Piperidine urea derivatives for cancer treatment

Abstract

Described herein are novel piperidine urea derivative compounds and pharmaceutical compositions thereof for the treatment of cancer as monotherapy or in combination with chemotherapeutic agents and / or checkpoint inhibitors.

Description

[Technical Field]

[0001] The subject matter disclosed herein is generally directed to methods and compositions for preventing, inhibiting, or treating cancer, specifically to selective piperidine urea-derived compounds as monotherapy or in combination with chemotherapeutic agents and / or checkpoint inhibitors for the treatment of cancer. [Background technology]

[0002] Epoxyeicosatrienoic acids (EETs) are catalyzed by cytochrome P450 (CYP) epoxygenases It is a metabolite of arachidonic acid by the β-glucanase enzyme, and has four positions: 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET. EETs have beneficial effects against inflammation and neuronal damage. Acute inflammatory states are usually resolved by the action of EETs, which allows tissues and associated immune cells to return to their pre-inflammatory baseline state. EET concentrations are regulated by soluble epoxide hydrolase (sEH), an enzyme that degrades EETs. and converts them to inactive or weakly active dihydroxyeicosatrienoic acids (DHETs). Increased expression of sEH is a key factor in many pathological chronic inflammation conditions, including neuroinflammation and diabetic inflammatory states. This has been shown to be a key factor in the regulation of EETs and the tumor microenvironment (PNAS 2021, vol 118 No. 41 e2107771118). sEH thereby limits many of the biological actions of EETs. Inhibiting sEH reduces the activity of EETs. This increases the half-life, leading to beneficial therapeutic effects.

[0003] sEH inhibitors have potential applications in the treatment of neuropathic and inflammatory pain, neurodegenerative diseases, cancer, and acute respiratory distress. syndrome (ARDS), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and Crohn's disease. It may be useful in the treatment of [Biomolecules (2020), 10, 703-724; Proc. Natl. Acad. Sciences. (2018), 115, E5815-E5823, Neurotherapeutics. (2020), 17(3), 900-916; Proc. Natl. Acad. Sciences. (2008), 105 (48), 18901-18906; Pharmacology & Therapeutics 180 (2017) 62-76; Nat. Rev. Drug. Discov. (2009), 8(10), 794-805; Cardiovasc. Hematol. Agents Med. Chem. (2012), Sep, 10(3), 212-22; Prostaglandins and Other Lipid Mediators 140 (2019) 31-39, Progress in Neurobiology, (2019), 172, 23-39, Inflamm.Allergy Drug Targets (2012) Apr, 11(2), 143-58; Mol.Pain (2011), 4, 7-78; Drug Discov Today.2015 Nov; 20(11):1382-90, Biomolecules. 2020 May 1;10(5):703, Prostaglandins Other Lipid Mediat.(2011), 96, 76-83, Pharmacology & Therapeutics 180 (2017) 62-76; Pharmacol Ther. 2017 Jun 19, S0163-7258(17)30154-7; Biochimie 159 (2019) 59-65. sEH inhibitors reduce the expression of inflammatory genes, suggesting their potential usefulness in inflammatory diseases (Inflamm.Allergy Drug Targets (2012) Apr, 11(2):143-58). 14,15-EET is approximately 35 times more potent than morphine and stimulates metencafrin in the brain. This suggests its usefulness as an analgesic (J Pharmacol Exp. Ther. (2008), Aug, 326(2), 614-22).

[0004] Despite the emergence of innovative treatments, cancer remains a leading cause of death worldwide. Chemotherapy remains the frontline treatment for many malignancies, but accumulating evidence suggests that tumor cell debris (e.g., apoptotic and necrotic cells) generated by chemotherapy and radiation promote tumor growth and metastasis, possibly through the production of inflammatory eicosanoids and suppression of the cancer-immune cycle (PNAS 2021, vol. 118 No. 41 e2107771118; Molecules 2020, vol. 25, 5488; Frontiers in Immunology, 2020, vol. 11, March, article 324). Common chemotherapy drugs (e.g., cisplatin, paclitaxel) A large body of literature confirms that cytotoxic agents (e.g., cyclosporine, 5-fluorouracil, and doxorubicin) also induce neuronal damage [JAMA Oncol. 2019;5(5):750]. The severity of the inflammatory response, neuronal damage, and toxicity can significantly limit the usefulness of cytotoxic agents. Combining therapeutic agents with agents that help resolve tumor-associated inflammation, neuronal damage, and associated immunity may provide novel treatments with improved efficacy and reduced adverse effects.

[0005] Advances over the past decade have led to the identification of immunotherapy as a novel treatment for many malignancies. Representative examples include checkpoint inhibitors (CPIs), tumor-infiltrating lymphocytes, Car-T cells, and oncolytic viruses. Immune checkpoint inhibitors have become the primary immunological tool in the treatment of cancer. Under homeostatic conditions, immune checkpoints maintain a balance between pro- and anti-inflammatory pathways that affect immune cell function. Cancer cells subvert this condition by promoting a highly immunosuppressive tumor environment. Immune checkpoint inhibitors block these pathways, enhancing the host's immune system to fight cancer. However, the efficacy of checkpoint inhibitors is limited to a small number of patients, and many attempts have been made to improve both the response rate and duration of response. Combining checkpoint inhibitors has been shown to improve response rates. A good example is the combination of ipilimumab (anti-CTLA4) and nivolumab (anti-PD1) in melanoma. Unfortunately, when different checkpoint inhibitors are combined, toxicity is clearly additive or even greater. In particular, immune system overactivation can lead to treatment discontinuation, hospitalization, and management with systemic immunosuppressants. [JAMA Oncol 2021, May 1;7(5):744-748; Nature Reviews Clinical Oncology 16, 563-580 (2019)]

[0006] Numerous attempts to enhance the response rate and / or mitigate the adverse effects of checkpoint inhibitors by combining them with other drugs have been made and are currently under investigation. In this context, tumor-associated chronic inflammation poses a serious obstacle to immunological antitumor responses. Therefore, resolving the chronic inflammatory state in the tumor microenvironment may be a promising way to achieve better efficacy in cancer therapies such as checkpoint inhibitors.

[0007] A novel approach to control immunological responses in solid and liquid tumors would be to use inhibitors of soluble epoxide hydrolase. Growing experimental data confirm the role of sEH inhibitors in resolving inflammation and preventing neuronal damage in multiple diseases. (PNAS, 2018, 115 (25) E5815-E5823; Mol Neurobiol.2015 Aug; 52(1):187-95; Mol Neurobiol.2015 Aug; 52(1):187-95) Thus, resolving chronic inflammation in the tumor microenvironment may be a promising approach to achieving greater efficacy in cancer treatment.

[0008] Several studies have confirmed that inhibition of EETs and she has neuroprotective properties. sEH is highly expressed in the brain, and the production and metabolism of EETs in the brain extend to many regions. It also extends to peripheral neurons, central neurons, astroglia, oligodendrocytes, vascular endothelial cells, and smooth muscle cells [J Histochem Cytochem.2008 Jun; 56(6):551-9, Am J Physiol 263: H519-25 1992, J Neurochem 61: 150-9 1993 Prostaglandins Other Lipid Mediat.91: 68-84 2010]. Studies have shown that inhibition of EETs or sEH i) prevents cytokine- and oxidant-mediated injury in neurons, ii) prevents endoplasmic reticulum (ER) stress, which is a major contributor to dopaminergic neuron loss, and iii) inhibits vascular endothelial growth. Enhances astrocyte release of factors and neuronal recovery after oxygen-glucose deprivation and iv) promotes axonal growth. [Am J Physiol Heart Circ Physiol 296:H1352-63, 2009, Expert Rev Mol Med 13: 7-12, 2011, Expert Rev Mol Med 13: 7-12, 1998, Expert Rev Mol Med 13: 7-12, 2014, Neuropathol Appl Neurobiol.42:607-620, 2016, Proc Natl Acad Sci USA. 112: 9082-9087, 2015, J Neurosci 27: 4642-9 2007, J Neurochem.117: 632-42 2011 and Neuroscience 223: 68-76 2012]. Deficiency of sEH attenuates dopaminergic neuronal loss in multiple animal models of Parkinson's disease [Mol Neurobiol. 52(1):187-95 2015]. In multiple animal models, inhibition of sEH alleviates disease symptoms and promotes neuronal healing, including diabetic neuropathic pain [Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18901-6, Eur J Pharmacol. 2013 Jan 30;700 (1-3):93-101, J Pain.2014 Sep;15(9):907-14, Proc Natl Acad Sci U S A. 2015 Jul 21;112(29):9082-7, Behav Brain Res. 2017 May 30;326:69-76]. sEH levels are associated with cognitive function. sEH inhibition is elevated in the cortical brain tissue of subjects with Alzheimer's disease sEH inhibition prevents H2O2-induced hyperphosphorylation of tau protein, a key factor in the pathogenesis of stroke [Prostaglandins Other Lipid Mediat.2014 Oct;113-115:30-7, J Huazhong Univ Sci Technolog Med Sci. 2016 Dec;36(6):785-790]. sEH inhibition is protective in rodent models of ischemic and diabetic stroke [Future Neurol.2009 Mar 1;4(2):179-199, Am J Pathol.2009 Jun;174(6):2086-95, PLoS One.2014 May 13;9(5):e97529, Am J Physiol Heart Circ Physiol. 2013 Dec 1;305(11):H1605-13]. Summary of the Invention

[0009] It is therefore an object of the present disclosure to provide methods and compositions for preventing, suppressing, or treating cancer using a combination of chemotherapeutic agents and / or immune checkpoint inhibitors, specifically methods and compositions for combining selective piperidine urea derived compounds with chemotherapeutic agents and / or immune checkpoint inhibitors to extend survival and / or reduce tumor growth in cancer subjects.

[0010] Citation or identification of any document in this application is not an admission that such document is available as prior art to the present disclosure.

[0011] overview The above objects are achieved, according to the present disclosure, by providing a method for treating cancer, which may include administering to a subject a therapeutically effective amount of at least one compound of formula I:

[0012] [ka]

[0013] where R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , or COR 3 is substituted with R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl It's okay;R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkyamine, or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , or COR 3 R 5 may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X may be selected from O, (CH2)p, NH, where p is 0 to 2; Y1-Y2 may be selected from CH-CH2, CH-O or C=CH, provided that when Y1-Y2 are CH-O, X is O or N H or R 1 is not hydrogen; Y3 may be selected from H or Me. It may be a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0014] Additionally, the present disclosure may provide a method of treating cancer comprising administering to a subject a therapeutically effective amount of at least one compound of formula I:

[0015] [ka]

[0016] where R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , or COR 3 is substituted with R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkyamine, or alkoxy; R 4 is hydrogen, alkyl , halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , or COR 3 mosquito R may be selected from the group consisting of 5 is alkyl, haloalkyl, cycloalkyl, R may be selected from the group consisting of aryl or amine; 6 is alkyl, cycloalkyl X may be selected from the group consisting of O, (CH2)p, NH, where p is 0 to 2, provided that when p=0, Y1-Y2 are not CH-CH2 or CH-O, and R 1 is not aryl; Y1-Y2 may be selected from CH-CH2, CH-O or C=CH, provided that when Y1-Y2 is CH-O, X may be selected from O or NH; R 1 is not hydrogen or alkyl; Y3 may be selected from H or Me; a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The salt may be a salt.

[0017] Additionally, Y3 can be H, and the compound is a compound according to formula II:

[0018] [ka]

[0019] where R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , or COR 3 is substituted with R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; Good;R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkyamine, or alkoxy; R 4 is hydrogen, alkyl, Halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , or COR 3 R 5 may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X may be selected from O, (CH2)p, NH, where p is 0 to 2; Y1-Y2 are selected from CH-CH2, CH-O, or C=CH When Y1-Y2 are CH-O, X may be selected from O or NH, or R 1is not hydrogen; Y3 may be selected from H or Me; a stereoisomer thereof or a pharmaceutical It may also be a salt that is acceptable to the public.

[0020] Additionally, Y3 may be H and the compound may be a compound according to formula II:

[0021] [ka]

[0022] where R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , or COR 3 is substituted with R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkyamine, or alkoxy; R 4 is hydrogen, alkyl aryl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , C.O.R. 3 R 5 may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X may be selected from O, (CH2)p, NH, where p is 0 to 2, provided that when p=0, Y1-Y2 are not CH-CH2 or CH-O, and R 1is not aryl; and Y1-Y2 are selected from CH-CH2, CH-O, or C=CH. However, when Y1-Y2 are CH-O, X may be selected from O or NH, and R 1 is hydrogen or alkyl It may be a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0023] Additionally, when Y3 is H, Y1-Y2 may be C=CH, and the compound is a compound according to formula III. It can also be an object.

[0024] [ka]

[0025] R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 , SO2NHR 2 , or COR 3 is substituted with R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkyamine, or alkoxy; R 4 is hydrogen, alkyl, Halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , SO2NHR 2 , C.O.R. 3 R 5may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X may be selected from O, (CH2)p, NH, where p is 0 to 2; a stereoisomer thereof or a pharmaceutically acceptable salt thereof. It may be an acceptable salt.

[0026] Nevertheless, when Y3 is H, Y1-Y2 may be CH-CH2, and the compound has formula IV It is a compound made by

[0027] [ka]

[0028] where R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 1 may be aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 , SO2NHR 2 , C.O.R. 3 may be substituted with R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkyamine or alkoxy; R 4 is hydrogen , alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , C.O.R. 3 may be selected from the group consisting of: 5may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl. The aryl or heteroaryl may be optionally substituted one or more times with groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, etc.; X may be selected from O, (CH)p, NH wherein p is selected from 0 to 2; a stereoisomer thereof or a pharmaceutically acceptable salt thereof. It is also possible.

[0029] Additionally, when Y3 is H, Y1-Y2 may be CH-CH2 and the compound may be a compound according to formula IV.

[0030] [ka]

[0031] where R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 , SO2NHR 2 , C.O.R. 3 is substituted with R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkyamine or alkoxy; R 4 is hydrogen, alkane alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , C.O.R.3 may be selected from the group consisting of: R 5 may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted one or more times with a group or substituent such as alkyl, hydroxy, halogen, haloalkyl, etc.; X may be selected from O, (CH)p, NH; Here, p may be selected from 0 to 2, but when p=0, R 1 is not aryl; or a pharmaceutically acceptable salt thereof.

[0032] Additionally, the compound of formula 1 may be one or more of the following compounds:

[0033] [ka]

[0034] [ka]

[0035] [ka]

[0036] a stereoisomer or a pharmaceutically acceptable salt thereof.

[0037] Furthermore, the compound of formula 1 may be one of the following compounds:

[0038] [ka]

[0039] A stereoisomer or a pharmaceutically acceptable salt thereof.

[0040] Furthermore, the compound of formula 1 may be one or more of the following compounds:

[0041] [ka]

[0042] a stereoisomer or a pharmaceutically acceptable salt thereof.

[0043] Furthermore, the compound inhibits the activity of the compound at concentrations below 10 μM (IC 50 ) inhibits soluble epoxide hydrolase It may harm.

[0044] Furthermore, the compound inhibits the activity of the compound at concentrations below 100 nM (IC 50 ) inhibits soluble epoxide hydrolase It may harm.

[0045] Furthermore, the compound was detected at concentrations below 100 nM (IC 50 ) to detect soluble epoxide hydrolase. Inhibits fatty acid amide hydrolase (IC 50 , FAAH (SEQ ID NO: 5)) It may have up to 10 times the selectivity.

[0046] Furthermore, this compound inhibits inflammatory cytokines at concentrations below 100 nM (IC 50 ) to detect soluble epoxide hydrolase. Inhibitory concentrations above 1000 nM (IC 50 ) may inhibit fatty acid amide hydrolase (FAAH (SEQ ID NO: 5)).

[0047] Furthermore, the cancer may be selected from the group consisting of ovarian cancer, leukemia, lymphoma, hematopoietic cancer, liver cancer, bone cancer, lung cancer, brain tumor, bladder cancer, gastrointestinal cancer, kidney cancer, breast cancer, heart cancer, cervical cancer, uterine cancer, head and neck cancer, gallbladder cancer, laryngeal cancer, lip and oral cavity cancer, eye cancer, skin cancer, melanoma, pancreatic cancer, prostate cancer, reproductive cancer, colon cancer, colorectal cancer, testicular cancer, and pharyngeal cancer.

[0048] Furthermore, the cancer may be selected from the group consisting of glioblastoma, melanoma, breast cancer, and colon cancer. good.

[0049] Additionally, the compounds can be administered to reduce tumor size and / or inhibit tumor growth.

[0050] Additionally, the compounds can be administered to inhibit metastasis of primary tumors.

[0051] Furthermore, the compounds can be administered in doses of from about 1 mg / day to about 1,000 mg / day.

[0052] Additionally, the compounds can be administered in doses ranging from about 4 mg / day to about 800 mg / day.

[0053] Additionally, the method may further comprise administering to the subject therapies comprising at least one selected from at least one chemotherapeutic agent, at least one immune checkpoint inhibitor, at least one anti-inflammatory agent, or a combination thereof. The method may also include administering one or more additional compounds.

[0054] Furthermore, the at least one chemotherapeutic agent may be cisplatin, paclitaxel, 5-fluroxen, or cisplatin. It may be selected from the group consisting of olouracil, doxorubicin, daunorubicin, carboplatin, gemcitabine, oxaliplatin, temozolomide, or a combination thereof.

[0055] Additionally, the at least one immune checkpoint inhibitor may be selected from the group consisting of PD-1 (SEQ ID NO: 2), PD-L1 (SEQ ID NO:3) or CTLA4 (SEQ ID NO:1).

[0056] Additionally, at least one immune checkpoint inhibitor is being tested, including pembrolizumab, nivolumab, and nivolumab. The antibody is selected from the group consisting of umab, semipilimumab, ipilimumab, atezolizumab, avelumab, urvalumab, or a combination thereof.

[0057] Furthermore, the at least one anti-inflammatory agent may be a nonsteroidal anti-inflammatory drug (NSAID), a selective cyclooxygenase-2 (cox-2) (SEQ ID NO: 4) inhibitor, an omega-3 fatty acid, or any combination thereof. The combination may be selected from the group consisting of:

[0058] Further, the NSAID or cox-2 (SEQ ID NO: 4) inhibitor may be naproxen, diclofenac, It may be selected from the group consisting of acetaminophen, ibuprofen, flurbiprofen, ketoprofen, celecoxib, aspirin, meloxicam, piroxicam, fenoprofen, salicylates, or combinations thereof.

[0059] The omega-3 fatty acid may be selected from the group consisting of alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), or a combination thereof.

[0060] The present disclosure also includes administering to a subject at least one compound of formula I, A method for reducing the toxicity and / or adverse effects experienced by a patient receiving a chemotherapeutic agent, or checkpoint inhibitor(s) may be provided:

[0061] [ka]

[0062] where R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , or COR 3 is substituted with R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkyamine, or alkoxy; R 4 is hydrogen, alkyl, Halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , or COR 3 R 5 may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X is selected from O, (CH2)p, NH, where p is 0 to 2; Y1-Y2 may be selected from CH-CH2, CH-O, or C=CH. However, when Y1-Y2 are CH-O, X may be selected from O or NH, or R 1 is hydrogen Y3 may be selected from H or Me; a stereoisomer thereof or a pharmaceutically acceptable salt thereof. It may also be a salt thereof.

[0063] Further, the present disclosure includes administering to a subject at least one compound of Formula I, The present invention may provide a method for reducing the toxicity and / or adverse effects experienced by a patient receiving the above chemotherapeutic agents, or checkpoint inhibitor(s):

[0064] [ka]

[0065] where R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , or COR 3 is substituted with R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkyamine, or alkoxy; R 4 is hydrogen, alkyl, halo Alkyl, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , or COR 3 Consists of may be selected from the group; R 5 may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X may be selected from O, (CH2)p, NH, where p is 0 to 2; provided that when p=0, Y1-Y2 are not CH-CH2 or CH-O, and R 1is not aryl; Y1-Y2 may be selected from CH-CH2, CH2-O or C=CH, provided that when Y1-Y2 is CH-O, X is selected from O or NH, or R 1 is hydrogen or alkane Y3 may be selected from H or Me; its stereoisomers or pharmaceutically acceptable salts thereof. The salt may be a salt obtained by the method described above.

[0066] Furthermore, compounds of formula I may reduce neuronal damage resulting from the administration of one or more chemotherapeutic agents.

[0067] Additionally, the present disclosure may provide a method for treating cancer, comprising administering to a subject a therapeutically effective amount of a soluble epoxide hydrolase inhibitor.

[0068] Further, the present disclosure provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of a soluble epoxide hydrolase inhibitor together with a therapeutically effective amount of one or more immune checkpoint inhibitors. The present invention may provide a method of treatment.

[0069] The present disclosure also provides a method for treating a patient receiving one or more chemotherapeutic agents, or a checkpoint inhibitor(s), comprising administering a soluble epoxide hydrolase inhibitor to a subject. The present invention may provide methods for reducing the toxicity and / or adverse effects experienced by subjects.

[0070] Nevertheless, the present disclosure can provide compounds of formula I:

[0071] [ka]

[0072] where R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 1may be aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , or COR 3 may be substituted with R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; —R 4 is hydrogen, alkyl, halogen amine, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , or COR 3 A group consisting of may be selected from;-R 5 is alkyl, haloalkyl, cycloalkyl, aryl, or or amines;

[0073] R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X may be selected from O, (CH)p, NH, where p is 0 to 2; Y1-Y2 may be selected from CH-CH 2, CH-O , or C=CH, provided that when Y1-Y2 are CH-O, X is selected from O or NH, or R 1 is not hydrogen; Y3 may be selected from H or Me; It may be a stereoisomer or a pharmaceutically acceptable salt thereof for use in therapy.

[0074] The present disclosure also provides compounds of Formula I, including:

[0075] [ka]

[0076] where R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 1 may be aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , or COR 3 may be substituted with R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkyamine, or alkoxy; R 4 is hydrogen, alkyl, halo Gen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , or COR 3 A group consisting of may be selected from; R 5 may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X may be selected from O, (CH2)p, NH, where p is 0 to 2, provided that when p=0, Y1-Y2 are not CH-CH2 or CH-O, and R 1 is not aryl; Y1-Y2 may be selected from CH-CH2, CH-O or C=CH, provided that when Y1-Y2 are CH-O, X may be selected from O or NH, and R 1 is not hydrogen or alkyl; Y3 is H or Me; or a stereoisomer or pharmaceutically acceptable salt thereof for use in the treatment of cancer.

[0077] The present disclosure relates to a method for treating a patient receiving one or more chemotherapeutic agents or a checkpoint inhibitor. Soluble epoxide hydrolase inhibitors can also be provided for use in reducing the toxic and / or adverse effects experienced by a subject.

[0078] The present disclosure can also provide soluble epoxide hydrolase inhibitors for use in the treatment of cancer.

[0079] Additionally, the present disclosure can provide a combination comprising a soluble epoxide hydrolase and an immune checkpoint inhibitor for use in treating cancer or for mitigating the deleterious effects of immune checkpoint inhibitors.

[0080] These and other aspects, objects, features, and advantages of the exemplary embodiments will become apparent to those skilled in the art upon consideration of the following detailed description of the exemplary embodiments.

[0081] An understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments in which the principles of the disclosure may be utilized, and the accompanying drawings of which: [Brief explanation of the drawings]

[0082] [Figure 1-1] FIG. 1 shows the soluble epoxide hydrolase inhibitory potency of compounds of formula I in Table 1. [Figure 1-2] FIG. 1 shows the soluble epoxide hydrolase inhibitory potency of compounds of formula I in Table 1. [Figure 1-3] FIG. 1 shows the soluble epoxide hydrolase inhibitory potency of compounds of formula I in Table 1. [Figure 2] FIG. 2 shows the antitumor efficacy of compound A of formula I in a melanoma cancer model as monotherapy and in combination with an anti-CTLA4 antibody. [Figure 3]FIG. 3 shows the antitumor efficacy of compound A of formula I in a melanoma cancer model as monotherapy and in combination with an anti-PD1 antibody. [Figure 4] FIG. 4 shows the anti-tumor responsiveness of compound A of formula I administered as monotherapy and in combination with an anti-CTLA4 antibody in a melanoma cancer model. [Figure 5] FIG. 5 shows serum levels of antinuclear antibodies (ANA) in a melanoma cancer model when compound A of formula I is administered as monotherapy and in combination with an anti-CTLA4 antibody. [Figure 6] FIG. 6 shows the antitumor efficacy of compound A of formula I in a breast cancer model as monotherapy and in combination with checkpoint inhibitors (anti-CTLA4 antibody±anti-PD1 antibody). [Figure 7] FIG. 7 shows lung metastases in a syngeneic breast cancer model when treated with compound A of formula I as monotherapy and in combination with checkpoint inhibitors (anti-CTLA4 antibody±anti-PD1 antibody). [Figure 8] FIG. 8 shows survival time / lifespan in a brain tumor (glioblastoma) model when compound A of formula I is used as a monotherapy and in combination with an anti-CTLA4 antibody. [Figure 9] FIG. 9 shows the efficacy of compound A of formula I in blocking paclitaxel-induced nerve damage. [Figure 10] FIG. 10 shows the antitumor efficacy of compound A of formula I in a colon cancer model as monotherapy and in combination with an anti-CTLA4 antibody. [Figure 11] FIG. 11 shows survival / longevity of compound A of formula I in a colon cancer model as monotherapy and in combination with an anti-CTLA4 antibody. DETAILED DESCRIPTION OF THE INVENTION

[0083] The figures depicted in the drawings are for illustrative purposes and are not necessarily drawn to scale.

[0084] DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS Before describing the present disclosure in more detail, it is to be understood that this disclosure is not limited to particular embodiments described, and as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0085] Unless otherwise expressly stated, terms, phrases, and variations thereof used herein should be construed as open ended rather than limiting. Similarly, a group of items joined by the conjunction "and" should not be read as requiring the presence of every single one of those items in the group, but rather should be read as "and / or" unless expressly stated otherwise. Similarly, a group of items joined by the conjunction "or" should not be read as requiring mutual exclusivity between the group, but rather should be read as "and / or" unless expressly stated otherwise.

[0086] Furthermore, although items, elements, or components of the disclosure may be described or claimed in the singular, the plural is also contemplated within its scope unless limitation to the singular is expressly stated. In some cases, the terms "one or more," "at least," "but not limited to," "one or more ... The presence of a broader term, such as "shall not" or other similar term, shall not be read to mean that a narrower case is intended or required where such broader term might not be present.

[0087] Unless otherwise defined, all technical and scientific terms used herein are defined by the principles of the present disclosure. The terms "antibody" and "antibody" have the same meaning as commonly understood by one of ordinary skill in the art to which they pertain. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of this disclosure, the preferred methods and materials are now described.

[0088] All publications and patents cited herein are cited to disclose and describe the methods and / or materials in connection with which the publications are cited. All such publications and patents are incorporated by reference herein as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. Such incorporation by reference is expressly limited to the methods and / or materials described in the cited publications and patents and does not extend to dictionary definitions of the cited publications and patents. Lexical definitions in cited publications and patents that are not expressly repeated in this application should not be treated as such and should not be read as defining terms recited in the appended claims. The citation of publications is for their disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publications by prior disclosure. Further, the stated publication dates may differ from the actual publication dates, which may need to be independently confirmed.

[0089] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has distinct components and features that may be readily separated from, or combined with, the features of any of the other several embodiments without departing from the scope or spirit of the disclosure. Any described method can be carried out in the order of events described or in any other order that is logically possible.

[0090] When a range is expressed, a further embodiment includes from the one particular value and / or to the other particular value. The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within each range, as well as the recited endpoints. When a range of values ​​is provided, unless the context clearly dictates otherwise, each intervening value, to one-tenth of the unit of the lower limit, between the upper and lower limit of that range, and every other recited value within that recited range. or any intervening value is understood to be encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure. For example, if a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure. For example, the phrase "from x to y" includes not only a range from "x" to "y," but also a range greater than "x" but less than "y." Ranges can also be expressed as upper limits, e.g., "about x, y, z, or less." and should be interpreted to include the specific ranges of "about x," "about y," and "about z," as well as the ranges "less than x," "less than y," and "less than z." Similarly, the phrase "about x, y, z, or more" should be interpreted to include not only the specific ranges of "about x," "about y," and "about z," but also the ranges "greater than x," "greater than y," and "greater than z." Furthermore, the expression "about 'x' to 'y'" includes "about 'x' to about 'y'" when 'x' and 'y' are numerical values.

[0091] It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format. It is further understood that the endpoints of each range are significant in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values ​​disclosed herein, and that each value is also disclosed herein as "about" (approximately) that particular value, in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Ranges can be expressed herein as from "about" (approximately) one particular value and / or to "about" (approximately) another particular value. Similarly, when values ​​are expressed as approximations, the use of the antecedent "about" will understand that the particular value forms a further aspect. For example, if the value "about 10" is disclosed, then "10" is also disclosed.

[0092] It should be understood that such range formats are used for convenience and brevity and, therefore, should be interpreted flexibly to include not only the numerical values ​​explicitly recited as the limits of the range, but also all individual numerical values ​​or subranges subsumed within the range, as if each numerical value and subrange were expressly recited. As an example, a numerical range of "about 0.1% to about 5%" should be interpreted to include not only the explicitly recited numerical values ​​of about 0.1% to about 5%, but also individual numerical values ​​(e.g., about 1%, about 2%, about 3%, about 4%) and subranges (e.g., about 0.5% to about 1.1%, about 5% to about 2.4%, about 0.5% to about 3.2%, about 0.5% to about 4.4%, and other possible subranges) within the indicated range.

[0093] As used herein, the singular forms "a," "an," and "the" include both the singular and the plural referents unless the context clearly indicates otherwise.

[0094] As used herein, terms such as "about," "approximately," and "substantially" are used. When used in connection with a measurable variable such as a parameter, quantity, or time duration, it means that the result is within the limits of experimental error, e.g., variation of the stated value by no more than ±10%, no more than ±5%, no more than ±1%, or no more than ±0.1%. It is meant to encompass variations of the specified value and variations from the specified value, including those within a given difference (e.g., that can be determined by a given data set, an art-recognized standard, and / or, for example, a predetermined confidence interval (e.g., a 90%, 95% or higher confidence interval from the mean)). As used herein, the terms "about," "approximate," "at or about," and "substantially" can mean that the amount or value in question can be an exact value or a value that will provide an equivalent result or effect as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximated and / or larger or smaller, as desired, to reflect tolerances, conversion factors, rounding, measurement error, etc., and other factors known to those skilled in the art that will provide an equivalent result or effect. In some circumstances, it may not be possible to reasonably determine a value that will provide an equivalent result or effect. Generally, any reference to an amount, size, formulation, parameter, or other quantity or characteristic may be made to "about," "approximately," or "at or about," whether or not expressly stated as such. Use "about," "approximately," or "at or about" before quantitative values. is used, unless specifically stated otherwise, it is understood that the parameter also includes the specific quantitative value itself.

[0095] As used herein, a "biological sample" may include whole cells and / or viable cells and / or cell debris. A biological sample may include (or be derived from) a "body fluid." The present disclosure provides that a body fluid may include, but is not limited to, amniotic fluid, aqueous humor, vitreous humor, bile, blood serum, breast milk, cerebrospinal fluid, earwax, chyle, chyme, endolymph, perilymph, and the like. Perilymph, exudate, feces, female ejaculate, gastric acid, gastric juice, lymph Fluid, mucus (including nasal discharge and phlegm), pericardial fluid, peritoneal fluid, pleural fluid, pus, catarrhal discharge (rheum), saliva Examples of biological samples include those selected from the group consisting of body fluids, sebum (skin oils), semen, sputum, synovial fluid, sweat, tears, urine, vaginal fluids, vomit, and mixtures of one or more of these. Biological samples include cell cultures, body fluids, and cell cultures from body fluids. Body fluids may be obtained from a mammalian organism, for example, by lancing or other withdrawal or sampling procedures.

[0096] As used herein, "drug" refers to any substance, compound, molecule, etc., that can be administered to a subject. A drug can be inactive. A drug can be an active agent. Drug can be a primary active agent, in other words, the component(s) of the composition that are responsible for all or part of the composition's effect. The agent can be a secondary agent, in other words, the component(s) of the composition that are additional parts of the composition and / or responsible for other effects of the composition.

[0097] As used herein, "active agent" or "active ingredient" refers to a substance, compound, or molecule that is biologically active or otherwise induces a biological or physiological effect in a subject to which it is administered. In other words, "active agent" or "active ingredient" refers to the component or components of a composition that are responsible for all or part of the effect of the composition.

[0098] As used herein, "administration" refers to any suitable administration of the agent(s) to be delivered and / or to the subject receiving said agent(s), including oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, Intra-articular, intra-joint, parenteral, intra-arterial, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal The administration may be intravenously, intralesionally, intranasally, intracardially, intraarticularly, intracavernosally, intrathecally, intravenously, intracerebrally and intraventricularly, intratympanically, intracochlearly, intrarectally, intravaginally, by inhalation, by catheter, by stent, or via an implanted reservoir or other device that actively or passively (e.g., by diffusion) administers the composition to the perivascular space and adventitia. For example, a medical device such as a stent can contain a composition or formulation disposed on its surface, which can then dissolve or otherwise distribute into surrounding tissues and cells. The term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Examples of administration routes include auricle (ear), cheek, conjunctiva, skin, dental, electroosmotic, intracervical, intranasal sinus, intratracheal, enteral, epidural, extra-amniotic, extracorporeal, hemodialysis, infiltration, interstitial, intraperitoneal, intra-amniotic, intra-arterial, intra-articular, intra-biliary duct, intra-bronchial, intra-synovial bursa, intracardiac, intracartilage, intra-coccygeal, intracavernous, intracavity, intracerebral, intra-cistern, intracorneal, intradental cavity, intracoronary artery, intracavernous body cavity, intradermal, intravertebral disc, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intracavity, intralesional, intraluminal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intraovarian, intrapericardium, intraperitoneum, intrapleural, and intraprostatic. pulmonary, intraanal, intraspinal, intrasynovial, intratendinous, intratesticular, intrathecal, intrathoracic, intraluminal, intratumoral, intratympanic, intrauterine, intravascular, intravenous, bolus injection, intravenous drip, intraventricular, intravesical, intravitreal, iontophoresis, perfusion, laryngeal, nasal, nasogastric, occlusive dressing, ophthalmic, oral, oropharyngeal, other, parenteral, transdermal, periarticular, peridural, perineural, periodontal, rectal, respiratory (inhalation), retrobulbar, soft tissue, subarachnoid, subconjunctival, subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transplacental, transtracheal, transtympanic, ureteral, urethral, ​​and / or vaginal administration; and and / or any combination of the above routes of administration, which are typically It depends on the disease, the subject being treated, and / or the agent(s) being administered.

[0099] As used herein, a "control" can refer to a substitute subject or sample used in an experiment for comparison purposes and included to minimize or distinguish the effects of variables other than the independent variable.

[0100] The term "optional" or "optionally" means that the subsequently described event, circumstance, or substituent may or may not occur, and the description includes instances in which the event or circumstance occurs and instances in which it does not occur.

[0101] As used herein, "dose," "unit dose," or "dosage" can refer to physically discrete units suitable for administration to a subject, each unit containing a predetermined quantity of a pharmaceutical formulation calculated to produce a desired response or reaction associated with its administration.

[0102] As used herein, the term "molecular weight" may generally refer to the mass or average mass of a substance.

[0103] As used herein, the terms "subject," "individual," and "patient" are used interchangeably to refer to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, rodents, apes, humans, farm animals, sport animals, and pets. Tissues, cells, and their progeny of biological entities obtained in vivo or cultured in vitro are also encompassed by the term "subject."

[0104] As used herein, "substantially pure" can mean that the target species is the predominant species present (i.e., more abundant than other individual species in the composition on a molar basis); preferably, a substantially purified fraction is one in which the target species constitutes about 50% of all species present. Generally, a substantially pure composition constitutes about 80% or more of all species present in the composition, more preferably about 85%, 90%, 95%, or 99% or more. Most preferably, the target species is purified to essential homogeneity (contaminating species cannot be detected in the composition by conventional detection methods), and the composition consists essentially of a single species.

[0105] When used interchangeably herein, the terms "sufficient" and "effective" refer to an amount (e.g., an amount) necessary to achieve one or more desired and / or described results. For example, a therapeutically effective amount can refer to the amount needed to achieve one or more therapeutic effects.

[0106] As used herein, a "tangible medium of expression" refers to a medium that is physically tangible or accessible and is not merely an abstract thought or unrecorded spoken word. "Tangible medium of expression" includes, but is not limited to, words on a cellulosic or plastic material, or data stored in a suitable computer-readable memory form. Data can be stored on a unit device such as a flash memory or CD-ROM, or on a server accessible to a user, for example, via a web interface.

[0107] As used herein, the terms "treat" and "treatment" can generally refer to obtaining a desired pharmacological and / or physiological effect. The effect can be, but is not necessarily, preventative, in that it prevents or partially prevents a disease, symptom, or condition, such as cancer and / or indirect radiation damage. The effect can be therapeutic, in that it partially or completely cures a disease, condition, symptom, or adverse effects resulting from a disease, disorder, or condition. As used herein, the term "treatment" covers any treatment of cancer and / or indirect radiation damage in a subject, particularly a human and / or companion animal, and can include any one or more of the following: (a) (b) preventing disease or injury from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed as having the disease; (c) alleviating the disease, i.e., preventing its onset; and / or alleviating or ameliorating the disease, disorder, or condition. As used herein, the term "treatment" can refer to therapeutic treatment only, prophylactic treatment only, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and / or those in whom a disorder is to be prevented. As used herein, the term "treating" can include inhibiting a disease, disorder, or condition, e.g., preventing its progression; and alleviating a disease, disorder, or condition, e.g., causing regression of a disease, disorder, and / or condition. Treating a disease, disorder, or condition can include improving at least one symptom of a particular disease, disorder, or condition even if the underlying pathophysiology is not affected, e.g., reducing a subject's pain through administration of a painkiller. Treating pain can be included even if such analgesics do not treat the cause of the pain.

[0108] As used herein, the terms "weight percent," "wt%," and "wt.%" mean: The terms "wt%" and "wt%" can be used interchangeably and refer to the weight percent of a given component based on the total weight of the composition of which it is a component, unless otherwise specified. That is, all wt% values ​​are based on the total weight of the composition, unless otherwise specified. It should be understood that the sum of the wt% values ​​of all components in a disclosed composition or formulation equals 100. Alternatively, wt% values ​​may be used to refer to the weight percent of a subset of components in a composition. When based on total weight, the sum of the wt% values ​​of the specified ingredients in a disclosed composition or formulation should be understood to equal 100.

[0109] "Halogen or halo" means fluorine, chlorine, bromine or iodine.

[0110] An "alkyl" group refers to a straight-chain or branched alkyl group. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl, and the like. Unless otherwise specified, alkyl groups typically have from about 1 to about 10 carbon atoms.

[0111] A "cycloalkyl" group refers to a cyclic alkyl group that may be monocyclic or bicyclic. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Unless otherwise specified, a cycloalkyl group typically has from about 3 to about 10 carbon atoms.

[0112] A "haloalkyl" group is an alkyl group in which at least one hydrogen has been replaced with a halogen or halo group. It refers to a straight or branched chain alkyl group. Exemplary haloalkyl groups include trifluoromethyl, chloroethyl, difluoromethyl, difluoroethyl, and the like.

[0113] A "hydroxyalkyl" group means a linear monovalent hydrocarbon radical of one to three carbon atoms or a branched monovalent hydrocarbon radical of three to five carbon atoms, substituted with one or two hydroxy groups. Representative examples include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, and the like.

[0114] "Alkoxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, substituted with an alkoxy group, as defined above, such as methoxymethyl, 2-methoxyethyl, and 1-, 2-, or 3-methoxypropyl.

[0115] "Heterocycloalkyl" means a group consisting of carbon and hydrogen atoms and at least one heterocyclic group. A heterocycloalkyl group refers to a non-aromatic monocyclic or polycyclic ring containing one or more carbon-carbon double bonds or carbon-heteroatoms in the ring, unless their presence renders the ring aromatic. Examples of heterocycloalkyl groups include pyrrolidinyl and pyrrolidinyl. Examples include pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, tetrahydrofuranyl, tetrahydropyranyl, and pyranyl.

[0116] "Alkoxy" refers to the group -O(alkyl), where alkyl is as defined above. Exemplary alkoxyl groups include methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, and the like. Unless otherwise specified, alkoxy groups typically have from 1 to about 10 carbon atoms.

[0117] "Amine" refers to primary, secondary, and tertiary amino groups. Secondary and tertiary amines may contain alkyl, cycloalkyl, or aryl substitutions. Examples of amines include: Examples include NH2, NHMe, NMe2NH (cyclopropyl), etc. Unless otherwise specified, The alkyl or cycloalkyl group on the amine typically has from 1 to about 8 carbon atoms.

[0118] "Aryl" means an optionally substituted monocyclic or polycyclic ring having from about 6 to about 14 carbon atoms. "aryl" means an aromatic ring system of the formula: aryl, phenyl, naphthyl, and the like. Unless otherwise specified, aryl groups typically have from 6 to about 14 carbon atoms.

[0119] "Heteroaryl" refers to an aromatic monocyclic or polycyclic ring system of about 4 to about 12 carbon atoms having at least one heteroatom or heterogroup selected from -O-, -N-, -S-, -SO2, or -CO-. Exemplary heteroaryl groups include pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, imidazolyl, triazolyl, pyridazinyl, thienopyrimidylfuranyl, indolyl, isoindolyl, benzo[1,3]dioxolyl, benzimidazolyl, 1,3-benzoxathiolyl, pyrrolidine 2,4-dionyl, quinazolinyl, pyridyl, pyrimidinyl, thiophenyl, and the like. Unless otherwise specified, heteroaryl groups typically have from 4 to about 10 carbon atoms.

[0120] The "5- to 6-membered heteroaryl" is a 5- to 6-membered heteroaryl selected from -O-, -N-, -S-, -SO2, or -CO-. Aromatic monocyclic rings of 5 or 6 ring atoms with at least one heteroatom or hetero group Exemplary "5- to 6-membered heteroaryl" groups include one or more of pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, pyridazinyl, pyridyl, thienopyrimidyl, tetrazolyl, imidazolyl, triazolyl, furanyl, and the like. .

[0121] "Optionally substituted" means that substitution is optional, and therefore the specified atom or molecule can be unsubstituted. If substitution is desired, such substitution means that any number of hydrogens on the specified atom are replaced with a selection from the indicated group, provided that the substitution does not exceed the normal valence of the specified atom and that the substitution results in a compound that is sufficiently stable for use.

[0122] "Salt" refers to any acid or base salt, pharmaceutically acceptable solvate, or any complex of a compound that, when administered to a recipient, can provide (directly or indirectly) a compound as described herein. However, it should be understood that non-pharmaceutically acceptable salts are also within the scope of the present disclosure. Salts can be prepared using known methods. For example, pharmaceutically acceptable salts of compounds contemplated as useful herein can be synthesized by conventional chemical methods using a parent compound that contains a basic or acid functional group. Generally, such salts can be prepared, for example, by preparing the free acid or base form of the compound and reacting it with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixture thereof. Generally, non-aqueous media such as one or more solvents, such as ether, ethyl acetate, ethanol, isopropanol, acetonitrile, etc., can be utilized. Examples of acid addition salts include one or more of mineral acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc., and organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, etc. Examples of base addition salts include one or more of inorganic salts such as sodium salt, potassium salt, calcium salt, ammonium salt, magnesium salt, lithium salt, etc., and organic base salts such as ethylenediamine salt, ethanolamine salt, N,N-dialkylethanolamine salt, triethanolamine salt, basic amino acid salt, etc.

[0123] The phrase "therapeutically effective" refers to the treatment of a disorder or disease while generally avoiding adverse effects. It indicates the ability of an agent or combination to prevent or reduce the severity of symptoms. Therapeutically effective compositions of the present disclosure may contain a compound of the present disclosure in a dose of about 10 to about 3000 mg. The exact dosage can be determined based on many factors, including the characteristics of the patient and the degree of treatment required.

[0124] As used herein, "effective amount" or "therapeutically effective amount" refers to the dose or amount and frequency of administration of the compound of the present disclosure administered to a subject to produce a therapeutic response.The dose or effective amount to be administered to a subject and the frequency of administration to a subject can be easily determined by those skilled in the art by using known techniques and observing the results obtained under similar circumstances.When determining the effective amount or dosage, the attending physician can take into account many factors, including but not limited to the potency and duration of action of the compound used, the nature and severity of the disease being treated, and the gender, age, weight, general health and individual responsiveness of the subject being treated, and other relevant circumstances.

[0125] The compounds described herein may be used in admixture with one or more pharmaceutically acceptable excipients or carriers. The compound or compounds can be administered in the form of a pharmaceutical composition. A "pharmaceutical composition" is any composition that is useful or potentially useful in producing a physiological response in a subject to which such pharmaceutical composition is administered.

[0126] The term "pharmaceutically acceptable" is used with respect to excipients to define a non-toxic substance generally suitable for use in human or veterinary medicine. Pharmaceutical compositions may be in commonly employed forms such as tablets, capsules, powders, syrups, solutions, suspensions, and the like. Pharmaceutical compositions may contain suitable solid or liquid carriers or diluents to form injectable solutions or suspensions, or flavoring agents, sweeteners, and the like, in a suitable sterile vehicle. Such compositions typically contain from about 0.1 to about 50% by weight of the active compound, some active ingredient, and / or some non-active ingredient. In this embodiment, it contains about 1 to about 20% by weight, and the remainder of the composition is a pharmaceutically acceptable carrier, diluent or or a solvent.

[0127] Various embodiments are described below. It should be noted that a particular embodiment is not intended as an exhaustive description or as a limitation on the broad aspects discussed herein. An aspect described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment(s). Throughout this specification, the terms "one embodiment," "an ... Reference to an "exemplary embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Various places throughout this specification refer to "in one embodiment," ... Appearances of phrases such as "in an embodiment," "in one embodiment," or "one exemplary embodiment" do not necessarily all refer to the same embodiment, but may. Furthermore, it will be apparent to those skilled in the art from this disclosure that a particular feature, structure, or characteristic may be used in one or more embodiments. As will be apparent from the following description, the features and combinations of the present invention may be combined in any suitable manner. Furthermore, while some embodiments described herein may include some features but not others included in other embodiments, it is intended that combinations of features from different embodiments are within the scope of the present disclosure. For example, in the appended claims, any of the claimed embodiments may be used in any combination.

[0128] All patents, patent applications, published applications, and publications, databases, websites, and other published materials cited herein are incorporated by reference to the same extent as if each individual publication, published patent document, or patent application was specifically and individually indicated to be incorporated by reference.

[0129] kit Any of the compounds and / or formulations described herein can be presented as a combination kit. As used herein, the term "combination kit" or "kit of parts" refers to any additional components used to package, sell, sell, deliver, and / or administer multiple or single elements, such as compounds, compositions, formulations, particles, cells, and combinations of elements or active ingredients contained therein. Such additional components include, but are not limited to, packaging, syringes, blister packs, bottles, etc. One or more of the compounds, compositions, formulations, particles, cells, or combinations thereof (e.g., drug(s)) described herein contained in the kit can be simultaneously administered. When used in combination, the kit can contain the active agent(s) in a single formulation, such as a pharmaceutical formulation (e.g., a tablet, a liquid formulation, a dehydrated formulation, etc.), or in separate formulations. When the compounds, compositions, formulations, particles, and cells described herein, or combinations thereof and / or kit components are not administered simultaneously, the kit can contain each agent or other component in a separate pharmaceutical formulation. Separate kit components can be included in a single package or in separate packages within the kit.

[0130] In some embodiments, the combination kit also includes instructions printed on or otherwise contained in a tangible medium. The instructions may provide information regarding the contents of the compounds and / or formulations, safety information regarding the contents of the compounds and formulations (e.g., pharmaceutical formulations), dosages of the compounds and / or pharmaceutical formulations contained therein, indications for use, and / or recommended treatment regimen(s). In some embodiments, the instructions may provide directions and protocols for administering the compounds and / or formulations described herein to a subject in need thereof. In some embodiments, the instructions may provide one or more embodiments of methods for administering the pharmaceutical formulations, such as any of the methods described in more detail elsewhere herein.

[0131] Detailed Description of Disclosure Reference will now be made in detail to the embodiments of the present disclosure, one or more examples of which are set forth below. The examples are provided to illustrate, but not to limit, the disclosure. Indeed, it will be apparent to those skilled in the art that various modifications can be made in the disclosure without departing from the scope or spirit of the disclosure. For example, as part of one embodiment, The illustrated or described features can be used in other embodiments to yield further embodiments. Accordingly, the present disclosure is intended to cover such modifications and variations as come within the scope of the appended claims and their equivalents. Other objects, features, and aspects of the present disclosure are disclosed in or are apparent from the following detailed description.

[0132] For ease of reference, the present disclosure will be described in terms of administration to human subjects, however, it will be understood that such description is not limited to administration to humans and also includes administration to other animals unless expressly stated otherwise.

[0133] Contemplated derivatives are those that may improve the solubility or increase the bioavailability of the compounds of the present disclosure when such compounds are administered to a subject (e.g., by making an orally administered compound more easily absorbed). Compounds of Formula I: The compound may be amorphous, semi-crystalline, or crystalline, and may be administered in the form of the parent compound, its salt, and / or solvate. The solvate may be part of the crystal lattice or may be superficially associated. All of these forms are intended to be within the scope of the present disclosure. Solvation methods are generally known in the art. Suitable solvates are pharmaceutically acceptable solvates. In one embodiment, the solvate is a hydrate.

[0134] In one aspect, the present disclosure is directed to novel compounds of formula I: [ka]

[0135] its stereoisomers, stable labels (e.g., deuterated variants), or pharmaceutically acceptable salts; where R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 is alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , C.O.R. 3 and optionally one or more times with a group or substituent such as It may be substituted. R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R5 , C.O.R. 3 is selected from the group consisting of R 5 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted one or more times with groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, etc. X is selected from O, (CH2)p, and NH; where p is selected from 0 to 2, but when p=0, , Y1-Y2 are not CH-CH2 or CH-O, and R 1 is not aryl; and Y1-Y2 are selected from CH2-CH2, CH2-O, or CH=CH, provided that when Y1-Y2 are CH2-O, X is selected from O or NH; R 1 is not hydrogen or alkyl. Y3 is selected from H or Me.

[0136] In another aspect, the present disclosure is directed to novel compounds of formula II: [ka]

[0137] a stereoisomer or a pharmaceutically acceptable salt thereof;

[0138] where R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 is alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, Alkoxy, amine, SO2NHR 2 , C.O.R. 3 and optionally one or more times with a group or substituent such as It may be substituted. R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , C.O.R. 3 is selected from the group consisting of R 5 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted one or more times with groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, etc. X is selected from O, (CH2)p, and NH; where p is selected from 0 to 2, but when p=0, , Y1-Y2 are not CH-CH2 or CH-O, and R 1 is not aryl; and Y1-Y2 are selected from CH-CH2, CH-O, or C=CH, provided that when Y1-Y2 are CH2-O, X is O. or NH, and R 1 is not hydrogen or alkyl.

[0139] In another aspect, the present disclosure is directed to novel compounds of formula III: [ka]

[0140] a stereoisomer or a pharmaceutically acceptable salt thereof;

[0141] where R 1is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 is alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 , SO2NHR 2 , C.O.R. 3 and the like. R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , C.O.R. 3 is selected from the group consisting of R 5 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted one or more times with groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, etc. X is selected from O, (CH2)p, and NH, where p is selected from 0 to 2, and when p=0, R 1 is not aryl.

[0142] In another aspect, the present invention is directed to novel compounds of formula IV: [ka]

[0143] a stereoisomer or a pharmaceutically acceptable salt thereof;

[0144] where R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 is alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 , SO2NHR 2 , C.O.R. 3 and optionally substituted one or more times with a group or substituent such as R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl R 3 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , C.O.R. 3 Selected from the group consisting of R 5 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted one or more times with groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, etc. X is selected from O, (CH2)p, and NH, where p is selected from 0 to 2, and when p=0, R 1 is not aryl.

[0145] Additionally, the composition may include one or more of the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof;

[0146] [ka]

[0147] [ka]

[0148] [ka]

[0149] In one embodiment, the disclosure may include a compound of Formula I, wherein the compound is an inhibitor of soluble epoxide hydrolase (sEH) with greater than 10-fold selectivity over fatty acid amide hydrolase (FAAH (SEQ ID NO: 5)).

[0150] In one embodiment, the present disclosure provides compounds of formula I that inhibit fatty acid amide hydrolase (IC 50 , FAAH (SEQ ID NO: 5)) with an IC of < 100 nM 50 The method may include inhibiting soluble epoxide hydrolase with

[0151] In another embodiment, the compound of formula I has an IC of < 100 nM 50 inhibits soluble epoxide hydrolase with an IC of >1000 nM 50 can inhibit fatty acid amide hydrolase (FAAH (SEQ ID NO: 5)).

[0152] In a further embodiment, the compound of formula I is 50 Soluble epoxide hydrolase at <50 nM inhibits enzymes and IC 50 Inhibits fatty acid amide hydrolase (FAAH (SEQ ID NO: 5)) at >1000 nM possible.

[0153] In a further embodiment, the compound of formula I is 50 Soluble epoxide hydrolase at <20 nM inhibits enzymes and IC 50 Inhibits fatty acid amide hydrolase (FAAH (SEQ ID NO: 5)) at >1000 nM possible.

[0154] In other embodiments, the therapeutically effective amount of the compound of Formula I is from about 0.5 mg / day to about 3,000 mg / day. In embodiments, the therapeutically effective amount of the compound of Formula I is from about 1 mg / day to about 2,000 mg / day. In embodiments, the therapeutically effective amount of the compound of Formula I may be from about 2 mg / day to about 1000 mg / day. In embodiments, the therapeutically effective amount of the compound of Formula I may be from 3 mg / day to about 700 mg / day. In embodiments, the therapeutically effective amount of the compound of Formula I may range from 4 mg / day to about 500 mg / day. In embodiments, the therapeutically effective amount of the compound of Formula I may range from 3 mg / day to about 400 mg / day. In embodiments, the therapeutically effective amount of the compound of formula I may be from 10 mg / day to about 300 mg / day.

[0155] In some embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 2 mg to about 1,500 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 4 mg to about 750 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 1 mg to about 1,500 mg per day. A therapeutically effective amount of a compound of Formula I for an adult subject may be from about 6 mg to about 600 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 10 mg to about 500 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 20 mg to about 400 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 20 mg to about 300 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 20 mg to about 300 mg per day. A therapeutically effective amount of the compound may be from about 20 mg to about 200 mg per day.

[0156] In further embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 20 mg to about 120 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 20 mg to about 100 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 20 mg to about 75 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 20 mg to about 60 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 20 mg to about 50 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 20 mg to about 40 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 20 mg to about 40 mg per day. An effective amount may be about 24 mg to about 40 mg per day. A therapeutically effective amount of a compound of Formula I for a non-adult subject can be from about 0.1 mg to about 700 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for a non-adult subject can be from about 0.25 mg to about 350 mg per day. In embodiments, the therapeutically effective amount of a compound of Formula I for a non-adult subject may be from about 0.5 mg to about 300 mg per day. The therapeutically effective amount may be from about 1 mg to about 200 mg per day. A therapeutically effective amount of a compound of Formula I for a non-adult subject may be from about 2 mg to about 100 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for a non-adult subject may be from about 3 mg to about 80 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for a non-adult subject may be from about 4 mg to about 60 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for a non-adult subject may be from about 5 mg to about 80 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for a non-adult subject may be from about 5 mg to about 80 mg per day. A therapeutically effective amount of the compound may be from about 6 mg to about 60 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for a non-adult subject may be from about 6 mg to about 50 mg per day. In this embodiment, the therapeutically effective amount of the compound of Formula I for a non-adult subject is about 6 mg to about 40 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for a non-adult subject may be from about 6 mg to about 30 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for a non-adult subject may be from about 7 mg to about 25 mg per day.

[0157] In yet other embodiments, a therapeutically effective amount of a compound of Formula I is administered in a single dose or over a period of time. The treatment may be administered once or in several repeated doses after intervals. An effective amount is administered daily, or once every two or three days, or once a week. Administration may be once, twice, or three times daily. In embodiments, a therapeutically effective amount is administered daily or every other day for two weeks or more, ten weeks or more, thirty weeks or more, one year or more, or as long as the symptoms or disease are present. In embodiments, a therapeutically effective amount is administered daily or every other day for 30 weeks or more. or more will be administered.

[0158] Additionally, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds described herein. A pharmaceutical composition comprising the compound of formula (I) may be provided.

[0159] In some embodiments, the present disclosure provides a method of inhibiting or reducing metastasis of a primary tumor in a cancer subject, the method comprising a regimen of administering to the subject a therapeutically effective amount of a compound of formula I, with or without one or more chemotherapeutic agents and / or checkpoint inhibitors.

[0160] In yet another aspect, the present disclosure provides inhibitors of soluble epoxide hydrolase (sEH). The novel compounds of formula I, their stereoisomers, stable labels (e.g., heavy and / or its pharmaceutically acceptable salts. There are.

[0161] In another aspect, the present disclosure provides a method for the prevention and / or treatment of pain, neurodegenerative diseases, cancer, and inflammatory disorders in a subject in need of such treatment, comprising administering to a subject a therapeutically effective amount of a compound of Formula I, its stereoisomers, and / or its pharmaceutically acceptable salts. The compounds of formula I may be used in various forms, including stereoisomers and and / or its pharmaceutically acceptable salts, as monotherapy or in combination with one or more chemotherapeutic agents and / or immune checkpoint inhibitors , can be used in the prevention or treatment of cancer.

[0162] Furthermore, the compounds of formula I, their stereoisomers and / or pharmaceutically acceptable salts are of interest. The method can be used to prevent, inhibit or treat cancer in a subject in need of such treatment, comprising administering to a subject a therapeutically effective amount of at least one compound of formula I to one or more This includes regimens administered with or without chemotherapy and / or immune checkpoint inhibitors.

[0163] In another embodiment, the stereoisomers and / or pharmaceutically acceptable salts of Formula I are It may be used in the treatment of cancer in combination with an anti-cancer (NSAID or cox-2 (SEQ ID NO: 4) inhibitor) agent, one or more chemotherapeutic agents and / or immune checkpoint inhibitors.

[0164] For ease of reference, the present disclosure will be described in terms of administration to human subjects, however, it will be understood that such description is not limited to administration to humans and also includes administration to other animals unless expressly stated otherwise.

[0165] Contemplated derivatives are those that may improve the solubility or increase the bioavailability of the compounds of the present disclosure when such compounds are administered to a subject (e.g., by making an orally administered compound more easily absorbed). Compounds of Formula I: The compound may be amorphous, semi-crystalline, or crystalline, and may be administered in the form of the parent compound, its salt, and / or solvate. The solvate may be part of the crystal lattice or may be superficially associated. All of these forms are intended to be within the scope of the present disclosure. Solvation methods are generally known in the art. Suitable solvates are pharmaceutically acceptable solvates. In one embodiment, the solvate is a hydrate.

[0166] In one embodiment, the compounds of the present disclosure (compounds of Formula I) are useful for treating inflammatory pain, neuropathic pain, The compounds of formula I are useful in the treatment of inflammatory and / or pain disorders, rheumatoid arthritis, osteoarthritis, diabetic nephropathy, hypertension, diabetes, and / or metabolic syndrome. It may be useful to increase the levels of epoxyeicosatrienoic acids (EETs) in a subject to prevent and treat conditions.

[0167] The compounds of formula I, their pharmaceutically acceptable salts, and / or solvates thereof may be and thus may be used in the prevention and / or treatment of the diseases or conditions discussed herein. A therapeutically effective amount of a compound of formula I, its pharmaceutically acceptable salt, and / or a solvent thereof. Pharmaceutical compositions comprising the solvate, optionally together with a pharmaceutically acceptable excipient, are a further aspect of the disclosure.

[0168] The therapeutic properties of the compound of formula I, its pharmaceutically acceptable salts and / or solvates to be administered The efficacy and dosage for treating a pathological condition with said compounds will depend on many factors, such as the age and condition of the patient, the severity of the disease, the route and frequency of administration, and the modulator compound used.

[0169] Suitable pharmaceutically acceptable carriers may include solid fillers or diluents and sterile aqueous or organic solutions. The active ingredient may be present in such pharmaceutical compositions in an amount sufficient to provide a desired dosage within the ranges described above. Thus, for oral administration, the active ingredient may be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions, and the like. For parenteral administration, the active ingredient may be combined with a sterile aqueous or organic medium to form an injectable solution or suspension. For example, sesame oil, peanut oil, aqueous propylene glycol, and the like may be used, as may aqueous solutions of water-soluble pharmaceutically acceptable acid addition salts or base salts of the compound. Alternatively, an aqueous solution of the active ingredient dissolved in a pharmaceutically acceptable solvent such as polyhydroxylated castor oil may be used for injection. The injection solution prepared in this manner may be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration generally being preferred for humans.

[0170] The following examples describe exemplary embodiments of the present disclosure. Other embodiments within the scope of the claims herein will be apparent to those skilled in the art from consideration of the specification or examples of the present disclosure disclosed herein. It is intended that the specification, together with the examples, be considered exemplary, with the scope and spirit of the disclosure being indicated by the claims which follow the examples.

[0171] General synthetic procedure

[0172] Compounds of the present disclosure can be synthesized according to the procedures outlined in Schemes I-VIII. The suggested methodologies are not intended to be limiting: variations on these synthetic methodologies or methodologies reported in the literature can be employed to synthesize compounds within the scope of this disclosure.

[0173] [ka]

[0174] Scheme I illustrates a method for synthesizing compound 7 of formula I of the present disclosure. In the first step, a substitutional halogenation Benzyl 1 (Z = Cl, Br) reacts with trialkyl phosphite to give substituted benzyl phosphonate 2. This reaction can be carried out by heating 1 with trialkyl phosphate at 120-150 °C for 10-20 h with or without a solvent such as dimethylacetamide. Substituted alkenes 4 can be prepared from intermediate 2 by generating ylides and reacting them with substituted piperidones 3. The synthesis of 3 is achieved by the following reaction. The formation of the ylide from 2 can be carried out in a solvent such as THF, dimethoxyethane, or diethyl ether in the presence of a crown ether using a base such as sodium hydride or potassium hydride. This reaction can be initiated at low temperature (0±5°C), after which the reaction mixture can be warmed to approximately 20°C and stirred for an additional 20-60 minutes. The reaction of the ylide formed from 2 with 3 can be carried out in a solvent such as THF, dimethoxyethane, diethyl ether, or toluene. The reaction is initiated at a low temperature (0±5°C), and the reaction mixture is then heated to approximately 20-40°C and stirred for 8-20 hours. Deprotection of the carbamate from 4 in the presence of an acid provides the piperidine intermediate 5. This reaction is carried out in a solvent such as dichloromethane or dichloroethane with an acid such as trifluoroacetic acid by stirring the reaction mixture at a temperature between 0 and 25°C for 20 to 90 minutes. The reaction of 5 with the substituted cyclopropane carbamate intermediate 6 gives the target compound 7. This reaction can be carried out in a solvent such as dimethyl sulfoxide or dimethylacetamide. The reaction components are mixed with a base such as triethylamine or diisopropylethylamine for 40-60 minutes. This can be done by heating at 0°C for 3-6 hours.

[0175] Substituted cyclopropane carbamates 6 can be prepared in solvents such as dichloromethane and diisopropyl Reaction with allyl chloroformate (R=Ph or Ar) using a base such as ethylamine The reaction can be carried out by reacting the corresponding cyclopropylamine 8 with the The reaction mixture can be started at low temperature (0±5° C.), and then warmed to about 20-30° C. and stirred for 20-40 minutes. The substituted benzyl halides 1 and substituted piperidones 3 used in Scheme I are , can be purchased commercially or synthesized from readily available reagents.

[0176] [ka]

[0177] Scheme II illustrates a method for synthesizing compound 11 of formula I of the present disclosure. In the first step, compound 4, synthesized using the methodology described in Scheme I, is hydrogenated to give saturated compound 9. This reaction can be carried out using catalytic hydrogenation (e.g., using Pd / C or Pt / C) in a Parr hydrogenation apparatus in a solvent such as methanol or ethanol. In the presence of an acid, carbamate 9 is formed. Deprotection of the compound gives the piperidine intermediate 10. This reaction is carried out in a solvent such as dichloromethane or dichloroethane using an acid such as trifluoroacetic acid, and the reaction mixture is heated to a temperature of 0-25°C. The reaction can be carried out by stirring at rt for 20-90 min. The reaction of 10 with the substituted cyclopropane carbamate intermediate 6 gives the desired compound 11. This reaction is carried out in the presence of dimethylsulfoxide. The reaction can be carried out by heating the reactants at 40-60° C. for 3-6 hours using a solvent such as acetamide or dimethylacetamide and a base such as triethylamine or diisopropylethylamine.

[0178] [ka]

[0179] Scheme III illustrates a method for synthesizing compounds 18 and 19 of the present disclosure. In the first step, hetero Compound 12 containing an aryl ring A (pyridine, pyrimidine, pyrazine, etc.) is reacted with substituted phenol 13 to give 14. This reaction can be carried out in a wide range of amides, such as dimethylacetamide, dimethylformamide, etc. The reaction mixture can be heated at 80-120°C for 3-6 hours in any solvent using a base such as potassium carbonate, sodium carbonate, or cesium carbonate. The alcohol is converted to the corresponding benzyl halide 15 by reaction with thionyl chloride. This reaction is carried out in a solvent such as dichloromethane with thionyl chloride at 0-25°C for 1-3 hours. The substituted benzyl halide 15 can be reacted with a trialkyl phosphite to give the substituted benzyl phosphonate 16. This reaction can be carried out by heating 15 with the trialkyl phosphite at 120-150°C for 10-20 hours, with or without a solvent such as dimethylacetamide. The ylide from intermediate 16 is then reacted with substituted piperidone 3 to give the substituted alkene 17. The synthesis was carried out in the presence of crown ether in solvents such as THF, dimethoxyethane, and diethyl ether. The reaction can be carried out using a base such as sodium hydride or potassium hydride in the presence of 1,2,3,4-trimethylsilyl. The reaction can be initiated at a low temperature (0±5°C), followed by warming the reaction mixture to about 20°C and stirring for an additional 20 to 60 minutes. The reaction of the ylide generated from 16 with 3 can be carried out in a solvent such as THF, dimethoxyethane, diethyl ether, or toluene by initiating the reaction at a low temperature (0±5°C), followed by warming the reaction mixture to about 20 to 40°C and stirring for 8 to 20 hours. 17 to 18 The conversion to HCl can be achieved by deprotecting the carbamate in the presence of acid, as described in Scheme I. , which may be carried out after the step of reacting with substituted cyclopropane carbamate intermediate 6 The conversion of 17 to 19 can be achieved in successive steps, including hydrogenation, carbamate deprotection, and reaction with the substituted cyclopropane carbamate intermediate 6, as described in Scheme II. This can be achieved using

[0180] [ka]

[0181] Scheme IV shows a method for synthesizing compounds 26 and 27 of the present disclosure. In the first step, compound 20 is reacted with a substituted phenol 21 to give 22. This reaction can be carried out using dimethylacetamide or The reaction mixture can be heated in a solvent such as ethylformamide using a base such as cesium carbonate at 80 to 120°C for 3 to 8 hours. The benzyl halide 23 is converted to the corresponding benzyl halide 24 by reaction with thionyl chloride. This reaction is carried out in a solvent such as dichloromethane at 0-25°C for 1-3 hours. The substituted benzyl halide 23 can be reacted with a trialkyl phosphate to give the substituted benzyl phosphonate 24. This reaction can be carried out by heating 23 with the trialkyl phosphite at 120-150°C for 10-20 hours, with or without a solvent such as dimethylacetamide. Substituted alkenes 25 can be synthesized by generating the ylide from intermediate 24 and reacting it with a substituted piperidone 3. The generation of the ylide from 24 can be carried out using a base such as sodium hydride or potassium hydride in the presence of a crown ether in a solvent such as THF, dimethoxyethane, or diethyl ether. The reaction can be initiated at low temperature (0±5°C), after which the reaction mixture can be warmed to approximately 20°C and stirred for an additional 20-60 minutes. The reaction of the ylide generated from 24 with 3 can be carried out in a solvent such as THF, dimethoxyethane, diethyl ether, or toluene by initiating the reaction at low temperature (0±5°C), then warming the reaction mixture to about 20-40°C and stirring for 8-20 hours. As described in Section I, the carbamate is deprotected in the presence of acid to give the substituted cyclopropanol. This can be carried out after the reaction of 25 with the benzophenone carbamate intermediate 6. Conversion of is accomplished using sequential steps including hydrogenation, carbamate deprotection, and reaction with a substituted cyclopropane carbamate intermediate 6, as described in Scheme II. It is possible.

[0182] [ka]

[0183] Scheme V shows a method for synthesizing compounds 33 and 34 of the present disclosure. In the first step, a substituted halogen The benzyl phosphate 28 is reacted with a trialkyl phosphite to give the substituted benzyl phosphonate 29. This reaction can be carried out by heating 28 with the trialkyl phosphate at 120-150 °C for 10-20 hours, with or without a solvent such as dimethylacetamide. The substituted alkene 30 can be obtained by generating the ylide from intermediate 29 and reacting it with the substituted piperidone 3. The synthesis of the ylide from 29 is carried out in THF, dimethoxyethane, diethyl ether, The reaction can be carried out in a solvent such as ether in the presence of a crown ether using a base such as sodium hydride or potassium hydride. The reaction can be initiated at low temperature (0±5°C), after which the reaction mixture is warmed to about 20°C and stirred for an additional 20-60 minutes. The ylide formed from 29 and 3 are reacted to form a cyclohexanediamine. The reaction is carried out in a solvent such as THF, dimethoxyethane, diethyl ether or toluene. The reaction is initiated at a low temperature (0±5°C), and the reaction mixture is then heated to approximately 20-40°C and stirred for 8-20 hours. Intermediate 31 containing heterocyclyl ring A can be prepared by stirring the mixture of pyrrolidine It can be synthesized from 30 by reacting with the corresponding heterocycle, such as morpholine or piperidine. This reaction is carried out with cesium carbonate and palladium acetate and 2,2'-bis(diphenyl)- The conversion of 31 to 33 can be achieved by treating 30 with the ring A heterocycle using a catalyst such as (1,1'-(2-phenylphosphino)-1,1'-binaphthyl (BINAP). The reaction can be carried out using a solvent such as 1,4-dioxane at 20-100°C for 5-20 hours. The conversion of 31 to 33 can be achieved by deprotection of the carbamate in the presence of acid, as described in Scheme I. and the step of reaction with substituted cyclopropane carbamate intermediate 6 is carried out after can be done.

[0184] Conversion of 31 to 32 can be achieved using catalytic hydrogenation (Pd / C, H), as described in Scheme II. Similarly, conversion of 32 to 34 can be achieved by carbamate deprotection and subsequent reaction with the substituted cyclopropane carbamate intermediate 6, as described in Scheme II. The reaction can be carried out according to the methodology comprising the reaction.

[0185] [ka]

[0186] Scheme VI illustrates a method for synthesizing compound 40 of the present disclosure. In the first step, compound 35 containing a heteroaryl ring A (pyridine, pyrimidine, pyrazine, etc.) is reacted with a substituted phenol 36. This reaction can be carried out in a solvent such as dimethylacetamide or dimethylformamide using a base such as potassium carbonate, sodium carbonate, or cesium carbonate by heating the reaction mixture at 80-120°C for 3-8 hours. The reaction with mesylate 38 gives 39. This reaction is carried out in a solvent such as dimethylacetamide or dimethylformamide using a base such as potassium carbonate, sodium carbonate, or cesium carbonate. Conversion of 39 to 40 can be achieved by deprotecting the carbamate in the presence of acid and then adding the substituted silyl group, as described in Scheme I. This can be carried out after the step of reacting with chloropropane carbamate intermediate 6.

[0187] [ka]

[0188] Scheme VII illustrates a method for synthesizing compounds of formula 45 and 46 of the present disclosure. In the first step, The arylboronate-containing compound 41 is reacted with an aryl halide 42 to give 43. This reaction is carried out by reacting 41 and 42 in a solvent such as dimethylacetamide or dimethylformamide with 2N aqueous sodium carbonate and tetrakis(triphenylphosphine)palladium (0 ) at ambient temperature 20-25°C for 12-18 hours. Conversion of 43 to 45 can be achieved by the reaction of 45 with a carbamate in the presence of an acid, as described in Scheme I. and reacting with a substituted cyclopropane carbamate intermediate 6. It is possible.

[0189] Conversion of 43 to 44 can be achieved using catalytic hydrogenation (Pd / C, H), as described in Scheme II. Similarly, conversion of 44 to 46 can be achieved by deprotection of the carbamate and reaction with the substituted cyclopropane carbamate intermediate 6, as described in Scheme II. The method may be carried out according to a methodology including:

[0190] [ka]

[0191] Scheme VIII illustrates a method for synthesizing compounds of formula 54 of the present disclosure. In the first step, substituted benzyl halide 47 is reacted with a trialkyl phosphate to give substituted benzyl phosphonate 48. This reaction can be carried out by heating 47 with trialkyl phosphite at 120-150°C for 10-20 hours. Substituted alkenes 49 are synthesized by generating the ylide from intermediate 48 and reacting it with substituted piperidone 3. The generation of the ylide from 48 can be carried out using a base such as sodium hydride or potassium hydride in the presence of a crown ether in a solvent such as THF, dimethoxyethane, or diethyl ether. The reaction can be initiated at low temperature (0±5°C), after which the reaction mixture can be warmed to approximately 20°C and stirred for an additional 20-60 minutes. The reaction of the ylide generated from 48 with 3 can be carried out in a solvent such as THF, dimethoxyethane, diethyl ether, or toluene by initiating the reaction at low temperature (0±5°C), then warming the reaction mixture to about 20-40°C and stirring for 8-20 hours. Conversion of 49 to 50 can be achieved by catalytic hydrogenation. This reaction can be accomplished using catalytic hydrogenation (e.g., Pd / C or Pt / C) in a Parr hydrogenation apparatus in a solvent such as methanol or ethanol. In the next step, 52 is synthesized by the substitution reaction of substituted 1-fluoro-2-nitrobenzene 51 with 50. This reaction is carried out in a solvent such as dimethylformamide. 50 and 51 are treated in a solvent, and the reaction mixture is heated in the presence of cesium carbonate at 80-120°C for 10-20 hours. The synthesis of benzimidazole compound 53 can be achieved by treating 52 with formic acid and sodium formate in the presence of Pd / C at around 25°C and heating the mixture at around 100-120°C for 12-20 hours. Conversion of 53 to 54 can be achieved by treatment with substituted cyclopropanecarbamate intermediate 6, as described in Scheme II. [Example]

[0192] One embodiment of the present disclosure is the preparation of novel compounds of Formula I using the procedures described in the Examples below. Those skilled in the art will understand that known variations of the conditions and steps of the following preparative procedures can be used to prepare these compounds. Moreover, by utilizing the procedures described herein, one skilled in the art can prepare additional compounds of the present disclosure claimed herein.

[0193] Example 1 4-(3-Methoxy-benzylidene)-piperidine-1-carboxylic acid (2-phenyl- Synthesis of chloropropyl-amide: [ka]

[0194] Step 1: To a mixture of (3-methoxy-phenyl)-methanol (20.0 g, 0.14 mol) and pyridine (5.8 mL, 0.72 mol) in benzene (120 mL) was added thionyl chloride (74 mL, 1.01 mol) dropwise while stirring in an ice bath. After removing from the ice bath, the resulting reaction mixture was diluted with saturated sodium bicarbonate. Quench with aqueous sodium solution (100 mL), extract with ethyl acetate (2X300 mL), and add over sodium sulfate. The crude product obtained by evaporating the volatiles was then passed through a silica gel (230-400) column ( Purification with 5% ethyl acetate in ether gave product 2 as a yellow oil, 20.01 g (88%). Ta. 1 H NMR (300 MHz, CDCl3) δ(ppm):3.84 (s, 3H), 4.58 (s, 2H), 6.86-6.90 (m, 1H), 6.95-7.00 (m, 2H), 7.26-7.32 (m, 1H).

[0195] Step 2: Dissolve 2 (20 g, 0.12 mol) in triethyl phosphite (29.0 mL, 0.16 mol). The mixture was heated at 150°C for 17 hours. The reaction mixture was cooled to room temperature and the volatiles were evaporated. The resulting crude product was purified on a silica gel (230-400) column (20% ethyl acetate in petroleum ether) to give product 3 as a colorless oil 27.0 g (81%). 1 H NMR (300 MHz, CDCl3) δ(ppm): 1.26 (t, J=7.2 Hz, 6H), 3.11 (s, 1H), 3.18 (s, 1H), 3.81 (s, 3H), 4.01-4.03 (m, 4H), 6.79-6.91 (m, 3H), 7.21-7.28 (m, 1H).

[0196] Step 3 To a solution of 3 (11.0 g, 43.0 mmol) in THF (44 mL) was added 15-crown ether (0.2 mL, 0.9 mmol). The reaction was cooled (ice bath) and NaH (580 mg, 24.2 mmol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and re-cooled using an ice bath. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 4 (8.5 g, 43.0 mmol) in THF (44 mL) was added to the above reaction mixture at ice temperature and stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (100 mL), extracted with ethyl acetate, and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (25% ethyl acetate in petroleum ether). The product 5 was obtained as a yellow oil, 7.0 g (54%). 1 H NMR (300 MHz, CDCl3) δ(ppm): 1.49 (s, 9H), 2.32-2.36 (m, 2H), 2.44-2.50 (m, 2H), 3.42 (t, J=5.7 Hz, 2H), 3.52 (t, J=5.7 Hz, 2H), 3.84 (s, 3H), 6.35 (s, 1H), 6.75-6.81 (m, 3H), 7.25-7.25 (m, 1H).

[0197] Step 4: To a solution of 5 (1.0 g, 3.2 mmol) in dichloromethane (8.0 mL) was added trifluoroacetic acid (4.25 mL, 4.25 vol) at ice temperature, and the reaction mixture was stirred at room temperature for 1 h. The crude product obtained after evaporation of the volatiles was washed with diethyl ether to give 6 (600 mg, 89%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ(ppm): 2.54-2.62 (m, 4H), 3.07-3.17 (m, 4H), 3.75 (s, 3H), 6.44 (s, 1H), 6.77-6.84 (m, 3H), 7.27 (t, J=7.8 Hz, 1H), 8.79 (BS, 2H).

[0198] Step 5: To a suspension of trans-2-phenylcyclopropylamine 2A (3.5 g, 0.02 mol) in dichloromethane (35 mL) was added triethylamine (0.06 mol) and phenyl chloroformate 1A (4.8 g, 0.03 mol) at ice bath temperature. The ice bath was then removed and the reaction mixture was stirred at room temperature for 30 min. The resulting reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (2x100 mL). The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (10% ethyl acetate in petroleum ether) to give product 7 as a white solid, 2.6 g (50%), 113.6–115.3 °C. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.14-1.26 (m, 2H), 2.03-2.09 (m, 1H), 2.72-2.75 (m, 1H), 7.10-7.40 (m, 10H), 8.18 (bs, 1H).MS: 254 (M+H).

[0199] Step 6: To a solution of amine 6 (300 mg, 0.94 mmol) in dimethyl sulfoxide (6 mL), Diisopropylethylamine (0.5 mL, 2.82 mmol) and carbamate 7 (238 mg, 0.94 mmol) were added at 25°C. The resulting reaction mixture was diluted with ethyl acetate (250 mL), washed with water (4 x 75 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to give product 8 as a white solid, 226 mg (65%). MP: 104.7-106.4°C. 1 H NMR (300 MHz, CDCl3) δ(ppm): 1.15-1.27 (m, 2H), 2.02-2.09 (m, 1H), 2.40 (t, J=5.7 Hz, 2H), 2.54 (t, J=5.7 Hz, 2H), 2.87 (bs, 1H), 3.39 (t, J=5.7 Hz, 2H), 3.49 (t, J=5.7 Hz, 2H), 3.82 (s, 3H), 4.87 (s, 1H, -CONH-, interchangeable 1 H), 6.37 (s, 1H), 6.75-6.81 (m, 3H), 7.18-7.30 (m, 6H). 13 C NMR (75 MHz, CDCl3) δ (ppm): 16.44, 25.10, 29.14, 33.19, 35.72, 44.60, 45.60, 55.18, 111.88, 114.60, 121.36, 124.76, 125.95, 126.65, 128.28, 129.16, 137.90, 138.70, 140.88, 157.95, 159.53.MS: 363 (M+H)

[0200] Example 2 4-[3-(pyridin-2-yloxy)-benzylidene]-piperidine-1-carvone Synthesis of acid (2-phenyl-cyclopropyl)-amide [ka]

[0201] Step 1 To a solution of 2-fluoro-pyridine (25.8 g, 0.27 mol) in DMF (300 mL) was added 3-hydroxybenzoate. Hydroxyphenyl-methanol (30.0 g, 0.24 mol) and cesium carbonate (117.3 g, 0.36 mol) were added at room temperature. The reaction mixture was stirred at 100°C for 5 hours. The resulting mixture was allowed to cool to room temperature, diluted with water (250 mL), extracted with ethyl acetate (3 x 500 mL), and the organic layer was dried over sodium sulfate. The volatiles were evaporated and the crude product was purified by silica gel (230-400) column chromatography. The product 2 was purified with hexane (30% ethyl acetate in petroleum ether) to give 34.5 g (71% ethyl acetate) of a pale yellow oil. ) was obtained. 1 H NMR (300 MHz, DMSO-d6) δ(ppm):4.49-4.51 (m, 2H), 5.24-5.30 (m, 1H), 6.98-7.15 (m, 5H), 7.33-7.40 (m, 1H), 7.82-7.89 (m, 1H), 8.14-8.16 (m, 1H).

[0202] Step 2: To a solution of 2 (34.5 g, 0.17 mol) in dichloromethane (345 mL) was added thionyl chloride (13.9 mL, 0.18 mol) dropwise while stirring the reaction in an ice bath. After removing the ice bath, the reaction The mixture was stirred at room temperature for 1 h. The volatiles were then evaporated under reduced pressure and toluene (25 m The mixture was diluted with 1 L of toluene and the toluene was evaporated under reduced pressure. This azeotropic process was repeated three times to give the product 3 as a brown oil (36.8 g, 98%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm):4.77 (s, 2H), 7.04-7.20 (m, 4H), 7.27-7.29 (m, 1H), 7.42 (t, J=8.4 Hz, 1H), 7.84-7.90 (m, 1H), 8.14-8.16 (m, 1H).

[0203] Step 3: 3 (36.7 g, 0.16 mol) in triethyl phosphite (41.6 mL, 0.26 mol) The solution was heated at 150° C. for 6 hours. The reaction mixture was allowed to cool to room temperature, and the volatiles were evaporated to give a crude product, which was then purified by silica gel (230-400) column (60% ethyl acetate in petroleum ether). Purification gave the product 4 as a colorless oil, 41.33 g, which contained unused triethyl phosphate and was used in the next step without further purification.

[0204] Step 4 [3-(pyridin-2-yloxy)-benzyl]-phosphonic acid diene in THF (120 mL) To a solution of ethyl ester 4 (30.0 g, 93.0 mmol), 15-crown ether (0.41 g, 1.8 mmol) was added. The reaction was cooled (ice bath) and NaH (3.35 g, 0.14 mol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and then cooled to ice again. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 5 (18.6 g, 93.0 mmol) in THF (120 mL) was added to the above reaction mixture at ice temperature and stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (500 mL), extracted with ethyl acetate (3×500 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (3% ethyl acetate in petroleum ether) to give product 6 as a yellow oil, 24.3 g (71%). 1 H NMR (300 MHz, CDCl3) δ (ppm): 1.41 (s, 9H), 2.27 (t, J=5.4 Hz, 2H), 2.40 (t, J=5.4 Hz, 2H), 3.33 (bs, 2H), 3.40 (t, J=5.4 Hz, 2H), 6.37 (s, 1H), 6.95-7.15 (m, 4H), 7.37 (t, J=7.8 Hz, 2H), 7.83-7.88 (m, 1H), 8.14-8.16 (m, 1H).

[0205] Step 5: To a solution of 4-[3-(pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester 6 (12.0 g, 33.0 mmol) in dichloromethane (120.0 mL) was added trifluoroacetic acid (51 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 1 h. Evaporation of the volatiles afforded a brown oil 7 (13.7 g, 85%), which was used in the next step without further purification. Used (13.7 g, 85%). 1 H NMR (300 MHz, DMSO-d6) δ(ppm): 2.56-2.63 (m, 4H), 3.10-3.16 (m, 4H), 6.46 (s, 1H), 6.99-7.15 (m, 5H), 7.39 (t, J=7.5 Hz, 1H), 7.83-7.88 (m, 1H), 8.14-8.16 (m, 1H).

[0206] Step 6 To a solution of amine 7 (15.0 g, 26.0 mmol) in dimethyl sulfoxide (150 mL) To the mixture, diisopropylethylamine (13.6 mL, 78.0 mmol) and the product of Step 5, Example 1 (6.7 g, 26.0 mmol) were added at 25° C. The resulting reaction mixture was diluted with ethyl acetate (1.2 L). The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to give the crude product. Product 8 was obtained as a pale yellow solid, 9.1 g (81%), mp: 52.3-54.1°C. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.06-1.18 (m, 2H), 1.88 (bs, 1H), 2.26 (m, 2H), 2.28 (m, 2H), 2.69-2.72 (m, 1H), 3.29-3.38 (m, 4H), 6.36 (s, 1H), 6.85-6.86 (bs, 1H, -CONH-, exchange Possible 1 H), 6.95-7.40 (m, 10H), 7.86 (t, J=6.3 Hz, 1H), 8.14-8.16 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) δ (ppm): 15.99, 27.74, 29.40, 34.42, 36.08, 44.41, 45.47, 112.09, 119.31, 119.52, 121.60, 123.58, 125.24, 125.80, 126.41, 128.52, 129.88, 139.19, 140.09, 140.56, 142.42, 147.91, 154.42, 158.09, and 163.45. MS: 426 (M+H)

[0207] Example 3 4-[3-(5-trifluoromethyl-pyridin-2-yloxy)-benzylidene]- Synthesis of piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide [ka]

[0208] Step 1: A solution of 5-trifluoromethyl-2-chloro-pyridine (23.0 g, 0.12 mol) in DMF (230 mL) was added with 3-hydroxyphenyl-methanol (17.4 g, 0.13 mol) and carbonate at room temperature. Potassium (26.3 g, 0.19 mol) was added. The reaction mixture was stirred at 100° C. for 5 hours. The mixture was allowed to cool to room temperature, diluted with water (200 mL), extracted with ethyl acetate (3×400 mL), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (12% ethyl acetate in petroleum ether) to give product 2 as a pale yellow oil, 28.1 g (82%). 1H NMR (300 MHz, CDCl3) δ (ppm):4.75 (s, 2H), 7.03-7.10 (m, 2H), 7.19 (s, 1H), 7.26-7.28 (m, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.90-7.94 (m, 1H), 8.45 (s, 1H).

[0209] Step 2: To a solution of 2 (28.0 g, 0.10 mol) in dichloromethane (280 mL), thionyl chloride (8.5 mL, 0.11 mol) was added dropwise while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 h. The volatiles were then evaporated under reduced pressure, diluted with toluene (15 mL), and the toluene was evaporated under reduced pressure. This azeotropic step was repeated three times to give the product 3 as a red oil (29.6 g, 99%). 1 H NMR (300 MHz, CDCl3) δ (ppm):4.62 (s, 2H), 7.05 (d, J=8.7 Hz, 1H), 7.12-7.13 (m, 1H), 7.23-7.32 (m, 2H), 7.42-7.47 (m, 1H), 7.92-7.95 (m, 1H), 8.46 (s, 1H).

[0210] Step 3: 3 (29.0 g, 0.10 mol) in triethyl phosphite (26.2 mL, 0.15 mol) The solution was heated at 150° C. for 6 hours. The reaction mixture was allowed to cool to room temperature and the mixture was diluted with n-heptane (150 mL) to give a pale orange precipitate. The resulting precipitate was filtered and dried under vacuum to give the product. Product 4 was obtained as a white solid (30.8 g, 94%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.16 (t, J=6.9 Hz, 6H), 3.24 and 3.31(2s, 2H), 3.90-4.00 (m, 4H), 7.07-7.10 (m, 2H), 7.17-7.25 (m, 2H), 7.39 (d, J=8.7 Hz, 1H), 8.23-8.26 (m, 1H), 8.55 (s, 1H).

[0211] Step 4 To a solution of ester 4 (25.0 g, 64.0 mmol) in THF (100 mL) was added 15-crown Ether (0.28 g, 1.3 mmol) was added. The reaction was cooled (ice bath) and NaH (2.3 g, 96.0 mmol) was added portionwise over 5 min. The reaction mixture was stirred at room temperature for 30 min and then cooled to ice again. To the above reaction mixture, a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 5 (12.81 g, 64.0 mmol) in THF (100 mL) was added at ice temperature, and the mixture was stirred at room temperature for 16 hours. The precipitate was filtered off. Filtration and drying gave the product 6 as a white solid (24.4 g, 87%). 1 H NMR (300 MHz, CD3OD) δ (ppm): 1.48 (s, 9H), 2.36 (t, J=5.1 Hz, 2H), 2.49 (t, J=5.4 Hz, 2H), 3.43 (t, J=5.7 Hz, 2H), 3.52 (t, J=5.7 Hz, 2H), 6.43 (s, 1H), 7.01-7.03 (m, 2H), 7.14 (d, J=8.4 Hz, 2H), 7.38-7.44 (m, 1H), 8.09-8.12 (m, 1H), 8.44 (bs, 1H).

[0212] Step 5 A solution of 6 (10.0 g, 23.0 mmol) in dichloromethane (100 mL) was added to the solution at ice temperature. Fluoroacetic acid (42.5 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. After that, the volatiles were removed under reduced pressure to give the product as a red oil (10.7 g, 83%). The crude product 7 was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.60-2.64 (m, 4H), 3.11-3.17 (m, 4H), 6.47 (s, 1H), 7.08-7.26 (m, 4H), 7.43 (t, J=8.1 Hz, 1H), 8.21-8.23 (m, 1H), 8.56 (s, 1H), 8.76 (bs, 1H).

[0213] Step 6 To a solution of amine 7 (10.5 g, 18.7 mmol) in dimethyl sulfoxide (10 mL) was added diisopropylethylamine (9.8 mL, 56.1 mmol) and the product of Step 5, Example 1 (4.74 g, 18.7 mmol) at 25 °C. The resulting reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (1.0 L), washed with water (3x150 mL), and The crude product obtained after evaporation of the volatiles was purified by silica gel (230-400). Purification by column (40% ethyl acetate in petroleum ether) gave product 8 as a white solid 7.0 g (76%). MP: 98.9-101.5°C. 1 H NMR (300 MHz, DMSO-d6) δ(ppm): 1.08-1.18 (m, 2H), 1.85-1.90 (m, 1H), 2.77 (bs, 2H), 2.39 (bs, 2H), 2.69-2.72 (m, 1H), 3.32-3.39 (m, 4H), 6.37 (s, 1H), 6.85 (s, 1H, D2O interchangeable 1 H), 7.04-7.24 (m, 9H), 7.41 (t, J=7.8 Hz, 1H), 8.22-8.25 (m, 1H), 8.58 (s, 1H). 13C NMR (75 MHz, DMSO-d6) δ (ppm): 15.99, 24.74, 29.39, 34.44, 36.07, 44.37, 45.44, 112.25, 118.97, 119.81, 120.23, 120.66, 121.09, 121.53, 122.08, 122.57, 123.42, 125.79, 126.15, 126.38, 128.52, 129.76, 130.08, 137.98, 138.01, 139.42, 140.34, 142.42, 145.72, 145.77, 153.38, 158.08, 166.01. MS: 494 (M+H).

[0214] Example 4 Synthesis of 4-[3-(pyridin-2-yloxy)-benzyl]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide: [ka]

[0215] Step 1: To a solution of the product of Step 4, Example 2 (6), in methanol (17 mL) at room temperature, 10% Pd / C (900 mg) was added, and the reaction mixture was stirred under hydrogen balloon pressure for 1 hour. The resulting reaction mixture was filtered through a celite bed, and the filtrate was concentrated under reduced pressure to give product 7. was obtained as a yellow oil (850 mg, 66%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 0.98-1.04 (m, 2H), 1.37 (s, 9H), 1.43-1.56 (m, 3H), 2.60 (m, 4H), 3.88-3.92 (m, 2H), 6.91-7.02 (m, 2H), 7.10-7.17 (m, 2H), 7.25-7.31 (m, 2H), 7.84-7.89 (m, 1H), 8.14-8.16 (m, 1H).

[0216] Step 2: A solution of ester 7 (800 mg, 2.17 mmol) in dichloromethane (8 mL) was added to the reaction mixture at ice temperature. Trifluoroacetic acid (3.4 mL, 4.25 vol) was added and the reaction mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure to give the product as a brown oil (800 mg, 74%). The crude product 8 was used in the next step without further purification.

[0217] Step 3: To a solution of crude amine 8 (500 mg, 1.0 mmol) in dimethyl sulfoxide (10 mL) To the resulting mixture, diisopropylethylamine (0.5 mL, 2.82 mmol) and the product of Step 5, Example 1 (256 mg, 1.0 mmol) were added at 25° C. The resulting reaction mixture was stirred at 60° C. for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (250 mL), washed with water (4×75 mL), and concentrated over sodium sulfate. The crude product obtained by evaporating the volatiles was then passed through a silica gel (230-400) column ( Purification with 60% ethyl acetate in ether afforded product 9 as a white solid, 230 mg (53%). .mp:126.8-128.6℃. 1 H NMR (300 MHz, CDCl3) δ (ppm): 1.12-1.27 (m, 4H), 1.68-1.71 (m, 3H), 1.89-2.06 (m, 1H), 2.56 (d, J=6.6 Hz, 2H), 2.73 (t, J=11.4 Hz, 2H), 2.82-2.86 (m, 1H), 3.92 (d, J=13.5 Hz, 2H), 4.84 (s, 1H, -CONH-, interchangeable 1 H), 6.90-7.03 (m, 5H), 7.15-7.35 (m, 6H), 7.68-7.74 (m, 1H), 8.21-8.23 (m, 2H). 13C NMR (75 MHz, CDCl3) δ (ppm): 16.45, 25.06, 29.65, 31.82, 33.18, 37.88, 42.86, 44.24, 111.61, 118.48, 118.61, 121.66, 125.36, 125.88, 126.66, 128.24, 129.40, 139. 37, 141.02, 141.99, 147.80, 154.28, 158.21 and 163.73. MS: 428 (M+H)

[0218] Example 5 Chiral separation of the racemate of Example 2

[0219] A chiral column (CHIRALPACK IA 250 mm x 10 mm 5 μm) was equilibrated with 15 column volumes of mobile phase (n-hexane:isopropyl alcohol; 80:20 v / v) prior to elution of the compound. 500 mg of the product of Example 2 was then eluted in 5 mL of n-hexane and isopropyl alcohol (8:2). 500 μL of the stock solution prepared by dissolving in 5-chloro-2-propanol (5-chloro-2-propanol) was injected, and fractions were collected based on the separation observed in the chromatogram. Fraction F1 was the first fraction to elute from the chiral column (retention time: 11.5 min - 13.00 min), and F2 was the second fraction to elute (retention time: 13.50 min - 15.50 min). The remaining stock solution (4.5 mL) was repeatedly injected to ensure complete separation. The solvents in F-1 and F-2 were then removed separately under reduced pressure to give the chiral products 5A (entA) (140 mg) and 5B (entB) (150 mg), respectively.

[0220] 5A 4-[3-(Pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid {(1S,2R)-2-phenyl-cyclopropyl)}-amide - HPLC: 99.98% (Chiral purity: 98.55%). mp: 45.0-47.1°C. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.06-1.10 (m, 1H), 1.15-1.18 (m, 1H), 1.87 (m, 1H), 2.24-2.28 (m, 2H), 2.38-2.40 (m, 2H), 2.69-2.72 (m, 1H), 3.29-3.40 (m, 4H), 6.36 (s, 1H), 6.85-6.86 (m, 1H), 6.95-7.27 (m, 10H), 7.37 (t, J=7.8 Hz, 1H), 7.83-7.85 (m, 1H), 8.14-8.16 (m, 1H). MS: 426 (M+H).

[0221] 5B 4-[3-(Pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid {(1R,2S)-2-phenyl-cyclopropyl)}-amide - HPLC: 99.89% (Chiral purity: 98.93%). mp: 51.0-54.3°C. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.06-1.08 (m, 1H), 1.15-1.18 (m, 1H), 1.87 (m, 1H), 2.24-2.26 (m, 2H), 2.38-2.40 (m, 2H), 2.69-2.72 (m, 1H), 3.29-3.40 (m, 4H), 6.36 (s, 1H), 6.84-6.85 (m, 1H), 6.95-7.27 (m, 10H), 7.37 (t, J=7.8 Hz, 1H), 7.83-7.85 (m, 1H), 8.14-8.16 (m, 1H) MS: 426 (M+H).

[0222] [ka]

[0223] Example 6 4-[3-(pyrimidin-2-yloxy)-benzylidene]-piperidine-1-carbo Synthesis of 2-phenyl-cyclopropyl-amino- [ka]

[0224] Step 1: To a solution of 3-hydroxyphenyl-methanol (500 mg, 4.0 mmol) in DMF (5 mL), cesium carbonate (2.6 g, 8.0 mmol) and 2-chloropyrimidine (680 mg, 6.0 mmol) were added. The resulting reaction mixture was stirred at 100° C. for 5 hours, cooled to room temperature, filtered to remove cesium carbonate, and the filtrate was diluted with water (50 mL). Extraction with ethyl acetate (100 mL) was performed, and the organic layer was dried over sodium sulfate. The crude product obtained by evaporation of the volatiles was purified by silica gel (230-400) column (50% ethyl acetate in petroleum ether). ) to give the product 1 as a pale yellow oil, 440 mg (54%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm):4.52 (s, 2H), 5.28 (bs, 1H), 7.03-7.99 (m, 5H), 8.63 (d, J = 1.2 Hz, 2H).

[0225] Step 2: To a solution of 1 (440 mg, 2.1 mmol) in dichloromethane (8 mL) was added thionyl chloride (0.19 mL, 2.6 mmol) dropwise while stirring in an ice bath. After removing the ice bath, the reaction mixture was The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice-cold water (10 mL), extracted with ethyl acetate (100 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (25% ethyl acetate in petroleum ether) to give product 2 as a pale pink solid (400 mg, 83%). 1H NMR (300 MHz, DMSO-d6) δ (ppm):4.78 (s, 2H), 7.17-7.19 (m, 1H), 7.28-7.34 (m, 3H), 7.42-7.45 (m, 1H), 8.65 (d, J = 4.5 Hz, 2H).

[0226] Step 3: A solution of 2-(3-chloromethyl-phenoxy)-pyrimidine 2 (400 mg, 1.8 mmol) in triethyl phosphite (0.45 mL, 2.7 mmol) was heated at 150 °C for 6 h. The mixture was returned to room temperature, and the volatiles were evaporated. The resulting crude product was then separated on a silica gel (230-400) column. The product 3 was purified with hexane (50% ethyl acetate in petroleum ether) to give 400 mg (69%) of a white solid. I got it. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.16 (t, J = 6.9 Hz, 6H), 3.23 (s, 1H), 3.30 (s, 1H), 3.90-4.00 (m, 4H), 7.06-7.09 (m, 2H), 7.16-7.18 (m, 1H), 7.25-7.28 (m, 1H), 7.37 (t, J = 7.5 Hz, 1H), 8.64 (d, J = 4.8 Hz, 2H).

[0227] Step 4: To a solution of ester 3 (400 mg, 1.2 mmol) in THF (2.5 mL) was added 15-crown ether (5 μL, 0.02 mmol). The reaction was cooled (ice bath) and NaH (44 mg, 1.8 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 30 min and cooled to ice again. To the above reaction mixture was added a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (250 mg, 1.2 mmol) in THF (2.5 mL) at ice temperature and stirred at room temperature for 16 h. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (25% ethyl acetate in petroleum ether) to give the product. Product 4 was obtained as a white solid, 360 mg (80%). 1 H NMR (300 MHz, DMSO-d6) δ(ppm): 1.41 (s, 9H), 2.28 (t, J = 5.4 Hz, 2H), 2.41 (t, J = 5.7 Hz, 2H), 3.33-3.41 (m, 4H), 6.38 (s, 1H), 7.03-7.13 (m, 3H), 7.26 (t, J = 4.8 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 8.65 (d, J = 4.8 Hz, 2H).

[0228] Step 5 To a solution of 4 (360 mg, 0.97 mmol) in dichloromethane (4.0 mL) was added trichloromethane at ice temperature. Fluoroacetic acid (1.7 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The crude product was washed with diethyl ether to give product 5 as an off-white solid, 0.31 g (83%), which was carried forward without further purification.

[0229] Step 6 To a solution of amine 5 (310 mg, 0.6 mmol) in dimethyl sulfoxide (4.0 mL) was added diisopropylethylamine (0.5 mL, 3.1 mmol) and the product of Step 5, Example 1 (0.58 g, 2.4 mmol) at 25° C. The resulting reaction mixture was stirred at 60° C. for 5 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (3X50 mL), and evaporated over sodium sulfate. The crude product obtained by evaporating the volatiles was purified by silica gel (230-400) column (petroleum Purification with 60% ethyl acetate in ether gave product 6 as a white solid in 210 mg (77%). MP: 52.7-57.6°C. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.04-1.06 (m, 1H), 1.14-1.20 (m, 1H), 1.85-1.88 (m, 1H), 2.27 (bs, 2H), 2.39 (bs, 2H), 2.70-2.71 (m, 1H), 3.32-3.39 (m, 4H), 6.37 (s, 1H), 6.85 (bs, 1H, CONH replaceable 1 H), 7.03-7.15 (m, 6H), 7.22-7.28 (m, 3H), 7.39 (t, J = 7.8 Hz, 1H), 8.65 (d, J = 7.8 Hz, 2H). 13 C NMR (75 MHz, DMSO-d₆) δ (ppm): 16.03, 24.76, 29.37, 34.50, 36.10, 44.37, 45.41, 117.37, 119.95, 122.23, 123.49, 125.80, 126.00, 126.34, 128.54, 129.91, 139.19, 140.21, 142.44, 153.20, 158.05, 160.47, and 165.21. MS: 427 (M+H).

[0230] Example 7 Synthesis of 4-{3-[1-(2-phenyl-cyclopropylcarbamoyl)-piperidin-4-ylidenemethyl]-phenoxy}-benzoic acid methyl ester [ka]

[0231] Step 1: 3-Hydroxyphenyl-methanol 2 (5.0 g, 40.2 mmol) in DMF (50 mL) To this was added cesium carbonate (26.2 g, 80.5 mmol) and ester 1 (7.5 g, 48.3 mmol) at room temperature. The resulting reaction mixture was stirred at 100 °C for 5 h. The resulting reaction mixture was allowed to cool to room temperature and filtered to remove the cesium carbonate. The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 250 mL), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (30% ethyl acetate in petroleum ether) to give product 3 as a pale yellow oil, 3.2 g (31%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm):3.81 (s, 3H), 4.51 (d, J = 5.7 Hz, 2H), 5.28 (t, J = 5.7 Hz, 1H), 6.98-7.06 (m, 4H), 7.17-7.19 (m, 1H), 7.38-7.40 (m, 1H), 7.95-7.98 (m, 2H).

[0232] Step 2: To a solution of alcohol 3 (3.2 g, 12.3 mmol) in dichloromethane (50 mL), add ice. Thionyl chloride (1.7 mL, 14.8 mmol) was added dropwise while stirring the reaction in the bath. After the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was quenched with ice-cold water (50 mL), extracted with ethyl acetate (250 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (5% ethyl acetate in petroleum ether) to give product 4 as a colorless oil (2.3 g, 67%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm):3.83 (s, 3H), 4.78 (s, 2H), 7.06-7.12 (m, 3H), 7.21 (bs, 1H), 7.30-7.33 (m, 1H), 7.44-7.49 (m, 1H), 7.98 (d, J = 8.7 Hz, 2H).

[0233] Step 3: A solution of compound 4 (2.3 g, 7.9 mmol) in triethyl phosphite (2.3 mL, 11.9 mmol) was added to 150 mL of ° The reaction mixture was heated at 4°C for 6 hours. The reaction mixture was then cooled to room temperature, and the volatiles were evaporated to give a crude product, which was purified on a silica gel (230-400) column (50% ethyl acetate in petroleum ether). This gave product 5 as a pale yellow oil, 3.5 g (91%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.15 (t, J = 6.9 Hz, 6H), 3.23 (s, 1H), 3.30 (s, 1H), 3.83 (s, 3H), 3.89-3.99 (m, 4H), 7.00-7.06 (m, 4H), 7.15-7.17 (m, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.97 (d, J = 8.7 Hz, 2H).

[0234] Step 4 To a solution of 5 (3.5 g, 9.2 mmol) in THF (20 mL) was added 15-crown ether (40 The reaction was cooled (ice bath) and NaH (560 mg, 13.8 mmol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and cooled to ice temperature again. To the above reaction mixture, a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 6 (1.9 g, 9.2 mmol) in THF (15 mL) was added at ice temperature and stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with saturated ammonium chloride and cooled to ice temperature. The mixture was quenched with sodium hydroxide (50 mL), extracted with ethyl acetate (500 mL), dried over sodium sulfate, and The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (10% ethyl acetate in petroleum ether) to give product 7 as a white solid, 1.8 g (46%). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.40 (s, 9H), 2.27-2.40 (m, 4H), 3.40-3.60 (m, 4H), 3.83 (s, 3H), 6.37 (s, 1H), 6.94-6.99 (m, 2H), 7.05-7.12 (m, 3H), 7.39-7.41 (m, 1H), 7.98 (d, J = 8.7 Hz, 2H).

[0235] Step 5: A solution of tert-butyl ester 7 (1.8 g, 4.2 mmol) in dichloromethane (18.0 mL) To the solution was added trifluoroacetic acid (9.0 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 1 hour. The crude product obtained by evaporation of the solvent was washed with n-hexane, and the product 8 was obtained as a thick black liquid 1.5 g (83%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 2.63-2.72 (m, 4H), 3.16-3.28 (m, 4H), 3.91 (s, 3H), 6.49 (s, 1H), 6.86 (s, 1H), 6.95-7.02 (m, 4H), 7.36 (t, J = 8.1 Hz, 1H), 8.03 (t, J = 8.4 Hz, 2H).

[0236] Step 6: To a solution of amine 8 (1.5 g, 3.4 mmol) in dimethyl sulfoxide (15.0 mL) was added diisopropylethylamine (2.0 mL, 10.2 mmol) and the product of Step 5, Example 1 (0.86 g, 3.4 mmol) at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (250 mL), washed with water (2X100 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by filtration onto a silica gel (230-400) column (petroleum ether). Purification with 25% ethyl acetate in hexane gave product 9 as a white solid, 0.9 g (54%). MP: 48.5-53.2°C.1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.10-1.20 (m, 2H), 1.88 (bs, 1H), 2.26 (bs, 2H), 2.37 (bs, 2H), 2.70-2.71 (m, 1H), 3.31-3.38 (m, 4H), 3.83 (s, 3H), 3.83 (s, 3H), 6.36 (s, 1H), 6.84 (bs, 1H, CONH interchangeable 1 H), 6.94-7.26 (m, 10H), 7.42 (t, J = 7.8 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ (ppm): 16.02, 24.76, 29.40, 34.49, 36.07, 44.32, 45.38, 52.44, 117.81, 118.27, 120.49, 123.40, 124.51, 125.61, 125.79, 126.33, 128.53, 130.59, 132.02, 139.85, 140.45, 142.43, 155.40, 158.04, 161.73, and 166.11. MS: 483 (M+H).

[0237] Example 8 Synthesis of 4-{3-[1-(2-phenyl-cyclopropylcarbamoyl)-piperidin-4-ylidenemethyl]-phenoxy}-benzoic acid: [ka]

[0238] To a solution of the product of Step 6, Example 7 (0.5 g, 1.03 mmol) in methanol (3.0 mL) was added a solution of sodium hydroxide (120 mg, 3.1 mmol) in water (2.0 mL) at 25° C. The reaction mixture was stirred at 55° C. for 16 hours. The crude product obtained by evaporation of the solvent was diluted with water (20.0 mL) and the resulting mixture was concentrated in water. The aqueous layer was then acidified (pH=2, 1.0N HCl) to remove the solid. The mixture was saturated with NaCl and the product was extracted with ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and concentrated to give the product as a white solid, 350 mg (72%). MP: 99.4-102.5°C. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.15-1.29 (m, 2H), 1.88 (bs, 1H), 2.26 (bs, 2H), 2.37 (bs, 2H), 2.71 (bs, 1H), 3.32-3.38 (m, 4H), 6.36 (s, 1H), 6.84 (bs, 1H, CONH interchangeable 1 H), 6.93-7.44 (m, 11H), 7.95 (d, J = 8.4 Hz, 2H), 12.83 (bs, 1H). 13 C NMR (75 MHz, DMSO-d₆) δ (ppm): 16.02, 24.75, 29.40, 34.51, 36.07, 44.31, 45.37, 117.76, 118.17, 120.38, 123.43, 125.47, 125.79, 126.32, 128.54, 130.57, 132.13, 139.81, 140.41, 144.44, 155.59, 158.03, 163.36, and 167.22. MS: 467 (M−H).

[0239] Example 9 Synthesis of 4-(3-pyrrolidin-1-yl-benzyl)-piperidine-1-carboxylic acid-(2-phenyl-cyclopropyl)-amide: [ka]

[0240] Step 1: A solution of 3-bromobenzyl bromide (6.0 g, 24.0 mmol) in triethyl phosphite (6.2 mL, 36.0 mmol) was heated at 130 °C for 16 h. The reaction mixture was cooled to room temperature and evaporated. The crude product obtained by evaporation of the remaining fractions was then purified by silica gel (230-400) column chromatography (acetic acid in petroleum ether). Purification with ethyl acetate (30%) gave the product 2 as a colorless oil 6.5 g (89%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.17 (t, J = 7.2 Hz, 6H), 3.24 (s, 1H), 3.31 (s, 1H), 3.91-4.01 (m, 4H), 7.28-7.29 (m, 2H), 7.43-7.50 (m, 2H). MS: 307.0 (M+) and 309.0 (M+2).

[0241] Step 2 To a solution of 2 (3.0 g, 9.7 mmol) in THF (20 mL) was added 15-crown ether (0.04 mL, 0.19 mmol) was added. The reaction was cooled (ice bath) and NaH (0.58 g, 14.6 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 30 minutes and cooled to ice temperature again. To the above reaction mixture was added a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.95 g, 9.7 mmol) in THF (10 mL) at ice temperature and allowed to stir at room temperature for 16 hours. The resulting reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (3X100 mL) and dried over sodium sulfate. Volatile The crude product obtained by evaporating the volatiles was then passed through a silica gel (230-400) column (in petroleum ether). Purification with ethyl acetate (5%) gave the product 3 as a yellow oil 1.8 g (53%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.41 (s, 9H), 2.28 (bs, 2H), 2.38 (bs, 2H), 3.34-3.41 (m, 4H), 6.36 (s, 1H), 7.25-7.30 (m, 2H), 7.41-7.43 (m, 2H). MS:252.0 (M-BOC).

[0242] Step 3: To a solution of compound 3 (2.0 g, 7.0 mmol) in 1,4-dioxane (20.0 mL) was added pyrrolidine (0.9 mL, 10.6 mmol), cesium carbonate (7.0 g, 21.2 mmol) and HCl at room temperature under an argon atmosphere. To the resulting mixture, racemic BINAP (0.9 g, 1.4 mmol) and palladium acetate (0.95 g, 1.4 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes, followed by stirring under reflux for 16 hours. The resulting reaction mass was filtered through a pad of Celite and washed with ethyl acetate (250 mL). The ethyl acetate layer was washed with water (2×100 mL), dried over sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (15% ethyl acetate in petroleum ether) to give product 4 as a pale yellow oil, 0.6 g (32%). 1 H NMR (300 MHz, CDCl3) δ (ppm): 1.49 (s, 9H), 2.01 (bs, 4H), 2.33-2.35 (m, 2H), 2.50-2.53 (m, 2H), 3.27-3.29 (m, 4H), 3.39-3.49 (m, 2H), 3.50-3.54 (m, 2H), 6.36-6.53 (m, 4H), 7.19 (t, J= 8.1 Hz, 1H). MS: 343.7 (M+H).

[0243] Step 4: To a solution of compound 4 (0.6 g, 1.7 mmol) in tetrahydrofuran (10.0 mL), 10% Pd / C (240 mg) was added. The mixture was heated under hydrogen gas pressure (1 kg / cm 2 The reaction mass was stirred at room temperature for 2 hours under hydrogen pressure. After releasing the hydrogen pressure, the reaction mixture was filtered through a pad of Celite, washed with tetrahydrofuran, and the filtrate was concentrated to give product 5 as a pale yellow liquid (0.6 g). The crude product was carried on to the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.10-1.21 (m, 2H), 1.49 (s, 9H), 1.64-1.72 (m, 3H), 1.98-2.03 (m, 4H), 2.49 (d, J= 6.9 Hz, 2H), 2.65 (t, J= 12.3 Hz, 2H).3.27-3.31 (m, 2H), 4.07-4.15 (m, 2H), 6.35 (s, 1H), 6.42-6.47 (m, 2H), 7.14 (t, J= 7.8 Hz, 1H). MS: 345.7 (M+H).

[0244] Step 5 To a solution of compound 5 (0.6 g, 1.7 mmol) in dichloromethane (6.0 mL) at ice temperature Trifluoroacetic acid (3 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated. The resulting brown oil 6 (0.6 g) was used in the next step without further purification.

[0245] Step 6: To a solution of amine 6 (600 mg, 1.9 mmol) in dimethyl sulfoxide (6.0 mL) was added N,N-diisopropylethylamine (1.1 mL, 5.8 mmol) and the product of Step 5, Example 1 (0.5 g, 1.9 mmol) at 25 °C. The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3 × 100 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230-400) column (petroleum ether). Purification by preparative HPLC (phenomenex 250x221.20 mm, 10 μM, 0.1% TFA in water and acetonitrile mobile phase) gave 160 mg (23%) of product 7 as a pale yellow solid. mp: 145.6°C-151.5°C. IR: 3334, 2842, 1620, 1600, 1545, 1252, 752 cm -1 . 1 H NMR: (300 MHz, DMSO-d6) δ (ppm): 0.95-1.19 (m, 3H), 1.13-1.17 (m, 1H), 1.50-1.55 (m, 2H), 1.63-1.66 (m, 1H), 1.81-1.87 (m, 1H), 1.93 (bs, 4H).93 (bs, 4H), 2.40-2.42 (m, 2H), 2.56-2.60 (m, 2H), 2.67-2.68 (m, 1H), 3.19 (bs, 4H), 3.90 (d, J= 12.9 Hz, 2H), 6.32-6.40 (m, 3H), 6.71 (bs, 1H), 7.02-7.15 (m, 4H), 7.21-7.26 (m, 2H). MS:404.5 (M+H).

[0246] Example 10 4-(3-morpholin-4-yl-benzyl)-piperidine-1-carboxylic acid (2-phenyl Synthesis of (cyclopropyl)-amide: [ka]

[0247] Step 1 Step 2 To a solution of the product of Example 9 (1.5 g, 4.2 mmol) in 1,4-dioxane (15.0 mL) was added morpholine (0.45 mL, 5.1 mmol), cesium carbonate, and HCl at room temperature under an argon atmosphere. (4.1 g, 12.6 mmol), racemic BINAP (0.52 g, 0.84 mmol) and palladium acetate (0.56 g , 0.84 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, followed by stirring under reflux for 16 hours. The resulting reaction mass was cooled, filtered through a pad of Celite, and washed with ethyl acetate (250 mL). The ethyl acetate layer was washed with water (2X100 mL), and the organic layer was dried over sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (15% acetic acid in petroleum ether). Et 3) to give crude product 2 as a pale yellow oil (0.35 g).

[0248] Step 2: To a solution of compound 2 (0.85 g, 2.37 mmol) in tetrahydrofuran (10.0 mL), 10% Pd / C (350 mg) was added. The mixture was heated under hydrogen gas pressure (1 kg / cm 2 The reaction mass was stirred at room temperature for 2 hours under hydrogen pressure. After releasing the hydrogen pressure, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to give product 3. Obtained as a yellow liquid (0.8 g). This product was carried on to the next step without further purification. Ta.

[0249] Step 3: To a solution of crude compound 3 (0.8 g, 2.2 mmol) in dichloromethane (8.0 mL) was added 100 mL of HCl at ice-cold Trifluoroacetic acid (4 mL) was added at room temperature and the reaction mixture was stirred for 1 hour. The resulting brown oil 4 (0.8 g) was carried on to the next step without further purification.

[0250] To a solution of amine 4 (800 mg, 2.3 mmol) in dimethyl sulfoxide (8.0 mL) was added diisopropyl ether. Pyroethylamine (1.3 mL, 7.0 mmol) and the product of Step 5, Example 1 (0.6 g, 2.3 mmol) were added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3x100 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230-400) column (50% ethyl acetate in petroleum ether). The product 5 was purified by HPLC (chill) to give 420 mg of a pale yellow solid. MP: 182.3°C-186.0°C. IR: 3330, 2841, 1620, 1600, 1545, 1247, 756 cm -1 . 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 0 .95-1.08 (m, 3H), 1.11-1.18 (m, 1H), 1.49-1.53 ​​(m, 2H), 1.61-1.67 (m, 1H), 1.85-1.88 (m, 1H), 2.43-2.61 (m, 4H), 2.67-2.68 (m, 1H), 3.08 (t, J= 4.5 Hz, 4H), 3.74 (t, J= 4.5 Hz, 4H), 3.90 (d, J= 12.6 Hz, 2H), 6.61 (d, J= 7.2 Hz, 1H), 6.70-6.76 (m, 3H, one 1 H is interchangeable with D2O), 7.07-7.15 (m, 4H), 7.22-7.27 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) δ (ppm): 16.01, 24.75, 32.08, 34.56, 37.96, 43.17, 43.98, 49.00, 66.61, 113.09, 116.43, 120.52, 125.77, 126.29, 128.53, 129.12, 141.31, 142.51, 151.50, 158.28. MS: 420.2 (M+H).

[0251] Example 11 Synthesis of 4-[3-(pyridin-2-yloxy)-phenoxy]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide: [ka]

[0252] Step 1 To a solution of 1,3-dihydroxybenzene (1.0 g, 9.0 mmol) in DMF (10.0 mL) was added Cs2CO3 (5.92 g, 18.0 mmol) and 2-fluoropyridine (0.8 mL, 9.0 mmol). The mixture was stirred at 100° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (250 mL), and added with acetic acid. The crude product obtained after evaporation of the volatiles was purified by silica gel (230-400) column (10% ethyl acetate in petroleum ether). to give product 3 as a pale yellow oil in 400 mg (23%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 6.20 (s, 1H), 6.48-6.53 (m, 1H), 6.61 (d, J= 8.1Hz, 1H), 6.98 (d, J= 8.1Hz, 1H), 7.11-7.21 (m, 2H), 7.84 (t, J= 8.1Hz, 1H), 8.18 (bs, 1H), 9.61 (s, 1H, D2O replaceable 1 H). MS: 187.9 (M+H).

[0253] Step 2: To a solution of compound 3 (400 mg, 2.14 mmol) in DMF (8.0 mL) was added Cs2CO3 (1.4 g, 4.2 mmol) at room temperature. After stirring the reaction mixture for 5 minutes, compound 4 (600 mg, 2.14 mmol) in DMF (2.0 mL) was added to the reaction mixture at room temperature, and the reaction mixture was stirred at 65 °C for 8 hours. The resulting reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3 x 50 mL), and the ethyl acetate layer was diluted with sulfuric acid. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to give 540 mg (67%) of product 5 as a pale yellow oil. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.40 (s, 9H), 1.48-1.51 (m, 2H), 1.89-1.92 (m, 2H), 3.14-3.16 (m, 2H), 3.63-3.68 (m, 2H), 4.56-4.58 (m, 1H), 6.65-6.68 (m, 1H), 6.75 (s, 1H), 6.80-6.84 (m, 1H), 6.99-7.02 (m, 1H), 7.14 (d, J= 5.1 Hz, 1H), 7.29 (t, J= 7.8 Hz, 1H), 7.85 (t, J= 7.5 Hz, 1H), 8.17 (d, J= 5.1 Hz, 1H).MS: 371.4 (M+H).

[0254] Step 3: A solution of compound 5 (0.4 g, 0.8 mmol) in dichloromethane (8.0 mL) was added to trichloromethane (10 mL) at ice temperature. Fluoroacetic acid (2.0 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated to give The resulting brown oil 6 was used in the next step without further purification.

[0255] To a solution of amine 6 (390 mg, 0.78 mmol) in dimethyl sulfoxide (5.0 mL) was added diisopropylethylamine (0.67 mL, 3.9 mmol) and the product of Step 5, Example 1 (198 mg, 0.78 mmol). The reaction mixture was stirred at 60° C. for 5 hours. The resulting reaction mixture was diluted with acetic acid Diluted with ethyl acetate (250 mL), washed with water (3X10 mL) and dried over sodium sulfate. The crude product obtained by evaporation was then purified by silica gel (230-400) column (70% acetic acid in petroleum ether). The product was purified with ethyl acetate (ethyl acetate) to give the product as an off-white, low-melting solid. The product was further purified by preparative HPLC to give 200 mg of product 7 as an off-white, low-melting solid. mp: 43.9°C-46.8°C. IR: 3313, 1621, 1586, 1423 and 1235 cm -1 . 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.07-1.09 (m, 1H), 1.14-1.18 (m, 1H), 1.46-1.49 (m, 2H), 1.86 (bs, 3H), 2.68-2.69 (m, 1H), 3.08 (t, J= 9.6 Hz, 2H), 3.64-3.68 (m, 2H), 4.53 (bs, 1H), 6.64-6.67 (m, 1H), 6.74 (bs, 1H), 6.80 (bs, 1H), 6.83 (bs, 1H, D2O exchangeable 1 H), 7.00 (d, J= 8.0 Hz, 1H), 7.08-7.14 (m, 4H), 7.21-7.31 (m, 3H), 8.82 (t, J= 7.2 Hz, 2H), 8.16 (d, J= 5.1 Hz, 1H). MS: 430.4 (M+H).

[0256] Example 12 Synthesis of 4-[3-(1H-pyrazol-4-yl)-benzyl]-piperidine-1-carboxylic acid (-2-phenyl-cyclopropyl)-amide: [ka]

[0257] Step 1 To a cooled (0-5 °C) solution of compound 1 (2.0 g, 10.3 mmol, Sigma Aldrich) in dimethylformamide (20.0 mL) was added 4-dimethylaminopyridine (0.25 g, 2.0 mmol) and Di-tert-butyl dicarbonate (3.0 mL, 15.4 mmol) was added. The resulting reaction mass was stirred at room temperature for 12 hours. The reaction was quenched with water (50.0 mL) and extracted with ethyl acetate (200 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (15% ethyl acetate in petroleum ether) to give product 2 as an off-white solid 1.25 g (40%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.27 (s, 12H), 1.58 (s, 9H), 7.87 (s, 1H), 8.37 (s, 1H). MS: 195.3 (M-BOC+H).

[0258] Step 2: A solution of the compound product of Step 2, Example 9 (1.0 g, 2.8 mmol) in DMF (10 mL) Compound 2 (1.9 g, 5.6 mmol) and 2N sodium carbonate solution (4.3 mL, 8.5 mmol) were added to the mixture at room temperature. The reaction mixture was stirred under an argon atmosphere for 10 minutes. Then, tetrakis(triphenyl To the reaction mixture was added (0.33 g, 0.28 mmol) of methyl phosphine palladium(0) under an argon atmosphere. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL), extracted with ethyl acetate (500 mL), and washed with water (2×250 mL) and brine (100 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (40% ethyl acetate in petroleum ether) to give product 3 as an off-white solid, 550 mg (57%). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.42 (s, 9H), 2.28-2.31 (m, 2H), 2.42-2.44 (m, 2H), 3.34-3.44 (m, 4H), 6.39 (s, 1H), 7.03 (d, J= MS: 338.1 (MH).

[0259] Step 3 Compound 3 (0.5 g, 1.4 mmol) in 20% methanol in chloroform (10.0 mL) To the solution was added 10% Pd / C (200 mg). The reaction mixture was heated at room temperature under hydrogen gas pressure (1 kg / cm 2 ) bottom, 24 hours The reaction mass was filtered through a pad of celite and the filtrate was concentrated to give the product 4 as a pale yellow liquid (0.5 g). This crude product was used in the next step without further purification.

[0260] Step 4: Compound 4 (0.5 g, 1.6 mmol) in dichloromethane (5.0 mL) was added to the solution of trichloromethane (Trichloromethane) at ice temperature. Fluoroacetic acid (2.5 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated to give The resulting brown oil 5 (0.5 g) was used in the next step without further purification.

[0261] Step 5: To a solution of amine 5 (500 mg, 1.0 mmol) in dimethyl sulfoxide (5.0 mL) was added N,N-diisopropylethylamine (0.8 mL, 4.2 mmol) and the product of Step 5, Example 1 (270 mg, 1.0 mmol) at 25 °C. The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction The mixture was diluted with ethyl acetate (500 mL), washed with water (3×100 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230-400) column (chloroform). The product was purified with 3% methanol in hexane to give 210 mg of product 6 as an off-white solid. MP: 157.4°C-163.4°C IR: 3330, 1619, 1545, 1475, 753 cm -1 . 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.01-1.17 (m, 4H), 1.51-1.55 (m, 2H), 1.82 (bs, 1H), 1.83-1.85 (m, 1H), 2.54-2.68 (m, 5H), 3.90 (d, J= 12.6 Hz, 2H), 6.71 (d, J= 2.7Hz, 1H, D2O replaceable Noh 1 H), 6.98 (d, J= 7.5 Hz, 1H), 7.07-7.15 (m, 3H), 7.21-7.27 (m, 3H), 7.41-7.43 (m, 2H), 7.90 (s, 1H), 8.17 (s, 1H), 12.91 (s, 1H, D2O replaceable 1 H). 13 C NMR (75 MHz, DMSO-d6) δ (ppm): 16.00, 24.74, 32.06, 34.53, 37.88, 42.81, 43.98, 121.69, 123.17, 125.77, 126.31, 127.05, 128.52, 128.99, 133.22, 141.06, 142.50, 158.22. MS: 401.3 (M+H).

[0262] Example 13 Synthesis of 4-[3-(1-methyl-1H-pyrazol-4-yl)-benzyl]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide: [ka]

[0263] Step 1: To a cooled (0-5° C.) solution of the product of Step 2, Example 12 (0.7 g, 2.0 mmol) in THF (25 mL) was added sodium hydride (0.25 g, 6.1 mmol) and methyl iodide (0.4 mL, 6.1 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (500 mL). The organic layer was washed with water (2×250 mL) and brine (100 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to give product 1 as an off-white solid, 600 mg (83%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.45 (s, 9H), 2.30-2.31 (m, 2H), 2.42-2.44 (m, 2H), 3.35-3.44 (m, 4H), 3.89 (s, 3H), 6.39 (s, 1H), 7.02-7.05 (m, 1H), 7.30 (t, J= 7.5 Hz, 1H), 7.39-7.43 (m, 2H), 7.85 (s, 1H), 8.14 (s, 1H). MS: 298.0 (Mt-butyl+H).

[0264] Step 2: Compound 1 (0.6 g, 1.7 mmol) in 20% methanol in chloroform (10.0 mL) To the reaction mixture was added 10% Pd / C (240 mg), and the reaction mixture was heated at room temperature under hydrogen gas pressure (1 kg / cm 2 ) and stirred for 16 hours. The reaction was filtered through a pad of Celite, and the filtrate was concentrated to give product 2 as a pale yellow liquid. The product obtained was carried to the next step without further purification. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.02-1.09 (m, 2H), 1.38 (s, 9H), 1.54-1.58 (m, 2H), 1.68-1.70 (m, 1H), 2.50-2.52 (m, 1H), 2.62-2.73 (m, 2H), 3.85-3.93 (m, 2H), 3.89 (s, 3H), 6.98 (d, J= 7.2 Hz, 1H), 7.25 (t, J= 7.5 Hz, 1H), 7.36 (s, 2H), 7.83 (s, 1H), 8.11 (s, 1H).MS: 300.2 (Mt-butyl+H).

[0265] Step 3: Compound 2 (0.6 g, 1.6 mmol) in dichloromethane (6.0 mL) was added to a solution of 1,2-dichloromethane (1.2 mL) at ice temperature. Fluoroacetic acid (3.0 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated to give The resulting brown oil 3 (0.6 g) was used in the next step without further purification.

[0266] Step 4 To a solution of amine 3 (600 mg, 1.6 mmol) in dimethyl sulfoxide (6.0 mL) was added diisopropylethylamine (1.2 mL, 6.4 mmol) and the product of Step 5, Example 1 (370 mg, 1.4 mmol) at 25° C. The reaction mixture was stirred at 60° C. for 5 h. The resulting The reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3×100 mL), and dried over sodium sulfate. The crude product obtained by evaporation of the volatiles was purified by silica gel (230-400) column ( Purification with 3% methanol in chloroform gave product 4 as an off-white solid, 350 mg (53%). mp: 158.4°C-160.3°C. IR: 3353, 1619, 1544, 1473, 752 cm -1 . ( 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.01-1.15 (m, 4H), 1.51-1.55 (m, 2H), 1.82-1.83 (m, 1H), 1.84-1.86 (m, 1H), 2.57-2.68 (m, 4H), 3.34-3.37 (m, 1H), 3.85 (s, 3H), 3.85 (s, 3H), 3.90 (d, J= 13.2 Hz, 2H), 6.71 (d, J= 2.7Hz, 1H, D2O exchangeable 1 H), 6.98 (d, J= 7.5 Hz, 1H), 7.07-7.15 (m, 3H), 7.21-7.27 (m, 3H), 7.36-7.38 (m, 2H), 7.83 (s, 1H), 8.11 (s, 1H). 13 C NMR (75 MHz, DMSO-d6) δ(ppm): 16.00, 24.74, 32.05, 34.53, 37.89, 42.79, 43.99, 122.44, 122.97, 125.77, 126.10, 126.31, 127.15, 128.19, 128.52, 129.05, 132.91, 136.43, 141.11, 142.50, 158.21. MS: 415.0 (M+H).

[0267] Example 14 Synthesis of 4-(3-benzimidazol-1-yl-benzyl)-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide: [ka]

[0268] Step 1: A solution of compound 1 (5.0 g, 23.14 mmol) in triethyl phosphite (5.9 mL, 37.7 mmol) was heated at 130 °C for 16 h. The reaction mixture was cooled to room temperature and the volatiles were evaporated. The crude product obtained by evaporation was purified on a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to give product 2 as a pale yellow oil 4.9 g (89%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.09-1.21 (m, 6H), 3.44 (s, 1H), 3.51 (s, 1H), 3.93-4.07 (m, 4H), 7.60-7.66 (m, 1H), 7.73-7.76 (m, 1H), 8.11-8.14 (m, 1H), 8.19 (s, 1H). MS: 274.1 (M+1).

[0269] Step 2: To a solution of compound 2 (4.9 g, 20.3 mmol) in THF (50 mL) was added 15-crown ether (0.08 mL, 0.04 mmol). The reaction was cooled (ice bath) and NaH (1.22 g, 30.5 mmol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and cooled to ice temperature again. To the above reaction mixture, a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.05 g, 20.3 mmol) in THF (10 mL) was added at ice temperature and stirred at room temperature for 4 hours. The resulting reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (3×250 mL), and dried over sodium sulfate. The volatiles were evaporated. The crude product obtained by this reaction was purified by silica gel (230-400) column (5% ethyl acetate in petroleum ether). Purification gave the product 3 as a yellow oil, 4.0 g (62%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.42 (s, 9H), 2.33 (t, J= 5.7 Hz, 2H), 2.41 (t, J= 5.7 Hz, 2H), 3.38-3.41 (m, 2H), 3.44 (t, J= 5.7 Hz, 2H), 6.50 (s, 1H), 7.61-7.71 (m, 2H), 8.02 (s, 1H), 8.07-8.10 (m, 1H).MS: 219.2 (M-BOC+H), 263.1 (Mt-Butyl+1).

[0270] Step 3: To a solution of compound 3 (4.0 g, 12.5 mmol) in 90% methanol in dichloromethane (40.0 mL), 10% Pd / C (3.0 g) was added. The reaction mixture was heated at room temperature under hydrogen gas pressure (1 kg / cm). 2 ) bottom, 20:00 The reaction was filtered through a pad of Celite and the filtrate was concentrated to give product 4 as a pale yellow liquid. (1.5 g, 41%). This product was carried on to the next step without further purification. 1 H NMR (300 MHz, DMSO-d6) δ(ppm): 0.81-1.00 (m, 2H), 1.38 (s, 9H), 1.77-1.80 (m, 2H), 2.28-2.34 (m, 2H), 2.60-2.72 (m, 1H), 3.90 (t, J= 12.6 Hz, 2H) 4.92 (s, 2H), 6.28-6.38 (m, 3H), 6.90 (t, J= 12.6 Hz, 1H). MS: 191.1 (M-BOC+1).

[0271] Step 4: To a solution of compound 4 (1.5 g, 3.4 mmol) in DMF (8.0 mL) was added Cs2CO3 (8.9 g, 25.7 mmol) at room temperature. The reaction mixture was stirred for 5 min and then dissolved in 1-fluoro-2-nitrobenzoate in DMF (2.0 mL). C. Hydrogenbenzene (0.8 g, 3.7 mmol) was added to the reaction mixture at room temperature, and the mixture was stirred at 100.degree. C. for 16 hours. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with water (3.times.100 mL). The ethyl acetate layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (7% ethyl acetate in petroleum ether) to give product 5 as a red-yellow oil, 500 mg (35%). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 0.97-1.08 (m, 2H), 1.38 (s, 9H), 1.54-1.58 (m, 2H), 1.65-1.68 (m, 1H), 2.40-2.52 (m, 2H), 2.64-2.73 (m, 2H), 3.91 (d, J = 12.9 Hz, 2H), 6.87 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 7.13-7.20 (m, 3H), 7.30-7.35 (m, 1H), 7.50 (t, J = 6.6 Hz, 1H), 8.11 (d, J = 7.5 Hz, 1H), 9.35 (s, 1H). MS: 410.0 (MH).

[0272] Step 5 To a solution of compound 5 (500 mg, 1.2 mmol) in formic acid (10 mL) was added sodium formate (290 mg, 4.3 mmol) and Pd / C (10 mol %, 120 mg, 0.01 mmol) at room temperature (25 °C). The reaction mixture was then stirred at 110 °C for 18 h. After cooling to room temperature, the reaction mixture was filtered through Celite with the aid of 20 mL of formic acid. The crude product obtained after evaporation of the volatiles was dissolved in 5% methanol in dichloromethane (50 mL) and filtered to remove inorganic salts. The filtrate was concentrated to give product 6 as an off-white solid (350 mg). The crude product was used for further analysis without further purification. Moved to.

[0273] Step 6: To a solution of amine 6 (350 mg, 1.2 mmol) in dimethyl sulfoxide (5.0 mL) was added diisopropylethylamine (1.03 mL, 6.0 mmol) and the product of Step 5, Example 1 (186 mg, 1.2 mmol) at 25° C. The reaction mixture was stirred at 60° C. for 6 h. The resulting reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3×50 mL), and dried over sodium sulfate. The crude product obtained by evaporating the volatiles was purified by silica gel (230-400) column (dichloromethane). Purification with 1.5% methanol in hexane gave product 7 as an off-white solid, 170 mg (31%). MP: 72.5°C-76.4°C. IR: 3347, 2931, 16161, 1542, 742 cm -1 . 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.00-1.14 (m, 4H), 1.54-1.57 (m, 2H), 1.71-1.79 (m, 1H), 1.80-1.84 (m, 1H), 2.48-2.65 (m, 5H), 3.92 (d, J= 12.9 Hz, 2H), 6.72 (d, J= 2.7Hz, 1H, D2O replaceable 1 H), 7.07-7.15 (m, 3H), 7.21-7.26 (m, 3H), 7.30-7.35 (m, 3H), 7.50-7.54 (m, 3H), 7.60-7.62 (m, 1H), 7.77-7.79 (m, 1H), 8.55 (s, 1H). MS: 451.0 (M+H).

[0274] Example 15 Synthesis of 4-(3-pyrrolidin-1-yl-benzylidene)-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide: [ka]

[0275] Step 1: To a solution of the product of Step 2, Example 9 (2.0 g, 7.0 mmol) in 1,4-dioxane (20.0 mL) was added pyrrolidine (0.9 mL, 10.6 mmol), cesium carbonate, and HCl at room temperature under an argon atmosphere. (7.0 g, 21.2 mmol), racemic BINAP (0.9 g, 1.4 mmol) and palladium acetate (0.95 g, 1.4 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes, followed by stirring under reflux for 16 hours. The resulting reaction mass was filtered through a pad of Celite and washed with ethyl acetate (250 mL). The ethyl acetate layer was washed with water (2X100 mL), dried over sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (15% ethyl acetate in petroleum ether) to give the product. Product 2 was obtained as a pale yellow oil, 0.6 g (32%). 1 H NMR (300 MHz, CDCl3) δ (ppm): 1.49 (s, 9H), 2.01 (bs, 4H), 2.33-2.35 (m, 2H), 2.50-2.53 (m, 2H), 3.27-3.29 (m, 4H), 3.39-3.49 (m, 2H), 3.50-3.54 (m, 2H), 6.36-6.53 (m, 4H), 7.19 (t, J= 8.1 Hz, 1H). MS: 343.7 (M+1).

[0276] Step 2: Compound 2 (0.6 g, 1.7 mmol) in dichloromethane (6.0 mL) was added to a solution of 1,2-dichloromethane (1.2 mL) at ice temperature. Fluoroacetic acid (3 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The resulting brown oil 3 (0.6 g) was used in the next step without further purification.

[0277] Step 3: To a solution of amine 3 (600 mg, 1.9 mmol) in dimethyl sulfoxide (6.0 mL) was added diisopropylethylamine (1.1 mL, 5.8 mmol) and the product of Step 5, Example 1 (0.5 mL). g, 1.9 mmol) was added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3X100 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (40% ethyl acetate in petroleum ether) to give product 4 as an off-white solid in 300 mg (42%). mp :145.7℃-147.4℃ IR: 3292, 2963, 1626, 1533, 1263, 746 cm -1 . 1 H NMR (300 MHz, CDCl3) δ (ppm): 1.22-1.26 (m, 2H), 2.02 (bs, 5H), 2.38-2.41 (m, 2H), 2.56-2.59 (m, 2H), 2.56-2.59 (m, 2H), 2.88 (bs, 1H), 3.30 (bs, 4H), 3.36-3.40 (m, 2H), 3.47-3.51 (m, 2H), 4.87 (bs, 1H, D2O exchangeable 1 H), 6.38-6.52 (m, 3H), 7.19-7.46 (m, 7H). 13 C NMR (75 MHz, CDCl3) δ (ppm): 16.01, 24.75, 32.08, 34.56, 37.96, 43.17, 43.98, 49.00, 66.61, 113.09, 116.43, 120.52, 125.77, 126.29, 128.53, 129.12, 141.31, 142.51, 151.50, 158.28.MS: 402.7 (M+H).

[0278] Example 16 Synthesis of phenyl N-[(1R,2S)-2-phenylcyclopropyl]carbamate : [ka]

[0279] The chiral intermediates described above can be prepared using the general methodology described in the literature (WO 2013 / 057322). The body was synthesized.

[0280] Step 1: Mix trans-2-phenyl-cyclopropylamine hydrochloride (100 g) in water (500 mL). To a suspension of 1,2-dimethyl-3,4-trimethyl-2,4-trimethyl-1 ...1,4-trimethyl-2,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl-1,4-trimethyl (3X700 mL), and the separated organic phase was dried over sodium sulfate and concentrated to give 2-phenyl-cyclopropylamine as an off-white solid 2 (71.2 g, 92%).

[0281] Step 2: Trans-2-phenyl-cyclopropylamine (70 g, 0.52 mol) in ethanol To a solution of 2-phenyl-cyclopropylamine in 700 mL of ethanol was added L(+) tartaric acid (79 g, 0.52 mol) at 0-5°C and the mixture was stirred at 25-30°C for 1 hour. After the reaction was completed, the solid was filtered and dried to obtain 2-phenyl-cyclopropylamine as a tartrate salt. The salt (130 g) was added to isopropanol:water (3:1) (1.3 L). The mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature over 1 hour. The separated solid was collected by filtration and treated with HCl to give (1R,2S)-N-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-2,3-dihydroxypropanoyl]oxy. {Ci}-2-phenylcyclopropan-1-aminium (3) was obtained as a white solid (60 g, 90%).

[0282] Step 3: (1R,2S)-N-{[(2R,3R)-3-carboxy-2,3-dihydroxypropyl]propionate in water (200 mL) To a solution of {[propanoyl]oxy}-2-phenylcyclopropan-1-aminium (3) (60 g, 0.19 mol), 1.0 M sodium hydroxide (194 mL, 0.19 mol) was added over 20 minutes at 0-5°C and stirred for 1 hour. The aqueous phase was extracted with ethyl acetate (2×700 mL). The combined extracts were washed with water (2×400 mL), brine (400 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (1R,2S)-2-phenyl- Chlopropylamine was obtained as a pale yellow solid 4 (25 g, 87%).

[0283] Step 4 To a suspension of amine 4 (15.0 g, 88.0 mmol) in dichloromethane (150 mL) was added ice Triethylamine (36.0 mL, 0.26 mol) and phenyl chloroformate (20.7 g, 0.13 mol) were added at bath temperature. The ice bath was then removed, and the reaction mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was diluted with ethyl acetate (1.0 L), washed with water (2x200 mL), and dried over sodium sulfate. The crude product obtained by evaporating the volatiles was purified by silica gel (230-400) column (petroleum ether Purification with 10% ethyl acetate in hexane gave the product 5 as a white solid, 16.0 g (71%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 1.15-1.25 (m, 2H), 2.04-2.08 (m, 1H), 2.72-2.75 (m, 1H), 7.10-7.40 (m, 10H), 8.17 (bs, 1H). MS (M+H) 254.3.

[0284] Step 5 To a stirred solution of (1R,2S)-2-phenyl-cyclopropylamine 4 (25.0 g, 0.19 mol) in diethyl ether (150 mL) was added 2.0 M hydrochloric acid in ether (140 mL, 0.28 mol) at 0-5 °C. The reaction mixture was stirred at 20-25 °C for 30 min. The reaction mixture was concentrated under reduced pressure. The collected reaction mass was washed with diethyl ether (2×100 mL) to give product 6, the hydrochloride salt of (1R,2S)-2-phenyl-cyclopropylamine as an off-white solid 30.0 g (95%). mp: 179.2-180.1 °C; IR: 3643, 3054, 1979, 1501, 1160, 799, 743, 696 cm -1 . 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 1.14-1.19 (m, 1H), 1.43-1.48 (m, 1H), 2.38-2.43 (m, 1H), 2.72-2.76 (m, 1H), 7.09-7.24 (m, 3H), 7.22-7.33 (m, 2H), 8.81 (bs, 3H).MS (M+H) 134.3. Chiral HPLC purity: 100%. The chirality of 6 was consistent with that of the authentic sample, (1R,2S)-2-phenylcyclopropylamine hydrochloride, purchased from Sigma-Aldrich. This was further confirmed by

[0285] Example 17 Synthesis of 4-[3-(5-trifluoromethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid [(1S,2R)-2-phenyl-cyclopropyl]-amide: [ka]

[0286] Step 1: To a suspension of (1S,2R)-2-phenylcyclopropan-1-amine 2 (500 mg, 2.95 mmol) in dichloromethane (5.0 mL) was added triethylamine (1.21 mL, 8.85 mol) at ice bath temperature. Phenyl chloroformate 1 (0.41 mL, 3.3 mol) was added. The ice bath was removed and the reaction mixture was The mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was diluted with ethyl acetate (1.0 L), washed with water (2×200 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (10% ethyl acetate in petroleum ether) to give product 3 as a white solid. The yield was 500 mg (71%). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 1.19-1.26 (m, 2H), 2.05-2.08 (m, 1H), 2.72-2.75 (m, 1H), 7.11-7.38 (m, 10H), 8.18 (bs, 1H). MS (M+H) 254.5.

[0287] Step 2: To a solution of the product of Step 5, Example 3 (1.0 g, 2.2 mmol) in dimethyl sulfoxide (10 mL) was added diisopropylethylamine (1.2 mL, 6.6 mmol) and 3 (556 mg, 2.2 The reaction mixture was stirred at 60° C. for 4 hours. The resulting reaction mixture was diluted with acetic acid The crude product obtained after evaporation of the volatiles was purified by column chromatography on silica gel (230-400) (40% acetic acid in petroleum ether). Purification with ethyl acetate gave product 4 as a white solid. MP: 100.2°C-101.0°C. IR: 3329, 1622, 1531, 1487, 1329, 1076 cm -1 . 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.08-1.18 (m, 2H), 1.85-1.90 (m, 1H), 2.27 (t, J=5.6 Hz, 2H), 2.40 (t, J=5.6 Hz, 2H).40 (t, J=5.2 Hz, 2H), 2.69-2.72 (m, 1H), 3.32 (t, J=6.0 Hz, 2H), 3.38 (t, J=6.0 Hz, 1H), 6.37 (s, 1H), 6.85 (d, J=3.2 Hz, 1H), 7.04-7.41 (m, 10H), 8.22-8.25 (m, 1H), 8.58 (bs, 1H). MS: 494.3 (M+H). HPLC purity: 99.78%. Chiral HPLC purity: 100%.

[0288] Example 18 Synthesis of 4-[3-(5-trifluoromethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid [(1R,2S)-2-phenyl-cyclopropyl]-amide [ka]

[0289] Step 1: To a suspension of (1R,2S)-2-phenyl-cyclopropylamine 2 (500 mg, 2.95 mmol) in dichloromethane (5.0 mL) was added triethylamine (1.21 mL, 8.85 mol), fluorine (1.0 mL), and HCl at ice bath temperature. Phenyl chloroformate 1 (0.41 mL, 3.3 mol) was added. The ice bath was removed and the reaction mixture was heated to room temperature. The reaction mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate (250 mL) and water (2×100 mL). The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (10% ethyl acetate in petroleum ether) to give product 3 as a white solid, 495 mg (70%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.15-1.25 (m, 2H), 2.04-2.08 (m, 1H), 2.72-2.75 (m, 1H), 7.10-7.40 (m, 10H), 8.17 (bs, 1H). MS (M+H) 254.3.

[0290] Step 2: To a solution of the product of Step 5, Example 3 (1.0 g, 2.2 mmol) in dimethyl sulfoxide (10 mL) was added diisopropylethylamine (1.2 mL, 6.6 mmol) and 3 (556 mg, 2.2 The reaction mixture was stirred at 60° C. for 4 hours. The resulting reaction mixture was diluted with acetic acid The crude product obtained after evaporation of the volatiles was purified by column chromatography on silica gel (230-400) (40% acetic acid in petroleum ether). Purification with ethyl acetate gave product 4 as a white solid, 715 mg (65%). MP: 101.8°C-103.2°C. IR: 3329, 1623, 1531, 1388, 1329, 1076, 697 cm -1 . 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 1.07-1.18 (m, 2H), 1.85-1.90 (m, 1H), 2.25-2.40 (m, 4H), 2.67-2.75 (m, 2H), 2.67-2.75 (m, 2H), 2.69-2.72 (m, 1H), 3.31 (t, J=6.0 Hz, 2H), 3.38 (t, J=5.6 Hz, 1H), 6.36 (s, 1H), 6.85 (s, 1H), 7.04-7.15 (m, 6H), 7.22 -7.41 (m, 4H), 8.22-8.24 (m, 1H), 8.58 (bs, 1H). MS: 494.3 (M+H). HPLC purity: 99.96%. Chiral HPLC purity: 100%.

[0291] Example 19 Synthesis of 4-({3-[(5-methylpyridin-2-yl)oxy]phenyl}methylidene)-N-[2-phenylcyclopropyl]piperidine-1-carboxamide: [ka]

[0292] Step 1: To a solution of 2-fluoro-5-methyl-pyridine 1 (14.76 g, 0.13 mol) in DMF (150 mL) was added 3-hydroxyphenyl-methanol (15.0 g, 0.12 mol) and cesium carbonate (59.0 g, 0.18 mol) at room temperature. The reaction mixture was stirred at 100 °C for 5 h. The resulting mixture was cooled and The mixture was cooled to room temperature, diluted with water (250 mL), extracted with ethyl acetate (3×500 mL), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (30% ethyl acetate in petroleum ether) to give product 2 as a pale yellow oil (6.0 g). (23%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 2.25 (s, 3H), 4.40 (d, J=6.0 Hz, 2H), 5.22 (t, J=6.0 Hz ,1H), 6.91- 6.94 (m, 2H), 7.01 (s, 1H), 7.11 (d, MS: (M+H) 216.2.

[0293] Step 2: To a solution of [3-(5-methyl-pyridin-2-yloxy)-phenyl]-methanol 2 (6.0 g, 0.027 mol) in dichloromethane (60 mL), add thionichloride while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. The volatiles were then evaporated under reduced pressure, diluted with toluene (25 mL), and the toluene was reduced. This azeotropic process was repeated three times to give product 3 as a light brown oil (6.2 g, 95%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 2.25 (s, 3H), 4.76 (s, 2H), 6.95-6.98 (m, 2H), 7.15-7.26 (m, 2H), 7.38-7.40 (m, 1H), 7.66-7.69 (m, 1H), 7.99-8.0 (m, 1H). MS: (M+H) 234.3.

[0294] Step 3 A solution of 2-(3-chloromethyl-phenoxy)-5-methyl-pyridine (6.2 g, 0.026 mol) in triethyl phosphite (7.3 mL, 0.042 mol) was heated at 150° C. for 6 hours. The reaction mixture was allowed to cool to room temperature, and the volatiles were evaporated. The resulting crude product was then purified by silica gel (230-400). Purification by column (60% ethyl acetate in petroleum ether) gave product 4 as a pale yellow oil, 8.3 g. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.13-1.23 (m, 6H), 2.25 (s, 3H), 3.20-3.27 (m, 2H), 3.89-3.99 (m, 4H), 6.91-6.99 (m, 3H), 7.09 (d, J=7.4 Hz, 1H), 7.32 (t, J=8.1 Hz, 1H), 7.66-7.69 (m, 1H), 7.98-8.32 (m, 1H).MS: (M+H) 336.1.

[0295] Step 4 [3-(5-methyl-pyridin-2-yloxy)-benzyl]-phosphoric acid in THF (40 mL) A solution of 15-crown ether (0.1 g, 0.48 The reaction was cooled (ice bath) and NaH (1.44 g, 0.036 mol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and cooled to ice again. To the above reaction mixture was added a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.9 g, 0.024 mol) in THF (40 mL). The reaction mixture was diluted with water (250 mL) and stirred at room temperature for 16 hours. Extraction with ethyl acetate (3×500 mL) and drying over sodium sulfate were performed. Evaporation of the volatiles gave The crude product was purified on a silica gel (230-400) column (3% ethyl acetate in petroleum ether), The product 5 was obtained as a pale yellow oil (6.7 g, 76%). 1 H NMR (300 MHz, CDCl3) δ(ppm): 1.41 (s, 9H), 2.25-2.29 (m, 5H), 2.39 (t, J=6.0 Hz, 2H), 3.36-3.42 (m, 4H), 6.36 (s, 1H), 6.90-6.95 (m, 3H), 7.02 -7.05 (m, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.66 -7.70 (m, 1H), 7.98 (d, J=2.4 Hz, 1H). MS: (M+H) 381.2.

[0296] Step 5. Solution of 4-[3-(5-methyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester 5 (6.7 g, 0.017 mol) in dichloromethane (67.0 mL) Trifluoroacetic acid (27 mL) was added to the mixture at ice temperature, and the reaction mixture was stirred at room temperature for 1 h. The product 6 (6.96 g) obtained by evaporation of the volatiles was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ(ppm): 2.24 (s, 3H), 2.61 (t, J = 6.1 Hz, 2H), 3.10-3.30 (m, 4H), 6.36 (s, 1H), 6.90-6.95 (m, 3H), 7.02 -7.05 (m, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.66 -7.70 (m, 1H), 7.98 (d, J=2.4 Hz, 1H), 8.70 (bs, 2H). MS: (M+H) 281.3.

[0297] Step 6: To a solution of amine 6 (3.0 g, 7.0 mmol) in dimethyl sulfoxide (30 mL) was added diisopropylethylamine (4.2 mL, 22.0 mmol) and the product of Step 5, Example 1 (1.93 g, 7.0 mmol) was added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3X150 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to give product 7 as an off-white solid, 2.33 g (70%). mp: 87.8°C-91.0°C. IR: 3250, 2895, 1624, 1425, 1263, 848, 774 cm -1 . 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.05-1.18 (m, 2H), 1.80-1.95 (m, 1H), 2.23-2.33 (m, 5H), 2.40 (t, J = 5.1 Hz, 2H), 2.71 (m, 1H), 3.31 (t, J = 5.5 Hz, 2H), 3.38 (t, J = 5.5 Hz, 2H), 6.37 (s, 1H), 6.86-6.97 (m, 4H), 7.04 -7.22 (m, 3H), 7.23-7.33 (m, 3H), 7.40 (td, J = 7.9, 2.0 Hz, 1H), 7.70 (dt, J = 8.3, 2.5 Hz, 1H), 7.99 (bs, 1H). MS: (M+H) 440.5.

[0298] Example 20 Synthesis of 4-[3-(pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid [2-(4-methyl)phenyl-cyclopropyl]-amide: [ka]

[0299] Step 1: Add ammonium acetate (13.4 g, 0.17 mol) to acetic acid (100 mL) and dissolve completely. Nitromethane (30.46 g, 0.49 mol) was then added to the reaction mixture, followed by Then 4-methylbenzaldehyde (9.82 mL, 0.083 mol) was added. The reaction mixture was heated at 100°C for 6 The mixture was refluxed for 1 hour. The reaction mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was quenched with 2M aqueous sodium hydroxide (pH = 7), extracted with ethyl acetate (2x300 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude was washed with hexane to give product 2 as a yellow solid. Obtained (10 g, 74%). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.361(s, 3H), 7.303(d, 2H), 7.755(d, 2H), 8.072-8.213(m, 2H). MS (MH) 162.9.

[0300] Step 2: In mineral oil (0.98 g, 0.024 mol) in dimethyl sulfoxide (10 mL) To a solution of 2 (2 g, 2 mol) in dimethyl sulfoxide (10 mL) was added trimethyloxosulfonium iodide (6.7 g, 0.03 mol) and stirred at room temperature for 30 min. 0.012 mol) was added and the reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with 2 mL of ethyl acetate, extracted with ethyl acetate (2×300 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400 mesh) column (2% ethyl acetate in hexane) to give the product 3 as a pale yellow oil (300 mg, 14%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.653-1.704 (m, 1H), 2.203-2.273(m, 1H), 2.353(s, 3H), 3.112-3.157(m, 1H), 4.370-4.417 (m, 1H), 7.015-7.042 (d, 2H), 7.14-7.166 (d, 2H). MS (M+H) 178.1.

[0301] Step 3: To a solution of 3 (0.3 g, 0.0016 mol) in isopropyl alcohol (12 mL) was added hydrochloric acid (6.2 mL of a 2.7 N solution, 0.0169 mol), followed by the portionwise addition of zinc dust (1.1 g, 0.0169 mol). The reaction was stirred at room temperature for 16 h. The reaction was neutralized with 10% aqueous sodium hydroxide solution and The filtrate was filtered through a celite bed, diluted with ethyl acetate (150 mL) and It was washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product obtained by evaporation was purified on a silica gel (230-400 mesh) column (2% methanol in chloroform) to give product 4 as a yellow oil (150 mg, 60%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 0.879 (m, 2H), 1.667 (m, 1H), 2.229 (s, 3H), 2.293-2.331 (m, 1H), 7.018(d, J=8.1, 2H), 6.879 (d, J=8.1, 2H). MS (M+H) 148.2.

[0302] Step 4 To a solution of 4 (90 mg, 0.0006 mol) in dichloromethane (2 mL), add triethylamine. Methylamine (0.17 mL, 0.0012 mol) and phenyl chloroformate (115 mg, 0.0007 mol) were added at 0°C. The reaction mass was stirred at room temperature for 1 hour. The resulting reaction mass was diluted with ethyl acetate (150 mL), washed with water (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained after evaporation of volatiles was purified by silica gel (230-400 mesh) column (10% ethyl acetate in hexane). to give the product 5 as a white solid (30 mg, 18%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.115-1.123 (m, 2H), 2.245 (s, 3H), 7.000-7.120 (m, 6H), 7.181-7.356 (m, 1H), 7.361-7.395 (m, 2H). MS (M+H) 268.3.

[0303] Step 5: To a solution of the product of Step 4, Example 2 (1.0 g, 0.002 mol) in dichloromethane (10 mL) was added trifluoroacetic acid (4 mL) at 0° C., and the reaction mixture was stirred at room temperature for 1 h. Evaporation of the volatiles afforded product 7 (1.3 g, 97%), which was used in the next step without further purification.

[0304] Step 6: To a solution of 7 (0.29 g, 0.0006 mol) in dimethyl sulfoxide (3 mL) was added diisopropylethylamine (0.59 mL, 0.0034 mol) and 5 (0.16 g, 0.0006 mol) at room temperature. The reaction was stirred at 60 °C for 5 hours. The resulting reaction mass was diluted with ethyl acetate (200 mL), washed with water (3 × 50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400 mesh) column (40% ethyl acetate in hexane) to give product 8 as an off-white solid (180 mg, 69%). MP: 87.8-91.0 °C. IR: 3250, 3013, 1624, 1573, 1425, 1263, 1117, 775 cm -1 . 1 H NMR (300 MHz, DMSO-d6) δ(ppm): 1.001-1.046 (m, 1H), 1.085-1.133 (m, 1H), 1.836-1.845 (m, 1H), 2.249 (s, 5H), 2.382-2.44 (m, 2H), 2.643-2.665 (m, 1H), 3.29-3.326 (m, 2H), 3.365-3.401 (m, 2H), 6.360 (s, 1H), 6.952-7.082 (m, 8H), 7.117-7.157 (m, 1H), 7.348-7.401 (m, 1H), 7.830-7.888 (m, 1H), 8.156-8.166 (m, 1H). MS (M+H) 440.4.

[0305] Example 21 Synthesis of 4-[3-(pyrimidin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid [(1R,2S)-2-phenyl-cyclopropyl]-amide: [ka]

[0306] Step 1: Preparation of amine 1, Step 5, Example 6 in dimethyl sulfoxide (30.0 mL) To a solution of the compound (3.02 g, 7.89 mmol) was added diisopropylethylamine (4.13 mL, 23.6 mmol) and The product of Step 4, Example 16 (2.0 g, 7.89 mmol) was added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3x150 mL), and dried over sodium sulfate. The volatiles were evaporated and the resulting crude product was purified by silica gel chromatography. Purification on a gel (230-400) column (60% ethyl acetate in petroleum ether) gave product 3 as a white solid, 2.3 g (70%). MP: 62.8-65.2 °C. IR: 3627, 3310, 1732, 1629, 1570, 1526, 1310, 1249, 1148, 753, 696 cm -1 . 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.04-1.18 (m, 2H), 1.85-1.88 (m, 1H), 2.27 (t, J = 5.7 Hz, 2H), 2.39 (t, J = 5.8 Hz, 2H), 2.71 (dt, 7.03-7.12 (m, 6H), 7.20-7.30 (m, 3H), 7.39 (t, J = 4.7 Hz, 1H), 8.64 (dd, J = 4.7 Hz, 1.1 Hz, 2H). MS: 427.4 (M+H). HPLC pure Resolution: 99.79%. Chiral HPLC Purity: 99.92%. Optical Rotation Number: -1.190. Specific Rotation: -111.71.

[0307] Example 22 Synthesis of 4-[3-(5-methyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide: [ka]

[0308] Step 1: To a solution of amine 1, the product of Step 5, Example 19 (3.0 g, 7.0 mmol) in dimethyl sulfoxide (30 mL) was added diisopropylethylamine (4.2 mL, 22.0 mmol) and the product of Step 4, Example 16 (1.93 g, 7.0 mmol) at 25 °C. The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3 × 150 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to give product 3 as a pale yellow solid (2.7 g). (81%), mp: 53.1-53.9°C. IR: 3321, 3024, 1628, 1526, 1475, 1249, 752, 695 cm -1 . 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.06-1.21 (m, 2H), 1.80-1.95 (m, 1H), 2.23-2.33 (m, 5H), 2.40 (t, J = 5.6 Hz, 2H), 2.71 (m, 1H), 3.31 (t, J = 5.5 Hz, 2H), 3.38 (t, J = 5.5 Hz, 2H), 6.37 (s, 1H), 6.86-6.97 (m, 4H), 7.04 -7.22 (m, 3H), 7.23-7.33 (m, 3H), 7.40 (td, J = 7.9, 2.0 Hz, 1H), 7.70 (dt, J = 8.3, 2.5 Hz, 1H), 7.99 (d, J = 2.8 Hz, 1H). MS (M+H) 440.5. HPLC purity: 98.5%. Chiral HPLC Purity: 100%.

[0309] Example 23 Synthesis of 4-[3-(pyrimidin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid methyl-((1R,2S)-2-phenyl-cyclopropyl)-amide: [ka]

[0310] Step 1: To a solution of 1, the product of Example 21 (150 mg, 7.89 mmol) in dimethylformamide (30.0 mL) was added sodium hydride (4.13 mL, 23.6 mmol) and methyl iodide (2.0 g, 7.89 mmol) at 0-5° C. The reaction mixture was stirred at 25-30° C. for 1 hour. Diluted with water (50 mL), extracted with ethyl acetate (2x100 mL) and dried over sodium sulfate. The crude product obtained by evaporation of the volatiles was purified by silica gel (230-400) column (25% in petroleum ether) ethyl acetate) to give 2 as a pale yellow solid, 77 mg (50%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.24 (dt, J = 7.8 Hz, 5.9 Hz, 2H), 2.02-2.07 (m, 1H), 2.27 (q, J = 5.9 Hz, 2H), 2.38-2.41 (m, 2H), 2.79 (s, 4H), 2.79 (s, 4H), 3.12-3.33 (m, 4H), 6.34 (s, 1H), 6.97 -7.21 (m, 6H), 7.20-7.31 (m, 3H), 7.39 (t, J = 7.9 Hz, 1H), 8.65 (d, J = 4.8 Hz, 2H). MS: 441.5 (M+H). HPLC purity: 98.1%.

[0311] Example 24 Synthesis of 4-[3-(5-methyl-pyrazin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide: [ka]

[0312] Step 1 To a solution of 2-chloro-5-methyl-pyrazine (10 g, 0.078 mol) in DMF (100 mL) To the resulting mixture, 3-hydroxyphenyl-methanol (11.6 g, 0.094 mol) and cesium carbonate (76.0 g, 0.23 mol) were added at room temperature. The reaction mixture was stirred at 100°C for 5 hours. The resulting mixture was cooled to room temperature, diluted with water (250 mL), extracted with ethyl acetate (3 x 500 mL), and the organic layer was dried over sodium sulfate. The volatiles were evaporated and the resulting crude product was purified by silica gel (230-400) column chromatography. (30% ethyl acetate in petroleum ether) to give the product 1 as a pale yellow oil 6.8 g (40%). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.45 (s, 3H), 4.50 (d, J=4.5 Hz, 2H), 5.26 (t, J=5.26 Hz ,1H), 7.0 - 7.18 (m,3H), 7.37 (t, J=7.5 Hz, 1H), 8.1 (s, 1H), 8.4 (d, J=1.2 Hz, 1H). MS (M+H) 217.2.

[0313] Step 2: To a solution of 1 (6.0 g, 0.027 mol) in dichloromethane (60 mL), add the reaction mixture in an ice bath. While stirring the mixture, thionyl chloride (2.3 mL, 0.03 mol) was added dropwise. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. Volatiles were then evaporated under reduced pressure and the resulting solution was concentrated in toluene. The mixture was diluted with toluene (25 mL) and the toluene was evaporated under reduced pressure. This azeotropic step was repeated three times to give product 2 as a light brown oil (6.2 g). This crude product was used in the next step without further purification. MS (M+H) 235.3.

[0314] Step 3: Dissolve 2 (6.2 g, 0.026 mol) in triethyl phosphite (7.3 mL, 0.042 mol) The solution was heated at 150°C for 6 hours. The reaction mixture was cooled to room temperature, and the volatiles were evaporated to give a crude product, which was purified on a silica gel (230-400) column (60% ethyl acetate in petroleum ether) to give 8.3 g of product 3 as a pale yellow oil. The product was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 1.16 (t, J=7.0 Hz, 6H), 2.45 (s, 3H), 3.23 (s, 1H), 3.23 (s, 1H), 3.94 (dq, J=8.2 Hz, 7.0 Hz, 4H), 7.0-7.12 (m, MS (M+H) 337.1.

[0315] Step 4: To a solution of 3 (8.3 g, 0.024 mol) in THF (40 mL) was added 15-crown ether (0.1 g, 0.48 mmol). The reaction was cooled (ice bath) and NaH (1.44 g, 0.036 mol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and cooled to ice again. To the above reaction mixture, a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 5 (4.9 g, 0.024 mol) in THF (40 mL) was added at ice temperature and stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (250 mL). The mixture was extracted with ethyl acetate (3×500 mL) and dried over sodium sulfate. The volatiles were evaporated to give The crude product obtained was a pale yellow oil to give product 4 (6.7 g). MS (M+H) 382.3. Product 4 was used in the next step without further purification.

[0316] Step 5: To a solution of 4 (6.7 g, 0.017 mol) in dichloromethane (67.0 mL) was added trifluoroacetic acid (27 mL, 4V) under ice cooling, and the reaction mixture was stirred at room temperature for 1 h. The product 6 (6.96 g, 90%) obtained after evaporation of the volatiles was used in the next step without further purification. . 1H NMR (400 MHz, DMSO-d6) δ(ppm): 2.45 (s, 3H), 2.60-2.67 (m, 4H), 3.10-3.17 (m, 4H), 6.46 (s, 1H), 7.04 -7.12 (m, 4H), 7.38 (t, J=7.8 Hz, 1H), 8.09 (s, 1H), 8.40 (d, J=4.4 Hz, 1H), 8.61 (bs, 2H). MS (M+H) 282.3.

[0317] Step 6: To a solution of amine 6 (1.0 g, 2.5 mmol) in dimethyl sulfoxide (30 mL) was added diisopropylethylamine (1.4 mL, 7.5 mmol) and the carbamate from Step 4, Example 16. The resulting product (0.7 g, 2.75 mmol) was added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3×150 mL), and dried over sodium sulfate. The crude product obtained by evaporation of the volatiles was purified by silica gel (230-400) column ( Purification with 60% ethyl acetate in petroleum ether gave product 7 as a pale yellow solid, 0.7 g (68%). Ta. mp:50.8℃. IR: 3305, 2923, 1627, 1528, 1473, 1337, 1266, 695 cm -1 . 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.02-1.20 (m, 2H), 1.82-1.84 (m, 1H), 2.21-2.41 (m, 4H), 2.46 (s, 3H), 2.46 (s, 3H), 2.60-2.70 (m, 1H), 3.26-3.34 (m, 4H), 6.32 (s, 1H), 6.80-7.22 (m, 9H), 7.35 (t, J = 7.6, 1H), 8.06 (bs, 1H), 8.37 (bs, J = 8.3, 1H). MS: 441.4 (M+H). HPLC: 99.91%.

[0318] Example 25 Synthesis of 4-[3-pyrazin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide [ka]

[0319] The target compound 7 was prepared by substituting 2-chloro-5-methyl-pyrazine for 2-chloro-5-methyl-pyrazine as described in Example 24. Prepared according to the synthesis method described for the product of Example 24, starting from -chloro-pyrazine.

[0320] Example 26 Synthesis of 4-[5-methyl-3-(pyrimidin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide [ka]

[0321] The target compound 6 was prepared by substituting 2-chloro-pyrimidine for 2-chloro-pyrimidine as described in Example 6. Prepared according to the synthesis method described for the product of Example 6, starting from 5-methyl-pyrimidine.

[0322] Example 27 Synthesis of 4-[3-(5-chloro-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide. [ka]

[0323] Step 1: 5-chloro-2-fluoropyridine (10.0 g, 0.0760 mol) in DMSO (100 mL) The solution was added with 3-hydroxyphenyl-methanol (9.42 g, 0.0760 mol) and sesquioxane carbonate at room temperature. To the resulting solution was added ammonium (29.72 g, 0.0912 mol). The reaction mixture was stirred at 100°C for 6 hours. The reaction was monitored by TLC. The resulting mixture was cooled to room temperature, diluted with water (200 mL), extracted with ethyl acetate (2x400 mL), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (12% ethyl acetate in petroleum ether). The product 1 was obtained as a pale yellow oil, 12.0 g (67%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.17 (t, J=2.4 Hz, 1H), 7.94-7.91 (m, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.14-7.1 (m, 1H), 7.06-7.03 (m, 2H), 6.98-6.95 (m, 1H), 5.22 (t, J=5.6 Hz, 1H), 4.48 (d, J=5.6 Hz, 2H). MS m / z (M+H): 236.0

[0324] Step 2: To a solution of 1 (12.0 g, 0.0509 mol) in dichloromethane (120 mL) was added thionyl chloride (4.1 mL, 0.0560 mol) dropwise while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 h. After complete consumption of the starting material, the volatiles were removed under reduced pressure. The mixture was evaporated and diluted with ethyl acetate (250 mL), and the organic layer was washed with saturated aqueous sodium bicarbonate and water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product 2 obtained after evaporation was directly carried to the next step without further purification (12.5 g, 96%). 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.20 (d, J=2.4 Hz, 1H), 8.19-7.95 (m, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.21 (t, J=2.0 Hz, 1H), 7.12-7.09 (m, 2H), 4.75 (s, 1H). MS m / z (M+H): 254.1

[0325] Step 3: 2 (12.5 g, 0.0494 mol) in triethyl phosphite (20.0 mL, 0.1235 mol) A solution of ) was heated at 150°C for 6 hours. The reaction mixture was allowed to reach room temperature and the volatiles were removed. The crude product obtained after the addition of n-heptane (150 mL) gave a pale orange precipitate, which was filtered and dried under vacuum to give product 3 as an off-white solid (16.5 g, 91%), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.19-8.18 (m, 1H), 7.97-7.94 (m, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.13-7.06 (m, 1H), 7.03-6.99 (m, 3H), 3.95 (m, 4H), 3.27 and 3.21(2s, 2H), 1.15 (t, J=4.4 Hz, 6H). MS m / z (M+H): 356.2

[0326] Step 4: To a solution of 3 (15.5 g, 0.0435 mol) in THF (100 mL), 15-crown ether (0.19 g, 0.87 mmol) was added. The reaction was cooled (ice bath) and NaH (2.07 g, 0.0870 mol) was added portionwise over 5 min. The reaction mixture was stirred at room temperature for 30 min and cooled to ice again. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 5 (8.66 g, 0.0435 mol) in THF (50 mL) was added at ice temperature and stirred at room temperature for 16 h. The resulting reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product obtained after evaporation of the volatiles was purified by silica gel column chromatography to obtain product 4. Obtained as a yellow liquid (13.1 g, 75%). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.19 (d, J=2.0 Hz, 1H), 7.96-7.93 (m, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.09-7.06 (m, 2H), 6.99-6.96 (m, MS m / z (M+Na):423.2

[0327] Step 5: To a solution of 4 (13.0 g, 0.0325 mol) in dichloromethane (130 mL) was added trifluoroacetic acid (52.0 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. After complete consumption of the starting material, the volatiles were removed under reduced pressure to give the product as a light brown oil. The crude product was washed with ether (3×50 mL) to give 6 as a thick light brown liquid (13.8 g crude product). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.82 (bs, 2H), 8.19 (d, J=2.8 Hz, 1H), 7.96-7.93 (m, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.09 (d, J=8.8 Hz, 2H), 7.02-7.00 (m, 2H), 6.44 (s, 1H), 3.38-3.33 (m, 4H), 2.60 (t, J=5.6 Hz, 2H), 2.53-2.48 (m, 2H). MS m / z (M+H): 301.2

[0328] Step 6: To a solution of 6 (15.8 g, 0.0381 mol) in dimethyl sulfoxide (78 mL) was added diisopropyl ether. Isopropyl-ethyl-amine (20.34 mL, 0.1149 mol) and the carbamate from Step 4, Example 16 The mate product (10.62 g, 0.0419 mol) was added at 25°C. The reaction mixture was stirred at 60°C for 6 hours. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3X200 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230-400). Purification by column (40% ethyl acetate in petroleum ether) gave product 7 as a pale yellow fluffy solid (11.6 g, 66%). Melting range (MR): 44.8-62.6°C. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.18 (d, J=2.4 Hz, 1H), 7.94-7.91 (m, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.23-7.19 (m, 2H), 7.12-7.05 (m, 5H), 6.95-6.82 (m, 2H), 6.32 (s, 1H), 3.37-3.26 (m, 4H), 2.71-2.69 (m, 1H), 2.36-2.33 (t, J=5.2 Hz, 2H), 2.24-2.22 (t, J=5.6 Hz, 2H), 1.85 (m, 1H), 1.13 (d, J=4.8 Hz, 1H), 1.04 (d, J=7.6 Hz, 1H). 13 C NMR: (100 MHz, DMSO-d6):δ 161.69, 157.57, 153.49, 145.56, 141.99, 139.92, 139.75, 138.80, 129.56, 128.08, 125.85, 125.34, 125.21, 123.04, 121.29, 119.02, 113.05, 44.93, 43.89, 35.63, 34.07, 28.91, 24.32 and 15.58. MS m / z (M+H): 460.32, HPLC purity: 99.36%, Chiral purity: 99.71%.

[0329] Example 28 Synthesis of 4-[3-(5-fluoro-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide

[0330] [ka]

[0331] Step 1: To a solution of 2,5-difluoropyridine (8.2 g, 0.0719 mol) in DMSO (80 mL) was added 3-hydroxyphenyl-methanol (8.9 g, 0.0719 mol) and cesium carbonate (28.12 g, 0.0863 mol) at room temperature, and the reaction mixture was stirred at 85 °C for 6 h. The reaction was monitored by TLC. The resulting mixture was cooled to room temperature, diluted with water (200 mL), extracted with ethyl acetate (3×400 mL), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (12% ethyl acetate in petroleum ether) to give product 1 as a pale yellow oil, 4.3 g (28%). 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.17 (t, J=2.4 Hz, 1H), 7.84-7.78 (m, 1H), 7.35 (t, J=10.4 Hz, 1H), 7.15-6.95 (m, 4H), 5.25 (t, J=7.6 Hz, 1H), 4.50 (d, J=7.6 Hz, 2H). MS m / z (M+H): 220.0

[0332] Step 2: To a solution of 1 (6.5 g, 0.0296 mol) in dichloromethane (65 mL) was added thionyl chloride (2.4 mL, 0.0326 mol) dropwise while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 2 h. After complete consumption of the starting material, the volatiles were evaporated under reduced pressure. The mixture was evaporated and diluted with ethyl acetate (200 mL), and the organic layer was washed with saturated aqueous sodium bicarbonate and water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product 2 obtained after evaporation was directly used in the next step without further purification (6.7 g, 95%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.15 (d, J=2.4 Hz, 1H), 7.83-7.80 (m, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.27-7.25 (m, 1H), 7.19-7.06 (m, 3H), 4.75 (s, 1H). MS m / z (M+H): 238.0

[0333] Step 3: A solution of 2 (6.5 g, 0.0274 mol) in triethyl phosphite (12.6 mL, 0.0685 mol) was heated at 150 °C for 6 h. The reaction mixture was cooled to room temperature, and the mixture obtained after evaporation of volatiles was purified by silica gel (230-400) column chromatography. The product 3 was obtained as a pale yellow liquid (9.0 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.15 (d, J=4.0 Hz, 1H), 7.86-7.80 (m, 1H), 7.34 (t, J=10.4 Hz, 1H), 7.12-6.97 (m, 4H), 4.02-3.89 (m, 4H), 3.28 and 3.21 (2s, 2H), 1.15 (t, J=9.2 Hz, 6H). MS m / z (M+H): 340.2

[0334] Step 4: To a solution of 3 (9.0 g, 0.0256 mol) in THF (60 mL) was added 15-crown ether (0.12 g, 0.53 mmol). The reaction was cooled (ice bath) and 60% NaH (1.26 g, 0.0530 mol) was added to 5 The mixture was added in portions over 1 minute. The reaction mixture was stirred at room temperature for 30 minutes and cooled to ice temperature again. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 5 (5.28 g, 0.0256 mol) in THF (30 mL) was added at ice temperature and stirred at room temperature for 16 hours. The resulting reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product obtained after evaporation of the volatiles was purified by silica gel column chromatography to obtain product 4. Obtained as a yellow solid (8.0 g, 78%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.15 (d, J=3.2 Hz, 1H), 7.84-7.79 (m, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.12-7.04 (m, 2H), 6.96-6.92 (m, 2H), 6.35 (s, 1H), 3.40-3.32 (m, 4H), 2.37 (t, J=5.6 Hz, 2H), 2.25 (t, J=5.2 Hz, 2H), 1.39 (s, 9H). MS m / z (M+Na):407.2

[0335] Step 5: To a solution of 4 (8.2 g, 0.0213 mol) in dichloromethane (82 mL) was added trifluoroacetic acid (32.5 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. After complete consumption of the starting material, the volatiles were removed under reduced pressure to give the product as a red oil. The crude product was washed with ether (3×50 mL) to give 6 as a dark brown oil (9.0 g crude). 1 H NMR (300 MHz, DMSO-d6) δ(ppm): 8.73 (bs, 2H), 8.15 (d, J=3.2 Hz, 1H), 7.84-7.79 (m, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.12-7.06 (m, 2H), 7.00-6.96 (m, 2H), 6.44 (s, 1H), 3.15-3.09 (m, 4H), 2.59 (t, J=6.0 Hz, 2H), 2.49-2.48 (m, 2H). MS m / z (M+H): 285.4

[0336] Step 6: To a solution of 6 (8.4 g, 0.021 mol) in dimethyl sulfoxide (42 mL) was added diisopropyl ether. Propyl-ethyl-amine (11.1 mL, 0.063 mol) and the carbamate from Step 4, Example 16 The resulting product (5.8 g, 0.023 mol) was added at 25°C. The reaction mixture was stirred at 60°C for 6 hours. The reaction mixture was diluted with ethyl acetate (400 mL), washed with water (3x100 mL), and dried over sodium sulfate. The crude product obtained by evaporation of the volatiles was purified by silica gel (230-400) column ( Purification with 40% ethyl acetate in petroleum ether afforded product 7 as a pale yellow fluffy solid. Obtained (7.15 g, 66%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.15 (d, J=2.4 Hz, 1H), 7.82-7.80 (m, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.24-7.21 (m, 2H), 7.14-7.04 (m, 5H), 6.96-6.94 (m, 2H), 6.84 (d, J=2.8 Hz, 1H), 6.34 (s, 1H), 3.38-3.28 (m, 4H), 2.71-2.69 (m, 1H), 2.34 (t, J=5.2 Hz, 2H), 2.23 (t, J=4.8 Hz, 2H), 1.86 (m, 1H), 1.13 (d, J=4.8 Hz, 1H), 1.04 (d, J=7.6 Hz, 1H). 13 C NMR: (100 MHz, DMSO-d6):δ 159.15, 157.57, 156.01 (d, J=244.7 Hz), 154.08, 141.99, 139.69, 138.76, 134.13 (d, J=26.3 Hz), 129.54, 128.09, 127.85 (d, J=20.9 Hz), 125.86, 125.35, 124.91, 123.09, 120.97, 118.71, 113.01, 44.94, 43.90, 35.63, 34.07, 28.91, 24.32 and 15.58. MS m / z (M+H): 444.3, HPLC purity: 99.21%, Chiral HPLC: 99.37%.

[0337] Example 29: 6-{3-[1-((1R,2S)-2-phenyl-cyclopropylcarbamoyl)-piperazinyl}- Synthesis of lysin-4-ylidenemethyl]-phenoxy}-nicotinic acid methyl ester [ka]

[0338] Step 1: 6-chloropyridine-3-carboxylic acid methyl ester in dimethylacetamide (500 mL) To a solution of 3-hydroxyphenyl-methanol (50.0 g, 0.29 mol) was added 3-hydroxyphenyl-methanol (39.79 g, 0.32 mol) and potassium carbonate (60.4 g, 0.43 mol) at room temperature. The reaction mixture was stirred at 100°C for 6 hours. The reaction was monitored by TLC. The resulting mixture was cooled to room temperature and diluted with water (300 mL). The mixture was diluted and extracted with ethyl acetate (2 x 500 mL), and the organic layer was dried over sodium sulfate. The crude product obtained by evaporation of the volatiles was purified by silica gel (230-400) column (12% acetic acid in petroleum ether). Purification with ethyl acetate gave the product 1 as a pale yellow oil (30.0 g, 40%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.82 (d, J=2.0 Hz, 1H), 8.30-8.27 (m, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.27-7.19 (m, 2H), 7.09-7.07 (m, 1H), 6.96 (d, J=8.8 Hz, 1H), 4.73 (s, 2H), 3.93 (d, J=3.6 Hz, 3H). MS m / z (M+H): 259.8

[0339] Step 2: A solution of 1 (30.0 g, 0.115 mol) in dichloromethane (300 mL) was reacted in an ice bath. Thionyl chloride (9.4 mL, 0.127 mol) was added dropwise while stirring the reaction. After removing the ice bath, The reaction mixture was stirred at room temperature for 2 hours. After complete consumption of the starting material, the volatiles were removed under reduced pressure. The mixture was evaporated, diluted with ethyl acetate (500 mL), and the organic layer was washed with saturated sodium bicarbonate (200 mL) and water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product obtained by evaporation was purified by silica gel (230-400) column chromatography to give the product. Product 2 was obtained as a pale yellow liquid (28.0 g, 87%). 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.82 (d, J=0.8 Hz, 1H), 8.31-8.28 (m, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.29-7.27 (m, 1H), 7.21 (t, J=2.0 MS m / z (M+H): 278.0

[0340] Step 3: Solution of 2 (28.0 g, 0.10 mol) in triethyl phosphite (41.0 mL, 0.25 mol) The mixture was heated at 150° C. for 6 hours. The reaction mixture was cooled to room temperature, and the mixture obtained after evaporation of the volatiles was purified by silica gel column chromatography to give 3 as a pale yellow solid. Obtained as a colored liquid (32.0 g, 84%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.65-8.64 (m, 1H), 8.30-8.27 (m, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.16-7.03 (m, 4H), 3.96-3.88 (m, 4H), 3.82 (s, 3H), 3.27 and 3.21(2s, 2H), 1.15-1.11 (m, 6H). MS m / z (M+H): 380.2

[0341] Step 4: To a solution of 3 (35.5 g, 0.093 mol) in THF (200 mL) was added 15-crown ether (0.41 g, 1.8 mmol). The reaction was cooled (ice bath) and 60% NaH (5.5 g, 0.14 mol) was added portionwise over 5 min. The reaction mixture was stirred at room temperature for 30 min and cooled to ice again. 4-Oxo-piperidine-1-carboxylic acid tert-butyl ester 5 (18.7 g, 0.093 mol) in THF (150 mL) was added. The solution was added at ice temperature and stirred at room temperature for 16 hours. The resulting reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product (30.0 g) obtained after evaporation of the volatiles was dissolved in methanol (300 mL), and aqueous lithium hydroxide solution (3.0 g, 0.0707 mol) was added at ice temperature. The resulting reaction mixture was stirred at 50 °C for 2 hours. The reaction was monitored by TLC. The crude product obtained after evaporation of the volatiles was dissolved in water (200 mL) and washed with methyl tert-butyl ether (2 x 200 mL). The aqueous layer was acidified to pH 2.0 with 1.0 N aqueous hydrochloric acid. The precipitated product was filtered and dried to give 4 as an off-white solid (23.0 g, 61%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 13.19 (bs, 1H), 8.66-8.65 (m, 1H), 8.28-8.25 (m, 1H), 7.39 (t, J=8.0 Hz, 1H), 7.11-7.00 (m, 4H), 6.37 (s, 1H), 3.40-3.32 (m, 4H), 2.39 (t, J=5.6 Hz, 2H), 2.27 (t, J=5.2 Hz, 2H), 1.39 (s, 9H). MS m / z (M+H): 433.2

[0342] Step 5: To a solution of 4 (13.0 g, 0.0317 mol) in methanol (130 mL) was added trimethylsilyl chloride (8.9 mL, 0.0697 mol) at ice temperature, and the reaction mixture was stirred at room temperature for 12 h. TLC showed The reaction mixture was monitored at RT. After complete consumption of the starting material, the volatiles were removed under reduced pressure. The resulting crude product was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product obtained after evaporation of the volatiles was purified by silica gel (230-400) column chromatography to give product 6 as a pale yellow liquid (5.2 g, 51%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.68-8.67 (m, 1H), 8.31-8.28 (m, 1H), 7.39-7.36 (m, 1H), 7.13-6.97 (m, 4H), 6.24 (s, 1H), 3.84 (s, 3H), 2.78-2.65 (m, 4H), 2.34 (t, J=5.2 Hz, 2H), 2.21 (t, J=5.2 Hz, 2H). MS m / z (M+H): 325.3

[0343] Step 6: To a solution of 6 (5.2 g, 0.016 mol) in dimethyl sulfoxide (52 mL, 10 V), Diisopropyl-ethyl-amine (8.9 mL, 0.048 mol) and the carbamate product of Step 4, Example 16 (4.0 g, 0.016 mol) were added at 25° C. The reaction mixture was stirred at 60° C. for 6 hours. The reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3×100 mL), and dried over anhydrous sodium sulfate. The crude product obtained by evaporation of the volatiles was The product was purified on a silica gel (230-400) column (40% ethyl acetate in petroleum ether) to give product 7 was obtained as a pale yellow fluffy solid (5.0 g, 65%). Melting point range (MR): 52.6-72.8°C. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.68 (d, J=2.0 Hz, 1H), 8.31-8.28 (m, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.24-7.20 (m, 2H), 7.13-7.01 (m, 7H), 6.84-6.83 (m, 1H), 6.35 (s, 1H), 3.84 (s, 3H), 3.38-3.30 (m, 4H), 2.71-2.69 (m, 1H), 2.37 (t, J=5.2 Hz, 2H), 2.25 (t, J=5.2 Hz, 2H), 1.86 (m, 1H), 1.15 (d, J=4.8 Hz, 1H), 1.05 (d, J=6.0 Hz, 1H). 13C NMR: (100 MHz, DMSO-d): δ 165.87, 164.78, 157.57, 152.92, 149.45, 141.99, 140.87, 139.87, 138.88, 129.66, 128.08, 125.85, 125.67, 125.34, 122.97, 121.66, 120.97, 119.39, 111.21, 52.23, 44.92, 43.88, 35.63, 34.07, 28.90, 24.31, and 15.57. MS m / z (M+H): 484.3, HPLC purity: 98.65%, Chiral HPLC: 99.08

[0344] Example 30: 6-{3-[1-((1R,2S)-2-phenyl-cyclopropylcarbamoyl)-piperazinyl}- Synthesis of lysin-4-ylidenemethyl]-phenoxy}-nicotinic acid [ka]

[0345] A solution of 1, the product of Example 27 (1.8 g, 0.0038 mol) in methanol (18 mL) was added to water at ice temperature. An aqueous solution of lithium oxide (0.32 g, 0.0076 mol) was added dropwise, and the reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC. The crude product obtained by evaporating the volatiles was diluted with water (10 mL), and the aqueous layer was washed with methyl tert-butyl ether. The resulting aqueous layer was adjusted to pH 2 with 1.5 N hydrochloric acid. The mixture was acidified with HCl. The precipitated product was filtered and dried to give 2 as an off-white solid, 1.52 g (87%), melting point range (MR) 141-159°C. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 13.19 (bs, 1H), 8.66-8.65 (m, 1H), 8.28-8.26 (m, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.24-7.21 (m, 2H), 7.13-7.01 (m, 7H), 6.83 (d, J=3.2 Hz, 1H), 6.35 (s, 1H), 3.38-3.28 (m, 4H), 2.71-2.69 (m, 1H), 2.37 (t, J=5.2 Hz, 2H), 2.25 (t, J=5.2 Hz, 2H), 1.86 (m, 1H), 1.15 (d, J=4.4 Hz, 1H), 1.05 (d, J=7.6 Hz, 1H). 13 C NMR: (100 MHz, DMSO-d6) :δ 165.84, 165.69, 157.57, 153.03, 149.57, 142.0, 141.05, 139.84, 138.86, 129.64, 128.09, 125.85, 125.59, 125.34, 123.0, 122.02, 121.66, 119.40, 111.06, 44.92, 43.89, 35.64, 34.08, 28.91, 24.30 and 15.57. MS m / z (M+H): 470.3, HPLC purity: 99.88%, Chiral HPLC: 99.50%.

[0346] Example 31: Synthesis of 4-[3-(5-hydroxymethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide [ka]

[0347] Step 1: 1, the product of Example 27 from Step 4 (3.6 g, 0.01 mL) in dimethoxyethane (35 mL). To a solution of N-methylmorpholine (1.4 mL, 0.0128 mol) and chloroformic acid was added at ice temperature. Isobutyl ether (1.21 mL, 0.0093 mol) was added and the reaction mixture was stirred at room temperature for 30 minutes. Sodium borate (1.9 g, 0.0512 mol) was added portionwise to the reaction mass and stirred for 12 hours. The reaction mixture was monitored by TLC. After complete consumption of starting material 1, the reaction mass was quenched with water (100 mL) and extracted with ethyl acetate (300 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel (230-400) column chromatography to give product 2 as an off-white solid (3.2 g, 92%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.06 (m, 1H), 7.79-7.76 (m, 1H), 7.34 (t, J=8.0 Hz, 1H), 7.05-6.95 (m, 4H), 6.35 (s, 1H), 5.24 (t, J=6.0 Hz, 1H), 4.45 (d, J=5.6 Hz, 1H), 3.40-3.32 (m, 4H), 2.38 (t, MS m / z (M+H): 397.3

[0348] Step 2: To a solution of 2 (3.2 g, 0.08 mol) in dichloromethane (32 mL) was added trifluoroacetic acid (12.8 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. After complete consumption of the starting material, the volatiles were removed under reduced pressure to give the crude product as a brown-red oil. The crude product was washed with ether (3×50 mL) to give 3 as an off-white solid (crude product 3.3 g). MS m / z (M+H): 297.17

[0349] Step 3: To a solution of 3 (3.3 g, 0.08 mmol) in dimethyl sulfoxide (30 mL) was added diisopropyl ether. Propyl-ethyl-amine (4.2 mL, 0.024 mol) and the carbamate product of Step 4, Example 16 (2.0 g, 0.08 mmol) were added at 25° C. The reaction mixture was stirred at 60° C. for 6 hours. The reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3x100 mL), and dried over sodium sulfate. The crude product obtained by evaporating the volatiles was purified by silica gel (230-400) column chromatography (Silica Gel). Purification with 40% ethyl acetate in oil ether gave 4 as a pale yellow fluffy solid (1.82 g, 58%). Melting point range (MR): 51-65°C. 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.07 (d, J=2.0 Hz, 1H), 7.80-7.77 (m, 1H), 7.34 (t, J=8.0 Hz, 1H), 7.26-6.92 (m, 7H), 6.83 (d, J=3.2 Hz, 1H), 6.35 (s, 1H), 5.25 (t, J=6.0 Hz, 1H), 4.45 (d, J=7.2 Hz, 1H), 3.40-3.32 (m, 4H), 2.38 (t, J=5.6 Hz, 2H), 2.25 (t, J=5.2 Hz, 2H), 1.87 (m, 1H), 1.16 (d, J=6.0 Hz, 1H), 1.05 (d, J=7.6 Hz, 1H). 13 C NMR: (100 MHz, DMSO-d): δ 162.03, 157.55, 154.11, 145.64, 141.94, 139.57, 139.09, 138.65, 132.95, 129.43, 128.04, 125.84, 125.31, 124.66, 123.11, 120.95, 118.69, 111.17, 60.09, 44.92, 43.87, 35.59, 34.00, 28.88, 24.26, and 15.52. MS m / z (M+H) 456.3, HPLC purity: 98.99%, Chiral HPLC: 98.95%.

[0350] Example 32: Synthesis of 4-[3-(5-methoxymethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide [ka]

[0351] Step 1: To a solution of 1 (3.2 g, 8.0 mmol), the product of Step 1 of Example 29, in tetrahydrofuran (32 mL) was added 60% NaH (0.97 g, 0.024 mol) at ice temperature, and the reaction mixture was stirred at room temperature for 10 min. Methyl iodide (1.56 mL, 0.024 mol) was added to the reaction mass at the same ice temperature, and the mixture was stirred for 12 h. Stirring was continued. The reaction was monitored by TLC. After complete consumption of the starting material, the reaction was saturated. The mixture was quenched with aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (230-400) column chromatography to give product 2 as an off-white solid (2.6 g, 78%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.08 (d, J=2.0 Hz, 1H), 7.80-7.78 (m, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.06-6.93 (m, 4H), 6.35 (s, 1H), 4.37 (s, 2H), 3.40-3.32 (m, 4H), 3.26 (s, 3H), 2.38 (t, J=5.6 Hz, 2H), 2.25 (t, J=5.6 Hz, 2H), 1.39 (s, 9H). MS m / z (M+H): 411.3

[0352] Step 2: To a solution of 2 (2.6 g, 6.3 mmol) in dichloromethane (26.0 mL) was added trifluoroacetic acid (10.4 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. After complete consumption of the starting material, the volatiles were removed under reduced pressure to give the product as a brown oil. The crude product was washed with ether (3×50 mL) to give 3 as a pale yellow thick liquid (crude product 2.9 g). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.69 (bs, 2H), 8.09-8.08 (m, 1H), 7.81-7.78 (m, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.08-6.97 (m, 4H), 6.45 (s, 1H), 4.37 (s, 2H), 3.27 (s, 3H), 3.15-3.09 (m, 4H), 2.60 (t, J=5.6 Hz, 2H), 2.45 (t, J=5.6 Hz, 2H). MS m / z (M+H): 311.3

[0353] Step 3: To a solution of 3 (2.9 g, 6.8 mmol) in dimethyl sulfoxide (30 mL, 10 V) was added diisopropyl-ethyl-amine (3.5 mL, 0.0205 mol) and the carbamate from Step 4, Example 16. The mate product 5 (1.7 g, 6.8 mmol) was added at 25° C. The reaction mixture was stirred at 60° C. for 6 h. The reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3×100 mL), and dried over sodium sulfate. The crude product was obtained by evaporation of the volatiles. The product 4 was purified on a silica gel (230-400) column (30% ethyl acetate in n-hexane) to give a pale yellow green color. It was obtained as a milky solid (2.6 g, 86%). 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.08 (d, J=2.0 Hz, 1H), 7.81-7.78 (m, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.25-7.21 (m, 2H), 7.09-6.93 (m, 7H), 6.83 (d, J=3.2 Hz, 1H), 6.34 (s, 1H), 4.37 (s, 2H), 3.38-3.28 (m, 4H), 3.27 (s, 3H), 2.71-2.69 (m, 1H), 2.36 (t, J=5.6 Hz, 2H), 2.25 (t, J=5.6 Hz, 2H), 1.85 (m, 1H), 1.13 (d, J=4.8 Hz, 1H), 1.04 (d, J=7.6 Hz, 1H). 13 C NMR: (100 MHz, DMSO-d6):δ162.60, 157.57, 153.87, 146.76, 142.00, 140.15, 139.65, 138.71, 129.52, 128.87, 128.10, 125.86, 125.35, 124.90, 123.12, 121.21, 118.96, 111.26, 70.58, 57.49, 44.94, 43.90, 35.63, 34.08, 28.92, 24.31, and 15.57. MS m / z (M+H): 470.3, HPLC purity: 99.57%, Chiral HPLC: 99.60%

[0354] Example 33: 4-({3-[(5-methylpyrimidin-2-yl)oxy]phenyl}methylidene Synthesis of )-N-[(1R,2S)-2-phenylcyclopropyl]piperidine-1-carboxamide: [ka]

[0355] Step 1: To a solution of 2-chloro-5-methylpyrimidine 1 (33.0 g, 0.256 mol) in DMF (330 mL) was added 3-(hydroxymethyl)phenol (31.86 g, 0.256 mol) and cesium carbonate (100.36 g, 0.308 mol) at room temperature. The reaction mixture was stirred at 100 °C for 5 h. The resulting mixture was allowed to cool to room temperature. Cool at 40°C, dilute with dichloromethane (330 mL), add water (2 x 330 mL), 1N aqueous KOH (2 x 165 mL) The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (8% ethyl acetate in hexane) to give product 2 as a white solid (22.0 g, 40%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 8.4 (s, 2H), 7.3 (t, J = 8.1 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.07 (s, 1H), 7.0 (d, J = 7.5 Hz, 1H), 5.26 (m, 1H), 4.49 (d, J = 5.4, 2H), 2.19 (s, 3H). MS m / z (M+H): 217.1

[0356] Step 2: To a solution of {3-[(5-methylpyrimidin-2-yl)oxy]phenyl}methanol 2 (22.0 g, 0.101 mol) in dichloromethane (220 mL), add thichloride while stirring the reaction in an ice bath. Onil (8.1 mL, 0.111 mol) was added dropwise. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated under reduced pressure and diluted with ethyl acetate (220 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (110 mL) and water (2X220 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give product 3 as a white solid (21.5 g, 90%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.45 (s, 2H), 7.4 (t, J = 8 Hz, 1H), 7.28 (d, J = MS m / z (M+H): 235.3

[0357] Step 3: A solution of 2-[3-(chloromethyl)phenoxy]-5-methylpyrimidine 3 (21.0 g, 0.0894 mol) in triethyl phosphite (25.0 mL, 0.143 mol) was heated at 130°C for 16 h. o The reaction mixture was cooled to room temperature, and the volatiles were evaporated to give a crude product, which was purified on a silica gel (230-400) column (86% ethyl acetate in hexane) to give product 4 as a pale green oil (21.6%). g, 72%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.44 (s, 2H), 7.3 (t, J = 8 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 7.02 (t, J = 8 Hz, 2H), 3.95-3.88 (m, 4H), 3.31-3.20 (m, 2H), 2.18 (s, 3H), 1.15-1.11 (m, 6H). MS m / z (M+H): 337.3

[0358] Step 4: Diethyl ({3-[(5-methylpyrimidin-2-yl)oxy]phenanthrin) in THF (147 mL) A solution of 15-crown-5 ether (methyl)phosphonate 4 (21.0 g, 0.062 mol) was added to the solution at room temperature. To the reaction mixture was added tert-butyl 4-oxopiperidine-1-carboxylate (12.4 g, 0.0624 mol). The reaction mixture was cooled (ice bath) and 60% NaH (3.73 g, 0.093 mol) was added in portions. The reaction mixture was stirred at room temperature for 30 min and cooled to ice again. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (12.4 g, 0.0624 mol) in THF (63 mL) was added. The mixture was added at ice temperature and stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with ethyl acetate (210 mL). The resulting mixture was washed with water (3×210 mL) and dried over sodium sulfate. The volatiles were evaporated to give The crude product was purified on a silica gel (230-400) column (15% ethyl acetate in hexane) to give product 5. Obtained as a white solid (17.0 g, 72%). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.44 (s, 2H), 7.34 (t, J = 8 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.99-6.97 (m, 2H), 6.34 (s, 1H), 3.38 (t, J = 5.6 Hz, 2H), 2.37 (t, J = 5.6 Hz, 2H), 2.24 (t, J = 5.6 Hz, 2H), 2.18 (s, 3H), 1.38 (s, 9H). MS m / z (M+H): 382.3

[0359] Step 5: tert-Butyl 4-({3-[(5-methylpyrimidine-2- To a solution of (methyl)(oxy)phenyl}methylidene)piperidine-1-carboxylate 5 (17.0 g, 0.0445 mol), trifluoroacetic acid (68.0 mL) was added at ice temperature, and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was evaporated under reduced pressure to give the crude product as a yellow oil, which was washed with diethyl ether (3×50 mL) to give product 6 as an off-white solid (crude product 15.8 g). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.83 (bs, 2H), 8.45 (s, 2H), 7.37 (t, J = 8.4 Hz, 1H), 7.08 (d, J = 7. 6 Hz, 1H), 7.08 (d, J = 7. 6 MS m / z (M+H): 282.33

[0360] Step 6: To a solution of the trifluoroacetate salt of 5-methyl-2-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyrimidine 6 (15.0 g, 0.0379 mol) in dimethyl sulfoxide (150 mL) was added diisopropylethylamine (20.0 mL, 0.113 mol) and the carboxylate from Step 4, Example 16. Bamate product 5 (10.57 g, 0.0417 mol) was added at 25-30°C. The reaction mixture was heated at 60°C for 5 h. The reaction mixture was diluted with ethyl acetate (150 mL), washed with water (3×150 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (70% ethyl acetate in hexane) to give product 7 as a pale yellow solid. (12.0 g, 72%). Melting range: 58°C-67.5°C. 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.4 (s, 2H), 7.3 (t, J = 7.6 Hz, 1H), 7.23-7.19 (m, 2H), 7.12-7.06 (m, 4H), 6.9 (d, J = 8 Hz, 2H), 6.8 (s, 1H), 6.3 (s, 1H), 3.36-3.29 (m, 4H), 2.6 (s, 2H), 2.3 (s, 2H), 2.2-2.1(m, 5H), 1.87-1.84 (m, 1H), 1.16-1.06 (m, 2H). MS m / z (M+H): 441.4, HPLC purity: 99.67%

[0361] Example 34: N-[(2S)-2-phenylcyclopropyl]-4-{[3-(pyrazin-2-yl)oxy]-4-(phenylcyclopropyl)-4 ... Synthesis of {(phenyl)methylidene}piperidine-1-carboxamide:

[0362] [ka]

[0363] Step 1: To a solution of 2-chloropyrazine 1 (15.0 g, 0.130 mol) in DMF (150 mL) was added 10 mL of chloropyrazine at room temperature. 3-(hydroxymethyl)phenol (16.25 g, 0.130 mol) and cesium carbonate (51.2 g , 0.157 mol) was added. The reaction mixture was stirred at 100°C for 5 hours. The resulting mixture was then cooled to room temperature, diluted with water (250 mL), extracted with ethyl acetate (3 x 500 mL), the resulting organic layer was washed with 1N KOH (2 x 250 mL), and the separated organic layer was dried over sodium sulfate. The crude product obtained by evaporation of the volatiles was purified by silica gel (230-400) column (10% acetic acid in hexane). Et 3) to give the product 2 as an off-white solid (9.3 g, 35%). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.50 (d, J = 1.2 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.18-8.17 (m, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.17 (d, J MS m / z (M+1):203.2

[0364] Step 2: To a solution of {3-[(pyrazin-2-yl)oxy]phenyl}methanol 2 (10.0 g, 0.049 mol) in dichloromethane (100 mL) was added thionyl chloride (3.94 mL, 0.054 mol) dropwise while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 h. The effervescent material was evaporated under reduced pressure and diluted with ethyl acetate (250 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (150 mL) and water (2×200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give product 3 as a yellow solid (9.0 g, 82%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.54-8.54 (m, 1H), 8.36 (d, J = 2.8, 1H), 8.19-8.18 (m, 1H), 7.43 (t, J = 7.6, 1H), 7.31-7.14 (m, 3H), 4.75 (s, 2H). MS m / z (M+1):221.2.

[0365] Step 3: 2-[3-(chloromethyl)phenoxy]pyrazine 3 (10.0 g, 0.045 mol) triethyl 130 ml of bisphosphonate (12.3 mL, 0.072 mol) solution o The reaction mixture was then heated at 40°C for 6 hours. The reaction mixture was then cooled to room temperature, and the volatiles were evaporated. The crude product was purified by column chromatography on silica gel (230-400) (60% in hexane). Purification with ethyl acetate) gave the product 4 as a colorless oil (9.49 g 64.5%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.51 (d, J = 1.6 Hz, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.18-8.17 (m, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.14(d, J = 7.6 Hz, 1H), 7.08-7.05 (m, 2H), 3.95-3.88 (m, 4H), 3.26 (2s, 2H), 1.13 (t, J = 3.2 Hz, 6H). MS m / z (M+1):323.2

[0366] Step 4: Diethyl{[3-(pyrazin-2-yloxy)phenyl]methyl}methyl in THF (70 mL) To a solution of {ethyl}phosphonate 4 (10.0 g, 0.031 mol) was added 15-crown-5 ether (136 mg, 0.62 mmol) at room temperature. 60% NaH (1.86 g, 0.046 mol) was added in portions to the above reaction mixture at 0-5 °C. The reaction mixture was stirred at room temperature for 30 min and then cooled to ice again. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (6.18 g, 0.031 mol) in THF (30 mL) was added at ice temperature and stirred at room temperature for 16 h. The resulting reaction mixture was diluted with water (500 mL), extracted with ethyl acetate (3 × 500 mL), and dried over sodium sulfate. The crude product obtained after evaporation of volatiles was purified on a silica gel (230-400) column (15% ethyl acetate in hexane) to give product 5 as an off-white solid (9.1 g, 80%). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.51 (d, J = 1.2 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.18-8.17 (m, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.04-7.02 (m, 3H), 6.34 (s, 1H), 3.37 (t, J = 5.2 Hz, 2H), 3.32-3.29 (m, 2H), 2.37 (t, J = 5.6 Hz, 2H), 2.24 (t, J = 5.6 Hz, 2H), 1.37 (s, 9H). MS m / z (M+1):368.4

[0367] Step 5: To a solution of tert-butyl 4-{[3-(pyrazin-2-yloxy)phenyl]methylidene}piperidine-1-carboxylate 5 (10.0 g, 0.027 mol) in dichloromethane (100 mL) was added ice-cold Trifluoroacetic acid (40 mL) was added at room temperature and the reaction mixture was stirred for 1 hour. The volatiles were evaporated from the reaction mixture under reduced pressure to give the crude product as a red oil, which was washed with ether (3×50 mL) to give 6 as an off-white solid (9.5 g, 92%). 1 H NMR (300 MHz, DMSO-d6) δ(ppm): 8.72 (bs, 2H), 8.52 (d, J = 1.6 Hz, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.18-8.17 (m, 1H), 7.42-7.38 (m, 1H), 7.12-7.06 (m, 3H), 6.44 (s, 1H), 3.13-3.07 (m, 4H), 2.58 (t,J = 5.6 Hz, 2H). MS m / z (M+1):268.3

[0368] Step 6: To a solution of the trifluoroacetate salt of 2-[3-(piperidin-4-ylidenemethyl)phenoxy]pyrazine 6 (10.0 g, 0.026 mol) in dimethyl sulfoxide (100 mL, 10 V), diisopropylethylamine (13.7 mL, 0.078 mol) and the carbamate product 5 (7.3 g, 0.028 mol) from Step 4, Example 16, were added at 25-30 °C. The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3 × 150 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by filtration onto a silica gel (230-400) column (50% in hexane). Purification with ethyl acetate gave product 7 as a pale yellow solid (8.0 g, 71%). Melting range: 41.7°C-52.6°C; 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.52 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 1.2 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 7.6 Hz, 2H), 7.12-7.01 (m, 6H), 6.83 (d, J = 2.4 Hz, 1H), 6.33 (s, 1H) 3.37-3.27 (m, 4H), 2.67 (d, J = 3.2 Hz, 1H), 2.35 (s, 1H), 2.23 (s, 1H), 1.87-1.82 (m, 1H), 1.16-1.01 (m, 2H). MS m / z (M+1):427.4. HPLC purity:99.49

[0369] Example 35: Synthesis of 4-[3-(5-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide [ka]

[0370] Step 1: To a solution of 5-bromo-2-fluoropyridine 1 (7.72 g, 44.3 mmol) in DMSO (40 mL) was added 3-hydroxymethylphenol (5 g, 40.3 mmol) and cesium carbonate (15.75 g, 48.3 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 8 h. The resulting mixture was allowed to cool to room temperature, diluted with water (70 mL), and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was washed with sodium sulfate. The solution was dried over sodium and the solvent was evaporated under reduced pressure using a rotary evaporator (rotovap). The crude product obtained by evaporating the volatiles was then passed through a silica gel (230-400) column (n-hexane). Purification with 30% ethyl acetate in xanthan gum gave the product 2 as a pale yellow oil (7.1 g, 63% yield). 1 H NMR (400 MHz, CDCl3) δ8.19 (dd, J = 2.6, 0.6 Hz, 1H), 7.77 (dd, J = 8.7, 2.6 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.20 (ddd, J = 7. 6, 1.7, 0.6 Hz, 1H).6, 1.7, 0.9 Hz, 1H), 7.13 (ddd, J = 2.1 Hz, 1H), 7.03 (ddd, J = 8.1, 2.5, 1.0 Hz, 1H), 6.84 (dd, J = 8.7, 0.7 Hz, 1H), 4.68 (s, 2H).MS m / z (M): 280.21

[0371] Step 2: To a solution of {3-[(5-bromopyridin-2-yl)oxy]phenyl}methanol 2 (5.2 g, 18.57 mmol) in dichloromethane (52 mL) was added thionichloride while stirring the reaction in an ice bath. To the resulting solution was added dropwise ethanol (2.43 g, 20.4 mmol). After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated under reduced pressure and diluted with ethyl acetate (80 mL). The organic layer was diluted with saturated carbonate The organic layer was dried over anhydrous sodium sulfate and concentrated to give product 3 as a white solid (4.12 g, 75% yield). 1 H NMR ( 400 MHz, CDCl3) δ8.22 (dd, J = 2.6, 0.7 Hz, 1H), 7.79 (dd, J = 8.7, 2.6 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.29-7.21 (m, 2H), 7.17 (t, J = MS m / z (M+2):299.9

[0372] Step 3: A solution of 5-bromo-2-[3-(chloromethyl)phenoxy]pyridine 3 (4 g, 13.5 mmol) in triethyl phosphite (5.78 mL, 33.7 mmol) was heated at 150 °C for 6 h. The mixture was returned to room temperature, and the volatiles were evaporated. The resulting crude product was then separated on a silica gel (230-400) column. The product was purified by elution with hexane (60% ethyl acetate in petroleum ether) to give the product 4 as a colorless oil (3.88 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J = 2.6, 0.7 Hz, 1H), 7.76 (dd, J = 8.7, 2.6 Hz, 1H), 7.40-7.29 (m, 1H), 7.16 (dt, J = 7.3, 1.7 Hz, 1H), 7.07 (q, J = 2.3 Hz, 1H), 7.02 (dtd, J = 8.1, 2.3, 1.0 Hz, 1H), 6.83 (dd, J = 8.7, 0.7 Hz, 1H), 4.03 (dqd, J = 8.7, 7.1, 1.6 Hz, 4H), 3.16 (d, J = 21.6 Hz, 2H), 1.25 (t, J = 7.1 Hz, 6H). MS m / z (M+1):401

[0373] Step 4: To a solution of diethyl ({3-[(5-bromopyridin-2-yl)oxy]phenyl}methyl)phosphonate 4 (3.8 g, 9.52 mmol) in THF (19 mL) was added 15-crown ether (41 mg, 0.190 mmol). The reaction was cooled (ice bath) and 60% NaH (342 mg, 14.2 mol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and cooled to ice again. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.9 g, 9.52 mmol) in THF (19 mL) was added at ice temperature and stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (3×40 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (5% ethyl acetate in n-hexane) to give product 5 as a white solid (2.58 g, 61% yield). 1 H NMR (400 MHz, CDCl3) δ8.22 (dd, J = 2.6, 0.7 Hz, 1H), 7.77 (dd, J = 8.7, 2.6 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.04 (ddt, J = 7. 7.7, MS m / z (M+Na):469.21

[0374] Step 5: As reported in the literature (Reference: J. Am. Chem. Soc. 2016, 138, 13493-13496) The experiment was carried out using the methodology described in the literature. To a degassed solution of [(bromo-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester 5 (2 g, 4.49 mmol), LiOH.HO (396 mg, 9.43 mmol) and the ligands, L-1 (110 mg, 0.337 mmol) and Cu(acac) (88 mg, 0.337 mmol), were added sequentially and the mixture was degassed for 10 min. The resulting reaction mixture was heated at 85°C for 48 hours. The progress of the reaction was monitored using TLC. The reaction mixture was cooled to ambient temperature and quenched by the addition of 5% aqueous NH4Cl (12 mL). The resulting mixture was washed with ethyl acetate (25 mL) and diluted with ethyl acetate (25 mL). The organic layer was separated, washed with brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The resulting crude product was further purified by silica gel flash chromatography using 40-45% ethyl acetate in hexanes to give 4-[3-(5-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxamide. The tert-butyl carboxylic acid ester (6) was obtained as a light brown solid (738 mg, 43% yield). 1 H NMR (400 MHz, CDCl3) δ9.69 (bs, 1H), .83 (s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 4.9 Hz, 1H), 6.92 (d, J = 7.8 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 6.30 (s, 1H), 3.48 (t, J = 5.7 Hz, 2H), 3.35 (t, J = 5.9 Hz, 2H), 2.41 (t, J = 5.9 Hz, 2H), 2.29 (t, J = 5.8 Hz, 2H), 1.47 (s, 9H). MS m / z (M+Na):405.44

[0375] Step 6: To a solution of 6 (600 mg, 1.57 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2.4 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. After complete consumption of the starting material, the volatiles were removed under reduced pressure to give the crude product 7 as a red-orange The crude product was washed with ether (3 x 5 mL) to give the trifluoroacetate salt of 6-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyridin-3-ol as a brown oil (400 mg crude product). MS m / z (M+1): 283.21

[0376] Step 7: To a solution of 7 (300 mg, 1.06 mmol) in dimethyl sulfoxide (3 mL, 10 V), Diisopropylethylamine (1.48 mL, 8.51 mmol) and the carbamate from Step 4, Example 16 Mate product 5 (269 mg, 1.06 mmol) was added at 25° C. The reaction mixture was stirred at 60° C. for 4 h. The reaction was monitored by TLC. The resulting reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (3 x 20 mL) and dried over anhydrous sodium sulfate. The product was purified by reverse phase HPLC, the collected fractions were concentrated, and the resulting residue was lyophilized to give the product 8 as an off-white solid (93 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ9.70 (s, 1H), 7.77-7.67 (m, 1H), 7.37-7.15 (m, 4H), 7.17-7.07 (m, 3H), 6.98 (d, J = 7.6 Hz, 1H), 6.93-6.79 (m, 4H), 6.33 (s, 1H), 3.37 (d, J = 6.0 Hz, 2H), 3.32-3.25 (m, 2H), 2.75-2.61 (m, 1H), 2.30 (dt, J = 42.8, 5.8 Hz, 4H), 1.88 (ddd, J = 9.4, 6.1, 3.2 Hz, 1H), 1.16 (dt, J = 9.6, 5.1 Hz, 1H), 1.09-1.02 (m, 1H). MS m / z (M+1):442.4; HPLC purity: 96.70%; Chiral HPLC purity: 96.0

[0377] Example 36: Synthesis of 4-[3-(4-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide: [ka]

[0378] Step 1: To a solution of 4-bromo-2-fluoropyridine 1 (7.72 g, 44.3 mmol) in DMSO (40 mL, 8 V) was added 3-hydroxymethylphenol (5 g, 40.3 mmol) and cesium carbonate (15.75 g, 48.3 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 8 h. The resulting mixture was allowed to cool to room temperature, diluted with water (70 mL), extracted with ethyl acetate (3 x 100 mL), and the organic layer was washed with sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230-400). Purification by column (30% ethyl acetate in n-hexane) gave product 2 as a pale yellow oil (4.8 g, 43% yield). 1H NMR (400 MHz, CDCl3) δ8.00 (dd, J = 5.4, 1.8 Hz, 1H), 7.40 (td, J = 7.8, 1.8 Hz, 1H), 7.28-7.22 (m, 1H), 7.15 (dt, J = 5.3, 2.0 Hz, 2H), 7.11 (d, J = 1.8 Hz, 1H), 7.05 (dd, J = 8.0, 2.3 Hz, 1H), 4.72 (s, 2H). MS m / z (M+2):281.9

[0379] Step 2: To a solution of {3-[(4-bromopyridin-2-yl)oxy]phenyl}methanol 2 (4.8 g, 17.1 mmol) in dichloromethane (48 mL), thionyl chloride (2.24 g, 18.8 mmol) was added dropwise while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 h. The volatiles were evaporated under reduced pressure and diluted with ethyl acetate (80 mL). The organic layer was washed with saturated aqueous sodium chloride. The organic layer was washed with aqueous sodium chloride (25 mL) and water (25 mL), dried over anhydrous sodium sulfate, and concentrated to give product 3 as a white solid (4.05 g, 80% yield). 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 5.5 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.25 (q, J = 2.0, 1.3 Hz, 1H), 7.21-7.14 (m, 2H), 7.13-7.05 (m, 2H), 4.59 (s, 2H). MS m / z (M+2):299.9

[0380] Step 3: A solution of 3 (4 g, 13.5 mmol) in triethyl phosphite (5.78 mL, 33.7 mmol) was heated at 150 °C for 6 h. The reaction mixture was allowed to cool to room temperature, and the volatiles were evaporated to give a crude product, which was purified on a silica gel (230-400) column (60% ethyl acetate in petroleum ether) to give the product 4 as a colorless oil (3.88 g, 72% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.00 (d, J = 5.4 Hz, 1H), 7.36 (m, 1H), 7.20-7.13 (m, 2H), 7.07 (t, J = 1.9 Hz, 2H), 7.03 (m, 1H), 4.03 (m, 4H), 3.16 (d, J = 21.7 Hz, 2H), 1.25 (t, J = 7.1 Hz, 6H). MS m / z (M+H): 401.20

[0381] Step 4: To a solution of 4 (3.8 g, 9.52 mmol) in THF (19 mL) was added 15-crown ether (41 mg, 0.190 mmol). The reaction was cooled (ice bath) and 60% NaH (342 mg, 14.2 mol) was added in portions. The reaction mixture was stirred at room temperature for 30 min and cooled to ice again. 4- in THF (19 mL) A solution of oxo-piperidine-1-carboxylic acid tert-butyl ester (1.9 g, 9.52 mmol) was added to ice bath. The mixture was added to the flask and stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (3 x 40 mL), and dried over anhydrous sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400 mesh) column (5% ethyl acetate in n-hexane) to give the crude product. Product 5 was obtained as a white solid (2.75 g, 65% yield). 1 H NMR (400 MHz, CDCl3) δ8.02 (d, J = 5.4 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.15 (dd, J = 5.4, 1.6 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 7.00-6.93 (m, 2H), 6.34 (s, 1H), 3.45 (dt, J = 40.2, 5.9 Hz, 5H), 2.50-2.27 (m, 4H), 1.47 (s, 9H). MS m / z (M+Na):467.6

[0382] Step 5: To a degassed solution of 5 (2 g, 4.49 mmol) in DMSO (40 mL, 20 V) and water (2 mL, 1 V), LiOH.HO (396 mg, 9.43 mmol) and the ligands L-1 (110 mg, 0.337 mmol) and Cu(acac) (88 mg, 0.337 mmol) were added sequentially, and the degassing was continued for 10 min. The resulting reaction mixture was heated at 85 °C. The reaction mixture was heated at ambient temperature for 48 hours. The progress of the reaction was monitored by TLC. The mixture was cooled to room temperature, quenched by the addition of 5% aqueous NH4Cl (12 mL, 20 V), and diluted with ethyl acetate (25 mL). The organics were separated, washed with brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was further purified by silica gel flash chromatography using 40-45% ethyl acetate in hexanes to give 4-[3-(5-hydroxy-pyridin-2-yl)- [(1-hydroxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester (6) was obtained as a light brown solid. The compound was obtained as a compound (686 mg, yield 40%). 1 H NMR (400 MHz, chloroform-d) δ 8.02 (d, J = 5.4 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.15 (dd, J = 5.4, 1.6 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 7.00-6.93 (m, 2H), 6.34 (s, 1H), 3.45 (dt, J = 40.2, 5.9 Hz, 5H), 2.50-2.27 (m, 4H), 1.47 (s, 9H). MS m / z (M+1):383.2

[0383] Step 6: 4-[3-(4-hydroxy-pyridin-2-yloxy)- in dichloromethane (4 mL) To a solution of [benzylidene]-piperidine-1-carboxylic acid tert-butyl ester 6 (400 mg, 1.04 mmol) was added trifluoroacetic acid (1.2 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After complete consumption of the starting material, the volatiles were removed under reduced pressure. The product 7 was obtained as a red oil. The crude product was washed with ether (3 x 50 mL) to give the trifluoroacetate salt of 6-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyridin-3-ol as a brown oil (400 mg crude product). MS m / z (M+1): 283.2

[0384] Step 7: To a solution of the trifluoroacetate salt of 6-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyridin-3-ol 7 (280 mg, 0.992 mmol) in dimethyl sulfoxide (2.8 mL) was added diisopropylethylamine (1.38 mL, 7.94 mmol) and the carbamethoxazole from Step 4, Example 16. The ester product 5 (251 mg, 0.992 mmol) was added at 25°C. The reaction mixture was stirred at 60°C for 4 hours. The reaction was monitored by TLC. The resulting reaction mixture was diluted with ethyl acetate (20 mL), washed with water (3x20 mL), and dried over sodium sulfate. The volatiles were evaporated to give the crude product, which was then purified by reverse NMR. Purification by phase HPLC gave the product 8 as an off-white solid (137 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.24 (tt, J = 7.9, 1.3 Hz, 2H), 7.15-7.08 (m, 3H), 7.04 (d, J = 7.7 Hz, 1H), 6.95-6.88 (m, 2H), 6.83 (d, J = 3.2 Hz, 1H), 6.55 (dd, J = 5.7, 2.1 Hz, 1H), 6.35 (s, 1H), 6.28 (d, J = 2.0 Hz, 1H), 3.38 (t, J = 5.8 Hz, 2H), 3.32 (m, 2H), 2.70 (tt, J = 6. 9.9, 3.6 Hz, 1H), 2.37 (t, J = 5.8 Hz, 2H), 2.29-2.22 (m, 2H), 1.88 (ddd, J = 9.4, 6.1, 3.2 Hz, 1H), 1.16 (dt, J = 9.6, 5.1 Hz, 1H), 1.07 (dt, J = 7.6, 5.8 Hz, 1H). MS m / z (M+H): 442.19, HPLC purity: 98.50%; Chiral HPLC purity: 97.9%.

[0385] Example 37: Synthesis of 4-[3-(6-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide: [ka]

[0386] Step 1: 2-Bromo-6-fluoropyridine 1 (2.5 g, 14.2 mmol) in DMF (25 mL, 10 V) A solution of 3-hydroxymethylphenol (2.64 g, 21.3 mmol) and cesium carbonate was added at room temperature. The reaction mixture was stirred at 100°C for 8 hours. The mixture was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (3 x 50 mL), and the organic layer was dried over anhydrous sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (30% ethyl acetate in n-hexane) to give product 2 as a pale yellow oil (2.48 g, 62% yield). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.79 (t, J = 7.9 Hz, 1H), 7.39 (t, J = 7.9 Hz, 2H), 7.19 (dt, J = 7.7, 1. 2 Hz, 1H), 7.19 (dt, J = 7.7, 1. 2 Hz, 1H).2 Hz, 1H), 7.09 (t, J = 1.9 Hz, 1H), 7.04-6.97 (m, 2H), 5.29 (t, J = 5.8 Hz, 1H), 4.52 (d, J = 5.8 Hz, 2H). MS m / z (M): 280.

[0387] Step 2: To a solution of {3-[(6-bromopyridin-2-yl)oxy]phenyl}methanol 2 (2.48 g, 8.85 mmol) in dichloromethane (25 mL) was added thionichloride while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated under reduced pressure and diluted with ethyl acetate (60 mL). The organic layer was washed with saturated carbonate The organic layer was dried over anhydrous sodium sulfate and concentrated to give product 3 as a brown oil (2.56 g, 86%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 7.86-7.76 (m, 1H), 7.50-7.36 (m, 2H), 7.33 (dt, J = 7.7, 1. 3 Hz, 1H), 7.25 (t, J = 2.1 Hz, 1H), 7.161- 7.071 (m, J = 8.1, 2.4, 1.1 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 4.79 (s, 2H). MS m / z (M): 298.19

[0388] Step 3: A solution of 2-bromo-6-[3-(chloromethyl)phenoxy]pyridine 3 (2.55 g, 8.50 mmol) in triethyl phosphite (3.67 mL, 21.0 mmol) was heated at 150 °C for 6 h. The reaction mixture was allowed to cool to room temperature, and the volatiles were evaporated to give a crude product, which was then loaded onto a silica gel (230-400) column. Purification with hexane (60% ethyl acetate in petroleum ether) gave the product 4 as a light brown oil (crude 2.97 g). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.88-7.72 (m, 1H), 7.52-6.96 (m, 6H), 4.011-3.90 (m, J = 14.7, 7.3, 4.0 Hz, 4H), 1.16 (tt, J = 7.7, 5.3 Hz, 6H). MS m / z (M+Na):422.5

[0389] Step 4: To a solution of diethyl ({3-[(6-bromopyridin-2-yl)oxy]phenyl}methyl)phosphonate 4 (2.96 g, 7.39 mmol) in THF (20 mL) was added 15-crown ether (32 mg, 0.147 mmol). The reaction was cooled (ice bath) and 60% NaH (266 mg, 11.0 mmol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and then cooled to ice again. A solution of 1.76g of 1-iso-piperidine-1-carboxylic acid tert-butyl ester (1.76g, 8.86mmol) was added to the The mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (3×40 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (5% ethyl acetate in n-hexane) to give product 5 as a yellow oak. The compound was obtained as a methyl ester (2.11 g, 65% yield). 1 H NMR (400 MHz, DMSO) δ (ppm): 7.84-7.77 (m, 1H), 7.44-7.35 (m, 2H), 7.14-6.99 (m, 4H), 6.39 (s, 1H), 3.47-3.36 (m, 3H), 3.35 (s, 2H), 2.42 (t, J = 5.8 Hz, 2H), 2.30-2.24 (m, 2H), 1.40 (s, 9H). MS m / z (M+Na):467.6

[0390] Step 5: To a degassed solution of 4-[3-(6-bromo-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester 5 (1.8 g, 4.04 mmol) in DMSO (36 mL, 20 V), water (1.8 mL), LiOH.HO (356 mg, 8.49 mmol), ligand L-1 (99.6 mg, 0.303 mmol), and Cu(acac) (79 mg, 0.303 mmol) were added sequentially, and degassing was continued for 10 min. The resulting reaction mixture was heated at 100 °C under MW irradiation for 4 h. The reaction progress was monitored by TLC. The above reaction mixture The mixture was cooled to ambient temperature, quenched by the addition of 5% aqueous NH4Cl (12 mL), and diluted with ethyl acetate (25 mL). The organics were separated, washed with brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was further purified by silica gel flash chromatography using 40-45% ethyl acetate in hexanes to give 4-[3-(6-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester (6) as a light brown solid. This was obtained as a yellow solid (730 mg, 47% yield).1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.80 (bs, 1H), 7.64 (t, J =8.0 Hz, 1H), 7.53 (t, J =8.0 Hz, 1H), 7.03 (d, J =7.6 Hz, 1H), 6.96-6.90 (m, 2 H), 6.36-6.33 (m, 3H), 3.40 (t, J = 5.2 Hz, 1H), 3.38-3.31(m, 2H), 2.39 (t, J = 5.6 Hz, 2H), 2.27 (t, J = 5.6 Hz, 2H), 1.45 (s, 9H), MS m / z (M+Na):405.17

[0391] Step 6: 4-[3-(6-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester 6 (720 mg, 1.88 mmol) in dichloromethane (5.6 mL) To the solution was added trifluoroacetic acid (1.44 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the starting material was completely consumed, the volatiles were removed under reduced pressure. The crude product was washed with ether (3×5 mL) and purified by trifluoromethanesulfonylation of 6-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyridin-2-ol 7. The acetate salt was obtained as a brown oil (750 mg crude). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.64 (s, 2H), 7.65 (t, J = 7.9 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.29-6.89 MS m / z (M+H): 283.33

[0392] Step 7: 2-Bromo-6-{3-[(piperidin-4-yl)methyl]phenyl}-3-(piperidin-4-yl)methyl ... To a solution of the trifluoroacetate salt of {(2-phenyl)methyl}phenoxy}pyridine 7 (730 mg, 2.5 mmol), Diisopropylethylamine (1.9 mL, 12.9 mmol) and the carbamate product 5 from Step 4, Example 16 (570 mg, 2.25 mmol) were added at 25° C. The reaction mixture was stirred at 60° C. for 5 h. The reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (70 mL), washed with water (3x20 mL), and dried over sodium sulfate. The crude product obtained by evaporation of the volatiles was Purification by phase HPLC twice gave the product 8 as an off-white solid (120 mg, 11%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 10.83 (s, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.24 (dd, J = 8. 2, 6.9 Hz, 2H).2, 6.9 Hz, 2H), 7.17-7.00(m, 4H), 6.99-6.81(m, 3H), 6.35(s, 3H), 3.38(t, J = 5.7 Hz, 3H), 3.30(t, J = 5.9 Hz, 2H), 2.70(dd, J = 7.9, 5.5, 2.4 Hz, 1H), 2.37(t, J = 5.8 Hz, 2H), 2.26(t, J = 5.7 Hz, 2H), 1.88(dd, J = 9.4, 6.1, 3.2 Hz, 1H), 1.16 (m, 1H), 1.07 (m, 1H). MS m / z (M+H): 442.7, HPLC purity: 98.48%; Chiral HPLC: 98.6

[0393] Example 38 - Soluble Epoxide Hydrolase (sEH) Inhibition Assay:

[0394] The sEH enzyme inhibition assay was performed using a commercially available kit from Cayman Chemical Company, Ann Arbor, Michigan (Cayman Cat. No. 10011671). The substrate used was 3-phenyl-cyano(6-methoxy-2-naphthalenyl)-methyl ester-2-oxiraneacetic acid. Hydrolysis of the substrate yielded a highly fluorescent product that could be monitored at excitation and emission wavelengths of 330 and 465 nm, respectively. The assay mixture consisted of 185-190 μL of assay buffer and 5 μL of sEH enzyme in a 96-well plate. Different concentrations of compounds (in 5 μL of DMSO) or DMSO (vehicle) alone were added, and the reaction was initiated by adding 5 μL of substrate. The plate was incubated for 15 minutes at 25° C. Data was analyzed to determine the percent inhibition.

[0395] Example 39 - Fatty acid amide hydrolase (FAAH (SEQ ID NO: 5)) inhibition assay:

[0396] The FAAH enzyme inhibition assay is commercially available from Cayman Chemical Company, Ann Arbor, Michigan. The assay was performed using a commercially available kit (Cayman Cat. No. 10010183). The assay uses AMC arachidonoylamide (7-amino-4-methyl-2H-1-benzopyran-2-one-5Z,8Z,11Z,14Z-eicosatetraenamide, Cayman Chemical Cat. No. 10005098) as a substrate for FAAH. FAAH hydrolyzes AMC arachidonoylamide to produce the fluorescent product, 7-amino-4-methylcoumarate. This fluorophore emits an amine (AMC) at an excitation wavelength of 340-360 nm and an emission wavelength of 450-465 nm. The assay can be performed in 24 hours. Different concentrations of compounds (in DMSO) or DMSO (vehicle) alone were added. After the addition of FAAH, the plate was incubated for 20 minutes at ambient temperature. The assay was performed using AMC amide The reaction was initiated by the rapid addition of arachidonoylamide and proceeded for 60 min at ambient temperature, during which the release of AMC was observed with a concomitant increase in fluorescence intensity (excitation wavelength 340-360 nm, emission wavelength 450-465 nm). Fluorescence intensity measurements were performed kinetically, and reaction rates were calculated from the linear portion of the reaction using linear regression analysis. Initial activity % = (inhibited fluorescence / 100% active fluorescence)*100 Inhibition rate % = 100-(initial activity %)

[0397] Concentrations below 10 μM (IC 50 ) inhibits soluble epoxide hydrolase. The inhibitory activity of compounds of Formula I against sEH and FAAH enzymes is shown in Table 1 (see Figure 1). The selectivity of sEH inhibition is determined by dividing the inhibitory potency of FAAH to sEH [IC 50 FAAH / IC 50 , sEH].

[0398] Efficacy of compounds of general formula I in cancer as monotherapy and in combination with other drugs can be assessed using animal models known in the literature.

[0399] Example 40 B16F10 Syngenic Mouse Tumor Model ) was used to evaluate the potential of compounds of formula 1 for treating melanoma cancer.

[0400] The syngenic murine melanoma cell line B16F10 (ATCC® CRL-6475™) obtained from ATCC was used in this study. B16F10 cells stored in liquid nitrogen were thawed and revived according to the recommended method. Cells were cultured and expanded in complete DMEM growth medium. Subconfluent monolayers were harvested, pelleted, and resuspended in growth medium before being counted in a hemocytometer by trypan blue exclusion. Cell suspensions with >98% viability were prepared in 1X HBSS, pH 7.4. and kept on ice before transplantation. 6 0.1 mL of the cell suspension containing the cells was then injected through a 22-gauge needle. After cell implantation, mice were randomly assigned to different treatment groups (N = 8 mice / group) based on their body weight.

[0401] The control group received vehicle only, and the treatment groups received either test compound A or checkpoint inhibitors. Compound A was administered orally at 5 mg / kg once daily on days 0 to 21, and anti-PD-1 or anti-CTLA4 antibodies were administered at 10 mg / kg on days 4, 7, 10, 13, and 16. The tumors were injected intraperitoneally (IP). Tumor growth was measured using digital calipers.

[0402] All animals were observed daily for clinical signs and twice daily (morning and evening) for mortality and morbidity. Individual animal weights were recorded three times a week at the time of tumor measurements. Visible tumor size, ulceration, and The presence or absence of necrotic tumors and animal health criteria were considered for determining humane endpoints. Tumor size (~1500 mm) 3 Animals were sacrificed when they became moribund according to predefined criteria, including weight loss (≥20%), decreased ambulatory ability, respiratory distress, and inability to drink or eat.

[0403] Antinuclear antibody (IgG) was measured using CUSABIO Mouse Antinuclear Antibody (IgG) ELISA. ANA was analyzed using a sandwich enzyme-linked immunosorbent assay kit (Cat. No. CSB-E12912m). The mouse ANA in serum samples was quantified using an ANA-specific monoclonal antibody (ELISA). The ANA in the samples bound to a plate coated with anti-mouse IgG antibody. Detection was performed using an enzyme-linked detection antibody and tetramethylbenzidine (TMB) as a substrate. The enzyme reaction produces a blue product, which turns yellow upon addition of a stop solution. The absorbance of each well was measured at 450 nm using a microplate reader (Thermo Scientific, Varioskan® Flash). ANA concentrations in serum samples were measured according to the manufacturer's instructions. This was determined by plotting a standard curve using known concentrations of ANA according to the instructions.

[0404] Compound A demonstrated significant tumor growth inhibition effects compared to vehicle-treated control animals (Figures 2 and 3). Combination of Compound A with anti-CTLA4 antibody (Figure 2) or anti-PD1 antibody (Figure 3) demonstrated improved tumor growth inhibition compared to checkpoint inhibitor (anti-CTLA4 antibody or anti-PD1 antibody) monotherapy. Response rates of animals showing at least 40% tumor growth inhibition compared to the control group were compared between treatment groups. In this melanoma model, Compound A administration (monotherapy or combination therapy with anti-CTLA4 antibody) demonstrated improved responses compared to anti-CTLA4 antibody-treated animals (Figure 4). Treatment with Compound A (monotherapy or combination therapy with anti-CTLA4 antibody) demonstrated improved tumor growth inhibition compared to anti-CTLA4 antibody-treated animals. It also reduced serum ANA levels compared with monotherapy (Figure 5).

[0405] Example 41 The compound of Formula 1 was evaluated for its potential to treat breast cancer using the 4T1 syngenic mouse tumor model.

[0406] The study included the mouse breast cancer cell line 4T1 (ATCC® CRL-2539) obtained from ATCC. Cells were thawed from liquid nitrogen storage and reactivated according to the recommended method. Cells were cultured and expanded in complete RPMI-1640 growth medium. Subconfluent Monolayers were harvested, pelleted, resuspended in growth medium, and counted in a hemocytometer by trypan blue exclusion. Cell suspensions with viability greater than 96% were mixed 1:1 with ice-cold Matrigel® in 1X HBSS (pH 7.4) and kept on ice before transplantation. 0.1 x 10 6 individual cells 50 μL of the cell suspension containing α-glucose was implanted into the mammary fat pad using a 22-gauge needle (day 0). Tumor volume was measured using a digital caliper, and tumor sizes of 50–80 mm were determined. 3 Animals were selected based on an average tumor size of ~50 mm. Tumor-bearing mice were divided into different groups (N = 10) based on tumor size. The animals were randomly assigned to one group (8 animals / group).

[0407] Control animals received vehicle only, and treatment animals received test compound A or checkpoint inhibitor. The tumor inhibitors (anti-CTLA4 antibody or anti-PD-1 antibody) were administered as monotherapy or in combination with Compound A and anti-CTLA4 antibody ± anti-PD-1 antibody. Compound A was orally administered at 5 mg / kg once daily from days 0 to 21, and anti-PD-1 antibody or anti-CTLA4 antibody was administered intraperitoneally (IP) at 10 mg / kg on days 0, 3, and 6. The antitumor effects of the treatment and its combination with checkpoint inhibitors were evaluated by monitoring tumor growth kinetics, lung metastasis, and survival rate. Tumor growth inhibition was assessed by comparing tumor volume in the treated group with that in the control group.

[0408] All animals were observed daily for clinical signs, mortality, and morbidity. Individual animal weights were recorded three times a week at the time of tumor measurement. Visible tumor size, ulcerated or necrotic tumors, and and animal health criteria were considered for determining humane endpoints. Tumor size (~2000 mm 3 Animals were sacrificed when they became moribund according to predefined criteria, including weight loss (≥20%), decreased ambulatory ability, respiratory distress, and inability to drink or eat.

[0409] Lung metastasis Three animals from each of the vehicle control group, compound A monotherapy group, and checkpoint inhibitor (anti-CTLA4 ± anti-PD1) combination therapy groups were sacrificed on day 21 for lung metastasis assay. The mice were sacrificed by euthanasia, and lung tissue was isolated for metastasis assessment. The lungs were removed and visually inspected for metastatic cancer cell colonies. The lungs were fixed in Bouin's solution, and the number of superficial lung nodules was counted. All The lung specimens were preserved in 10% NBF.

[0410] Compound A demonstrated significant tumor growth inhibition (p<0.0001) compared to vehicle-treated control animals. The combination therapy of Compound A with anti-CTLA4 + anti-PD1 antibody (Figure 6) also showed significant tumor growth inhibition compared to monotherapy with Compound A (Figure 6).

[0411] The number of metastatic lung nodules in the compound A-treated group was significantly reduced by 37% (p<0.001) compared to the control group (Figure 7). The combination of compound A and checkpoint inhibitors (anti-CTLA-4 + anti-PD-1 antibodies) showed an 85% reduction in lung nodules (p<0.0001) compared to the control group (Figure 7).

[0412] Example 42 G261 Syngenic Murine Tumor Model was used to evaluate the potential of compounds of formula 1 for treating brain tumors (glioblastoma).

[0413] The mouse glioma GL261 (Luc2) tumor cell line was cultured in vitro according to the supplier's specifications. DMEM supplemented with 10% FBS, 1% penicillin-streptomycin, and 1 mM HEPES was used for 200 The cells were cultured under selective pressure using 1 μg / mL G418. Cells were first checked and verified to be free of mycoplasma. Prior to inoculation into mice, cell viability was assessed by flow cytometry and viable cell gating. Cell suspensions were prepared according to viable cell count.

[0414] Mouse glioma cells (GL261(Luc2)) were stereotactically transplanted into the brains of immunodeficient C57BL / 6J mice ( On the day of inoculation, 0.1 mg / kg of buprenorphine was injected intraperitoneally to provide analgesia. Mice were anesthetized using gas anesthesia, with anesthesia induced with 4% isoflurane and maintained with 2% isoflurane. The scalp was shaved and an incision was made to view the skull, particularly the bregma. The mice were then mounted in a stereotaxic apparatus. To transplant the cells, they were suspended in sterile PBS and The required amount was collected using a Hamilton syringe (25,000 cells / 1 μL). The syringe was then placed in a stereotaxic instrument. The skull was then fixed and aligned to the appropriate injection point. A 26G needle was used to open the skull, and a 10 μL Hamilton syringe was placed at the edge of the opening formed in the brain and lowered to the appropriate depth for injection into the striatum. The injection site was cleaned with Betadine gauze before suturing the skin. The anesthetized mice were placed on a warming blanket and monitored until they woke up. Approximately 6 days after tumor inoculation, tumor size was measured. Based on initial bioluminescence imaging (BLI) performed before treatment to confirm engraftment, Mice were randomized and assigned to different pharmacological groups, and BLI was then performed weekly over a 5-week monitoring period on days 14, 21, 28, 35, and 42 (6 BLI measurements in total) according to the survival rate of mice within the group.

[0415] Control animals received vehicle only, and treatment animals received test compound A or anti-PD-1 antibody. Compound A was administered orally at 5 mg / kg once daily from day 6 to day 37 after tumor inoculation, and then every other day until day 41. Anti-PD1 antibody was administered intraperitoneally at 5 mg / kg once daily on days 6, 9, 12, and 15 after tumor inoculation.

[0416] From day 6 after tumor cell inoculation, tumors were detected by bioluminescence imaging in all mice. Tumor growth was monitored, as well as survival, taking into account body weight and time to endpoint / sacrifice, expressed in Kaplan-Meier plots. Animals were sacrificed when they showed clear clinical signs, such as a loss of more than 15% of their body weight.

[0417] Adequate tumor engraftment was achieved in all inoculated animals, as demonstrated by bioluminescence imaging (BLI) measurements from day 6 to day 28 after tumor cell inoculation. Animals showed adequate tumor growth, which progressed dynamically, as visualized through BLI values ​​measured over time. It was shown that this is the case.

[0418] When compound A was administered alone, it showed antitumor effects and improved survival / lifespan compared to the control group. One of the ten animals administered Compound A showed complete tumor rejection ( (confirmed by a significant decrease in bioluminescence imaging values ​​and the absence of tumor at brain autopsy).

[0419] Example 43: Compounds of Formula 1 reduce or block chemotherapy-induced peripheral neuropathy Methods for assessing the potential for chemotherapy-induced neuroprotection using animal (zebrafish) models described below and in the literature (Lisse TS et al PNAS 113 (15) E2189-E2198). The potential of compounds of formula 1 to reduce or block cytotoxicity was evaluated.

[0420] To induce peripheral neuropathy in adult zebrafish, 10-μM Paclitaxel in 0.15% DMSO was used. Zebrafish weighing an average of 200 mg were administered 3 μL of the taxel solution using a 33-gauge Hamilton syringe. Vehicle alone or paclitaxel was administered for 4 consecutive days (days 2–5). Or, paclitaxel and Compound A (10 or 30 ng) were administered in combination. Compound A was administered to the fish. The test compound was mixed into food pellets and administered orally. The fish were adjusted to consume three pellets per day. The test compound-added food was given in the morning, and regular compound-free food was given in the afternoon and evening. To prepare the test compound-infused pellets, a known amount of the test compound was mixed with a known amount of food powder and molded into 4 mg pellets containing the desired dose per pellet. The number of pellets and The concentration of test compound administered per fish was determined by the size of the pellet and the amount of compound per pellet. Food pellets containing no test compound but vehicle served as a placebo control.

[0421] To assess peripheral nerve damage, fish were wrapped in plastic foil until they were calm, and the distal tail fin was stimulated with an insect pin until the fish was observed to convulse. The number of stimulations required to convulse was recorded. Compared to vehicle alone, paclitaxel significantly increased the number of stimulations required, as indicated by an increase in the number of stimulations required. Compound A + paclitaxel treatment group showed relief from nerve damage caused by paclitaxel. Treatment with Compound A (30 ng) also rescued or reversed paclitaxel-induced neuronal loss (FIG. 9).

[0422] Example 44 CT26 Syngenic Murine Tumor Model was used to evaluate the potential of compounds of formula 1 for the treatment of colon cancer.

[0423] CT26 cells (ATCC®, CRL-2638™) were cultured in complete DMEM growth medium. Subconfluent cell monolayers were harvested and cell suspensions containing >97% viable cells were collected using Hank's The cells were prepared in Hank's Balanced Salts Solution, pH 7.4. 0.1 mL of the cell suspension containing 50,000 cells was subcutaneously implanted into the flank of 6- to 8-week-old female BALB / c mice under anesthesia.

[0424] After cell implantation, mice were randomly assigned to various treatment groups (N=10). After inoculation, animals were monitored three times a week until tumors became palpable (measurable). Test compound A was orally administered to one set of mice (group G2) at a dose of 5 mg / kg body weight on the day of tumor inoculation. The control group (G1) received vehicle only. Tumors between 25 and 50 mm in size were treated with the test compound A. 3に Once this is reached, Test Compound A (Group G4) or anti-CTLA4 (Group G3) therapy was initiated. Group G4) was orally administered 5 mg / kg body weight. Anti-mouse CTLA-4 (CD152, clone 9H10, Bio X cell, West Lebanon, NH) at a dose of 2.5 mg / kg body weight, equivalent to 50 μg per mouse. The combination therapy of compound A (5 mg / kg, oral administration once daily) and anti-mouse CTLA-4 antibody (2.5 mg / kg, intraperitoneal administration once every 3 days) (Group G5) also significantly improved tumor size in the 25-50 mm 3に Compound A was orally administered using a formulation consisting of 5% (v / v) ethanol + 50% (v / v) PEG400 + 20% (v / v) propylene glycol + 25% (v / v) sterile water for injection. The CTLA-4 antibody was diluted in an appropriate dilution buffer at pH 7.0. Tumor size was measured using a digital microscope. Tumor volume was measured three times a week using a GI device and calculated as [length (L) × width (W)]. 2 The tumor size, body weight, clinical symptoms, and survival rate were calculated based on the predefined endpoint criteria of tumor size ⩾1500 mm. 3 to The animals were monitored until they reached maturity and then sacrificed based on ethical considerations.

[0425] The antitumor effects of test compound A as monotherapy and in combination with anti-CTLA4 were evaluated by monitoring tumor growth rate, tumor growth delay, and survival rate. Tumor growth inhibition was evaluated by comparing tumor volume at 30 days after administration with that of the control group. Survival rate analysis was then performed using the Kaplan-Meier method.

[0426] Compound A (Groups G2 and G4) compared to vehicle-treated control animals Group G1 , showed significant tumor growth inhibition (p<0.0001) (Figure 10). The combination of Compound A with anti-CTLA4 antibody (Group G5, Figure 10) also improved and significantly inhibited tumor growth compared to Compound A monotherapy G4. Compound A (groups G2 and G4) significantly improved survival time compared to the control group G1. The combination therapy of Compound A and anti-CTLA4 antibody (Group G5, FIG. 11) also showed a significant improvement in survival time (FIG. 11).

[0427] The therapeutically effective amount of the compound of formula I can be administered once or repeatedly at regular intervals.As mentioned above, many factors can be considered by the attending physician when selecting the dosage, including but not limited to the efficacy and duration of action of the compound used, the nature and severity of the disease to be treated, and the sex, age, weight, general health and individual response of the treated subject, and other relevant circumstances.The therapeutic dose for humans can be estimated based on the data of animal experiments, taking into account factors such as body surface area, pharmacokinetic profile, and related parameters.To estimate the human equivalent dose, literature [e.g. Allometric scaling and related methodologies can be used, as described in [J Basic Clin Pharm. March 2016-May 2016; 7(2): 27-31].

[0428] Therapeutically effective compositions of the present disclosure for the treatment of a neurodegenerative disease in a subject may include a compound of Formula I administered at a dose of about 0.5 mg / day to about 3000 mg / day.

[0429] Sequence table xml embedding statement

[0430] The sequence listing XML provided herein is incorporated herein by reference. The XML file is named NeuroPnCancerTherapy.xml, created on 2023 / 09 / 29, and is 7 kilobytes in size. It is thread. <110> NeuroPN Therapeutics, Inc. <120> Piperidine urea derivatives for cancer treatment <130> 0039486.0000022 <140> not clear <141> *** <150> U.S. Application No. <151> 09 / 30 / 2023 <160> 1 <170> WIPO Sequence <210> 1 <211> 223 <212> PRT <213> Homo sapiens <221> CDS <222> 1-223 <400> 1 MCLGFQRHKAQLNLATRTWPCTLLFFLLFIPVFCKAMHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQ VNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEPCPDSDFLLWILAAVSSGLFFYSFLLTAVSLSKMLKRSPLTTGVYVKMPPTEPECEKQFQPYFIPIN <210> 2 <211> 288 <212> PRT <213> Homo sapiens <221> CDS <222> 1-288 <400> 2 MQIPQAPWPVWAVLQLGWRPGWLDSPDRPWNPPTFSPALLVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVRARRNDSGTYLCGAISLAPKAQIKESLRA ELVTERRAEVPTAHPSPRPAGQFQTLVGVGGLLGSLVVWLAVICSRAARGTARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSPARRGSADGPRSAQPLRPEDGHCSWPL <210> 3 <211> 290 <212> PRT <213> Homo sapiens <221> CDS <222> 1-290 <400> 3 MRIFAVFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQHSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVTSELTCQAEGYPKAEV IWTSDHQVLSGKTTNSKREEFKLNVTSTLRINTTTNEIFYCTFRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVALTFRLKGRMMDVKCGIQDTNSKQSDTHLEET <210> 4 <211> 227 <212> PRT <213> Homo sapiens <221> CDS <222> 1-227 <400> 4 MAHAAQVGLQDATSPIMEELITFHDHALMIIFLICFLVLYALFLTLTKLTNTNISDAQEMETVWTILPAIILVLIALPSLILYMTDEVNDPSLTIKSIGHQWYWTYEYTDYGGLIFNSYMLPPLFLEPGDLRLDVDNRVLPIEAPIRMMITSQDVLHSWAVPTLGLKTDAIPGRLNQTTATRPGVYYGQCSEICGANHSFMPIVLELIPLKIFEMGPVFTL <210> 5 <211> 579 <212> PRT <213>ホモ·サピエンス <221> CDS <222> 1-579 <400> 5 MVQYELWAALPGASGVALACCFVAAAVALRWSGRRTARGAVVRARQRQRAGLENMDRAAQRFRLQNPDLDSEALLALPLPQLVQKLHSRELAPEAVLFTYVGKAWEVNKGTNCVTSYLADCETQLSQAPRQGLLYGVPVSLKEC FTYKGQDSTLGLSLNEGVPAECDSVVVHVLKLQGAVPFVHTNVPQSMFSYDCSNPLFGQTVNPWKSSKSPGGSSGGEGALIGSGGSPLGLGTDIGGSIRFPSFCCGLKPTGNRLSKSGLKGCVYGQEAVRLSVGPMARDVES LALCLRALLCEDMFRLDPTVPPLPFREEVYTSSQPLRVGYYETDNYTMPSPAMRRAVLETKQSLEAAGHTLVPFLPSNIPHALETLSTGGLFSDGGHHTFLQNFKGDFVDPCLGDLVSILKLPQWLKGLLAFLVKPLLPRLSAFLS NMKSRSAGKLWELQHEIEVYRKTVIAQWRALLDDVVLTPMLAPALDLNAPGRATGAVSYTMLYNCLDFPAGVVPVTTVTAEDEAQMEHYRGYFGDIWDKMLQKGMKKSVGLPVAVQCVALPWQEELCLRMFMREVERLMTPEKQSS

Claims

1. 1. A method for treating cancer comprising administering to a subject a therapeutic amount of at least one compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 【Chemical 1】 R １ is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １ When is aryl, heteroaryl, or heterocycloalkyl, R １ is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO ２ NHR ２ , or COR ３ is replaced by; R ２ is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R ３ is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R ４ is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO ２ R ５ , or COR ３ selected from the group consisting of: R ５ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R ６ is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X is O, (CH ２ ) p, NH, where p is selected from 0 to 2; Y １ -Y ２ is CH-CH ２ , CH—O or C═CH, but Y １ -Y ２ is CH—O, X is selected from O or NH, or R １ is not hydrogen; and Y ３ is selected from H or Me.

2. 1. A method for treating cancer comprising administering to a subject a therapeutic amount of at least one compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 2】 R １ is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １ When is aryl, heteroaryl, or heterocycloalkyl, R １ is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO ２ NHR ２ , or COR ３ is replaced by; R ２ is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R ３ is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R ４ is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO ２ R ５ , or COR ３ selected from the group consisting of: R ５ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R ６ is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X is O, (CH ２ ) p, NH, where p is selected from 0 to 2, but when p=0, Y １ -Y ２ is CH-CH ２ Or R instead of CH-O １ is not aryl; Y １ -Y ２ is CH-CH ２ , CH—O or C═CH, but Y １ -Y ２ is CH—O, X is selected from O or NH, and R １ is not hydrogen or alkyl; and Y ３ is selected from H or Me.

3. Y ３ is H and the compound is a compound of formula II, a stereoisomer or a pharmaceutically acceptable salt thereof: 【Chemistry 3】 R １ is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １ When is aryl, heteroaryl, or heterocycloalkyl, R １ is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO ２ NHR ２ , or COR ３ is replaced by; R ２ is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R ３ is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R ４ is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO ２ R ５ , or COR ３ selected from the group consisting of: R ５ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R ６ is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X is O, (CH ２ ) p, NH, where p is selected from 0 to 2; Y １ -Y ２ is CH-CH ２ , CH—O or C═CH, but Y １ -Y ２ is CH—O, X is selected from O or NH, or R １ is not hydrogen; and Y ３ is selected from H or Me.

4. Y ３ is H and the compound is a compound of formula II, a stereoisomer or a pharmaceutically acceptable salt thereof: 【Chemistry 4】 R １ is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １ When is aryl, heteroaryl, or heterocycloalkyl, R １ is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO ２ NHR ２ , or COR ３ is replaced by; R ２ is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R ３ is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R ４ is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO ２ R ５ , C.O.R. ３ selected from the group consisting of: R ５ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R ６ is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X is O, (CH ２ ) p, NH, where p is 0 to 2, but when p=0, Y １ -Y ２ is CH-CH ２ Or R instead of CH-O １ is not aryl; and Y １ -Y ２ is CH-CH ２ , C—H ， or C=CH, but Y １ -Y ２ is CH—O, X is selected from O or NH, and R １ is not hydrogen or alkyl,

5. Y ３ is H and Y １ -Y ２ 2. The method of claim 1, wherein: is C=CH and the compound is a compound of Formula III, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 5】 R １ is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １ When is aryl, heteroaryl, or heterocycloalkyl, R １ is unsubstituted or is selected from the group consisting of alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO ２ R ５ , S.O. ２ NHR ２ , or COR ３ is replaced by; R ２ is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R ３ is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R ４ is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO ２ R ５ , S.O. ２ NHR ２ , C.O.R. ３ selected from the group consisting of: R ５ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R ６ is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; and X is O, (CH ２ ) p, NH, where p is 0-2.

6. Y ３ is H and Y １ -Y ２ is CH-CH ２ 10. The method of claim 1, wherein the compound is a compound of formula IV, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 6】 R １ is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １ When is aryl, heteroaryl, or heterocycloalkyl, R １ is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO ２ R ５ , S.O. ２ NHR ２ , C.O.R. ３ is replaced by; R ２ is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R ３ is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R ４ is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO ２ R ５ , C.O.R. ３ selected from the group consisting of: R ５ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R ６ is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl, where the aryl or heteroaryl may be optionally substituted one or more times with groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, and the like; and X is O, (CH ２ ) p, NH, where p is selected from 0-2.

7. Y ３ is H and Y １ -Y ２ is CH-CH ２ 3. The method of claim 2, wherein the compound is a compound of formula IV, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 7】 R １ is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １ When is aryl, heteroaryl, or heterocycloalkyl, R １ is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO ２ R ５ , S.O. ２ NHR ２ , C.O.R. ３ is replaced by; R ２ is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R ３ is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R ４ is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO ２ R ５ , C.O.R. ３ selected from the group consisting of: R ５ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R ６ is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl, where the aryl or heteroaryl may be optionally substituted one or more times with groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, and the like; and X is O, (CH ２ ) p, NH, where p is selected from 0 to 2, provided that when p=0, R １ is not aryl, method.

8. The compound of formula 1 may be one or more of the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof: The method of claim 1, wherein the salt is 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】

9. 2. The method of claim 1, wherein said compound of Formula 1 is one of the following compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 11】

10. 2. The method of claim 1, wherein said compound of Formula 1 is one or more of the following compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 12】

11. The compound is administered at a concentration of less than 10 μM (IC ５０ 2. The method of claim 1, wherein soluble epoxide hydrolase is inhibited with

12. The compound is administered at a concentration of less than 100 nM (IC ５０ 2. The method of claim 1, wherein soluble epoxide hydrolase is inhibited with

13. The compound is administered at a concentration of less than 100 nM (IC ５０ ) inhibits soluble epoxide hydrolase and inhibits fatty acid amide hydrolase (IC ５０ , FAAH (SEQ ID NO: 5)) at least 10-fold selectively.

14. The compound is administered at a concentration of less than 100 nM (IC ５０ ) inhibits soluble epoxide hydrolase and at concentrations above 1000 nM (IC ５０ 2. The method of claim 1, wherein fatty acid amide hydrolase (FAAH (SEQ ID NO: 5)) is inhibited with

15. 2. The method of claim 1, wherein the cancer is selected from the group consisting of ovarian cancer, leukemia, lymphoma, hematopoietic cancer, liver cancer, bone cancer, lung cancer, brain tumor, bladder cancer, gastrointestinal cancer, kidney cancer, breast cancer, heart cancer, cervical cancer, uterine cancer, head and neck cancer, gallbladder cancer, laryngeal cancer, oral cavity cancer, eye cancer, skin cancer, melanoma, pancreatic cancer, prostate cancer, reproductive cancer, colon cancer, colorectal cancer, testicular cancer, pharyngeal cancer, or a combination thereof.

16. 10. The method of claim 1, wherein the cancer is selected from the group consisting of glioblastoma, melanoma, breast cancer, colon cancer, or a combination thereof.

17. 10. The method of claim 1, wherein the compound is administered to reduce tumor size and / or inhibit tumor growth.

18. The method of claim 1 , wherein the compound is administered to inhibit metastasis of a primary tumor.

19. 10. The method of claim 1, wherein the compound is administered at a dose of about 1 mg / day to about 1,000 mg / day.

20. 10. The method of claim 1, wherein the compound is administered at a dose of about 4 mg / day to about 800 mg / day.

21. 10. The method of claim 1, further comprising administering at least one additional compound selected from at least one chemotherapeutic agent, at least one immune checkpoint inhibitor, at least one anti-inflammatory agent, or combinations thereof.

22. 22. The method of claim 21, wherein the at least one chemotherapeutic agent is selected from the group consisting of cisplatin, paclitaxel, 5-fluorouracil, doxorubicin, daunorubicin, carboplatin, gemcitabine, oxaliplatin, and temozolomide.

23. 22. The method of claim 21 , wherein the at least one immune checkpoint inhibitor is an antibody against at least one of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO:

3.

24. 22. The method of claim 21, wherein the immune checkpoint inhibitor is selected from the group consisting of pembrolizumab, nivolumab, semipilimumab, ipilimumab, atezolizumab, avelumab, urvalumab, or a combination thereof.

25. 22. The method of claim 21, wherein the at least one anti-inflammatory agent is selected from the group consisting of a nonsteroidal anti-inflammatory drug (NSAID), a selective cyclooxygenase-2 (cox-2) (SEQ ID NO: 4) inhibitor, an omega-3 fatty acid, or a combination thereof.

26. 26. The method of claim 25, wherein the NSAID or cox-2 (SEQ ID NO: 4) inhibitor is selected from the group consisting of naproxen, diclofenac, acetaminophen, ibuprofen, flurbiprofen, ketoprofen, celecoxib, aspirin, meloxicam, piroxicam, fenoprofen, salicylates, or combinations thereof.

27. 26. The method of claim 25, wherein the omega-3 fatty acid is selected from the group consisting of alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or a combination thereof.

28. 1. A method of reducing toxicity and / or adverse effects experienced by a patient receiving one or more chemotherapeutic agents, or checkpoint inhibitors, comprising administering to the subject at least one compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 13】 R １ is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １ When is aryl, heteroaryl, or heterocycloalkyl, R １ is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO ２ NHR ２ , or COR ３ is replaced by; R ２ is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R ３ is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R ４ is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO ２ R ５ , or COR ３ selected from the group consisting of: R ５ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R ６ is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X is O, (CH ２ ) p, NH, where p is selected from 0 to 2; Y １ -Y ２ is CH-CH ２ , CH—O or C═CH, but Y １ -Y ２ is CH—O, X is selected from O or NH, or R １ is not hydrogen; and Y ３ is selected from H or Me.

29. 1. A method of reducing toxicity and / or adverse effects experienced by a patient receiving one or more chemotherapeutic agents, or checkpoint inhibitors, comprising administering to the subject at least one compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 14】 R １ is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １ When is aryl, heteroaryl, or heterocycloalkyl, R １ is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO ２ NHR ２ , or COR ３ is replaced by; R ２ is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R ３ is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R ４ is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO ２ R ５ , or COR ３ selected from the group consisting of: R ５ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R ６ is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X is O, (CH ２ ) p, NH, where p is selected from 0 to 2, but when p=0, Y １ -Y ２ is CH-CH ２ Or R instead of CH-O １ is not aryl; Y １ -Y ２ is CH-CH ２ , C.H. ２ -O, or C=CH, but Y １ -Y ２ is CH—O, X is selected from O or NH, or R １ is not hydrogen or alkyl; and Y ３ is selected from H or Me.

30. 30. The method of claim 28 or 29, wherein the compound of formula I reduces nerve damage resulting from the administration of one or more chemotherapeutic agents.

31. A method for treating cancer comprising administering to a subject a therapeutic amount of a soluble epoxide hydrolase inhibitor.

32. 1. A method of treating cancer comprising administering to a subject a therapeutic amount of a soluble epoxide hydrolase inhibitor together with a therapeutic amount of one or more immune checkpoint inhibitors.

33. A method of reducing the toxicity and / or adverse effects experienced by a patient receiving one or more chemotherapeutic agents, or a checkpoint inhibitor, comprising administering a soluble epoxide hydrolase inhibitor.

34. A compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer: 【Chemistry 15】 R １ is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １ When is aryl, heteroaryl, or heterocycloalkyl, R １ is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO ２ NHR ２ , or COR ３ is replaced by; R ２ is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R ３ is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R ４ is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO ２ R ５ , or COR ３ selected from the group consisting of: R ５ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R ６ is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl. Selected; X is O, (CH ２ ) p, NH, where p is selected from 0 to 2; Y １ -Y ２ is CH-CH ２ , CH—O or C═CH, but Y １ -Y ２ is CH—O, X is selected from O or NH, or R １ is not hydrogen; and Y ３ is selected from H or Me.

35. A compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer: 【Chemistry 16】 R １ is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １ When is aryl, heteroaryl, or heterocycloalkyl, R １ is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO ２ NHR ２ , or COR ３ is replaced by; R ２ is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R ３ is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R ４ is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO ２ R ５ , or COR ３ selected from the group consisting of: R ５ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R ６ is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X is O, (CH ２ ) p, NH, where p is 0 to 2, but when p=0, Y １ -Y ２ is CH-CH ２ Or R instead of CH-O １ is not aryl; Y １ -Y ２ is CH-CH ２ , CH—O or C═CH, but Y １ -Y ２ is CH—O, X is selected from O or NH, and R １ is not hydrogen or alkyl; and Y ３ is selected from H or Me.

36. A soluble epoxide hydrolase inhibitor used to reduce the toxicity and / or adverse effects experienced by patients receiving one or more chemotherapeutic agents or checkpoint inhibitors.

37. Soluble epoxide hydrolase inhibitors for use in cancer treatment.

38. A combination comprising a soluble epoxide hydrolase and an immune checkpoint inhibitor, used in the treatment of cancer or to reduce the deleterious effects of immune checkpoint inhibitors.

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