. Res. commun. 2016 Jan 1; 469(1): 1-7) (iii) by promoting remyelination by increasing the content of CXCL12, enhancing the maturation of CXCR4-mediated progenitor oligodendrocytes (Williams J.L. et al.; Targeting CXCR7/ACKR3 as a therapeutic strategy to promote remyelination in the adult central nervous system system; J. Exp. Med. 2014, 5; 211(5):791-9; Gottle P. et al.; Activation of CXCR7 receptor promotes oligodendroglial cell maturation; Ann. Neurol. 2010, 68(6):915- 24). Thus, CXCR7 antagonism may therapeutically prevent inflammation and promote myelin repair in the demyelinated adult CNS.

Moreover, CXCR7 antagonism has been shown to be effective in a mouse model of Guillain-Barré syndrome. Moreover, Brunn et al. (Brunn A. et al.; Differential effects of CXCR4-CXCL12- and CXCR7CXCL12-mediated immune reactions on murine P0106-125 -induced experimental autoimmune neuritis; Neuropathol. Appl. Neurobiol. 2013, 39(7):772-87) indicate that CXCR7 antagonization reduces disease spread by up to 75% and significantly reduces disease activity in a mouse model of experimental autoimmune neuritis. The authors conclude that the CXCR7/CXCL12 interaction is a gatekeeper for pathogenic cells.

In particular, the potential role of CXCR7 in rheumatoid arthritis is known from the literature. It is noted that CXCR7 is expressed on the endothelial cells of the synovial membrane. In addition, elevated levels of CXCL12 and CXCL11 mRNA have been found in the synovial tissue of patients with rheumatoid arthritis (Ueno et al.; The production of CXCR3-agonistic chemokines by synovial fibroblasts from patients with rheumatoid arthritis; Rheumatol. Int. 2005, 25(5) :361-7). CXCL12 has been shown to play a central role in the accumulation of CD4+ T cells and monocytes in the synovial membrane (Nanki T. et al.; Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis synovium; J. Immunol. 2000, 165(11):6590-8; Blades M. C. et al.; Stromal cell-derived factor 1 (CXCL12) induces monocyte migration into human synovium transplanted onto SCID Mice; Arthritis Rheum. 2002 Mar 46(3):824-36). In addition, CXCL12 is involved in the process of rheumatoid arthritis through its pro-angiogenic functions and its effect on osteoclast recruitment and differentiation. Therefore, CXCL12 pathway modulators, including CXCR7 modulators, have been proposed as potential therapeutic agents for the treatment of rheumatoid arthritis. Villalvilla et al. (Villalvilla A. et al.; SDF-1 signaling: a promising target in rheumatic diseases; Expert Opin. Ther. Targets. 2014, 18(9): 1077-87) have recently discussed preclinical and clinical data that support the potential use of anti -CXCL12 agents in the treatment of rheumatoid arthritis. Watanabe et al. (Watanabe K. et al.; Pathogenic role of CXCR7 in rheumatoid arthritis; Arthritis Rheum. 2010, 62(11):3211-20) indicate that a CXCR7 inhibitor prophylactically and therapeutically reduces clinical signs of disease and angiogenesis in a mouse model with collagen- induced arthritis.

In particular, CXCR7 is involved in several inflammatory diseases. For example, CXCL12 and CXCL11 are involved in chronic inflammatory processes in the lungs (Petty J.M. et al.; Pulmonary stromal-derived factor-1 expression and effect on neutrophil recruitment during acute lung injury; J. Immunol. 2007, 178(12):8148- 57; Porter, J. C. et al., Polarized localization of epithelial CXCL11 in chronic obstructive pulmonary disease and mechanisms of T cell egression, J. Immunol. 2008, 180(3): 1866-77. CXCL12 has been found to be upregulated in lungs in human and animal models (Phillips R.J. et al.; Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis; J. Clin. Invest. 2004, 114(3):438-46). Anti-CXCL12 agents have been shown to attenuate lung inflammation and airway hyperresponsiveness in models of asthma (Gasparik V. et al.; Prodrugs of a CXC Chemokine-12 (CXCL12) Neutraligand Prevent Inflammatory Reactions in an Asthma Model in Vivo; ACS Med Chem Lett. 2012 Jan 12; 3(1): 10-4; Lukacs N. W. et al.; AMD3100, a CXCR4 antagonist, attenuates allergic lung inflammation and airway hyperreactivity; Am. J. Pathol. 2002, 160(4):1353- 60). Petty et al. (Petty J.M. et al.; Pulmonary stromal-derived factor-1 expression and effect on neutrophil recruitment during acute lung injury. J Immunol. 2007, 178(12):8148-57) indicate that blockade of CXCL12 attenuates late neutrophilia in acute lung injury lungs in mice. Cao et al (Cao Z. et al.; Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis; Nat Med. 2016,; 22(2):154-62) indicate that a CXCR7 modulator after lung injury promotes alveolar bone healing and reduced fibrosis in a mouse model of pulmonary fibrosis.

It has also been noted that CXCL12 and CXCL11 are upregulated in inflammatory bowel diseases (Koelink P.J. et al.; Targeting chemokine receptors in chronic inflammatory diseases: an extensive review; Pharmacol. Ther. 2012, 133(1): 1-18). CXCR7 has been found to be upregulated on peripheral blood T cells in inflammatory bowel disease (Werner L. et al.; Reciprocal regulation of CXCR4 and CXCR7 in intestinal mucosal homeostasis and inflammatory bowel disease; J. Leukoc. Biol. 2011, 90(3 ):583-90). The author suggests that increased expression of CXCR7 in the peripheral blood of patients with inflammatory bowel disease may increase the influx of T-cells to sites of mucosal inflammation'' (Wemer L. et al.; Involvement of CXCR4/CXCR7/CXCL12 Interactions in Inflammatory bowel disease; Theranostics 2013, 3(1):40-6). In a mouse model of inflammatory bowel disease, modulators of the CXCL12 pathway can reduce T cell infiltration and reduce

- 7 040620 tissue damage (Mikami S. et al.; Blockade of CXCL12/CXCR4 axis ameliorates murine experimental colitis; J. Pharmacol. Exp. Ther. 2008, 327(2):383-92; Xia X. M. et al.; CXCR4 antagonist AMD3100 modulates claudin expression and intestinal barrier function in experimental colitis, PLoS One 2011, 6(11):e27282).

Elevated levels of CXCL12 and CXCL11 have also been found in psoriatic skin (Chen S.C. et al.; Expression of chemokine receptor CXCR3 by lymphocytes and plasmacytoid dendritic cells in human psoriatic lesions; Arch. Dermatol. Res. 2010, 302(2): 113- 23; Zgraggen S. et al.; An important role of the SDF-1/CXCR4 axis in chronic skin inflammation; PLoS One. 2014, 9(4):e93665). Zgragen et al. indicate that blockade of CXCL12 improved the course of chronic skin inflammation in two different models of psoriasis-like skin inflammation.

A number of other autoimmune disorders, such as systemic lupus erythematosus (SLE), show altered CXCR7/CXCR4 expression correlated with impaired CXCL12-stimulated SLE B cell migration (Biajoux V. et al.; Expression of CXCL12 receptors in B cells from Mexican Mestizos patients with systemic Lupus erythematosus, J. Transl. Med. 2012, 18; 10:251). In addition, CXCL12 was significantly upregulated in nephrite kidneys in multiple mouse models of lupus. Wang et al. (Wang A. et al.; CXCR4/CXCL12 hyperexpression plays a pivotal role in the pathogenesis of lupus; J Immunol. 2009, 182(7):4448-58) indicate that targeting the CXCL12 axis is a good therapeutic target in lupus, since the CXCR4 antagonist significantly alleviates the disease, increasing survival and reducing nephritis and lymphoproliferation.

CXCR7 modulators may also be useful in the treatment of fibrosis: Cao Z. et al. 62) demonstrated that administration of a CXCR7 modulator after lung injury promotes alveolar bone healing and reduces fibrosis. The role of CXCR7 in liver fibrosis has also been described (Ding B.S. et al.; Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis; Nature. 2014, 505(7481):97-102).

The biological properties of CXCR7 modulators also include, but are not limited to, any physiological functions and/or cellular functions associated and/or controlled by its CXCL11, CXCL12, BAM22 ligands and related peptides. Therefore, CXCL12 depletion increases the sensitivity of cancer cells to in vivo chemotherapy, and CXCL12 treatment blocks colon cancer metastasis (Duda et al.; CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies?; Clin. Cancer Res 2011 17(8) 2074-2080; Naumann et al.; CXCR7 function as a scavenger for CXCL12 and CXCL11; Plos One. 2010, 5(2) e9175). CXCR7 is also the receptor for CXCL11 (also known as small inducible cytokine b subfamily member 11; scyb11, also known as interferon-gamma inducible protein 9; ip9, also known as small inducible cytokine b subfamily member 9b; scyb9b) and, therefore, modulators of CXCR7 activity may also be used in indications with CXCL11-associated pathology (Rupertus K. et al.; Interaction of the chemokines I-TAC (CXCL11) and SDF-1 (CXCL12) in the regulation of tumor angiogenesis of colorectal cancer; Clin Exp Metastasis 2014, 31(4):447-59 Zohar Y et al CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis J Clin Invest 2014 124(5): 2009-22 Antonelli A. et al. Increase of interferon-y inducible CXCL9 and CXCL11 serum levels in patients with active Graves' disease and modulation by methimazole therapy Thyroid 2013, 23(11): 1461-9. CXCR7 also functions as a receptor for the BAM22 opioid peptide and its related peptides (peptide E, BAM12, BAM14, BAM18 peptides) and therefore modulators of CXCR7 activity may also be used in indications with opioid peptide related pathologies (Ikeda et al .; Modulation of circadian glucocorticoid oscillation via adrenal opioidCXCR7 signaling alters emotional behavior; Cell. 2013, 155, 1323-1336). CXCR7 has also been shown to function as a phagocytic receptor for CXCl11 and CXCL12. Thus, CXCR7 targeting has been proven to alter the local concentration of CXCl11 and CXCL12, resulting in dysregulation of CXCl11 and CXCL12 concentration gradients.

Separate isoxazole compounds that are blockers of the SMYD protein are known from WO 2016/040515, where in the compounds from WO 2016/040515 the isoxazole ring is substituted with some (cyclo-)alkyl substituents instead of the present Ar ² phenyl substituent; and the piperidine moiety does not contain the carboxamide substituent R1-CO-. Some pyrrole compounds are known as antibacterial agents from WO 2006/087543, WO2005/026149 and J. Med. Chem 2014, 57(14), 60606082. Cyclic diamines as factor Xa inhibitors are known from WO 2005/032490. WO 2004/050024 discloses pyrrolidine compounds as chemokine receptor modulators.

The present invention provides novel trans-3,4-disubstituted piperidine derivatives of formula (I) which are CXCR7 receptor modulators, i.e. they act as CXCR7 receptor antagonists, and are useful in the prevention or treatment of diseases that respond to activation of CXCL12 receptors and/ or CXCL11 receptors, especially on malignancies. For the prevention or treatment of malignant neoplasms, the compounds of formula (I) may also be used in combination with one or more chemotherapeutic agents and/or radiation therapy and/or targeted therapy.

- 8 040620

1) This document describes new piperidine derivatives of the formula (ID);

Formula (Id) where the two substituents on the piperidine ring, R1-CO- and -NH-CO-Ar1-Ar ² , are in the relative trans configuration (i.e., the relative configuration of the two chiral carbons at positions 3 and 4 of the piperidine ring is (3R*,4R*));

Ar ¹ is a 5-membered heteroarylene group (especially a 5-membered heteroarylene containing from one to a maximum of three heteroatoms, each independently selected from oxygen, nitrogen and sulfur; especially oxazoldiyl, isoxazoldiyl, oxadiazoldiyl, triazoldiyl, isothiazolediyl, or thiadiazoldiyl), where the -NH-CO- group and Ar ² are attached in the meta position to the Ar ¹ ring atoms; where the specified 5-membered heteroarylene is unsubstituted, or monosubstituted RAr ¹ ; where RAr ¹ is ( _C1.4 )alkyl, ( _C1.4 )alkoxy, halogen, ( _C1.3 )fluoroalkyl, or ( _C1.3 )fluoroalkoxy (especially said 5-membered heteroarylene is unsubstituted);

Ar ² is phenyl (preferred) or 6-membered heteroaryl; where the specified phenyl or 6-membered heteroaryl is independently mono-, di - or trisubstituted, where the substituents are independently selected from fluorine, chlorine, methyl, cyano, methoxy, or (C1)fluoroalkyl;

[in particular one or two of said substituents are independently selected from fluorine, chlorine and methyl, and the remaining(s), if present(s), is(are) fluorine; especially Ar ² is phenyl which is mono-, di- or tri-substituted, where the substituents are independently fluorine or chlorine; in particular Ar ² is phenyl which is mono-, di- or tri-substituted with fluorine];

R ¹ is R ^n1rn2 N-, where

R ⁿ¹ is hydrogen;

( _C1.6 ) alkyl (especially methyl, ethyl, isopropyl, isobutyl, t-butyl, 1,2,2-trimethylpropyl);

( _C1.6 )alkyl which is monosubstituted with hydroxy;

( _C1.3 ) alkoxy (especially methoxy, ethoxy);

2-hydroxyethoxy;

- CO-NH2;

- SO ₂ -(C ₁ . ₃ )alkyl (especially methanesulfonyl);

cyano;

( _C1.3 )fluoroalkoxy (especially trifluoromethoxy);

- NR ^n3rn4 where RN ³ and RN ⁴ are independently hydrogen or (C _m )alkyl (especially -NR ^n3rn4 is dimethylamino);

(especially such an R ^N1 group, being a monosubstituted ( _C1.6 ) alkyl, is 2hydroxyethyl, 2-hydroxy-1-methylethyl, 2-hydroxy-1,1-dimethylethyl, 2-methoxyethyl, 3-methoxypropyl, 2ethoxyethyl, 2- ethoxy-1-methylethyl, 2-methoxy-1,1-dimethylethyl, 3-methoxy-1,1-dimethylpropyl, 2-(2hydroxyethoxy)ethyl, carbamoylmethyl, 2-methanesulfonyl-1,1-dimethylethyl, 1-cyano-1 -methylethyl, 2dimethylaminoethyl, 2-trifluoromethoxyethyl);

(C ₂ . ₆ )alkynyl (especially 1-methylprop-2-ynyl);

(C _2-5 ) fluoroalkyl (especially 2-fluoroethyl, 2,2-difluoroethyl, 2-fluoro-1-methylethyl, 2-fluoro-1,1dimethylethyl, 2,2-difluoro-1-methylethyl, 3,3,3 -trifluoro-1,1-dimethylpropyl);

( _C1.4 ) alkoxy (especially methoxy);

2-(2-oxopyrrolidin-1-yl)ethyl;

group -L1-Cy1; Where

L ¹ is _a direct bond, -( _C1.3 )alkylene-, or -( _C3.5 )cycloalkylene-; And

Cy ¹ is (C ₃ . ₆ )cycloalkyl; where the specified (C ₃ . ₆ )cycloalkyl optionally contains one ring oxygen atom; where the specified (C ₃ . ₆ )cycloalkyl is independently unsubstituted; or monosubstituted with fluorine, methyl, hydroxy, -CO-( _C1.4 )alkoxy, or cyano; or disubstituted with fluorine, or trisubstituted with methyl and two fluorine atoms;

(especially such group -L ¹ -Cy ¹ is cyclopropyl, cyclopentyl, 1-methylcyclopropyl, 1-methylcyclobutyl, 1-cyclopropylcyclopropan-1-yl, 1-cyclobutylethyl, 3-methyltetrahydrofuran-3-yl, tetrahydrofuran-3-yl- methyl, tetrahydrofuran-2-yl-methyl, 1-tetrahydrofuran-2yl-ethyl, oxetan-3-yl-methyl, 3,3-difluoro-1-methylcyclobutyl, 1-(ethoxycarbonyl)cyclopropyl, or 1

- 9 040620 cyano-cyclobutyl);

group -L ² -Ar ³ , where

L ² is a direct link; -(C1_4)alkylene-; *-(C3_5)cycloalkylene-(C0_2)alkylene-, wherein said (C3-5)cycloalkylene optionally contains one ring oxygen atom, where the asterisk denotes the bond to which Ar ³ is attached; *-(C1_ ₂ )alkylene-(C ₃ _ ₅ )cycloalkylene-, wherein said (C _3-5 )cycloalkylene optionally contains one ring oxygen atom, where the asterisk denotes the bond to which Ar ³ is attached; or -(C _1-3 )alkylene-, which is monosubstituted with hydroxy, trifluoromethyl, or -CO-(C _1-4 )alkoxy; And

Ar ³ is phenyl, or 5- or 6-membered heteroaryl; where the specified phenyl or 5 - or 6-membered heteroaryl is independently unsubstituted, or mono-, or disubstituted; where the substituents are independently selected from (C _1-4 )alkyl, (C _1-4 )alkoxy, halo, hydroxy, (C _1-3 )fluoroalkyl, or (C1-3)fluoroalkoxy; where, in the case where Ar ³ is a 6-membered heteroaryl that is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present as the corresponding N-oxide (for the avoidance of doubt, it should be understood that the term 6-membered heteroaryl includes 1-hydroxy-pyridinyl, and 1-hydroxy-pyrimidinyl groups); (especially such group -L ² -Ar ³ is phenyl, benzyl, 1-phenylethyl, 2-phenylethyl, 2-(2-chlorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(2-methylphenyl)ethyl , 2-(3-methylphenyl)ethyl, 2-(4-methylphenyl)ethyl, 2-(2-methoxyphenyl)ethyl, 2-phenylpropyl, 2-hydroxy-1-phenylethyl, 2-hydroxy-2-phenylethyl, 2- phenylcyclopropyl, or 1-(3-bromophenyl)ethyl, 1-phenylcyclopropyl, 1-phenylcyclobutyl, 2-phenylcyclobutyl, 1-(3-chlorophenylpropyl, 1-(4-fluorophenyl)cyclopropyl, 1-(3-fluorophenyl)cyclopropyl, 1 -(2-fluorophenyl)cyclopropyl, 1-(2-methylphenyl)cyclopropyl, 1-(2-hydroxyphenyl)cyclopropyl, 1-(2-methoxyphenyl)ethyl, 2-methyl-2-(2-chlorophenyl)propyl, 1- (4-chlorophenyl)cyclopropylmethyl, 3-(3-chlorophenyl)oxetan3-yl, 3-(4-fluorophenyl)oxetan-3-yl, 3-(phenyl)oxetan-3-yl-methyl, 3-(benzyl)oxetane -3-yl, 1-(2-methoxyphenyl)cyclopropyl, 1-(3-methoxyphenyl)cyclopropyl, 1-(2-trifluoromethylphenyl)cyclopropyl, 2-ethoxy2-oxo-1-phenylethyl, or 4,5-dimethylthiazole-2 -yl, 1H-imidazol-4-yl-methyl, thiazol-2-yl-methyl, 4-methylthiazol-5-yl-methyl, 4-methylthiazol-2-yl-m ethyl, 5-methylthiazol-2-yl-methyl, 2-methylthiazol-4-yl-methyl, oxazol-5-yl-methyl, 1-(2H-pyrazol-3-yl)ethyl, (1-methyl-1 H -pyrazol-3 -yl)methyl, 1-([1,2,4]oxadiazol-3 yl)ethyl, 1-(isoxazol-3-yl)ethyl, 3-methylisoxazol-5-yl-methyl, 5-methylisoxazole -3-yl-methyl, 1-(1H[1,2,4]triazol-3-yl)ethyl, (1,5-dimethyl-1 H-pyrazol-3-yl)methyl, (2,5-dimethyl -2H-pyrazol-3-yl)methyl, (3 ethyl([ 1,2,4]oxadiazol-5-yl)methyl, 1 -(5-methyl([ 1,3,4]oxadiazol-2-yl) ethyl, 1-methyl-1-(1-methyl-1H-pyrazol-4-yl)ethyl, 1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)ethyl, or 1 -(4-methylthiazol-2-yl)cyclobutyl; or pyridin-3-yl, pyridin-2-yl-methyl, pyridin-3-yl-methyl, pyridin-4-yl-methyl, pyrimidin-2-ylmethyl, pyrimidin-4-yl-methyl, pyrazin-2-yl -methyl, 1-(pyridin-2-yl)ethyl, 1-(pyridin-3-yl)ethyl, 2(pyridin-2-yl)ethyl, 1-methyl-1-(pyridin-2-yl)ethyl, 1-(pyrazin-2-yl)ethyl, 1-(pyrimidin-4-yl)ethyl, 1-(5fluoropyrimidin-2-yl)ethyl, 1-(3-fluoropyridin-2-yl)ethyl, 1-(5 -fluoropyridin-2-yl)ethyl, 1-(6-methylpyridin-2-yl)ethyl, 2-hydroxy-1-(pyridin-2-yl)ethyl, 1-(1-hydroxypyridin-2-yl)ethyl, 1-(pyridin-2-yl)cyclopropyl, 1-(pyridin-4-yl)cyclopropyl, 1-(pyrazin-2-yl)cyclopropyl, 1-(pyridazin-3-yl)cyclopropyl, 1-(pyrimidin-2 -yl)cyclopropyl, 1-(5-fluoropyridin-2-yl)cyclopropyl, 1-(3,5-difluoropyridin-2yl)ethyl, 2,2,2-trifluoro-1-(pyridin-2-yl)ethyl, 1-(4,6-dimethylpyrimidin-2-yl)cyclopropyl; or (6methylpyridin-2-yl)methyl, 1-(pyrimidin-2-yl)ethyl, 1-methyl-1-(pyrimidin-2-yl)ethyl, 1-(pyrimidin-4yl)cyclopropyl, 2-(pyrimidin- 2-yl)cyclobutyl, 2-(pyrimidin-2-yl)cyclopentyl, 1-(1-hydroxypyrimidin-2-yl)cyclopropyl, 1-(3-fluoropyridin-2-yl)cyclopropyl, [1-(pyridin-2 -yl)cyclopropyl]-methyl, 1(pyridin-2-yl)cyclobutyl, 1-(1-oxypyridin-2-yl)cyclopropyl, 2-methyl-2-(pyridin-2-yl)propyl, 2methyl-2- (3-methylpyridin-2-yl)propyl);

and R ⁿ² is independently hydrogen, (C _1-4 )alkyl (especially methyl, ethyl, isopropyl) or (C 2-3)fluoroalkyl (especially 2-fluoroethyl);

or R ⁿ¹ and R ⁿ² together with the nitrogen atom to which they are attached form a 4-6 membered ring selected from the following:

azetidinyl, pyrrolidinyl or piperidinyl; each is independently unsubstituted;

or monosubstituted with fluorine, methyl, or hydroxy;

or disubstituted with fluorine;

or monosubstituted Ar ⁴ where Ar ⁴ represents phenyl, or 5 - or 6-membered heteroaryl (especially pyridinyl); where the specified phenyl or 5 - or 6-membered heteroaryl is independently (especially) unsubstituted, or mono-, or disubstituted; where the substituents are independently selected from (C1-4)alkyl, (C1-4)alkoxy, halo, ( _C1-3 )fluoroalkyl, or ( _C1-3 )fluoroalkoxy; or morpholinyl;

(especially such a cyclic group R ^n1rn2 N- is azetidin-1-yl, pyrrolidin-1-yl, morpholin-4-yl, 3-fluoro-azetidin-1-yl, 3,3-difluoroazetidin-1-yl, 3 -hydroxypyrrolidin-1-yl, 3-phenylpyrrolidin-1-yl, 3-(pyridin-2-yl)-pyrrolidin-1-yl);

R ² is hydrogen;

- 10 040620 (C _1-6 )alkyl (especially ethyl, isopropyl, isobutyl, tert-butyl, 2,2-dimethylpropyl, 3-methylbutyl,

3,3-dimethylbutyl);

(C _2-6 )alkyl which is monosubstituted with (C _1-3 )alkoxy (especially methoxy), or hydroxy (especially 2hydroxyethyl, 2-methoxyethyl, 2-hydroxy-1-methylpropyl);

(C _3-5 )alkenyl (especially allyl);

cyanomethyl;

(C ₂ - ₃ )fluoroalkyl (especially 3-fluoropropyl);

(C _{3 .8} )cycloalkyl(C _{0 .3} )alkyl; where (C ₃ .§)cycloalkyl is unsubstituted, or mono- or disubstituted, where the substituents are independently selected from (C _1-3 )alkyl (especially methyl), fluoro, hydroxy, hydroxy(C _1-3 )alkyl (especially hydroxymethyl) , (C _1-3 )alkoxy (especially methoxy), or (C ₁ . ₃ )fluoroalkyl (especially difluoromethyl);

(especially cyclobutyl, 2-methylcyclobutyl, 2,2-dimethylcyclobutyl, 3,3-dimethylcyclobutyl, cyclopentyl, cyclohexyl, spiro[2.4]hept-4-yl, spiro[3.3]hept-2-yl, bicyclo[2.2.1] hept-2-yl, 2methylcyclopentyl, 2-(hydroxymethyl)cyclopentyl, 3,3-dimethylcyclopentyl, 2-ethylcyclopentyl, 3,3dimethylcyclohexyl, 2-fluorocyclohexyl, 4-fluorocyclohexyl, 4,4-difluorocyclohexyl, 2-hydroxycyclohexyl, 2-methoxycyclohexyl , 3-methoxycyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopropylethyl, (1-methylcyclopropyl)methyl, (1-methylcyclobutyl)methyl, 2cyclopropylethyl; or (1-fluorocyclopropyl)methyl, spiro[2.3]hex-5-yl, bicyclo [3.1.0]hex-3-yl, 3,3difluorocyclobutyl, (2,2-difluorocyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1-difluoromethylcyclopropyl)methyl);

thietan-3-yl;

(C ₃ .g) cycloalkenyl-(C ₁ . ₃ ) alkyl (especially cyclopenten-1-yl-methyl); or

Ar ⁵ -CH2-, where Ar ⁵ is phenyl, or 5- or 6-membered heteroaryl (especially pyrrolyl), where phenyl or 5- or 6-membered heteroaryl is independently unsubstituted, or mono- or disubstituted, where the substituents are independently selected from (C1.4) alkyl, ( _C1.4 ) alkoxy, halogen _, (C1.3) fluoroalkyl, or (C ₁ - ₃ ) fluoroalkoxy; [especially such an Ar ⁵ -CH ₂ - group is benzyl, where the phenyl ring of said benzyl is unsubstituted, or mono- or disubstituted, where the substituents are independently selected from (C _1-4 )alkyl, ( _C1.4 )alkoxy, halogen, _{( C1.3} )fluoroalkyl, or ( _C1.3 )fluoroalkoxy; in particular benzyl, wherein the phenyl ring of said benzyl is unsubstituted or monosubstituted with halogen (especially benzyl, 2-chlorobenzyl, 2-fluorobenzyl, 4-fluorobenzyl)]; And

R ³ is hydrogen, or methyl (especially hydrogen).

The compounds of formula (I) and/or (ID) contain at least two stereogenic centers which are located at positions 3 and 4 of the piperidine moiety. It should be understood that the two substituents on the piperidine ring, R1-CO- and -NH-CO-Ar ¹ -Ar ² , are in the relative trans configuration (i.e., the relative configuration of these two chiral carbons at positions 3 and 4 of the piperidine ring is (3R*,4R*)). Thus, a compound of formula (I) and/or (ID) is either a compound of formula (I _R )/(ID _R ) or a compound of formula (IS)/ (IDS), or any mixture thereof

^{R2R2 _}

Formula (Idr) Formula (Ids)

Accordingly, the relative configuration of stereoisomers is indicated as follows:

e.g. (3R*,4R*)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxazole3-carbonyl]amino}piperidine-3-carboxylic acid [2-(2-chlorophenyl)ethyl]amide stands for (3R,4R)-1cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid [2-(2-chlorophenyl)ethyl]amide, [2 (3S,4S)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid -(2-chlorophenyl)ethyl]amide, or any mixture these two enantiomers, including the racemate.

In addition, the compounds of formulas (I), ( _IR ), (IS), (ID), (ID _R ) and (IDS) may contain one or more additional stereogenic or asymmetric centers, such as one or more additional asymmetric carbon atoms . Thus, the compounds of formulas (I), (I _R ), ( _IS ), ( _ID ), (I _DR ) and (I _DS ) may be present as mixtures of stereoisomers, or preferably as pure stereoisomers. Mixtures of stereoisomers can be separated in a manner known to those skilled in the art.

Where a particular compound (or general structure) is designated as the (R)- or (S) enantiomer/as having the absolute (R)- or S-configuration, such designation should be understood to refer to the corresponding compound (or general structure) in enriched, especially essentially pure, enantiomeric form. Similarly, in the case where a particular asymmetric center in

- 11 040620 compound is designated as being in the (R) - or (S) -configuration or as having a certain relative configuration, such a designation should be understood as referring to a compound that is in an enriched, especially essentially pure, form relative to the corresponding configuration of the specified asymmetric center. By analogy, cis or trans designations (or (R*, R*) designations) should be understood to refer to the corresponding stereoisomer of the corresponding relative configuration in enriched form, especially in substantially pure form.

The term enriched, when used in the context of stereoisomers, should be understood in the context of the present invention to mean that the corresponding stereoisomer is present in a ratio of at least 70:30, especially at least 90:10 (i.e. at least 70% pure by weight). .%, especially at least 90 wt.%) in relation to the corresponding other stereoisomer/set of the corresponding other stereoisomers.

The term substantially pure, when used in the context of stereoisomers, should be understood in the context of the present invention to mean that the corresponding stereoisomer is present in a purity of at least 95% by weight, especially at least 99% by weight relative to the corresponding other stereoisomer/set corresponding other stereoisomers.

In some cases, the compounds of formula (I) or ( _ID ) may contain tautomeric forms. Such tautomeric forms are included within the scope of the present invention. For example, if the present compounds contain heteroaromatic aromatic rings containing unsubstituted ring nitrogen atoms having a free valence, such as imidazole-2,4-diyl, or [1,2,4]-triazole-3,5-diyl, such rings can present in tautomeric forms. For example, the imidazole-2,4-diyl group is the tautomeric forms 1H-imidazole-2,4-diyl and 3H-imidazole-2,4-diyl; and the [1,2,4]-triazole-3,5diyl group are tautomeric forms of 1H-[1,2,4]-triazole-3,5-diyl, 2H-[1,2,4]-triazole-3 ,5-diyl and 4H-[1,2,4]-triazole-3,5-diyl.

The present invention also includes isotopically labeled, especially ² H(deuterium)-labeled, compounds of formula (I) which are identical to compounds of formula (I) except that one or more atoms are each replaced by an atom having the same atom number , but the atomic mass is different from the atomic mass normally found in nature. Isotopically labeled, especially ² H(deuterium) labeled compounds of formula (I) and their salts are included within the scope of the present invention. Replacement of hydrogen with the heavier isotope ^2H (deuterium) may result in greater metabolic stability, which results, for example, in increased in vivo half-life or reduced dosages, or may result in decreased inhibition of cytochrome P450 enzymes, resulting, for example, in improved security profile. In one embodiment of the invention, the compounds of formula (I) are not labeled with isotopes or they are labeled with only one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labeled at all. Isotopically labeled compounds of formula (I) can be prepared in analogy to the methods described below, but using appropriate isotopic variation of the appropriate reagents or starting materials.

Deuterated groups are designated as follows: for example, the group (1,1,2,2,2-d ₅ -ethyl) denotes a residue

D

In this patent application, a bond drawn with a dotted line indicates the point of attachment of the drawn radical. For example, the radical shown below

is an isoxazole-3,5-diyl group.

Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases, and the like, this also includes a single compound, salt, or the like.

Any reference to compounds of formula (I) and/or ( _ID ) should be understood as referring also to salts (and especially pharmaceutically acceptable salts) of such compounds, if necessary and appropriate.

The term pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the target compound and exhibit minimal undesirable toxicological effects. Such salts include addition salts with inorganic or organic acids and/or bases, depending on the presence of basic and/or acidic groups in the compound in question. 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 definitions given in this application are intended to apply uniformly to

- 12 040620 compounds of formula (I) as defined in any of options A)-G), and mutatis mutandis throughout the description and claims, unless expressly stated otherwise with respect to whether a broader or narrower definition is given. It should be understood that the definition or preferred definition of a term defines and may replace the corresponding term independently of (and in conjunction with) any definition or preferred definition of any or all other terms defined herein. Unless explicitly defined otherwise in the respective embodiment or claims, the groups defined herein are unsubstituted.

The term halogen means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, especially fluorine.

The term alkyl, alone or in combination, refers to a straight or branched chain saturated hydrocarbon group containing one to six (especially one to four) carbon atoms. The term (C _x-y )alkyl (where x and y are each an integer) refers to an alkyl group, as defined above, containing x to y carbon atoms. For example, a (C _1-6 )alkyl group contains from one to six carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 1,1dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl and 1,1,2- trimethylpropyl. Specific examples of (C1_ ₆ )alkyl groups used for R ² are ethyl, isopropyl, 2,2-dimethylpropyl, 3-methylbutyl and 3,3-dimethylbutyl. Specific examples of (C1_6)alkyl groups used for R ^N1 are methyl, ethyl, isopropyl, isobutyl, t-butyl and 1,1,2-trimethylpropyl. Specific examples of (C1_4)alkyl groups used for R ^N2 are methyl, ethyl and isopropyl, especially methyl. Particular examples of (C _1-4 )alkyl groups which are substituents to Ar ¹ , Ar ³ or Ar ⁴ are methyl and ethyl, especially methyl.

Examples of (C _1-6 )alkyl which is monosubstituted with (C _1-3 )alkoxy or hydroxy used for R ² are 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-1-methylpropyl, and 2-methoxyethyl.

The term -(C _x - _y )alkylene-, used alone or in combination, refers to a divalently bonded alkyl group as defined above containing from x to y carbon atoms. Preferably, the attachment points of any divalently bonded alkyl group are in the 1,1-diyl or 1,2-diyl arrangement. In the case where a (C ₀ _ _y )alkylene group is used in combination with another substituent, the term means that any of the indicated substituents is directly attached to the rest of the molecule (i.e. the (C ₀ )alkyl group is a direct bond linking the indicated substituent with the rest of the molecule), or or attached through a (C1- _y ) alkylene group to the rest of the molecule. Examples of -( _C1-4 )alkylene- are the -( _{C1_3} )alkylene groups methylene, ethylene, ethane-1,1-diyl, propane-1,2-diyl, and propane-2,2-diyl, as well as -( C4) alkylene group of 2-methylpropan-1,2-diyl. In the case where the linker group is a -(C0)alkylene group, this group refers to a direct link.

Examples of -( _{C1_3} )alkylene-, which is monosubstituted with hydroxy or trifluoromethyl, which is used for L ² are 1-trifluoromethylethane-1,1-diyl, 2-hydroxyethane-1,2-diyl, and 2-hydroxyethane-1,1diyl .

The term alkynyl, alone or in combination, refers to a straight or branched chain hydrocarbon group containing from one to six (especially one to four) carbon atoms, wherein said hydrocarbon group contains at least one carbon-carbon triple bond. The term ( _Cx-y )alkynyl (where x and y are each an integer) refers to an alkynyl group, as defined above, containing x to y carbon atoms. For example, a (C ₂ . ₆ )alkynyl group contains two to six carbon atoms. An example of an alkynyl group is 1-methylprop-2-ynyl.

The term alkenyl, alone or in combination, refers to a straight or branched chain hydrocarbon group containing from 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 (where x and y are each an integer) refers to an alkenyl group, as defined above, containing x to y carbon atoms. For example, a (C ₂ _ ₆ )alkenyl group contains two to six carbon atoms. An example of an alkenyl group is allyl.

The term alkoxy, alone or in combination, refers to an alkyl-O-group, where the alkyl group is as defined above. The term ( _Cx-y )alkoxy (where x and y are each an integer) refers to an alkoxy group, as defined above, containing x to y carbon atoms.

For example, (C _1-4 )alkoxy means a group of formula (C _1-4 )alkyl-O-, where the term (C _1-4 )alkyl has the previously defined meaning. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. A preferred example is methoxy.

The term fluoroalkyl refers to an alkyl group, as defined above, containing from one to five carbon atoms, in which one or more (especially 1, 2 or 3; and possibly all) hydrogen atoms have been replaced by fluorine. The term (C _x _ _y )fluoroalkyl (where x and y are each an integer

- 13 040620 lo) refers to a fluoroalkyl group, as defined above, containing from x to y carbon atoms. For example, a ( _C1-3 )fluoroalkyl group contains one to three carbon atoms, with one to seven hydrogen atoms replaced by fluorine. Typical examples of fluoroalkyl groups include the (C1)fluoroalkyl groups difluoromethyl and trifluoromethyl, as well as the ( _C2.5 )fluoroalkyl groups 2-fluoroethyl, 2,2-difluoroethyl _, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 3, 3,3-trifluoropropyl, 2-fluoro-1-methylethyl, 2-fluoro-1,1-dimethylethyl, 2,2-difluoro-1-methylethyl, and 3,3,3-trifluoro-1,1-dimethylpropyl.

The term ( _Cx-y )fluoroalkylene, used alone or in combination, refers to a divalently bonded fluoroalkyl group as defined above, containing from x to y carbon atoms. Preferably, the attachment points of any divalently bonded fluoroalkyl group are in the 1,1-diyl arrangement. An example is 2,2,2-trifluoroethane-1,1-diyl.

The term fluoroalkoxy refers to an alkoxy group, as defined above, containing from one to three carbon atoms, in which one or more (and possibly all) hydrogen atoms have been replaced by fluorine. The term ( _Cx-y )fluoroalkoxy (where x and y are each an integer) refers to a fluoroalkoxy group, as defined above, containing x to y carbon atoms. For example, a (C1 ₃ )fluoroalkoxy group contains one to three carbon atoms, where one to seven hydrogen atoms are replaced by fluorine. Typical examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. A preferred example is trifluoromethoxy.

The term cyano refers to the -CN group.

The term cycloalkyl, used alone or in combination, refers to a saturated mono or bicyclic carbocyclic ring containing from three to eight carbon atoms, where the term bicyclic cycloalkyl includes fused, bridged and spirobicyclic cycloalkyl groups. The term ( _Cx-y )cycloalkyl (where x and y are each an integer) refers to a cycloalkyl group, as defined above, containing x to y carbon atoms. For example, a (C _3-8 )cycloalkyl group contains three to eight carbon atoms. Examples of cycloalkyl groups are the monocyclic cycloalkyl groups cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; as well as bicyclic cycloalkyl groups such as spiro[2.4]hept-4-yl, spiro[3.3]hept-2-yl, bicyclo[2.2.1]hept-2-yl, spiro[2.3]hex-5-yl, and bicyclo[3.1.0]hex-3-yl. Preferred are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term -(C _x _ _y )cycloalkylene-, used alone or in combination, refers to a bivalently bonded cycloalkyl group as defined above, containing from x to y carbon atoms. Preferably, the attachment points of any divalently bonded cycloalkyl group are in the 1,1-diyl or 1,2-diyl arrangement. Examples are cyclopropan-1,1-diyl, cyclopropan-1,2-diyl, cyclobutan-1,1-diyl and cyclopentan-1,3-diyl; preferred are cyclopropan-1,1-diyl and cyclobutan-1,1-diyl.

The term (C _x-y )cycloalkyl wherein said (C _x-y )cycloalkyl optionally contains one ring oxygen atom refers to a (C _x-y )cycloalkyl group containing x to y carbon atoms, especially a monocyclic (C ₃ - ₆ )cycloalkyl group as defined above. In addition, one ring carbon atom of the specified ((C _x-y )cycloalkyl may be replaced by an oxygen atom. Such groups are unsubstituted or substituted, as clearly defined. Examples are, in particular, (C ₃ - ₆ )cycloalkyl groups, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, as well as oxetanyl, tetrahydrofuranyl and tetrahydropyranyl Preferred ( _Cx - _y )cycloalkylene, wherein said (Cx-y)cycloalkylene optionally contains one ring oxygen atom, is oxetane-3,3diyl.

The term (C ₃ _ ₈ )cycloalkyl-(C ₀ _ ₃ )alkyl refers to a (C _3-8 )cycloalkyl group as defined above (i.e. such a group may optionally contain a ring oxygen atom, as explicitly defined), wherein this group is linked to the rest of the molecule via a (C0-3)alkylene group as defined above. The (C _3-8 ) cycloalkyl portion of (C ₃ _ ₈ ) cycloalkyl-(C ₀ _ ₃ ) alkyl is unsubstituted or substituted as defined. Part of the (C _0-3 )alkylene group of (C _3-8 )cycloalkyl(C _0-3 )alkyl is unsubstituted or substituted as defined.

The term cycloalkenyl, used alone or in combination, refers to a non-aromatic, unsaturated (i.e., containing at least one carbon-carbon double bond) mono- or bicyclic carbocyclic ring containing three to eight carbon atoms, where the term bicyclic cycloalkenyl includes fused, bridged and spirobicyclic cycloalkenyl groups. The term (C _x-y )cycloalkenyl (where x and y are each an integer) refers to a cycloalkenyl group as defined above having x to y carbon atoms. For example, a (C3-8)cycloalkenyl group contains three to eight carbon atoms. Examples of cycloalkenyl groups are cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl; especially cyclopenten-1-yl.

The term aryl, used alone or in combination, means phenyl or naphthyl, preferably phenyl. Similarly, an arylene group is an aryl group, as defined above, which has two points of attachment to the corresponding residues of the molecule. The aforementioned aryl/aryl groups are unsubstituted or substituted as expressly defined.

For an Ar ² substituent representing phenyl, wherein said phenyl is mono-, di-, or tri-substituted, where the substituents are independently selected from fluorine, chlorine, methyl, cyano, methoxy, or (C1)fluoroalkyl, specific groups are those where one or two of the indicated substituents are independently selected from fluorine, chlorine and methyl, and the remaining, if present, are fluorine. Especially Ar ² is phenyl which is mono-, di- or tri-substituted, where the substituents are independently fluorine or chlorine; in particular Ar ² is phenyl which is mono-, di- or tri-substituted with fluorine, or phenyl which is mono-, di- or tri-substituted, wherein one substituent is chlorine and the remaining substituents, if present, are fluorine. Examples of Ar ² are 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, 2,3, 4-trifluorophenyl, 2,4-dimethylphenyl, 2-methylphenyl, 3,4-dimethylphenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, and 2-fluoro-4-methoxyphenyl. Preferred examples are 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 2,4-dichlorophenyl, 2,3,4-trifluorophenyl, and 2,4-dimethylphenyl (especially 2,4-difluorophenyl).

For the Ar ³ substituent representing phenyl, phenyl is unsubstituted, or substituted, as clearly defined. Examples are phenyl, 2-chlorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, and 2-methoxyphenyl; as well as 3-bromophenyl, 3-chlorophenyl, 4-fluorophenyl, 3fluorophenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 4-chlorophenyl, 3-methoxyphenyl, and 2trifluoromethylphenyl.

The term aryl-(C _x - _y )alkyl refers to an aryl group, as defined above, which is attached to the rest of the molecule via a (C _x - _y )alkylene group, as defined above. The aryl group portion of aryl-(C _x - _y )alkyl is unsubstituted or substituted as defined. The (C _x _ _y )alkylene group portion of aryl-(C _x - _y )alkyl is unsubstituted or substituted as defined.

The term aryl(C _x-y )cycloalkyl refers to an aryl group as defined above that is attached to the rest of the molecule via a (C _x _ _y )cycloalkylene group as defined above. The aryl group portion of the aryl(C _x _ _y )cycloalkyl is unsubstituted or substituted as defined. The (C _x _ _y ) cycloalkylene group portion of the aryl-(C _x _ _y ) cycloalkyl is unsubstituted or substituted as defined.

The term heteroaryl, used alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one to a maximum of four heteroatoms (in particular, one to a maximum of three heteroatoms), each independently selected from oxygen, nitrogen, and 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 , бензоксазолил, бензизоксазолил, бензотиазолил, бензоизотиазолил, бензотриазолил, бензоксадиазолил, бензотиадиазолил, хинолинил, изохинолинил, нафтиридинил, циннолинил, хиназолинил, хиноксалинил, фталазинил, пирролопиридинил, пиразолопиридинил, пиразолопиримидинил, пирролопиразинил, имидазопиридинил, имидазопиридазинил, и имидазотиазолил. Similarly, a heteroarylene group is a heteroaryl group, as defined above, which has two points of attachment to the corresponding residues of the molecule. The aforementioned heteroaryl/heteroarylene groups are unsubstituted or substituted as defined.

For an Ar ¹ group representing a 5-membered heteroarylene, the term means a 5-membered heteroarylene group as defined above (wherein said 5-membered heteroarylene specifically contains from one to a maximum of three heteroatoms); which is attached to the rest of the molecule as well defined. The term meta position in the context of a heteroarylene group such as Ar ¹ means that the corresponding substituents are attached in the relative 1,3-position. Examples of Ar ¹ representing a 5-membered heteroarylene are especially 5-membered heteroarylene groups containing from one to a maximum of three heteroatoms, each of which is independently selected from oxygen, nitrogen and sulfur (especially a 5-membered heteroarylene containing from one to a maximum of three heteroatoms each independently selected from oxygen and nitrogen, or a 5-membered heteroarylene containing one ring sulfur atom and one to a maximum of two ring nitrogen atoms); in particular oxazoldiyl, isoxazoldiyl, oxadiazoldiyl, or triazoldiyl; or thiadiazoldiyl or isothiazoldiyl; especially oxazol-2,5-diyl, oxazol-2,4-diyl, isoxazol-3,5-diyl, [1,3,4]oxadiazol-2,5-diyl, [1,2,4]oxadiazol- 3,5-diyl, or 1H-[1,2,3]triazole-1,4-diyl; or [1,3,4]thiadiazole-2,5-diyl, or isothiazole-3,5-diyl. Preferred examples of Ar ¹ representing a 5-membered heteroarylene group are oxazol-2,5-diyl, where the Ar ² substituent is attached to the carbon atom at position 5; oxazol-2,4-diyl, where the substituent Ar ² attached to the carbon atom in position 4; isoxazole-3,5-diyl, where the substituent Ar ² attached to the carbon atom in position 5; isoxazol-3,5-diyl, where the Ar ² substituent is attached to the carbon atom in position 3; [1,3,4]oxadiazole-2,5-diyl; [1,2,4]oxadiazol-3,5-diyl, where the Ar ² substituent is attached to the carbon atom in position 5; 1H-[1,2,3]triazole-1,4-diyl, where the substituent Ar ² at - 15 040620 is attached to the nitrogen atom in position 1; [1,3,4]thiadiazole-2,5-diyl; and isothiazole-3,5-diyl, where the substituent

Ar ² is attached to the carbon atom in position 5.

For an Ar ² substituent that is a 6-membered heteroaryl, wherein said 6-membered heteroaryl is independently mono-, di-, or tri-substituted, where two of said substituents are independently selected from fluorine, chlorine, methyl, cyano, methoxy, or (C1)fluoroalkyl ; and the remaining substituent, if present, is fluorine, examples being in particular pyridinyl groups which are mono- or di-substituted with fluorine. An example is 5-fluoropyridin-2-yl.

For an Ar ³ substituent which is a 5- or 6-membered heteroaryl, the term means 5- or 6-membered heteroaryl groups as defined above. Examples of Ar ³ , which is a 6-membered heteroaryl, are pyrimidinyl, pyridinyl, pyridazinyl, and pyrazinyl. For the avoidance of doubt, the term 6-membered heteroaryl, used for the Ar ³ substituent, additionally includes the 1-hydroxypyridinyl, and 1-hydroxypyrimidinyl groups. Particular examples are pyrazin-2-yl, pyridazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; as well as 1-hydroxypyrimidin-2-yl and 1-hydroxypyridin-2-yl N-oxides. The 6-membered heteroaryl groups used for the Ar ³ substituent are preferably unsubstituted; or said groups are substituted as expressly defined (especially mono- or disubstituted, where the substituents are independently selected from fluorine or methyl). Examples of Ar ³ , which is a 5-membered heteroaryl, are oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, and triazolyl; especially oxazol-5-yl, isoxazol-3-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-5-yl, thiazol-4-yl, imidazol-4yl, 2H-pyrazol-3-yl, 1H-pyrazol-3-yl, 2H-pyrazol-3-yl, 1H-pyrazol-4-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]oxadiazol-2-yl, and 1H-[1,2,4]triazol-3-yl. The 5-membered heteroaryl groups used for the Ar ³ substituent are unsubstituted; or said groups are substituted as defined (especially mono- or di-substituted, where the substituents are independently selected from methyl or ethyl).

An example of Ar ⁴ , which is a 5- or 6-membered heteroaryl, is pyridinyl.

An example of Ar ⁵ -CH2-, where Ar ⁵ is a 5- or 6-membered heteroaryl, is (1-methylpyrrol-3-yl)methyl.

The term heteroaryl(C _{x y} )alkyl refers to a heteroaryl group as above which is attached to the rest of the molecule via a (C _{x y} )alkylene group as above, part of the heteroaryl group of heteroaryl-(C _{x y} )alkyl is unsubstituted or substituted, as expressly defined. The (C _{x y} )alkylene group portion of heteroaryl-(C _{x y} )alkyl is unsubstituted, or substituted, as defined.

The term heteroaryl(C _{x y} )cycloalkyl refers to a heteroaryl group as defined above that is attached to the rest of the molecule via a (C _{x y} )cycloalkylene group as defined above. The heteroaryl group portion of heteroaryl(C _{x y} ) cycloalkyl is unsubstituted or substituted as defined. The (C _{x y} ) cycloalkylene group portion of the heteroaryl(C _{x y} ) cycloalkyl is unsubstituted, or substituted, as defined.

A) The first aspect of the invention relates to compounds of formula (I)

^R2

Formula (I) where two substituents of the piperidine ring: R1-CO- and -NH-CO-Ar1-Ar ² are in the relative trans configuration;

Ar ¹ is an unsubstituted 5-membered heteroarylene group containing one ring sulfur atom and one or two ring nitrogen atoms, where the -NH-CO- group and Ar ² are attached in the meta position to the Ar ¹ ring atoms;

Ar ² is phenyl which is mono-, di- or tri-substituted; where one or two of these substituents are independently selected(s) from fluorine, chlorine and methyl, and the remaining one(s), if present, is(are) fluorine;

R ¹ is R ^N1 R ^N2 N-, where

RN ¹ is a -L ² -Ar ³ group, where

L ² is a direct bond, -(C1.4)alkylene-; *-(C3-5)cycloalkylene-(C0.2)alkylene-, wherein said (C3.5)cycloalkylene optionally contains one ring oxygen atom, where the asterisk denotes the bond to which Ar ³ is attached; *-(C1.2)alkylene(C _{3 .5} )cycloalkylene-, wherein said (C _{3 .5} )cycloalkylene optionally contains one ring oxygen atom, where the asterisk denotes the bond to which Ar ³ is attached; or -( _C1.3 )alkylene-, which is monosubstituted with hydroxy, trifluoromethyl,

- 16 040620 or -CO-(C1_ ₄ )alkoxy; And

Ar ³ is phenyl, or a 5- or 6-membered heteroaryl containing one to four heteroatoms independently selected from oxygen, nitrogen and sulfur; where the specified phenyl or 5 - or 6-membered heteroaryl is independently unsubstituted, or mono-, or disubstituted; where the substituents are independently selected from ( _C1-4 ) alkyl, ( _C1-4 ) alkoxy, halo, hydroxy, ( _C1-3 ) fluoroalkyl, or ( _C1-3 ) fluoroalkoxy; where, in the case where Ar ³ is a 6-membered heteroaryl which is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present as the corresponding N-oxide;

and RN ² is hydrogen; R ² is hydrogen;

( _C1-6 )alkyl; or (C ₃ _ ₈ )cycloalkyl-(Co- ₃ )alkyl; where (C ₃ - ₈ )cycloalkyl is unsubstituted, or mono- or disubstituted, where the substituents are independently selected from (C 1 - ₃ ) alkyl, fluorine, hydroxy, hydroxy (C 1 - ₃ ) alkyl, (C 1_ ₃ ) alkoxy, or (C 1 - ₃ ) fluoroalkyl; And

R ³ is hydrogen;

or a pharmaceutically acceptable salt thereof.

B) Another embodiment relates to compounds of formula (I) according to embodiment A), which are also compounds of formula (IS), where two piperidine ring substituents: R1-CO- and -NH-CO-Ar1-Ar ² are in the relative trans configuration, where the absolute configuration of the two chiral carbons at positions 3 and 4 of the piperidine ring is (3S,4S)

^R2

Formula (Is);

or a pharmaceutically acceptable salt thereof.

C) Another embodiment relates to compounds of formula (I) according to any one of embodiments A or B); where Ar ¹ is [1,3,4]thiadiazole-2,5-diyl, or isothiazole-3,5-diyl.

D) Another embodiment relates to compounds of formula (I) according to any one of embodiments A), B) or C); where R ¹ represents R ⁿ¹ R ⁿ² N-, where RN ¹ represents heteroaryl(C1- ₄ )alkylene-, where the specified 6-membered heteroaryl contains one or two nitrogen atoms; and where the specified 6-membered heteroaryl is unsubstituted, or mono-, or disubstituted; where the substituents are independently selected from ( _C1-4 )alkyl, ( _C1-4 )alkoxy, halogen, ( _C1-3 )fluoroalkyl, or ( _C1-3 )fluoroalkoxy; where, in the case where Ar ³ is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present as the corresponding N-oxide;

6-membered heteroaryl(C ₃ - ₅ )cycloalkylene-, where the specified 6-membered heteroaryl contains one or two nitrogen atoms; and where the specified 6-membered heteroaryl is unsubstituted, or mono-, or disubstituted; where the substituents are independently selected from ( _C1-4 ) alkyl, ( _C1-4 ) alkoxy, halo, ( _C1-3 ) fluoroalkyl, or ( _C1-3 ) fluoroalkoxy; where, in the case where Ar ³ is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present as the corresponding Noxide;

and RN ² is hydrogen;

or a pharmaceutically acceptable salt thereof.

E) Another embodiment relates to compounds of formula (I) according to any one of embodiments A), B), C) or D); where R ² represents (C ₃ _ ₈ )cycloalkyl(C1_ ₃ )alkyl, where (C ₃ _ ₈ )cycloalkyl is unsubstituted; or monosubstituted, where the substituent is ( _C1-3 )alkyl, fluoro, or ( _C1-3 )fluoroalkyl; or disubstituted with fluorine; or (C ₃ _ ₈ )cycloalkyl, where (C ₃ - ₈ )cycloalkyl is unsubstituted, or mono- or disubstituted, where the substituents are independently selected from (C _1-3 )alkyl or fluorine;

or a pharmaceutically acceptable salt thereof.

F) Another embodiment relates to compounds of formula (I) according to any one of embodiments A), B), C), D) or E); where R ² represents unsubstituted (C _3-8 )cycloalkyl( _C1-3 )alkyl; or unsubstituted (C _3-6 )cycloalkyl; or (C _3-8 )cycloalkyl, where (C _3-8 )cycloalkyl is disubstituted with fluorine; or (C ₃ _ ₈ )cycloalkyl(C1_ ₃ )alkyl; where (C ₃ - ₈ )cycloalkyl is monosubstituted with methyl, fluorine, or (C1) fluorine

- 17 040620 alkyl; or disubstituted with fluorine;

or a pharmaceutically acceptable salt thereof.

Further disclosure is provided below.

2) An additional disclosure relates to compounds of formula (ID) in accordance with disclosure 1) which are also compounds of formula (IDR), where two substituents of the piperidine ring: R1-CO- and -NH-CO-Ar1-Ar ² are in relative trans configurations, where the absolute configuration of the two chiral carbons at positions 3 and 4 of the piperidine ring is (3R,4R)

^R2

Formula (Idr)

3) An additional disclosure relates to compounds of formula ( _ID ) in accordance with disclosure 1), which are also compounds of formula (IDS), where two substituents of the piperidine ring: R1-CO- and -NH-CO-Ar ¹ -Ar ² , are in the relative trans configuration, where the absolute configuration of the two chiral carbons at positions 3 and 4 of the piperidine ring is (3S,4S)

^R2

Formula (Ids)

4) Additional disclosure refers to compounds in accordance with any of the disclosures 1)3), where R ³ represents hydrogen.

5) An additional disclosure relates to compounds of formula (ID) in accordance with any of the disclosures 1)-4), where Ar ¹ represents a 5-membered heteroarylene group (especially a 5-membered heteroarylene containing from one to a maximum of three heteroatoms, each independently selected from oxygen and nitrogen (especially oxazoldiyl, isoxazoldiyl, oxadiazoldiyl, or triazoldiyl); or a 5-membered heteroarylene containing one ring sulfur atom and one or two ring nitrogen atoms (especially isothiazolyl, or thiadiazoldiyl)), where -NH-CO- the group and Ar ² are attached in the meta position to the Ar ¹ ring atoms; where the specified 5-membered heteroarylene is unsubstituted.

6) An additional disclosure relates to compounds of formula (ID) in accordance with any of the disclosures 1)-4), where Ar ¹ represents a 5-membered heteroarylene group selected from oxazoldiyl, isoxazoldiyl, oxadiazoldiyl, or triazoldiyl, where -NH-CO - the group and Ar ² are attached in the meta position to the ring atoms of Ar ¹ ; where the specified 5-membered heteroarylene is unsubstituted, or monosubstituted R ^Ar1 ; where R ^Ar1 represents methyl, methoxy, fluorine, chlorine, trifluoromethyl, or trifluoromethoxy (especially said 5-membered heteroarylene is unsubstituted).

7) An additional disclosure relates to compounds of formula (ID) in accordance with any of the disclosures 1)-4), where Ar ¹ represents a 5-membered heteroarylene group selected from the following: oxazol-2,5-diyl, oxazol-2, 4-diyl, isoxazol-3,5-diyl, [1,3,4]oxadiazol-2,5-diyl, [1,2,4]oxadiazol-3,5-diyl, 1Н-[1,2,3 ]triazole-1,4-diyl, [1,3,4]thiadiazole-2,5-diyl, or isothiazole-3,5diyl; where the specified 5-membered heteroarylene is unsubstituted [especially Ar ¹ is a 5-membered heteroarylene group selected from the following: oxazol-2,5-diyl, where the Ar ² substituent is attached to the carbon atom in position 5; oxazol-2,4-diyl, where the substituent Ar ² attached to the carbon atom in position 4; isoxazole-3,5-diyl, where the substituent Ar ² attached to the carbon atom in position 5; isoxazol-3,5-diyl, where the Ar ² substituent is attached to the carbon atom in position 3; [1,3,4]oxadiazole-2,5-diyl; [1,2,4]oxadiazol-3,5-diyl, where the Ar ² substituent is attached to the carbon atom in position 5; 1H-[1,2,3]triazole-1,4-diyl, where the Ar ² substituent is attached to the nitrogen atom in position 1; [1,3,4]thiadiazole-2,5-diyl; or isothiazole-3,5-diyl, where the substituent Ar ² is attached to the carbon atom in position 5].

8) An additional disclosure relates to compounds of formula (ID) in accordance with any of the disclosures 1)-4), where Ar ¹ is (preferably) unsubstituted isoxazol-3,5-diyl, where the Ar ² substituent is attached to the carbon atom in the position 5; or Ar ¹ is [1,3,4]thiadiazole-2,5-diyl.

- 18 040620

9) An additional disclosure relates to compounds of formula ( _ID ) in accordance with any of the disclosures 1)-8), where Ar ² represents phenyl, which is mono-, di- or trisubstituted; where one or two of these substituents are independently selected from fluorine, chlorine and methyl, and the remaining(s), if present, is(are) fluorine (especially 2,4-difluorophenyl).

10) An additional disclosure relates to compounds of formula ( _ID ) in accordance with the disclosure 9), where Ar ² represents phenyl, which is mono-, di - or trisubstituted, where the substituents are independently fluorine or chlorine; in particular Ar ² is phenyl which is mono-, di- or tri-substituted with fluorine (especially 2,4-difluorophenyl).

11) An additional disclosure relates to compounds of formula ( _ID ) in accordance with any of the disclosures 1)-8), where Ar ² represents 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4,6trifluorophenyl, 4 -chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, 2,3,4-trifluorophenyl, 2,4dimethylphenyl, 2-methylphenyl, 3,4-dimethylphenyl, 2,3-difluorophenyl, 3 ,4-difluorophenyl, 4-cyano-phenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, or 2-fluoro-4-methoxyphenyl. In a sub-embodiment, Ar ² is 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4,6trifluorophenyl, 4-chloro-2-fluorophenyl, or 2-chloro-4-fluorophenyl (particularly Ar ² is 2,4difluorophenyl).

12) An additional disclosure relates to compounds of formula ( _ID ) in accordance with any of the disclosures 1)-11), where R ¹ represents R ^n1rn2 N-, where

R ^N1 is ( _{C1_6} )alkyl (especially methyl, ethyl, isopropyl, isobutyl, t-butyl, 1,2,2-trimethylpropyl);

( _C1.6 )alkyl which is monosubstituted with hydroxy;

(C1_ ₃ )alkoxy (especially methoxy, ethoxy);

2-hydroxyethoxy;

-CO-NH ₂ ;

-SO ₂ -(C ₁ . ₃ )alkyl (especially methanesulfonyl);

cyano;

(C1_ ₃ )fluoroalkoxy (especially trifluoromethoxy);

-NR ^N3rN4 where R ^N3 and R ^N4 are independently hydrogen or ( _{C1_4} )alkyl (especially -NR ^N3rN4 is dimethylamino);

(especially such a group R ^N1 , being monosubstituted (C1_ ₆ ) alkyl, is 2-hydroxyethyl, 2-hydroxy-1-methylethyl, 2-hydroxy-1,1-dimethylethyl, 2-methoxyethyl, 3-methoxypropyl, 2ethoxyethyl, 2 -ethoxy-1-methylethyl, 2-methoxy-1,1-dimethylethyl, 3-methoxy-1,1-dimethylpropyl, 2-(2hydroxyethoxy)ethyl, carbamoylmethyl, 2-methanesulfonyl-1,1-dimethylethyl, 1-cyano- 1-methylethyl, 2dimethylaminoethyl, 2-trifluoromethoxyethyl);

(C ₂ - ₆ )alkynyl (especially 1-methylprop-2-ynyl);

(C _2-5 )fluoroalkyl (especially 2-fluoroethyl, 2,2-difluoroethyl, 2-fluoro-1-methylethyl, 2-fluoro-1,1-dimethylethyl, 2,2-difluoro-1-methylethyl, 3.3 ,3-trifluoro-1,1-dimethylpropyl);

2-(2-oxopyrrolidin-1-yl)ethyl;

group -L ¹ -Cy ¹ ; Where

L ¹ is a direct bond, -(C1_ ₃ )alkylene-, or -(C ₃ _ ₅ )cycloalkylene-; And

Cy ¹ represents (C ₃ _ ₆ )cycloalkyl, where the specified (C ₃ _ ₆ )cycloalkyl optionally contains one ring oxygen atom; where the specified (C ₃ _ ₆ )cycloalkyl is independently unsubstituted; or monosubstituted with fluoro, methyl, hydroxy, -CO-( _{C1_4} )alkoxy, or cyano; or disubstituted with fluorine, or trisubstituted with methyl and two fluorine atoms;

(especially such group -L ¹ -Cy ¹ is cyclopropyl, cyclopentyl, 1-methylcyclopropyl, 1-methylcyclobutyl, 1-cyclopropylcyclopropan-1-yl, 1-cyclobutylethyl, 3-methyltetrahydrofuran-3-yl, tetrahydrofuran-3-yl- methyl, tetrahydrofuran-2-yl-methyl, 1-tetrahydrofuran-2-ylethyl, oxetan-3-yl-methyl, 3,3-difluoro-1-methylcyclobutyl, 1-(ethoxycarbonyl)cyclopropyl, or 1-cyanocyclobutyl);

group -L ² -Ar ³ , where

L ² is -(C1_4)alkylene-; -(C3_5)cycloalkylene-, wherein said (C3_5)cycloalkylene optionally contains one ring oxygen atom; *-(C3.5)cycloalkylene-(C1.2)alkylene-, where said (C3_5)cycloalkylene optionally contains one ring oxygen atom, where the asterisk denotes the bond to which Ar ³ is attached; *-( _C1.2 )alkylene-( _C3.5 )cycloalkylene-, wherein said ( _{C3_5} )cycloalkylene optionally contains one ring oxygen atom, where the asterisk denotes the bond to which Ar ³ _{is attached} ; or -( _{C1_3} )alkylene- which is monosubstituted with hydroxy or trifluoromethyl; And

Ar ³ is phenyl, or a 5-membered heteroaryl containing one oxygen atom and one or two nitrogen atoms, or a 6-membered heteroaryl containing one or two nitrogen atoms; where the specified phenyl or 5 - or 6-membered heteroaryl is independently unsubstituted, or mono-, or disubstituted; where the substituents are independently selected from ( _C1-4 ) alkyl, ( _C1-4 ) alkoxy, halogen, ( _C1-3 ) fluoroalkyl, or ( _{C1_3} ) fluoroalkoxy; where, in the case where Ar ³ is a 6-membered heteroaryl which is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present as the corresponding N-oxide; (especially such group -L ² -Ar ³ is benzyl, 1-phenylethyl, 2-phenylethyl, 2-(2-chlorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(2-methylphenyl)ethyl, 2 -(3methylphenyl)ethyl, 2-(4-methylphenyl)ethyl, 2-(2-methoxyphenyl)ethyl, 2-phenylpropyl, 2-hydroxy-1-phenylethyl, 2-hydroxy-2-phenylethyl, 2-phenylcyclopropyl, or 1 -(3-bromophenyl)ethyl, 1-phenylcyclopropyl, 1-phenylcyclobutyl, 2-phenylcyclobutyl, 1-(3-chlorophenyl)cyclopropyl, 1-(4-fluorophenyl)cyclopropyl, 1-(3-fluorophenyl)cyclopropyl, 1-( 2-fluorophenyl)cyclopropyl, 1-(2-methylphenyl)cyclopropyl, 1-(2-hydroxyphenyl)cyclopropyl, 1-(2-methoxyphenyl)ethyl, 2-methyl-2-(2-chlorophenyl)propyl, 1-(4 -chlorophenyl)cyclopropyl-methyl, 3-(3-chlorophenyl)oxetan-3-yl, 3-(4-fluorophenyl)oxetan-3-yl, 3-(phenyl)oxetan-3-yl-methyl, 3-(benzyl )oxetan-3-yl, 1-(2-methoxyphenyl)cyclopropyl, 1-(3-methoxyphenyl)cyclopropyl, 1-(2-trifluoromethylphenyl)cyclopropyl, or oxazol-5-yl-methyl, 1-([1,2 ,4]oxadiazol-3yl)ethyl, 1-(isoxazol-3-yl)ethyl, 3-methylisoxazol-5-yl-methyl, 5-methylisoxazol-3-yl-methyl, (3-ethyl( [1,2,4]oxadiazol-5-yl)methyl, 1-(5-methyl-([1,3,4]oxadiazol-2-yl)ethyl, 1-methyl-1-(5-methyl-[ 1,2,4]oxadiazol-3-yl)ethyl; pyridin-2-yl-methyl, pyridin-3-yl-methyl, pyridin-4-yl-methyl, pyrimidin-2-ylmethyl, pyrimidin-4-yl-methyl, pyrazin-2-yl-methyl, 1-(pyridine -2-yl)ethyl, 1-(pyridin-3-yl)ethyl, 2(pyridin-2-yl)ethyl, 1-methyl-1-(pyridin-2-yl)ethyl, 1-(pyrazin-2- yl)ethyl, 1-(pyrimidin-4-yl)ethyl, 1-(5fluoropyrimidin-2-yl)ethyl, 1-(3-fluoropyridin-2-yl)ethyl, 1-(5-fluoropyridin-2-yl) ethyl, 1-(6-methylpyridin-2-yl)ethyl, 2-hydroxy-1-(pyridin-2-yl)ethyl, 1-(1-hydroxypyridin-2-yl)ethyl, 1-(pyridin-2yl) cyclopropyl, 1-(pyridin-4-yl)cyclopropyl, 1-(pyrazin-2-yl)cyclopropyl, 1-(pyridazin-3-yl)cyclopropyl, 1-(pyrimidin-2-yl)cyclopropyl, 1-(5 -fluoropyridin-2-yl)cyclopropyl, 1-(3,5-difluoropyridin-2-yl)ethyl, 2,2,2-trifluoro-1-(pyridin-2-yl)ethyl, 1-(4,6- dimethylpyrimidin-2-yl)cyclopropyl; or (6-methylpyridin-2-yl)methyl, 1-(pyrimidin-2-yl)ethyl, 1-methyl-1-(pyrimidin-2-yl)ethyl, 1-(pyrimidin4-yl)cyclopropyl, 2-( pyrimidin-2-yl)cyclobutyl, 2-(pyrimidin-2-yl)cyclopentyl, 1-(1-hydroxypyrimidin-2-yl)cyclopropyl, 1-(3-fluoropyridin-2-yl)cyclopropyl, [1-(pyridine -2-yl)cyclopropyl]methyl, 1-(pyridin-2-yl)cyclobutyl, 1-(1-hydroxypyridin-2-yl)cyclopropyl, 2-methyl-2-(pyridin-2-yl)propyl, 2methyl- 2-(3-methylpyridin-2-yl)propyl);

and R ⁿ² is independently hydrogen or ( _{C1_4} )alkyl (especially methyl, ethyl, isopropyl).

13) An additional disclosure relates to compounds of formula ( _ID ) in accordance with any of the disclosures 1) - 11), where R ¹ represents R ^n1rn2 N-, where

R ⁿ¹ represents (C ₃ _ ₆ )cycloalkyl, where the specified (C ₃ _ ₆ )cycloalkyl optionally contains one ring oxygen atom; where the specified (C ₃ _ ₆ )cycloalkyl is independently unsubstituted, or monosubstituted with fluorine, methyl, or hydroxy, or disubstituted with fluorine, or trisubstituted with methyl and two fluorine atoms (especially cyclopropyl, cyclopentyl, 1-methylcyclopropyl, 1-methylcyclobutyl, 3-methyltetrahydrofuran -3yl, 3,3-difluoro-1-methylcyclobutyl);

(C _{3 .6} )cycloalkyl-(C _{1 .3} )alkylene-, where the specified (C ₃ _ ₆ )cycloalkyl optionally contains one ring oxygen atom (especially 1-cyclobutyl-ethyl, tetrahydrofuran-3-yl-methyl, tetrahydrofuran- 2-yl-methyl, 1-tetrahydrofuran-2-yl-ethyl, oxetan-3-yl-methyl);

(C ₃ _ ₆ )cycloalkyl(C ₃ _ ₅ ) cycloalkylene- (especially 1-cyclopropylcyclopropan-1 -yl);

phenyl-( _{C1_4} )alkylene-, wherein said phenyl is unsubstituted, or mono-, or disubstituted; where the substituents are independently selected from (C1_ ₄ )alkyl, (C1_ ₄ )alkoxy, halogen, (C1_ ₃ )fluoroalkyl, or (C ₁ . ₃ )fluoroalkoxy; (particularly such a group is benzyl, 1-phenylethyl, 2-phenylethyl, 2-(2chlorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(2-methylphenyl)ethyl, 2-(3-methylphenyl)ethyl, 2-(4-methylphenyl)ethyl, 2-(2-methoxyphenyl)ethyl, 2-phenylpropyl, or 1-(3-bromophenyl)ethyl, 1-(2-methoxyphenyl)ethyl, 2-methyl-2-(2- chlorophenyl)propyl);

phenyl( _C1-3 )alkylene-, wherein said -( _{C1_3} )alkylene is monosubstituted with hydroxy (especially 2-hydroxy-2-phenylethyl, 2-hydroxy-1-phenylethyl);

phenyl(C ₃ - ₅ )cycloalkylene-, where the specified (C ₃ _ ₅ )cycloalkylene optionally contains one ring oxygen atom, and where the specified phenyl is unsubstituted, or mono-, or disubstituted; where the substituents are independently selected from (C1_ ₄ )alkyl, (C1_ ₄ )alkoxy, halogen, hydroxy, (C ₁ . ₃ )fluoroalkyl, or (C1_ ₃ )fluoroalkoxy; (especially 2-phenylcyclopropyl, 1-phenylcyclopropyl, 1-phenylcyclobutyl, 2phenylcyclobutyl, 1-(3-chlorophenyl)cyclopropyl, 1-(4-fluorophenyl)cyclopropyl, 1-(3-fluorophenyl)cyclopropyl, 1-(2-fluorophenyl) cyclopropyl, 1-(2-methylphenyl)cyclopropyl, 1-(2-hydroxyphenyl)cyclopropyl, 3-(3-chlorophenyl)oxetan-3-yl, 3-(4-fluorophenyl)oxetan-3-yl, 1-(2 -methoxyphenyl)cyclopropyl, 1(3-methoxyphenyl)cyclopropyl, 1-(2-trifluoromethylphenyl)cyclopropyl);

phenyl(C _{3 .5} )cycloalkylene-(C _{1 .2} )alkylene-, wherein said (C ₃ _ ₅ )cycloalkylene optionally contains one ring oxygen atom, and wherein said phenyl is unsubstituted, or monosubstituted with halogen (especially 1-(4 -chlorophenyl)cyclopropylmethyl, 3-(phenyl)oxetan-3-yl-methyl);

phenyl(C ₁ .2)alkylene-(C _{3 .5} )cycloalkylene-, wherein said (C ₃ _ ₅ )cycloalkylene optionally contains one ring oxygen atom (especially 3-(benzyl)oxetan-3-yl);

5-membered heteroaryl( _C1-3 )alkylene-, wherein said 5-membered heteroaryl contains one oxygen atom and one or two nitrogen atoms; and where the specified 5-membered heteroaryl is unsubstituted, or mono-, or disubstituted; where the substituents _are independently selected from ( _{C1_4} ) alkyl, ( _C1.4 ) alkoxy, halogen,

- 20040620 ( _C1-3 )fluoroalkyl or ( _C1-3 )fluoroalkoxy; (especially oxazol-5-yl-methyl, 1-([1,2,4]oxadiazol-3-yl)ethyl,

-(isoxazol-3-yl)ethyl, 3-methylisoxazol-5-yl-methyl, 5-methylisoxazol-3-yl-methyl, (3-ethyl-([1,2,4]oxdiazol-5-yl)methyl , 1-(5-methyl-([1,3,4]oxadiazol-2-yl)ethyl, 1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3yl)ethyl);

6-membered heteroaryl(C _1-4 )alkylene-, where the specified 6-membered heteroaryl contains one or two nitrogen atoms; and where the specified 6-membered heteroaryl is unsubstituted, or mono, or disubstituted; where the substituents are independently selected from ( _C1-4 )alkyl, ( _C1-4 )alkoxy, halogen, ( _C1-3 )fluoroalkyl, or ( _C1-3 )fluoroalkoxy; where, in the case where Ar ³ is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present as the corresponding N-oxide; (especially pyridin-2-yl-methyl, pyridin-3-yl-methyl, pyridin-4-yl-methyl, pyrimidin-2-yl-methyl, pyrimidin-4-yl-methyl, pyrazin-2-yl-methyl, 1-(pyridin-2-yl)ethyl, 1-(pyridin-3-yl)ethyl, 2-(pyridin-2-yl)ethyl, 1-methyl-1-(pyridin-2-yl)ethyl, 1- (pyrazin-2-yl)ethyl, 1-(pyrimidin-4-yl)ethyl, 1-(5-fluoropyrimidin-2yl)ethyl, 1-(3-fluoropyridin-2-yl)ethyl, 1-(5-fluoropyridine) -2-yl)ethyl, 1-(6-methylpyridin-2-yl)ethyl, 1-(3,5difluoropyridin-2-yl)ethyl, (6-methylpyridin-2-yl)methyl, 1-(pyrimidin-2 -yl)ethyl, 1-methyl-1-(pyrimidin-2-yl)ethyl, 2-methyl-2-(pyridin-2-yl)propyl, 2-methyl-2-(3-methylpyridin-2-yl) propyl);

6-membered heteroaryl-( _C1-3 )alkylene-, wherein said -( _C1-3 )alkylene-monosubstituted with hydroxy or trifluoromethyl; where the specified 6-membered heteroaryl contains one or two nitrogen atoms; (especially 2hydroxy-1-(pyridin-2-yl)ethyl, 2,2,2-trifluoro-1-(pyridin-2-yl)ethyl);

6-membered heteroaryl-(C ₃ - ₅ )cycloalkylene-, where the specified 6-membered heteroaryl contains one or two nitrogen atoms; and where the specified 6-membered heteroaryl is unsubstituted, or mono-, or disubstituted; where the substituents are independently selected from ( _{C1_4} )alkyl, ( _{C1_4} )alkoxy, halogen, ( _C1-3 )fluoroalkyl, or ( _C1-3 )fluoroalkoxy; where, in the case where Ar ³ is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present as the corresponding N oxide (especially 1-(pyridin-2-yl)cyclopropyl, 1-(pyridin-4-yl)cyclopropyl, 1 -(pyrazin-2-yl)cyclopropyl, 1-(pyridazin-3-yl)cyclopropyl, 1-(pyrimidin-2-yl)cyclopropyl, 1-(5-fluoropyridin-2-yl)cyclopropyl, 1-(4, 6-dimethylpyrimidin-2-yl)cyclopropyl, 1-(pyrimidin-4-yl)cyclopropyl, 2(pyrimidin-2-yl)cyclobutyl, 2-(pyrimidin-2-yl)cyclopentyl, 1-(1-hydroxypyrimidin-2 -yl)cyclopropyl, 1-(3-fluoropyridin-2-yl)cyclopropyl, 1-(pyridin-2-yl)cyclobutyl, 1-(1-oxypyridin-2-yl)cyclopropyl);

6-membered heteroaryl(C ₃ _ ₅ )cycloalkylene(C ₁ _ ₂ )alkylene-, where the specified 6-membered heteroaryl contains one or two nitrogen atoms; and where the specified 6-membered heteroaryl is unsubstituted; (especially [1-(pyridin-2-yl)cyclopropyl]methyl);

and R ⁿ² is independently hydrogen (preferably) or ( _{C1_4} )alkyl (especially methyl, ethyl, isopropyl);

or R ⁿ¹ is (C _1-3 )alkyl (especially methyl, ethyl); and R ^N2 is hydrogen or methyl.

14) A further disclosure relates to compounds of formula ( _ID ) according to any of disclosures 1)-11), where R ¹ is R ^n1rn2 N-, where R ^N1 is (C ₃ _ ₆ )cycloalkyl(C ₁ _ ₃ )alkylene-, where the specified (C _3-6 )cycloalkyl optionally contains one ring oxygen atom (especially 1-cyclobutylethyl, tetrahydrofuran-3-yl-methyl, tetrahydrofuran-2-yl-methyl, 1-tetrahydrofuran-2-yl- ethyl, oxetan-3-yl-methyl);

phenyl-( _C1-4 )alkylene-, wherein said phenyl is unsubstituted, or mono-, or disubstituted; where the substituents are independently selected from ( _C1-4 )alkyl, ( _C1-4 )alkoxy, halogen, ( _C1-3 )fluoroalkyl, or ( _C1-3 )fluoroalkoxy; (particularly such a group is benzyl, 1-phenylethyl, 2-phenylethyl, 2-(2chlorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(2-methylphenyl)ethyl, 2-(3-methylphenyl)ethyl, 2-(4-methylphenyl)ethyl, 2-(2-methoxyphenyl)ethyl, 2-phenylpropyl, or 1-(3-bromophenyl)ethyl, 1-(2-methoxyphenyl)ethyl, 2-methyl-2-(2- chlorophenyl)propyl);

phenyl(C ₃ - ₅ )cycloalkylene-, wherein said (C _{3 .5} )cycloalkylene optionally contains one ring oxygen atom, and wherein said phenyl is unsubstituted, or mono-, or disubstituted; where the substituents are independently selected from ( _C1-4 )alkyl, ( _C1-4 )alkoxy, halo, hydroxy, ( _C1-3 )fluoroalkyl, or ( _C1-3 )fluoroalkoxy; (especially 2-phenylcyclopropyl, 1-phenylcyclopropyl, 1-phenylcyclobutyl, 2phenylcyclobutyl, 1-(3-chlorophenyl)cyclopropyl, 1-(4-fluorophenyl)cyclopropyl, 1-(3-fluorophenyl)cyclopropyl, 1-(2-fluorophenyl) cyclopropyl, 1-(2-methylphenyl)cyclopropyl, 1-(2-hydroxyphenyl)cyclopropyl, 3-(3-chlorophenyl)oxetan-3-yl, 3-(4-fluorophenyl)oxetan-3-yl, 1-(2 -methoxyphenyl)cyclopropyl, 1(3-methoxyphenyl)cyclopropyl, 1-(2-trifluoromethylphenyl)cyclopropyl);

6-membered heteroaryl( _C1-4 )alkylene-, wherein said 6-membered heteroaryl contains one or two nitrogen atoms; and where the specified 6-membered heteroaryl is unsubstituted, or mono-, or disubstituted; where the substituents are independently selected from ( _C1-4 )alkyl, ( _C1-4 )alkoxy, halogen, ( _C1-3 )fluoroalkyl, or ( _C1-3 )fluoroalkoxy; where, in the case where Ar ³ is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present as the corresponding N-oxide; (especially pyridin-2-yl-methyl, pyridin-3-yl-methyl, pyridin-4-yl-methyl, pyrimidin-2-yl-methyl, pyrimidin-4-yl-methyl, pyrazin-2-yl-methyl, 1-(pyridin-2-yl)ethyl, 1-(pyridin-3-yl)ethyl, 2-(pyridin-2-yl)ethyl,

- 21 040620

-methyl-1-(pyridin-2-yl)ethyl, 1-(pyrazin-2-yl)ethyl, 1-(pyrimidin-4-yl)ethyl, 1-(5-fluoropyrimidin-2yl)ethyl, 1-( 3-fluoropyridin-2-yl)ethyl, 1-(5-fluoropyridin-2-yl)ethyl, 1-(6-methylpyridin-2-yl)ethyl, 1-(3,5difluoropyridin-2-yl)ethyl, ( 6-methylpyridin-2-yl)methyl, 1-(pyrimidin-2-yl)ethyl, 1-methyl-1-(pyrimidin-2-yl)ethyl, 2-methyl-2-(pyridin-2-yl)propyl , 2-methyl-2-(3-methylpyridin-2-yl)propyl);

6-membered heteroaryl-(C ₃ _ ₅ )cycloalkylene-, where the specified 6-membered heteroaryl contains one or two nitrogen atoms; and where the specified 6-membered heteroaryl is unsubstituted, or mono-, or disubstituted; where the substituents are independently selected from (C1_ ₄ )alkyl, (C1_ ₄ )alkoxy, halo, ( _{C1_3} )fluoroalkyl, or ( _{C1_3} )fluoroalkoxy; where, in case Ar ³ is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present as the corresponding N-oxide (especially 1-(pyridin-2-yl)cyclopropyl, 1-(pyridin-4-yl)cyclopropyl , 1-(pyrazin-2-yl)cyclopropyl, 1-(pyridazin-3-yl)cyclopropyl, 1-(pyrimidin-2-yl)cyclopropyl, 1-(5-fluoropyridin-2yl)cyclopropyl, 1-(4, 6-dimethylpyrimidin-2-yl)cyclopropyl, 1-(pyrimidin-4-yl)cyclopropyl, 2(pyrimidin-2-yl)cyclobutyl, 2-(pyrimidin-2-yl)cyclopentyl, 1-(1-hydroxypyrimidin-2 -yl)cyclopropyl, 1-(3-fluoropyridin-2-yl)cyclopropyl, 1-(pyridin-2-yl)cyclobutyl, 1-(1-oxypyridin-2-yl)cyclopropyl);

and R ⁿ² is independently hydrogen or ( _{C1_4} )alkyl (especially methyl, ethyl, isopropyl).

15) An additional disclosure relates to compounds of formula ( _ID ) in accordance with any of the disclosures 1) - 11), where R ¹ represents R ^n1rn2 N-, where

R ⁿ¹ represents a 6-membered heteroaryl-(C1_ ₄ )alkylene-, where the specified 6-membered heteroaryl contains one or two nitrogen atoms; and where the specified 6-membered heteroaryl is unsubstituted, or mono-, or disubstituted; where the substituents are independently selected from ( _C1-4 ) alkyl, ( _C1-4 ) alkoxy, halogen, ( _C1-3 ) fluoroalkyl, or ( _{C1_3} ) fluoroalkoxy; where, in the case where Ar ³ is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present as the corresponding N-oxide; (especially pyridin-2-yl-methyl, pyridin-3-yl-methyl, pyridin-4-yl-methyl, pyrimidin-2yl-methyl, pyrimidin-4-yl-methyl, pyrazin-2-yl-methyl, 1- (pyridin-2-yl)ethyl, 1-(pyridin-3-yl)ethyl, 2(pyridin-2-yl)ethyl, 1-methyl-1-(pyridin-2-yl)ethyl, 1-(pyrazin- 2-yl)ethyl, 1-(pyrimidin-4-yl)ethyl, 1-(5fluoropyrimidin-2-yl)ethyl, 1-(3-fluoropyridin-2-yl)ethyl, 1-(5-fluoropyridin-2- yl)ethyl, 1-(6-methylpyridin-2-yl)ethyl, 1-(3,5-difluoropyridin-2-yl)ethyl, (6-methylpyridin-2-yl)methyl, 1-(pyrimidin-2yl) ethyl, 1-methyl-1-(pyrimidin-2-yl)ethyl, 2-methyl-2-(pyridin-2-yl)propyl, 2-methyl-2-(3-methylpyridin-2-yl)propyl);

6-membered heteroaryl(C ₃ _ ₅ )cycloalkylene-, where the specified 6-membered heteroaryl contains one or two nitrogen atoms; and where the specified 6-membered heteroaryl is unsubstituted, or mono-, or disubstituted; where the substituents are independently selected from (C1_ ₄ )alkyl, (C1_ ₄ )alkoxy, halo, ( _{C1_3} )fluoroalkyl, or ( _{C1_3} )fluoroalkoxy; where, in the case where Ar ³ is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present as the corresponding N oxide (especially 1-(pyridin-2-yl)cyclopropyl, 1-(pyridin-4-yl)cyclopropyl, 1 -(pyrazin-2-yl)cyclopropyl, 1-(pyridazin-3-yl)cyclopropyl, 1-(pyrimidin-2-yl)cyclopropyl, 1-(5-fluoropyridin-2-yl)cyclopropyl, 1-(4, 6-dimethylpyrimidin-2-yl)cyclopropyl, 1-(pyrimidin-4-yl)cyclopropyl, 2-(pyrimidin-2-yl)cyclobutyl, 2-(pyrimidin-2-yl)cyclopentyl, 1-(1-oxypyrimidin- 2-yl)cyclopropyl, 1-(3fluoropyridin-2-yl)cyclopropyl, 1-(pyridin-2-yl)cyclobutyl, 1-(1-hydroxypyridin-2-yl)cyclopropyl);

and R ⁿ² is independently hydrogen or methyl.

16) Additional disclosure relates to compounds of formula ( _ID ) in accordance with any of the disclosures 1) - 11), where R ¹ represents R ^n1rn2 N-, where

R ⁿ¹ is hydrogen;

methyl, ethyl, isopropyl, isobutyl, t-butyl, or 1,2,2-trimethylpropyl;

2-hydroxyethyl, 2-hydroxy-1-methylethyl, 2-hydroxy-1,1-dimethylethyl, 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, 2-ethoxy-1-methylethyl, 2-methoxy-1,1- dimethylethyl, 3-methoxy-1,1-dimethylpropyl, 2-(2-hydroxyethoxy)ethylcarbamoylmethyl, 2-methanesulfonyl-1,1-dimethylethyl, 1-cyano-1-methylethyl, 2-dimethylaminoethyl, or 2-trifluoromethoxyethyl;

1-methylprop-2-ynyl;

2-fluoroethyl, 2,2-difluoroethyl, 2-fluoro-1-methylethyl, 2-fluoro-1,1-dimethylethyl, 2,2-difluoro-1-methylethyl, or 3,3,3-trifluoro-1,1 -dimethylpropyl;

methoxy;

2-(2-oxopyrrolidin-1-yl)ethyl;

cyclopropyl, cyclopentyl, 1-methyl-cyclopropyl, 1-methylcyclobutyl, 1-cyclopropylcyclopropan-1-yl, 1-cyclobutylethyl, 3-methyltetrahydrofuran-3-yl, tetrahydrofuran-3-yl-methyl, tetrahydrofuran-2-yl-methyl, 1-tetrahydrofuran-2-yl-ethyl, oxetan-3-yl-methyl, or 3,3-difluoro-1-methylcyclobutyl, 1-(ethoxycarbonyl)cyclopropyl, or 1-cyanocyclobutyl;

phenyl, benzyl, 1-phenylethyl, 2-(2-chlorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(2-methylphenyl)ethyl, 2(3-methylphenyl)ethyl, 2-(4-methylphenyl) ethyl, 2-(2-methoxyphenyl)ethyl, 2-phenylpropyl, 2-hydroxy-1phenylethyl, 2-hydroxy-2-phenylethyl, or 2-phenylcyclopropyl, 1-(3-bromophenyl)ethyl, 1-phenylcyclopropyl , 1-phenylcyclobutyl, 2-phenylcyclobutyl, 1-(3-chlorophenyl)cyclopropyl, 1-(4-fluorophenyl)cyclopropyl, 1-(3-fluorophenyl)cyclopropyl, 1-(2-fluorophenyl)cyclopropyl, 1-(2- methylphenyl)cyclopropyl, 1-(2-hydroxyphenyl)cyclopropyl, 1-(2-methoxyphenyl)ethyl, 2-methyl-2-(2-chlorophenyl)propyl, 1-(4-chlorophenyl)cyclopropylmethyl, 3-(3-chlorophenyl) oxetan-3-yl, 3-(4-fluorophenyl)oxetan-3-yl, 3-(phenyl)oxetan-3-yl-methyl, 3-(benzyl)oxetan-3-yl, 1-(2-methoxyphenyl) cyclopropyl, 1-(3-methoxyphenyl)cyclopropyl, 1-(2-trifluoromethylphenyl)cyclopropyl, or 2-ethoxy-2-oxo-1-phenylethyl;

4,5-dimethylthiazol-2-yl, 1H-imidazol-4-yl-methyl, thiazol-2-yl-methyl, 4-methylthiazol-5-yl-methyl, 4-methylthiazol-2-yl-methyl, 5-methylthiazol- 2-yl-methyl, 2-methylthiazol-4-yl-methyl, oxazol-5-yl-methyl, 1(2H-pyrazol-3-yl)ethyl, (1-methyl-1H-pyrazol-3-yl) methyl, 1-([1,2,4]oxadiazol-3-yl)ethyl, 1-(isoxazol-3yl)ethyl, 3-methylisoxazol-5-yl-methyl, 5-methylisoxazol-3-yl-methyl, 1 -(1H-[1,2,4]triazol-3-yl)ethyl, (1,5-dimethyl-1H-pyrazol-3-yl)methyl, (2,5-dimethyl-2H-pyrazol-3-yl )methyl, (3-ethyl-([1,2,4]oxadiazol-5yl)methyl, 1-(5-methyl-([1,3,4]oxadiazol-2-yl)ethyl, 1-methyl-1 -(1-methyl-1H-pyrazol-4-yl)ethyl or 1methyl-1-(5-methyl-[1.2.4]oxadiazol-3-yl)ethyl or pyridin-3-yl, pyridin-2 -yl-methyl, pyridin-3-yl-methyl, pyridin-4-yl-methyl, pyrimidin-2-ylmethyl, pyrimidin-4-yl-methyl, pyrazin-2-yl-methyl, 1-(pyridin-2- yl)ethyl, 1-(pyridin-3-yl)ethyl, 2(pyridin-2-yl)ethyl, 1-methyl-1-(pyridin-2-yl)ethyl, 1-(pyrazin-2-yl)ethyl , 1-(pyrimidin-4-yl)ethyl, 1-(5fluoropyrimidin-2-yl)ethyl, 1-(3-fluoropyridin-2-yl)ethyl, 1-(5-fluoropyridin-2 -yl)ethyl, 1-(6-methylpyridin-2-yl)ethyl, 2-hydroxy-1-(pyridin-2-yl)ethyl, 1-(1-oxypyridin-2-yl)ethyl, 1-(pyridine -2-yl)cyclopropyl, 1-(pyridin-4-yl)cyclopropyl, 1-(pyrazin-2-yl)cyclopropyl, 1-(pyridazin-3-yl)cyclopropyl, 1-(pyrimidin-2-yl)cyclopropyl , 1-(5-fluoropyridin-2-yl)cyclopropyl, 1-(3,5-difluoropyridin-2yl)ethyl, 2,2,2-trifluoro-1-(pyridin-2-yl)ethyl, or 1-( 4,6-dimethylpyrimidin-2-yl)cyclopropyl; or (6-methylpyridin-2-yl)methyl, 1-(pyrimidin-2-yl)ethyl, 1-methyl-1-(pyrimidin-2-yl)ethyl, 1-(pyrimidin4-yl)cyclopropyl, 2-( pyrimidin-2-yl)cyclobutyl, 2-(pyrimidin-2-yl)cyclopentyl, 1-(1oxypyrimidin-2-yl)cyclopropyl, 1-(3-fluoropyridin-2-yl)cyclopropyl, [1-(pyridin-2 -yl)cyclopropyl]methyl, 1-(pyridin-2-yl)cyclobutyl, 1-(1-oxypyridin-2-yl)cyclopropyl, 2-methyl-2-(pyridin2-yl)propyl, or 2-methyl-2 -(3-methylpyridin-2-yl)propyl;

and R ⁿ² is independently hydrogen, methyl, ethyl, isopropyl, or 2-fluoroethyl;

or R ⁿ¹ and R ⁿ² together with the nitrogen atom to which they are attached form a 4-6 membered ring selected from azetidin-1-yl, pyrrolidin-1-yl, morpholin-4-yl, 3-fluoroazetidin-1- yl, 3,3-difluoroazetidin-1-yl, 3-hydroxypyrrolidin-1-yl, 3-phenylpyrrolidin-1-yl, 3-(pyridin-2-yl)pyrrolidin1-yl.

17) Additional disclosure relates to compounds of formula ( _ID ) in accordance with any of the disclosures 1) - 16), where R ² represents hydrogen;

( _C1.6 ) alkyl (especially ethyl, isopropyl, isobutyl, t-butyl, 2,2-dimethylpropyl, 3-methylbutyl, 3,3-dimethylbutyl);

(C ₂ - ₆ )alkyl which is monosubstituted with (C1_ ₃ )alkoxy (especially methoxy) or hydroxy;

(especially 2-hydroxyethyl, 2-methoxyethyl, 2-hydroxy-1-methylpropyl);

(C ₃ . ₈ )cycloalkyl-(C1. ₃ )alkyl, where (C ₃ _ ₈ )cycloalkyl is unsubstituted; or monosubstituted, where the substituent is (C1_ ₃ )alkyl (especially methyl), fluoro, or (C1_ ₃ )fluoroalkyl (especially difluoromethyl); or disubstituted with fluorine;

(especially cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopropylethyl, (1-methylcyclopropyl)methyl, (1-methylcyclobutyl)methyl, 2-cyclopropylethyl, (1-fluorocyclopropyl)methyl, (2,2difluorocyclopropyl)methyl, (3,3-difluorocyclobutyl )methyl, (1-difluoromethylcyclopropyl)methyl);

(C _3-8 ) cycloalkyl, where (C _3-8 ) cycloalkyl is unsubstituted, or mono- or disubstituted, where the substituents are independently selected from (C _1-3 ) alkyl (especially methyl), fluorine, hydroxy, hydroxy (C 1_ ₃ ) alkyl (especially hydroxymethyl), or (C1_ ₃ )alkoxy (especially methoxy);

(especially cyclobutyl, 2-methylcyclobutyl, 2,2-dimethylcyclobutyl, 3,3-dimethylcyclobutyl, cyclopentyl, cyclohexyl, spiro[2.4]hept-4-yl, spiro[3.3]hept-2-yl, bicyclo[2.2.1] hept-2-yl, 2methylcyclopentyl, 2-(hydroxymethyl)cyclopentyl, 3,3-dimethylcyclopentyl, 2-ethylcyclopentyl, 3,3dimethylcyclohexyl, 2-fluorocyclohexyl, 4-fluorocyclohexyl, 4,4-difluorocyclohexyl, 2-hydroxycyclohexyl, 2-methoxycyclohexyl , 3-methoxycyclohexyl, spiro[2.3]hex-5-yl, bicyclo[3.1.0]hex-3yl, 3,3-difluorocyclobutyl);

( _C3.8 )cycloalkenyl( _C1.3 )alkyl ( _especially cyclopenten-1-ylmethyl); or benzyl, where the phenyl ring of said benzyl is unsubstituted or monosubstituted with halogen (especially benzyl, 2-chlorobenzyl, 2-fluorobenzyl, 4-fluorobenzyl).

18) An additional disclosure relates to compounds of formula ( _ID ) in accordance with any of the disclosures 1)-16), where R ² represents (C ₃ _ ₈ )cycloalkyl(C ₁ _ ₃ )alkyl, where (C _3-8 )cycloalkyl is unsubstituted; or monosubstituted, where the substituent is (C ₁ . ₃ )alkyl (especially methyl), fluoro, or (C1_ ₃ )fluoroalkyl (especially difluoromethyl); or disubstituted with fluorine; (especially cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopropylethyl, (1-methylcyclopropyl)methyl, (1-methylcyclobutyl)methyl, 2-cyclopropylethyl,

- 23 040620 (1-fluorocyclopropyl)methyl, (2,2-difluorocyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1difluoromethylcyclopropyl)methyl); or (C _3-8 )cycloalkyl, where (C _3-8 )cycloalkyl is unsubstituted, or mono- or disubstituted, where the substituents are independently selected from (C _1-3 )alkyl (especially methyl), or fluorine; (especially cyclobutyl, 2-methylcyclobutyl, 2,2-dimethylcyclobutyl, 3,3-dimethylcyclobutyl, cyclopentyl, cyclohexyl, spiro[2.4]hept-4-yl, spiro[3.3]hept-2-yl, bicyclo[2.2.1] hept-2-yl, 2-methylcyclopentyl, 3,3-dimethylcyclopentyl, 2-ethylcyclopentyl, 3,3-dimethylcyclohexyl, 2-fluorocyclohexyl, 4-fluorocyclohexyl, 4,4difluorocyclohexyl, spiro[2.3]hex-5-yl, bicyclo[ 3.1.0]hex-3-yl, 3,3-difluorocyclobutyl).

19) An additional disclosure relates to compounds of formula (ID) in accordance with any of the disclosures 1)-16), where R ² represents unsubstituted (C _3-8 )cycloalkyl(C _1-3 )alkyl (especially cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl , 1-cyclopropylethyl, 2-cyclopropylethyl); or unsubstituted (C _3-6 )cycloalkyl (especially cyclobutyl, cyclopentyl, cyclohexyl); or (C _3-8 )cycloalkyl, where (C _3-8 )cycloalkyl is disubstituted with fluorine (especially 3,3-difluorocyclobutyl); or (C _3-8 )cycloalkyl(C _1-3 )alkyl; where (C _3-8 )cycloalkyl is monosubstituted with methyl, fluorine, or (C1)fluoroalkyl (especially difluoromethyl); or disubstituted with fluorine (especially (1-methylcyclopropyl)methyl, (1methylcyclobutyl)methyl, (1-fluorocyclopropyl)methyl, (2,2-difluorocyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1-difluoromethylcyclopropyl)methyl).

20) An additional disclosure relates to compounds of formula ( _ID ) in accordance with any of the disclosures 1)-16), where R ² represents hydrogen;

ethyl, isopropyl, 2,2-dimethylpropyl, 3-methylbutyl, 3,3-dimethylbutyl;

isobutyl, tert-butyl;

2-hydroxyethyl, 2-methoxyethyl, 2-hydroxy-1-methylpropyl; allyl;

cyanomethyl;

3-fluoropropyl;

cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopropylethyl, (1-methyl-cyclopropyl)methyl, (1-methyl-cyclobutyl)methyl, 2-cyclopropylethyl;

(1-fluorocyclopropyl)methyl, (2,2-difluorocyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1difluoromethylcyclopropyl)methyl;

cyclobutyl, cyclopentyl, cyclohexyl;

2-methylcyclobutyl, 2,2-dimethylcyclobutyl, 3,3-dimethylcyclobutyl;

2-methylcyclopentyl, 2-(hydroxymethyl)cyclopentyl, 3,3-dimethylcyclopentyl, 2-ethylcyclopentyl, 3,3-dimethylcyclohexyl, 2-fluorocyclohexyl, 4-fluorocyclohexyl, 4,4-difluorocyclohexyl, 2hydroxycyclohexyl, 2-methoxycyclohexyl, 3-methoxycyclohexyl ;

3,3-difluorocyclobutyl;

spiro[2.4]hept-4-yl, spiro[3.3]hept-2-yl, bicyclo[2.2.1]hept-2-yl;

spiro[2.3]hex-5-yl, bicyclo[3.1.0]hex-3-yl;

thietan-3-yl;

cyclopenten-1-ylmethyl; or benzyl, 2-chlorobenzyl, 2-fluorobenzyl, or 4-fluorobenzyl.

21G) Another embodiment of the invention relates to compounds according to embodiment A) which are selected from the following compounds:

(1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1-cyclobutyl-4- {[5-(2,4-difluorophenyl) [1,3,4]thiadiazole-2-carbonyl]amino }piperidine-3-carboxylic acid;

(1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{[5-(2,4-difluorophenyl)[1,3,4]thiαdiαzol-2-carbonyl]amino}-1- (1-fluorocyclopropylmethyl)piperidine-3-carboxylic acid; and (1-pyrimidin-2-yl-cyclopropyl)amide (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluorophenyl)[1,3,4]thiadiazole-2-carbonyl]amino }piperidine-3-carboxylic acid.

21) Additional disclosure relates to new piperidine derivatives of formula (II);

ABOUT

NIR ²

Formula (II) wherein the two substituents on the piperidine ring, R1-CO- and -NH-CO-Ar1-Ar ² , are in the relative trans configuration (i.e., the relative configuration of the two chiral carbons at positions 3 and 4 of the piperidine ring is (3R*,4R*));

- 24 040620

Ar ¹ is a 5-membered heteroarylene group (especially a 5-membered heteroarylene containing from one to a maximum of three heteroatoms, each independently selected from oxygen and nitrogen; especially oxazoldiyl, isoxazoldiyl, oxadiazoldiyl, or triazoldiyl), where -NH-CO group and Ar ² attached in the meta position to the ring atoms of Ar ¹ ; where the specified 5-membered heteroarylene is unsubstituted, or monosubstituted R ^Ar1 ; where R ^Ar1 represents (C _1-4 )alkyl, (C ₁₄ )alkoxy, halogen, (C ₁ . ₃ )fluoroalkyl, or (C _1-3 )fluoroalkoxy (especially said 5-membered heteroarylene is unsubstituted);

Ar ² is phenyl which is mono-, di- or tri-substituted, where the substituents are independently fluorine or chlorine (especially Ar ² is phenyl which is mono-, di- or tri-substituted with fluorine);

R ⁵ is (C ₁ .b) alkyl;

R ² is hydrogen;

(C ₁ .b) alkyl (especially ethyl, isopropyl, 2,2-dimethylpropyl, 3-methylbutyl, 3,3-dimethylbutyl);

(C _2-6 )alkyl which is monosubstituted with (C _1-3 )alkoxy (especially methoxy), or hydroxy (especially 2hydroxyethyl, 2-methoxyethyl, 2-hydroxy-1-methylpropyl);

(C ₂ _ ₃ )fluoroalkyl;

(C ₃ _ ₈ )cycloalkyl(C ₀ _ ₃ )alkyl; where the specified (C ₃ _ ₈ )cycloalkyl group may optionally contain one ring oxygen atom; where (C ₃ _ ₈ )cycloalkyl is unsubstituted, or mono- or disubstituted, where the substituents are independently selected from (C _1-3 )alkyl (especially methyl), fluorine, hydroxy, hydroxy(C _1-3 )alkyl (especially hydroxymethyl) , or (C _1-3 )alkoxy (especially methoxy);

(especially cyclobutyl, 2-methylcyclobutyl, 2,2-dimethylcyclobutyl, 3,3-dimethylcyclobutyl, cyclopentyl, cyclohexyl, spiro[2.4]hept-4-yl, spiro[3.3]hept-2-yl, bicyclo[2.2.1] hept-2-yl, 2-methylcyclopentyl, 2-(hydroxymethyl)cyclopentyl, 3,3-dimethylcyclopentyl, 2-ethylcyclopentyl, 3,3-dimethylcyclohexyl, 2-fluorocyclohexyl, 4-fluorocyclohexyl, 4,4-difluorocyclohexyl, 2-hydroxycyclohexyl , 2methoxycyclohexyl, 3-methoxycyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopropylethyl, (1-methylcyclopropyl)methyl, (1-methylcyclobutyl)methyl, 2-cyclopropylethyl); or (C ₃ _ ₈ )cycloalkenyl(C ₁ _ ₃ )alkyl (especially cyclopenten-1-yl-methyl); And

R ³ is hydrogen, or methyl (especially hydrogen).

Compounds of formula (II) are important intermediates suitable for the preparation of compounds of formula (I) and/or ( _ID ) as described in Reaction Scheme A below. In addition, such compounds of formula (II) may also act as CXCR7 receptor antagonists and thus may be useful in the prevention or treatment of diseases that respond to activation of CXCL12 receptors and/or CXCL11 receptors, especially cancer.

The compounds of formula (I) according to embodiments A)-G) and their pharmaceutically acceptable salts can be used as drugs, for example in the form of pharmaceutical compositions for enteral (especially such as oral) or parenteral administration (including topical application or inhalation ).

The manufacture of pharmaceutical compositions can be carried out in a manner that 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 administering the described compounds of formula (I), ( _ID ) or (II), or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, in a galenic form of administration together with suitable, non-toxic, inert, therapeutically compatible materials in in the form of a solid or liquid carrier and, if desired, with conventional pharmaceutical adjuvants.

The invention also relates to a method for the prevention or treatment of the disease or disorder mentioned herein, comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) as defined in any of embodiments A)-G).

In a preferred embodiment of the invention, the amount administered is from 1 to 1000 mg per day, in particular from 5 to 500 mg per day, more specifically from 25 to 400 mg per day, especially from 50 to 200 mg per day.

Whenever the word between is used to describe a numeric range, it should be understood that the endpoints of the specified range are explicitly included in the range. For example: if a temperature range of 40 to 80°C is described, this means that the endpoints of 40 and 80°C are included in the range; or if the variable is defined as an integer between 1 and 4, it means that the variable is an integer 1, 2, 3, or 4.

Unless used in relation to temperatures, the term approximately placed before the numerical value of X refers in the present invention to the range extending from X minus 10% of X to X plus 10% of X, and preferably to the range extending from X minus 5 % of X to X plus 5% of X. In the particular case of temperatures, the term roughly placed before temperature Y refers in the present invention to the range extending from temperature Y

- 25 040620 minus 10°C to Y plus 10°C and preferably up to a range extending from Y minus 5°C to Y plus 5°C.

For the avoidance of doubt, where compounds are described as being useful in the prevention or treatment of certain diseases, such compounds are also suitable for use in the preparation of a medicament for the prevention or treatment of said diseases.

Compounds of formula (I) as defined in any of embodiments A)-G) are useful in the prevention/prevention or treatment of disorders associated with the CXCR7 receptor or its ligands, which are particularly related to disorders associated with dysfunction of the CXCR7 receptor, or ligand signaling dysfunction through CXCR7, or CXCR7 ligand signaling dysfunction (CXCL12 and CXCL11) through their other receptors (CXCR4 and CXCR3).

Diseases or disorders associated with the CXCR7 receptor or its ligands are mainly selected from the group consisting of a malignant neoplasm (in particular, brain tumors, including malignant gliomas, glioblastoma multiforme; neuroblastomas; pancreatic cancer, including pancreatic adenocarcinoma/ pancreatic duct adenocarcinoma; gastrointestinal cancer, including colon cancer, hepatocellular carcinoma; Kaposi's sarcoma; leukemias, including adult T-cell leukemia; lymphoma; lung cancer; breast cancer; rhabdomyosarcoma; prostate cancer; squamous cell carcinoma of the esophagus; oral squamous cell carcinoma; endometrial cancer; thyroid cancer, including papillary thyroid cancer; metastatic cancer; lung metastases; skin cancer, including melanoma and metastatic melanoma; bladder cancer; multiple myelomas; osteosarcoma; cancers of the head and neck; and cancer kidneys, including clear cell kidney cancer, metastatic clear cell kidney cancer);

inflammatory diseases (particularly chronic rhinosinusitis, asthma, chronic obstructive pulmonary disease, atherosclerosis, myocarditis and sarcoidosis; especially chronic rhinosinusitis, asthma and atherosclerosis);

autoimmune disorders (especially (inflammatory) demyelinating diseases; multiple sclerosis (MS); Guillain-Barré syndrome; rheumatoid arthritis (RA); inflammatory bowel diseases (IBD, especially including Crohn's disease and ulcerative colitis); systemic lupus erythematosus (SLE); lupus nephritis; interstitial cystitis, celiac disease; autoimmune encephalomyelitis; osteoarthritis; and type I diabetes; especially autoimmune disorders that have an inflammatory component, such as (inflammatory) demyelinating diseases, multiple sclerosis, Guillain-Barré syndrome, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, lupus nephritis and autoimmune encephalomyelitis);

transplant rejections (particularly renal allograft rejection, cardiac allograft rejection, and graft-versus-host reactions induced by hematopoietic stem cell transplantation); as well as fibrosis (especially liver fibrosis, cirrhosis of the liver, pulmonary fibrosis, especially idiopathic pulmonary fibrosis).

In particular, such diseases or disorders associated with the CXCR7 receptor or its ligands are cancers, autoimmune disorders (especially autoimmune disorders that have an inflammatory component), and fibrosis.

In addition, other diseases or disorders associated with the CXCR7 receptor or its ligands are diseases associated with metastasis mediated by CXCR7 and/or CXCL12 and/or CXCL11, chemotaxis, cell adhesion, transendothelial migration, proliferation and/or cell survival.

In addition, other specific diseases or disorders associated with the CXCR7 receptor or its ligands are proliferative diabetic retinopathy; West Nile viral encephalitis; pulmonary vascular disease, acute renal failure, ischemia, including cerebral ischemia, acute coronary syndrome, damaged central nervous system, hypertension, pulmonary hypertension, Shiga toxin-associated hemolytic uremic syndrome, preeclampsia, vascular damage, HIV/AIDS, angiogenesis, and brain and neuronal dysfunctions (such as the inflammatory components of Alzheimer's disease), stress-related disorders (such as anxiety, depression, and post-traumatic stress disorder), and diseases involving opioid receptors. In a further embodiment, such additional specific disease or disorder associated with the CXCR7 receptor or ligands thereof is, in particular, pulmonary hypertension.

The term malignant neoplasm refers to all types of cancer, such as carcinomas; adenocarcinomas; leukemia; sarcomas; lymphomas; myeloma; metastatic cancer; brain tumors; neuroblastomas; pancreas cancer; cancer of the gastrointestinal tract; lungs' cancer; mammary cancer; prostate cancer; endometrial cancer; skin cancer; bladder cancer; cancers of the head and neck; neuroendocrine tumors; ovarian cancer; cervical cancer; tumors of the mouth 26 040620; tumors of the nasopharynx; chest cancer; and virus-induced tumors.

In particular, the term refers to brain tumors, including brain metastases, malignant gliomas, glioblastoma multiforme, medulloblastoma, meningiomas; neuroblastoma; pancreatic cancer, including pancreatic adenocarcinoma/pancreatic ductal adenocarcinoma; gastrointestinal cancer, including colon cancer, colorectal adenoma, colorectal adenocarcinoma, metastatic colorectal cancer, familial adenomatous polyposis (FAP), gastric cancer, gallbladder cancer, cholangiocarcinoma, hepatocellular carcinoma; Kaposi's sarcoma; leukemias, including acute myeloid leukemia, adult T-cell leukemia; lymphomas, including Burkitt's lymphoma, Hodgkin's lymphoma, MALT-type lymphoma, and primary intraocular B-cell lymphoma; lung cancer, including non-small cell lung cancer; breast cancer, including triple negative breast cancer; rhabdomyosarcoma; prostate cancer, including castration-resistant prostate cancer; squamous cell carcinoma of the esophagus; squamous cell carcinoma (oral cavity); endometrial cancer; thyroid cancer, including papillary thyroid cancer; metastatic cancer; lung metastases; skin cancer, including melanoma and metastatic melanoma; bladder cancer, including the tumor marker of bladder cancer, urothelial carcinoma; multiple myeloma; osteosarcoma; cancers of the head and neck; and kidney cancer, including renal cell carcinoma, clear cell renal cell carcinoma, metastatic renal cell carcinoma, metastatic clear cell carcinoma of the kidney; as well as neuroendocrine tumors; ovarian cancer; cervical cancer; tumors of the oral cavity; tumors of the nasopharynx; chest cancer; choriocarcinoma; Ewing's sarcoma; and virus-induced tumors.

Especially the term cancer refers to malignant glioma, in particular glioblastoma multiforme, neuroblastoma; pancreatic cancer, in particular adenocarcinoma of the pancreatic ducts; Kaposi's sarcoma; adult T-cell leukemia, lymphoma; lung cancer; breast cancer; rhabdomyosarcoma; prostate cancer; squamous cell carcinoma of the esophagus; squamous cell carcinoma (oral cavity); endometrial cancer; papillary thyroid cancer; metastatic cancer; lung metastases; melanoma; bladder cancer; multiple myeloma; osteosarcoma; cancer of the gastrointestinal tract, especially colon cancer, hepatocellular carcinoma; cancers of the head and neck; and clear cell kidney cancer. Preferably, the term cancer refers to malignant glioma, in particular glioblastoma multiforme; pancreatic cancer, especially pancreatic ductal adenocarcinoma; papillary thyroid cancer; hepatocellular carcinoma; lung cancer; breast cancer; metastatic cancer; lung metastases; melanoma; colon cancer; and cancers of the head and neck.

The compounds of formula (I) as defined in any of embodiments A) to G) are particularly useful as therapeutic agents for the prevention/prevention or treatment of a cancer as defined above, which is a metastatic cancer/cancer which forms metastases.

Compounds of formula (I) as defined in any of embodiments A)-G) are particularly useful as therapeutic agents for the prevention/prevention or treatment of cancer. They can be used as standalone therapeutic agents or in combination with one or more chemotherapeutic agents and/or radiation therapy and/or targeted therapy. In a further embodiment, when a compound of formula (I) is used in the prevention/prevention or treatment of cancer in combination with one or more chemotherapeutic agents and/or radiation therapy and/or targeted therapy, such cancer is primarily malignant glioma, especially glioblastoma multiforme; pancreatic cancer, especially adenocarcinoma of the pancreatic ducts; papillary thyroid cancer; pulmonary metastasis; melanoma; lung cancer; metastatic cancer; hepatocellular carcinoma; breast cancer; colorectal cancer; or cancers of the head and neck. Such combined treatment can be carried out simultaneously, separately or over a period of time.

The invention thus also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier material and a compound of formula (I) as defined in any of embodiments A)-G);

and one or more chemotherapeutic cytotoxic agents.

Thus, the invention further relates to a kit containing a pharmaceutical composition, said composition comprising a pharmaceutically acceptable carrier material and a compound of formula (I) as defined in any of embodiments A)-G);

and instructions on how to use said pharmaceutical composition for the prevention or treatment of cancer (especially malignant glioma, in particular glioblastoma multiforme), in combination with chemotherapy and/or radiotherapy and/or targeted therapy.

The terms radiotherapy or radiation therapy or radiation oncology refer to

- 27 040620 medical use of ionizing radiation in the prevention (adjuvant therapy) and/or treatment of cancer; including external and internal radiation therapy.

The term targeted therapy refers to the prevention/prevention (adjuvant therapy) and/or treatment of cancer with one or more antineoplastic agents, such as small molecules or antibodies, that act on specific types of cancer cells or stromal cells. Some targeted therapies block the action of certain enzymes, proteins, or other molecules involved in the growth and spread of cancer cells. Other targeted therapies help the immune system destroy cancer cells (immunotherapy); or deliver toxic substances directly to cancer cells and destroy them. An example of a targeted therapy that is particularly suitable for combination with the compounds of the present invention is immunotherapy, in particular immunotherapy targeting the programmed cell death receptor 1 (PD-1 receptor) or its PD-L1 ligand (Feig C et al, PNAS 2013).

When used in combination with compounds of formula (I), the term targeted therapy specifically refers to agents such as:

a) epidermal growth factor receptor (EGFR) inhibitors or blocking antibodies (eg, gefitinib, erlotinib, afatinib, icotinib, lapatinib, panitumumab, zalutumumab, nimotuzumab, matuzumab, and cetuximab);

b) B-RAF inhibitors (eg vemurafenib, sorafenib, dabrafenib, GDC-0879, PLX-4720, LGX818);

c) aromatase inhibitors (eg exemestane, letrozole, anastrozole, vorozol, formestane, fadrozole);

d) immune response checkpoint inhibitors (e.g. anti-PD1 antibodies such as pembrolizumab (lambrolizumab, MK-3475), nivolumab, pidilizumab, AMP-514/MED10680; small molecular weight anti-PD1 agents such as, for example, compounds described in WO 2015/033299, WO 2015/044900 and WO 2015/034820; anti-PD1L antibodies such as BMS-936559, atezolizumab (MPDL3280A), MEDI4736, avelumab (MSB0010718C); anti-PDL2 such as AMP224, anti -CTLA-4 antibodies such as ipilimumab, tremelimumab);

e) vaccination methods (eg dendritic cell vaccination, peptide or protein vaccination (eg gp 100 peptide or MAGE-A3 peptide);

f) re-introduction of cancer cells, obtained from the patient himself or allogeneic (foreign), genetically modified so as to secrete immunomodulatory factors, such as a tumor cell vaccine transfected with the granulocyte-monocyte colony stimulating factor (GMCSF) (GVAX) gene or a vaccine against tumor cells transfected with the Fms-related tyrosine kinase 3 ligand gene (Flt-3) (FVAX) or a GM-CSF tumor-based vaccine enhanced with a toll-like receptor (TEGVAX);

g) T cell-based adoptive immunotherapy, including chimeric antigen receptor (CAR) engineered T cells (eg, CTL019);

h) cytokine or immunocytokine based therapy (eg interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 15);

i) Toll-like receptor (TLR) agonists (eg reciquimod, imiquimod, glucopyranosyl lipid A, CpG oligodeoxynucleotides);

j) thalidomide analogues (eg lenalidomide, pomalidomide);

k) indoleamine-2,3-dioxenase (IDO) and/or tryptophan-2,3-dioxygenase (TDO) inhibitors (eg NLG919/indoxymod, 1MT (1-methyltryptophan), INCB024360);

l) T cell costimulatory receptor activators (e.g. lymphocyte activation antigen-3 (LAG-3) antibodies (e.g. BMS-986016), anti-T cell immunoglobulin mucin-3 (TIM-3) antibodies, anti-CD137/ 4-1BB antibodies (eg, BMS-663513/urelumab), anti-killer cell immunoglobulin-like receptors (KIRs), eg lirilumab (IPH2102/BMS-986015), anti-OX40 CD134 (tumor necrosis factor superfamily receptor, member 4), anti-OX40 ligand/CD252, antiglucocorticoid-induced TNFR family gene (GITR) (such as TRX518), anti-CD40 (member 5 of the TNF receptor superfamily) antibodies (such as CP-870,893), anti-CD40 ligand antibodies (such as as BG9588), anti-CD28 antibodies);

m) tumor-specific antigen-binding molecules, as well as a T cell surface marker such as bispecific antibodies or antibody fragments, antibody mimetic proteins such as engineered ankyrin repeat proteins (DARPINS), a bispecific T-cell-attracting activator (BITE, for example, AMG103, AMG330);

n) antibodies or small molecule inhibitors targeting colony stimulating factor 1 receptor (CSF-1R) (eg RG7155 or PLX3397).

When used in combination with compounds of formula (I), immune checkpoint inhibitors such as those listed under d) are preferred, and especially those that target programmed cell death receptor 1 (PD-1 receptor) or its PD-L1 ligand. .

The term chemotherapy refers to the treatment of cancer with one or more cytotoxic antineoplastic agents (cytotoxic chemotherapeutic agents). Chemotherapy is often used in combination with other cancer treatments such as radiation therapy or surgery. The term especially refers to conventional chemotherapy drugs that work by killing rapidly dividing cells, which is one of the main properties of most cancer cells. Chemotherapy can use one drug at a time (single-component chemotherapy) or several drugs at the same time (combination chemotherapy or polychemotherapy). Chemotherapy using drugs that are converted to cytotoxic activity only when exposed to light is called photochemotherapy or photodynamic therapy.

As used herein, the term cytotoxic chemotherapeutic agent or chemotherapeutic agent refers to an active antineoplastic agent that causes apoptosis or death of necrotic cells. When used in combination with compounds of formula (I), the term specifically refers to conventional cytotoxic chemotherapeutic agents such as:

a) alkylating agents (eg mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, busulfan, dacarbazine, temozolomide, thiotepa or altretamine; in particular temozolomide);

b) platinum-based drugs (eg cisplatin, carboplatin or oxaliplatin);

c) antimetabolite drugs (eg 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine or pemetrexed);

d) anticancer antibiotics (eg daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C or mitoxantrone);

e) mitosis inhibitors (eg paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine or estramustine); or

f) topoisomerase inhibitors (eg etoposide, teniposide, topotecan, irinotecan, diflomotecan or elomotecan).

When used in combination with compounds of formula (I), the preferred cytotoxic chemotherapeutic agents are the above alkylating agents (namely, mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, busulfan, dacarbazine, 3-methyl(triazene-1 -yl)imidazole-4-carboxamide (MTIC) and its prodrugs, such as in particular temozolomide, thiotepa, altretamine; or pharmaceutically acceptable salts of these compounds, in particular temozolomide); and inhibitors of mitosis (namely, paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine, estramustine; or pharmaceutically acceptable salts of these compounds; in particular, paclitaxel). The most preferred cytotoxic chemotherapeutic agents used in combination with the compounds of formula (I) are those whose use has become routine in the treatment of glioblastoma multiforme, in particular temozolomide. Radiotherapy is equally preferred.

Chemotherapy may be given to cure or may be aimed at prolonging life or temporarily relieving symptoms.

a) Combination chemotherapy is the use of drugs with other cancer therapies such as radiation therapy or surgery.

b) Induction chemotherapy is the primary treatment of cancer with a chemotherapy drug. This type of chemotherapy is used for curative purposes.

c) Consolidation chemotherapy is given after remission to prolong overall relapse-free time and improve overall survival. The drug that is administered is the same drug that provided the remission.

d) Intensification chemotherapy is identical to consolidation chemotherapy but uses a drug different from induction chemotherapy.

e) Combination chemotherapy involves the simultaneous treatment of a patient with several different drugs. Drugs differ in their mechanism and side effects. The biggest benefit is minimizing the chances of developing resistance to any drug. In addition, drugs can often be used at lower doses, reducing toxicity.

f) Neoadjuvant chemotherapy is given before a topical treatment such as surgery and is designed to shrink the primary tumor. It is also performed for cancers with a high risk of micrometastatic lesions.

g) Adjuvant chemotherapy is given after local treatment (radiotherapy or surgery). It can be used when there is little evidence of cancer but there is a risk of recurrence. It is also helpful in killing any cancer cells that have spread to other parts of the body. These micrometastases can be treated with adjuvant chemotherapy and may reduce the recurrence rate caused by these disseminated cells.

h) Maintenance chemotherapy is repeated low-dose treatment to prolong remission.

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i) Backup chemotherapy or palliative chemotherapy is given without curative intent, but simply to reduce tumor burden and increase life expectancy. For these regimens, a better toxicity profile is generally expected.

In combination with compounds of formula (I), prophylactic or curative forms of chemotherapy (or mutatis mutandis: radiotherapy) such as those listed under a), b) c), d), e), and especially g) and/or h above ) are preferred.

Simultaneously, when referring to the type of application, in this application means that the corresponding type of application is the application of two or more active ingredients and/or treatments at approximately the same time; it is understood that simultaneous use will result in the subject being exposed to two or more active ingredients and/or treatments at the same time. When used simultaneously, these two or more active ingredients can be used in combination with fixed doses or in an equivalent combination with non-fixed doses (for example, using two or more different pharmaceutical compositions that are used by the same route of administration at approximately the same time) or a combination non-fixed doses using two or more different routes of administration; wherein said use results in substantially simultaneous exposure of the subject to two or more active ingredients and/or treatments.

Fixed dose combination, when referring to the type of administration, in this application means that the appropriate type of administration consists in the use of one pharmaceutical composition containing two or more active ingredients.

Separately, when referring to the type of application, in this application means that the appropriate type of application is the application of two or more active ingredients and/or treatments at different points in time; it is understood that a separate application will result in a treatment phase (for example, at least 1 hour, in particular at least 6 hours, especially at least 12 hours) when the subject is exposed to two or more active ingredients and/or treatments in the same time; where such separate application may, under certain circumstances, also cover the treatment phase when, for a certain period of time (for example, at least 12 hours, in particular at least one day), the subject is exposed to only one of two or more active ingredients and/or methods treatment. Thus, separate use particularly refers to situations in which one active ingredient and/or treatment is administered, for example, once a day, and the other is administered, for example, twice a day, three times a day, every other day, when due to this type of application, the subject is exposed to two or more active ingredients and/or treatments at the same time for essentially the entire period of treatment. Single use also refers to situations where at least one of the active ingredients and/or treatments is administered at a frequency significantly greater than daily (e.g., once or twice a day) use (e.g., when one active ingredient and/or a treatment method is prescribed, for example, once or twice a day, and the other is prescribed once a week). For example, when used in conjunction with (eg, weekly or biweekly) radiotherapy, the present CXCR7 modulators may be used alone.

Under the use for a certain period of time in this application means the subsequent use of two or more active ingredients and/or treatments at different times. The term particularly refers to a mode of administration in which the full application of one of the active ingredients and/or treatments is completed before the other/others are started. Thus, one of the active ingredients and/or treatments may be used for several months before the other active ingredient(s) and/or treatment(s) is administered.

Use over a period of time also covers situations in which CXCR7 modulators of formula (I) or (II) will be used in treatment that begins after cessation of the initial chemotherapy or radiotherapy treatment or targeted therapy (e.g., induction chemotherapy), where said treatment is optional will be combined with additional/current chemotherapy or radiotherapy treatment or targeted therapeutic treatment (for example, in combination with consolidation chemotherapy, intensive chemotherapy, adjuvant chemotherapy or maintenance chemotherapy; or their radiotherapeutic equivalents); where such further/ongoing chemotherapeutic or radiotherapeutic treatment or targeted therapy should be carried out simultaneously or separately from treatment using the CXCR7 modulator.

Autoimmune disorders can be defined as including (inflammatory) demyelinating diseases; multiple sclerosis (MS); Guillain-Barré syndrome; rheumatoid arthritis (RA); inflammatory bowel disease (IBD, especially including Crohn's disease and ulcerative colitis); systemic lupus erythematosus (SLE); lupus nephritis; interstitial cystitis; celiac disease autoimmune encephalomyelitis; osteoarthritis; and type I diabetes. In addition, autoimmune diseases further include disorders such as psoriasis; psoriatic arthritis; antiphospholipid syndrome; thyroiditis such as Hashimoto's thyroiditis; lymphocytic thyroiditis; myasthenia gravis

- 30 040620 gravity; uveitis; episcleritis; scleritis; Kawasaki syndrome; uveoretinitis; posterior uveitis; uveitis associated with Behçet's disease; uveomeningeal syndrome; allergic encephalomyelitis; atopic diseases such as rhinitis, conjunctivitis, dermatitis; and post-infectious autoimmune diseases, including acute rheumatic fever and post-infectious glomerulonephritis. In a sub-embodiment, autoimmune disorders specifically refer to autoimmune disorders that have an inflammatory component, where specific examples are (inflammatory) demyelinating diseases, multiple sclerosis (MS), Guillain-Barré syndrome, rheumatoid arthritis (RA), inflammatory bowel disease ( IBD, especially including Crohn's disease and ulcerative colitis), systemic lupus erythematosus (SLE), lupus nephritis, and autoimmune encephalomyelitis.

Inflammatory diseases can be defined as including, in particular, chronic rhinusitis, as well as asthma, chronic obstructive pulmonary disease (COPD), atherosclerosis, myocarditis, dry eye syndrome, sarcoidosis, inflammatory myopathies, and acute lung injury.

Transplant rejection can be defined as rejection of transplanted organs such as kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host disease caused by hematopoietic stem cell transplantation; chronic allograft rejection; and chronic allograft vasculopathy.

Fibrosis can be defined as including, but not limited to, hepatic fibrosis, hepatic cirrhosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, renal fibrosis, endomyocardial fibrosis, and arthrofibrosis.

Compounds of formula (I) according to embodiments A)-G) are also useful in a method for preventing or treating tumors, comprising administering an effective amount of a compound of formula (I), wherein said effective amount results in a change in properties of the tumor, and wherein said modification is achieved by modulating the CXCL11/CXCL12 receptor pathway; wherein said prophylaxis or treatment may optionally be carried out in combination with conventional chemotherapeutic or radiotherapeutic treatment (in which case the tumor is in particular a malignant glioma, in particular glioblastoma multiforme). Such combined treatment may be carried out simultaneously, separately and/or over a period of time.

Compounds of formula (I) are also useful in a method for modulating an immune response, comprising the use of an effective amount of a compound of formula (I), wherein said effective amount modulates an inflammatory disease and wherein said response is mediated by the CXCL11/CXCL12 receptor pathway.

Preparation of compounds of formula (I) or (ID).

Compounds of formula (I) or (ID) can be prepared by the methods given below, by the methods given in the experimental section below, or by analogous methods. Optimum reaction conditions may vary depending on the particular reagents or solvents used, but such conditions can be determined by one of ordinary skill in the art by conventional optimization techniques. In the schemes below, the general groups Ar ¹ , Ar ² , R ¹ , R ² , R ³ , RAr ¹ , R ^N1 , R ^N2 have the meanings defined for the compounds of formula (I) or (ID). In some cases, the common groups Ar ¹ , Ar ² , R ¹ , R ² , R ³ , RAr ¹ , R ^N1 , R ^N2 may not be compatible with the assembly shown in the diagrams or require the use of protecting groups (PG). The use of protecting groups is well known in the art (see, for example, Protecting Groups in Organic Synthesis, TW Greene, PGM Wuts, Wiley-Interscience, 1999, TW Greene, PGM Wuts, Wiley-Interscience, 1999). For the purposes of this discussion, such protecting groups are assumed to exist as needed. In some cases, the final product may be further modified, such as by manipulating substituents to produce a new final product. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions, which are generally known to those skilled in the art. The resulting compounds can also be converted into salts, especially pharmaceutically acceptable salts, in a manner known per se.

The compounds of formula (I) of the present invention can be obtained in accordance with the general sequence of reactions indicated below.

Compounds of formula (I) or (ID) are prepared by reacting an acid of Structure 1 (L ¹ = OH) or a salt such as its sodium or lithium salt with an amine of structure 2 in the presence of an amide-coupling reagent such as TBTU, HATU, COMU, EDC, DCC, T ₃ P or PyBOP, and a base such as DIPEA or TEA in a solvent such as DCM, MeCN or DMF

Compounds of structure 1 can be obtained using one of the synthetic routes described below.

Compounds of structure 1 can be prepared using the procedure illustrated in Scheme

- 31 040620 reactions A. Commercially available alkyl (3R*,4R*)-4-((tert-butoxycarbonyl)amino)nineridine-3carboxylate A-1 (R ⁵ = alkyl) N-alkylated by treatment with an aldehyde or ketone in the presence of a reductive a reagent such as NaBH ₄ , NaBH ₃ CN, NaBH(OAc) ₃ in a solvent such as DCM, MeOH, THF; or in the presence of a titanium salt such as TiCl ₄ or tetraisopropyl orthotitanate to give tertiary amine A-2. Intermediate A-2 is deprotected with Boc by treatment with an acid, preferably 4M HCl in dioxane or TFA in DCM, to give the corresponding amine A-3. Amine A-3 can be acylated by reaction with acid A-4 in the presence of an amide-matched reagent such as TBTU, HATU, COMU, EDC, DCC, T ₃ P or PyBOP and a base such as DIPEA or TEA in a solvent, such as DXM, MeCN or DMF. Hydrolysis of the A-5 ester by treatment of a base such as NaOH or LiOH in a solvent such as methanol, ethanol or water/THF at a temperature between RT and 60°C gives the corresponding acid of structure 1.

Reaction Scheme A

Compounds of formula (I) or (ID) can alternatively be prepared as illustrated in Reaction Scheme B. A-4 (L=OH) in the presence of an amide-coupling reagent such as TBTU, HATU, COMU, EDC, DCC, T3P or PyBOP and a base such as DIPEA or TEA in a solvent such as DCM, MeCN or DMF; or the corresponding acyl chloride (L ¹ = Cl) and a base such as DIPEA or TEA in a solvent such as DCM gives the corresponding amide B-2. The N-benzyl protecting group is removed by catalytic hydrogenation in the presence of Pd on activated charcoal in a solvent such as AcOEt, preferably at atmospheric hydrogen pressure, in the presence of di-t-butyl dicarbonate to give the Boc-N-protected derivative B-3. Hydrolysis of the ester group B-3 by treatment with a base such as NaOH or LiOH in a solvent such as methanol, ethanol or a water/THF mixture at a temperature between RT and 60° C. gives the corresponding acid B-4. Type B-5 3-piperidine carboxamides are prepared by amidating B-4 with an amine of structure 2 in the presence of an amide-coupling reagent such as TBTU, HATU, COMU, EDC, DCC, T3P or PyBOP and a base such as DIPEA or TEA in a solvent such as DXM, MeCN or DMF. The Boc carbamate is deprotected as described above to give piperidine B-6. N-alkylation of B-6 by treatment with an aldehyde or ketone in the presence of a reducing agent such as NaBH4, NaBH3CN, NaBH(OAc)3 in a solvent such as DCM, MeOH, THF, DMF; and in the case where R ^3a = alkyl, in the presence of a titanium salt such as TiCl4 or tetraisopropyl orthotitanate to give a compound of formula (I) or (ID). Alternatively, compounds of formula (I) or (ID) can be prepared by alkylation of intermediate B-6 with an alkyl halide or alkyl sulfonate in the presence of a base such as DIPEA, TEA, or K ₂ CO ₃ in a solvent such as DMF, MeCN or EtOH. In the case where R ² is (C _1-6 )alkyl or (C _3-8 )cycloalkyl which is monosubstituted with a hydroxyl group, compounds of formula (I) or ( _ID ) can be obtained by condensation of an amine of structure B-6 and mono or a disubstituted epoxide in a polar aprotic solvent such as MeCN in the presence of calcium trifluoromethanesulfonate at RT or in water at a temperature between RT and reflux.

- 32 040620

Reaction scheme B

Compounds of formula (I) or (ID) can alternatively be prepared as illustrated in Reaction Scheme C. Commercially available alkyl (3R*,4R*)-4-((tert-butoxycarbonyl)amino)piperidine-3-carboxylate A- 1 (R ⁵ = alkyl) is N-alkylated by treatment with an aldehyde or ketone as described for B-6 above to give the tertiary amine A-2. N-substituted alkyl (3R*,4R*)-4((tert-butoxycarbonyl)amino)piperidine-3-carboxylate A-2 can be hydrolyzed to acid C-1 by treatment with a base such as NaOH or LiOH in a solvent such as as methanol, ethanol or water/THF mixture between RT and 60°C. Piperidinylcarboxamide C-2 is prepared by condensation of an amine of Structure 2 in the presence of an amide-matched reagent such as TBTU, HATU, COMU, EDC, DCC, T ₃ P or PyBOP and a base such as DIPEA or TEA in a solvent such as DCM , MeCN or DMF. Intermediate C-2 is deprotected with Boc as described above to give the corresponding amine C-3. Acylation of 4-amino-3-carboxamide C-3 can be achieved by in situ treatment of the resulting 4-dimethylaluminum amide obtained by reacting a trialkylaluminum compound such as trimethylaluminum with C-3 in a solvent such as toluene, DCM or DCE at temperatures between RT and reflux temperature, followed by condensation with an A-4 ester or carboxylic acid (L1 = O-alkyl or OH) to give a compound of formula (I) or (ID).

Reaction Scheme C

For the synthesis of [S,S] 3,4-disubstituted piperidines, the sequence shown in Scheme D can be used following the procedure described by S. Gellman et al. Eur. J. Org. Chem. 2003, 721. Enamine D-2 of N-Boc-protected 4-ketopiperidine D-1 can be prepared by heating (S)-(-)-amethylbenzylamine in toluene in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid using a nozzle Dean Stark. Reduction of enamine D-2 with a reducing agent such as sodium triisobutyroxyborohydride, sodium trifluoroacetoxyborohydride, or with sodium triacetoxyborohydride in toluene, THF, or dioxane at temperatures between -78°C and RT gives mainly the cis-amino ester D-3. Epimerization to the D-4 transamino ester can be carried out by treatment with a base such as sodium ethoxide, sodium methoxide or potassium t-butoxide in a solvent such as EtOH, MeOH, t-BuOH in the presence of ethyl acetate, methyl acetate or t-butyl acetate at a temperature between 0°C and reflux temperature. Hydrogenolysis of the benzyl group by catalytic hydrogenation in the presence of Pd on activated charcoal or Pd hydroxide in a solvent such as AcOEt, EtOH or MeOH, preferably at atmospheric hydrogen pressure, gives the D-5 trans-amino ester.

- 33 040620

Amidation with an acid of structure A-4 (L ¹ =OH) in the presence of an amide-matching reagent such as TBTU, HATU, COMU, EDC, DCC, T3P or PyBOP and a base such as DIPEA or TEA in a solvent such as as DXM, MeCN or DMF; or the corresponding acyl chloride (L ¹ =Cl) and a base such as DIPEA or TEA in a solvent such as DCM gives the corresponding amide D-6. [S,S]Trans-amidoester D-6, which corresponds to intermediate B-3 in Scheme B, can be converted to the final compound of formula (I) or ( _ID ) following the sequence: ester hydrolysis, amide formation, Boc cleavage -groups and N-alkylation as described in Scheme B. The same sequence can be used to synthesize [R,R] 3,4-disubstituted piperidines starting from (R)-(+)-α-methylbenzylamine as the chiral auxiliary .

Reaction Scheme D

Alternatively, [S,S]3,4-disubstituted piperidines can be prepared as illustrated in Reaction Scheme E by substituting the sequence of reactions shown in Scheme D. In general, the cis-amino ester D-3 can be prepared as described above. Hydrogenolysis of the benzyl group as described above gives mainly the cis-amino ester E-4. Amidation with an acid of structure A-4 (L ¹ =OH) or the corresponding acyl chloride (L ¹ =Cl) using the conditions described above gives the corresponding substantially cis-amidoester E-5. Epimerization to complex trans-amidoester B-3 can be carried out using the conditions described above. The B-3 transamidoester can be converted to the final compound of formula (I) or ( _ID ) as described in Scheme B. The same sequence can be used to synthesize [R,R] 3,4-disubstituted piperidines starting from (R) -(+)-α-methylbenzylamine as a chiral auxiliary.

Reaction scheme E

- 34 040620

Reaction scheme F

Structure 1 compounds can alternatively be prepared from the B-3 trans-amidoester. Intermediate B-3 is Boc deprotected as described above to give the corresponding amine F-1, which is N-alkylated as described for A-2 above to give N-alkylpiperidine F-2. The N-substituted alkyl (3R*,4R*)-4-amidopiperidine-3-carboxylate ester F-2 can be hydrolyzed to acid 1 by treatment with base as described for C-1 above.

Compounds of formula (I) or (ID) can alternatively be prepared as illustrated in Reaction Scheme G. Commercially available alkyl 4-((tert-butoxycarbonyl)amino)piperidine-3carboxylate G-1 C-alkylated at the 3-position by treatment with an alkyl halide at the presence of a base such as potassium carbonate in a solvent such as acetone at a temperature between 0° C. and a reflux temperature to give the ketoester G-2. Enamine G-3 can be obtained as described above. Reduction of enamine G-3 as described above gives the trans-amino ester G-4. Hydrogenolysis of the benzyl group as described above gives the G-5 transamino ester. Amidation with an acid of structure A-4 (L ¹ = OH); or the corresponding acyl chloride (L ¹ = Cl) as described above gives the corresponding amide G-6 which can be converted to the final compound of formula (I) or ( _ID ) following the sequence described in Scheme B. Ester G-6 saponified to acid G-7 which is condensed with amine 2. The resulting bisamide G-8 can be deprotected to give piperidine G-9 which is finally N-alkylated to give a compound of formula (I) or (ID).

Reaction scheme G

Alternatively, the trans-amido ester Intermediate B-3 can be prepared by heating the keto ester D-1 with ammonia or ammonium acetate in MeOH at a temperature between RT and reflux. Reduction of enamine H-1 as described above gives the amino ester H-2 as a cis/trans mixture. Amidation of H-2 with an acid of structure A-4 (L ¹ = OH); or the corresponding acyl chloride (L ¹ = Cl) as described above gives the corresponding amide H-3 as a cis/trans mixture. Epimerization to the B-3 transamidoester can be accomplished by treating H-3 with base as described above. The trans-amidoester B-3 can be converted to the final compound of formula (I) or ( _ID ) following the sequence as described in Scheme B. Reaction Scheme H

n-o to-o

Reaction Scheme I

Alternatively, [S,S]3,4-disubstituted piperidines can be prepared as illustrated in Reaction Scheme I. The cis-amino ester E-4 can be converted to the corresponding cis-4-benzylcarbamate derivative I-1 by treatment with N-(benzyloxycarbonyloxy)succinimide in THF or DXM. Epimerization to the trans-amidoester 1-2 can be carried out using the conditions described above. 1-2 can be converted to intermediate 1-6 by following the sequence: ester hydrolysis, amide formation, Boc cleavage, and N-alkylation as described in Scheme B. The benzyl carbamate protecting group is removed by catalytic hydrogenation in the presence of Pd on the activated carbon or Pd hydroxide in a solvent such as AcOEt, EtOH or MeOH, preferably under atmospheric hydrogen pressure, to give 4-trans-amino-3-carboxamide I-7. Amidation of I-7 with an acid of structure A-4 (L ¹ = OH) or the corresponding acyl chloride (L ¹ = Cl), using the conditions described above, gives the final compound of formula (I) or (ID) as described in Scheme B. The same sequence can be used to synthesize [R,R] 3,4-disubstituted piperidines starting from (R)-(+)-α-methylbenzylamine as a chiral auxiliary.

When compounds of formula (I) or (ID) are obtained as mixtures of enantiomers, the enantiomers can be separated using methods known to the person skilled in the art, for example: by formation and separation of diastereomeric salts or by HPLC using a chiral stationary phase, such as a column Regis Whelk-O1 (R, R) (10 µm), Daicel ChiralCel OD-H (510 µm) or Daicel ChiralPak IA (10 µm), IA, IB, IC, IE, or IF (5 µm) or AD- H (5 µm) column. Typical chiral HPLC conditions are an isocratic mixture of eluent A (EtOH, in the presence or absence of an amine such as triethylamine or diethylamine) and eluent B (heptane), at a flow rate of 0.8 to 150 ml/min.

The following examples are given to illustrate the invention. These examples are illustrative only and should not be construed as limiting in any way.

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Experimental Part I

Chemistry.

All temperatures are in °C. Commercially available starting materials were used as received without further purification. Unless otherwise indicated, all reactions were carried out in oven-dried glassware under nitrogen or argon. Compounds were purified by silica gel flash column chromatography or preparative HPLC. The compounds disclosed in the specification are characterized by LC-MS data (retention time t _R given in min; molecular weight derived from the mass spectrum given in g/mol) using the conditions listed below. In cases where the compounds of the present invention are formed as a mixture of conformational isomers, especially visible in their LC-MS spectra, the retention time of the most predominant conformer is given.

NMR spectroscopy.

A Bruker Avance II spectrometer equipped with a 400 MHz (1H) Ultrashield™ Magnet and a 5 mm BBO probe or a 1 mm PAXTI probe, or a Bruker Avance III HD equipped with a 500 MHz Ascend (1H) magnet, with a DCH cryoprobe is used. Chemical shifts (δ) are given in parts per million (ppm) relative to proton resonances obtained by incomplete deuteration of the NMR solvent, e.g. for dimethyl sulfoxide δ(H) 2.49 ppm, for chloroform δ(H) 7.24 ppm. The abbreviations s, d, t, q, and t refer to singlet, doublet, triplet, quartet, multiplet, and br, to wide, respectively. Interaction constants J are given in Hz. When NMR spectra are measured using 1 mm Microprobe® tubes and a 1 mm PAXTI measuring head, the compounds are dissolved in non-deuterated DMSO. The spectra are then measured by double irradiation to suppress the DMSO and H ₂ O peaks. In this case, only a selection of representative NMR peaks of the compound is given.

Quality control (QC), analytical LC-MS.

Equipment and conditions.

Pump: Waters Acquity Binary, Solvent Manager, MC: Waters SQ Detector, DAD: Acquity UPLC PDA Detector, ELSD: Acquity UPLC ELSD. Columns: Acquity UPLC CSH C18 1.7 µm 2.1x50 mm or Acquity UPLC HSS T3 C18 1.8 µm 2.1x50 mm from Waters, thermostated in Acquity UPLC Column Manager at 60°C. Eluents: A1: H ₂ O + 0.05% formic acid; B1: AcCN + 0.045% formic acid. Method: Gradient: 2% B 98% B over 2.0 min. Flow: 1.0 ml/min. Detection: UV 214nm and ELSD and MS, t _R is in min.

Analytical LC-MS.

Equipment.

Agilent G4220A binary gradient pump or equivalent with mass spectrometry detection (single quadrupole mass analyzer, Thermo Finnigan MSQPlus or equivalent).

Conditions.

Method A (acid conditions): column: Zorbax SB-aq (3.5 µm, 4.6 x 50 mm); conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]; gradient: 95% B ^ 5% B over 1.5 min (flow: 4.5 ml/min). Detection: UV/Vis. + MS.

Method B (acid conditions): column: Waters XBridge C18 (2.5 µm, 4.6 x 30 mm); conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]; gradient: 95% B ^ 5% B over 1.5 min (flow: 4.5 ml/min). Detection: UV/Vis. + MS.

Method C (acid conditions): column: Waters VEN C18 (2.5 µm, 3.0 x 50 mm); conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]; gradient: 95% B ^ 5% B over 1.5 min (flow: 4.5 ml/min). Detection: UV/Vis. + MS.

Method D (basic conditions): column: Waters BEN C18 (2.5 µm, 3.0 x 50 mm); conditions: MeCN [eluent A]; H ₂ O+0.05% NH ₄ OH [eluent B]; gradient: 95%B^5%B over 1.9 min (flow 1.6ml/min), Detection : UV/Vis. + MS.

Preparative LC-MS.

Equipment.

Gilson 333/334 binary gradient pump or equivalent with mass spectrometry detection (single quadrupole mass analyzer, Thermo Finnigan MSQPlus or equivalent).

Conditions.

Method E (basic conditions): column: Waters XBridge C18 (10 µm, 30 x 75 mm); conditions: MeCN [eluent A]; water + 0.5% NH4OH (25% aq.) [eluent B]; gradient: 95% B^5% B, over 6.5 min (flow: 75 ml/min). Detection: UV/Vis. + MS.

Method F (acid conditions): column: Waters XBridge C18 (10 µm, 30 x 75 mm); conditions: MeCN [eluent A]; water + 0.5% formic acid [eluent B]; gradient: 95% B^5% B, over 6.5 min (flow: 75 ml/min). Detection: UV/Vis. + MS.

Chiral analytical chromatography.

- 37 040620

Equipment.

HPLC: Dionex HPG-3200SD pump with Dionex DAD-3000 UV detector.

SLC: CO ₂ supply: Aurora Fusion A5 Evolution; pump: Agilent G4302A; UV detector: Agilent

G1315C.

Conditions.

HPLC: columns: ChiralPak AY-H, 5 µm, 250x4.6 mm or Regis (R,R) Whelk-O1 250x4.6 mm, 5 µm; eluent: A: Hept, 0.05% DEA, B: ethanol, 0.05% DEA, flow 0.8-1.2 ml/min.

SLC: column: Regis (R,R) Whelk-O1, 4.6x250 mm, 5 µm; eluent: A: 60% CO ₂ , B: 40% DCM/EtOH/DEA 50:50:0.1.

Chiral preparative chromatography.

Equipment.

HPLC: 2 Varian SD1 pump with Dionex DAD-3000 UV detector.

SLC: CO ₂ supply: Maximator DLE15-GG-C; pumps: 2 SSI HF SR 300; UV detector: Dionex DAD-3000.

Conditions.

HPLC: columns: ChiralPak IA, IB, IC, IE, or IF, 5 µm, 20x250 mm, or Regis (R,R) Whelk-O1, 21.1x250 mm, 5 µm; eluent: appropriate mixture of A (0-90% Hept) and B (10-100% EtOH, 0.1% DEA), flow: appropriate flow 16, 23 or 34 ml/min.

SLC: columns: Regis (R,R) Whelk-O1, 30x250 mm, 5 µm or ChiralPak IC, 30x250 mm, 5 µm; eluent: appropriate mixture of A (60-70% CO ₂ ) and B (30-40% DCM/EtOH/DEA 50:50:0.1), flow 160 ml/min.

Abbreviations (used above and below).

aq. water atm. atmosphere BSA bovine serum albumin Vos butyloxycarbonyl SE structural element CDI carbonyl diimidazole

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COMU hexafluorophosphate 1-cyano-2-ethoxy-2- oxoethylideneaminooxy)dimethylamino-morpholino carbenium

d. days dba dibenzylideneacetone DCC dicyclohexyl carbodiimide DXM dichloromethane DEA diethylamine DIPEA diisopropyl-ethylamine, Hunig's base, ethyldiisopropylamine DMAP 4-dimethylaminopyridine DMF dimethylformamide DMSO dimethyl sulfoxide EDC X-(3-dimethylaminopropyl)-X'-ethyl-carbodiimide equiv. equivalent(s) Et ethyl EtOAc ethyl acetate EtOH ethanol Note. example(s) h watch) HATU hexafluorophosphate 2-(7-aza-1H-benzotriazol-1-yl)- 1,1,3,3-tetramethyluronium HBTU O-(benzotriazol-1-yl)-X,X,X',X'tetramethyluronium hexafluorophosphate Hept HOBt heptane 1-hydroxybenzotriazole HOAT 7-aza-1-hydroxybenzotriazole HPLC high performance liquid chromatography BB in high vacuum 'bu isobutyl 'Pr isopropyl KO^u potassium pspg-butoxide LC-MS liquid chromatography - mass spectrometry LiHMDS lithium bis(trimethylsilyl)amide

- 39 040620

lit. literature Me methyl MeCN acetonitrile Meon methanol ml milliliter MTVE methyl-i/rheot-butyl ether min minute(s) No. number NaOAc sodium acetate NBS N-bromosuccinimide NMP N-methylpyrrolidone Pr n-propyl OAC acetate Ph phenyl PPh ₃ triphenylphosphine POC1 ₃ phosphorus(V) oxychloride prey. preparative pybop benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium- hexafluorophosphate rac racemic KT room temperature c second(s) sat. saturated Selectfluor® 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) SKHH: supercritical liquid chromatography p-p solution tBu tert-butyl = tertiary butyl TBTU 2-(1H-benzotriazol-1-yl)-1,2,3,3-tetramethyluronium tetrafluoroborate TEA triethylamine TFU trifluoroacetic acid THF tetrahydrofuran those thin layer chromatography T ₃ P propylphosphonic anhydride tR Hold Time

Obtaining esters and carboxylic acids of structure A-4, which are used for the synthesis of structural elements 1.07-1.17 and examples 3.001-3.022.

A-4.01: 5-(2,4,6-trifluorophenyl)isoxazole-3-carboxylic acid.

A-4.01a: 5-(2,4,6-trifluorophenyl)isoxazole-3-carboxylic acid ethyl ester.

The title compound A-4.01a was prepared in analogy to the procedure described in Eur. J. Org. Chem. 2006, 4852-4860, by stirring a solution of ethyl nitroacetate (1.36 ml, 12 mmol), 2ethynyl-1,3,5-trifluorobenzene (312 mg, 2 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.156 ml, 1.4 mmol) in NMP (1.2 ml), at 65°C overnight. The solvent was evaporated and the product was used in the next step without further purification, LC-MS method A: t _R =1.07 min.

A-4.01: 5-(2,4,6-trifluorophenyl)isoxazole-3-carboxylic acid.

To a solution of ester A-4.01a (542 mg, 2 mmol) in THF (4 ml) was added LiOH·H ₂ O (12 mmol) dissolved in 10 ml of water. After stirring for 64 h, 4M HCl solution (10 mmol) was added followed by water (1.5 ml). The precipitated product is filtered, washed with water (2 x 2.5 ml) and DCM (2 x 2.5 ml) and dried under BB conditions. The title compound was obtained as a white powder, LC-MS method A: t _R = 0.83 min; [M+H]+ = 407.05; 1H NMR (400 MHz, DMSO) δ: 14.3 (bs, 1H), 7.54 (t, 7=9.3 Hz, 2H), 7.19 (s, 1H).

A-4.02: 5-(2-chloro-4-fluorophenyl)isoxazole-3-carboxylic acid.

A-4.02a: 5-(2-Chloro-4-fluorophenyl)isoxazole-3-carboxylic acid ethyl ester.

- 40 040620

The title compound was prepared according to Method A-4.01a starting from 2-chloro1-ethynyl-4-fluoro-benzene; LC-MS method A: t _R = 1.15 min.

A-4.02: 5-(2-chloro-4-fluorophenyl)isoxazole-3-carboxylic acid.

The title compound was prepared according to Method A-4.01b starting from ester A-4.02a; LCMS method A: tR = 0.9 min; 1Н NMR (500 MHz, DMSO) δ: 8.00 (m, 1H), 7.73 (m, 1H), 7.45 (m, 1H), 7.14 (s, 1H).

A-4.03: 5-(4-Chloro-2-fluorophenyl)isoxazole-3-carboxylic acid A-4.03a: 5(4-Chloro-2-fluorophenyl)isoxazole-3-carboxylic acid ethyl ester.

The title compound was prepared according to Method A-4.01a starting from 4-chloro1-ethynyl-2-fluoro-benzene; LC-MS method A: t _R = 1.18 min.

A-4.03: 5-(4-chloro-2-fluorophenyl)isoxazole-3-carboxylic acid.

The title compound was prepared according to Method A-4.01b starting from ester A-4.03a; LCMS method D: t _R = 0.93 min; ¹ H NMR (500 MHz, DMSO) δ: 8.03 (m, 1H), 7.77 (m, 1H), 7.52-7.54 (m, 1H), 7.18-7.19 (m, 1H).

A-4.04: 5-(2,6-difluorophenyl)isoxazole-3-carboxylic acid.

A-4.04a: 5-(2,6-difluorophenyl)isoxazole-3-carboxylic acid ethyl ester.

The title compound was prepared according to Method A-4.01a starting from 2ethynyl-1,3-difluorobenzene; LC-MS method A: t _R = 1.06 min.

A-4.04: 5-(2,6-difluorophenyl)isoxazole-3-carboxylic acid.

The title compound was prepared according to Method A-4.01b starting from ester A-4.04a; LCMS method A: tR = 0.84 min; ^1H NMR (500 MHz, DMSO) δ: 7.65 (m, 1H), 7.35 (m, 2H), 6.91 (s, 1H).

A-4.05: 3-(2,4-difluorophenyl)-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester.

The title compound was prepared in analogy to the procedure described in ChemMedChem 2012, 7, 1020-1030. To a solution of 2,4-difluorobenzamidoxime (344 mg, 2 mmol) dissolved in THF (5 ml) was added ethyl 2-chloro-2-oxoacetate (0.279 ml, 2.5 mmol) followed by DIPEA (0.437 ml, 2.5 mmol) . The reaction mixture was stirred at 75° C. for 3 hours. The mixture was then quenched with water (25 ml) and extracted with EtOAc (25 ml). The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure to give the desired product as a yellow solid. LC-MS method C: t _R =1.01 min. 1H NMR (400 MHz, DMSO) δ: 8.15 (m, 1H), 7.62 (m, 1H), 7.37 (m, 1H), 4.49 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H).

A-4.06: 5-(2,4-difluorophenyl)oxazole-2-carboxylic acid lithium salt.

The title compound was prepared in analogy to the procedure described in ChemMedChem 2012, 7, 1020-1030.

A-4.06a: ethyl 2-((2-(2,4-difluorophenyl)-2-oxoethyl)amino)-2-oxoacetate.

Ethylchloroxoacetate (0.226 ml, 2.02 mmol) was added to a solution of 2,4-difluorophenacylamine hydrochloride (415 mg, 2 mmol) in DCM (8 mL) and TEA (0.591 mL, 4.2 mmol) cooled to 0°C. The reaction mixture was stirred 1 h 30 min at 0°C and then quenched with water (10 ml), extracted twice with DCM (2 x 10 ml). The combined organic layers were dried over MgSO4 and the solvent was evaporated to give the title compound as a brown oil. LC-MS method C: t _R =0.82 min; [M+H]+ = 272.20.

A-4.O6b: 5-(2,4-difluorophenyl)oxazole-2-carboxylic acid ethyl ester POCl ₃ (0.52 ml, 5.58 mmol) is added dropwise to a solution of A-4.06a (480 mg, 1.77 mmol), dissolved in toluene (5 ml). The mixture is stirred overnight at 110°C. After cooling the solution to 0°C, it is quenched by adding dropwise water (2 ml) and then neutralized with sat. aq. NaHCO ₃ and extracted with DCM (20 ml). The organic layer is evaporated and the product is purified with prep. LC-MS method F. LC-MS method D: t _R =1.01 min; [M+H]+ = 253.98.

A-4.06: 5-(2,4-difluorophenyl)oxazole-2-carboxylic acid lithium salt.

To a solution of ester A-4.06b (574 mg, 2.13 mmol) in THF (10 ml) was added 1M LiOH aq. Solution (6.4 ml, mg, 6.4 mmol). After stirring for 1 h, the solvents are evaporated under reduced pressure to give the title compound as a beige powder, LC-MS method D: t _R = 0.65 min; [M+H]+ = 226.30.

A-4.07: 5-(2,4-difluorophenyl)-[1,3,4]oxadiazole-2-carboxylic acid lithium salt.

A-4.07a: 5-(2,4-difluorophenyl)-[1,3,4]oxadiazole-2-carboxylic acid ethyl ester.

The title compound was prepared in analogy to the procedure described in ChemMedChem 2012, 7, 1020-1030.

To a solution of 2,4-difluorobenzoic acid hydrazide (2.65 g, 15.4 mmol) in 50 ml DCM was added TEA (9.67 ml, 69.4 mmol). The mixture is cooled to 0°C and ethylchlorooxoacetate (2.44 ml, 21.2 mmol) is added. The mixture is stirred for 2 hours at 0°C. Then, toluene-4-sulfonyl chloride (4.40 g, 23.1 mmol) is added and stirring is continued overnight at RT. Add satiety. aq. NaHCO3 solution (50 ml) and the reaction mixture was extracted twice with DCM (2 x 50 ml). United organic layers

- 41 040620 dried over MgSO ₄ , filtered and evaporated. The residue was purified by flash chromatography using a heptane/AcOEt (9:1-4:1) gradient eluent to give a light yellow solid. LCMS method A: t _R =0.80 min; [M+H]+ = 255.13, [M+H+MeCN]+= 296.10.

A-4.07: 5-(2,4-difluorophenyl)-[1,3,4]oxadiazole-2-carboxylic acid lithium salt.

To a solution of A-4.07a ester (25.4 mg, 0.1 mmol) in THF (0.2 mL) was added LiOH hydrate (5 mg, 0.1 mmol) dissolved in water (0.2 mL). After stirring for 1 h, the solvents are evaporated under reduced pressure to give the title compound as a white powder, LC-MS method D: tR = 0.41 min; 1H NMR (400 MHz, DMSO) δ: 8.07 (m, 1H), 7.58 (m, 1H), 7.34 (m, 1H).

A-4.08: 1-(2,4-difluorophenyl)-1H-[1,2,3]triazole-4-carboxylic acid.

A-4.08a: 1-(2,4-difluorophenyl)-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester.

To a solution of ethyl 2-diazo-3-oxopropanoate (prepared according to the procedure described in Journal of American Chemical Society, 2011, 133(4), 1044-1051) (1.6 g, 8.85 mmol) in EtOH (3.15 ml) glacial acetic acid (1.27 ml, 22.1 mmol) is added followed by 2,4-difluoroaniline (1.22 g, 9.47 mmol). After stirring overnight, the reaction mixture was concentrated and the residue was diluted with cold water (40 ml). The precipitate is filtered, washed with cold water (10 ml) and dried under BB conditions to give the title compound as a beige solid. LCMS method A: t _R = 0.8 min; [M+H]+ = 254.12.

A-4.08: 1-(2,4-difluorophenyl)-1H-[1,2,3]triazole-4-carboxylic acid.

To a solution of ester A-4.08a (1.93 g, 7.62 mmol) in THF (16 ml) was added LiOH hydrate (11.4 mmol) dissolved in water (16 ml). After stirring for 45 min, the THF was evaporated and aq. The residue is cooled to 0°C. A 1M HCl solution was added until a pH of 2 was reached. The precipitated product was filtered, washed with water (15 ml), and dried under BB conditions. The title compound was obtained as a beige powder, LC-MS method A: : t _R = 0.61 min; [M+H]+ = 225.96, [M+H+MeCN]+= 267.10.

A-4.09: 5-(2,4-difluorophenyl)-[1,2,4]oxadiazole-3-carboxylic acid A-4.09a: 5-(2,4-difluorophenyl)-[1,2, 4]oxadiazole-3-carboxylic acid.

The title compound is prepared following a procedure which is similar to that described in WO 2012/168315. Ethyl 2-amino(hydroxyimino)acetate (2.27 g, 16.7 mmol) dissolved in 2,6dimethylpyridine (5.88 ml, 50 mmol) was treated dropwise with a solution of 2,4-difluorobenzoyl chloride (1.39 ml, 11.1 mmol) in DCM (30 ml) . The reaction mixture is stirred overnight. The slurry was dissolved in DCM (150 ml) and washed with water (50 ml), then 1M HCl (50 ml) and brine (50 ml). The organic layer is dried over MgSO ₄ , filtered and the solvent is evaporated. The white powder intermediate ethyl 2-(2,4-difluorobenzamido)-2-(hydroxyimino)acetate was then heated for 1 h at 200°C in a DrySyn metal block (from Asynt Ltd.). After cooling, the title compound was purified by flash chromatography using a gradient of 2-20% EtOAc in n-heptane as eluent. LCMS method A: t _R =0.85 min; [M+H]+ = 255.02.

A-4.09: 5-(2,4-difluorophenyl)-[1,2,4]oxadiazole-3-carboxylic acid.

LiOH.H ₂ O (799 mg, 19 mmol) was added to compound A-4.09a (3.84 g, 14.1 mmol) dissolved in THF (25 ml) and water (25 ml) and the mixture was stirred for 1 h. THF evaporate and aq. the phase is diluted with water (50 ml), cooled to 0°C and acidified to pH 2-3 with aq. 1M HCl solution. The precipitated product is filtered, washed with water (20 ml) and dried under BB conditions. LCMS method A: t _R =0.57; 1H NMR (400 MHz, DMSO) δ: 8.27 (m, 1H), 7.67 (m, 1H), 7.41 (m, 1H).

A-4.10: 3-(2,4-difluorophenyl)isoxazole-5-carboxylic acid.

A-4.10a: 3-(2,4-difluorophenyl)isoxazole-5-carboxylic acid ethyl ester.

The title compound is prepared in analogy to the preparation described in Bioorganic & Medicinal Chemistry Letters 18 (2008), 4521-4524.

2,4-Difluorobenzaldehyde oxime (prepared according to the procedure described in Bioorganic & Medicinal Chemistry Letters, 20 (2010), 1272-1277) (4.25 g, 24.4 mmol) was dissolved in THF (50 ml). Pyridine (2.46 ml, 30.5 mmol) is then added. The mixture is heated to 60° C. and N-chlorosuccinimide (3.58 g, 26.8 mmol) is added. The reaction mixture was stirred at 60° C. for 45 min and then TEA (4.11 ml, 29.2 mmol) and ethyl propiolate (2.72 ml, 26.8 mmol) were added. The reaction mixture is stirred overnight at 60° C. and then concentrated under BB conditions. The residue is taken up in DCM (100 ml) and diluted with aq. 1M HCl (100 ml). The separated organic phase is washed with water (100 ml). The organic phase is dried over MgSO ₄ , filtered and the solvent is evaporated under HV conditions. The crude product is purified by flash chromatography using n-heptane/EtOAc 9/1 as eluent to give the title compound. LC-MS method A: t _R =0.92 min.

A-4.10: 3-(2,4-difluorophenyl)isoxazole-5-carboxylic acid.

The title compound was prepared according to Method A-4.09 starting from building block A-4.10a. LC-MS method A: t _R = 0.68 min. 1H NMR (400 MHz, DMSO) δ: 14.48 (bs, 1H), 7.99-8.05 (m, 1H), 7.50-7.56 (m, 2H), 7.30 (m, 1H).

A-4.11: 4-Fluoro-5-(4-fluorophenyl)isoxazole-3-carboxylic acid.

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A-4.11a: 4-fluoro-5-(4-fluorophenyl)isoxazole-3-carboxylic acid methyl ester.

To a solution of methyl 5-(4-fluorophenyl)isoxazole-3-carboxylate (246 mg, 1.11 mmol) in tetramethylene sulfone (4 ml, 41.6 mmol) was added Selectfluor® (498 mg, 1.33 mmol). The reaction mixture is stirred at 150° C. overnight. DCM (20 ml) and water (20 ml) are added. After layer separation, aq. the phase is extracted with DCM (20 ml). The combined organic layers are washed with water (3 x 20 ml), dried over MgSO ₄ , filtered and evaporated. The crude product is purified by flash chromatography using n-heptane to n-heptane/ethyl acetate (7:3) as eluent to give the title compound. LC-MS method A: t _R =1.01 min.

A-4.11: 4-fluoro-5-(4-fluorophenyl)isoxazole-3-carboxylic acid.

The title compound was prepared according to Method A-4.09 starting from building block A-4.11a. LC-MS method A: t _R = 0.79 min. A-4.12: 5-(2,4-Difluorophenyl)-4-fluoro-isoxazole-3-carboxylic acid A-4.12a: 5-(2,4-Difluorophenyl)-4-fluoro-isoxazole-3-carboxylic acid ethyl ester .

The title compound was prepared according to Method A-4.11 starting from 5-(2,4-difluorophenyl)isoxazole-3-carboxylic acid ethyl ester. LC-MS method A: t _R =1.01 min.

A-4.12: 5-(2,4-difluorophenyl)-4-fluoro-isoxazole-3-carboxylic acid.

The title compound was prepared according to Method A-4.09 starting from building block A-4.12a. LC-MS method A: t _R = 0.76 min. A-4.13: 5-(2-trifluoromethylphenyl)isoxazole-3-carboxylic acid A-4.13a: 2,4-dioxo-4-(2-trifluoromethylphenyl)butyric acid ethyl ester.

To a solution of sodium ethoxide (21% in EtOH) (2.16 ml, 5.79 mmol) at RT was added diethyl oxalate (0.929 ml, 6.84 mmol) in one portion. A solution of 2-(trifluoromethyl)acetophenone (0.797 ml, 5.26 mmol) in THF (3 ml) was added dropwise to the reaction mixture. The brown reaction mixture was stirred for 1 h at RT. The reaction mixture was slowly quenched by dropwise addition of 1M HCl (8 ml). The THF is evaporated. The residue was partitioned between DCM (10 ml) and sat. NaHCO ₃ solution (10 ml) and aq. the phase is extracted with DCM (2x10 ml), dried over MgSO ₄ , filtered and evaporated to give the title compound as an orange oil; LC-MS method A: t _R =1.00 min. [M+H]+ = 289.16.

A-4.13b: 5-(2-trifluoromethylphenyl)isoxazole-3-carboxylic acid ethyl ester.

Hydroxylamine hydrochloride (0.372 ml, 5.46 mmol) is added to a solution of 2,4-dioxo-4-(2-trifluoromethylphenyl)butyric acid ethyl ester (1500 mg, 5.2 mmol) in EtOH (20 ml). The mixture is heated to 70° C. overnight. To the hot mixture, add water (10 ml) dropwise. After addition, the mixture is allowed to cool to RT. Add DCM (10 ml) and sat. NaHCO ₃ solution (10 ml) and aq. the phase is extracted with DCM (2x10 ml), dried over MgSO ₄ , filtered and evaporated. The crude product is purified by LC-MS method E. LC-MS method A: t _R =1.01 min. [M+H]+ = 286.17.

A-4.13: 5-(2-trifluoromethylphenyl)isoxazole-3-carboxylic acid.

The title compound was prepared according to method A-4.09 starting from structural element A-4.13b LC-MS method A: t _R = 0.80 min. [M+H+MeCN]+ = 299.13.

A-4.14: 5-(2,6-difluorophenyl)isoxazole-3-carboxylic acid.

A-4.14a: 4-(2,6-Difluorophenyl)-2,4-dioxobutyric acid ethyl ester.

The title compound was prepared according to Method A-4.13a starting from 1-(2,6difluorophenyl)ethan-1-one. LC-MS method A: t _R = 1.00 min.

A-4.14b: 5-(2,6-difluorophenyl)isoxazole-3-carboxylic acid ethyl ester.

The title compound was prepared according to procedure A-4.13b starting from building block A-4.14a. LC-MS method A: t _R = 0.97 min. [M+H]+= 254.20.

A-4.14: 5-(2,6-difluorophenyl)isoxazole-3-carboxylic acid.

The title compound was prepared according to Method A-4.09 starting from building block A-4.14b. LC-MS method A: t _R = 0.74 min. [M+H+MeCN]+ = 267.14.

A-4.15: 5-(4-trifluoromethylphenyl)isoxazole-3-carboxylic acid.

A-4.15a: 2,4-dioxo-4-(4-trifluoromethylphenyl)butyric acid ethyl ester.

The title compound was prepared according to Method A-4.13a starting from 1-(4(trifluoromethyl)phenyl)ethan-1-one. LC-MS method A: t _R = 1.05 min. [M+H]+= 288.96.

A-4.15b: 5-(4-trifluoromethylphenyl)isoxazole-3-carboxylic acid ethyl ester.

The title compound was prepared according to procedure A-4.13b starting from building block A-4.15a. LC-MS method A: t _R = 1.05 min. [M+H+MeCN]+ = 327.06.

A-4.15: 5-(4-trifluoromethylphenyl)isoxazole-3-carboxylic acid.

The title compound was prepared according to Method A-4.09 starting from building block A-4.15b. LC-MS method A: t _R = 0.85 min. A-4.16: 5-(3-trifluoromethylphenyl)isoxazole-3-carboxylic acid.

A-4.16a: 2,4-dioxo-4-(3-trifluoromethylphenyl)butyric acid ethyl ester.

The title compound was prepared according to Method A-4.13a starting from 1-(3(trifluoromethyl)phenyl)ethan-1-one. LC-MS method A: t _R = 1.05 min. [M+H]+ = 289.17.

- 43 040620

A-4.16b: 5-(3-trifluoromethylphenyl)isoxazole-3-carboxylic acid ethyl ester.

The title compound was prepared according to Method A-4.13b starting from building block A-4.16a. LC-MS method A: t _R = 1.05 min. [M+H]+ = 286.18.

A-4.16: 5-(3-trifluoromethylphenyl)isoxazole-3-carboxylic acid.

The title compound was prepared according to Method A-4.09 starting from building block A-4.16b. LC-MS method A: t _R = 0.85 min.

A-4.17: 5-(2,3,4-trifluorophenyl)isoxazole-3-carboxylic acid.

A-4.17a: 2,4-dioxo-4-(2,3,4-trifluorophenyl)butyric acid ethyl ester.

The title compound was prepared according to Method A-4.13a starting from 1(2,3,4-trifluorophenyl)ethan-1-one. LC-MS method A: t _R = 1.04 min. [M+H]+ = 275.17.

A-4.17b: 5-(2,3,4-trifluorophenyl)isoxazole-3-carboxylic acid ethyl ester.

The title compound was prepared according to procedure A-4.13b starting from building block A-4.17a. LC-MS method A: t _R = 1.02 min. A-4.17: 5-(2,3,4-trifluorophenyl)isoxazole-3-carboxylic acid.

The title compound was prepared according to Method A-4.09 starting from building block A-4.17b. LC-MS method A: t _R = 0.79 min.

A-4.18: 5-(5-fluoro-pyridin-2-yl)isoxazole-3-carboxylic acid.

A-4.18a: 4-(5-Fluoropyridin-2-yl)-2,4-dioxobutyric acid ethyl ester.

The title compound was prepared according to Method A-4.13a starting from 1-(5fluoropyridin-2-yl)ethan-1-one. LC-MS method A: t _R = 0.89 min. [M+H]+ = 240.25.

A-4.18b: 5-(5-Fluoropyridin-2-yl)isoxazole-3-carboxylic acid ethyl ester.

The title compound was prepared according to procedure A-4.13b starting from building block A-4.18a. LC-MS method A: t _R = 0.85 min. [M+H]+ = 237.28.

A-4.18: 5-(5-Fluoropyridin-2-yl)isoxazole-3-carboxylic acid.

The title compound was prepared according to Method A-4.09 starting from building block A- _4.18b . LC-MS method A: t _R = 0.59 min. [M+H]+ = 209.37.

A-4.19: 4-(2,4-Difluorophenyl)oxazole-2-carboxylic acid.

A-4.19a: 4-(2,4-difluorophenyl)oxazole-2-carboxylic acid ethyl ester.

2-Acetoxy-2',4'-difluoroacetophenone (200 mg, 0.934 mmol) was dissolved in p-xylene (10 ml). Add ethyl oxamate (437 mg, 3.74 mmol) and boron trifluoride diethyl etherate (0.248 ml, 0.934 mmol). The reaction mixture is heated to 150°C for 20 h.

The reaction mixture was diluted with EtOAc (40 ml) and washed with saturated NaHCO ₃ solution (20 ml). After separating the layers of aq. layer is extracted with EtOAc (2 x 20 ml). The combined organic layers are dried over MgSO ₄ , filtered and evaporated. The crude product is purified by LC-MS method E. LC-MS method A: t _R =0.96 min. [M+H]+ = 254.11.

A-4.19: 4-(2,4-Difluorophenyl)oxazole-2-carboxylic acid.

The title compound was prepared according to Method A-4.09 starting from building block A-4.19b. LC-MS method A: t _R = 0.69 min. [M+H]+ = 226.23.

A-4.20: 1-(2,4,6-trifluorophenyl)-1H-[1,2,3]triazole-4-carboxylic acid.

A-4.20a: 1-(2,4,6-trifluorophenyl)-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester.

The title compound was prepared according to Method A-4.08a starting from ethyl 2diazo-3-oxopropanoate and 2,4,6-trifluoroaniline. LC-MS method A: t _R = 0.84 min. [M+H]+ = 272.29.

A-4.20: 1-(2,4,6-trifluorophenyl)-1H-[1,2,3]triazole-4-carboxylic acid.

The title compound was prepared according to Method A-4.08 starting from building block A-4.20a. LC-MS method A: t _R = 0.65 min. [M+H]+ = 244.24.

A-4.21: 5-(2,4-difluorophenyl)isothiazole-3-carboxylic acid.

A-4.21a: 5-(2,4-difluorophenyl)-3-methylisothiazole.

Pd(PPh ₃ ) ₄ (892 mg, 0.77 mmol) is added to a degassed solution of 5-bromo-3-methylisothiazole (1446 mg, 7.72 mmol), 2,4,difluorophenylboronic acid (1462 mg, 9.26 mmol) and K3PO4 (8355 mg , 748 mmol) in dioxane (64 ml) and water (10 ml).

The resulting solution was stirred for 24 hours at 90° C. under argon. The resulting mixture was diluted with DCM (100 ml) and washed with H ₂ O (100 ml). The organic layer is separated and aq. the phase is extracted twice with DCM (2 x 100 ml). The combined organic layers are dried over anhydrous sodium sulfate and filtered. The resulting mixture was concentrated in vacuo. The crude product was purified by silica gel flash chromatography using an n-heptane-n-heptane/EtOAc 85:15 gradient as eluent to give the title compound as a white powder. LC-MS method A: t _R = 1.01 min. [M+H]+ = 212.19.

A-4.21b: 3-bromomethyl-5-(2,4-difluorophenyl)isothiazole.

A mixture of 5-(2,4-difluorophenyl)-3-methylisothiazole (1042 mg, 4.93 mmol), N-bromosuccinimide (966 mg, 5.43 mmol) and benzoyl peroxide (119 mg, 0.49 mmol) in trifluorotoluene (40 ml) was heated at reflux refrigerate for 30 hours. Add more NBS (500 mg, 2.8 mmol), benzoyl peroxide (80 mg, 0.33

- 44 040620 mmol) and the mixture is then heated under reflux for 2 hours. The mixture is diluted with DCM (100 ml) and water (100 ml). The organic layer is separated and aq. layer is extracted with DCM (100 ml). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel flash chromatography using DCM/n-heptane 1:1 as eluent to give the title compound as a viscous oil. LC-MS method A: tR = 1.06 min. [M+H]+ = 292.09.

A-4.21c: 5-(2,4-difluorophenyl)isothiazole-3-carboxylic acid ethyl ester.

A suspension of 3-bromomethyl-5-(2,4-difluorophenyl)isothiazole (1150 mg, 3.96 mmol) in water (10 ml) was treated at reflux with small portions of potassium permanganate (860 mg, 5.39 mmol) for 30 min. The reaction mixture is stirred for 5 hours. During this time, the purple color turns into a colorless liquid with a black suspension, which is filtered through Whatmann GF/A and evaporated. The crude product was diluted with DCM (25 ml) and sat. HCl 1n. (25 ml) aq. the phase is extracted three times with DCM (3.times.25 ml). The combined organic extracts are dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product contains mainly the starting material. The black residue was diluted in ethanol (200 ml) and 4N was added. HCl in dioxane (25 ml). The reaction mixture is heated under reflux overnight. The black suspension turns into a clear solution and the corresponding ester is formed. The solution is concentrated in vacuo. The crude product was purified by silica gel flash chromatography using a nheptane-n-heptane/EtOAc 95:5 gradient as eluent to give the title compound as a white powder. LCMS method A: tR = 1.06 min. [M+H]+ = 270.17.

A-4.21: 5-(2,4-difluorophenyl)isothiazole-3-carboxylic acid.

A solution of 5-(2,4-difluorophenyl)isothiazole-3-carboxylic acid ethyl ester (216 mg, 0.8 mmol) in EtOH/1N aq. NaOH (4 ml) was stirred for 24 h at RT. The reaction mixture was washed with EtOAc (10 ml). Water the phase is acidified with 1N. HCl (5 ml) and then extracted five times with DCM (5x10 ml). The combined extracts are dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound as a white powder. LC-MS method A: t _R = 0.84 min. [M+H]+ = 241.83.

General method A for the synthesis of compounds of formula (I) or (ID).

structural elements.

Retrieving Structural Elements of Structure 1

SE 1.01: rac-(3R*,4R*)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

.01a: rac-(3R*,4R*)-4-tert-butoxycarbonylamino-1-cyclohexylpiperidine-3-carboxylic acid methyl ester.

To a solution of rac-(3R*,4R*)-4-tert-butoxycarbonylaminopiperidine-3carboxylic acid methyl ester (3.0 g, 11.3 mmol) in DCM (56.4 ml) at RT was added cyclohexanone (1.42 ml, 13.5 mmol), followed by acetic acid (0.966 ml, 16.9 mmol) and sodium triacetoxyborohydride (3.39 g, 15.2 mmol). After stirring for 5 h, more cyclohexanone (0.23 ml, 2.3 mmol), acetic acid (0.17 ml, 2.8 mmol) and sodium triacetoxyborohydride (590 mg, 2.8 mmol) are added. The reaction mixture is stirred overnight. The reaction mixture was diluted with DCM (200 ml) and treated with aq. sat. NaHCO ₃ (250 ml). The organic phase is dried over MgSO ₄ and evaporated. The crude title compound was used in the next step without further purification; LC-MS method D t _R = 1.09 min; [M+H]+ = 341.19.

.01b: rac-(3R*,4R*)-4-amino-1-cyclohexyl-piperidine-3-carboxylic acid methyl ester.

Rαc-(3R*,4R*)-4-tert-Butoxycarbonylamino-1-cyclohexylpineridine3-carboxylic acid methyl ester 1.01a (3.85 g, 11.3 mmol) was dissolved in MeOH (56.5 ml). A 4M solution of HCl in dioxane (56.5 ml, 226 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated, dissolved in DCM (250 ml) and treated with aq. sat. NaHCO ₃ (200 ml). The organic layer is separated and aq. the phase is extracted with DCM (150 ml). The combined organic layers are dried over MgSO ₄ and evaporated.

The crude title compound is obtained as a yellow oil; LC-MS method D t _R = 0.79 min; [M+H]+ = 241.20.

.01c: rac-(3R*,4R*)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxazole-3 methyl ester

- 45 040620 carbonyl]amino}piperidine-3-carboxylic acid.

5-(2,4difluorophenyl) isoxazole-3-carboxylic acid (2.42 g, 10.4 mmol). DIPEA (5.83 ml, 33.4 mmol) is then added followed by HATU (4.16 g, 10.9 mmol). The reaction mixture is stirred overnight (17 h). The reaction mixture was concentrated, dissolved in DCM (300 ml) and treated with aq. sat. NaHCO3 (225 ml). The organic layer is dried over MgSO ₄ and evaporated. The crude residue is purified with prep. LC-MS under basic conditions (method E). The title compound is obtained as a white powder; LC-MS method D t _R = 1.15 min; [M+H]+ = 448.19.

1.01: rac-(3R*,4R*)-1-cyclohexyl-4-([5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid rac-(3R) methyl ester *,4R*)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid 1.01c (2.24 g, 5 mmol) is dissolved in THF ( 30.6 ml) at RT Aqueous 1M NaOH solution (15 ml, 15 mmol) was then added and the mixture stirred for 6.5 h. the suspension is filtered, washed twice with water (2 x 4 ml) and dried under BB condition The title compound is obtained as a white powder, LC-MS method D t _R = 0.61 min, [M+H]+ = 433.89.

Obtaining structural elements of structure 1 used as intermediates to obtain examples 1.001-1.199.

The following intermediate compounds are obtained by analogy with SE 1.01.

SE 1.02: rac-(3R*,4R*)-1-cyclohexyl-4- {[ 1 -(2,4-difluorophenyl)- 1H-[1,2,3]triazole-4-carbonyl]amino}piperidine- 3-carboxylic acid.

1.02c: rac-(3R*,4R*)-1-cyclohexyl-4-{[1-(2,4-difluorophenyl)-1H[1,2,3]triazole-4-carbonyl]amino} methyl ester piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01c starting from structural element 1.01b and structural element A-4.08; LC-MS method D: t _R =1.03 min; [M+H]+ = 448.15.

1.02: rac-(3R*,4R*)-1-cyclohexyl-4-([ 1 -(2,4-difluorophenyl)-1H-[ 1,2,3]triazole-4-carbonyl]amino}piperidine -3-carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.02c; LCMS method D: t _R =0.54 min; [M+H]+ = 433.88.

SE 1.03: rac-(3R*,4R*)-1-cyclopentyl-4- {[ 1 -(2,4-difluorophenyl)-1 H-[1,2,3]triazole-4-carbonyl]amino}piperidine -3-carboxylic acid.

1.03a: rac-(3R*,4R*)-4-tert-butoxycarbonylamino-1-cyclopentylpiperidine-3-carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01a starting from rac-(3R*,4R*)-4-tert-butoxycarbonylamino-piperidine-3-carboxylic acid methyl ester and cyclopentanone; LCMS method D: t _R =1.0 min; [M+H] ⁺ = 327.18.

1.03b: rac-(3R*,4R*)-4-amino-1-cyclopentylpiperidine-3-carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01b starting from building block 1.03a; LCMS method D: t _R =0.71 min; [M+H] ⁺ = 227.18.

1.03c: rac-(3R*,4R*)-1-cyclopentyl-4-{[1-(2,4-difluorophenyl)-1H[1,2,3]triazole-4-carbonyl]amino} methyl ester piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01c starting from building block 1.03b and building block A-4.08; LCMS method D: t _R =0.95 min; [M+H] ⁺ =433.9.

1.03: rac-(3R*,4R*)-1-cyclopentyl-4- {[ 1 -(2,4-difluorophenyl)-1 H-[1,2,3]triazole-4-carbonyl]amino} piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.03c; LCMS method D: t _R = 0.49 min; [M+H] ⁺ =420.07.

SE 1.04: rac-(3R*,4R*)-1-cyclopropylmethyl-4- {[ 1 -(2,4-difluorophenyl)-1H-[ 1,2,3]triazole-4-carbonyl]amino}piperidine- 3-carboxylic acid.

1.04a: rac-(3R*,4R*)-4-tert-butoxycarbonylamino-1-cyclopropylmethylpiperidine-3-carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01a, starting from rac-(3R*,4R*)-4-tert-butoxycarbonylaminopiperidine-3-carboxylic acid methyl ester and cyclopropanecarbaldehyde; LCMS method D: t _R =0.94 min; [M+H]+ = 313.18.

1.04b: rac-(3R*,4R*)-4-amino-1-cyclopropylmethylpiperidine-3-carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01b starting from building block 1.04a; LCMS method D: t _R =0.64 min; [M+H]+ = 213.21.

1.04c: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[1-(2,4-difluorophenyl)-1H[1,2,3]triazole-4-carbonyl]amino} methyl ester piperidine-3-carboxylic acid.

- 46 040620

The title compound was prepared according to procedure 1.01c starting from building block 1.04b and building block A-4.08; LCMS method D: t _R =0.89 min; [M+H] ⁺ =420.1.

1.04: rac-(3R*,4R*)-1-cyclopropylmethyl-4- {[ 1 -(2,4-difluorophenyl)-1H-[ 1,2,3]triazole-4-carbonyl]amino}piperidine-3 -carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.04c; LCMS method D: t _R =0.48 min; [M+H] ⁺ =406.09.

SE 1.05: rac-(3R*,4R*)-4-{ [ 1 -(2,4-difluorophenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-1-(2- methylcyclopentyl)piperidine-3-carboxylic acid.

.05a: rac-(3R*,4R*)-4-tert-butoxycarbonylamino-1-(2-methylcyclopentyl)piperidine-3-carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01a, starting from rac-(3R*,4R*)-4-tert-butoxycarbonylamino-piperidine-3-carboxylic acid methyl ester and 2-methylcyclopentanone; LCMS method D: t _R =1.16 min; [M+H] ⁺ = 341.2.

1.0 5b: rac-(3R*,4R*)-4-amino-1-(2-methylcyclopentyl)piperidine-3carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01b starting from building block 1.05a; LCMS method D: t _R =0.83 min; [M+H] ⁺ = 241.19.

1.0 5c: methyl ester rac-(3R*,4R*)-1-(2-methylcyclopentyl)-4-{[1-(2,4-difluorophenyl)1H-[1,2,3]triazole-4- carbonyl]amino}piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01c starting from structural element 1.05b and structural element A-4.08; LCMS method D: t _R =1.08 min; [M+H] ⁺ =448.15.

1.0 5: rac-(3R*,4R*)-1 -(2-methylcyclopentyl)-4- {[ 1 -(2,4-difluorophenyl)- 1H-[1,2,3]triazole-4-carbo- nyl]amino}piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.05c; LC-MS method D: t _R = 0.53 min; [M+H] ⁺ = 433.82.

SE 1.06: rac-(3R*,4R*)-1-cyclopentyl-4-{[5-(2,4,6-trifluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

1.0 6c: rac-(3R*,4R*)-1-cyclopentyl-4-{[5-(2,4,6-trifluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01c starting from building block 1.03b and building block A-4.01; LCMS method D: t _R =1.06 min; [M+H] ⁺ = 452.13.

1.0 6: rac-(3R*,4R*)-1-cyclopentyl-4-([5-(2,4,6-trifluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.06c; LCMS method D: t _R =0.55 min; [M+H] ⁺ = 438.1.

SE 1.07: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2,4,6-trifluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

1.0 7c: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2,4,6-trifluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester:

The title compound was prepared according to procedure 1.01c starting from building block 1.04b and building block A-4.01; LCMS method D: t _R =1.0 min; [M+H] ⁺ = 438.11.

1.0 7: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2A6-trifluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.07c; LCMS method D: t _R =0.53 min; [M+H] ⁺ = 424.09.

SE 1.08: rac-(3R*,4R*)-1-(2-methylcyclopentyl)-4-{[5-(2,4,6-trifluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid .

1.0 8c: rac-(3R*,4R*)-1-(2-methylcyclopentyl)-4-{[5-(2,4,6-trifluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3 methyl ester -carboxylic acid.

The title compound was prepared according to procedure 1.01c starting from building block 1.05b and building block A-4.01; LCMS method D: t _R =1.09 min; [M+H] ⁺ = 448.14.

1.0 8: rac-(3R*,4R*)-1-(2-methylcyclopentyl)-4-{[5-(2,4,6-trifluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid .

The title compound was prepared according to procedure 1.01 starting from building block 1.08c; LC-MS method D: t _R = 0.53 min; [M+H] ⁺ = 433.82.

SE 1.09: rac-(3R*,4R*)-1-cyclohexyl-4-{[3-(2,4-difluorophenyl)isoxazole-5-carbonyl]amino}piperidine-3-carboxylic acid.

1.09 s: rac-(3R*,4R*)-1-cyclohexyl-4-{[3-(2,4-difluorophenyl)isoxazole-5carbonyl]amino}piperidine-3-carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01c starting from building block 1.01b and building block A-4.10; LCMS method D: t _R =1.11 min; [M+H] ⁺ = 448.14.

1.09 : rac-(3R*,4R*)-1-cyclohexyl-4-{[3-(2,4-difluorophenyl)isoxazole-5-carbonyl]amino}piperi-

- 47 040620 din-3-carboxylic acid:

The title compound was prepared according to procedure 1.01 starting from building block 1.09c; LCMS method D: t _R = 0.58 min; [M+H]+ = 433.88.

SE 1.10: rac-(3R*,4R*)-1-cyclopentyl-4-{[3-(2,4-difluorophenyl)isoxazole-5-carbonyl]amino}piperidine-3-carboxylic acid.

1.10 s: rac-(3R*,4R*)-1-cyclopentyl-4-{[3-(2,4-difluorophenyl)isoxazole5-carbonyl]-amino}-piperidine-3-carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01c starting from building block 1.03b and building block A-4.10; LC-MS method D: t _R =1.03 min; [M+H]+ = 433.88.

1.10 : rac-(3R*,4R*)-1-cyclopentyl-4-{[3-(2,4-difluorophenyl)isoxazole-5-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.10c; LC-MS method D: t _R = 0.54 min; [M+H]+ = 420.12.

SE 1.11: rac-(3R*,4R*)-1-cyclohexyl-4-{[5-(2,4,6-trifluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

1.11 s: rac-(3R*,4R*)-1-cyclohexyl-4-{[5-(2,4,6-trifluorophenyl)isoxazole-3-carbonyl]amino} piperidine-3-carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01c starting from building block 1.01b and building block A-4.01; LCMS method D: t _R =1.14 min; [M+H]+ = 465.9.

1.11 : rac-(3R*,4R*)-1-cyclohexyl-4-{[5-(2,4,6-trifluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.11c; LCMS method D: t _R =0.59 min; [M+H]+ = 452.1.

SE 1.12: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[3-(2,4-difluorophenyl)isoxazole-5-carbonyl]amino}piperidine-3-carboxylic acid.

1.12 s: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[3-(2,4-difluorophenyl)isoxazole-5-carbonyl1-amino}piperidine-3-carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01c starting from building block 1.04b and building block A-4.10; LCMS method D: t _R =0.98 min; [M+H]+ = 420.11.

1.12 : rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[3-(2,4-difluorophenyl)isoxazole-5-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.12c; LCMS method D: t _R = 0.52 min; [M+H]+ = 406.07.

SE 1.13: rac-(3R*,4R*)-1-(2-methylcyclopentyl)-4-{[3-(2,4-difluorophenyl)isoxazole-5-carbonyl]amino}piperidine-3-carboxylic acid.

1.13 s: rac-(3R*,4R*)-1-(2-methylcyclopentyl)-4-{[3-(2,4-difluorophenyl)isoxazole-5-carbonyl]amino}piperidine-3-carboxylic methyl ester acids.

The title compound was prepared according to procedure 1.01c starting from building block 1.05b and building block A-4.10; LCMS method D: t _R =1.15 min; [M+H]+ = 448.14.

1.13 : rac-(3R*,4R*)-1-(2-methylcyclopentyl)-4-1H-(2,4-difluorophenyl)isoxazole-5-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.13c; LCMS method D: t _R = 0.59 min; [M+H]+ = 433.87.

SE 1.14: rac-(3R*,4R*)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)-[1,2,4]oxadiazole-3-carbonyl]amino}piperidine-3 - carboxylic acid.

1.14 s: rac-(3R*,4R*)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)-[1,2,4]oxadiazole-3-carbonyl]amino}piperidine methyl ester -3-carboxylic acid.

The title compound was prepared according to procedure 1.01c starting from structural element 1.01b and structural element A-4.09; LCMS method D: t _R =1.07 min; [M+H]+ = 449.03.

1.14 : rac-(3R*,4R*)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)-[1,2,4]oxadiazole-3-carbonyl]amino}piperidine-3 -carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.14c; LCMS method D: t _R = 0.55 min; [M+H]+ = 435.1.

SE 1.15: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2,4-difluorophenyl)-[1,2,4]oxadiazole-3-carbonyl]amino}piperidine-3- carboxylic acid.

1.15 s: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2,4-difluorophenyl)[1,2,4]oxadiazole-3-carbonyl]amino}piperidine- methyl ester 3-carboxylic acid.

The title compound was prepared according to procedure 1.01c starting from structural element 1.04b and structural element A-4.09; LCMS method D: t _R =0.93 min; [M+H]+ = 421.1.

1.15 : rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2,4-difluorophenyl)-[1,2,4]oxadiazole-3-carbonyl]amino}piperidine-3 -carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from structural element 1.15c; LCMS method D: t _R = 0.49 min; [M+H]+ = 407.05.

SE 1.16: rac-(3R*,4R*)-1-cyclopentyl-4-{[5-(2,4-difluorophenyl)-[1,2,4]oxadiazole-3-carbonyl]amino}piperidine-3- carboxylic acid 1.16c: rac-(3R*,4R*)-1-cyclopentyl-4{[5-(2,4-difluorophenyl)-[1,2,4]oxadiazole-3-carbonyl]amino} methyl ester piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01c starting from building block 1.03b and building block A-4.09; LCMS method D: t _R =0.99 min; [M+H]+ = 435.1.

1.16 : rac-(3R*,4R*)-1-cyclopentyl-4-([5-(2,4-difluorophenyl)-[1,2,4]oxadiazole-3-carbonyl]amino}piperidine-3 -carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.16c; LC-MS method D: t _R = 0.51 min; [M+H]+ = 421.1.

SE 1.17: rac-(3R*,4R*)-1-(2-methylcyclopentyl)-4-{[5-(2,4-difluorophenyl)-[1,2,4]oxadiazole-3-carbonyl]amino} piperidine-3-carboxylic acid 1.17с: methyl ester rac-(3R*,4R*)-1-(2methylcyclopentyl)-4-{[5-(2,4-difluorophenyl)-[1,2,4]oxadiazole -3-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01c starting from structural element 1.05b and structural element A-4.09; LCMS method D: t _R =1.12 min; [M+H]+ = 449.02.

1.17 : rac-(3R*,4R*)-1-(2-methylcyclopentyl)-4-([5-(2,4-difluorophenyl)-[1,2,4]oxadiazole-3-carbonyl]amino }piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.17c; LCMS method D: t _R = 0.56 min; [M+H]+ = 435.1.

SE 1.18: rac-(3R*,4R*)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)[1,3,4]oxadiazole-2-carbonyl]amino}piperidine- methyl ester 3-carboxylic acid

The title compound was prepared according to procedure 1.01c starting from structural element 1.01b and structural element A-4.07; LCMS method D: t _R =1.05 min; [M+H]+ = 449.08.

SE 1.19: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2,4-dichlorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

1.19 s: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2,4-dichlorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01c starting from structural element 1.04b and 5-(2,4-dichlorophenyl)-1,2-oxazole-3-carboxylic acid; LCMS method A: t _R =0.75 min; [M+H]+ = 451.98.

1.19 : rac-(3R*,4R*)-1-cyclopropylmethyl-4-([5-(2,4-dichlorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.19c; LCMS method A: t _R = 0.70 min; [M+H]+ = 438.11.

SE 1.20: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2-trifluoromethylphenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

1.20 s: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2-trifluoromethylphenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01c starting from building block 1.04b and building block A-4.13; LCMS method A: t _R =0.73 min; [M+H]+ = 452.11.

1.20 : rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2-trifluoromethylphenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.20c; LCMS method A: t _R = 0.67 min; [M+H]+ = 438.22.

SE 1.21: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2,6-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

1.21 s: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2,6-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01c starting from building block 1.04b and building block A-4.14; LCMS method A: t _R =0.68 min; [M+H]+ = 420.11.

1.21 : rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2,6-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.21c; LCMS method A: t _R = 0.62 min; [M+H]+ = 406.22.

SE 1.22: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(4-trifluoromethylphenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

1.22 s: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(4-trifluoromethylphenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01c starting from building block 1.04b and building block A-4.15; LCMS method A: t _R =0.75 min; [M+H]+ = 452.07.

1.22 : rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(4-trifluoromethylphenyl)isoxazole-3-carbonyl]ami-

- 49 040620 but} piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.22c; LCMS method A: t _R = 0.70 min; [M+H]+ = 438.25.

SE 1.23: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(3-trifluoromethylphenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

1.23 s: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(4-trifluoromethylphenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01c starting from building block 1.04b and building block A-4.16; LCMS method A: t _R =0.74 min; [M+H]+ = 452.09.

1.23 : rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(3-trifluoromethylphenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.23c; LC-MS method A: t _R = 0.69 min; [M+H]+ = 438.25.

SE 1.24: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2,3,4-trifluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

1.24 s: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2,3,4-trifluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01c starting from building block 1.04b and building block A-4.17; LCMS method A: t _R =0.72 min; [M+H]+ = 438.16.

1.24 : rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2,3,4-trifluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.24c; LCMS method A: t _R = 0.66 min; [M+H]+ = 424.15.

SE 1.25: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2-fluoro-4-methoxyphenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

1.25 s: rac-(R*,4R*)-1-cyclopropylmethyl-4-{[5-(2-fluoro-4-methoxyphenyl)isoxazole-3-carbonyl]amino} piperidine-3-carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01c starting from structural element 1.04b and 5-(2-fluoro-4-methoxyphenyl)isoxazole-3-carboxylic acid; LCMS method A: t _R =0.69 min; [M+H]+ = 432.29.

1.25 : rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(2-fluoro-4-methoxyphenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.25c; LCMS method A: t _R = 0.67 min; [M+H]+ = 418.07.

SE 1.26: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(5-fluoropyridin-2-yl)isoxazol-3-carbonyl]amino}piperidine-3-carboxylic acid.

1.26 s: rac-(3R*,4R*)-1-cyclopropylmethyl-4-{[5-(5-fluoropyridin-2yl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester.

The title compound was prepared according to procedure 1.01c starting from building block 1.04b and building block A-4.18; LCMS method A: t _R =0.59 min; [M+H]+ = 403.16.

1.26 : rac-(3R*,4R*)-1-cyclopropylmethyl-4-([5-(5-fluoropyridin-2-yl)isoxazol-3-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 1.01 starting from building block 1.26c; LC-MS method A: t _R = 0.54 min; [M+H]+ = 389.22.

General procedures for obtaining examples 1.001-1.199.

Method A.

To a solution of the corresponding carboxylic acid (SE 1.01-SE 1.26) (0.1 mmol) in 1 ml of DMF is added the corresponding amine (commercially available) (0.12-0.15 mmol). DIPEA (0.3 mmol; 0.6 mmol if the amine is the hydrochloride salt) is then added followed by HATU (0.105 mmol). The reaction mixture is stirred overnight at RT. The crude mixture is directly purified with prep. LC-MS using method E.

Method B.

To a solution of the corresponding carboxylic acid (SE 1.01-SE 1.26) (0.05 mmol) in pyridine (1 ml) at RT was added the corresponding commercially available amine ((0.1 mmol). Then POC13 (0.1 mmol) was added and the mixture was stirred at RT for 2 hours Water (50 µl) was added and the resulting solution was evaporated The crude residue was purified by prep LC-MS using method E.

Method C.

To a solution of the corresponding carboxylic acid (SE 1.01-SE 1.26) (0.07 mmol) and a commercially available amine (0.067 mmol) in 2 ml of DCM, TEA (0.29 mmol) and T3P 50% in DCM (0.08 ml, 0.135 mmol) are added. The mixture is stirred for 24 h at RT and then the reaction mixture is washed with aq. sat. NaHCO ₃ and water. The organic solvent is evaporated and the residue is purified with prep. HPLC using method E.

- 50 040620

Example 1.001. (1-Methyl-1-pyridin-2-yl-ethyl)amide rac-(3R*,4R*)-1-cyclohexyl-4-{[5-(2,4difluorophenyl)isoxazol-3-carbonyl]amino}piperidine -3-carboxylic acid.

To a solution of rac-(3K*,4K*)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid (43.3 mg, 0.1 mmol) 2-(2pyridyl)-2-propylamine dihydrochloride (41.8 mg, 0.2 mmol) is added to DMF (1 ml). DIPEA (0.055 ml, 0.32 mmol) is then added followed by HATU (39.9 mg, 0.105 mmol). The reaction mixture is stirred overnight at RT. The crude mixture is directly purified using prep. LC-MS using method E. LC-MS method D: t _R = 1.07 min; [M+H]+ = 552.15.

The compounds of Examples 1.001a-1.199 listed in Table 1 below are prepared by applying one of the above general procedures A, B or C to building blocks CE1.01-CE-1.26 in combination with commercially available amines of structure 2.

Enantiomerically pure compounds are obtained using one of the above chiral preparative chromatography methods.

Table 1. Reference examples 1.001-1.199

Reference Example No. Substance name QC LC-MS 1r (min) Detected mass [M+H] ⁺ 1.001 (1-methyl-1-pyridin-2-yl-ethyl)-amide paii-(3R*,4R*)-1 cyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl] -amino }-piperidine-3-carboxylic acid 0.65 552 1.001a (1-methyl-1-pyridin-2-yl-ethyl)-amide (enantiomer 1) (3R*,4K*)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxazol -3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.66 552.3

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1.001b (1-methyl-1-pyridin-2-yl-ethyl)-amide (enantiomer 2) (3R*,4R*)-l-cyclohexyl-4-{[5-(2,4-diφτop-φenyl)isoxazol -3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.66 552.2 1.002 (1-pyrimidin-2-yl-cyclopropyl)-amide pau-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazol-3carbonyl]-amino}-piperidine -3-carboxylic acid 0.64 551 1.002a (1-pyrimidin-2-yl-cyclopropyl)-amide (enantiomer 1) (3R*, 4P*)-1-cyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazol-3-carbonyl ]-amino }-piperidine-3-carboxylic acid 0.64 551.2 1.002b (1-pyrimidin-2-yl-cyclopropyl)-amide (enantiomer 2) (3R*, 4P*)-1-cyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazol-3-carbonyl ]-amino }-piperidine-3-carboxylic acid 0.64 551 1.003 rac-(3P*,4P*)-1-cyclohexyl-4-{[5(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid cyclopentylamide 0.71 501.1 1.004 [(3R*,4R*)-1-cyclohexyl-3-(pyrrolidine-1-carbonyl)piperidin-4-yl]-amide of rac-5-(2,4-difluorophenyl)isoxazole-3-carboxylic acid 0.67 487.4 1.005 (2-hydroxy-ethyl)-methyl-amide pau-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino}-piperidine-3 -carboxylic acid 0.6 491.3 1.006 (2-methoxy-ethyl)-amide pau-(3R*,4R*)-1-cyclohexyl-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}piperidine-3 -carboxylic acid 0.61 491.1 1.007 pau-(3R*,4R*)-l-uHKnoreKcnn-4-{[5-(2,4difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3-carboxylic acid isobutylamide 0.71 489.4 1.008 pau-(3R*,4R*)-l-uHKnoreKcnn-4-{[5-(2,4difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3-carboxylic acid isopropylamide 0.66 475.3 1.009 pau-(3R*,4R*)-l-uHKnoreKcnn-4-{[5-(2,4difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 0.63 461.1 1.010 pau-(3R*,4R*)-l-uHKnoreKcnn-4-{[5-(2,4difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3-carboxylic acid methylamide 0.58 447.3 1.011 (2-fluoro-ethyl)-amide pau-(3R*,4R*)-l-uHKnoreKcnn-4-{[5(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}piperidine-3 -carboxylic acid 0.61 479.3 1.012 rac-(ЗR*,4R*)-l-cycloheκcyl-4-{[5-(2,4-diφtorphenyl)-isoxazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid ethylamide 0.62 461.3 1.013 pau-(3R*,4R*)-l-unKfloreKCHfl-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3-carboxylic acid cyclopropylmethylamide 0.68 487.3 1.014 pan-(3R*,4R*)-l-nHMoreKCHfl-4-{[5(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3-carboxylic acid carbamoylmethylamide 0.54 490.1 1.015 (2-hydroxy-ethyl)-amide pau-(3R*,4R*)-l-unKfloreKCHfl-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}piperidine-3 -carboxylic acid 0.56 477.3

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1.016 [(3R*, 4R*)-1-cyclohexyl-3-(morpholine-4-carbonyl)piperidin-4-yl]-amide of rac-5-(2,4-difluorophenyl)isoxazole-3-carboxylic acid 0.63 503.1 1.017 pan-(3R*,4R*)-l-4HKnoreKCHn-4-{[5(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3-carboxylic acid isopropylmethylamide 0.72 489.1 1.018 (2-dimethylamino-ethyl)-methyl-amide pan-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino}-piperidine-3 -carboxylic acid 0.42 518.2 1.019 (2-is xy-ethyl)-methyl-amide pan-(3R*,4R*)-l-uHKnoreKcnn4-{ [5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine -3-carboxylic acid 0.71 519.3 1.020 (5-methyl-thiazol-2-ylmethyl)-amide pap-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazol-3carbonyl]-amino}-piperidine -3-carboxylic acid 0.66 544.1 1.021 (2-methoxy-ethyl)-methyl-amide pan-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino}-piperidine-3 -carboxylic acid 0.67 505.1 1.022 (5-methyl-isoxazol-3-ylmethyl)-amide pau-(3R*,4R*)-lcyclohexyl-4-{ [5-(2,4-difluoro-phenyl)-isoxazol-3 carbonyl]-amino}- piperidine-3-carboxylic acid 0.65 528.3 1.023 (2-dimethylamino-ethyl)-amide pap-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino}-piperidine-3-carboxylic acids 0.4 504.2 1.024 pan-(3R*,4R*)-l-nHKnoreKcnn-4-{[5-(2,4difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3-carboxylic acid ethylmethylamide 0.67 475.3 1.025 (pyridin-2-ylmethyl)-amide pan-(3R*,4R*)-l-nHKnoreKcnn4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3- carboxylic acid 0.58 524.1 1.026 (2,2-difluoro-ethyl)-amide pan-(3R*,4R*)-l-nHKnoreKcnn-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine -3-carboxylic acid 0.64 497.3 1.027 (3-Methoxy-propyl)-methyl-amide pan-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino}-piperidine-3 -carboxylic acid 0.7 519.3 1.028 [(3R*, 4R*)-1-cyclohexyl-3-((3RS)-3-hydroxy- 5-(2,4difluoro-phenyl)-isoxazole-3-carboxylic acid pyrrolidine-1-carbonyl)-piperidin-4-yl]-amide (mixture of isomers) 0.58 503.3 1.029 (3-methyl-isoxazol-5-ylmethyl)-amide pan-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazol-3carbonyl]-amino}-piperidine -3-carboxylic acid 0.63 528.3 1.030 [(3R*, 4R*)-3-(azetidine-1-carbonyl)-1-cyclohexylpiperidin-4-yl]-amide of rac-5-(2,4-difluorophenyl)isoxazole-3-carboxylic acid 0.62 473.3 1.031 (2-methyl-thiazol-4-ylmethyl)-amide pan-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazol-3carbonyl]-amino}-piperidine -3-carboxylic acid 0.65 544.3 1.032 (pyrimidin-2-ylmethyl)-amide pan-(3R*,4R*)-lcyclohexyl-4-{ [5-(2,4-difluoro-phenyl)-isoxazole-3 carbonyl]-amino}-piperidine-3- carboxylic acid 0.58 525.3 1.033 (4-methyl-thiazol-5-ylmethyl)-amide pan-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazol-3carbonyl]-amino}-piperidine -3-carboxylic acid 0.61 544.1

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1.034 (pyrimidin-4-ylmethyl)-amide acids 0.57 525.1 1.035 (oxazol-5-ylmethyl)-amide rac-(3C*,4C*)-1-cyclohexyl-4{[5-(2,4-difluoro-phenyl)-isoxazol-3-carbonyl]-amino}piperidine-3 -carboxylic acid 0.58 514.3 1.036 [(3R*,4R*) -1-cyclohexyl-3 -(3-fluoro-azetidine-1 carbonyl)-piperidin-4-yl]-amide rac-5-(2,4-difluorophenyl)-isoxazole-3- carboxylic acid 0.63 491.3 1.037 (pyrazin-2-ylmethyl)-amide rac-(3C*,4C*)-1-cyclohexyl4-{ [5 -(2,4-difluoro-phenyl)-isoxazol-3-carbonyl]-amino}piperidine-3- carboxylic acid 0.58 525.3 1.038 (2-trifluoromethoxy-ethyl)-amide pan-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino }-piperidine-3-carboxylic acid acids 0.71 545.3 1.039 methyl oxetan-3-ylmethyl-amide acids 0.62 517.1 1.040 ((III8)-1-pyridin-2-yl-ethyl)-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid (mixture of isomers) 0.62 539 1.041 [2-(2-oxopyrrolidin-1-yl)-ethyl]-amide pap-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl] - amino }-piperidine-3-carboxylic acid 0.61 544 1.042 (1-methyl-1H-pyrazol-3-ylmethyl)-amide pan-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazol-3carbonyl]-amino } -piperidine-3-carboxylic acid 0.61 527.2 1.043 (1H-imidazol-4-ylmethyl)-amide pan-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazol-3carbonyl]-amino}-piperidine-3 -carboxylic acid 0.39 513.1 1.044 ((2E8)-tetrahydrofuran-2-ylmethyl)-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino}-piperidine-3 -carboxylic acid (mixture of isomers) 0.64 517.1 1.045 (1,5-dimethyl-1Н-pyrazo l-3-ylmethyl)-amide pan-(3R*,4R*)1-cyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl ]-amino }-piperidine-3-carboxylic acid 0.63 541.2 1.046a ((18,2C)-2-phenyl-cyclopropyl)-amide (3R,4R)-1cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3carbonyl]-amino}- piperidine-3-carboxylic acid or ((III,28)-2-phenyl-cyclopropyl)-amide (3R,4R)-1cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole -3carbonyl]-amino}-piperidine-3-carboxylic acid or ((18,2C)-2-phenyl-cyclopropyl)-amide (3S,4S)-1cyclohexyl-4-{[5-(2,4,6 -trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid or ((III,28)-2-phenyl-cyclopropyl)-(38.48)-1-cyclohexyl-4{[5- (2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino }-piperidine-3-carboxylic acid amide (first-eluting enantiomer) 0.78 567.3 1.047 (3-ethyl-[1,2,4]oxadiazol-5-ylmethyl)-amide pan-(3R*,4R*)1-cyclohexyl-4-{[5-(2,4-difluoro-phenyl)- isoxazole-3carbonyl]-amino }-piperidine-3-carboxylic acid 0.66 543.3

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1.048 (pyridin-3-ylmethyl)-amide rac-(3K*,4I*)-1-cyclohexyl4-{[5-(2,4-difluoro-phenyl)-isoxazol-3-carbonyl]-amino}piperidine-3- carboxylic acid 0.5 524.1 1.049 rac-(3R*,4K*)-1-cyclohexyl-4-{[5(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3-carboxylic acid methylphenethylamide 0.82 551 1.050 (pyridin-4-ylmethyl)-amide rac-(3K*,4K*)-1-cyclohexyl4-{[5-(2,4-difluoro-phenyl)-isoxazol-3-carbonyl]-amino}piperidine-3- carboxylic acid 0.46 524.1 1.051 (thiazol-2-ylmethyl)-amide rac-(3K*,4K*)-1-cyclohexyl-4{[5-(2,4-difluoro-phenyl)-isoxazol-3-carbonyl]-amino}piperidine-3 -carboxylic acid 0.63 530.3 1.052 [(3R*,4R*) -1-cyclohexyl-3 -(3,3-difluoro-azetidine-1 carbonyl)-piperidin-4-yl]-amide rac-5-(2,4-difluorophenyl)-isoxazol- 3-carboxylic acid 0.67 509.3 1.053 ((3RS)-tetrahydropoφyran-3-ylmethyl)-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazol-3carbonyl]-amino}-piperidine-3 -carboxylic acid (mixture of isomers) 0.61 517.4 1.054 (2,5-dimethyl-2H-pyrazol-3-ylmethyl)-amide pau-(3R*,4R*)1-cyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl] -amino}-piperidine-3-carboxylic acid 0.61 541.2 1.055 [2-(2-hydroxy-ethoxy)-ethyl]-isopropyl-amide rac(3R*, 4R*)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxazol-3 -carbonyl]-amino}-piperidine-3-carboxylic acid 0.46 563.2 1.056 (2-o-tolyl-ethyl)-amide pau-(3R*,4R*)-l-uHKnoreKcnn-4{[5-(2,4-difluoro-phenyl)-isoxazol-3-carbonyl]-amino } piperidine-3-carboxylic acid 0.8 551.2 1.057 [2-(2-Metho xy-phenyl)-ethyl]-amide pau-(3R*,4R*)-l-cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino }-piperidine-3-carboxylic acid 0.78 567.4 1.058 [2-(2-chloro-phenyl)-ethyl]-amide pau-(3R*,4R*)-l-cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino} -piperidine-3-carboxylic acid 0.81 571 1.059 [2-(4-fluoro-phenyl)-ethyl]-amide pau-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino} -piperidine-3-carboxylic acid 0.77 555.1 1.060 ((2RS)-2-φenyl-πpopyl)-amide (3R*,4R*)-l-4HKnoreKcnn-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine -3-carboxylic acid (mixture of isomers) 0.8 551.4 1.061 ((1R*,28*)-2-phenyl-cyclopropyl)-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino} -piperidine-3-carboxylic acid and ((lS*,2R*)-2-φenyl-cycloπpopyl)-amide (mixture of isomers) (3R*, 4R*)-1-cyclohexyl-4-{[5-(2 ,4-difluoro-phenyl)isoxazo l-3-carbonyl]-amino }-piperidine-3-carboxylic acid 0.79 549.4 1.062 (2-p-tolyl-ethyl)-amide pau-(3R*,4R*)-1-cyclohexyl-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}piperidine -3-carboxylic acid 0.82 551 1.063 ((IRS)-l-(pyrimidin-4-yl)-ethyl)-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]- amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.59 539

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1.064 rac-(3K*,4K*)-1-cyclohexyl-4-{[5-(2,4difluoro-phenyl)-isoxazole-3-carbonyl]-amino }-piperidine-3-carboxylic acid phenylamide 0.74 509.3 1.065 (4,5-dimethyl-thiazol-2-yl)-amide pau-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid 0.77 544.1 1.066 (2-m-tolyl-ethyl)-amide paii-(3R*,4R*)-1-cyclohexyl-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}piperidine -3-carboxylic acid 0.81 551.2 1.067 pau-(3R*,4R*)-l-uHKnoreKCHn-4-{[5(2,4-difluoro-phenyl)-isoxazol-3-carbonyl]-amino }piperidine-3-carboxylic acid pyridin-3-ylamide 0.57 510.1 1.068 (4-methyl-thiazol-2-ylmethyl)-amide pau-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazol-3carbonyl]-amino}-piperidine -3-carboxylic acid 0.66 544.1 1.069 ((1 RS )-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-a mid (3R*, 4R*)-l-uHKnoreKCHn-4-{ [5-(2,4- difluoro-phenyl)isoxazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.73 592.3 1.070 [(3R*,4R*)-1-cyclohexyl-3-((3RS)-3-phenyl-pyrrolidine1-carbonyl)-piperidin-4-yl]-amide 5-(2,4-difluoro-phenyl)isoxazole -3-carboxylic acid (mixture of isomers) 0.81 563 1.071 (1-pyridin-2-yl-cyclopropyl)-amide pap-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino }- piperidine-3-carboxylic acid 0.63 550.2 1.072 ((R)-2-hydroxy-2-φenyl-ethyl)-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid (mixture of isomers) 0.69 553 1.073 ((8)-2-hydroxy-2-phenyl-ethyl)-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid (mixture of isomers) 0.69 553.3 1.074 (2-pyridin-2-yl-ethyl)-amide pau-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazol-3carbonyl]-amino}-piperidine -3-carboxylic acid 0.52 538.3 1.075 methyl-(2-pyridin-2-yl-ethyl)-amide pau-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid 0.57 552.2 1.076 ((1 RS)-2-hydroxy-κci-1-methyl-ethyl)-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.58 491.1 1.077 ((1 RS)-2,2-diφτop-1 -methyl-ethyl)-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl] -amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.67 511.3 1.078 ((1 RS)-1 -cyclobutyl-ethyl)-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino}-piperidine- 3-carboxylic acid (mixture of isomers) 0.77 515.4 1.079 (2-fluoro-1,1-dimethyl-ethyl)-amide pau-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid 0.7 507

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1.080 (3,3,3-trifluoro-1,1-dimethyl-propyl)-amide paii-(3R*,4R*)1-cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole- 3carbonyl]-amino }-piperidine-3-carboxylic acid 0.78 557.3 1.081 (2-methanesulfonyl-1,1-dimethyl-ethyl)-amide rac(3R*,4R*)-1-cyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazol-3-carbonyl ]-amino }-piperidine-3-carboxylic acid 0.63 567.1 1.082 ((1 RS)-2-φτop-l-methyl-ethyl)-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.64 493.3 1.083 ((1 RS)-2-3toxy-1-methyl-ethyl)-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.69 519.4 1.084 ((ЗRS)-3-methyl-τeτpahydropφypan-3-yl)-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid (mixture of isomers) 0.64 517.2 1.085 [(IRS) -1-(5-methyl-[1,3,4]oxadiazol-2-yl)-ethyl]-amide (3R*, 4R*)-l-HHKnoreKCHn-4-{ [5-(2 ,4-difluoro-phenyl)isoxazo l-3-carbonyl]-amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.62 543 1.086 [(lRS)-l-(3,5-difluoro-pyridin-2-yl)-ethyl]-amide (3R*, 4H*)-1-cyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid acids (mixture of isomers) 0.74 574 1.087 (3,3-difluoro-1-methyl-cyclobutyl)-amide paH-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid (mixture of isomers) 0.73 537.3 1.088 (2-hydroxy-1,1-dimethyl-ethyl)-amide paH-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid 0.63 505.2 1.089 [(3R*,4R*)-l-cyclohexyl-3-((3RS)-3-pyridin-2-ylpyrrolidin-1-carbonyl)-piperidin-4-yl]-amide 5-(2,4difluoro-phenyl) -isoxazole-3-carboxylic acid (mixture of isomers) 0.64 564 1.090 ((R)-l-pyrazin-2-yl-ethyl)-amide (3R*,4R*)-l-HHKnoreKcnn4-{ [5 -(2,4-difluoro-phenyl)-isoxazole-3-carbonyl] - amino }piperidine-3-carboxylic acid (mixture of isomers) 0.61 539.4 1.091 ((R)-l-cyclobutyl-ethyl)-amide (3R*,4R*)-l-HHKnoreKcnn-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine -3-carboxylic acid (mixture of isomers) 0.77 515.4 1.092 [(R)-l-(3-fluoro-pyridin-2-yl)-ethyl]-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole -3carbonyl]-amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.72 556.4 1.093 ((R)-l,2,2-τpimethyl-propyl)-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid (mixture of isomers) 0.79 517.4 1.094 [(R)-l-(5-fluoro-pyrimidin-2-yl)-ethyl]-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole -3carbonyl]-amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.66 557

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1.095 rac-(3I*,4I*)-1-cyclohexyl-4-{[1-(2,4difluorophenyl)- 1H-[1,2,3]triazole-4-carbonyl]-amino}piperidine-3 dimethylamide -carboxylic acid 0.55 461.3 1.095a (3I,4I)-1-cyclohexyl-4-{[1-(2,4-difluorophenyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-piperidine3-carboxylic acid dimethylamide or dimethylamide (3S,4S)-1cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole4-carbonyl]-amino }-piperidine-3-carboxylic acid (eluting first enantiomer) 0.55 461.3 1.096 rac-(3I*,4I*)-1-cyclopentyl-4-{[1-(2,4difluorophenyl)- 1H-[1,2,3]triazole-4-carbonyl]-amino}piperidine-3 dimethylamide -carboxylic acid 0.5 447.2 1.097 rac-(3I*,4I*)-1-cyclopropylmethyl-4-{[1(2,4-difluorophenyl)-1H-[1,2,3]triazole-4-carbonyl]-dimethylamide amino }-piperidine-3-carboxylic acid 1 433.3 1.098 dimethylamide (3I*,4I*)-4-{[1-(2,4-difluoro-phenyl)-1H- [ 1,2,3]triazole-4-carbonyl]-amino }-l-((lRS,2I8)-2-methylcyclopentyl)-piperidine-3-carboxylic acid (mixture of isomers) 0.55 461.3 1.099 rac-(3I*,4I*)-1-cyclopentyl-4-{[5-(2,4,6trifluoro-phenyl)-isoxazol-3-carbonyl]-amino }-piperidine-3-carboxylic acid dimethylamide 0.59 465.3 1.100 rac-(3E*,4E*)-1-cyclopropylmethyl-4-{[5(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 0.58 451.3 1.101 dimethylamide (3R*,4R*)-l-((lRS,2RS)-2-MeTHn-cyclopentyl)-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3carbonyl]-amino }-piperidine -3-carboxylic acid (mixture of isomers) 0.63 479.3 1.102 rac-(3R*,4R*)-1-cyclohexyl-4-{[3-(2,4difluoro-phenyl)-isoxazol-5-carbonyl]-amino }-piperidine-3-carboxylic acid dimethylamide 0.62 461 1.103 rac-(3I*,4I*)-1-cyclopentyl-4-{[3-(2,4difluoro-phenyl)-isoxazol-5-carbonyl]-amino }-piperidine-3-carboxylic acid dimethylamide 0.57 447 1.104 [(3R*, 4R*)-3-(azetidine-1-carbonyl)-1-cyclohexylpiperidin-4-yl]-amide rac-1-(2,4-difluoro-phenyl)-1H- [1,2,3]triazole-4-carboxylic acid 0.54 473.3 1.105 [(3R*, 4R*)-3-(azetidine-1-carbonyl)-1-cyclohexylpiperidin-4-yl]-amide of rac-5-(2,4,6-trifluorophenyl)isoxazole-3-carboxylic acid 0.62 491 1.106 [(3R*, 4R*)-3-(azetidine-1-carbonyl)-1-cyclopentylpiperidin-4-yl]-amide of rac-5-(2,4,6-trifluorophenyl)isoxazole-3-carboxylic acid 0.58 477.1 1.107 [(3R*,4R*)-3-(azetidine-1-carbonyl)-1-cyclopropylmethylpiperidin-4-yl]-amide rac-5-(2,4,6-trifluorophenyl)isoxazole-3-carboxylic acids 0.57 463.3 1.108 [(ZI*,4I*)-3-(azetidine-1-carbonyl)-1-((1I8,2I8)-2methyl-cyclopentyl)-piperidin-4-yl]-amide 5-(2,4,6trifluoro- phenyl)-isoxazole-3-carboxylic acid (mixture of isomers) 0.62 491.3 1.109 (2-methoxy-1,1-dimethyl-ethyl)-amide pau-(3R*,4R*)-lcyclopentyl-4-{ [1-(2,4-difluoro-phenyl)-1H-[ 1,2, 3]triazole4-carbonyl]-amino }-piperidine-3-carboxylic acid 0.6 505

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1.110 (2-Methoxy-1,1-dimethyl-ethyl)-amide paH-(3R*,4R*)-lcyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H[ 1,2,3 ]triazole-4-carbonyl]-amino }-piperidine-3 carboxylic acid 1.1 491.3 1.111 (2-Methoxy-1,1-dimethyl-ethyl)-amide paij-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3carbonyl] - amino }-piperidine-3-carboxylic acid 0.71 537.3 1.111a (2-Methoxy-1,1-dimethyl-ethyl)-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid (enantiomer 1) 0.71 537.3 1.111b (2-Methoxy-1,1-dimethyl-ethyl)-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid (enantiomer 2) 0.71 537.2 1.112 (2-methoxy-1,1-dimethyl-ethyl)-amide paH-(3R*,4R*)-lcyclopentyl-4-{ [5-(2,4,6-trifluoro-phenyl)-isoxazole-3carbonyl] - amino }-piperidine-3-carboxylic acid 0.68 523 1.113 (2-methoxy-1,1-dimethyl-ethyl)-amide paH-(3R*,4R*)-lcyclopropylmethyl-4-{ [5-(2,4,6-trifluoro-phenyl)isoxazol-3-carbonyl ]-amino }-piperidine-3-carboxylic acid 0.67 509 1.113a (2-methoxy-1,1-dimethyl-ethyl)-amide (3R*,4R*)-1cyclopropylmethyl-4-{ [5-(2,4,6-trifluoro-phenyl)isoxazol-3-carbonyl] - amino}-piperidine-3-carboxylic acid (enantiomer 1) 0.67 509.1 1.113b (2-methoxy-1,1-dimethyl-ethyl)-amide (3R*,4R*)-1cyclopropylmethyl-4-{ [5-(2,4,6-trifluoro-phenyl)isoxazol-3-carbonyl] - amino}-piperidine-3-carboxylic acid (enantiomer 2) 0.67 509.3 1.114 (2-methoxy-1,1-dimethyl-ethyl)-amide (3R*,4R*)-1- ((lRS,2RS)-2-methyl-cyclopentyl)-4-{[5-(2,4,6-τpiφtorphenyl)-isoxazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.7 537 1.115 (2-Methoxy-1,1-dimethyl-ethyl)-amide paH-(3R*,4R*)-lcyclohexyl-4-{ [3-(2,4-difluoro-phenyl)-isoxazol-5 carbonyl] - amino }-piperidine-3-carboxylic acid 0.69 519 1.116 (2-Methoxy-1,1-dimethyl-ethyl)-amide paH-(3R*,4R*)-lcyclopentyl-4-{ [3-(2,4-difluoro-phenyl)-isoxazol-5 carbonyl] - amino }-piperidine-3-carboxylic acid 0.67 505.3 1.117 ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-l-HHKnoreKCHn4-{[1-(2,4-difluoro-phenyl)-1H-[1,2, 3]triazole-4-carbonyl]amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.54 538.2 1.117a ((R)-l-pyridin-2-yl-ethyl)-amide (38.48)-1-cyclohexyl-4{[1-(2,4-difluoro-phenyl)-1H-[1.2.3 ]triazole-4-carbonyl]amino}-piperidine-3-carboxylic acid or ((R)-lpyridin-2-yl-ethyl)-amide (3R,4R)-l-HHKnoreKCHn-4-{[l(2, 4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-piperidine-3-carboxylic acid (second enantiomer eluting) 0.54 538.1 1.118 ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-1cyclopentyl-4-{ [1-(2,4-difluoro-phenyl)-1H-[ 1.2, 3]triazole4-carbonyl]-amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.5 524.2

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1.118a ((R)-l-pyridin-2-yl-ethyl)-amide (3 S,4S)-l-cyclopentyl-4{[1-(2,4-difluoro-phenyl)-1H-[1,2, 3]triazole-4-carbonyl]amino}-piperidine-3-carboxylic acid or ((R)-l-pyridin-2-yl-ethyl)-amide (3K,4K)-1-cyclopentyl-4-{[1(2 ,4-difluoro-phenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-piperidine-3-carboxylic acid (second-eluting enantiomer) 0.51 524.1 1.119 ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-1cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1Н- [ 1,2,3 ]triazole-4-carbonyl]-amino }-piperidine-3 carboxylic acid (mixture of isomers) 0.49 510.1 1.120 ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-4-{[1-(2,4difluoro-phenyl)- 1H-[ 1,2,3]triazole- 4-carbonyl]-amino }-1 - ((lRS.2RS)-2-MCTH.T-miK.ToncHTH.T)-niincpiifliiH-3- carboxylic acid (mixture of isomers) 0.53 538.2 1.121 ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-l-uHKnoreKCHn4-{ [5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl ]amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.63 556.1 1.121a ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-l-uHKnoreKCHn4-{ [5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl ]amino}-piperidine-3-carboxylic acid (enantiomer 1) 0.61 556.1 1.121b ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-l-uHKnoreKCHn4-{ [5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl ]amino}-piperidine-3-carboxylic acid (enantiomer 2) 0.63 556.1 1.122 ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-1cyclopentyl-4-{ [5-(2,4,6-trifluoro-phenyl)-isoxazole-3carbonyl] - amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.6 542.3 1.122a ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-1cyclopentyl-4-{ [5-(2,4,6-trifluoro-phenyl)-isoxazole-3carbonyl] - amino }-piperidine-3-carboxylic acid (enantiomer 1) 0.58 542.1 1.122b ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-1cyclopentyl-4-{ [5-(2,4,6-trifluoro-phenyl)-isoxazole-3carbonyl] - amino }-piperidine-3-carboxylic acid (enantiomer 2) 0.6 542.1 1.123 ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-1cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)isoxazol-3-carbonyl ]-amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.57 528.1 1.123a ((R)-l-pyridin-2-yl-ethyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)isoxazol-3-carbonyl] - amino }-piperidine-3-carboxylic acid or ((R)-l-pyridin-2-yl-ethyl)-amide (3R,4R)-1cyclopropylmethyl-4-{[5-(2,4,6-trifluoro- phenyl)isoxazo l-3-carbonyl]-amino }-piperidine-3-carboxylic acid (second enantiomer eluting) 0.58 528 1.124 ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-1-((1RS,2RS)2-methyl-cyclopentyl)-4-{ [5-(2,4 ,6-trifluoro-phenyl)isoxazo l-3-carbonyl]-amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.62 556.1 1.125 ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-l-uHKnoreKCHn4-{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl] - amino }piperidine-3-carboxylic acid (mixture of isomers) 0.61 538.2

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1.125a ((R)-l-pyridin-2-yl-ethyl)-amide (38.48)-1-cyclohexyl-4{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino }piperidine-3-carboxylic acid or ((R)-l-pyridin-2 yl-ethyl)-amide (3K,4K)-1-cyclohexyl-4-{[3-(2,4-difluorophenyl)-isoxazol -5-carbonyl]-amino}-piperidine-3 carboxylic acid (eluting second enantiomer) 0.62 538.2 1.126 ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-1cyclopentyl-4-{ [3-(2,4-difluoro-phenyl)-isoxazol-5 carbonyl] - amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.58 524.1 1.127 ((R)-l-pyrazin-2-yl-ethyl)-amide (3K*,4P*)-1-cyclohexyl4-{[1-(2,4-difluoro-phenyl)-1H-[1,2, 3]triazole-4-carbonyl]amino}-piperidine-3-carboxylic acid (mixture of isomers) 1 539.1 1.128 ((R)-l-pyrazin-2-yl-ethyl)-amide (3R*,4R*)-1-cyclopentyl4-{[1-(2,4-difluorophenyl)-1H-[1,2, 3]triazole-4-carbonyl]amino}-piperidine-3-carboxylic acid (mixture of isomers) 1 525.1 1.129 ((K)-1-pyrazin-2-yl-ethyl)-amide (3K*,4K*)-1-cyclohexyl4-{ [5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl ]amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.6 557.2 1.129a ((R)-l-pyrazin-2-yl-ethyl)-amide (3L*,4H*)-1-cyclohexyl4-{ [5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl ]amino}-piperidine-3-carboxylic acid (enantiomer 1) 0.6 557.4 1.129b ((R)-l-pyrazin-2-yl-ethyl)-amide (3R*,4R*)-l-uHKnoreKcnn4-{ [5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl ]amino}-piperidine-3-carboxylic acid (enantiomer 2) 0.63 557.2 1.130 ((R)-l-pyrazin-2-yl-ethyl)-amide (3R*,4R*)-1-cyclopentyl4-{ [5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl ]amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.59 543.3 1.131 ((R)-l-pyrazin-2-yl-ethyl)-amide (3R*,4R*)-1cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)isoxazol-3-carbonyl ]-amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.59 529 1.132 ((R)-1-pyrazin-2-yl-ethyl)-amide (3R*,4R*)-l-((lRS,2RS)-2methyl-cyclopentyl)-4-{ [5-(2,4, 6-trifluoro-phenyl)isoxazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.62 557.3 1.133 ((R)-l-pyrazin-2-yl-ethyl)-amide (3R*,4R*)-l-uHKnoreKcnn4-{[3 -(2,4-difluoro-phenyl)-isoxazole-5-carbonyl] - amino }piperidine-3-carboxylic acid (mixture of isomers) 0.59 539.3 1.134 ((R)-l-cyclobutyl-ethyl)-amide (3R*,4R*)-l-uHKnoreKcnn-4{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole -4-carbonyl]amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.69 515.4 1.135 ((R)-l-cyclobutyl-ethyl)-amide (3R*,4R*)-l-uHKnoneHTnn4-{[1-(2,4-difluorophenyl)-1H-[1,2,3]triazole- 4-carbonyl]amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.66 501.4 1.136 ((R)-l-cyclobutyl-ethyl)-amide (3R*,4R*)-1cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1Н- [ 1,2,3 ]triazole-4-carbonyl]-amino }-piperidine-3 carboxylic acid (mixture of isomers) 0.64 487.3

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1.137 ((R)-l-cyclobutyl-ethyl)-amide (3R*,4R*)-4-{[l-(2,4difluorophenyl)-1H-[1,2,3]triazole-4-carbonyl] -amino}-1- ((lRS,2RS)-2-methyl-cyclopentyl)-piperidine-3carboxylic acid (mixture of isomers) 0.68 515.4 1.138 ((R)-l-cyclobutyl-ethyl)-amide (3R*,4R*)-l-uHKnoneHTnn4-{ [5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl] amino}- piperidine-3-carboxylic acid (mixture of isomers) 0.74 519.3 1.138a ((R)-l-cyclobutyl-ethyl)-amide (3R*,4R*)-l-uHKnoneHTnn4-{ [5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl] amino}- piperidine-3-carboxylic acid (enantiomer 1) 0.73 519.2 1.138b ((R)-l-cyclobutyl-ethyl)-amide (3R*,4R*)-l-uHKnoneHTnn4-{ [5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl] amino}- piperidine-3-carboxylic acid (enantiomer 2) 0.74 519.1 1.139 ((R)-l-cyclobutyl-ethyl)-amide (3R*,4R*)-1cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)isoxazol-3-carbonyl]-amino } -piperidine-3-carboxylic acid (mixture of isomers) 0.72 505.3 1.139a ((R)-l-cyclobutyl-ethyl)-amide (3R*,4R*)-1cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)isoxazol-3-carbonyl]-amino } -piperidine-3-carboxylic acid (enantiomer 1) 0.71 505.1 1.139b ((R)-l-cyclobutyl-ethyl)-amide (3R*,4R*)-1cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)isoxazol-3-carbonyl]-amino } -piperidine-3-carboxylic acid (enantiomer 2) 0.73 505.3 1.140 ((R)-l-cyclobutyl-ethyl)-amide (3R*,4R*)-l-uHKnoreKCHn-4{[3-(2,4-difluoro-phenyl)-isoxazole-5-carbonyl]-amino }piperidine -3-carboxylic acid (mixture of isomers) 0.75 515.4 1.141 ((R)-l-cyclobutyl-ethyl)-amide (3R*,4R*)-l-uHKnoneHTnn4-{ [3-(2,4-difluoro-phenyl)-isoxazol-5-carbonyl]-amino }piperidine -3-carboxylic acid (mixture of isomers) 0.73 501.3 1.142 [1-(5-Fluoro-pyridin-2-yl)-cyclopropyl]-amide rac(ЗR*,4R*)-l-cycloheκcyl-4-{[l-(2,4-diφτop-φenyl)-lH[ 1,2,3 ]triazole-4-carbonyl]-amino }-piperidine-3 carboxylic acid 0.64 568.2 1.143 [1-(5-Fluoro-pyridin-2-yl)-cyclopropyl]-amide rac(ЗR*,4R*)-l-cycloheκcyl-4-{[5-(2,4,6-τpiφτop-φenyl)isoxazo l-3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.72 586.1 1.144 [1-(5-fluoro-pyridin-2-yl)-cyclopropyl]-amide rac(3R*,4R*)-l-uHKnonponnnMeTHn-4-{ [5-(2,4,6-trifluorophenyl)-isoxazol -3-carbonyl]-amino}-piperidine-3 carboxylic acid 0.68 558.3 1.145 ((1R*,28*)-2-phenyl-cyclopropyl)-amide (3R*,4R*)-1cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2, 3]triazole4-carbonyl]-amino}-piperidine-3-carboxylic acid and ((lS*,2R*)-2-φenyl-cycloπpopyl)-amide (3R*,4R*)-1cyclohexyl-4-{[1- (2,4-difluoro-phenyl)-1H-[1,2,3]triazole4-carbonyl]-amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.72 549.4

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1.146 ((1 S*,2R*)-2-φenyl-cyclopropyl)-amide (3R*,4R*)-1cyclopentyl-4-{[ 1-(2,4-difluoro-phenyl)-1Н-[ 1, 2,3]triazole4-carbonyl]-amino}-piperidine-3-carboxylic acid and ((1R*,2 8*)-2-phenyl-cyclopropyl)-amide (3R*,4R*)-1cyclopentyl-4- {[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole4-carbonyl]-amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.69 535.3 1.147 ((lS*,2R*)-2-φenyl-cycloπpopyl)-amide (3R*,4R*)-1cyclohexyl-4-{ [3-(2,4-difluoro-phenyl)-isoxazo l-5 carbonyl]- amino}-piperidine-3-carboxylic acid and ((1R*,28*)-2-phenyl-cyclopropyl)-amide (3R*,4R*)-1cyclohexyl-4-{[3-(2,4-difluoro- phenyl)-isoxazo l-5 carbonyl]-amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.77 549.4 1.148 ((lS*,2R*)-2-φenyl-cycloπpopyl)-amide (3R*,4R*)-1cyclopentyl-4-{ [3-(2,4-difluoro-phenyl)-isoxazol-5 carbonyl]- amino}-piperidine-3-carboxylic acid and ((1 R*,2S*)-2-φenyl-cycloπpopyl)-amide (3R*,4R*)-1cyclopentyl-4-{[3-(2,4-difluoro -phenyl)-isoxazo l-5 carbonyl]-amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.75 535.3 1.149 pan-(3R*,4R*)-l-nHKnonpominMeTHn-4-{[3(2,4-difluorophenyl)-isoxazole-5-carbonyl]-amino }piperidine-3-carboxylic acid dimethylamide 0.56 433.2 1.150 dimethylamide (3R*,4R*)-4-{[3-(2,4-diφτop-φenyl)isoxazol-5-carbonyl]-amino}-1-((lRS,2RS)-2-MeTHn-cyclopentyl)-piperidine -3-carboxylic acid (mixture of isomers) 0.61 461.3 1.151 (2-Methoxy-1,1-dimethyl-ethyl)-amide pan-(3R*,4R*)-lcyclopropylmethyl-4-{ [3-(2,4-difluoro-phenyl)-isoxazol-5 carbonyl] - amino }-piperidine-3-carboxylic acid 0.65 491.3 1.152 (2-methoxy-1,1-dimethyl-ethyl)-amide pan-(3R*,4R*)-lcyclohexyl-4-{ [5-(2,4-difluoro-phenyl)-[ 1,2,4] oxadiazole3-carbonyl]-amino }-piperidine-3-carboxylic acid 0.65 520.2 1.153 (2-methoxy-1,1-dimethyl-ethyl)-amide pan-(3R*,4R*)-lcyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)- [1,2,4]oxadiazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.61 492.3 1.154 ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-1- cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazol-5-carbonyl]-amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.57 510 1.154a (III)-1-pyridin-2-yl-ethyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazol-5 carbonyl]-amino}- piperidine-3-carboxylic acid or ((R)-l-pyridin-2-yl-ethyl)-amide (3R,4R)-1- cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazol-5-carbonyl]-amino}-piperidine-3-carboxylic acid (second enantiomer eluting) 0.58 510 1.155 ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-4-{[3-(2,4difluoro-phenyl)-isoxazol-5-carbonyl]-amino } - 1 - ((lRS,2RS)-2-methyl-cyclopentyl)-piperidine-3carboxylic acid (mixture of isomers) 0.61 538.2

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1.156 ((R)-l-pyridin-2-yl-ethyl)-amide (3K*,4K*)-1-cyclohexyl4-{ [5 -(2,4-difluoro-phenyl)-[ 1,2,4] oxadiazole-3-carbonyl]amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.56 539.2 1.156a ((R)-l-pyridin-2-yl-ethyl)-amide (38.48)-1-cyclohexyl-4{[5-(2,4-difluorophenyl)-[1,2,4]oxadiazole -3-carbonyl]amino}-piperidine-3-carboxylic acid or ((R)-l-pyridin-2-yl-ethyl)-amide (3R,4R)-l-uHKnoreKCHn-4-{[5(2,4- difluorophenyl)-[1,2,4]oxadiazole-3-carbonyl]amino}-piperidine-3-carboxylic acid (eluting second enantiomer) 0.57 539.2 1.157 ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-1- cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-[1,2,4]oxadiazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.53 525.1 1.158 ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-1- cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)- [1,2,4]oxadiazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.52 511.1 1.159 ((R)-l-pyrazine-2-yl-ethyl)-amide (3R*,4R*)-1- cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazol-5-carbonyl]-amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.55 510.9 1.160 ((R)-l-pyrazin-2-yl-ethyl)-amide (3R*,4R*)-l-uHKnoreKCHn4-{ [5 -(2,4-difluorophenyl)-[ 1,2,4] oxadiazole-3-carbonyl]amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.56 540.4 1.161 ((R)-l-cyclobutyl-ethyl)-amide (3R*,4R*)-1cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazol-5-carbonyl]-amino}-piperidine -3-carboxylic acid (mixture of isomers) 0.71 487.3 1.162 (II)-1-cyclobutyl-ethyl)-amide (3R*,4R*)-4-{[3-(2,4difluoro-phenyl)-isoxazol-5-carbonyl]-amino } -1 ((lRS, 2RS)-2-methyl-cyclopentyl)-piperidine-3carboxylic acid (mixture of isomers) 0.74 515.4 1.163 [1-(5-fluoro-pyridin-2-yl)-cyclopropyl]-amide rac(3R*,4R*)-l-uHKnonponnnMeTHn-4-{ [3-(2,4-difluoro-phenyl)isoxazol- 5-carbonyl]-amino}-piperidine-3-carboxylic acid 0.66 540.3 1.164 ((lS*,2R*)-2-φenyl-cycloπpopyl)-amide (3R*,4R*)-1cyclopropylmethyl-4-{ [3-(2,4-difluoro-phenyl)-isoxazol-5 carbonyl]- amino}-piperidine-3-carboxylic acid and ((1R*,28*)-2-phenyl-cyclopropyl)-amide (3R*,4R*)-1cyclopropylmethyl-4-{[3-(2,4-difluoro- phenyl)-isoxazo l-5 carbonyl]-amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.73 521.3 1.165 (1-pyridin-2-yl-cyclopropyl)-amide pau-(3R*,4R*)-lcyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1Н-[1,2,3] triazole4-carbonyl]-amino }-piperidine-3-carboxylic acid 0.55 550.2 1.165a (1-pyridin-2-yl-cyclopropyl)-amide (3R*,4R*)-1cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1H-[1,2,3]triazole4- carbonyl]-amino }-piperidine-3-carboxylic acid (enantiomer 1) 0.54 550.2

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1.165b (1-pyridin-2-yl-cyclopropyl)-amide (3R*,4R*)-1 cyclohexyl-4-{[1-(2,4-difluoro-phenyl)-1Н-[1,2,3]triazole4 -carbonyl]-amino }-piperidine-3-carboxylic acid (enantiomer 2) 0.55 550.1 1.166 (1-pyridin-2-yl-cyclopropyl)-amide paH-(3R*,4R*)-1 cyclopentyl-4-{ [1-(2,4-difluoro-phenyl)-1H-[ 1,2,3 ]triazole4-carbonyl]-amino }-piperidine-3-carboxylic acid 0.51 536.1 1.167 (1-pyridin-2-yl-cyclopropyl)-amide paii-(3R*,4R*)-1 cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H- [ 1,2,3 ]triazole-4-carbonyl]-amino }-piperidine-3 carboxylic acid 0.5 522 1.168 (1-pyridin-2-yl-cyclopropyl)-amide (3R*,4R*)-4-{ [1-(2,4difluoro-phenyl)- 1H-[1,2,3]triazole-4-carbonyl] -amino }-1 ((lRS,2RS)-2-methyl-cyclopentyl)-piperidine-3-carboxylic acid (mixture of isomers) 0.54 550.2 1.169 (1-pyridin-2-yl-cyclopropyl)-amide pau-(3R*,4R*)-1 cyclohexyl-4-{ [5-(2,4,6-trifluoro-phenyl)-isoxazole-3carbonyl]-amino }-piperidine-3-carboxylic acid 0.65 568.3 1.170 (1-pyridin-2-yl-cyclopropyl)-amide paH-(3R*,4R*)-1 cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3carbonyl]-amino }-piperidine-3-carboxylic acid 0.6 554.1 1.170a (1-pyridin-2-yl-cyclopropyl)-amide (3S,4S)-1- 4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid cyclopentyl or (1-pyridin-2-yl-cyclopropyl) -amide (3R,4R)-1 - cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (eluting first enantiomer) 0.6 554.1 1.171 (1-pyridin-2-yl-cyclopropyl)-amide paH-(3R*,4R*)-1 cyclopropylmethyl-4-{ [5-(2,4,6-trifluoro-phenyl)isoxazol-3-carbonyl] -amino}-piperidine-3-carboxylic acid 0.59 540.1 1.171a (1-pyridin-2-yl-cyclopropyl)-amide (3R*,4R*)-1 cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)isoxazol-3-carbonyl] -amino}-piperidine-3-carboxylic acid (enantiomer 1) 0.58 540.1 1.171b (1-pyridin-2-yl-cyclopropyl)-amide (3R*,4R*)-1 cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)isoxazol-3-carbonyl]-amino }-piperidine-3-carboxylic acid (enantiomer 2) 0.59 540.1 1.172 (1-pyridin-2-yl-cyclopropyl)-amide (3R*,4R*)-1 ((lRS,2RS)-2-methyl-cyclopentyl)-4-{[5-(2,4,6-τpiφtorphenyl )-isoxazo l-3-carbonyl]-amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.62 568.1 1.173 (1-pyridin-2-yl-cyclopropyl)-amide paH-(3R*,4R*)-1 cyclopentyl-4-{ [3-(2,4-difluoro-phenyl)-isoxazol-5 carbonyl]-amino }-piperidine-3-carboxylic acid 0.59 536.3 1.174 (1-pyridin-2-yl-cyclopropyl)-amide paH-(3R*,4R*)-1 cyclopropylmethyl-4-{ [3-(2,4-difluoro-phenyl)-isoxazole-5carbonyl]-amino }- piperidine-3-carboxylic acid 0.57 522.1 1.175 (1-pyridin-2-yl-cyclopropyl)-amide (3R*,4R*)-4-{ [3-(2,4difluoro-phenyl)-isoxazol-5-carbonyl]-amino } -1 - ((lRS,2RS)-2-methyl-cyclopentyl)-piperidine-3carboxylic acid (mixture of isomers) 0.61 550.2

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1.176 (1-pyrimidin-2-yl-cyclopropyl)-amide pau-(3R*,4R*)-lcyclopentyl-4-{ [5-(2,4,6-trifluoro-phenyl)-isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid 0.62 555.3 1.176a (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)isoxazole-3carbonyl]-amino}-piperidine-3 -carboxylic acid or (1-pyrimidin-2-yl-cyclopropyl)-amide (3R,4R)-1cyclopentyl-4-{[5-(2,4,6-trifluoro-phenyl)-isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid (eluting second enantiomer) 0.61 555.1 1.177 (1-pyrimidin-2-yl-cyclopropyl)-amide pan-(3R*,4R*)-lcyclopropylmethyl-4-{ [5-(2,4,6-trifluoro-phenyl)isoxazol-3-carbonyl] - amino}-piperidine-3-carboxylic acid 0.63 541.1 1.178 (1-pyrimidin-2-yl-cyclopropyl)-amide pau-(3R*,4R*)-l-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- carbonyl]-amino }-piperidine-3-carboxylic acid 0.61 523.1 1.179 (1-pyrazin-2-yl-cyclopropyl)-amide (3S,4S)-1- cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino}-piperidine-3-carboxylic acid 0.61 523 1.180 (1-pyridazin-3-yl-cyclopropyl)-amide (3S,4S)-1- cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino}-piperidine-3-carboxylic acid 0.56 523 1.181 (1-pyrazin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazol-3carbonyl]-amino }-piperidine-3-carboxylic acids 0.62 537.1 1.182 (1-pyridazin-3-yl-cyclopropyl)-amide (3 S,4 S)-1 cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino }-piperidine- 3-carboxylic acid 0.57 537.1 1.183 (cyano-dimethyl-methyl)-amide pau-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino }-piperidine-3-carboxylic acid acids 0.65 500.3 1.184 [ 1 -(4,6-dimethyl-pyrimidin-2-yl)-cyclopropyl]-amide (38.48)-1-cyclopentyl-4-{[5-(2,4-difluoro-phenyl)isoxazol-3 -carbonyl]-amino}-piperidine-3-carboxylic acid 0.71 565.4 1.185 [ 1 -(4,6-dimethyl-pyrimidin-2-yl)-cyclopropyl]-amide (38.48)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)isoxazol-3 -carbonyl]-amino}-piperidine-3-carboxylic acid 0.7 551.4 1.186 (3R,4R)-l-unKfloreKCHfl-4-{[5-(2,4-difluorophenyl)-isoxazole-3-carbonyl]-amino }-piperidine-3-carboxylic acid dimethylamide 0.63 461.3 1.187a ((8)-1-pyridin-2-yl-ethyl)-amide (3R*,4R*)-1-cyclohexyl4-{ [5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl] - amino }piperidine-3-carboxylic acid (enantiomer 1) 0.63 538.4 1.187b ((8)-1-pyridin-2-yl-ethyl)-amide (3R*,4R*)-l-unKfloreKCHfl4-{ [5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl] - amino }piperidine-3-carboxylic acid (enantiomer 2) 0.63 538.3 1.187c ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-l-unKfloreKCHfl4-{ [5 -(2,4-difluoro-phenyl)-isoxazole-3-carbonyl] - amino }piperidine-3-carboxylic acid (enantiomer 1) 0.63 538.3 1.187d ((R)-l-pyridin-2-yl-ethyl)-amide (3R*,4R*)-l-unKfloreKCHfl4-{ [5 -(2,4-difluoro-phenyl)-isoxazole-3-carbonyl] - amino }piperidine-3-carboxylic acid (enantiomer 2) 0.62 538.2

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1.188a [(R)-l-(6-methyl-pyridin-2-yl)-ethyl]-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole -3carbonyl]-amino}-piperidine-3-carboxylic acid (enantiomer 1) 0.6 552.2 1.188b [(R)-l-(6-methyl-pyridin-2-yl)-ethyl]-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole -3carbonyl]-amino}-piperidine-3-carboxylic acid (enantiomer 2) 0.59 552.2 1.188c [(8)-1-(6-methyl-pyridin-2-yl)-ethyl]-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole -3carbonyl]-amino}-piperidine-3-carboxylic acid (enantiomer 1) 0.6 552.2 1.188.d [(8)-1-(6-methyl-pyridin-2-yl)-ethyl]-amide (3R*,4R*)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole -3carbonyl]-amino}-piperidine-3-carboxylic acid (enantiomer 2) 0.59 552.2 1.189 (1-pyrimidin-2-yl-cyclopropyl)-amide pau-(3R*,4R*)-l-cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazol-3carbonyl]-amino}-piperidine -3-carboxylic acid 0.70 555 1.189a (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3carbonyl]-amino}-piperidine-3-carboxylic acids or (1-pyrimidin-2-yl-cyclopropyl)-amide (3R,4R)-1cyclopropylmethyl-4-{[5-(2,4-dichloro-phenyl)-isoxazole-3carbonyl]-amino}-piperidine-3 -carboxylic acid (first eluting enantiomer) 0.70 555.3 1.190 (1-pyrimidin-2-yl-cyclopropyl)-amide paij-(3R*,4R*)-lcyclopropylmethyl-4-{[5-(2-trifluoromethyl-phenyl)isoxazol-3-carbonyl]-amino}-piperidine -3-carboxylic acid 0.7 555.2 1.191 (1-pyrimidin-2-yl-cyclopropyl)-amide pau-(3R*,4R*)-l-cyclopropylmethyl-4-{[5-(2,6-difluoro-phenyl)-isoxazol-3carbonyl]-amino}-piperidine -3-carboxylic acid 0.6 523.4 1.192 (1-pyrimidin-2-yl-cyclopropyl)-amide pau-(3R*,4R*)-lcyclopropylmethyl-4-{[5-(4-trifluoromethyl-phenyl)isoxazol-3-carbonyl]-amino}-piperidine -3-carboxylic acid 0.70 555.4 1.192a (1-pyrimidin-2-yl-cyclopropyl)-amide (3R*,4R*)-1cyclopropylmethyl-4-{[5-(4-trifluoromethyl-phenyl)isoxazol-3-carbonyl]-amino}-piperidine-3 -carboxylic acid (enantiomer 1) 0.70 555.4 1.192b (1-pyrimidin-2-yl-cyclopropyl)-amide (3R*,4R*)-1cyclopropylmethyl-4-{[5-(4-trifluoromethyl-phenyl)isoxazol-3-carbonyl]-amino}-piperidine-3 -carboxylic acid (enantiomer 2) 0.70 555.4 1.193 (1-pyrimidin-2-yl-cyclopropyl)-amide pau-(3R*,4R*)-lcyclopropylmethyl-4-{[5-(3-trifluoromethyl-phenyl)isoxazol-3-carbonyl]-amino}-piperidine -3-carboxylic acid 0.70 555 1.193a (1-pyrimidin-2-yl-cyclopropyl)-amide (3R,4R)-1cyclopropylmethyl-4-{[5-(3-trifluoromethyl-phenyl)isoxazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid acid or (1-pyrimidin-2-yl-cyclopropyl)-amide (38.48)-1-cyclopropylmethyl-4-{[5-(3-trifluoromethylphenyl)-isoxazol-3-carbonyl]-amino}-piperidine- 3 carboxylic acid (eluting second enantiomer) 0.70 555.2

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1.194a (1-pyrimidin-2-yl-cyclopropyl)-amide (3R,4R)-1cyclopropylmethyl-4-{[5-(2,3,4-trifluoro-phenyl)isoxazol-3-carbonyl]-amino}-piperidine -3-carboxylic acid or (1-pyrimidin-2-yl-cyclopropyl)-amide (38.48)-1-cyclopropylmethyl-4-{[5-(2,3,4-trifluoro-phenyl)isoxazol-3 -carbonyl]-amino}-piperidine-3-carboxylic acid (eluting first enantiomer) 0.60 541 1.195 (1-pyrimidin-2-yl-cyclopropyl)-amide pau-(3R*,4R*)-lcyclopropylmethyl-4-{[5-(2-fluoro-4-methoxy-phenyl)isoxazol-3-carbonyl] - amino}-piperidine-3-carboxylic acid 0.60 535.1 1.196 (1-pyrimidin-2-yl-cyclopropyl)-amide pau-(3R*,4R*)-lcyclopropylmethyl-4-{[5-(5-fluoro-pyridin-2-yl)isoxazol-3-carbonyl] -amino}-piperidine-3-carboxylic acid 0.50 506 1.197 (1-pyridin-2-yl-cyclobutyl)-amide pau-(3R*,4R*)-lcyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- carbonyl]-amino }-piperidine-3-carboxylic acid 0.6 536.2 1.198 [1-(2-Methoxy-phenyl)-cyclopropyl]-amide pau-(3R*,4R*)1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl] - amino }-piperidine-3-carboxylic acid 0.8 551.2 1.199 (1-pyrimidin-2-yl-cyclopropyl)-amide pau-(3R*,4R*)-lcyclopropylmethyl-4-{[5-(2,3-difluoro-phenyl)-isoxazole-3- carbonyl]-amino }-piperidine-3-carboxylic acid 0.6 523.2

General method B for the synthesis of compounds of formula (I) or (ID).

structural elements.

Obtaining the structural elements of the B-6 structure

SE 2.01: rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid dimethylamide.

2.01a: rac-(3R*,4R*)-1-benzyl-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-3-carboxylic acid methyl ester.

5-(2,4- difluorophenyl)isoxazole-3-carboxylic acid (7.74 g, 33.4 mmol). DIPEA (24.5 ml, 140 mmol) is then added followed by HATU (13.32 g, 35 mmol). The reaction mixture was stirred for 1 hour. The reaction mixture was concentrated, diluted with DCM (750 ml) and treated with aq. sat. NaHCO ₃ (600 ml). The organic layer is dried over MgSO ₄ and evaporated. The crude residue is purified with prep. LC-MS under basic conditions to give the title compound; LC-MS method D t _R = 1.14 min; [M+H]+ = 456.18.

2.01b: 1-tert-butyl, 3-methyl ester rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-1,3 -dicarboxylic acid.

To a solution of rac-(3R*,4R*)-1-benzyl-4-{[5-(2,4-difluorophenyl)isoxazole3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester 2.01а (11.33 g, 24.9 mmol) in ethyl acetate (250 ml) under argon, 10 wt.% palladium on activated carbon (2.647, 2.49 mmol) and di-tert-butyl dicarbonate (6.03 g, 27.4 mmol) are added. After degassing the reaction flask, the mixture is hydrogenated for 5 hours at RT. The catalyst is filtered, washed with EtOAc and the solvent is evaporated. The crude residue is purified with prep. LC-MS under basic conditions to give the title compound; LC-MS method D t _R = 1.11 min; [M+H]+= 465.90.

2.01c: rac-(3R*,4R*)-4-([5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-1,3-dicarboxylic acid 1-tert-butyl ester.

Rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester 2.01b (8.71 g, 18.7 mmol) is dissolved in THF (114 ml). Then add aq. 1M NaOH solution (56.1 ml, 56.1 mmol) and the mixture was stirred at RT for 3 h. The reaction mixture was acidified to approximately pH 3 with 2M aq. HCl solution (30 ml) and concentrated. The resulting suspension is filtered, washed twice with water (2x14 ml) and dried under BB conditions. The title compound is obtained as a white powder; LC-MS method D t _R = 0.66 min; [M+H]+ = 452.17.

2.01 d: rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}-3-dimethylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester.

To a solution of 1-tert-butyl ester rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3

- 68 040620 carbonyl]amino}piperidine-1,3-dicarboxylic acid 2.01c (5 g, 11 mmol) in DMF (58 ml) a 2M solution of dimethylamine in THF (22 ml, 44 mmol) is added at RT. DIPEA (6.15 ml, 35.2 mmol) is then added followed by HATU (4.4 g, 11.6 mmol). The reaction mixture was stirred at RT for 4 h. The volatiles were evaporated and the crude mixture was purified with prep. LC-MS under basic conditions to give the title compound; LC-MS method D t _R =1. 01 min; [M+H]+ = 479.23.

2.01: rac-(3R*,4R*)-4-([5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine3-carboxylic acid dimethylamide rac-(3R*,4R) tert-butyl ester *)-4-{[5-(2,4-difluorophenyl)isoxazole3-carbonyl]amino}-3-dimethylcarbamoylpiperidine-1-carboxylic acid 2.01d (4.53 g, 9.47 mmol) was dissolved in MeOH (47.3 ml) at RT. 4M HCl in dioxane (47.3 mL, 189 mmol) was added and the reaction was stirred at RT for 1 h. Solvents were evaporated to give the title compound, LC-MS method D t _R = 0.75 min; = 379.11.

Preparation of structural elements of general formula (B-6) used as intermediates in the preparation of examples 2.001-2.108.

The following intermediate compounds are obtained by analogy with SE 2.01.

SE 2.02: rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-3-carboxylic acid methylphenethylamide hydrochloride.

2.02b: rac-(3R*,4R*)-4-([5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-3-(methyl-phenethylcarbamoyl)piperidine-1 tert-butyl ester -carboxylic acid.

The title compound was prepared according to procedure 2.01d starting from structural element 2.01c and N-methyl-2-phenylethylamine; LCMS method D: t _R =1.17 min; [M+H]+ = 569.14.

2.02: rac-(3R*,4R*)-4-([5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-3-carboxylic acid methylphenethylamide hydrochloride.

The title compound was prepared according to procedure 2.01 starting from building block 2.02b; LCMS method D: t _R = 0.92 min; [M+H]+ = 469.18.

SE 2.03: (1-pyridin-2-yl-ethyl)-amide hydrochloride rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazol-3-carbonyl]amino}piperidine- 3-carboxylic acid.

2.03b: rac-(3R*,4R*)-4-([5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino }-3-(1-pyridin-2-yl) tert-butyl ester -ethylcarbamoyl)piperidine-1-carboxylic acid.

The title compound was prepared according to procedure 2.01d starting from structural element 2.01c and 1-(2-pyridyl)ethylamine; LCMS method D: t _R =1.01 min; [M+H]+ = 556.13.

2.03: rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-3-carboxylic acid (1-pyridin-2-yl-ethyl)amide hydrochloride .

The title compound was prepared according to procedure 2.01 starting from building block 2.03b; LCMS method D: t _R = 0.77 min; [M+H]+ = 456.09.

SE 2.04: (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)amide hydrochloride.

2.04a: (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

The title compound was prepared by chiral preparative HPLC of rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl] 1-tert-butyl,3-methyl ester amino}piperidine-1,3-dicarboxylic acid using a ChiralPak IC column, 5 µm, 20x250 mm; with a mixture of A (25%Hept) and B (75% EtOH, 0.1% DEA) as eluent and a flow of 34 ml/min. Chiral HPLC: . t _R = 7.3 min.

1-tert-Butyl ester 2.04b: (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-1,3-dicarboxylic acid.

The title compound was prepared according to procedure 2.01c starting from building block 2.04a; LCMS method A: t _R = 0.77 min; [M+H]+ = 452.04.

2.04c: (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)piperidine tert-butyl ester -1-carboxylic acid.

The title compound was prepared according to procedure 2.01d starting from 2.04b and 1-(pyrimidin-2-yl)cyclopropan-1-amine hydrochloride; LCMS method A: t _R =0.94 min; [M+H]+ = 569.19.

2.04: (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)amide hydrochloride.

The title compound was prepared according to procedure 2.01 above, starting from structural element 2.04c; LC-MS method A: t _R = 0.62 min; [M+H]+ = 469.23.

SE 2.05: (3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid dimethylamide hydrochloride.

2.05a: (3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

The title compound was obtained by chiral preparative HPLC of rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazol- 3-carbonyl]amino}piperidine-1,3-dicarboxylic acid using ChiralPak IC column, 5 µm,

20x250mm; with a mixture of A (25% Hept) and B (75% EtOH, 0.1% DEA) as eluent and a flow of 34 ml/min.

Chiral HPLC: . t _R = 5.9 min.

2.05b: (3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-1,3-dicarboxylic acid 1-tert-butyl ester.

The title compound was prepared according to procedure 2.01c starting from building block 2.05a; LCMS method D: t _R = 0.62 min; [M+H]+ = 452.17.

2.05c: (3R,4R-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-3-dimethylcarbamoylpiperidine-1-carboxylic acid tert-butyl ester.

The title compound was prepared according to procedure 2.01 d starting from 2.05b and dimethylamine solution in 2M in THF; LCMS method D: t _R =1.00 min; [M+H]+ = 479.16.

2.05: (3R,4R-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid dimethylamide hydrochloride.

The title compound was prepared according to procedure 2.01 above, starting from structural element 2.05c; LC-MS method D: t _R = 0.75 min; [M+H]+ = 379.15.

SE 2.06: [(R)-1-(1-hydroxypyridin-2-yl)ethyl]amide hydrochloride rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazol-3- carbonyl]amino}piperidine-3-carboxylic acid.

2.06b: rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino }-3-(1-pyridin-2-yl) tert-butyl ester -ethylcarbamoyl)piperidine-1-carboxylic acid.

The title compound was prepared according to procedure 2.01d starting from structural element 2.01c and (R)-1-(pyridin-2-yl)ethanamine; LCMS method A: t _R =0.87 min; [M+H]+ = 556.26.

2.06c: 2-((R)-1-((3R*,4R*)-1-(tert-butoxycarbonyl)-4-(5-(2.4-difluorophenyl)isoxazole-3-carboxamido)piperidine-3 -carboxamido)ethyl)pyridine-1-oxide.

To a solution of 2.06b (90 mg, 0.162 mmol) in DCM (3 mL) at 0°C was added 3-chloroperbenzoic acid (47.2 mg, 0.211 mmol) in portions. The reaction mixture was stirred at RT for 1 h. The mixture was diluted with DCM and washed with aq. sat. _NaHC03 . Org. the phase is dried over MgSO ₄ , filtered and concentrated to give the title compound as a white powder; LCMS method A: t _R =0.96 min; [M+H]+ = 572.28.

2.06: [(R)-1-(1-hydroxypyridin-2-yl)ethyl]amide hydrochloride rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl ]amino} piperidine-3-carboxylic acid.

The title compound was prepared according to procedure 2.01 starting from structural element 2.06c; LCMS method A: t _R = 0.63 min; [M+H]+ = 472.19.

SE 2.07: [1-(1-Oxypyridin-2-yl)cyclopropyl]amide hydrochloride rac-(3R*,4R*)-4-{[5-(2,4difluorophenyl)isoxazol-3-carbonyl]amino}piperidine- 3-carboxylic acid.

2.07b: rac-tert-butyl (3R*,4R*)-4-(5-(2,4-difluorophenyl)isoxazole-3-carboxamido)-3-((1-(pyridin2-yl)cyclopropyl)carbamoyl) piperidine-1-carboxylate.

The title compound was prepared according to procedure 2.01d starting from structural element 2.01c and 1-(pyridin-2-yl)cyclopropan-1-amine; LCMS method A: t _R =0.88 min; [M+H]+ = 568.26.

2.07c: rac-2-((3R*,4R*)-1-(tert-butoxycarbonyl)-4-(5-(2.4-difluorophenyl)isoxazole-3-carboxamido)piperidine-3-carboxamido)cyclopropyl)pyridine 1 -oxide.

The title compound was prepared according to procedure 2.06c starting from building block 2.07b; LCMS method A: t _R =0.91 min; [M+H]+ = 584.27.

2.07: [1-(1-Oxypyridin-2-yl)cyclopropyl]amide hydrochloride (3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazol-3-carbonyl]amino}piperidine-3 -carboxylic acid.

The title compound was prepared according to procedure 2.01 starting from structural element 2.07c; LCMS method A: t _R = 0.63 min; [M+H]+ = 484.19.

SE 2.08: [1-(1-Oxypyridin-2-yl)cyclopropyl]amide hydrochloride (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3- carboxylic acid.

2.08b: tert-butyl (3S,4S)-4-(5-(2,4-difluorophenyl)isoxazole-3-carboxamido)-3-((1-(pyridin-2yl)cyclopropyl)carbamoyl)piperidine-1- carboxylate.

The title compound was prepared according to procedure 2.01d starting from structural element 2.04b and 1-(pyridin-2-yl)cyclopropan-1-amine; LCMS method A: t _R =0.82 min; [M+H]+ = 568.02.

2.08c: 2-(1-((3S,4S)-1-(tert-butoxycarbonyl)-4-(5-(2,4-difluorophenyl)isoxazole-3-carboxamido)piperidine-3-carboxamido)cyclopropyl )pyridine 1-oxide.

The title compound was prepared according to procedure 2.06c starting from building block 2.08b; LCMS method A: t _R =0.87 min; [M+H]+ = 583.99.

2.08: [1-(1-Oxypyridin-2-yl)cyclopropyl]amide (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino} piperidine-3-carboxylic hydrochloride acids.

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The title compound was prepared according to procedure 2.01 starting from structural element 2.08c; LCMS method A: t _R = 0.58 min; [M+H]+ = 484.06.

EC 2.09: Rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid (1-cyano-cyclobutyl)-amide hydrochloride .

2.09b: rac-(3R*,4R*)-3-(1-cyanocyclobutylcarbamoyl)-4-{[5-(2,4difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-1-carboxylic tert-butyl ester acids.

The title compound was prepared according to procedure 2.01d starting from building block 2.01c and 1-aminocyclobutanecarbonitrile; LCMS method A: t _R =1.03 min; [M+H]+ = 550.02.

2.09: rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-3-carboxylic acid (1-cyanocyclobutyl)amide hydrochloride.

The title compound was prepared according to procedure 2.01 starting from building block 2.09b; LCMS method A: t _R = 0.70 min; [M+H]+ = 430.2.

SE 2.10: (3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)amide hydrochloride.

2.10c: (3R,4R)-4-([5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)piperidine tert-butyl ester -1-carboxylic acid.

The title compound was prepared according to procedure 2.01d starting from 2.05b and 1-(pyrimidin-2-yl)cyclopropan-1-amine hydrochloride; LCMS method A: t _R =0.86 min; [M+H]+ = 569.19.

2.10: (1-pyrimidin-2-yl-cyclopropyl)-amide (3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid hydrochloride.

The title compound is prepared according to procedure 2.01 above, starting from building block 2.10c; LC-MS method A: t _R = 0.61 min; [M+H]+ = 469.19.

SE 2.11: (3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid ethylmethylamide hydrochloride.

2.11c: (3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-3-(ethylmethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester.

The title compound was prepared according to method 2.01d starting from 2.05b and N-ethylmethylamine; LC-MS method A: t _R =0.99 min; [M+H]+ = 493.18.

2.11: (3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid ethylmethylamide hydrochloride.

The title compound was prepared according to procedure 2.01 above, starting from building block 2.11c; LC-MS method A: t _R = 0.69 min; [M+H]+ = 393.18.

SE 2.12: (Methyl-(2-pyridin-2-yl-ethyl)-amide hydrochloride 3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acids.

2.12c: (3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-3-[methyl-(2-pyridin-2-yl-) tert-butyl ester ethyl)carbamoyl]piperidine-1-carboxylic acid.

The title compound was prepared according to procedure 2.01d starting from 2.05b and Nmethyl-2-(pyridin-2-yl)ethan-1-amine; LCMS method A: t _R =0.78 min; [M+H]+ = 570.17.

2.12: (3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole3-carbonyl]amino}piperidine-3-carboxylic acid methyl-(2-pyridin-2-yl-ethyl)-amide hydrochloride.

The title compound was prepared according to procedure 2.01 above, starting from building block 2.12c; LC-MS method A: t _R = 0.57 min; [M+H]+ = 470.18.

SE 2.13: (3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-3-carboxylic acid (2-pyridin-2-yl-ethyl)amide hydrochloride.

2.13c: (3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-3-(2-pyridin-2-yl-ethylcarbamoyl)piperidine tert-butyl ester -1-carboxylic acid.

The title compound was prepared according to procedure 2.01d starting from 2.05b and 2(pyridin-2-yl)ethan-1-amine; LCMS method A: t _R =0.76 min; [M+H]+ = 557.15.

2.13: (2-pyridin-2-yl-ethyl)(3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-3-carboxylic acid (2-pyridin-2-yl-ethyl)amide hydrochloride.

The title compound was prepared according to procedure 2.01 above, starting from building block 2.12c; LC-MS method A: t _R = 0.56 min; [M+H]+ = 456.18.

SE 2.14: (1-pyrimidin-2-yl-cyclopropyl)amide (3S,4S)-4-{[5-(2,4-difluorophenyl)-[1,3,4]thiadiazole2-carbonyl]amino}piperidine- 3-carboxylic acid.

2.14a: 1-tert-butyl, 3-ethyl ester (3S,4S)-4-{[5-(2,4-difluorophenyl)[1,3,4]thiadiazole-2-carbonyl]amino}piperidine- 1,3-dicarboxylic acid.

Sodium salt 5-( 2,4difluorophenyl)[1,3,4]thiadiazole-2-carboxylic acid (3.73 g, 14.1 mmol). TEA (7.56 ml, 54.3 mmol) is then added followed by HATU (6.2 g, 16.3 mmol). The reaction mixture was stirred for 1 hour. The reaction mixture was concentrated, diluted with DCM (250 ml) and treated with aq. sat. NaHCO ₃ (250 ml). The organic layer is dried over MgSO ₄ and evaporated. The crude residue was purified by flash chromatography using n-heptane/EtOAc 3:1 as eluent to give 1-tert-butyl, 3-ethyl ester (3R,4S)-4-{[5-(2, 4-Difluorophenyl)[1,3,4]thiadiazole-2-carbonyl]amino}piperidine-1,3-dicarboxylic acid as a white powder. This compound was dissolved in EtOH (40 ml) and EtOAc (20 ml). At the same time, 95% sodium ethoxide powder (3.44 g, 48 mmol) was added and the resulting mixture was stirred under argon at RT for 4 days. The reaction mixture was quenched with a sat. aq. NH ₄ Cl (100 ml) and extracted three times with DCM (3 x 100 ml). The combined organic extracts are dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product is purified by prep-LC-MS, under basic conditions (method E), followed by chiral preparative SLC to remove traces of the [R,R]-isomer (Column: Regis (R,R) WhelkO1, 30x250 mm, 5 µm or ChiralPak IC, 30x250 mm, 5 µm, eluent: mixture of A (65% CO ₂ ) and B (35% DCM/EtOH/DEA 50:50:0.1), flow 160 ml/min, t _R = 1.18 min). The title product is obtained as a white powder; LCMS method A: t _R = 1.07 min; [M+H]+ = 496.96.

2.14b: (3S,4S)-4-{[5-(2,4-difluorophenyl)1,3,4-thiadiazole-2-carbonyl]amino}piperidine-1,3-dicarboxylic acid, 1-tert-butyl ester acids.

The title compound is prepared by treating (3S,4S)-4-{[5-(2,4-difluorophenyl)-[1,3,4]thiadiazole-2-carbonyl]amino, 1-tert-butyl, 3-ethyl ester }piperidine-1,3dicarboxylic acid with sodium hydroxide followed by HCl according to procedure 2.01c; LC-MS method A: t _R = 0.94 min; [M+H]+ = 468.88.

2.14c: (3S,4S)-4-{[5-(2,4-difluorophenyl)-[1,3,4]thiadiazole-2carbonyl]amino }-3-(1-pyrimidine-2) tert-butyl ester -yl-cyclopropylcarbamoyl)piperidine-1-carboxylic acid.

The title compound was prepared according to procedure 2.01d starting from 2.14b and 1-(pyrimidin-2-yl)cyclopropan-1-amine hydrochloride; LCMS method D: t _R =0.94 min; [M+H]+ = 585.34.

2.14: (1-pyrimidin-2-yl-cyclopropyl)amide (3S,4S)-4-{[5-(2,4-difluorophenyl)-[1,3,4]thiadiazole-2carbonyl]amino}piperidine-3 -carboxylic acid.

The title compound was prepared according to procedure 2.01 above, starting from building block 2.14c; LC-MS method A: t _R = 0.67 min; [M+H]+ = 486.24.

General procedures for obtaining examples 2.001-2.109.

Method D

A commercially available aldehyde or ketone (0.12–1 mmol) is added to a solution of the corresponding amine (SE 2.01–SE 2.14) (0.1 mmol) in DCM (mL), followed by the addition of sodium triacetoxyborohydride (0.13–0.4 mmol).

The reaction mixture is stirred overnight at RT. The reaction mixture was then diluted with DCM or chloroform (3 ml) and treated with aq. sat. NaHCO3 (2 ml). The organic phase is dried over Na2SO4, filtered and the solvent is evaporated. The crude residue is purified with prep. LC-MS using method E.

Method E.

To a solution of the corresponding amine (SE 2.01-SE 2.14) (0.1 mmol) in DMF (ml) is added a commercially available aldehyde or ketone (0.2-1 mmol) followed by the addition of sodium triacetoxyborohydride (0.23 mmol). The reaction mixture is stirred overnight at RT. Add 150 µl of water and the product is purified using prep. LC-MS using method E.

Method F

Commercially available ketone (0.6 mmol) and titanium(IV) isopropoxide (1 mmol) are added to the corresponding amine (SE 2.01-SE 2.14) (0.5 mmol) and stirred in an argon atmosphere at 80°C for 4.5 h. Methanol ( 1.18 ml) followed by the addition of sodium borohydride (1.5 mmol) in one portion. The reaction mixture was stirred at RT for 1 h. Water (1.2 ml) was added. The resulting suspension is filtered, washed with 9 ml DCM/MeOH 3/1 and the solvents are evaporated. The crude residue is purified with prep. LC-MS using method E.

Method G

The corresponding amine (SE 2.01-SE 2.14) (0.1 mmol) is dissolved in water (0.7 ml). Add DIPEA (0.3 mmol) followed by the addition of commercially available epoxide (0.4 mmol). The reaction mixture was stirred at 100° C. for 17 hours. The solvent was evaporated and the crude mixture was dissolved in ml of MeOH/DMF and purified with prep. LC-MS using method E.

Method N.

Commercially available alkyl bromide (0.11 mmol) is added to an ice-cold solution of the corresponding amine (SE 2.01-SE 2.14) (0.1 mmol) and K ₂ CO ₃ (0.2 mmol) in acetone (5 ml). The mixture is stirred for 18 hours at RT. Add another equivalent of alkyl bromide and the mixture is stirred for 18 h at 50°C. The reaction mixture is filtered and the solvent is evaporated under reduced pressure. The residue is purified with prep. HPLC using method E.

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Example 2.001 rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-1isopropylpiperidine-3-carboxylic acid dimethylamide.

To a solution of rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid dimethylamide (SE 2.01) (41.5 mg, 0.1 mmol ) in DCM (0.5 mL) was added acetone (27.8 mg, 0.036 mL, 0.48 mmol) followed by sodium triacetoxyborohydride (61 mg, 0.27 mmol). The reaction mixture is stirred overnight at RT. The reaction mixture was then diluted with chloroform (3 ml) and treated with aq. sat. NaHCO ₃ (2 ml). The organic phase is dried over Na ₂ SO ₄ , filtered and the solvent is evaporated. The crude residue is purified with prep. LC-MS using method E. LC-MS QC method: t _R = 0.56 min; [M+H]+ = 421.1.

Compounds of examples 2.001-2.108 listed in Table 2 below are prepared by applying one of the above general procedures D, E, F, g, or H to building blocks SE-2.01-SE-2.14 or SE-8.01-SE-8.02 in in combination with commercially available aldehydes, ketones, alkyl halides or epoxides.

Enantiomerically pure compounds are obtained using one of the above methods of preparative chiral chromatography.

Table 2. Reference examples 2.001-2.104, 2.107-2.108 and examples 2.105-2.106

Reference Example/ Example No. Substance name QC LC-MS t _R (min) Detected mass [M+H] ⁺ 2.001 dimethylamide paH-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)isoxazol-3-carbonyl]-amino}-1-isopropyl-piperidine-3-carboxylic acid 0.56 421.1 2.002 paH-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)isoxazol-3-carbonyl]-amino}-1-ethyl-piperidine-3-carboxylic acid dimethylamide 0.54 407.3 2.003 paH-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)-isoxazol-3-carbonyl]-amino }-1-isopropylpiperidine-3-carboxylic acid methylphenethylamide 0.75 511 2.004 methylphenethylamide paH-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)-isoxazol-3-carbonyl]-amino } -1 -ethyl-piperidine-3 - carboxylic acid 0.73 497.3 2.005 rac-(3K*,4K*)-1-cyclopentyl-4-{[5-(2,4difluoro-phenyl)isoxazole-3-carbonyl]-amino}-piperidine3-carboxylic acid methylphenethylamide 0.78 537.4

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2.006 paii-(3R*,4R*)-l-cyclopropylmethyl-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3-carboxylic acid methylphenethylamide 0.77 523.3 2.007 (3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl] amino}-1-isopropyl-piperidine-3-carboxylic acid ((1 RS)-1-pyridin-2-yl-ethyl)-amide (mixture of isomers) 0.57 498 2.008 ((1 RS)-1-pyridin-2-yl-ethyl)-amide (3R*,4R*)-4-{[5-(2,4difluoro-phenyl)-isoxazol-3-carbonyl]-amino } -1-ethylpiperidine-3-carboxylic acid (mixture of isomers) 0.55 484.1 2.009 ((1 RS)-1-pyridin-2-yl-ethyl)-amide (3R*,4R*)-1cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.59 524.5 2.010 ((1 RS)-1-pyridin-2-yl-ethyl)-amide (3R*,4R*)-1- cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.58 510.1 2.011 [(R)-l-(l-hydroxy-pyridin-2-yl)-ethyl]-amide (3R*,4R*)-1cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole -3carbonyl]-amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.55 525.9 2.013 dimethylamide (3R*,4R*)-l-(( 1RS)-1 -cyclopropyl-ethyl)-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}piperidine-3 -carboxylic acid (mixture of isomers) 0.61 447.3 2.014 dimethylamide (3R*,4R*)-4-{[5-(2,4-diφτop-φenyl)isoxazole-3-carbonyl]-amino}-1-((lRS,2RS)-2hydroxymethyl-cyclopentyl)-piperidine- 3-carboxylic acid (mixture of isomers) 0.58 477.3 2.015 dimethylamide (3R*,4R*)-4-{[5-(2,4-diφτop-φenyl)isoxazole-3-carbonyl]-amino}-1-((lRS,2RS)-2-3Tnncyclopentyl)-piperidine- 3-carboxylic acid (mixture of isomers) 0.68 475.3 2.016 dimethylamide (ЗR*,4R*)-4-{[5-(2,4-diφτop-φenyl)isoxazole-3-carbonyl]-amino}-1-((lRS,2RS)-2-MeTnncyclobutyl)-piperidine- 3-carboxylic acid (mixture of isomers) 0.61 447.3 2.016a dimethylamide (3R,4R)-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino }-1 -((IRS,2RS)-2-MeTHn-UHKno6yTnn)piperidine-3- carboxylic acid, mixture of isomers 1 0.61 447.3 2.016b dimethylamide (3R,4R)-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino }-1 -((IRS,2RS)-2-MeTHn-UHKno6yTnn)piperidine-3- carboxylic acid, mixture of isomers 2 0.6 447.3 2.017 dimethylamide (ЗR*,4R*)-4-{[5-(2,4-diφτop-φenyl)isoxazole-3-carbonyl]-amino}-(IRS)-1-(2,2-dimethylcyclobutyl)-piperidine- 3-carboxylic acid (mixture of isomers) 0.65 461.1 2.018 dimethylamide (ЗR*,4R*)-4-{[5-(2,4-diφτop-φenyl)isoxazol-3-carbonyl]-amino} -1-((lRS)-3,3-dimethylcyclopentyl)-piperidine -3-carboxylic acid (mixture of isomers) 0.67 475.3 2.019 pau-(3R*,4R*)-l-uHKnoneHTnn-4-{[5-(2,4difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine3-carboxylic acid dimethylamide 0.59 447.3

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2.019a (3K,4K)-1-cyclopentyl-4-{[5-(2,4-difluorophenyl)-isoxazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide or (3S,4S)-1cyclopentyl dimethylamide -4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }-piperidine-3-carboxylic acid (first eluting enantiomer) 0.59 447.3 2.020 dimethylamide pan-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)isoxazole-3-carbonyl]-amino}-1-(2,2-dimethyl-propyl)- piperidine-3-carboxylic acid 0.65 449.1 2.021 dimethylamide pan-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)isoxazol-3-carbonyl]-amino } -1 -(3-methyl-butyl)piperidine-3- carboxylic acid 0.64 449 2.022 dimethylamide pan-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)isoxazol-3-carbonyl]-amino } -1 -(3,3-dimethyl-butyl)piperidine- 3-carboxylic acid 0.68 463.4 2.023 dimethylamide (3R*,4R*)-4-{[5-(2,4-diφτop-φenyl)isoxazole-3-carbonyl]-amino}-1-((lRS,2RS)-2-MeTnncyclopentyl)-piperidine- 3-carboxylic acid (mixture of isomers) 0.63 461.3 2.023a dimethylamide (3R,4R)-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino }-1 -((IRS,RS)-2-MeTHn-nHKnoneHTHn)piperidine-3- carboxylic acid, mixture of isomers 1 0.63 461.3 2.023b dimethylamide (3R,4R)-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino }-1 -((IRS,RS)-2-MeTHn-nHKnoneHTHn)piperidine-3- carboxylic acid, mixture of isomers 2 0.63 461.3 2.024 dimethylamide (ЗR*,4R*)-4-{[5-(2,4-diφτop-φenyl)isoxazol-3-carbonyl]-amino}-l-((lRS)-3,3-dimethylcyclohexyl)-piperidine -3-carboxylic acid (mixture of isomers) 0.72 489.3 2.025 dimethylamide pap-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)isoxazol-3-carbonyl]-amino }-1-spiro [3.3] hept-2-ylpiperidin-3 -carboxylic acid 0.66 473.3 2.026 dimethylamide (ЗR*,4R*)-4-{[5-(2,4-diφτop-φenyl)isoxazole-3-carbonyl]-amino}-1 -((lRS,4RS)-4-φτopcyclohexyl)-piperidine- 3-carboxylic acid (mixture of isomers) 0.61 479.3 2.027 dimethylamide pan-(3R*,4R*)-l -(4,4-difluoro-cyclohexyl)-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3 -carboxylic acid 0.63 497.3 2.028 pan-(3R*,4R*)-l-nHKno6yTnn-4-{[5-(2,4difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine3-carboxylic acid dimethylamide 0.56 433.4 2.029 pan-(3R*,4R*)-l-nHKnonnnMeTHn-4-{[5(2,4-difluorophenyl)-isoxazole-3-carbonyl]-amino }piperidine-3-carboxylic acid dimethylamide 0.58 433 2.030 pan-(3R*,4R*)-l-nHKnoneHTHnMeTnn-4-{[5(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3-carboxylic acid dimethylamide 0.66 461.3 2.031 dimethylamide pan-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)isoxazol-3-carbonyl]-amino } -1 -(3,3-dimethyl-cyclobutyl)- piperidine-3-carboxylic acid 0.64 461.3 2.032 dimethylamide (3R*,4R*)-4-{[5-(2,4-diφτop-φenyl)isoxazole-3-carbonyl]-amino}-1-((lRS,3RS)-3-methoxycyclohexyl)-piperidine- 3-carboxylic acid (mixture of isomers) 0.67 491

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2.033 dimethylamide (3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)isoxazole-3-carbonyl]-amino}-1-((1RS,2RS)-2-moto xycyclohexyl)-piperidine -3-carboxylic acid (mixture of isomers) 0.67 491 2.034 dimethylamide pap-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)isoxazol-3-carbonyl]-amino } -1 -(1 -methyl- cyclopropylmethyl)-piperidine-3-carboxylic acid 0.63 447.3 2.035 dimethylamide pau-(3R*,4R*)-4-{[5-(2,4-difluoro-phenyl)isoxazol-3-carbonyl]-amino } -1 -(1 -methyl- cyclobutylmethyl)-piperidine-3-carboxylic acid 0.67 461 2.036 pau-(3R*,4R*)-1-cyclopent-1-enylmethyl-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }-piperidine-3-carboxylic acid dimethylamide 0.66 459.1 2.037 dimethylamide (3R*,4R*)-(1RS,2RS,4RS)-1- Bicyclo[2.2.1]hept-2-yl-4-{[5-(2,4-difluoro-phenyl)isoxazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.64 473.3 2.038 pau-(3R*.4R*)-l-cyclobutylmstil-4-[[5-(2,4difluoro-phenyl)isoxazole-3-carbonyl]-amino}-piperidine3-carboxylic acid dimethylamide 0.62 447.3 2.039 pau dimethylamide acids 0.62 447.1 2.040 dimethylamide (ЗR*,4R*)-4-{[5-(2,4-diφτop-φenyl)isoxazole-3-carbonyl]-amino}-1 -((lRS,2RS)-2-φτopcyclohexyl)-piperidine- 3-carboxylic acid (mixture of isomers) 0.63 479.3 2.045 (3R,4R)-l-nHKnonponnnMeTHn-4-{[5-(2,4difluorophenyl)isoxazole-3-carbonyl]-amino}-piperidine3-carboxylic acid dimethylamide 0.58 433.3 2.046 dimethylamide (3R,4R)-l-((lRS)-l-UHKnonponHn-3THn)-4-{[5(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3-carboxylic acids (mixture of isomers) 0.62 447.3 2.047 dimethylamide (3R,4R)-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino }-(1RS)-1-spiro [2.4] hept-4-ylpiperidin-3-carboxylic acid acids (mixture of isomers) 0.68 473 2.048 dimethylamide (3R*,4R*)-4-{[5-(2,4-diφτop-φenyl)isoxazole-3-carbonyl]-amino}-1-((1RS, 2RS)-2-hydroκcicyclohexyl)-piperidine- 3-carboxylic acid (mixture of isomers) 0.61 477.3 2.049 dimethylamide (ЗR*,4R*)-4-{[5-(2,4-diφτop-φenyl)isoxazole-3-carbonyl]-amino}-1-((lRS,2RS)-2-hydroκci-l-methyl- propyl)-piperidine-3-carboxylic acid (mixture of isomers) 0.56 451 2.050 methylphenethylamide (ЗR*,4R*)-4-{[5-(2,4-diφτop-φenyl)isoxazole-3-carbonyl]-amino}-1-((1RS, 2RS)-2-hydroκcicyclohexyl)-piperidine- 3-carboxylic acid (mixture of isomers) 0.79 567.4 2.051 methylphenethylamide (3R*,4R*)-4-{[5-(2,4-diφτop-φenyl)isoxazole-3-carbonyl]-amino }-1 -((lRS,2RS)-2-hydroκci-l methyl- propyl)-piperidine-3-carboxylic acid (mixture of isomers) 0.75 541 2.052 pau-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)-isoxazole-3-carbonyl]-amino}-1-(2-hydroxyethyl)piperidine-3-carboxylic acid methylphenethylamide 0.72 513

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2.053 ((SH8)-1-pyridin-2-yl-ethyl)-amide (3R*,4R*)-4-{[5-(2,4difluoro-phenyl)-isoxazol-3-carbonyl]-amino} - 1 - ((1RS, 2RS)-2-hydroxy-cyclohexyl)-piperidine-3 carboxylic acid (mixture of isomers) 0.59 554.2 2.054 ((1 RS)-1-pyridin-2-yl-ethyl)-amide (3R*,4R*)-4-{[5-(2,4difluoro-phenyl)-isoxazol-3-carbonyl]-amino } -1 - ((lRS,2RS)-2-hydroxy-l-methyl-propyl)-piperidine-3carboxylic acid (mixture of isomers) 0.57 528 2.055 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{ [5-(2,4difluoro-phenyl)-isoxazol-3-carbonyl]-amino }-1 -(2methoxy-ethyl) -piperidine-3-carboxylic acid 0.6 527.1 2.056 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{ [5-(2,4difluoro-phenyl)-isoxazol-3-carbonyl]-amino } -1-ethylpiperidine-3- carboxylic acid 0.58 497 2.057 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{ [5-(2,4difluoro-phenyl)-isoxazol-3-carbonyl]-amino } -1 -((1, 1,2,2,2 b75-ethyl)-piperidine)-3-carboxylic acid 0.58 502.2 2.058 (SE 2.02) paii-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)-isoxazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid methylphenethylamide 0.71 469 2.059 (SE 2.04) (3S,4S)-4-{[5-(2,4difluoro-phenyl)-isoxazol-3-carbonyl]-amino }-piperidine3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 0.58 469.27 2.060 (1-pyrimidin-2-yl-cyclopropyl)-amide (3R*,4R*)-4-{[5(2,4-difluoro-phenyl)-isoxazol-3-carbonyl]-amino } -1 (( 1RS,2RS)-2-hydroxy-cyclohexyl)-piperidine-3carboxylic acid (mixture of stereoisomers) 0.60 567 2.061 [ 1 - (1 -oxy-pyridin-2-yl) -cyclopropyl] -amide rac (ЗR*,4R*) -l-cyclopropylmethyl-4-{[5- (2,4-diφτop-φenyl)isoxazol- 3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.60 538.4 2.062 [ 1 - (1 -oxy-pyridin-2-yl) -cyclopropyl] -amide rac (ЗR*,4R*) -l-cyclopentyl-4-{[5- (2,4-diφτop-φenyl)isoxazol- 3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.65 552.2 2.062a [1-(1-hydroxy-pyridin-2-yl)-cyclopropyl]-amide (3R*,4R*)-1cyclopentyl-4-{ [5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl] - amino }-piperidine-3-carboxylic acid (enantiomer 1) 0.65 552.2 2.062b [1-(1-hydroxy-pyridin-2-yl)-cyclopropyl]-amide (3R*,4R*)-1cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl] - amino }-piperidine-3-carboxylic acid (enantiomer 2) 0.65 552.17 2.063 [ 1 -(1-hydroxy-pyridin-2-yl)-cyclopropyl]-amide (3S,4S)-1-cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid 0.60 538.4 2.064 (1-cyano-cyclobutyl)-amide pau-(3R*,4R*)-1-cyclopentyl4-{ [5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}piperidine-3- carboxylic acid 0.60 498 2.065 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1- cyclopentylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino}-piperidine-3-carboxylic acid 0.70 551 2.066 (1-pyrimidin-2-yl-cyclopropyl)-amide (3R,4R)-1cyclopentyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino }-piperidine-3-carboxylic acid acids 0.60 537.1

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2.067 (1-pyrimidin-2-yl-cyclopropyl)-amide (3 S,4S)-1 -(1 difluoromethyl-cyclopropylmethyl)-4-{[5-(2,4-difluorophenyl)-isoxazol-3-carbonyl] -amino}-piperidine-3 carboxylic acid 0.60 573 2.068 (1-pyrimidin-2-yl-cyclopropyl)-amide (3 S, 4 S)-4-{ [5-(2,4difluoro-phenyl)-isoxazol-3-carbonyl]-amino }-1 -(4- fluorobenzyl)-piperidine-3-carboxylic acid 0.70 577 2.069 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{ [5-(2,4difluoro-phenyl)-isoxazol-3-carbonyl]-amino }-1 -(2,2dimethyl- propyl)-piperidine-3-carboxylic acid 0.70 539.1 2.070 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{ [5-(2,4difluoro-phenyl)-isoxazol-3-carbonyl]-amino } -1-isobutylpiperidine-3- carboxylic acid 0.60 525.2 2.071 (1-pyrimidin-2-yl-cyclopropyl)-amide (38.48)-1-benzyl-4{[5-(2,4-difluoro-phenyl)-isoxazol-3-carbonyl]-amino}piperidine-3 -carboxylic acid 0.70 559.1 2.072 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclobutylmethyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino }-piperidine-3-carboxylic acid acids 0.60 537.4 2.073 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{ [5-(2,4difluoro-phenyl)-isoxazol-3-carbonyl]-amino } -1-isopropylpiperidine-3- carboxylic acid 0.60 511.2 2.074 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclobutyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino }-piperidine-3-carboxylic acid acids 0.60 523.1 2.075 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopropyl-4-{[5-(2,4-difluoro-phenyl)-isoxazol-3carbonyl]-amino }-piperidine-3-carboxylic acid acids 0.60 509.1 2.076 ethylmethylamide (3K,4K)-1-cyclopentyl-4-{[5-(2,4-difluorophenyl)-isoxazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.60 461.3 2.077 ethylmethylamide (3 R, 4R) -1-cyclopropylmethyl l-4 - {[5 - (2,4 difluoro-phenyl)-isoxazole-3-carbonyl] -amino}-piperidine3-carboxylic acid 0.60 447 2.078 methyl-(2-pyridin-2-yl-ethyl)-amide (3R,4R)-l-uHKnoneHTnn4-{ [5 -(2,4-difluoro-phenyl)-isoxazol-3-carbonyl]-amino }piperidine- 3-carboxylic acid 0.50 538.1 2.079 methyl-(2-pyridin-2-yl-ethyl)-amide (3R,4R)-1- cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino}-piperidine-3-carboxylic acid 0.50 524 2.080 (2-pyridin-2-yl-ethyl)-amide (3R,4R)-l-uHKnonponnnMeTHn4-{ [5-(2,4-difluoro-phenyl)-isoxazol-3-carbonyl]-amino }piperidine-3- carboxylic acid 0.50 510.2 2.081 (ЗR,4R)-l-benzyl-4-{[5-(2,4-diφτop-φenyl)isoxazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 0.70 469.3 2.082 dimethylamide (3R,4R)-l-(2-xnop-6eH3nn)-4-{[5-(2,4-difluorophenyl)-isoxazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.70 503.3 2.083 (3R,4R)-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino }-1-(2-fluoro-benzyl)-piperidine-3-carboxylic acid dimethylamide 0.70 487.3 2.084 (1-pyrimidin-2-yl-cyclopropyl)-amide (3 S,48)-1-(( 1RS)2,2-difluoro-cyclopropylmethyl)-4-{[5-(2,4-difluoro-phenyl) isoxazo l-3-carbonyl]-amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.60 559.1

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2.085 dimethylamide (3R,4R)-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino}-1-(1-methyl-1H-pyrro l-3-ylmethyl)piperidine-3 -carboxylic acid 0.60 472.4 2.086 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{ [5-(2,4difluoro-phenyl)-isoxazol-3-carbonyl]-amino } -1-methylpiperidine-3- carboxylic acid 0.60 483.4 2.087 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{ [5-(2,4difluoro-phenyl)-isoxazol-3-carbonyl]-amino } -1 -(3-fluoropropyl )-piperidine-3-carboxylic acid 0.60 529 2.088 (1-pyrimidin-2-yl-cyclopropyl)-amide -3-carboxylic acid 0.60 523 2.089 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1-(3,3difluoro-cyclobutyl)-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3- carbonyl]-amino }-piperidine-3-carboxylic acid 0.7 559 2.090 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{ [5-(2,4difluoro-phenyl)-isoxazol-3-carbonyl]-amino } -1 -(1-methylcyclopropylmethyl )-piperidine-3-carboxylic acid 0.6 537.1 2.091 (1-pyridin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H[1,2,3]triazole-4-carbonyl ]-amino }-piperidine-3 carboxylic acid 0.5 522 2.092 (1-pyridin-2-yl-cyclopropyl)-amide (3 S,4 S)-1 cyclopentyl-4-{[ 1-(2,4-difluoro-phenyl)-1H-[ 1,2,3]triazole -4carbonyl]-amino }-piperidine-3-carboxylic acid 0.5 536.2 2.093 (1-pyrimidin-2-yl-cyclopropyl)-amide (38.48)-1-allyl-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}piperidine-3 -carboxylic acid 0.6 509.2 2.094 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1Bicyclo[3.1.0]hex-3-yl-4-{[5-(2,4-difluorophenyl)isoxazol-3 -carbonyl]-amino}-piperidine-3-carboxylic acid 0.6 549.2 2.095 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{ [5-(2,4difluoro-phenyl)-isoxazol-3-carbonyl]-amino } -1-propylpiperidine-3- carboxylic acid 0.5 511.2 2.096 (SE 8.02) (1-pyrimidin-2-yl-cyclopropyl)-(3S,4S)-4-{[5-(2,4difluoro-phenyl)-oxazol-2-carbonyl]-amino }-piperidine-3 carboxylic acid amide 0.6 469 2.097 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1- cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-oxazol-2-carbonyl]amino}-piperidine-3-carboxylic acid 0.6 523.1 2.098 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-oxazol-2carbonyl]-amino }-piperidine-3-carboxylic acids 0.6 537.1 2.099 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{ [5-(2,4difluoro-phenyl)-oxazol-2-carbonyl]-amino } -1-isopropylpiperidine-3-carboxylic acids 0.6 511.4 2.100 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{ [5-(2,4difluoro-phenyl)-oxazol-2-carbonyl]-amino }-1 -(1-fluorocyclopropylmethyl) -piperidine-3-carboxylic acid 0.6 541.3 2.101 (1-pyrimidin-2-yl-cyclopropyl)-amide (3 S,48)-1-(3,3 difluoro-cyclobutylmethyl)-4-{[5-(2,4-difluoro-phenyl)isoxazol-3 -carbonyl]-amino}-piperidine-3-carboxylic acid 0.6 573 2.102 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{ [5-(2,4difluoro-phenyl)-isoxazol-3-carbonyl]-amino } -1-thietan-3 yl -piperidine-3-carboxylic acid 0.6 541 2.103 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{[5-(2,4difluoro-phenyl)-isoxazol-3-carbonyl]-amino }-1spiro [2.3] hexa- 5-yl-piperidine-3-carboxylic acid 0.6 549 2.104 (SE 2.14) (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{[5-(2,4difluoro-phenyl)- [1,3,4]thiadiazol-2-carbonyl]-amino } piperidine-3-carboxylic acid 1.0 486.4 2.105 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-[1,3,4]thiadiazole-2carbonyl]-amino }-piperidine-3-carboxylic acid 0.6 540.1 2.106 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{[5-(2,4difluoro-phenyl)- [1,3,4]thiadiazol-2-carbonyl]-amino } -1 -(1 Fluoro-cyclopropylmethyl)-piperidine-3-carboxylic acid 0.6 558.1 2.107 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{[5-(2,4difluoro-phenyl)- [1,3,4]thiadiazol-2-carbonyl]-amino } -1 ethyl-piperidine-3-carboxylic acid 0.6 514.1 2.108 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1(cyclopropyl-(b7 ₂ - ^methyl ))-4-{[5-(2,4-difluoro-phenyl)isoxazol- 3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.6 525.3

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General method C for the synthesis of compounds of formula (I) or (ID).

structural elements.

Obtaining the structural elements of the C-3 structure

NH, O

Г <+r3 ^{R 4} it

R ² C-3

SE 3.01: rac-(3R*,4R*)-4-amino-1-cyclohexylpiperidine-3-carboxylic acid dimethylamide.

3.01a: rac-(3R*,4R*)-4-tert-butoxycarbonylamino-1-cyclohexylpiperidine-3-carboxylic acid.

1 rac-(3R*,4R*)-4-tert-butoxycarbonylamino-1-cyclohexyl-piperidine-3-carboxylic acid methyl ester 1.01a (2.85 g, 7.35 mmol) was dissolved in THF (45 ml) at RT. Then add aq. 1M NaOH solution (22.1 ml, 22.1 mmol) and the mixture was stirred at RT for 72 h. The reaction mixture was acidified to approximately pH = 3 with 2M HCl solution (12 ml) and evaporated. The resulting suspension is dissolved in DCM, the organic phase is dried over MgSO ₄ and the solvents are evaporated to give the title compound; LC-MS method D t _R = 0.54 min; [M+H]+ = 327.23.

3.01b: rac-((3R*,4R*)-1-cyclohexyl-3-dimethylcarbamoyl-piperidin-4-yl)-carbamic acid tert-butyl ester.

To a solution of rac-(3R*,4R*)-4-tert-butoxycarbonylamino-1-cyclohexyl-piperidine-3-carboxylic acid 3.01a (2.4 g, 7.35 mmol) in DMF (36.8 ml) was added a 40% solution of dimethylamine in water (2.79 ml, 22.1 mmol). DIPEA (4.11 ml, 23.5 mmol) is then added followed by HATU (2.93 g, 7.72 mmol). The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated, dissolved in DCM (150 ml) and treated with aq. sat. NaHCO ₃ (150 ml). The organic layer is separated and aq. the phase is further extracted with DCM (3x150 ml). The combined organic phases are dried over MgSO ₄ and evaporated. The crude residue is purified with prep. LC-MS under basic conditions (method E). The title compound is obtained; LC-MS method D t _R = 0.91 min; [M+H]+ = 353.96.

3.01: rac-(3R*,4R*)-4-Amino-1-cyclohexylpiperidine-3-carboxylic acid dimethylamide rac-((3R*,4R*)-1-cyclohexyl-3-dimethylcarbamoyl-piperidine tert-butyl ester -4-yl)carbamic acid (2.08 g, 5.88 mmol) was dissolved in MeOH (29.5 ml) at RT. A solution of 4M HCl in dioxane (29.5 ml, 118 mmol) was added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated, dissolved in DCM (150 ml) and treated with aq. sat. NaHCO3 (50 ml). The organic layer is separated and aq. the phase is extracted twice with DCM (2 x 100 ml) and twice with chloroform (2 x 100 ml). The combined organic phases are dried over MgSO ₄ , filtered and the solvent is evaporated to give the crude title compound; LC-MS method D t _R = 0.68 min; [M+H]+ = 254.24.

Preparation of structural elements of general formula (C-3) used as intermediates in the preparation of examples 3.001-3.022.

The following intermediate compounds are obtained by analogy with SE 3.01.

SE 3.02: Rac-(3R*,4R*)-4-amino-1-cyclohexylpiperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)-amide dihydrochloride.

3.02b: rac-[(3R*,4R*)-1-cyclohexyl-3-(1-pyridin-2-yl-cyclopropylcarbamoyl)piperidin-4-yl]-carbamic acid tert-butyl ester.

The title compound was prepared according to procedure 3.01b, starting from building block 3.01a and 1-(2-pyridyl)cyclopropylamine dihydrochloride; LCMS method D: t _R =0.97 min; [M+H]+ = 443.21.

3.02: rac-(3R*,4R*)-4-amino-1-cyclohexylpiperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)amide dihydrochloride.

The title compound was prepared according to procedure 3.01 starting from building block 3.02b; LCMS method D: t _R = 0.77 min; [M+H]+ = 343.17.

SE 3.03: rac-(3R*,4R*)-4-amino-1-cyclopentylpiperidine-3-carboxylic acid dimethylamide.

3.03a: rac-(3R*,4R*)-4-tert-butoxycarbonylamino-1-cyclopentylpiperidine-3-carboxylic acid.

The title compound was prepared according to procedure 3.01a starting from building block 1.03a; LC-MS method D: t _R = 0.51 min; [M+H]+ = 313.08.

3.03b: rac-((3R*,4R*)-1-cyclopentyl-3-dimethylcarbamoylpiperidin-4-yl)carbamic acid tert-butyl ester.

The title compound was prepared according to procedure 3.01b starting from building block 3.03a and 40% dimethylamine in water; LCMS method D: t _R =0.82 min; [M+H]+ =

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340.16.

3.02: rac-(3R*,4R*)-4-amino-1-cyclopentylpiperidine-3-carboxylic acid dimethylamide.

The title compound is prepared according to procedure 3.01 starting from building block 3.03b; LCMS method D: t _R = 0.59 min; [M+H]+ = 240.18.

SE 3.04: Rac-(3R*,4R*)-4-amino-1-cyclopropylmethylpiperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)-amide dihydrochloride.

3.04a: rac-(3R*,4R*)-4-tert-butoxycarbonylamino-1-cyclopropylmethylpiperidine-3-carboxylic acid.

The title compound was prepared according to procedure 3.01a starting from building block 1.04a; LCMS method D: t _R = 0.47 min; [M+H]+ = 299.13.

3.04b: rac-[(3R*,4R*)-1-cyclopropylmethyl-3-(1-pyridin-2-ylcyclopropylcarbamoyl)piperidin-4-yl]-carbamic acid tert-butyl ester.

The title compound was prepared according to procedure 3.01b, starting from building block 3.04a and 1-(2-pyridyl)cyclopropylamine dihydrochloride; LCMS method D: t _R =0.85 min; [M+H]+ = 415.17.

3.04 rac-(3R*,4R*)-4-amino-1-cyclopropylmethylpiperidine-3-carboxylic acid (1-pyridin-2-yl-cyclopropyl)amide dihydrochloride.

The title compound is prepared according to procedure 3.01 starting from building block 3.04b; LCMS method D: t _R = 0.64 min; [M+H]+ = 315.18.

SE 3.05: Rac-(3R*,4R*)-4-amino-1-cyclopropylmethylpiperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide dihydrochloride.

3.05b: rac-[(3R*,4R*)-1-cyclopropylmethyl-3-(1-pyrimidin-2-ylcyclopropylcarbamoyl)piperidin-4-yl]carbamic acid tert-butyl ester.

The title compound was prepared according to procedure 3.01b starting from structural element 3.04a and 1-(2-pyrimidyl)cyclopropylamine hydrochloride; LCMS method A: t _R =0.64 min; [M+H]+ = 416.34.

3.05: rac-(3R*,4R*)-4-amino-1-cyclopropylmethylpiperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)amide dihydrochloride.

The title compound is prepared according to procedure 3.01 starting from building block 3.04b; LC-MS method A: t _R = 0.38 min; [M+H]+ = 316.34.

General procedures for the preparation of compounds 3.001-3.022.

Method I

To a solution of the corresponding amine (SE 3.01-SE 3.05) (0.08 mmol) in 0.7 ml of DMF is added the corresponding carboxylic acid (commercially available or structures A-4) (0.08 mmol). DIPEA (0.336 mmol) is then added followed by HATU (0.084 mmol). The reaction mixture is stirred for 21 hours at RT. Up to 0.28 mmol of 2M HCl solution is added to the crude mixture to dissolve the precipitate, and the clear solution is directly purified with prep. LC-MS using method E.

Method J

A solution of the corresponding amine (SE 3.01-SE 3.05) (0.3 mmol) in toluene (0.4 ml) at 0°C in an argon atmosphere is treated with a 2M solution of trimethylaluminum in toluene (0.3 mmol). After stirring for 30 min at 0°C, a solution of an ester of structure A-4 (L1=O-alkyl) (0.1 mmol) in toluene (0.4 ml) was added and the mixture was stirred at RT for 4-22 h. quench with 1.25 M HCl solution in methanol (0.6 mmol) and the solvents are evaporated. The crude residue is purified with prep. LC-MS using method E.

Example 3.001. Rac-(3R*,4R*)-1-cyclohexyl-4-{[5-(2,6-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-3-carboxylic acid dimethylamide.

5-(2,6-Difluorophenyl)isoxazole- 3-carboxylic acid (18 mg, 0.08 mmol). DIPEA (0.044 ml, 0.256 mmol) is then added followed by HATU (31.9 mg, 0.084 mmol). The reaction mixture is stirred for 21 hours at RT. Up to 0.28 mmol of 2M HCl solution is added to the crude mixture to dissolve the precipitate, and the clear solution is directly purified with prep. LC-MS using method E. LC-MS method D: t _R = 0.61 min; [M+H]+ = 461.

The compounds of Examples 3.002-3.022 listed in Table 3 below are prepared by applying one of the above general procedures I or J to building blocks CE-3.01-CE-3.05 in combination with the appropriate carboxylic acid or ester of structure A-4 (L ¹ = OH or O-alkyl) which are commercially available or are prepared according to/similar to the methods described above.

Enantiomerically pure compounds are obtained using one of the above chiral preparative chromatography methods.

- 81 040620

Table 3 Reference Examples 3.001a-3.022

Reference Example No. Substance name QC LC-MS 1r (min) Detected mass [M+H] ⁺ 3.001 rac-(ZK*,4K*)-1-cyclohexyl-4-{[5-(2,6difluoro-phenyl)-isoxazol-3-carbonyl]-amino }-piperidine-3-carboxylic acid dimethylamide 0.61 461 3.002 rac-(3K*,4K*)-1-cyclohexyl-4-{[5-(4fluoro-phenyl)-isoxazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 0.62 443 3.003 rac-(ZK*,4K*)-1-cyclohexyl-4-{[5-(2,4difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino }piperidine-3-carboxylic dimethylamide acids 0.54 462.3 3.003a dimethylamide (3K*,4K*)-1-cyclohexyl-4-{[5-(2,4difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}- piperidine-3-carboxylic acid (enantiomer 1) 0.54 462.3 Z.OOZZ dimethylamide (3K*,4K*)-1-cyclohexyl-4-{[5-(2,4difluoro-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-amino}- piperidine-3-carboxylic acid (enantiomer 2) 0.54 462 3.004 paii-(3R*,4R*)-4-{[5-(2-chloro-4-fluorophenyl)-isoxazol-3-carbonyl]-amino}-1-cyclohexylpiperidine-3-carboxylic acid dimethylamide 0.67 477.1 3.005 paii-(3R*,4R*)-l-HHKnoreKCHn-4-{[5(2,4,6-trifluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3-carboxylic acid dimethylamide 0.63 479.3 3.006 paii-(3R*,4R*)-4-{[5-(4-chloro-2-fluorophenyl)-isoxazol-3-carbonyl]-amino}-1-cyclohexylpiperidine-3-carboxylic acid dimethylamide 0.69 477 3.007 dimethylamide pan-(3R*.4R*)-l-cycloxyl-4-[[5-(2,4difluoro-phenyl)-[1,2,4]oxadiazole-3-carbonyl]-amino }piperidine-3-carboxylic acid acids 0.56 462.3 3.009 (1-pyridin-2-yl-cyclopropyl)-amide paH-(3R*,4R*)-lcyclohexyl-4-{[5-(2-fluoro-phenyl)-isoxazole-3carbonyl]-amino}-piperidine-3 -carboxylic acid 0.62 532.2 3.010 (1-pyridin-2-yl-cyclopropyl)-amide paH-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)- [1,2,4]oxadiazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.57 551 3.011 (1-pyridin-2-yl-cyclopropyl)-amide paH-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)-oxazol-2carbonyl]-amino }-piperidine -3-carboxylic acid 0.61 550.3 3.012 (1-pyridin-2-yl-cyclopropyl)-amide paij-(3R*,4R*)-lcyclohexyl-4-{[5-(2,4-difluoro-phenyl)- [1,3,4]oxadiazol-2-carbonyl]-amino }-piperidine-3 carboxylic acid 0.56 551.1 3.013 (1-pyridin-2-yl-cyclopropyl)-amide paH-(3R*,4R*)-l-cyclopropylmethyl-4-{[5-(2-fluoro-phenyl)-isoxazole-3carbonyl]-amino}-piperidine-3 -carboxylic acid 0.56 504.1 3.014 (1-pyridin-2-yl-cyclopropyl)-amide paH-(3R*,4R*)-l-cyclopropylmethyl-4-{[5-(4-fluoro-phenyl)-isoxazole-3carbonyl]-amino}-piperidine-3 -carboxylic acid 0.58 504.1 3.015 (1-pyridin-2-yl-cyclopropyl)-amide paH-(3R*,4R*)-l-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-oxazol2-carbonyl]-amino}-piperidine -3-carboxylic acid 0.56 522.1 3.016 (1-pyridin-2-yl-cyclopropyl)-amide paH-(3R*,4R*)-lcyclopropylmethyl-4-{ [5-(2,4-difluoro-phenyl)- [1,3,4]oxadiazol-2-carbonyl]-amino }-piperidine-3 carboxylic acid 0.5 523.1

- 82 040620

3.016a (1-pyridin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)- [1,3,4]oxadiazol-2-carbonyl]-amino }-piperidine-3-carboxylic acid or (1-pyridin-2-ylcyclopropyl)-amide (3R,4R)-1-cyclopropylmethyl-4{[5- (2,4-difluoro-phenyl)-[1,3,4]oxadiazol-2-carbonyl]amino}-piperidine-3-carboxylic acid (first-eluting enantiomer) 0.51 523.1 3.017 pan-(3R*,4R*)-l-cyclopentyl-4-{ [5-(2,4difluoro-phenyl)-oxazole-2-carbonyl]-amino dimethylamide }- piperidine-3-carboxylic acid 0.57 447.3 3.018 dimethylamide pan-(3R*,4R*)-l-uHKnoreKCHa-4-{[5-(2,4difluoro-phenyl)-oxazole-2-carbonyl]-amino }- piperidine-3-carboxylic acid 0.61 461.3 3.019 pap-(3R*,4R*)-1-cyclohexyl-4-{[3-(2,4difluoro-phenyl)-[1,2,4]oxadiazol-5-carbonyl]-amino } piperidine-3- dimethylamide carboxylic acid 0.59 462.3 3.020a (1-pyrimidin-2-yl-cyclopropyl)-amide (3R*,4R*)-1cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)isoxazol-3-carbonyl]-amino } -piperidine-3- carboxylic acid (enantiomer 1) 0.61 541.28 3.020b (1-pyrimidin-2-yl-cyclopropyl)-amide (3R*,4R*)-1cyclopropylmethyl-4-{[5-(2,4,6-trifluoro-phenyl)isoxazol-3-carbonyl]-amino } -piperidine-3- carboxylic acid (enantiomer 2) 0.61 541.41 3.021 (1-pyrimidin-2-yl-cyclopropyl)-amide pap-(3R*,4R*)1-cyclopropylmethyl-4-{[4-fluoro-5-(4-fluoro-phenyl)isoxazol-3-carbonyl] -amino}-piperidine-3 carboxylic acid 0.60 523.4 3.022 (1-pyrimidin-2-yl-cyclopropyl)-amide paH-(3R*,4R*)1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-4-fluoroisoxazol-3-carbonyl ]-amino }-piperidine-3 carboxylic acid 0.60 541 3.022a (1-pyrimidin-2-yl-cyclopropyl)-amide (3R,4R)-1 cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-4-fluoroisoxazol-3-carbonyl]-amino } -piperidine-3-carboxylic acid or (1-pyrimidin-2-ylcyclopropyl)-amide (3S,4S)-1-cyclopropylmethyl-4{[5-(2,4-difluoro-phenyl)-4-fluoro-isoxazol -3-carbonyl]amino}-piperidine-3-carboxylic acid (eluting first enantiomer) 0.60 541.4

General method D for the synthesis of piperidines of formula (I) or (ID).

structural elements.

Retrieving Structural Elements of Structure 1

ABOUT

^R2

SE-4.01 (3S,4S)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3carboxylic acid.

4.01a: 4-((8)-1-phenylethylamino)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

In a dry flask equipped with a Dean-Stark tube and a reflux condenser, 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-methyl ester (10 g, 35 mmol) was dissolved in toluene (500 ml). (S)-(-)-α-methylbenzylamine (6.36 g, 52.5 mmol) and ptoluenesulfonic acid monohydrate (0.34 g, 1.75 mmol) are added and the mixture is heated at reflux for 3 h. The mixture is then cooled to RT, washed three times with aq. .saturated NaHCO ₃ (3 x 100 ml) and dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the product as a thick yellow oil. LCMS method A: t _R = 1.01 min; [M+H]+ = 375.18 . 1H NMR (400 MHz, CDCl ₃ ) δ: 9.28 (d, J= 7.4 Hz, 1H), 7.25-7.38 (m, 5 H), 4.63 (quint, J = 6.7 Hz, 1H), 4.19 (q, J = 7 Hz, 2H), 4.07 (s, 2H) 3.463.38 (m, 1H) 3.33-3.26 (m, 1H), 2.43-35 (m, 1H), 2.09-1.99 (m, 1H), 1.50 (d, J = 7.4 Hz, 3 H), 1.43 (s, 9 H), 1.29 (t, J = 7.0 Hz, 3 H).

4.01b: (3S,4S)-4-((S)-1-phenylethylamino)piperidine1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

Sodium borohydride (5.19 g, 137 mmol) is added in portions under N2 to a solution of isobutyric acid (68.1 ml, 734 mmol) in toluene (22 ml) at 0°C. The mixture is then stirred at RT for 20 minutes. The mixture is cooled again to 0°C. Slowly add a solution of complex 1-tert-butyl, 3-ethyl

- 83 040620 4-((S)-1-phenylethylamino)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid ester (13 g, 34.7 mmol) in toluene (50 ml) and the resulting mixture stirred for 60 min at 0°C. Additional sodium borohydride (817 mg, 21.6 mmol) was added in five portions over 4 h. Water (100 ml) was added carefully and the reaction mixture was stirred for 15 min at RT. A 3M aq. NaOH solution was added to bring the mixture to pH 10. The reaction mixture was extracted with EtOAc (3 x 150 ml), the combined organic layers were dried with MgSO ₄ and the solvent was evaporated under reduced pressure. The resulting yellow oil was purified on a pad of silica gel and chromatographed using heptane/EtOAc 2:1 to give a yellowish oil. This oil is dissolved in dry ethanol (50 ml) under N ₂ and the resulting solution is transferred to a solution previously obtained by mixing sodium ethoxide in ethanol (20 ml 21 wt%, 52 mmol) and EtOAc (7.6 ml, 78 mmol) . The resulting solution was stirred at 50° C. under N2 for 15 h. aq. NaOH. The resulting mixture was extracted with EtOAc (3 x 100 ml). The combined organic layers are dried over MgSO ₄ and concentrated under reduced pressure. The resulting oil is purified by flash chromatography over 100 g of silica gel using a heptane/EtOAc system (10:0 - 1:1 gradient) as eluent. The combined fractions are concentrated and dried in vacuo overnight to give a pale yellow oil. This oil is dissolved in diethyl ether (10 ml) and 4N is added dropwise. HCl in dioxane (1.45 ml, 5.8 mmol). The solution is stirred for 30 minutes, during which time a precipitate forms. The precipitation is completed by adding heptane (28.7 ml) and storing the mixture at 0°C for 1 h. The precipitate is isolated by filtration and washed with heptane to give 2.57 g of an off-white solid. The solid is suspended in acetonitrile (4.6 ml) and heated under reflux until the solid is completely dissolved. The solution is then cooled to 0° C. overnight. The resulting crystals are isolated by filtration and washed 3x with 1.15 ml portions of cold acetonitrile to give the hydrochloride salt as a colorless solid. The salt is then stirred in aq. 10% NaHCO ₃ solution (25 ml) and extracted with DCM (2 x 20 ml). Evaporation of the organic layers under reduced pressure gives the title product as a colorless oil. LCMS method A: tR = 0.73 min; [M+H]+ = 377.29 ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.79-7.40 (m, 5 H), 4.13-4.24 (m, 3 H), 3.70-4.09 (m, 2 H), 2.82-2.99 (m, 2H), 2.58-2.72 (m, 1H), 2.21-2.38 (m, 1H), 1.62-1.76 (m, 1H), 1.45 (m, 9H), 1.20-1.35 (m , 7 H), 1.02–1.14 (m, 1H).

4.01c: (3S,4S)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

A solution of (3S,4S)-4-((S)-1-phenylethylamino)piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester (1.833 g, 5.06 mmol) in MeOH (7 ml) added to a suspension of palladium on activated carbon (10%) (183 mg, 0.172 mmol) and ammonium formate (2.63 g, 40.5 mmol) in MeOH (40 ml) under N2. The mixture is heated at reflux for 6 hours. After completion of the reaction (peak disappearance, and ethyl ester is replaced by methyl ester), the cooled solution is filtered through celite and the filtrate is concentrated to give the title product as a yellowish oil. LCMS method A: t _R = 0.53 min; [M+H]+ = 259.23. 1Н NMR (400 MHz, CDCl ₃ ) δ: 3.873.49 (m, 4Н), 3.70 (s, 3Н), 3.31 (m, 1Н), 2.43-1.75 (m, 5Н), 1.43 (s, 9H).

4.01d: (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

5-( 2,4-difluorophenyl)isoxazole-3carboxylic acid (1.3 g, 5.81 mmol). DIPEA (2.12 ml, 12.4 mmol) is then added followed by HATU (1.55 g, 4.06 mmol). The reaction mixture is stirred overnight at RT. The reaction mixture was concentrated, dissolved in DCM (100 ml) and treated twice with aq. sat. NaHCO3 (100 ml). The organic layer is dried over MgSO4 and evaporated. The crude residue was purified by flash chromatography over 40 g of silica gel using heptane/EtOAc (1:0-3:1) as eluent to give the title compound as a white powder; LCMS method A: tR= 0.94 min; [M+H]+ = 466.04. 1H NMR (400 MHz, CDCl ₃ ) δ: 7.23-7.36 (m, 1H), 7.96 (m, 1H), 6.96-7.12 (m, 3H), 6.79-6.91 (m, 1H), 4.29-4.51 (m , 2Н), 4.00-4.22 (m, 1Н), 3.64-3.78 (m, 3Н), 2.85-3.09 (m, 2Н), 2.50-2.68 (m, 1Н), 2.10-2.27 (m, 1Н), 1.42 -1.69 (m, 11H), 1.21-1.38 (m, 1H).

4.01e: (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester hydrochloride.

(3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester (1152 mg, 2.48 mmol ) was dissolved in DCM (15 ml). Add dropwise HCl in dioxane 4M (12.4 ml, 49.5 mmol). The mixture was stirred at RT for 1 hour. The solvents were evaporated and the residue was dried in BB to give the crude title compound as a white powder. LCMS method A: t _R = 0.61 min; [M+H]+ = 366.18.

4.01f: (3S,4S)-1-cyclohexyl-4-([5-(2,4-difluorophenyl)isoxazole-3 methyl ester

- 84 040620 carbonyl]amino}piperidine-3-carboxylic acid.

To a suspension of (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester hydrochloride (0.99 g, 2.48 mmol) in DCM (20 ml) at RT cyclohexanone (0.75 ml, 6.9 mmol) is added followed by acetic acid (0.44 ml, 7.7 mmol) and sodium triacetoxyborohydride (1.58 g, 7.45 mmol). The reaction mixture is stirred overnight at RT. The reaction mixture was diluted with DCM (30 ml) and treated with aq. sat. NaHCO ₃ twice (50 ml). The organic phase is dried over MgSO ₄ and evaporated. A crude title compound is obtained; LCMS method A: t _R = 0.71 min; [M+H]+ = 448.17.

4.01: (3S,4S)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

(3S,4S)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester (1214 mg, 2.71 mmol) is dissolved in THF (14 ml) and add 1M aq. LiOH solution (6.98 ml, 6.98 mmol). The mixture is stirred overnight at RT. Add 1M aq. HCl solution (6.98 ml, 6.98 mmol) and the reaction mixture was stirred for 5 min. The solvents are evaporated to give the title compound as a yellow solid. LC-MS method A: t _R = 0.66 min; [M+H]+ = 434.06.

Obtaining structural elements of structure 1, used as intermediates in the preparation of examples 4.001-4.102.

The following carboxylic acids are obtained by analogy with example SE-4.01:

SE-4.02: (3R,4R)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxαzol-3-carbonyl]amino}piperidine3-carboxylic acid.

4.02a: 4-((R)-1-phenylethylamino)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

The title compound is prepared according to reaction 4.01a above using 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester and (R)-(-)-α-methylbenzylamine ; LCMS method A: t _R = 1.01 min; [M+H]+ = 375.28.

4.02b: (3R,4R)-4-(R)-1-phenylethylamino)piperidine1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

The title compound is prepared according to reaction 4.01b above by reduction of 4-((R)-1-phenylethylamino)-5,6dihydro-2H-pyridine-1, 1-tert-butyl, 3-ethyl ester, 3-dicarboxylic acid with a mixture of sodium borohydride and isobutyric acid followed by epimerization with sodium ethoxide in EtOH and EtOAc; LCMS method A: t _R = 0.72 min; [M+H]+ = 377.27.

4.02c: (3R,4R)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

The title compound is prepared according to reaction 4.01c above by working up:

complex 1-tert-butyl, 3-ethyl ester (3R,4R)-4-(R)-1-phenylethylamino)piperidine-1,3dicarboxylic acid with palladium on activated carbon (10%)) and ammonium formate in MeOH; LCMS method A: t _R = 0.52 min; [M+H]+ = 259.22.

4.02d: (3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

The title compound is prepared according to reaction 4.01d by treating )isoxazole-3-carboxylic acid; LC-MS A: t _R = 0.94 min; [M+H]+ = 466.02.

4.02e: (3R,4R)-4-([5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-3-carboxylic acid methyl ester hydrochloride.

The title compound is prepared according to reaction 4.01 e by treating (3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino 1-tert-butyl, 3-ethyl ester }piperidine-1,3-dicarboxylic acid with HCl in dioxane 4M; LCMS method A: t _R = 0.61 min; [M+H]+ = 366.14.

4.02f: (3R,4R)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxαzol-3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester.

The title compound is prepared according to reaction 4.01f by treating (3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine- methyl ester hydrochloride 3-carboxylic acid with cyclohexanone and sodium triacetoxyborohydride; LC-MS method A: t _R = 0.72 min; [M+H]+ = 448.19.

4.02: (3R,4R)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3carboxylic acid.

The title compound is prepared according to Reaction 4.01 by treating (3R,4R)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3- methyl ester carboxylic acid with 1M aq. LiOH solution. LCMS method A: t _R = 0.66 min; [M+H]+ = 434.07.

SE-4.03: (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

4.03f: (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-3-carboxylic acid methyl ester.

The title compound is prepared according to reaction 4.01f by treatment with (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester hydrochloride cyclopropanecarbaldehyde and sodium triacetoxyborohydride; LCMS method D: t _R = 1.02 min; [M+H]+ = 420.12.

4.03: (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound is prepared according to Reaction 4.01 by treating (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3- methyl ester carboxylic acid with 1M aq. LiOH solution. LC-MS method D: t _R = 0.54 min; [M+H]+ = 405.79.

SE-4.04: (3S,4S)-1-cyclopentyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine3-carboxylic acid.

4.04f: (3S,4S)-1-cyclopentyl-4-([5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-3-carboxylic acid methyl ester.

The title compound is prepared according to reaction 4.01f by treatment with (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester hydrochloride cyclopentanone and sodium triacetoxyborohydride; LCMS method D: t _R = 1.04 min; [M+H]+ = 434.14.

4.04g: (3 S,4S)-1-cyclopentyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound is prepared according to Reaction 4.01 by treating (3S,4S)-1-cyclopentyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3- methyl ester carboxylic acid with 1M aq. LiOH solution. LCMS method D: t _R = 0.56 min; [M+H]+ = 420.09.

SE-4.05: (3 S,4S)-1-Cyanomethyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

4.05f: (3S,4S)-1-Cyanomethyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid ethyl ester.

The title compound is prepared by treating (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid ethyl ester hydrochloride with bromoacetonitrile and DIPEA in EtOH; LC-MS method A: t _R = 0.95 min; [M+H]+ = 419.19.

4.05: (3S,4S)-1-cyanomethyl-4-([5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound is prepared according to Reaction 4.01 by treating (3S,4S)-1-cyanomethyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3- ethyl ester carboxylic acid with 1 M aq. LiOH solution. LCMS method D: t _R = 0.81 min; [M+H]+ = 391.20.

SE-4.06: (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-1-(1-fluorocyclopropylmethyl)piperidine-3-carboxylic acid.

4.06c: (3R,4S)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl ester.

The title compound is prepared according to reaction 4.01c above by working up:

(3R,4S)-4-(R)-1-phenylethylamino)piperidine-1,3dicarboxylic acid 1-tert-butyl, 3-ethyl ester with palladium hydroxide on activated carbon 20%) and hydrogen in EtOH at 20 bar and 80°C; LCMS method D: t _R = 0.81 min; [M+H]+ = 273.21.

4.06d: (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

The title compound is prepared according to reaction 4.01d by working up

- 86 040620 1-tert-butyl, 3-ethyl ester of (3S,4R)-4-aminopiperidine-1,3-dicarboxylic acid with 5(2,4-difluorophenyl)isoxazole-3-carboxylic acid followed by epimerization using ethoxide sodium in ethanol; LC-MS A: t _R = 0.96 min; [M+H]+ = 480.17.

4.06e: (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-3-carboxylic acid ethyl ester hydrochloride.

The title compound is prepared according to reaction 4.01e by treating (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino 1-tert-butyl, 3-ethyl ester }piperidine-1,3-dicarboxylic acid with HCl in dioxane 4M; LCMS method A: t _R = 0.70 min; [M+H]+ = 380.18.

4.06f: (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-1-(1fluorocyclopropylmethyl)piperidine-3-carboxylic acid ethyl ester.

The title compound is prepared by treating (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid ethyl ester hydrochloride with 1fluorocyclopropane-1-carbaldehyde and sodium triacetoxyborohydride; LCMS method A: t _R = 0.78 min; [M+H]+ = 452.19.

4.06: (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-1-(1-fluorocyclopropylmethyl)piperidine-3-carboxylic acid.

The title compound is prepared according to Reaction 4.01 by treating (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-1-(1-fluorocyclopropylmethyl) ethyl ester piperidine-3-carboxylic acid with 1M aq. LiOH solution. LCMS method D: t _R = 0.69 min; [M+H]+ = 424.20.

SE-4.07: (3R,4R)-1-cyclopropylmethyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

4.07f: (3R,4R)-1-cyclopropylmethyl-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-3-carboxylic acid methyl ester.

The title compound is prepared according to reaction 4.01f by treating (3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester hydrochloride cyclopropanecarbaldehyde and sodium triacetoxyborohydride; LCMS method A: t _R = 0.7 min; [M+H]+ = 420.14.

4.07: (3R,4R)-1-cyclopropylmethyl-4-([5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound is prepared according to Reaction 4.01 by treating (3R,4R)-1-cyclopropylmethyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3- methyl ester carboxylic acid with 1M aq. LiOH solution. LCMS method A: t _R = 0.64 min; [M+H]+ = 406.06.

SE-4.08 (3S,4S)-1-cyclobutyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3carboxylic acid.

4.08f: (3S,4S)-1-cyclobutyl-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-3-carboxylic acid methyl ester.

The title compound is prepared according to reaction 4.01f by treatment with (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester hydrochloride cyclobutanone and sodium triacetoxyborohydride; LC-MS method A: t _R =0.76 min; [M+H]+ = 420.21.

4.08: (3S,4S)-1-cyclobutyl-4-([5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound is prepared according to reaction 4.01g by treating (3S,4S)-1-cyclobutyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3 methyl ester -carboxylic acid with 1M aq. LiOH solution. LCMS method A: t _R = 0.64 min; [M+H]+ = 406.33.

SE-4.09 (3R,4R)-1-cyclobutyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3carboxylic acid.

4.09f: (3R,4R)-1-cyclobutyl-4-([5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-3-carboxylic acid methyl ester.

The title compound is prepared according to reaction 4.01f by treating (3R,4R)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester hydrochloride cyclobutanone and sodium triacetoxyborohydride; LC-MS method A: t _R =0.77 min; [M+H]+ = 419.83.

4.09: (3R,4R)-1-cyclobutyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

The title compound is prepared according to reaction 4.01g by treating (3R,4R)-1-cyclobutyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3 methyl ester -carboxylic acid with 1M aq. LiOH solution. LC-MS method A: t _R = 0.69

- 87 040620 min; [M+H]+ = 406.22.

SE-4.10: (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-1-ethyl-piperidine-3-carboxylic acid.

4.10f: (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-1ethyl-piperidine-3-carboxylic acid methyl ester.

The title compound is prepared according to reaction 4.01f by treatment with (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid methyl ester hydrochloride acetaldehyde and sodium triacetoxyborohydride; LC-MS method A: t _R = 0.66 min; [M+H]+ = 394.35.

4.10: (3S,4S)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-1-ethyl-piperidine-3-carboxylic acid.

The title compound is prepared according to reaction 4.01g by treating (3S,4S)-1-cyclobutyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3 methyl ester -carboxylic acid with 1M aq. LiOH solution. LCMS method A: t _R = 0.62 min; [M+H]+ = 380.96.

SE-4.11: rac-(3R*,4R*)-1-tert-butyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid.

4.11a: 4-Amino-1-tert-butyl-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester.

A solution of LiHMDS 1M in THF (6.73 ml, 6.73 mmol, 1.1 equiv.) is added dropwise at -78°C to a solution of 1-tert-butylpiperidin-4-one (1000 mg, 6.12 mmol) in THF (10 ml) in an atmosphere argon. The mixture was stirred at this temperature for 1 h. Methyl cyanoformate (0.486 ml, 6.12 mmol) was then added and the reaction mixture was stirred at -78°C for 1 h. MeOH (30 ml) was added at -78°C, followed by the addition of acetate ammonium (4813 mg, 61.2 mmol). The mixture is stirred at this temperature for 15 minutes and then allowed to warm to RT and stirred for 18 hours. The solvents are evaporated under reduced pressure. The residue is taken up in DCM (25 ml) and washed with sat. aq. NaHCO ₃ (25 ml). Water the phase is extracted twice with DCM (2.times.25 ml). The organic phase is washed with brine (25 ml). The combined organic layers are dried over MgSO ₄ , filtered and concentrated to give the crude title compound as a yellowish oil; LCMS method A: t _R = 0.43 min; [M+H]+ = 213.46.

4.11b: rac-[R*,R*1-methyl-4-amino-1-(tert-butyl)piperidine-3-carboxylate and rac-[R*,S*]-methyl 4-amino-1-(tert- butyl)piperidine-3-carboxylate.

A solution of 4-amino-1-tert-butyl-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester (1.29 g, 6.12 mmol) in methanol (10 ml) was treated with NaBH ₃ CN (774 mg , 12.3 mmol) and AcOH (1.06 ml, 9.25 mmol) at 0°C. The reaction mixture is then allowed to warm to RT. The reaction mixture was stirred at 50° C. for 1 h. NaBH ₃ CN (387 mg, 6.15 mmol, 1 eq.) was added and the reaction mixture was heated at 50° C. for 18 h. MeOH was evaporated under reduced pressure and the residue was taken up in DCM (20 ml) and washed with sat. aq. NaHCO ₃ (20 ml). Aq. the phases are extracted twice (2x15 ml) with DCM and the organic phases are combined, dried over MgSO4, filtered and concentrated under reduced pressure to give the crude title product as a yellowish oil; LC-MS method A: t _R = 0.21 min; [M+H]+ = 215.34.

4.11c: rac-(3R*,4R*)-1-tert-butyl-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-3-carboxylic acid methyl ester.

A solution of rac-[R*,R*]-methyl 4-amino-1-(tert-butyl)piperidine-3-carboxylate and rac-[R*,S*]-methyl 4-amino-1-(tert-butyl )piperidine-3-carboxylate (659 mg, 3.08 mmol) in DCM (5 mL), treated with 5(2,4-difluorophenyl)isoxazole-3-carboxylic acid (714 mg, 3.08 mmol), HATU (2338 mg, 3.08 mmol ), and DIPEA (0.526 ml, 3.08 mmol). The reaction mixture was stirred at RT for 1 h 30 min. DXM (10 ml) and sat. aq. NaHCO ₃ solution (10 ml) is added to the mixture. The organic phase is separated, aq. the phase is extracted with DCM (2x10 ml), the combined organic phases are dried over MgSO ₄ , filtered and evaporated. The crude product is purified with prep. LC-MS using method E to give the title compound as a colorless oil; LCMS method A: t _R = 0.71 min; [M+H]+ = 422.33.

4.11: rac-(3R*,4R*)-1-tert-butyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine3-carboxylic acid.

The title compound is prepared according to reaction 4.01g by treating rac-(3R*,4R*)-1-tert-butyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl methyl ester ]amino}piperidine-3-carboxylic acid with 1M aq. LiOH solution. LCMS method A: t _R = 0.64 min; [M+H]+ = 408.35.

Example 4.001. (3S,4S)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid (1-methylcyclopropyl)amide.

To a solution of (3S,4S)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-3-carboxylic acid (21.7 mg, 0.05 mmol) in DMF (0.55 ml) 1-methylcyclopropan-1-amine hydrochloride (11.3 mg, 0.1 mmol) is added. DIPEA (0.028 ml, 0.16 mmol) is then added followed by HATU (20 mg, 0.052 mmol). The reaction mixture is stirred overnight at RT. The crude mixture is directly purified using prep. LC-MS using method E. LC-MS method D: tR = 0.66 min; [M+H]+ = 487.2.

The compounds of Examples 4.001-4.102 listed in Table 4 below are prepared by applying one of the above general procedures A, B or C to building blocks SE-4.01-SE-4.11 in combination with commercially available amines or amine SE-9.01 of general structure 2. Enantiomerically pure compounds are obtained using one of the above chiral preparative chromatography methods.

Table 4 Reference Examples 4.002-4.102

Reference Example No. Substance name QC LC-MS 1r (min) Detected mass [M+H] ⁺ 4.001 (1-methyl-cyclopropyl)-amide (3S,4S)-1-cyclohexyl-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }-piperidine-3-carboxylic acid 0.66 487.2 4.002 (2-Methoxy-1,1-dimethyl-ethyl)-amide (3S,4S)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino}-piperidine-3 -carboxylic acid 0.71 519.2 4.003 (3-Methoxy-1,1-dimethyl-propyl)-amide (3S,4S)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino}-piperidine-3 -carboxylic acid 0.72 533.4 4.004 [1-(5-fluoro-pyridin-2-yl)-cyclopropyl]-amide (3S,4S)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid 0.72 568.1 4.005 (38.48)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid dimethylamide 0.63 461 4.006 (1-methyl-cyclobutyl)-amide (38.48)-1-cyclohexyl-4-{[5(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3-carboxylic acid 0.73 501.3 4.007 ((1C8)-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide (3S,4S)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazol- 3carbonyl]-amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.63 529.3 4.008 [(1C8)-1-(5-fluoro-pyridin-2-yl)-ethyl]-amide (3S,4S)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl ]-amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.71 556.3

- 89 040620

4.009 ((R)-l-cyclobutyl-ethyl)-amide (3K,4K)-1-cyclohexyl-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3 -carboxylic acid 0.76 515.2 4.010 ((R)-l-φenyl-ethyl)-amide (38.48)-1-cyclohexyl-4-{[5(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}piperidine-3 -carboxylic acid 0.77 537.4 4.011 ((8)-2-hydroxy-1-phenyl-ethyl)-amide (3S,4S)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino}-piperidine -3-carboxylic acid 0.67 553.4 4.012 (38.48)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)-isoxazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid benzylamide 0.72 523.4 4.013 ((SH8)-2-hydroxy-1-pyridin-2-yl-ethyl)-amide (3S,4S)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl] - amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.58 554.2 4.014 ((R)-l-cyclobutyl-ethyl)-amide (38.48)-1-cyclohexyl-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3 -carboxylic acid 0.77 515.2 4.015 (3K,4K)-1-cyclohexyl-4-{[5-(2,4difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid tert-butylamide 0.73 489 4.016 (1-methyl-cyclobutyl)-amide (3R,4R)-1-cyclohexyl-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3-carboxylic acid 0.73 501.3 4.017 (3R,4R)-l-cyclohexyl-4-{[5-(2,4-diφτop-φenyl)isoxazol-3-carbonyl]-amino }-piperidine-3-carboxylic acid amide 0.56 433.3 4.018 (3R,4R)-1-cyclohexyl-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }-piperidine-3-carboxylic acid (1-methyl-cyclopropyl)-amide 0.66 487 4.019 (cyano-dimethyl-methyl)-amide (3R,4R)-l-uHKfloreKCHfl-4{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3-carboxylic acid 0.65 500.3 4.020 ((8)-2-hydroxy-1-phenyl-ethyl)-amide (3R,4R)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino}-piperidine -3-carboxylic acid 0.67 553.4 4.021 ((K)-2-hydroxy-1-phenyl-ethyl)-amide (3R,4R)-1cyclohexyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino}-piperidine -3-carboxylic acid 0.68 553.3 4.022 ((R)-l-φenyl-ethyl)-amide (3R,4R)-l-uHKfloreKCHfl-4-{[5(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }piperidine-3 -carboxylic acid 0.75 537.4 4.023 [(IRS) -1 -(2H-pyrazo l-3 -yl)-ethyl] -amide (3 S,4S) -1 cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3 - carbonyl]-amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.55 499.1 4.024 ((R)-1-pyridin-3-yl-ethyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)isoxazole3-carbonyl]-amino}-piperidine -3-carboxylic acid 0.49 510.1 4.025 (1-pyrimidin-2-yl-cyclopropyl)-amide (3R,4R)-1cyclopropylmethyl-4-{ [5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino }-piperidine-3-carboxylic acid acids 0.61 523.3 4.026 (1-pyridin-4-yl-cyclopropyl)-amide (3S,4S)-1cyclopentyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino }-piperidine-3-carboxylic acid acids 0.43 536.1

-90040620

4.027 (1-pyridin-4-yl-cyclopropyl)-amide (3 S,4S)-1 cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3 -carboxylic acid 0.41 522.1 4.028 (1-pyridin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopentyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino }-piperidine-3-carboxylic acids 0.61 536.1 4.029 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopentyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino }-piperidine-3-carboxylic acid acids 0.62 537.3 4.030 (1-methyl-1-pyridin-2-yl-ethyl)-amide (3 S,4S)-1 cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino } -piperidine-3-carboxylic acid 0.63 538.2 4.031 (1-pyridin-2-yl-cyclopropyl)-amide (3 S,4S)-1 cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3 -carboxylic acid 0.59 522.1 4.032 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole- 3-carbonyl]-amino }-piperidine-3-carboxylic acid 0.61 523.1 4.033 (1-methyl-1-pyridin-2-yl-ethyl)-amide (3 S,4S)-1 cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino } -piperidine-3-carboxylic acid 0.61 524.1 4.034 [ 1 -methyl-1 -(1 -methyl- 1H-pyrazol-4-yl)-ethyl]-amide (38.48)-1-cyclopentyl-4-{[5-(2,4-difluoro-phenyl) isoxazo l-3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.64 541.1 4.035 [ 1 -methyl-1 - (5 - methyl- [ 1,2,4] oxadiazol-3 -yl) -ethyl] -amide (38.48) -1-cyclopentyl-4-{[5-(2.4 -difluoro-phenyl)isoxazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.65 543.1 4.036 bicyclopropyl-1-ylamide (38.48)-1-cyclopentyl-4-{[5(2,4-difluoro-phenyl)-isoxazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.69 499.3 4.037 [(SH8)-1-(tetrahydrofuran-2-yl)-ethyl]-amide (3S,4S)-1cyclopentyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid (mixture of isomers) 0.65 517.4 4.038 [(IRS) -1-(1H-[1,2,4]triazo l-3-yl)-ethyl]-amide (3S,4S)-1cyclopentyl-4-{[5-(2,4-difluoro- phenyl)-isoxazole-3carbonyl]-amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.55 514 4.039 ((1 RS)-1 -methyl-prop-2-ynyl)-amide (3S,4S)-1cyclopentyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino }- piperidine-3-carboxylic acid (mixture of isomers) 0.63 471.3 4.04 ((1 RS)-1-isoxazol-3-yl-ethyl)-amide (3S,4S)-1cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino }- piperidine-3-carboxylic acid (mixture of isomers) 0.63 514.3 4.041 [(IRS) -1 -(2H-pyrazo l-3 -yl)-ethyl] -amide (3S,4S)-1cyclopentyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl] -amino }-piperidine-3-carboxylic acid (mixture of isomers) 0.56 513.1 4.042 ((R)-1-pyridin-3-yl-ethyl)-amide (3 S,4S)-l-cyclopentyl4-{ [5 -(2,4-difluoro-phenyl)-isoxazole-3-carbonyl] amino } -piperidine-3-carboxylic acid 0.5 524.1

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4.043 [1-methyl-1-(1-methyl-1H-pyrazol-4-yl)-ethyl]-amide (38.48)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl) isoxazo l-3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.63 527.2 4.044 [ 1 -methyl-1 - (5 - methyl- [ 1,2,4] oxadiazol-3 -yl) -ethyl] -amide (38.48) -1-cyclopropylmethyl-4-{[5-(2.4 -difluoro-phenyl)isoxazol-3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.64 529.1 4.045 bicyclopropyl-1-ylamide (38.48)-1-cyclopropylmethyl4-{ [5 - (2,4-difluoro-phenyl)-isoxazol-3-carbonyl] - amino }-piperidine-3-carboxylic acid 0.67 485.3 4.046 [(H8)-1-(tetrahydrofuran-2-yl)-ethyl]-amide (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino} -piperidine-3-carboxylic acid (mixture of isomers) 0.64 503.3 4.047 [(SH8)-1-(1H-[1,2,4]triazol-3-yl)-ethyl]-amide (3S,4S)-1cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl )-isoxazole3-carbonyl]-amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.53 500.1 4.048 ((SH8)-1-methyl-prop-2-ynyl)-amide (3S,4S)-1- cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.62 457.3 4.049 ((IRS)-1 -isoxazol-3-yl-ethyl)-amide (3 S,4S)-1 - cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino}-piperidine-3-carboxylic acid (mixture of isomers) 0.61 500.3 4.050 [1-(1-hydroxy-pyridin-2-yl)-cyclopropyl]-amide (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino} -piperidine-3-carboxylic acid 0.6 538.4 4.051 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1Cyanomethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3 carbonyl]-amino}-piperidine-3 -carboxylic acid 0.9 508.3 4.052 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{ [5(2,4-difluoro-phenyl)-isoxazol-3-carbonyl]-amino)-1-(1fluoro- cyclopropylmethyl)-piperidine-3-carboxylic acid 0.6 541 4.053 (1-phenyl-cyclopropyl)-amide (3 S,4S)-1 - cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.7 521.4 4.054 [ 1-(3-fluoro-pyridin-2-yl)-cyclopropyl]-amide (3S,4S)-1 cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino} -piperidine-3-carboxylic acid 0.7 540.2 4.055 (1-pyrimidin-4-yl-cyclopropyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino}-piperidine-3-carboxylic acids 0.6 523.2 4.056 ethyl ester 1-[((3S,4S)-1- cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino}-piperidine-3-carbonyl)-amino]-cyclopropanecarboxylic acid 0.7 517.4 4.057 (1-phenyl-cyclobutyl)-amide (3 S,4S)-1 - cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.8 535.1 4.058 benzyl-(2-fluoro-ethyl)-amide (38.48)-1-cyclopropylmethyl4-{ [5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl] - amino }-piperidine-3-carboxylic acid 0.8 541.4

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4.059 [1-(3-Methoxy-phenyl)-cyclopropyl]-amide (3 S,4S)-1 cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine -3-carboxylic acid 0.7 551.1 4.060 [1-(2-trifluoromethyl-phenyl)-cyclopropyl]-amide (3S,4S)1-cyclopropylmethyl-4-{ [5-(2,4-difluoro-phenyl)- isoxazo l-3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.8 589.4 4.061 [ 1 -(2-Fluoro-phenyl)-cyclopropyl]-amide (3 S,4S)-1 cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine -3-carboxylic acid 0.7 539.1 4.062 [ 1 -(4-Fluoro-phenyl)-cyclopropyl]-amide (3 S,4S)-1 cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine -3-carboxylic acid 0.0 539 4.063 [ 1 -(3 -fluoro-phenyl)-cyclopropyl] -amide (3 S,4S)-1 cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino}-piperidine -3-carboxylic acid 0.7 539 4.064 (6-methyl-pyridin-2-ylmethyl)-amide (3S,4S)-1- cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.5 510 4.065 [2-(2-chloro-phenyl)-ethyl]-amide (3S,4S)-1- cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.86 543.2 4.066 (38.48)-1-cyclopropylmethyl-4-{[5-(2,4difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid diethylamide 0.7 461 4.067a [(3S,4S)-1-cyclopropylmethyl-3-((K)-2-phenyl-azetidine1-carbonyl)-piperidin-4-yl]-amide 5-(2,4-difluorophenyl)-isoxazol-3- carboxylic acid and [(3S,4S)-1cyclopropylmethyl-3-((8)-2-phenyl-azetidine-1carbonyl)-piperidin-4-yl]-amide or 5-(2,4-difluorophenyl)-isoxazo l- 3-carboxylic acid (epimer eluting first) 0.7 521.1 4.067b [(38.48)-1-cyclopropylmethyl-3-((K)-2-phenyl-azetidine1-carbonyl)-piperidin-4-yl]-5-(2,4-difluorophenyl)-isoxazole-3-carboxylic acid acids or [(3S,4S)-1cyclopropylmethyl-3-((8)-2-phenyl-azetidine-1- 5-(2,4-difluorophenyl)isoxazole-3-carboxylic acid carbonyl)-piperidin-4-yl]-amide (second-eluting epimer) 0.7 521.1 4.068 [ 1 -(3-chloro-phenyl)-cyclopropyl]-amide (3 S,4S)-1 cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine -3-carboxylic acid 0.8 555 4.069 (3K,4K)-1-cyclopropylmethyl-4-{[5(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid methoxymethyl-amide (3K,4K) 0.6 449.2 4.070 [ 1 -(4-methyl-thiazol-2-yl)-cyclobutyl] -amide (3 S,4S)-1 cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl] - amino }-piperidine-3-carboxylic acid 0.7 556.1 4.071 (3K,4K)-1-cyclopropylmethyl-4-{[5-(2,4difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid diethylamide 0.7 461.1 4.072 [(K,8)-1-(2-methoxy-phenyl)-ethyl]-amide (3S,4S)-1cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl] - amino }-piperidine-3-carboxylic acid 0.7 539.4

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4.072a [(R)-l-(2-methoxy-phenyl)-ethyl]-amide (3S,4S)-1cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino } -piperidine-3-carboxylic acid or [(8)-1-(2-methoxy-phenyl)-ethyl]-amide (3S,4S)-1cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl) -isoxazole-3-carbonyl]-amino }-piperidine-3-carboxylic acid (epimer eluting first) 0.8 539.4 4.073 ethyl ester (R,S)-[((3S,4S)-1- cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino}-piperidine-3-carbonyl)-amino]-phenyl-acetic acid 0.8 567.2 4.074 [1-(2-Methoxy-phenyl)-cyclopropyl]-amide (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino}-piperidine-3 -carboxylic acid 0.8 551 4.075 [(C)-1-(3-bromo-phenyl)-ethyl]-amide (3S,4S)-1- cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.8 587.1 4.076 [1-(2-Hydroxy-phenyl)-cyclopropyl]-amide (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino}-piperidine-3 -carboxylic acid 0.7 537 4.077 [1-(1-hydroxy-pyrimidin-2-yl)-cyclopropyl]-amide (3S,4S)1-cyclopropylmethyl-4-{ [5-(2,4-difluoro-phenyl)- isoxazo l-3-carbonyl]-amino}-piperidine-3-carboxylic acid 1.0 539.4 4.078 [(38.48)-1-cyclopropylmethyl-3-((C,8)-2-pyrimidin-2yl-pyrrolidin-1-carbonyl)-piperidin-4-yl]-amide 5(2,4-difluoro-phenyl )-isoxazo l-3-carboxylic acid 0.6 537 4.078b [(38.48)-1-cyclopropylmethyl-3-((C)-2-pyrimidin-2-ylpyrro lidin-1-carbonyl)-piperidin-4-yl]-amide 5-(2,4difluoro-phenyl)- isoxazol-3-carboxylic acid or [(38.48)-1-cyclopropylmethyl-3-((8)-2-pyrimidin-2-ylpyrrolidin-1-carbonyl)-piperidin-4-yl]-amide 5-(2 ,4difluoro-phenyl)-isoxazole-3-carboxylic acid (second-eluting epimer) 0.6 537.4 4.079a [(38.48)-1-cyclopropylmethyl-3-((C)-2-pyrimidin-2-ylazetidine-1-carbonyl)-piperidin-4-yl]-amide 5-(2,4difluoro-phenyl)-isoxazole -3-carboxylic acid or [(38.48)-1-cyclopropylmethyl-3-((8)-2-pyrimidin-2-ylazetidine-1-carbonyl)-piperidin-4-yl]-amide 5-(2, 4-difluoro-phenyl)-isoxazole-3-carboxylic acid (epimer eluting first) 0.6 523.4 4.079b [(38.48)-1-cyclopropylmethyl-3-((C)-2-pyrimidin-2-ylazetidine-1-carbonyl)-piperidin-4-yl]-amide 5-(2,4difluoro-phenyl)-isoxazole -3-carboxylic acid or [(38.48)-1-cyclopropylmethyl-3-((8)-2-pyrimidin-2-ylazetidine-1-carbonyl)-piperidin-4-yl]-amide 5-(2, 4difluoro-phenyl)-isoxazole-3-carboxylic acid (second-eluting epimer) 0.6 523 4.080 ((C,8)-1-pyrimidin-2-yl-ethyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino } -piperidine-3-carboxylic acid 0.6 511.1

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4.080a ((R)-l-pyrimidin-2-yl-ethyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3-carbonyl]-amino}-piperidine -3-carboxylic acid or ((8)-1-pyrimidin-2-yl-ethyl)-amide (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl ]-amino }-piperidine-3-carboxylic acid (epimer eluting first) 0.6 511 4.080b ((R)-l-pyrimidin-2-yl-ethyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3-carbonyl]-amino}-piperidine -3-carboxylic acid or ((8)-1-pyrimidin-2-yl-ethyl)-amide (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl ]-amino }-piperidine-3-carboxylic acid (second-eluting epimer) 0.6 511.4 4.081 (1-pyrimidin-5-yl-cyclopropyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole3-carbonyl]-amino}-piperidine-3-carboxylic acids 0.6 523.1 4.082 [ 1 - (3 -fluoro-pyridin-2-yl) -cyclopropyl] -amide (3 S,4S) -1 cyclobutyl-4-{ [5- (2,4-difluoro-phenyl) -isoxazole-3 carbonyl] - amino }-piperidine-3-carboxylic acid 0.6 540.4 4.083 (1-methyl-1-pyrimidin-2-yl-ethyl)-amide (3 S,4S)-1 cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino } -piperidine-3-carboxylic acid 0.6 525.1 4.084 ((R,S)-l-pyrimidin-2-yl-ethyl)-amide (3S,4S)-1cyclobutyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid 0.6 511 4.084b ((R)-l-pyrimidin-2-yl-ethyl)-amide (3S,4S)-1cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino}-piperidine -3-carboxylic acid or ((8)-1-pyrimidin-2-yl-ethyl)-amide (38.48)-1-cyclobutyl4-{[5-(2,4-difluoro-phenyl)-isoxazol-3 -carbonyl]amino}-piperidine-3-carboxylic acid (second-eluting epimer) 0.6 511 4.085 (3-Benzyl-oxetan-3-yl)-amide (3K,4K)-1-cyclobutyl-4{[5-(2,4-difluoro-phenyl)-isoxazol-3-carbonyl]-amino}piperidine-3 -carboxylic acid 0.7 551.1 4.086 [2-methyl-2-(3-methyl-pyridin-2-yl)-propyl]-amide (ЗR,4R)-l-cyclobutyl-4-{[5-(2,4-diφτop-φenyl)isoxazol -3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.6 552 4.087 (2-methyl-2-pyridin-2-yl-propyl)-amide (3R,4R)-1cyclobutyl-4-{[5-(2,4-difluoro-phenyl)isoxazole-3carbonyl]-amino}-piperidine -3-carboxylic acid 0.6 538.1 4.088 (1-o-tolyl-cyclopropyl)-amide acids 0.8 535 4.089 [3-(4-fluoro-phenyl)-oxetan-3-yl]-amide (3R,4R)-1 cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }-piperidine-3-carboxylic acid 0.7 555.1 4.090 (3-Phenyl-oxetan-3-ylmethyl)-amide (3R,4R)-1 cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3 - carboxylic acid 0.7 551 4.091 [2-(2-chloro-phenyl)-2-methyl-propyl]-amide (3R,4R)-1cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid 0.8 571.3

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4.092 [1-(4-chloro-phenyl)-cyclopropylmethyl]-amide (3R,4R)-1cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino}-piperidine- 3-carboxylic acid 0.8 569.4 4.093 (1-pyridin-2-yl-cyclopropylmethyl)-amide (3R,4R)-1 cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino}-piperidine- 3-carboxylic acid 0.6 536 4.094 [3-(3-chloro-phenyl)-oxetan-3-yl]-amide (3R,4R)-1 cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }-piperidine-3-carboxylic acid 0.7 571.1 4.095 [(H)-1-(6-mstyl-pyridin-2-yl)-ethyl]-amide (3S,4S)-4-{[5(2,4-difluoro-phenyl)-isoxazol-3-carbonyl ]-amino }-1 ethyl-piperidine-3-carboxylic acid 0.5 498 4.096 (1-methyl-1-pyrimidin-2-yl-ethyl)-amide (3S,4S)-4-{ [5(2,4-difluoro-phenyl)-isoxazol-3-carbonyl]-amino } -1 ethyl-piperidine-3-carboxylic acid 0.6 499 4.097 [3-(3-Chloro-phenyl)-oxetan-3-yl]-amide (3S,4S)-1cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino } -piperidine-3-carboxylic acid 0.7 571.4 4.098 [(R,S)-l-(3-φτop-pyridin-2-yl)-ethyl]-amide (3S,4S)-1cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole -3carbonyl]-amino }-piperidine-3-carboxylic acid 0.6 528 4.098a [(R)-l-(3-φτop-pyridin-2-yl)-ethyl]-amide (3S,4S)-1cyclobutyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl ]-amino}-piperidine-3-carboxylic acid or [(8)-1-(3-fluoro-pyridin-2-yl)-ethyl]-amide (3S,4S)-1cyclobutyl-4-{[5-( 2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino }-piperidine-3-carboxylic acid (second-eluting epimer) 0.6 528 4.099 (pyrimidin-2-ylmethyl)-amide (3R,4R)-1- cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.5 497.2 4.100 (pyrimidin-2-ylmethyl)-amide (3S,4S)-1- cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.5 497 4.101 (1-pyrimidin-2-yl-cyclopropyl)-amide pau-(3R*,4R*)-ltert-butyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3carbonyl]-amino } -piperidine-3-carboxylic acid 0.6 525.4 4.101a (1-pyrimidin-2-yl-cyclopropyl)-amide (3R*,4R*)-1tert-butyl-4-{[5-(2,4-difluoro-phenyl)isoxazol-3carbonyl]-amino}-piperidine -3-carboxylic acid (enantiomer 1) 0.6 525 4.101b (1-pyrimidin-2-yl-cyclopropyl)-amide (3R*,4R*)-1tert-butyl-4-{[5-(2,4-difluoro-phenyl)isoxazol-3carbonyl]-amino}-piperidine -3-carboxylic acid (enantiomer 2) 0.6 525 4.102 (1-methyl-1-pyrimidin-2-yl-ethyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)isoxazole3-carbonyl]-amino}-piperidine -3-carboxylic acid 0.6 525

General method G for the synthesis of piperidines of formula (I) or (ID).

structural elements.

Obtaining structural elements of the structure G-9

SE-5.01: rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-3methylpiperidine-3-carboxylic acid dimethylamide.

5.01a: 3-methyl-4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

Mixture of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester (1 g, 4 mmol), potassium carbonate (1.1 g, 8 mmol) and iodomethane (1.13 g, 8 mmol) in acetone (12 ml) is heated under reflux for 7 h. The mixture is then cooled to RT and filtered through a fritted filter. The filtrate was concentrated under reduced pressure to give the title compound as a yellowish oil. LCMS method A: t _R = 0.78 min; [M+H]+ = 272.21.

5.01b: 4-benzylamino-3-methyl-3,6-dihydro-2Hpyridine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

A solution of 1-tert-butyl, 3-ethyl ester 3-methyl-4-oxo-piperidine-1,3-dicarboxylic acid (1.02 g, 3.78 mmol) in toluene (30 ml) was treated with benzylamine (0.51 g , 4.76 mmol) and p-toluenesulfonic acid monohydrate (36 mg). The resulting mixture is refluxed for 2 hours using a Dean-Stark condenser. The reaction mixture was extracted 3 times with aq. sat. _NaHC03 . The organic phase is collected, dried over MgSO ₄ , filtered and the solvents are evaporated to give the crude product as a yellow oil.

5.01c: rac-(3R*,4R*)-4-benzylamino-3-methylpiperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

Crude 1-tert-butyl, 3-ethyl benzylamino-3-methyl-3,6-dihydro-2Hpyridine-1,3-dicarboxylic acid ester (1.23 g, 3.3 mmol) was dissolved in MeCN (15 ml) and cooled to 0 °C. AcOH (0.38 ml, 6.6 mmol) is added. Sodium triacetoxyborohydride (3.84 g, 18.1 mmol) is added in portions. The resulting mixture was stirred at 0° C. for 30 minutes and at RT for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (50 ml) and sat. aq. sodium carbonate solution (50 ml). The organic layer is separated, aq. the phase is again extracted with DCM (50 ml) and the combined organic layers are washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The two diastereomers are separated using silica gel column chromatography. Evaporation of the lower fraction gave the trans isomer as shown by 2D and NOE NMR as a colorless oil. LCMS method A: t _R = 0.67 min; [M+H]+ = 363.22.

5.01d: rac-(3R*,4R*)-4-amino-3-methylpiperidine-1,3dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

Dry Pd on activated carbon 10% (27 mg, 0.0254 mmol) is added to a solution of rac-(3R*,4R*)-4-benzylamino-3-methylpiperidine-1,3-dicarboxylic acid acids (0.3 g, 0.84 mmol) in MeOH (12 ml). After degassing the reaction flask, the mixture is hydrogenated for 1 hour at ambient temperature. The reaction mixture is filtered to remove the catalyst and then concentrated to give the crude product as a yellow oil. LCMS method A: t _R = 0.53 min; [M+H]+ = 273.22.

5.01e: rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino 1-3-methylpiperidine- 1-tert-butyl, 3-ethyl ester 1,3-dicarboxylic acid.

To a solution of rac-(3R*,4R*)-4-amino-3-methylpiperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester (225 mg, 0.83 mmol) in DMF (5 ml) at RT, 5-(2,4difluorophenyl)isoxazole-3-carboxylic acid (205 mg, 0.91 mmol) is added. DIPEA (0.283 ml, 1.65 mmol) is then added followed by HATU (346 mg, 0.91 mmol). The reaction mixture is stirred overnight at RT. The crude mixture is purified with prep. LC-MS under basic conditions. The title compound is obtained as a pale yellow solid. LCMS method A: t _R = 1.01 min; [M+H]+= 480.14.

5.01 f: rac-(3R*,4R*)-4-([5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino 1-3-methylpiperidine-1,3-dicarboxylic acid 1-tert-butyl ester .

Rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}-3-methylpiperidine-1,3-dicarboxylic 1-tert-butyl, 3-ethyl ester acids (240 mg, 0.5 mmol) are dissolved in THF (4 ml) at RT. Then add aq. 1M LiOH solution (4 ml, 4 mmol) and the mixture was stirred at RT for 72 h. The reaction mixture was acidified with 1M HCl solution (5 ml). The resulting suspension is extracted twice with DCM (10 ml). The organic layer is dried over MgSO ₄ and evaporated. The title compound is obtained as an off-white solid; LC-MS method A: t _R = 0.91 min; [M+H]+= 465.91.

5.01 g: rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}-3-dimethylcarbamoyl-3-methylpiperidine-1-carboxylic acid tert-butyl ester .

A solution of 1-tert-butyl ester of rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}-3-methylpiperidine-1,3-dicarboxylic acid (200 mg, 0.43 mmol) in DMF (6 mL) was treated with a 2M solution of dimethylamine in THF (0.277 mL, 0.554 mmol) and DIPEA (0.158 mL, 0.924 mmol). Then add HATU (193 mg, 0.508 mmol) and the reaction mixture is stirred over night. The DMF was evaporated and the crude product was taken up in DCM (10 ml) and extracted 3 times with NaHCO ₃ sat. solution (10 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate, filtered and evaporated to give the product as a pale orange oil which was used as the crude product in the next step. LC-MS method A: t _R = 0.97 min; [M+H]+ = 493.11.

5.01h: rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-3-methylpiperidine-3-carboxylic acid dimethylamide.

Rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-3-dimethylcarbamoyl-3-methylpiperidine-1-carboxylic acid tert-butyl ester ( 135 mg, 0.27 mmol) are dissolved in MeOH (5 ml) at RT. A 4M solution of HCl in dioxane (0.068 ml, 0.274 mmol) was added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated, dissolved in DCM (10

- 97 040620 ml) and treated with aq. sat. NaHCO3 (10 ml).

The organic layer is separated and the water phase is extracted twice with DCM (2x10 ml). The combined organic layers are dried over MgSO ₄ and evaporated. A crude title compound is obtained; LC-MS A: tR= 0.64 min; [M+H]+ = 393.15.

Obtaining building blocks of substituted piperidines of structure 1 used as intermediates in the preparation of examples 5.002.

By analogy with example SE-5.01, the following amides are obtained:

SE-5.02 ((R)-1-pyridin-2-yl-ethyl)amide (3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}-3-methylpiperidine -3-carboxylic acid.

5.02a: (3R*,4R*)-4-([5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-3-methyl-3-((R)-1 tert-butyl ester -niridin-2-yl-ethylcarbamoyl)piperidine-1-carboxylic acid.

The title compound was prepared according to the 5.01 g reaction described above using rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl 1-tert-butyl ester ]amino}-3-methylpiperidin-1,3-dicarboxylic acid and ((R)-1-n-pyridin-2-yl-ethyl)amine; LCMS method A: t _R = 0.78 min; [M+H] ⁺ = 570.12.

5.02: ((R)-1-pyridin-2-yl-ethyl)amide (3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-3- methylpiperidine-3-carboxylic acid.

The title compound is prepared according to the 5.01 h reaction above by treating (3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}- tert-butyl ester 3-methyl-3-((R)-1-pyridin-2-yl-ethylcarbamoyl)piperidine-1-carboxylic acid with 4M HCl in dioxane; LCMS method A: t _R = 0.56 min; [M+H] ⁺ = 470.09.

Example 5.001: ((R)-1-pyridin-2-yl-ethyl)amide (3R*,4R*)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl] amino}-3-methylpiperidine-3-carboxylic acid.

Solution of ((R)-1-niridin-2-yl-ethyl)amide rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazol-3carbonyl]amino}-3-methylpiperidine -3-carboxylic acid, cyclohexanone (0.046 ml, 0.45 mmol) and AcOH (0.032 ml, 0.56 mmol) in DCM (5 ml) at RT was treated with sodium triacetoxyborohydride (149 mg, 0.67 mmol). The reaction mixture is stirred overnight at RT.

The reaction mixture was diluted with DCM (5 ml) and washed with aq. sat. NaHCO ₃ (10 ml). The organic layer is dried over MgSO ₄ and evaporated. The crude residue is purified with prep. LC-MS under basic conditions. The title compound is obtained as a colorless powder. LC-MS method A: t _R = 0.69 min; [M+H] ⁺ = 552.15.

Example 5.002. Rac-(3R*,4R*)-1-cyclohexyl-4-{[5-(2,4-difluorophenyl)isoxαzol-3carbonyl]amino}-3-methylpiperidine-3-carboxylic acid dimethylamide.

The title compound was prepared according to Example 5.001 above by treating dimethylamide with rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-3methylpiperidine -3-carboxylic acid with cyclohexanone; LCMS method A: t _R = 0.76 min; [M+H] ⁺ = 475.13.

structural elements.

Obtaining the structural elements of the B-3 structure

ABOUT

AT 3

SE-6.01: rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-1, 1-tert-butyl, 3-ethyl ester, 3-dicarboxylic acid.

6.01a: 4-amino-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

A solution of complex 1-tert-butyl, 3-ethyl ester of 4-oxo-piperidine-1,3-dicarboxylic acid (10 g, 36.9 mmol), in MeOH (140 ml) is treated with 7N. a solution of ammonia in MeOH (25 ml, 1.14 mol) and the resulting solution is heated under reflux for 18 h. The mixture is then cooled to RT and concentrated under reduced pressure. The residue is taken up in DCM (100 ml) and washed twice with water (2 x 100 ml) and brine (2 x 100 ml). The organic layer is dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the crude product as a yellow solid. LC-MS method A: t _R = 0.83 min; [M+H-t-Bu] ⁺ = 202.27.

6.01b: mixture of rac-(3R*,4R*)-4-aminopiperidine-1,3dicarboxylic acid 1-tert-butyl, 3-ethyl ester and rac-(3S*) 1-tert-butyl, 3-ethyl ester ,4R*)-4-α-minopiperidine-1,3-dicarboxylic acid NaBH ₄ (1.73 g, 45.7 mmol) was dissolved in THF (100 ml) and obtained

- 98 040620 the resulting solution is cooled to -18°C. TFA (13 ml, 169 mmol) is added over 20 minutes. at (-14)-(-18)°С. A solution of crude 4-amino-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester (9.53 g, 33.9 mmol) in THF (15 mL) was added dropwise over 10 minutes the reaction mixture is allowed to warm to 0°C over 15 minutes and stirred at this temperature for 1 hour. Water (50 ml) is poured into the reaction mixture and stirring is continued for 10 minutes. The pH value of the resulting solution was adjusted to pH 11 with 10N. aq. NaOH. The mixture is extracted with DCM (2 x 100 ml). The combined organic layers are washed with brine (2 x 100 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The product is obtained as a cis-trans mixture of products, as a yellow foam: LC-MS method A: t _R = 0.55 min; [M+H]+ = 259.34 and 0.58 min; [M+H]+ = 259.5.

6.01c: rac-(3S*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-1, 1-tert-butyl, 3-ethyl ester mixture, 3-dicarboxylic acid and 1-tert-butyl, 3-ethyl ester rac-(3 R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}piperidine- 1,3 dicarboxylic acid.

To a solution of complex 1-tert-butyl, 3-ethyl ester rac-(3R*,4R*)-4-amino-3-methylpiperidine-1,3-dicarboxylic acid and complex 1-tert-butyl, 3-ethyl ester rac -(3S*,4R*)4-aminopiperidine-1,3-dicarboxylic acid (7.1 g, 23.6 mmol) in DCM (75 ml) 5(2,4-difluorophenyl)isoxazole-3-carboxylic acid (6.673 d, 29.1 mmol). Then DIPEA (9.98 ml, 58.3 mmol) was added followed by T ₃ R 50% solution in DCM (34.7 ml, 58.3 mmol). The reaction mixture is stirred for 1 h 30 min at RT. The pH value of the resulting solution was adjusted to pH 11 with 1N. aq. NaOH and the mixture was washed twice with aq. 1n. NaOH solution (2 x 100 ml). The organic phase is dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a mixture of cis-trans products (4:1 mixture) as a beige solid. LCMS method A: t _R = 1.07 min; [M+H]+= 465.94 and t _R = 1.10 min; [M+H]+= 465.94.

Pure cis isomer 1-tert-butyl, 3-ethyl ester rac-(3S*,4R*)-4-{[5-(2,4difluorophenyl)isoxazole-3-carbonyl]amino}piperidine-1,3- dicarboxylic acid is obtained by suspending the cis-trans mixture in MeOH and then filtered. LCMS method A: t _R = 1.07 min; [M+H]+ = 465.96.

6.01d: rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino} piperidine-1,3 1-tert-butyl, 3-ethyl ester -dicarboxylic acid.

A solution of sodium methoxide 25 wt.% in MeOH (7.43 ml, 0.0325 mol) is added to MeOH (15 ml) and methyl acetate (3.9 ml, 0.0488 salt). The mixture is heated under reflux for 30 min and cooled to RT. Then a mixture of 1-tert-butyl, 3-ethyl ester rac-(3S*,4R*)-4-{[5-(2,4difluorophenyl)isoxazole-3-carbonyl]amino}-3-methylpiperidine-1,3 -dicarboxylic acid and complex 1tert-butyl, 3-ethyl ester rac-(3R*,4R*)-4-{[5-(2,4-difluorophenyl)isoxazole-3-carbonyl]amino}-3-methylpiperidine-1 ,3-dicarboxylic acid (8.37 g, 16.3 mmol) is suspended under nitrogen in dry MeOH (10 ml) and the resulting suspension is injected into the previously prepared NaOMe solution. The mixture is stirred at RT for 1 day. The reaction mixture is treated with aq. sat. NaHCO ₃ (10 ml) and Meon evaporated under reduced pressure. DCM (25 ml) is added to the residue. The organic phase is separated and aq. the layer is extracted with 3x DCM (3x25 ml). The combined organic layers are dried over MgSO ₄ , filtered and concentrated. The crude residue was triturated with MeCN (10 ml) to give the title compound as an off-white solid. LC-MS method A: t _R = 1.07 min; [M+H]+ = 465.94.

General method I for the synthesis of piperidines of formula (I) or (ID).

structural elements.

Obtaining the structural elements of the structure I-7

SE 7.01: (3S,4S)-4-amino-1-cyclopropylmethylpiperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide.

7.01a: (3R,4S)-4-Benzyloxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

N-(Benzyloxycarbonyloxy)succinimide (12.2 g, 48.1 mmol) is added to a solution of (3R,4S)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester (13.1 g, 48.1 mmol) in THF (100 ml) at 0°C. The reaction mixture was stirred for 10 min at 0° C. and then at RT for 2 h. The THF was evaporated and the residue was taken up in DCM (100 ml). The mixture was washed with aq. sat. NaHCO3 (100 ml), dried over MgSO4, filtered, concentrated and dried in VV to give crude

- 99 040620 of the product in the form of a yellowish oil. LC-MS method At _R = 1.01 min; [M+H]+= 407.15.

7.01b: (3S,4S)-4-benzyloxycarbonylaminopiperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

A solution of sodium ethoxide 21 wt.% in EtOH (77.4 ml, 0.0465 mol) is added to EtOH (100 ml) and ethyl acetate (14.1 ml, 0.139 mol). The mixture is heated at reflux for 30 min and cooled to RT. A suspension of 1-tert-butyl, 3-ethyl ester (3R,4S)-4-benzyloxycarbonylaminopiperidine-1,3-dicarboxylic acid in dry ethanol (20 ml) was added dropwise to the NaOEt solution at RT under nitrogen. The mixture was stirred at RT for 24 hours. The reaction mixture was treated with water (10 ml) and the EtOH was evaporated under reduced pressure. Water (100 ml) was added and the pH of the solution was adjusted to 5 by treatment with aq. 2n. HCl. Add to the rest. Water the phase is extracted with 3x DCM (3x100 ml). The combined organic layers are dried over MgSO ₄ and filtered. Evaporation of the solvent gave the crude title compound as a yellowish oil contaminated with 15% acid 7.01c. LC-MS method A: t _R = 1.01 min; [M+H]+= 407.13.

7.01c: (3S,4S)-4-benzyloxycarbonylamino-piperidine-1,3dicarboxylic acid 1-tert-butyl ester.

(3S,4S)-4-benzyloxycarbonylamino-piperidine-1,3dicarboxylic acid 1-tert-butyl, 3-ethyl ester 7.01b (4.07 g, 10 mmol) was dissolved in THF (50 ml) at RT. Add 1M NaOH aq. solution (20 ml, 20 mmol) and the mixture was stirred at RT for 18 h. The reaction mixture was acidified to approximately pH 3 with 2M HCl solution (11 ml, 21 mmol) and evaporated. The resulting suspension is extracted twice with DCM (2 x 50 ml). The organic phase is dried over MgSO ₄ and the solvent is evaporated to give the title compound; LC-MS method At _R = 0.86 min; [M+H]+ = 379.18.

7.01 d: (3S,4S)-4-benzyloxycarbonylamino-3-(1-pyrimidin-2-ylcyclopropylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester.

A solution of (3S,4S)-4-benzyloxycarbonylaminopiperidin-1,3dicarboxylic acid 1-tert-butyl ester (4.26 g, 11.3 mmol) in DMF (40 mL) was treated with 1(pyrimidin-2-yl)cyclopropan-1-amine hydrochloride (2.17 g, 12.4 mmol), DIPEA (10.2 ml, 58.5 mmol) and HATU (5.136 g, 13.5 mmol). The mixture is stirred for 2 hours at RT. Add aq. saturated solution of NaHCO ₃ (50 ml) and DCM (80 ml) and aq. the phase is extracted with DCM (2 x 70 ml), dried over MgSO ₄ , filtered and evaporated. The crude product is purified with prep. HPLC using basic conditions. The title compound is obtained as a yellowish foam. LC-MS method A: t _R = 0.89 min; [M+H]+ = 496.11.

7.01f: [(3S,4S)-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)piperidin-4-yl]carbamic acid benzyl ester.

(3S,4S)-4-Benzyloxycarbonylamino-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (2622 mg, 5.29 mmol) in MeOH (35 ml) was treated with HCl 4M in dioxane (10.6 ml, 42.3 mmol). The reaction mixture was stirred at 50° C. for 2 hours. After evaporation of the solvents, the crude product was dried under BB conditions to give the crude title compound; LC-MS method D t _R = 0.56 min; [M+H]+ = 396.07.

7.01 f: [(3S,4S)-1-cyclopropylmethyl-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)piperidin-4-yl]-carbamic acid benzyl ester.

Cyclopropanecarboxaldehyde was added to a solution of [(3S,4S)-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)piperidin-4-yl]carbamic acid benzyl ester (3.06 g, 7.09 mmol) in DCM (100 ml) at RT. (0.54 ml, 7.09 mmol) followed by the addition of DIPEA (3.64 ml, 21.3 mmol) and sodium triacetoxyborohydride (3.96 g, 17.7 mmol). The reaction mixture is stirred overnight. The reaction mixture is treated with aq. sat. NaHCO ₃ (100 ml) and the resulting suspension is extracted twice with DCM (2 x 100 ml). The organic phase is dried over MgSO ₄ and evaporated. The crude product is purified with prep. HPLC using basic conditions. The title compound is obtained as a light yellowish solid. LCMS method A: t _R = 0.63 min; [M+H]+ = 450.17.

7.01: (3S,4S)-4-amino-1-cyclopropylmethylpiperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide.

The flask was purged with nitrogen, then loaded with Pd/C 10% (50 wt.%) (160 mg, 1.5 mmol) and dry MeOH (10 ml) was added. Nitrogen-purged suspension of [(3S,4S)-1-cyclopropylmethyl-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-carbamic acid benzyl ester (1349 mg, 3 mmol) in dry MeOH (20 ml ) is added to the Pd suspension. The atmosphere is changed to hydrogen and the mixture is stirred at RT for 3 h. The mixture is filtered and evaporated. The crude product is purified with prep. HPLC using basic conditions. The title compound is obtained as a light yellowish solid. LCMS method A: t _R = 0.34 min; [M+H]+ = 316.34.

SE 7.02: Rac-(3R*,4R*)-4-amino-1-cyclopropylmethylpiperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide.

7.02a: 1-tert-butyl, 3-ethyl ester rac-(3R*,4S*)-4-benzyloxycarbonylamino-

- 100 040620 piperidine-1,3-dicarboxylic acid.

The title compound was prepared according to procedure 7.01a, starting from the rac-(3S*,4R*)-4-aminopiperidine-1,3dicarboxylic acid 1-tert-butyl,3-ethyl ester building block. LC-MS method A t _R = 1.00 min; [M+H]+ = 393.26.

7.02b: rac-(3R*,4R*)-4-benzyloxycarbonylaminopiperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

The title compound was prepared according to procedure 7.01b starting from building block 7.0a. LC-MS method A: t _R = 0.96 min; [M+H]+ = 393.23.

7.02c: rac-(3R*,4R*)-4-benzyloxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester.

The title compound was prepared according to procedure 7.01c starting from building block 7.02b; LC-MS method A t _R = 0.86 min; [M+H]+ = 379.25.

7.02d: rac-(3R*,4R*)-4-benzyloxycarbonylamino-3-(1-pyrimidin2-yl-cyclopropylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester.

The title compound is prepared according to procedure 7.01 d starting from structural element 7.02c; LC-MS method A: t _R = 0.88 min; [M+H]+ = 496.25.

7.02e: rac-[(3R*,4R*)-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)piperidin-4-yl]-carbamic acid benzyl ester.

The title compound was prepared according to procedure 7.01e starting from building block 7.02d. LC-MS method D t _R = 0.56 min; [M+H]+ = 396.27.

7.02f: rac-[(3R*,4*)-1-cyclopropylmethyl-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)piperidin-4-yl]-carbamic acid benzyl ester.

The title compound was prepared according to procedure 7.01f, starting from building block 7.02e. LCMS method A: t _R = 0.66Min; [M+H]+ = 450.09.

7.02: Rac-(3R*,4R*)-4-amino-1-cyclopropylmethylpiperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)amide.

The title compound was prepared according to procedure 7.01 starting from building block 7.02f. LCMS method A: t _R = 0.37 min; [M+H]+ = 316.29.

Example 7.001: (1-pyrimidin-2-yl-cyclopropyl)amide (3S,4S)-1-cyclopropylmethyl-4-{[4-fluoro-5-(4fluorophenyl)isoxazol-3-carbonyl]amino}piperidine-3 - carboxylic acid.

4-Fluoro-4-fluoro- 5-(4fluorophenyl)isoxazole-3-carboxylic acid (35.7 mg, 0.08 mmol). DIPEA (0.067 ml, 0.396 mmol) is then added followed by HATU (72.3 mg, 0.19 mmol). The reaction mixture is stirred for 21 hours at RT. Up to 0.28 mmol of a 2M HCl solution is added to the crude mixture to dissolve the precipitate, and the pure solution is directly purified with prep. LC-MS using method E. LC-MS QC method: t _R = 0.60 min; [M+H]+ = 523.1.

The compounds of Examples 7.002-7.016 listed in Table 5 below are prepared by applying one of the above general procedures I or J to building blocks SE-7.01-SE-7.02 in combination with the appropriate carboxylic acid or ester of structure A-4 (L1= OH or O-alkyl), which are commercially available or are prepared in accordance with/in analogy with the methods described above.

Enantiomerically pure compounds are obtained using one of the above chiral preparative chromatography methods.

- 101 040620

Table 5 Reference Examples 7.002-7.015 and Example 7.016

Reference Example/ Example No. Substance name LC-MS tR (min) Detected mass [M+H] ⁺ 7.002 (1-pyrimidin-2-yl-cyclopropyl)-(3S,4S)-1cyclopropylmethyl-4-[(5-o-tolyl-isoxazol-3-carbonyl)amino]-piperidine-3-carboxylic acid amide 0.60 501.4 7.003 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopropylmethyl-4-{ [5-(3,4-dimethyl-phenyl)-isoxazole- 3-carbonyl]-amino }-piperidine-3-carboxylic acid 0.70 515.1 7.004 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[1-(2,4-difluoro-phenyl)-1H[1,2,3]triazol-4 - carbonyl]-amino}-piperidine-3 carboxylic acid 1.0 523.2 7.005 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1- cyclopropylmethyl-4-{[5-(2,4-dimethyl-phenyl)-isoxazole3-carbonyl]-amino}-piperidine-3-carboxylic acid 0.70 515.1 7.006 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isoxazole5-carbonyl]-amino }-piperidine-3-carboxylic acids 0.60 523.1 7.007 (3S,4S)-1cyclopropylmethyl-4-{[5-(4-fluoro-phenyl)-oxazol-2-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide 0.6 505 7.008 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1- cyclopropylmethyl-4-{ [5-(2,4-difluoro-phenyl)- [ 1,2,4]oxadiazol-3-carbonyl]-amino }-piperidine-3 carboxylic acid 0.5 524 7.009 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-4-{[5-(4- Cyano-phenyl)-isoxazo l-3-carbonyl]-amino } -1 cyclopropylmethyl-piperidine-3-carboxylic acid 0.5 512 7.010 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[4-(2,4-difluoro-phenyl)-oxazol-2carbonyl]-amino}-piperidine-3-carboxylic acids 0.6 523.4 7.011 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-oxazol-2carbonyl]-amino}-piperidine-3-carboxylic acids 0.6 523 7.012 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[ 1-(2,4,6-trifluoro-phenyl)-1H[1,2,3] triazo l- 4-carbonyl]-amino}-piperidine-3 carboxylic acid 1.0 541.4 7.013 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[5-(3,4-difluoro-phenyl)-isoxazole- 3-carbonyl]-amino }-piperidine-3-carboxylic acid 0.6 523 7.014 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[3-(2,4-difluoro-phenyl)-isothiazole5-carbonyl]-amino }-piperidine-3-carboxylic acid acids 0.6 539 7.015 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopropylmethyl-4-{ [5-(2,4-difluoro-phenyl)-isothiazole3-carbonyl]-amino }-piperidine-3-carboxylic acid acids 0.6 539.1 7.016 (1-pyrimidin-2-yl-cyclopropyl)-amide (3S,4S)-1cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)- [1,3,4]thiadiazole-2-carbonyl]-amino }-piperidine-3 carboxylic acid 0.6 540.1

General method I for the synthesis of piperidines of formula (I) or (ID) building blocks. Obtaining Structural Elements of Structure D-9

ABOUT

H

D-9

SE 8.01: (1-pyridin-2-yl-cyclopropyl)amide (3S,4S)-4-{[1-(2,4-difluorophenyl)-1H-[1,2,3]triazole-4carbonyl]amino} piperidine-3-carboxylic acid.

8.01a: 1-tert-butyl, 3-ethyl ester (3R,4S)-4-{[1-(2,4-difluorophenyl)-1H[1,2,3]triazole-4-carbonyl]amino} piperidine-1,3-dicarboxylic acid.

1-(2,4 -difluorophenyl)1H-[1,2,3]triazole-4-carboxylic acid (1157 mg, 5.14 mmol). DIPEA (4.67 ml, 26.7 mmol) is then added followed by HATU (2346 mg, 6.17 mmol). The reaction mixture is stirred overnight at RT. The crude mixture is purified with prep. LC-MS under basic conditions. Specified

- 102 040620 in the header, the compound is obtained as a pale yellow solid. LCMS method A: t _R = 1.01 min; [M+H] = 480.11.

8.01b: 1-tert-butyl, 3-ethyl ester (3S,4S)-4-{[1-(2,4-difluorophenyl)-1H-[

1,2,3]triazole-4-carbonyl]amino}piperidine-1,3-dicarboxylic acid.

To a solution of 1-tert-butyl, 3-ethyl ester (3R,4S)-4-{[1-(2,4-difluorophenyl)-1H[1,2,3]triazole-4-carbonyl]amino}piperidine -1,3-dicarboxylic acid (1587 mg, 3.41 mmol) in EtOH (14.9 mL, 256 mmol) and EtOAc (7.36 mL, 75 mmol) sodium methoxide powder (776 mg, 13.6 mmol) was added in one portion at RT under argon . The reaction mixture was stirred at RT overnight. The reaction mixture was quenched with sat. aq. NH ₄ Cl (200 ml) and extracted twice with DCM (2 x 250 ml). The combined organic extracts are dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product is purified with prep. LC-MS under basic conditions. LCMS method A: t _R = 0.98 min; [M+H] ⁺ = 480.13.

8.01c: (3S,4S)-4-{[1-(2,4-difluorophenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}piperidine-1-tert-butyl ester ,3-dicarboxylic acid.

To a solution of 1-tert-butyl, 3-ethyl ester (3S,4S)-4-{[1-(2,4-difluorophenyl)-1H-[1,2,3]triazole-4-carbonyl]amino} piperidine-1,3-dicarboxylic acid (1000 mg, 2.09 mmol) in THF (30 ml) was added with 1M NaOH (7 ml, 6.26 mmol). the mixture is stirred for 4 hours at RT. 2 M HCl (3.7 ml, 6.47 mmol, 3.1 eq.) is added until pH 3 is reached and THF is evaporated to dryness.

The white solid is dried under high vacuum overnight. LCMS method A: t _R = 0.85 min; [M+H] ⁺ = 451.8.

8.01d: (3S,4S)-4-{[1-(2,4-difluorophenyl)-1H-[1,2,3]triazole-4-carbonyl]amino 1-3-(1 -pyridin-2-yl-cyclopropylcarbamoyl)piperidine-1-carboxylic acid.

(3S,4S)-4-{[1-(2,4-difluorophenyl)-1H-[1,2,3]triazole-4carbonyl]amino}piperidine-1,3-dicarboxylic 1-tert-butyl ester solution acid (500 mg, 1.11 mmol) in DMF (12 mL) was treated with 1-(pyridin-2-yl)cyclopropan-1-amine dihydrochloride (226 mg, 1.11 mmol), DIPEA (1.01 mL, 5.76 mmol) and HATU (5.35 mg, 1.33 mmol). The mixture is stirred for 2 hours at RT. Add a saturated solution of NaHCO ₃ (20 ml) and DCM (20 ml) and aq. the phase is extracted twice with DCM (2 x 20 ml), dried over MgSO ₄ , filtered and evaporated. The crude product is purified with prep. HPLC using basic conditions. The title compound gives a white solid. LCMS method A: t _R = 0.77 min; [M+H] ⁺ = 568.29.

8.01: (1-pyridin-2-yl-cyclopropyl)amide hydrochloride (3S,4S)-4-{[1-(2,4-difluorophenyl)-1H[1,2,3]triazole-4-carbonyl]amino }piperidine-3-carboxylic acid.

(3S,4S)-4-{[1-(2,4-difluorophenyl)-1H-[1,2,3]triazole-4-carbonyl]amino}-3-(1-pyridine- 2-yl-cyclopropylcarbamoyl)piperidine-1-carboxylic acid (205 mg, 0.361 mmol) was dissolved in dioxane (8 ml) at RT. A 4M HCl solution in dioxane (1 mL, 4 mmol) was added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated. The white solid is dried under high vacuum overnight LC-MS A: t _R = 0.50 min; [M+H] ⁺ = 467.83.

SE 8.02: (3S,4S)-4-{[5-(2,4-difluorophenyl)oxazole-2-carbonyl]amino}piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)amide hydrochloride.

8.02a: (3R,4S)-4-{[5-(2,4-difluorophenyl)oxazole-2carbonyl]amino}piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

The title compound is prepared by treating (3R,4S)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester and 5-(2,4difluorophenyl)oxazole-2-carboxylic acid lithium salt in accordance with the procedure 8.01a. LCMS method A: t _R = 1.07 min; [M+H] ⁺ = 480.16.

8.02b: (3S,4S)-4-{[5-(2,4-difluorophenyl)oxazole-2carbonyl]amino}piperidine-1,3-dicarboxylic acid 1-tert-butyl, 3-ethyl ester.

The title compound was prepared according to procedure 8.01b starting from building block 8.02a; LCMS method A: t _R = 1.04Min; [M+H] ⁺ = 480.16.

8.02c (3S,4S)-4-{[5-(2,4-difluorophenyl)oxazole-2-carbonyl]amino} piperidine-1,3-dicarboxylic acid 1-tert-butyl ester.

The title compound was prepared according to procedure 8.01c starting from building block 8.02b; LC-MS method A: t _R = 0.91 min; [M+H] ⁺ = 452.18.

8.02d: (3S,4S)-4-{[5-(2,4-difluorophenyl)oxazole-2-carbonyl]amino}3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)piperidine- tert-butyl ester 1-carboxylic acid.

The title compound is prepared according to procedure 8.01d starting from 8.02c and 1-(pyrimidin-2-yl)cyclopropan-1-amine hydrochloride; LCMS method A: t _R = 0.93 min; [M+H] ⁺ = 569.24.

8.02: (3S,4S)-4-{[5-(2,4-difluorophenyl)oxazole2-carbonyl]amino}piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)amide hydrochloride.

The title compound was prepared according to procedure 8.01 above, starting from building block 2.04c; LC-MS method A: t _R = 0.62 min; [M+H]+ = 469.16.

structural elements.

Obtaining amines of structure 2 r№ _r N1 ^N ^x

Η

SE-9.01 1-(1-hydroxypyrimidin-2-yl)cyclopropylamine hydrochloride.

9.01a: [1-(1-hydroxypyrimidin-2-yl)cyclopropyl]-carbamic acid tert-butyl ester.

To a solution of (1-pyrimidin-2-yl-cyclopropyl)carbamic acid tert-butyl ester (200 mg, 0.834 mmol) in DCM (5 ml) at 0°C was added 3-chloroperbenzoic acid (226 mg, 0.917 mmol) in portions . The reaction mixture was stirred at RT for 72 hours. The mixture was diluted with DCM (20 ml) and washed with aq. sat. NaHCO ₃ (20 ml). The organic phase is separated and aq. the phase is extracted with DCM (20 ml). The combined organic layers are dried over MgSO ₄ , filtered and concentrated. The crude product is purified with prep. HPLC using basic conditions. The title compound is obtained as a white solid. LCMS method A: t _R = 0.77 min; [M+H]+ = 568.29. to give the title compound as a yellowish powder; LCMS method A: t _R =0.60 min; [M+H]+ = 252.27.

9.01: 1-(1-hydroxypyrimidin-2-yl)cyclopropylamine hydrochloride.

[1-(1-Hyropyrimidin-2-yl)cyclopropyl]carbamic acid tert-butyl ester (74 mg, 0.29 mmol) was dissolved in MeOH (3 ml) at RT. A 4M solution of HCl in dioxane (0.44 mL, 1.77 mmol) was added and the reaction mixture was stirred at RT for 18 h. The solvents were evaporated to give the title compound as a yellowish solid; LC-MS method A: t _R = 0.21 min; [M+H]+ = 152.31.

Examples of reference compounds.

Reference connection example 1.

rac-(3R*,4R*)-4-[(5-cyclopropylisoxazole-3-carbonyl)amino]-1-cyclopropylmethylpiperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)amide.

The title compound was prepared according to the procedure described for Example 7.001, starting from structural element 7.02 and 5-cyclopropylisoxazole-3-carboxylic acid. LCMS method A: t _R = 0.61 min; [M+H]+ = 451.27.

Chiral Preparative SLC of rac-(3R*,4R*)-4-[(5cyclopropylisoxazole-3-carbonyl)amino]-1-cyclopropylmethylpiperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)amide using a ChiralPak column IC, 5 µm, 4.6 x 250 mm; with a mixture of A (CO ₂ ) and B (DCM/MeOH/DEA 50:50:01)) as eluent gives both enantiomers:

Reference compound 1a: (1-pyrimidin-2-yl-cyclopropyl)-amide (3R,4R)-4-[(5-cyclopropylisoxazole-3-carbonyl)amino]-1-cyclopropylmethylpiperidine-3-carboxylic acid or (1-pyrimidine2 (3S,4S)-4-[(5-cyclopropylisoxazole-3-carbonyl)amino]-1-cyclopropylmethylpiperidine-3-carboxylic acid -yl-cyclopropyl)amide.

Chiral HPLC t _R = 1.80 min; QC LC-MS method: t _R = 0.5 min; [M+H]+ = 451;

IC ₅₀ : > 10,000 nM.

Reference compound 1b: (3R,4R)-4-[(5-cyclopropylisoxazole-3-carbonyl)amino]-1-cyclopropylmethylpiperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)amide or (1-pyrimidine2) (3S,4S)-4-[(5-cyclopropyl-isoxazole-3-carbonyl)amino]-1-cyclopropylmethylpiperidine-3-carboxylic acid -yl-cyclopropyl)amide.

Chiral HPLC t _R = 2.48 min; QC LC-MS method: t _R = 0.5 min; [M+H]+ = 451.3;

IC50: > 10000 nM.

Reference connection example 2.

(3R,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluorophenyl)isoxazol-3-carbonyl]amino}piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)amide and (3S,4R)-1-cyclopropylmethyl-4-{[5-(2,4-difluorophenyl)isoxazol-3-carbonyl]amino}piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)amide.

Step 1: Rac-(3R*,4S*)-4-{[5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}piperidine-1,3-dicarboxylic acid 1-tert-butyl ester.

The title compound was prepared according to method 2.01c starting from structural element 6.01c by treatment with NaOH in THF/H2O followed by aq. HCl; LCMS method A: t _R = 1.01 min; [M+H]+ = 452.22.

Stage 2: rac-(3R*,4S*)-4-([5-(2,4-difluorophenyl)isoxazole-3carbonyl]amino}-3-(1-pyrimidin-2-yl-cyclopropylcarbamoyl) tert-butyl ester )piperidine-1-carboxylic acid.

The title compound is prepared according to method 2.01 d starting from step 1 and 1-(pyrimidin-2-yl)cyclopropan-1-amine hydrochloride; LCMS method A: t _R =1.06 min; [M+H]+ =

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569.33.

Step 3: Rac-(3R*,4S*)-4-{[5-(2,4-difluorophenyl)isoxazole3-carbonyl]amino}piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)amide .

The title compound was prepared according to Method 2.01 starting from Step 2; LCMS method A: t _R = 0.74 min; [M+H]+ = 469.14.

Step 4: (1-pyrimidin-2-yl-cyclopropyl)amide rac-(3R*,4S*)-1-cyclopropylmethyl-4-{[5-(2,4difluorophenyl)isoxazol-3-carbonyl]amino}piperidine- 3-carboxylic acid.

The title compound is prepared according to method D starting from step 3; LCMS method A: t _R = 0.71 min; [M+H]+ = 523.18.

Chiral preparative HPLC of (1-pyrimidin-2-yl-cyclopropyl)amide rac-(3R*,4S*)-1-cyclopropylmethyl-4-{[5-(2,4-difluorophenyl)isoxazol-3-carbonyl]amino} piperidine-3-carboxylic acid using a ChiralPak IC column, 5 µm, 4.6x250 mm; with a mixture of A (10% heptane, 0.05% DEA)) and B (90% EtOH, 0.05% DEA) as eluent and a flow of 1.2 ml/min. Chiral HPLC: gives both enantiomers.

Example of reference compound 2a: (1-pyrimidin-2-yl-cyclopropyl)amide (3R,4S)-1-cyclopropylmethyl-4-([5-(2,4-difluorophenyl)isoxazol-3-carbonyl]amino}piperidine- 3-carboxylic acid.

Chiral HPLC t _R = 12.01 min; QC LC-MS method: t _R = 0.7 min; [M+H]+= 523.1;

IC ₅₀ : > 10,000 nM.

Example of reference compound 2b: (1-pyrimidin-2-yl-cyclopropyl)amide (3S,4R)-1-cyclopropylmethyl-4-{[5-(2,4-difluorophenyl)isoxazol-3-carbonyl]amino}piperidine- 3-carboxylic acid.

Chiral HPLC t _R = 18.35 min; QC LC-MS method: t _R = 0.7 min; [M+H]+= 523.4;

IC50: 2250 nM.

Reference connection example 3.

(3S,4S)-1-cyclopropylmethyl-4-[(5-phenyl-isoxazole-3-carbonyl)-amino]-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide.

Example of reference compound 3 was prepared according to example 7.001 starting from (1pyrimidin-2-yl-cyclopropyl)amide (3S,4S)-4-amino-1-cyclopropylmethylpiperidine-3-carboxylic acid and 4-phenylisoxazol-3-carboxylic acid . LCMS method A: t _R = 0.66 min; [M+H]+ = 487.13.

IC ₅₀ : 1330 nM.

Tab. 6 summarizes the NMR data of the selected exemplary compounds.

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Table 6. 1H NMR Data of Selected Exemplary Compounds

Example Chemical shift (δ) in parts per million (ppm) Solvent 1.004 (400 MHz) δ 8.72 (d, 7=8.6 Hz, 1H), 8.08 - 8.01 (m, 1H), 7.60 - 7.54 (m, 1H), 7.36 - 7.30 (m, 1H), 7.08 (d, 7= 2.7 Hz, 1Н), 4.10 - 4.05 (br, 1Н), 3.78 - 3.72 (m, 2Н), 3.22 - 3.15 (m, 1Н), 2.93 - 2.81 (m, 4Н), 2.29 - 2.19 (br, ZN) , 1.90 - 1.68 (m, 9H), 1.61 - 1.54 (m, 2H), 1.20 1.15 (m, 5H). DMSODb 1.095 (400 MHz) δ 8.93 (s, 1H), 8.54 (d, 7=8.6 Hz, 1H), 7.94 - 7.86 (t, 1H), 7.71 - 7.64 (t, 1H), 7.39 - 7.33 (t, 1H) , 4.15 - 4.05 (t, 1H), 3.25 - 3.17 (t, 1H), 3.07 (s, 3H), 2.88 - 2.81 (t, 2H), 2.75 (s, 3H), 2.32 - 2.16 (t, 3H) , 1.80 - 1.72 (t, 5H), 1.63 - 1.55 (t, 2H), 1.18 1.14 (t, 5H). DMCO-d6 1.107 (400 MHz) δ: 8.80 (d, 7=8.8 Hz, 1H), 7.51 (dd, 7=9.2, 9.2 Hz, 2H), 7.15 (s, 1H), 4.38 - 4.31 (t, 1H), 4.17 - 4.11 (t, 1H), 4.05 - 3.91 (t, 1H), 3.83 - 3.69 (t, 2H), 3.02 - 2.96 (t, 2H), 2.77 - 2.68 (t, 1H), 2.27 (dd, 7=6.4 , 12.7 Hz, 1H), 2.19 - 1.98 (t, 5H), 1.83 - 1.76 (t, 1H), 1.69 - 1.59 (t, 1H), 0.83 (dd, 7=6.2, 6.2 Hz, 1H), 0.48 - 0.44 (t, 2H), 0.10–0.05 (t, 2H). DMCO-d6 1.113b (400 MHz) δ: 8.57 (d, 7=8.8 Hz, 1H), 7.53 - 7.45 (t, 2H), 7.14 (d, 7=1.2 Hz, 2H), 3.95 - 3.87 (t, 2H), 3.12 ( s, 3H), 2.97 (d, 7=11.2 Hz, 2H), 2.62 -2.54 (t, 1H), 2.21 - 2.17 (t, 2H), 2.13 - 1.95 (t, 2H), 1.82 (dd, 7= 3.4, 13.0 Hz, 1H), 1.57 - 1.48 (t, 1H), 1.11 (s, 7=5.1 Hz, 6H), 0.87 - 0.77 (t, 1H), 0.45 (d, 7=7.1 Hz, 2H), 0.09 - 0.05 (t, 2H). DMCO-d6 1.118a (400 MHz) δ: 8.99 (s, 1H), 8.57 - 8.47 (t, 2H), 8.22 (d, 7=8.1 Hz, 1H), 7.94 - 7.87 (t, 1H), 7.72 - 7.64 (t, 2H ), 7.39 - 7.35 (t, 1H), 7.31 - 7.22 (t, 2H), 4.93 - 4.87 (t, 1H), 4.06 - 4.01 (t, 1H), 2.95 - 2.91 (t, 2H), 2.80 - 2.73 (t, W), 2.15 - 1.97 (t, 2H), 1.88 - 1.74 (t, 2H), 1.59 - 1.45 (t, 5H), 1.34 - 1.27 (t, 2H), 1.23 (s, 1H), 1.17 - 1.13 (t, ZN). DMCO-d6 1.189 (400 MHz) δ: 8.43-8.51 (t, 4 H), 7.99 (s, 1 H), 7.97 (s, 1 H), 7.92 (d, 7= 2.1 Hz, 1 H), 7.66 (dd, 7χ = 2.2 Hz, 7 ₂ = 8.5 Hz, 1 N), 7.38 (s, 1 N), 7.18 (1, 7= 4.9 Hz, 1 N), 3.99 (t, 1N), 2.70-3.18 (t, 3 N ), 1.80-2.23 (t, 6 N), 1.48 (d, 7 = 3.8 Hz, 1 N), 1.36-1.40 (t, 2 N), 1.16 (t, 1 N), 0.83 (t, 1 N) 0.49 -0.50 (t, 2 N), 0.10 (d, 7= 0.7 Hz, 2 N). DMCO-d6 2.019a (400 MHz) δ: 8.72 (d, 7=8.6 Hz, 1H), 8.07 - 8.00 (t, 1H), 7.58 7.51 (t, 1H), 7.35 - 7.29 (t, W), 7.08 (d, 7= 2.9 Hz, 1H), 4.14 - 4.05 (t, 1H), 3.19 - 3.15 (t, 1H), 3.05 (s, ZN), 2.98 - 2.92 (t, 2H), 2.76 (S, ZN), 2.51 (s , 1H), 2.00 - 1.92 (t, 2H), 1.80 - 1.76 (t, 3H), 1.62 1.59 (t, 3H), 1.48 (1, 7=5.5 Hz, 2H), 1.38 - 1.29 (t, 2H) . DMCO-d6 2.031 (400 MHz) δ: 8.73 (d, 7=8.6 Hz, 1H), 8.08 - 8.01 (t, 1H), 7.60 - 7.53 (t, 1H), 7.36 - 7.30 (t, 1H), 7.09 (d, 7 =2.9 Hz, 1H), 4.11-4.04 (t, 1H), 3.20-3.14 (t, 2H), 3.06 (s, 3H), 2.82-2.80 (t, 1H), 2.76 (s, 3H), 2.71 - 2.63 (t, 1H), 1.88 - 1.53 (t, 8H), 1.08 (d, 7=19.3 Hz, 6H). DMCO-d6 2.073 (400 MHz) δ: 8.49-8.55 (t, 3 H), 8.44 (s, 1 H), 8.05-8.09 (t, 1 H), 7.62 (d, 7 = 2.5 Hz, 1 H), 7.57-7.60 (t, 1 N), 7.32-7.37 (t, 1 N), 7.16-7.19 (t, 2 N), 3.96 (dd, 7χ = 4.2 Hz, 7 ₂ = 8.5 Hz, 1 N), 2.92 (d, J = 9.7 Hz, 1 N), 2.74-2.80 (t, 2 N), 2.62-2.68 (t, 1 N), 2.32 (t, 1 N), 2.29 (s, 1 N), 2.17-2.19 (t , 1 N), 1.85–1.89 (t, 1 N), 1.46–1.56 (t, 1 N), 1.36–1.40 (t, 1 N), 1.09 (t, 2 N), 0.99 (d, 7 = 6.5 Hz, 6 N). DMCO-d6

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2.074 (400MHz) δ: 8.57 (d, J= 8.5Hz, 1 Η), 8.45-8.50 (m, 3 Η), 8.08 (m, 1 Η), 7.60 (m, 1 Η), 7.34 (td, Λ = 2.2 Hz, 7 ₂ = 8.5 Hz, 1 Η), 7.16-7.19 (m, 2 Η), 3.98 (dd, Λ = 3.6 Hz, J ₂ = 8.1 Hz, 1 Η), 2.92 (d, J= 9.1 Hz , 1 Η), 2.63-2.82 (m, 3 Η), 1.74-1.99 (m, 7 Η), 1.46-1.65 (m, 4 Η), 1.35-1.39 (m, 1 Η), 1.06-1.10 (m , 2 H). dmso-ab 3.003b (500 MHz) δ: 9.26 (d, 7=8.5 Hz, 1 Η), 8.18-8.13 (m, 1 Η), 7.64 (m, 1 Η), 7.39 (td, Λ= 8.3 Hz, 7 ₂ =2.1 Hz, 1 N), 4.10 (br, 1 H), 3.21–3.15 (br, 1 H), 3.07 (s, 3 H), 2.90–2.78 (br, 2 H), 2.76 (s, 3 H), 2.38-2.25 (br, 2 N), 2.17 (t,7=11.2 Hz, 1 N), 1.85-1.82 (m, 1 N), 1.76-1.68 (t, 4 N), 1.63-1.56 (t, 2 N), 1.30–1.15 (t, 4 N), 1.07 (t, 1 N). dmso-ab 3.015 (400 MHz) δ: 8.98 (d, 7= 8.8 Hz, 1 H), 8.56 (s, 1 H), 8.32 (d, 7= 4.6 Hz, 1 H), 7.99-7.93 (t, 1 H), 7.78 (d, 7= 3.3 Hz, 1 N), 7.52 (t, 1 N), 7.34-7.20 (t, 3 N), 7.01-6.98 (t, 1 N), 4.05-4.02 (t, 1 N) , 3.113.01 (t, 2 N), 2.86-2.80 (t, 1 N), 2.51 (s), 2.29-2.01 (t, 4 N), 1.851.82 (t, 1 N), 1.68-1.64 ( t, 1 N), 1.49–1.44 (t, 1 N), 1.31 (t, 1 N), 0.87–0.82 (t, 1 N), 0.48 (t, 2 N), 0.09 (t, 2 N). dmso-ab 3.019 (400 MHz) δ: 9.35 (d, 7=8.3 Hz, 1H), 8.15 - 8.07 (t, 1H), 7.60 - 7.53 (t, 1H), 7.39 - 7.33 (t, 1H), 4.15 - 4.04 (t , W), 3.06 (s, SH), 2.93 - 2.80 (t, SH), 2.77 (s, SH), 2.34 - 2.12 (t, SH), 1.87 - 1.81 (t, 1H), 1.76 - 1.72 (t , 4H), 1.65 - 1.52 (t, 2H), 1.24 - 1.18 (t, 4H), 1.14 - 1.04 (t, 1H). dmso-ab 4.005 (400 MHz) δ: 8.70 (d, 7= 8.5 Hz, 1 N), 7.61 (d, 7= 2.3 Hz, 1 N), 7.58-7.56 (t, 1 N), 7.33 (td, L = 8.5 Hz , 7 ₂ = 1.9 Hz, 1 H), 7.09 (d, 7 = 2.8 Hz, 1 H), 4.12–4.03 (t, 1 H), 3.13 (td, L = 10.7 Hz, 7 ₂ = 3.3 Hz, 1 N), 3.06 (s, 3 N), 2.88-2.77 (t, 5 N), 2-38-2.12 (t, 2 N), 1.83 (dd, L = 12.5 Hz, ₇₂ = 3.9 Hz, 1 N ), 1.73 (d, 7= 7.3 Hz, 4 N), 1.57 (t, 2 N), 1.25-1.02 (t, 6 N). dmso-ab 4.032 (400 MHz) δ: 8.57 (d, 7 = 8.5 Hz, 1 H), 8.51 (d, 7 = 4.8 Hz, 2 H), 8.47 (s, 1 H), 8.05-8.11 (t, 1 H), 7.59-7.62 (t, 1 N), 7.35 (t, 1 N), 7.14-7.21 (t, 2 N), 3.94-4.04 (t, 1 N), 3.32-3.40 (t, 1 N), 3.133. 19 (t, 1 N), 2.95-3.03 (t, 1 N), 2.67-2.77 (t, 1 N), 2.45-2.60 (t, 19 N), 2.16-2.27 (t, 2 N), 2.09- 2.14 (t, 1 N), 1.98-2.04 (t, 1 N), 1.84-1.90 (t, 1 N), 1.55-1.66 (t, 1 N), 1.48-1.52 (t, 1 N), 1.351. 40 (t, 1 N), 1.04–1.14 (t, 2 N), 0.81–0.89 (t, 1 N), 0.45–0.52 (t, 2 N), 0.04–0.14 (t, 2 N) dmso-ab 4.033 (400 MHz) δ: 8.76 (d, 7=8.6 Hz, 1H), 8.37 (d, 7=4.4 Hz, 1H), 8.09 8.02 (t, 2H), 7.59 - 7.51 (t, W), 7.40 - 7.29 (t, GL), 7.15 - 7.06 (t, 2Н), 3.99 - 3.89 (t, 1Н), 3.07 - 2.99 (t, 2Н), 2.81 - 2.73 (t, 1Н), 2.24 - 2.16 (t, 2Н) , 2.12 - 1.98 (t, 2H), 1.88 - 1.82 (t, 1H), 1.62 - 1.55 (t, 1H), 1.51 (s, 3H), 1.43 (s, 3H), 0.86 - 0.82 (t, 1H) , 0.51 - 0.45 (t, 2H), 0.10 - 0.05 (t, 2H). dmso-ab 4.052 (400 MHz) δ: 8.57 (d, 7 = 8.5 Hz, 1 N), 8.48-8.51 (t, 3 N), 8.08 (t, 1 N), 7.59 (t, 1 N), 7.34 (t, 1 N), 7.16-7.20 (t, 2 N), 4.00 (d, 7 = 11.8 Hz, 1 N), 3.15-3.18 (t, 1 N), 3.00-3.03 (t, 1 N), 2.72-2.78 ( t, 3 N), 2.32 (d, 7= 11.6 Hz, 1 N), 2.21 (t, 1 N), 1.84-1.87 (t, 1 N), 1.62-1.65 (t, 1 N), 1.49 (d , 7 = 6.0 Hz, 1 N), 1.35–1.39 (t, 1 N), 0.99–1.10 (t, 4 N), 0.66–0.70 (t, 2 N). dmso-ab 4.055 (400 MHz) δ: 8.94-9.02 (t, 2 N), 8.81 (d, 7= 0.7 Hz, 1 N), 8.34 (t, 1 N), 8.09-8.14 (t, 2 N), 7.59-7.60 (t, 1 N), 7.26-7.37 (t, 3 N), 4.18 (s, 1 N), 3.26-3.46 (t, 7 N), 1.96-1.98 (t, 1 N), 1.47-1.52 (t , 2 N), 1.15–1.19 (t, 2 N), 1.00–1.03 (t, 1 N), 0.56–0.58 (t, 2 N), 0.250.25 (t, 2 N) . dmso-ab 4.081 (400 MHz) δ: 8.88 (s, 1 Η), 8.73 (d, 7= 8.6 Hz, 1 Η), 8.58 (s, 1 Η), 8.48 (s, 2 Η), 8.06-8.12 (m, 1 Η), 7.57-7.63 (m, 1 Η), 7.35 (td, 7ι = 2.0 Hz, 7 ₂ = 8.3 Hz, 1 Η), 7.12 (d, 7= 3.0 Hz, 1 Η), 4.00-4.03 (t , 1 Η), 3.34 (s, 4 Η), 2.99–3.08 (m, 2 Η), 2.68–2.72 (m, 1 Η), 2.01–2.25 (m, 4 Η), 1.81–1.85 (m, 1 Η), 1.61–1.62 (m, 1 Η), 1.05–1.30 (m, 1 Η), 0.74–0.86 (m, 3 Η), 0.47 (d, J = 7.8 Hz, 2 Η), 0.08 (s, 2 H) dmso-ab 4.101 (400 MHz) δ: 8.54 (d, J = 8.0 Hz, 1 Η), 8.50 (d, J = 4.7 Hz, 2 Η), 8.47 (s, 1 Η), 8.05-8.11 (m, 1 Η), 7.57-7.63 (m, 1 Η), 7.32-7.36 (m, 1 Η), 7.17 (m, 2 Η), 3.90-4.00 (m, 1 Η), 3.30-3.38 (m, 3 Η), 3.12- 3.18 (m, 1 Η), 2.97-3.03 (m, 1 Η), 2.68 (ddd, Λ = 2.5 Hz, ₇₂ = 6.3 Hz, 1 H), 2.51 (s, 46 H), 2.18-2.23 (t , 1 N), 2.08-2.14 (t, 1 N), 1.86-1.93 (t, 1 N), 1.47-1.57 (t, 2 N), 1.36-1.40 (t, 1 N), 1.05-1.15 (t , 11 N) dmso-ab 4.102 (400 MHz) δ: 8.59-8.63 (t, 3 N), 8.04-8.10 (t, 2 N), 7.61 (d, 7= 2.5 Hz, 1 N), 7.56-7.59 (t, 1 N), 7.31 -7.35 (t, 1 N), 7.25 (t, 7= 4.8 Hz, 1 N), 7.16 (d, 7= 3.0 Hz, 1 N), 3.87 (d, 7 = 11.9 Hz, 1 N), 3.34 ( s, 2 H), 2.96–3.01 (t, 1 H), 2.67–2.71 (t, 2 H), 2.19 (d, 7 = 5.8 Hz, 2 H), 1.97–2.05 (t, 1 H), 1.82 -1.86 (t, 1 N), 1.51-1.58 (t, 6 N), 0.810.83 (t, 1 N), 0.45-0.48 (t, 2 N), 0.07 (q, 7 = 4.7 Hz, 2 N ) dmso-ab

II. biological analyses.

In vitro analysis.

The antagonistic effect of the compounds of formula (I) or (ID) on the CXCR7 receptor is determined according to the following experimental method.

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The assay uses the Tango CXCR7-bla U2OS cell line from Invitrogen. These cells contain the human chemokine receptor CXCR7 coupled to the TEV protease site and the transcription factor Gal4-VP16 stably integrated into the Tango GPCR-bla U2OS parental cell line. This parental cell line stably expresses the β-arrestin/TEV protease fusion protein and the β-lactamase reporter gene under the control of the UAS response element. After ligand binding and receptor activation, a protease-labeled β-arrestin molecule is inserted into CXCR7, which is linked at the C-terminus by a protease cleavage site to a transcription factor. The protease cleaves a transcription factor from CXCR7, which translocates to the nucleus and activates β-lactamase expression. The FRET-enabled substrate allows the detection of β-lactamase expression.

Tango CXCR7-bla U2OS cells are detached from 0.05% trypsin-EDTA culture dishes and harvested in growth medium (5A 90% (v/v) McCoy dialyzed with FCS 10% (v/v) , 0.1 mM NEAA, 25 mM HEPES (pH 7.3), 1 mM sodium pyruvate, P/S 1% (v/v) 50 µg/ml hygromycin, 100 µg/ml geneticin, 200 µg/ml zeocin), centrifuged and resuspended in assay medium (5A 90% McCoy (v/v), dialyzed FCS 1% (v/v), 0.1 mM NEAA, 25 mM HEPES (pH 7.3 ), P/S 1% (v/v)). 10,000 cells per well (in 30 µl) are plated in a 384-well plate (black-walled, clear bottom). The plate is incubated at 37°C/5% CO ₂ for 24 h.

Test compounds are dissolved to 10 mM in DMSO and serially diluted in DMSO to 500X the final concentration for dose-response curves. Compounds are then diluted 1:100 in assay medium to 5X the final concentration. 10 ml/well of the diluted compound is added to the assay plate and incubated for 15 min at 37°C.

Thereafter, CXCL12/SDF1-a is diluted in assay medium to 5X the final concentration (EC80 value for receptor activation) and 10 μl/well is added to the assay plate. The agonist leads to the activation of the receptor and, consequently, to the uptake of β-arrestin. Compounds that act as antagonists reduce this activation. The plate is incubated for 22 at 37°C. 10 μl/well of detection reagent (LiveBLAzer™-FRET B/G (CCF4-AM) substrate) is transferred to the assay plate and the plate is incubated for 2 hours at room temperature protected from light. Fluorescent values are counted (scan 1: example 409/20 nm, Em 460/30 nm, scan 2: example 409/20 nm, Em 530/30 nm). The estimated emission factor is used to determine the IC50. The calculated IC50 values may fluctuate depending on the daily performance of the cell analysis. Fluctuations of this kind are known to those skilled in the art. Mean IC50 values from several measurements are given as geometric mean values.

Table 7

Ref. Example No. 1С ₅₀ [nmol/l] Ref. Example No. 1С ₅₀ [nmol/l] Ref. Example No. IC50 [nmol/l] Ref. Example No. 1С ₅₀ [nmol/l] 1.001 1 1.118a 75 2.016b 63 4.009 573 1.001a 0.3 1.119 146 2.017 73 4.01 6 1.001b 302 1.12 789 2.018 145 4.011 43 1.002 2 1.121 4 2.019 126 4.012 49 1.002a 359 1.121a 742 2.019a 44 4.013 145 1.002b 1 1.121b 2 2.02 248 4.014 363 1.003 564 1.122 10 2.021 293 4.015 783 1.004 764 1.122a 525 2.022 155 4.016 463 1.005 198 1.122b 17 2.023 37 4.017 114 1.006 414 1.123 15 2.023a 9 4.018 343 1.007 780 1.123a 4 2.023b 26 4.019 151 1.008 394 1.124 16 2.024 101 4.02 222 1.009 66 1.125 81 2.025 435 4.021 126 1.01 82 1.125a thirty 2.026 249 4.022 369 1.011 282 1.126 49 2.027 745 4.023 69

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1.012 58 1.127 360 2.028 60 4.024 56 1.013 238 1.128 124 2.029 60 4.025 439 1.014 289 1.129 105 2.03 74 4.026 15 1.015 429 1.129a 647 2.031 558 4.027 8 1.016 275 1.129b 35 2.032 192 4.028 32 1.017 489 1.13 140 2.033 132 4.029 2 1.018 317 1.131 102 2.034 87 4.03 1 1.019 145 1.132 410 2.035 121 4.031 4 1.02 198 1.133 594 2.036 165 4.032 3 1.021 282 1.134 266 2.037 161 4.033 0.3 1.022 198 1.135 592 2.038 99 4.034 255 1.023 743 1.136 202 2.039 83 4.035 56 1.024 118 1.137 919 2.04 475 4.036 127 1.025 51 1.138 816 2.045 114 4.037 280 1.026 627 1.138a 437 2.046 16 4.038 522 1.027 117 1.138b 83 2.047 145 4.039 393 1.028 916 1.139 50 2.048 501 4.04 86 1.029 315 1.139a 790 2.049 709 4.041 96 1.03 201 1.139b 29 2.05 15 4.042 74 1.031 855 1.14 358 2.051 42 4.043 158 1.032 154 1.141 379 2.052 267 4.044 75 1.033 591 1.142 472 2.053 26 4.045 164 1.034 772 1.143 719 2.054 138 4.046 290 1.035 520 1.144 178 2.055 49 4.047 318 1.036 693 1.145 363 2.056 48 4.048 247 1.037 295 1.146 904 2.057 50 4.049 148 1.038 490 1.147 443 2.058 347 4.05 21 1.039 492 1.148 769 2.059 169 4.051 356 1.04 7 1.149 276 2.06 4 4.052 24 1.041 91 1.15 155 2.061 41 4.053 1 1.042 532 1.151 554 2.062 23 4.054 1 1.043 843 1.152 569 2.062a 298 4.055 16 1.044 556 1.153 803 2.062b 14 4.056 64 1.045 565 1.154 54 2.063 219 4.057 13 1.046a 474 1.154a 46 2.064 84 4.058 90 1.047 127 1.155 315 2.065 1 4.059 61 1.048 275 1.156 92 2.066 359 4.06 60 1.049 10 1.156a 19 2.067 18 4.061 1 1.05 223 1.157 131 2.068 12 4.062 141 1.051 49 1.158 82 2.069 6 4.063 142 1.052 630 1.159 818 2.07 eleven 4.064 753 1.053 703 1.16 526 2.071 8 4.065 14 1.054 311 1.161 105 2.072 1 4.066 320 1.055 232 1.162 638 2.073 20 4.067a 20 1.056 4 1.163 953 2.074 25 4.067b 2 1.057 1 1.164 267 2.075 554 4.068 1 1.058 1 1.165 92 2.076 71 4.069 153 1.059 140 1.165a 43 2.077 112 4.07 73 1.06 727 1.165b 537 2.078 72 4.071 212 1.061 49 1.166 52 2.079 38 4.072 16 1.062 16 1.167 134 2.08 311 4.072a 8 1.063 107 1.168 728 2.081 118 4.073 173 1.064 968 1.169 5 2.082 342 4.074 27 1.065 567 1.17 16 2.083 777 4.075 2 1.066 16 1.170a 33 2.084 8 4.076 97

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1.067 319 1.171 16 2.085 179 4.077 4 1.068 512 1.171a 7 2.086 111 4.078 64 1.069 556 1.171b 446 2.087 84 4.078b 15 1.07 559 1.172 72 2.088 45 4.079a 186 1.071 4 1.173 BY 2.089 975 4.079b 18 1.072 32 1.174 36 2.09 3 4.08 46 1.073 118 1.175 673 2.091 62 4.080a 851 1.074 9 1.176 6 2.092 95 4.080b 15 1.075 44 1.176a 5 2.093 26 4.081 426 1.076 604 1.177 5 2.094 2 4.082 20 1.077 443 1.178 7 2.095 18 4.083 eleven 1.078 193 1.179 50 2.096 634 4.084 232 1.079 510 1.18 235 2.097 650 4.084b 77 1.08 564 1.181 104 2.098 94 4.085 61 1.081 118 1.182 218 2.099 343 4.086 472 1.082 445 1.183 79 2.1 396 4.087 342 1.083 76 1.184 3 2.101 29 4.088 138 1.084 223 1.185 9 2.102 411 4.089 299 1.085 268 1.186 37 2.103 4 4.09 34 1.086 154 1.187a 410 2.104 195 4.091 134 1.087 943 1.187b 981 Etc. 2.105 60 4.092 126 1.088 244 1.187s 3 Etc. 2.106 13 4.093 165 1.089 472 1.187d 353 2.107 114 4.094 201 1.09 35 1.188a 3 2.108 3 4.095 57 1.091 103 1.188b 519 3.001 965 4.096 33 1.092 1 1.188s 179 3.002 435 4.097 80 1.093 867 1.188d 362 3.003 105 4.098 18 1.094 100 1.189 36 3.003a 771 4.098a 12 1.095 254 1.189a 15 3.003b 54 4.099 852 1.095a 129 1.19 294 3.004 338 4.1 159 1.096 667 1.191 186 3.005 38 4.101 71 1.097 442 1.192 389 3.006 108 4.101a 18 1.098 276 1.192a 854 3.007 162 4.101b 712 1.099 131 1.192b 122 3.009 286 4.102 1 1.1 128 1.193 191 3.01 69 5.001 368 1.101 45 1.193a 97 3.011 22 5.002 857 1.102 111 1.194a 13 3.012 26 7.001 32 1.103 274 1.195 759 3.013 153 7.002 308 1.104 964 1.196 575 3.014 158 7.003 210 1.105 430 1.197 eleven 3.015 170 7.004 64 1.106 248 1.198 52 3.016 105 7.005 36 1.107 520 1.199 273 3.016a 90 7.006 8 1.108 581 2.001 209 3.017 661 7.007 140 1.109 902 2.002 670 3.018 198 7.008 51 1.11 535 2.003 34 3.019 778 7.009 240 1.111 332 2.004 118 3.020a 271 7.01 60 1.111a 944 2.005 25 3.020b 4 7.011 78 1.111b 114 2.006 15 3.021 40 7.012 356 1.112 227 2.007 88 3.022 28 7.013 252 1.113 118 2.008 405 3.022a 25 7.014 629 1.113a 561 2.009 10 4.001 133 7.015 201 1.113b 48 2.01 42 4.002 60 Etc. 7.016 2 1.114 626 2.011 114 4.003 333 SE 1.01s 206 1.115 566 2.013 28 4.004 319 SE 1.18s 119 1.116 614 2.014 269 4.005 388 1.117 68 2.015 54 4.006 149 1.117a 39 2.016 80 4.007 52 1.118 36 2.016a 49 4.008 150

The compounds of the invention may be further characterized in terms of their general pharmacokinetic and pharmacological properties using conventional assays well known in the art; for example, regarding their bioavailability in different species (such as rat or dog); or in relation to their drug safety and/or toxicological properties using conventional assays well known in the art, such as cytochrome P450 enzyme inhibition and time-dependent inhibition, X-pregnane receptor (PXR) activation, glutathione binding, or phototoxic behavior.

Claims (12)

Ar ¹ is an unsubstituted 5-membered heteroarylene group containing one ring sulfur atom and one or two ring nitrogen atoms, where the -NH-CO- group and Ar ² are attached in the meta position to the Ar ¹ ring atoms; Ar ² is phenyl which is mono-, di- or tri-substituted, wherein one or two of said substituents are independently selected from fluorine, chlorine and methyl, and the remaining(s), if present, is(are) is fluorine; R ¹ is R ^N1 R ^N2 N-, where RN ¹ is a -L ² -Ar ³ group, where L ² is a direct bond, -(C1-4)alkylene-; *-(C3-5)cycloalkylene(C0-2)alkylene-, where said (C3-5)cycloalkylene optionally contains one ring oxygen atom, where the asterisk denotes the bond to which Ar ³ is attached; *-(C1-2)alkylene(C _3-5 )cycloalkylene-, wherein said (C _3-5 )cycloalkylene optionally contains one ring oxygen atom, where the asterisk denotes the bond to which Ar ³ is attached; or -(C _1-3 )alkylene-, which is monosubstituted with hydroxy, trifluoromethyl, or -CO-(C _1-4 )alkoxy; And Ar ³ is phenyl, or a 5- or 6-membered heteroaryl containing one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said phenyl or 5- or 6-membered heteroaryl is independently unsubstituted, or mono-, or disubstituted, where the substituents are independently selected from (C _1-4 )alkyl, (C _1-4 )alkoxy, halogen, hydroxy, (C _1-3 )fluoroalkyl, or (C _1-3 )fluoroalkoxy, where in the case when Ar ³ is a 6-membered heteroaryl which is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present as the corresponding N-oxide; and RN ² is hydrogen; R ² is hydrogen; (C _1-6 )alkyl; or (C _3-8 )cycloalkyl(C _0-3 )alkyl, where (C _3-8 )cycloalkyl is unsubstituted, or mono- or disubstituted, where the substituents are independently selected from (C _1-3 )alkyl, fluorine, hydroxy, hydroxy-(C _1-3 )alkyl, (C _1-3 )alkoxy, or (C _1-3 )fluoroalkyl; And R ³ is hydrogen; or a pharmaceutically acceptable salt thereof. 2. The compound of formula (I) according to claim 1, which is also a compound of formula (IS) wherein the two piperidine ring substituents, R1-CO- and -NH-CO-Ar ¹ -Ar ² , are in the relative trans configuration, where the absolute the configuration of the two chiral carbons at positions 3 and 4 of the piperidine ring is (3S,4S) ^R2 Formula (Is); or a pharmaceutically acceptable salt thereof. 3. The compound according to any one of claims 1, 2, where Ar ¹ represents [1,3,4]thiadiazole-2,5-diyl or isothiazole-3,5-diyl; or a pharmaceutically acceptable salt thereof. 4. The compound according to any one of claims 1-3, where R ¹ is R ^N1 R ^N2 N-, where R ^N1 is - 111 040620 6-membered heteroaryl(C1.4)alkylene-, where the specified 6-membered heteroaryl contains one or two nitrogen atoms and where the specified 6-membered heteroaryl is unsubstituted, or mono-, or disubstituted; where the substituents are independently selected from ( _C1.4 ) alkyl, ( _C1.4 ) alkoxy, halogen, ( _C1.3 ) fluoroalkyl or ( _C1.3 ) fluoroalkoxy, where in the case where the 6-membered heteroaryl is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present as the corresponding N-oxide; 6-membered heteroaryl(C _{3 .5} )cycloalkylene-, wherein said 6-membered heteroaryl contains one or two nitrogen atoms, and wherein said 6-membered heteroaryl is unsubstituted, or mono-, or disubstituted, wherein the substituents are independently selected from (C1. ₄ )alkyl, (C1.4)alkoxy, halogen, ( _C1.3 )fluoroalkyl, or ( _C1.3 )fluoroalkoxy, where in the case where the 6-membered _heteroaryl is pyridyl or pyrimidinyl, such pyridyl or pyrimidinyl may additionally be present in the form of the corresponding N-oxide; and R ⁿ² is hydrogen; or a pharmaceutically acceptable salt thereof. 5. The compound according to any one of paragraphs.1-4, where R ² represents (C _{3 .8} )cycloalkyl( _C1.3 )alkyl, where (C _{3 .8} )cycloalkyl is unsubstituted; or monosubstituted, where the substituent is ( _C1.3 )alkyl, fluoro or ( _C1.3 )fluoroalkyl; or disubstituted with fluorine; or (C _{3 .8} )cycloalkyl, where (C _{3 .8} )cycloalkyl is unsubstituted or mono- or disubstituted, where the substituents are independently selected from ( _C1.3 )alkyl or fluorine; or a pharmaceutically acceptable salt thereof. 6. The compound according to any one of paragraphs.1-4, where R ² represents unsubstituted (C ₃ . ₈ )cycloalkyl(C1. ₃ )alkyl; or unsubstituted (C ₃ .b) cycloalkyl; or (C _{3 .8} )cycloalkyl, where (C _{3 .8} )cycloalkyl is disubstituted with fluorine; or (C _{3 .8} )cycloalkyl( _C1.3 )alkyl, where (C _{3 .8} )cycloalkyl is monosubstituted with methyl, fluorine, or (SCfluoroalkyl; or disubstituted with fluorine); or a pharmaceutically acceptable salt thereof. 7. The compound according to claim 1, which is (1-pyrimidin-2-yl-cyclopropyl)amide (3 S,4S)-1-cyclobutyl-4-{[5-(2,4-difluorophenyl)[ 1, 3,4]thiadiazole-2-carbonyl]amino}piperidine-3-carboxylic acid; (1-pyrimidin-2-yl-cyclopropyl)amide (38.48)-4-{[5-(2,4-difluorophenyl)[1,3,4]thiadiazole-2-carbonyl]amino}-1-( 1-fluorocyclopropylmethyl)piperidine-3-carboxylic acid; or (1-pyrimidin-2-yl-cyclopropyl)amide (38.48)-1-cyclopropylmethyl-4-{[5-(2,4-difluorophenyl)[1,3,4]thiadiazole-2-carbonyl]amino } piperidine-3-carboxylic acid; or a pharmaceutically acceptable salt thereof. 8. Compound (1-pyrimidin-2-yl-cyclopropyl)amide (38.48)-1-cyclopropylmethyl-4-{[5-(2,4-difluorophenyl)[1,3,4]thiadiazole-2-carbonyl ]amino}piperidine-3-carboxylic acid; or a pharmaceutically acceptable salt thereof. 9. A pharmaceutical composition which contains, as an active ingredient, one or more compounds according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient. 10. The use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, as a medicine. 11. The use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for the prevention or treatment of cancer, autoimmune disorders, inflammatory diseases, transplant rejection, or fibrosis. 12. The use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention or treatment of cancer, autoimmune disorders, inflammatory diseases, transplant rejection, or fibrosis. ^gj) Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2