Piperidine urea derivatives for treatment of cancer

Abstract

The present invention describes novel piperidine urea-derived compounds and pharmaceutical compositions thereof for the treatment of cancer as monotherapy or in combination therapy with chemotherapeutic agents and / or checkpoint inhibitors.

Description

Technical Field

[0001] The subject matter disclosed herein generally relates to methods and compositions for preventing, suppressing or treating cancer. Specifically, piperidine urea-derived compounds are selected as a single therapy for treating cancer or in combination therapy with chemotherapeutic agents and / or checkpoint inhibitors. Background Art

[0002] Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid by cytochrome P450 (CYP) epoxygenases, including four regioisomers: 5,6-EET, 8,9-EET, 11,12-EET and 14,15-EET. EETs confer beneficial effects against inflammation and neuronal injury. It is known that acute inflammatory states are usually resolved by the action of EETs, which allow tissues and their associated immune cells to return to a pre-inflammatory baseline state. EET levels are regulated by soluble epoxide hydrolase (sEH), which is the main enzyme responsible for its degradation and conversion to inactive or weakly active dihydroxyeicosatrienoic acids (DHETs). Elevated sEH expression has been shown in many pathological chronic inflammatory conditions, including neuroinflammation, diabetic inflammatory states and the tumor microenvironment (PNAS 2021, Vol. 118, No. 41, E2107771118). Thus, SEH limits many of the biological actions of EETs. Inhibiting sEH can prolong the half-life of EETs, which in turn translates into beneficial therapeutic effects.

[0003] sEH inhibitors can be used to treat neuropathic and inflammatory pain, neurodegenerative diseases, cancer, acute respiratory distress syndrome (ARDS), rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and Crohn's disease [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 reduced the expression of inflammatory genes and showed potential utility in inflammatory diseases (inflammation). Inflamm. Allergy Drug Targets (2012) Apr, 11(2):143 - 58). The potency of 14,15 - EET is approximately 35 - fold that of morphine and stimulates methionine enkephalin in the brain, indicating its potential analgesic utility. J Pharmacol Exp. Ther. (2008), Aug, 326(2), 614 - 22).

[0004] Despite the emergence of innovative therapies, cancer remains one of the leading causes of death globally. Chemotherapy remains the first - line treatment for many malignancies, but increasing evidence suggests that tumor cell debris generated by chemotherapy and radiotherapy (e.g., apoptotic and necrotic cells) may promote tumor growth and metastasis by producing pro - inflammatory eicosanoids and inhibiting 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). A large body of literature has confirmed that commonly used chemotherapeutic drugs (such as cisplatin, paclitaxel, 5 - fluorouracil, and doxorubicin) also induce neuronal injury [JAMA Oncol. 2019; 5(5):750]. The severity of the pro - inflammatory response, neuronal injury, and toxicity can significantly limit the utility of cytotoxic agents. Combinations of chemotherapeutic drugs with reagents that can help resolve tumor - associated inflammation, neuronal injury, and related immunity will provide new treatments with improved efficacy and reduced side effects.

[0005] Advances in the past decade have made immunotherapy a new treatment option for many malignancies. Some common examples include checkpoint inhibitors (CPIs), tumor-infiltrating lymphocytes, CAR-T cells, and oncolytic viruses. Checkpoint inhibitors (CPIs) have largely become the mainstay of cancer immunotherapy. Under steady-state conditions, immune checkpoints maintain a balance between pro-inflammatory and anti-inflammatory pathways that influence immune cell function. Cancer cells disrupt this state by promoting a highly immunosuppressive tumor environment. Immune checkpoint inhibitors can block these pathways and promote the host 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 increase the response rate and duration of response to checkpoint inhibitors. It has been shown that the combination of two or more checkpoint inhibitors results in a better response rate. A good example is ipilimumab (an anti-CTLA4 drug) and nivolumab (an anti-PD1 drug) for the treatment of melanoma. Unfortunately, when different checkpoint inhibitors are used in combination, the toxicity is significantly increased or worse. In particular, the overactivation of the immune system can lead to treatment interruption, hospitalization, or treatment with systemic immunosuppressive drugs. [JAMA Oncol 2021 May 1;7(5):744-748; Nature Reviews Clinical Oncology volume 16, pages 563–580 (2019)].

[0006] Numerous additional attempts have been made and are being investigated to increase the response rate and / or reduce the side effects of checkpoint inhibitors by combining them with other drugs. In the present invention, chronic tumor-associated inflammation poses a serious obstacle to any anti-tumor immune response. Therefore, addressing the underlying chronic inflammatory state in the tumor microenvironment may be an effective way to achieve better efficacy in cancer treatment, such as with the use of checkpoint inhibitors.

[0007] The use of soluble epoxide hydrolase inhibitors may be a new approach to modulating the immune response in solid and liquid tumors. There is increasing experimental data confirming the role of sEH inhibitors in resolving inflammation and preventing neuronal damage in a variety of diseases (PNAS, 2018, 115(25) E5815-E5823; Mol Neurobiol. 2015 Aug;52(1):187-95; Mol Neurobiol. 2015 Aug;52(1):187-95). Therefore, addressing chronic inflammation in the tumor microenvironment may be an effective way to achieve better efficacy in cancer treatment.

[0008] Several studies have confirmed that EETS and sEH inhibition have neuroprotective properties. sEH is highly expressed in the brain, and the production and metabolism of EETs in the brain span many regions and extend to peripheral and central neurons, astrocytes and 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 EETS or sEH inhibition - i) prevents cytokine - and oxidant - mediated neuronal cell damage; ii) prevents endoplasmic reticulum (ER) stress, which is a key factor in dopaminergic neuron loss; iii) increases the release of vascular endothelial growth factor by astrocytes and neuronal recovery after oxygen - glucose deprivation; and iv) promotes axon 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 U S A. 112:9082–9087 2015, J Neurosci 27:4642 - 9 2007, J Neurochem. 117:632 - 42 2011and Neuroscience 223:68 - 76 2012]. In multiple animal models of Parkinson's disease, sEH deficiency can reduce the loss of dopaminergic neurons Mol Neurobiol. 52(1):187 - 95 2015]. In multiple animal models, inhibition of sEH can alleviate disease symptoms and promote 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.May 30, 2017; 326:69 - 76]. The sEH level is elevated in the cortical brain tissue of subjects with cognitive impairment, and sEH inhibition can prevent H2O2 - induced hyperphosphorylation of tau protein, which is a key factor in the pathogenesis of Alzheimer's disease Prostaglandins Other Lipid Mediat. Oct, 2014; 113 - 115:30 - 7, J Huazhong Univ Sci Technolog Med Sci. Dec, 2016; 36(6):785 - 790]. sEH inhibition has a protective effect in rodent models of ischemic and diabetic stroke Future Neurol. Mar 1, 2009; 4(2):179 - 199, Am J Pathol. Jun, 2009; 174(6):2086 - 95, PLoS One. May 13, 2014; 9(5):e97529, Am J Physiol Heart Circ Physiol. Dec 1, 2013; 305(11):H1605 - 13].

[0009] Accordingly, an object of the present invention is to provide methods and compositions for use in combination with chemotherapeutic agents and / or immune checkpoint inhibitors for the prevention, inhibition, or treatment of cancer, in particular, piperidine urea - derived compounds are selected for use in combination with chemotherapeutic agents and / or immune checkpoint inhibitors to prolong the survival of cancer subjects and / or reduce tumor growth.

[0010] The citation or identification of any document in this invention does not admit that such a document can be used as the prior art of this invention. Summary of the Invention

[0011] According to the present invention, the above object is achieved by providing a method for treating cancer. The method may include administering to a subject a therapeutically effective amount of at least one compound of formula I:

[0012]

[0013] R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein when R 1 is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or substituted with alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; 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;4 may be selected from the group consisting of 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, and p is 0-2; Y1-Y2 may be selected from CH-CH2, CH-O or C=CH, provided that when Y1-Y2 is CH-O, X is selected from O or NH or R 1 is not hydrogen; and Y3 may be selected from H or Me; its stereoisomers or its pharmaceutically acceptable salts.

[0014] In addition, the present invention may provide a method for treating cancer, which comprises administering to a subject a therapeutically effective amount of at least one compound of formula I:

[0015]

[0016] wherein R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; 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 may be selected from the group consisting of 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 and p is 0-2, provided that when p = 0, Y1-Y2 is 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; and Y3 may be selected from H or Me; its stereoisomers or its pharmaceutically acceptable salts.

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

[0018]

[0019] wherein R 1 is optionally selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; R 2 can be selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl; R 3 can be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 can be selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 、COR 3 ; R 5 can be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 can be selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X can be selected from O, (CH2)p, NH, and p is 0-2; Y1-Y2 can be selected from CH-CH2, CH-O or C=CH, but when Y1-Y2 is CH-O, X is selected from O or NH or R 1 is not hydrogen; and Y3 can be selected from H or Me; its stereoisomers or its pharmaceutically acceptable salts.

[0020] In addition, Y3 can be H, and the compound can be a compound according to formula II:

[0021]

[0022] wherein R 1 is optionally selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; R 2 can be selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl; R 3may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 may be selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , 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 and p is 0-2, provided that when p = 0, Y1-Y2 is not CH-CH2 or CHO, 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 is selected from O or NH, R 1 is not hydrogen or alkyl; its stereoisomers or its pharmaceutically acceptable salts.

[0023] In addition, when Y3 is H, Y1-Y2 may be C=CH, and the compound may be a compound according to formula III,

[0024]

[0025] When R 1 is optionally selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 , SO2NHR 2 or COR 3 ; 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 may be selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , SO2NHR 2 , 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; and X may be selected from O, (CH2)p, NH, and p is 0-2; its stereoisomers or its pharmaceutically acceptable salts.

[0026] In addition, when Y3 is H, Y1-Y2 can be CH-CH2, and the compound is a compound according to formula IV

[0027]

[0028] wherein R 1 is optionally selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 may be unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 、SO2NHR 2 、COR 3 ; R 2 is optionally selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl; R 3 is optionally selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 is optionally selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 、COR 3 ; R 5 is optionally selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 is optionally selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl. The aryl or heteroaryl may be optionally substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl; and X may be selected from O, (CH2)p, NH; wherein p is selected from 0-2; its stereoisomers or its pharmaceutically acceptable salts.

[0029] In addition, when Y3 is H and Y1-Y2 can be CH-CH2, the compound can be a compound according to formula IV, its stereoisomers or its pharmaceutically acceptable salts

[0030]

[0031] wherein, R 1 is optionally selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 、SO2NHR 2 、COR 3 ; R 2 is optionally selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl; R3 may be selected from the group consisting of an alkyl, cycloalkyl, hydroxyl, amine, alkylamine or alkoxy; R 4 may be selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxyl, amine, alkoxy, SO2R 5 , COR 3 ; R 5 may be selected from the group consisting of an alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 may be selected from the group consisting of an alkyl, cycloalkyl, aryl or heteroaryl. The aryl or heteroaryl may be optionally substituted one or more times by a group or substituent such as an alkyl, hydroxyl, halogen, haloalkyl; and X may be selected from O, (CH2)p, NH; where p is selected from 0 - 2, provided that when p = 0, R 1 is not aryl; its stereoisomers or its pharmaceutically acceptable salts.

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

[0033]

[0034] its stereoisomers or its pharmaceutically acceptable salts

[0035] In addition, the compound of formula 1 may be one of the following compounds

[0036]

[0037] its stereoisomers or its pharmaceutically acceptable salts.

[0038] Still further, the compound of formula 1 may be one or more of the following compounds:

[0039]

[0040] its stereoisomers or its pharmaceutically acceptable salts.

[0041] In addition, the compound may inhibit soluble epoxide hydrolase at a concentration of < 10 μM (IC 50 ).

[0042] In addition, the compound may inhibit soluble epoxide hydrolase at a concentration of < 100 nM (IC 50 ).

[0043] In addition, the compound may inhibit soluble epoxide hydrolase at a concentration of < 100 nM (IC 50 ), and relative to fatty acid amide hydrolase (IC 50, the inhibition of FAAH (SEQ ID NO: 5) has a selectivity of at least 10-fold.

[0044] In addition, the compound can inhibit soluble epoxide hydrolase at a concentration of < 100 nM (IC 50 ), and inhibit fatty acid amide hydrolase (FAAH (SEQ ID NO: 5)) at a concentration of > 1000 nM (IC 50 ).

[0045] Furthermore, the cancer can be selected from the group consisting of: ovarian cancer, leukemia, lymphoma, hematopoietic cancer, liver cancer, bone cancer, lung cancer, brain cancer, bladder cancer, gastrointestinal cancer, kidney cancer, breast cancer, gastric cardia 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, genital cancer, colon cancer, colorectal cancer, testicular cancer and laryngeal cancer.

[0046] Again, the cancer can be selected from the group consisting of: glioblastoma, melanoma, breast cancer and colon cancer.

[0047] In addition, the compound can be administered to reduce tumor size and / or inhibit tumor growth.

[0048] In addition, the compound can be administered to inhibit the metastasis of primary tumors.

[0049] Again, the compound can be administered at a dose of about 1 mg / day to about 1,000 mg / day.

[0050] In addition, the compound can be administered at a dose of about 4 mg / day to about 800 mg / day.

[0051] However, the method can include 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 a combination of the above.

[0052] Again, at least one chemotherapeutic agent can be selected from the group consisting of: cisplatin, paclitaxel, 5-fluorouracil, doxorubicin, daunorubicin, carboplatin, gemcitabine, oxaliplatin, temozolomide, or a combination of the above.

[0053] In addition, at least one immune checkpoint inhibitor can be an antibody against at least one of PD-1 (SEQ ID NO: 2), PD-L1 (SEQ ID NO: 3), or CTLA4 (SEQ ID NO: 1).

[0054] In addition, the at least one immune checkpoint inhibitor is selected from the group consisting of: pembrolizumab, nivolumab, cemiplimab, ipilimumab, atezolizumab, avelumab, durvalumab, or a combination thereof.

[0055] In addition, the at least one anti-inflammatory agent can be selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase-2 (cox-2) (SEQ ID NO:4) inhibitors, ω-3 fatty acids, or a combination thereof.

[0056] In addition, the NSAID or cox-2 (SEQ ID NO:4) inhibitor can be selected from the group consisting of: naproxen, diclofenac, paracetamol, ibuprofen, flurbiprofen, ketoprofen, celecoxib, aspirin, meloxicam, piroxicam, fenoprofen, salicylates, or a combination thereof.

[0057] Similarly, the ω-3 fatty acid can be selected from the group consisting of α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), or a combination thereof.

[0058] The present invention can also provide a method for reducing the toxicity and / or adverse side effects experienced by a patient administered one or more chemotherapeutic agents or checkpoint inhibitors, the method comprising administering to the subject at least one compound of formula I:

[0059]

[0060] Wherein R 1 can be optionally selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein when R 1 is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; R 2 can be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 can be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R 4 can be selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ; R 5 can be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R 6may be selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X is selected from O, (CH2)p, NH, and p is 0-2; Y1-Y2 may be selected from CH-CH2, CH-O or C=CH, provided that when Y1-Y2 is CH-O, X is selected from O or NH or R 1 is not hydrogen; and Y3 may be selected from H or Me; its stereoisomers or its pharmaceutically acceptable salts.

[0061] In addition, the present invention also provides a method for reducing the toxicity and / or adverse side effects experienced by a patient administered one or more chemotherapeutic agents or checkpoint inhibitors, the method comprising administering to the patient at least one compound of formula I:

[0062]

[0063] wherein R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; 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 may be selected from the group consisting of 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 and p is 0-2, provided that when p = 0, Y1-Y2 is not CH-CH2 or CH-O, and R 1 is 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, R 1 is not hydrogen or alkyl; and Y3 may be selected from H or Me; its stereoisomers or its pharmaceutically acceptable salts.

[0064] In addition, the compound of formula I can reduce the nerve damage caused by administering one or more chemotherapeutic agents.

[0065] In addition, the present invention also provides a method for treating cancer, which comprises administering a therapeutically effective amount of a soluble epoxide hydrolase inhibitor to a subject.

[0066] In addition, the present invention also provides a method for treating cancer, which comprises administering a therapeutically effective amount of a soluble epoxide hydrolase inhibitor and a therapeutically effective amount of one or more immune checkpoint inhibitors to a subject.

[0067] In addition, the present invention also provides a method for reducing the toxicity and / or adverse side effects experienced by a patient administered one or more chemotherapeutic agents or checkpoint inhibitors, which method comprises administering a soluble epoxide hydrolase inhibitor to a subject.

[0068] In addition, the present invention may provide a compound of formula I:

[0069]

[0070] wherein R 1 is optionally selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein when R is 1 aryl, heteroaryl or heterocycloalkyl, R 1 may be unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; 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 may be selected from the group consisting of 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;

[0071] R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X may be selected from O, (CH2)p, NH, and p is 0 - 2; Y1 - Y2 may be selected from CH - CH2, CH - O or C═CH, but when Y1 - Y2 is CH - O, X is selected from O or NH or R 1 is not hydrogen; and Y3 may be selected from H or Me; its stereoisomers or its pharmaceutically acceptable salts, for treating cancer.

[0072] The present invention may also provide a compound of formula I, which comprises:

[0073]

[0074] R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; 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 may be selected from the group consisting of 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 and p is 0-2, provided that when p = 0, Y1-Y2 is 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 is selected from O or NH, R 1 is not hydrogen or alkyl; and Y3 may be selected from H or Me; its stereoisomers or its pharmaceutically acceptable salts, for treating cancer.

[0075] The present invention also provides a soluble epoxide hydrolase inhibitor for reducing the toxicity and / or adverse side effects experienced by a patient administered one or more chemotherapeutic agents or checkpoint inhibitors.

[0076] In addition, the present invention may provide a soluble epoxide hydrolase inhibitor for treating cancer.

[0077] In addition, the present invention may provide a composition comprising a soluble epoxide hydrolase and an immune checkpoint inhibitor for treating cancer or reducing the side effects of an immune checkpoint inhibitor.

[0078] Based on the following detailed description of exemplary embodiments, these and other aspects, objects, features and advantages of the exemplary embodiments will become apparent to those of ordinary skill in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[0079] An understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description and the accompanying drawings, which set forth illustrative embodiments in which the principles of the invention may be utilized, wherein:

[0080] Figure 1 Table 1 showing the soluble epoxide hydrolase inhibitory potency of the compounds of formula I is presented.

[0081] Figure 2 The anti-tumor efficacy of compound A of formula I as a single therapy and as a combination therapy with an anti-CTLA4 antibody in a melanoma model is shown.

[0082] Figure 3 The anti-tumor efficacy of compound A of formula I as a single therapy and as a combination therapy with an anti-PD1 antibody in a melanoma model is shown.

[0083] Figure 4 The response of the anti-tumor effect in a melanoma cancer model when treated with compound A of formula I as a single therapy and as a combination therapy with an anti-CTLA4 antibody is shown.

[0084] Figure 5 The serum levels of anti-nuclear antibodies (ANA) in a melanoma model when treated with compound A of formula I as a single therapy and as a combination therapy with an anti-CTLA4 antibody are shown.

[0085] Figure 6 The anti-tumor efficacy of compound A of formula I as a single therapy and as a combination therapy with checkpoint inhibitors (anti-CTLA4 antibody ± anti-PD1 antibody) in a breast cancer model is shown.

[0086] Figure 7 The lung metastases in a syngeneic breast cancer model when treated with compound A of formula I as a single therapy and as a combination therapy with checkpoint inhibitors (anti-CTLA4 antibody ± anti-PD1 antibody) are shown.

[0087] Figure 8 The survival / life span when compound A of formula I is used as a single therapy and as a combination therapy with an anti-CTLA4 antibody in a brain cancer (glioblastoma) model is shown.

[0088] Figure 9 The efficacy of compound A of formula I in blocking paclitaxel-induced nerve damage is shown.

[0089] Figure 10 The anti-tumor efficacy of compound A of formula I as a single therapy and as a combination therapy with an anti-CTLA4 antibody in a colon cancer model is shown.

[0090] Figure 11Shows the survival rate / lifespan of compound A of formula I as a single therapy and as a combination therapy with an anti-CTLA4 antibody in a colon cancer model.

[0091] The accompanying drawings herein are for illustrative purposes only and need not be drawn to scale. Detailed Description

[0092] Before describing the present invention in more detail, it should be understood that the present invention is not limited to the specific embodiments described and can, of course, be changed. It should also be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to be limiting.

[0093] Unless otherwise specified, the terms and phrases used in the context of the present invention and their variants, unless otherwise expressly stated, should be construed as open-ended rather than restrictive. Similarly, a group of items joined by the conjunction "and" should not be understood as requiring each of these items to be present in the group, but rather as "and / or", unless otherwise expressly stated. Similarly, a group of items linked by the conjunction "or" should not be understood as requiring mutual exclusivity between the groups, but should also be understood as "and / or", unless otherwise expressly stated.

[0094] Furthermore, although the items, elements or components of the present invention may be described or claimed in the singular, the plural form is also considered to be within the scope of the present invention unless expressly stated to be limited to the singular form. In some cases, the presence of expansive words and phrases such as "one or more", "at least", "but not limited to" or other similar phrases should not be construed as meaning that a narrower case was intended or required in the absence of such expansive phrases.

[0095] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described in the present invention can also be used in the practice or testing of the present invention, the preferred methods and materials are now described.

[0096] All publications and patents cited in this specification are for the purpose of disclosing and describing the methods and / or materials related to the cited publications. All such publications and patents are incorporated herein by reference as if each individual publication or patent was specifically and individually indicated to be incorporated herein by reference. This incorporation by reference is expressly limited to the methods and / or materials described in the cited publications and patents and does not extend to any dictionary definitions from the cited publications and patents. Any dictionary definitions not expressly repeated in this application from the cited publications and patents should not be so treated and should not be construed as defining any term that appears in the appended claims. The citation of any publication is only for the purpose of indicating that its publication date is earlier than the filing date of this application and should not be regarded as an admission that this disclosure does not have the right to antedate such publication by virtue of prior disclosure. In addition, the provided publication date may differ from the actual publication date that needs to be independently verified.

[0097] As will be apparent to those skilled in the art upon reading the present disclosure, each of the various embodiments described and illustrated herein has discrete components and features that can be readily separated from or combined with the features of any one of several other embodiments without departing from the scope or spirit of the present disclosure. Any of the described methods may be performed in the order of the recited events or in any other order that is logically possible.

[0098] In the case of representing a range, another embodiment includes from a specific value and / or to another specific value. A numerical range enumerated by endpoints includes all numbers and fractions included within each range, as well as the enumerated endpoints. In the case of providing a numerical range, it should be understood that, unless the context clearly dictates otherwise, each intermediate value between the upper and lower limits of the range, down to one-tenth of the unit of the lower limit, and any other stated or intermediate value within the said range, is included in the present invention. The upper and lower limits of these smaller ranges may be independently included within the smaller ranges and are also included within the scope of the present invention, subject to any specific exclusions within the said range. In the case where the range includes one or both limits, a range excluding one or both of the included limits is also included in the present invention. For example, in the case where the range includes one or both limits, a range excluding one or both of these included limits is also included in the present invention, such as the phrase "x to y" includes the range from "x" to "y" and the range greater than "x" and less than "y". The range may also be expressed as an upper limit, such as "about x, y, z or less", and should be interpreted as including the specific ranges of "about x", "about y", and "about z" as well as the ranges of "less than x", "less than y", and "less than z". Similarly, the phrase "about x, y, z or greater" should be interpreted as including the specific ranges of "about x", "about y", and "about z" as well as the ranges of "greater than x", "greater than y", and "greater than z". Additionally, the phrase "about 'x' to 'y' (where 'x' and 'y' are numerical values) includes "about 'x' to about 'y'".

[0099] It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed in range form in the present invention. It should also be understood that each endpoint of a range is significant relative to and independent of the other endpoint. It should further be understood that the present invention discloses multiple values, and in addition to the value itself, each value is also disclosed in the present invention as "about" that particular value. For example, if the value "10" is disclosed, then "about 10" is also disclosed. A range may be expressed in the present invention as from "about" one specific value, and / or to "about" another specific value. Similarly, when a value is expressed as an approximation by using the antecedent "about", it will be understood that the particular value forms another aspect. For example, if the value "about 10" is disclosed, then "10" is also disclosed.

[0100] It should be understood that this range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the values explicitly recited as the limits of the range, but also all individual values or sub-ranges included within that range, as if each value and sub-range were explicitly recited. By way of illustration, the numerical range of "about 0.1% to 5%" should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also the individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges).

[0101] As used in this invention, the singular forms "a", "an", and "the" include both singular and plural referents unless the context clearly dictates otherwise.

[0102] As used in this invention, terms such as "about", "approximate", "substantially", etc., when used in conjunction with measurable variables such as parameters, amounts, time durations, etc., are intended to cover variations of the specified value as well as variations outside the specified value, including variations within experimental error (which can be determined, for example, by a given data set, standards recognized in the art, and / or by using, for example, a given confidence interval (e.g., 90%, 95%, or a greater confidence interval), such as variations of the specified value + / - 10% or less, + / - 5% or less, + / - 1% or less, and + / - 0.1% or less, as long as such variations are suitable for implementation in this invention. As used in this invention, the terms "about", "approximate", "at or about", and "substantially" can mean that the quantity or value being discussed can be an exact value or a value that provides an equivalent result or effect as recited in the claims or taught by this invention. That is, it should be understood that quantities, dimensions, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and / or larger or smaller as needed, reflecting tolerances, conversion factors, rounding, measurement errors, etc., and other factors known to those skilled in the art, so as to obtain equivalent results or effects. In some cases, it is not reasonable to determine the value that provides an equivalent result or effect. Generally, a quantity, dimension, formulation, parameter, or other quantity or characteristic is "about", "approximate", or "at or about", whether or not explicitly stated. It should be understood that when "about", "approximate", or "equal to or about" is used before a quantitative value, unless otherwise stated, the parameter also includes the specific quantitative value itself.

[0103] As used herein, "biological sample" can include whole cells and / or living cells and / or cell debris. A biological sample can contain (or be derived from) "body fluid". The present invention includes embodiments in which the body fluid is selected from amniotic fluid, aqueous humor, vitreous humor, bile, serum, breast milk, cerebrospinal fluid, cerumen (ear wax), chyle, chyme, endolymph, perilymph, exudate, feces, female ejaculate, gastric acid, gastric juice, lymphatic fluid, mucus (including nasal fluid and sputum), pericardial fluid, peritoneal fluid, pleural fluid, pus, rheum, saliva, sebum (skin oil), semen, sputum, synovial fluid, sweat, tears, urine, vaginal secretion, vomit, and one or more mixtures thereof. Biological samples include cell cultures, body fluids, and cell cultures derived from body fluids. Body fluids can be obtained from a mammalian organism, for example, by puncture or other collection or sampling procedures.

[0104] As used herein, "reagent" refers to any substance, compound, molecule, etc., which can be administered to the subject to which it is administered. A reagent can be inert. A reagent can be an active reagent. A reagent can be the primary active agent, or in other words, a component of a composition, the whole or part of the effect of which is attributed to this component. A reagent can be a secondary reagent, or in other words, a component of a composition, the additional part and / or other effect of which is attributed to this component.

[0105] As used herein, "active reagent" or "active component" refers to a substance, compound, or molecule having biological activity, or a substance, compound, or molecule that induces a biological or physiological effect on the subject to which it is administered. In other words, "active reagent" or "active component" refers to a component of a composition, the whole or part of the effect of which is attributed to this component.

[0106] As used herein, "administering" refers to any suitable mode of administering an agent being delivered and / or a subject receiving the agent, which can be oral, topical, intravenous, subcutaneous, transdermal, percutaneous, intramuscular, intra-articular, parenteral, intra-arterial, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intra-articular, intracavernosal, intrathecal, intravenous, intracerebral, and intraventricular, intra-tympanic, intracochlear, rectal, vaginal, by inhalation, by catheter, stent, or other devices for delivering the composition to the perivascular space and adventitia actively or passively (e.g., by diffusion). For example, a medical device such as a stent can contain a composition or formulation disposed on its surface, and then the composition or formulation can dissolve or otherwise distribute into the surrounding tissues and cells. The term "parenteral" can include subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. The route of administration can be, for example, auricular (ear), oral, conjunctival, dermal, dental, iontophoretic, intracervical, intranasal sinus, intratracheal, enteral, epidural, extra-amniotic, extracorporeal, hemodialysis, osmotic, interstitial, intraperitoneal, intra-amniotic, intra-arterial, intra-articular, intra-biliary, intra-bronchial, intra-capsular, intracardiac, intra-cartilaginous, intra-coccygeal, intracavernosal, intracavitary, intracerebral, intracisternal, intracatheter, intracorneal, intracoronal (dental), intracoronary, intracavernosal, intradermal, intradiscal, intracatheter, intra-duodenal, intradural, intraepidermal, intra-esophageal, intragastric, intragingival, intra-ileal, intralesional, intraluminal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intra-ovarian, intra-pericardial, intraperitoneal, intra-pleural, intra-prostatic, intrapulmonary, intranasal, intraspinal, intrasynovial, intratendinous, intra-testicular, intra-capsular, intrathoracic, intratubular, intratumoral, intra-tympanic, intrauterine, intravascular, intravenous, intravenous bolus, intravenous infusion, intraventricular, intravesical, intravitreal, iontophoresis, irrigation, laryngeal, nasal, nasogastric tube, occlusive dressing technique (possibly referring to an operation method for local drug penetration), ophthalmic, oral, oropharyngeal, other routes of administration, parenteral (such as non-gastrointestinal routes like vein, muscle, etc.), transdermal, periaricular, epidural, perineural, periodontal, rectal, respiratory (inhalation), retrobulbar, soft tissue, subarachnoid, subconjunctival, subcutaneous, sublingual, submucosal, topical, transdermal, mucosal, transplacental, transtracheal, trans-tympanic, ureteral, urethral, and / or vaginal, and / or any combination of the above routes of administration, which typically depends on the disease to be treated, the subject being treated, and / or the agent being administered.

[0107] As used herein, "control" can refer to an alternative subject or sample used for comparison purposes in an experiment and is included to minimize or distinguish the effects of variables other than the independent variable.

[0108] The term "optional" or "optionally" means that the subsequently described event, circumstance or substituent may or may not occur, and the description includes the case where the event or circumstance occurs and the case where it does not occur.

[0109] As used in the present invention, "dose", "unit dose" or "dosage" may refer to a physically discrete unit suitable for a subject, each unit containing a predetermined amount of a pharmaceutical preparation, the predetermined amount being calculated to produce the desired response associated with its administration.

[0110] The term "molecular weight" as used in the present invention generally refers to the mass or average mass of a material.

[0111] The terms "subject", "individual" and "patient" are used interchangeably in the present invention and refer to vertebrates, preferably mammals, more preferably humans. Mammals include but are not limited to rodents, apes, humans, farm animals, sport animals and pets. The term "subject" also includes tissues, cells and their progeny of biological entities obtained in vivo or cultured in vitro.

[0112] As used in the present invention, "substantially pure" may mean that the target species is the major species present (i.e., more abundant, on a molar basis, than any other single species in the composition), and preferably, a substantially purified fraction is a composition in which the target species comprises about 50% of all species present. Generally, a substantially pure composition will contain more than about 80% of all substances present in the composition, more preferably about 85%, 90%, 95% and more than 99%. Most preferably, the target species is purified to substantial homogeneity (contaminants cannot be detected in the composition by conventional detection methods), where the composition consists essentially of a single substance.

[0113] As used interchangeably in the present invention, the terms "sufficient" and "effective" may refer to the amount (e.g., mass, volume, dose, concentration and / or time) required to achieve one or more desired and / or specified results. For example, a therapeutically effective amount refers to the amount required to achieve one or more therapeutic effects.

[0114] As used in the present invention, "tangible medium of expression" refers to a physically tangible or accessible medium, rather than just an abstract idea or unrecorded spoken word. "Tangible medium of expression" includes but is not limited to words on a cellulose or plastic material, or data stored in a suitable computer-readable memory. The data may be stored on a unit device such as a flash memory or a CD-ROM, or stored on a server accessible by a user via, for example, a web interface.

[0115] As used in the present invention, the terms "treatment" and "treating" can generally refer to obtaining the desired pharmacological and / or physiological effect. In terms of preventing or partially preventing a disease, its symptoms or disorders (such as cancer and / or indirect radiation damage), the effect can be, but does not necessarily have to be, prophylactic. In terms of partially or completely curing a disease, disorder, symptom or side effect attributable to a disease, disorder or condition, the effect can be therapeutic. The term "treatment" as used in the present invention encompasses any treatment of cancer and / or indirect radiation damage in a subject, particularly a human and / or a pet, and can include any one or more of the following: (a) preventing the occurrence of a disease or injury in a subject who may be susceptible to the disease but has not been diagnosed with the disease; (b) inhibiting the disease, i.e., preventing its development; and (c) alleviating the disease, i.e., reducing or improving the disease and / or its symptoms or conditions. The term "treatment" as used in the present invention can refer to a therapeutic treatment alone, a prophylactic treatment alone or a therapeutic and prophylactic treatment. A patient in need of treatment (a subject in need of treatment) can include a patient who already has the disease and / or a patient who needs to prevent the disease. As used in the present invention, the term "treatment" can include inhibiting a disease, disorder or condition, such as preventing its progression; and alleviating the disease, disorder or condition, such as causing regression of the 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, such as treating pain in a subject by administering an analgesic, even if such an agent does not treat the cause of the pain.

[0116] Unless otherwise specified, the terms "weight percent", "wt%", and "wt.%", as used in the present invention, are used interchangeably and represent the weight percentage of a given component based on the total weight of the composition of which it is a component. That is, unless otherwise specified, all wt% values are based on the total weight of the composition. It should be understood that the sum of the wt% values of all components in the disclosed composition or formulation is equal to 100. Alternatively, if the wt% values are based on the total weight of a subset of the components in the composition, it should be understood that the sum of the wt% values of the specified components in the disclosed composition or formulation is equal to 100.

[0117] "Halo" means fluorine, chlorine, bromine or iodine.

[0118] An "alkyl" group means a straight-chain or branched-chain alkyl group. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl, etc. Unless otherwise specified, an alkyl group generally has from about 1 to about 10 carbon atoms.

[0119] The "cycloalkyl" group refers to a cycloalkyl group that can be monocyclic or bicyclic. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Unless otherwise specified, the cycloalkyl group typically has from about 3 to about 10 carbon atoms.

[0120] "Haloalkyl" refers to a straight-chain or branched-chain alkyl group in which at least one hydrogen is replaced by a halogen or halo group. Exemplary haloalkyl groups include trifluoromethyl, chloroethyl, difluoromethyl, difluoroethyl, etc.

[0121] Hydroxyalkyl refers to a straight-chain monovalent hydrocarbon group of 1-3 carbon atoms or a branched-chain monovalent hydrocarbon group of 3-5 carbon atoms substituted by one or two hydroxy groups, provided that if two hydroxy groups are present, they are not both on the same carbon atom. Representative examples include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl.

[0122] "Alkoxyalkyl" refers to a straight-chain monovalent hydrocarbon group of 1-6 carbon atoms or a branched-chain monovalent hydrocarbon group of 3-6 carbon atoms substituted by an alkoxy group as defined above, such as methoxymethyl, 2-methoxyethyl, 1-, 2- or 3-methoxypropyl.

[0123] "Heterocycloalkyl" refers to a non-aromatic monocyclic or polycyclic ring containing carbon and hydrogen atoms and at least one heteroatom, preferably 1-4 heteroatoms selected from nitrogen, oxygen and sulfur. The heterocycloalkyl group may have one or more carbon-carbon double bonds or carbon-heteroatom double bonds in the ring, provided that the ring does not become aromatic due to their presence. Examples of heterocycloalkyl groups include: pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, tetrahydrofuryl, tetrahydropyranyl and pyranyl.

[0124] "Alkoxy" refers to the -O(alkyl) group, where the alkyl is as defined above. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, etc. Unless otherwise specified, the alkoxy group typically has 1 to about 10 carbon atoms.

[0125] "Amine" refers to a primary, secondary or tertiary amino group. Secondary and tertiary amines may contain alkyl, cycloalkyl or aryl substituents. Some examples of amines include NH2, NHMe, NMe2NH(cyclopropyl). Unless otherwise specified, the alkyl or cycloalkyl on the amine typically has 1 to about 8 carbon atoms.

[0126] "Aryl" means an optionally substituted monocyclic or polycyclic aromatic ring system having from about 6 to about 14 carbon atoms. Exemplary aryl groups include phenyl, naphthyl, and the like. Unless otherwise specified, aryl generally has 6 to about 14 carbon atoms.

[0127] "Heteroaryl" means an aromatic monocyclic or polycyclic system having from about 4 to about 12 carbon atoms and having at least one heteroatom or hetero group selected from -O-, -N-, -S-, -SO2 or -CO. Exemplary heteroaryl groups include pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, imidazolyl, triazolyl, pyridazinyl, thienopyrimidinyl, furyl, indolyl, isoindolyl, benzo[1,3]dioxolyl, benzimidazolyl, 1,3-benzoxathiolyl, pyrrolidine-2,4-dioneyl, quinazolinyl, pyridyl, pyrimidinyl, thienyl, and the like, one or more of which. Unless otherwise specified, heteroaryl generally has 4 to about 10 carbon atoms.

[0128] "5- to 6-membered heteroaryl" is an aromatic monocyclic system of 5 or 6 ring atoms having at least one heteroatom or hetero group selected from -O-, -N-, -S-, -SO2 or -CO. Exemplary "5- to 6-membered heteroaryl" groups include one or more of pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, pyridazinyl, pyridyl, thienopyrimidinyl, tetrazolyl, imidazolyl, triazolyl, furyl, and the like.

[0129] "Optionally substituted" means that the substitution is optional, so the specified atom or molecule may be unsubstituted. In cases where substitution is required, such substitution means that any number of hydrogens on the specified atom are replaced by the selected specified group, provided that the normal valence of the specified atom is not exceeded and the substitution results in a sufficiently stable compound for use.

[0130] "Salt" refers to any acid or base salt, pharmaceutically acceptable solvate or any complex of a compound which, when administered to a recipient, is capable of providing (directly or indirectly) the compounds described in the present invention. However, it should be understood that pharmaceutically unacceptable salts are also within the scope of the present invention. The preparation of salts can be carried out using known methods. For example, a useful pharmaceutically acceptable salt of a compound contemplated by the present invention can be synthesized by conventional chemical methods using a parent compound containing a basic or acidic functional group. Generally, such salts can be prepared, for example, by preparing the compound in free acid or base form and reacting it with a stoichiometric amount of a suitable base or acid in water or in an organic solvent or in a mixture of both. Generally, non-aqueous media can be used, such as one or more solvents, such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Examples of acid addition salts include one or more inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, and one or more organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, mesylate and tosylate. Examples of base addition salts include one or more inorganic salts such as sodium salt, potassium salt, calcium salt, ammonium salt, magnesium salt and lithium salt, and one or more organic base salts such as ethylenediamine, ethanolamine, N,N-dialkylethanolamine, triethanolamine and basic amino acid salts.

[0131] The phrase "therapeutically effective" means the ability of an agent or combination to prevent or reduce the severity of the symptoms of a disorder or disease while generally avoiding adverse side effects. The therapeutically effective compositions of the present invention can include doses of the compounds of the present invention from about 10 to about 3000 mg. The exact dose can be determined based on many factors, including the characteristics of the patient and the degree of treatment desired.

[0132] The terms "effective amount" or "therapeutically effective amount" or "dose" as used in the present invention refer to the dose or amount of the compounds of the present invention administered to a subject and the frequency of administration that results in a certain therapeutic response. A person of ordinary skill in the art can readily determine the dose or effective amount to be administered to a subject and the frequency of administration to the subject by using known techniques and by observing the results obtained in similar circumstances. In determining the effective amount or dose, the attending physician can consider many factors, including but not limited to the potency 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 reactivity of the subject to be treated, as well as other relevant circumstances.

[0133] The compounds of the present invention can be administered in admixture with one or more pharmaceutically acceptable excipients or carriers in the form of a pharmaceutical composition. A "composition" can contain one compound or a mixture of compounds. A "pharmaceutical composition" refers to any composition that can be used or may be used to produce a physiological response in a subject to which the pharmaceutical composition is administered.

[0134] The term "pharmaceutically acceptable" with respect to excipients is used to define non-toxic substances that are generally suitable for human or animal pharmaceutical products. The pharmaceutical composition can be in a commonly used form, such as tablets, capsules, powders, syrups, solutions, suspensions, etc. The pharmaceutical composition can contain edible flavors, sweeteners, etc. in a suitable solid or liquid carrier or diluent, or in a suitable sterile medium to form an injectable solution or suspension. Such compositions generally contain from about 0.1% to about 50% by weight, and in some embodiments from about 1% to about 20% by weight of the active compound, the remainder of the composition being a pharmaceutically acceptable carrier, diluent or solvent.

[0135] Various embodiments are described below. It should be noted that the specific embodiments are not intended as an exhaustive description or as a limitation on the broader aspects discussed in the present invention. An aspect described in connection with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment. References throughout this specification to "one embodiment", "an embodiment", "exemplary embodiment" mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the phrases "in one embodiment", "in an embodiment", or "exemplary embodiment" appearing throughout the specification do not necessarily all refer to the same embodiment, but may refer to the same embodiment. In addition, in one or more embodiments, the particular features, structures, or characteristics can be combined in any suitable manner, which will be apparent to those skilled in the art from the present invention. Further, although some embodiments described herein include some features that are not included in other embodiments, the combination of features of different embodiments is meant to be within the scope of the present invention. For example, in the appended claims, any of the claimed embodiments can be used in any combination.

[0136] All patents, patent applications, published applications and publications, databases, websites, and other publicly available materials cited in this invention are hereby incorporated by reference in their entirety, with the same effect as if each individual publication, published patent document, or patent application was specifically and individually indicated to be incorporated by reference.

[0137] Kit

[0138] Any compound and / or formulation described in the present invention can be provided as a combination kit. As used herein, the term "combination kit" or "active ingredient" refers to a compound, composition, formulation, granule, unit, and any additional components for packaging, selling, marketing, delivering, and / or administering a combination or single ingredient (such as an active ingredient) contained therein. These additional components include, but are not limited to, packaging, syringes, blister packs, bottles, etc. When one or more compounds, compositions, formulations, granules, units, or combinations thereof (e.g., reagents) described in the present invention contained in the kit are administered simultaneously, the combination kit can contain the active agent in a single formulation (such as a pharmaceutical formulation) or in separate formulations, e.g., tablets, liquid formulations, dehydrated formulations, etc. When the compounds, compositions, formulations, granules, and units or combinations thereof and / or kit components described in the present invention are not administered simultaneously, the combination kit can contain each reagent or other component in a separate pharmaceutical formulation. The separate kit components can be contained in a single package or in separate packages within the kit.

[0139] In some embodiments, the combination kit further includes instructions printed on or otherwise contained in a tangible expression medium. The instructions can provide information about the content of the compound and / or formulation, safety information about the content of the compound and formulation (such as a pharmaceutical formulation), information about dosage, usage indications, and / or recommended treatment regimens for the compound and / or pharmaceutical formulation contained therein. In some embodiments, the instructions can provide guidance and regimens for administering the compounds and / or formulations described in the present invention to a subject in need. In some embodiments, the instructions can provide one or more examples of methods of administering its pharmaceutical formulation, such as any method described in more detail elsewhere in the present invention.

[0140] Detailed description of the present invention

[0141] Reference will now be made in detail to embodiments of the present invention, one or more of which are set forth below. Each embodiment is provided by way of explanation of the present invention, and not as a limitation thereof. In fact, it will be apparent to those skilled in the art that various modifications can be made to the present invention without departing from the scope or spirit thereof. For example, features shown or described as part of one embodiment can be used in another embodiment to yield yet another embodiment. Accordingly, the present invention is intended to cover modifications and variations that fall within the scope of the appended claims and their equivalents. Other objects, features, and aspects of the present invention are disclosed in the following detailed description or are apparent from the following detailed description.

[0142] For ease of reference, the present invention will be described in terms of administration to human subjects. However, it should be understood that these descriptions are not limited to administration to humans unless otherwise explicitly stated, and also include administration to other animals.

[0143] The expected derivatives are those that can improve the dissolution of the compounds of the present invention or increase their bioavailability when the compounds of the present invention are administered to a subject (e.g., by making the orally administered compounds more readily absorbed). The compounds of formula I can be amorphous, semi-crystalline or crystalline, and can be given as the parent compound, its salts and / or solvated forms. The solvate can be part of the lattice or surface associated. All such forms are intended to be within the scope of the present invention. Solvation methods are well known in the art. Suitable solvates are pharmaceutically acceptable solvates. In one embodiment, the solvate is a hydrate.

[0144] In one aspect, the present invention relates to novel compounds of formula I:

[0145]

[0146] their stereoisomers, stable isotopes (e.g., deuterated variants) or their pharmaceutically acceptable salts;

[0147] wherein

[0148] R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein R 1 may optionally be substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , COR 3 ;

[0149] R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl;

[0150] R 3 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy;

[0151] R 4 is selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , COR 3 ;

[0152] R 5 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine;

[0153] R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl. The aryl or heteroaryl may optionally be substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl;

[0154] X is selected from the group consisting of O, (CH2)p, and NH; where p is selected from 0 - 2, provided that when p = 0, Y1 - Y2 is not CH - CH2 or CH - O, and R 1 is not aryl; and

[0155] Y1 - Y2 is selected from the group consisting of CH - CH2, CH2 - O, or C═CH; however, when Y1 - Y2 is CH2 - O, X is selected from O or NH, and R 1 is not hydrogen or alkyl;

[0156] Y3 is selected from H or Me.

[0157] On the other hand, the present invention relates to new compounds of formula II:

[0158]

[0159] their stereoisomers or their pharmaceutically acceptable salts;

[0160] wherein

[0161] R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 may be optionally substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 、COR 3 ;

[0162] R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl;

[0163] R 3 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy

[0164] R 4 is selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 、COR 3 ;

[0165] R 5 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine;

[0166] R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl. The aryl or heteroaryl may be optionally substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl;

[0167] X is selected from the group consisting of O, (CH2)p, and NH; where p is selected from 0 - 2, provided that when p = 0, Y1 - Y2 is not CH - CH2 or CH - O, and R 1 is not aryl; and

[0168] Y1 - Y2 is selected from CH - CH2, CH - O, or C═CH; however, when Y1 - Y2 is CH2 - O, X is selected from O or NH, and R 1 is not hydrogen or alkyl.

[0169] On the other hand, the present invention relates to a new compound of formula III:

[0170]

[0171] its stereoisomers or its pharmaceutically acceptable salts;

[0172] wherein

[0173] R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where R 1 may be optionally substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 , SO2NHR 2 , COR 3 ;

[0174] R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl;

[0175] R 3 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy;

[0176] R 4 is selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , COR 3 ;

[0177] R 5 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine;

[0178] R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl. The aryl or heteroaryl may be optionally substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl;

[0179] X is selected from O, (CH2)p, NH; where p is selected from 0 - 2; provided that when p = 0, R 1 is not aromatic.

[0180] On the other hand, the present invention relates to new compounds of formula IV:

[0181]

[0182] their stereoisomers or their pharmaceutically acceptable salts;

[0183] wherein

[0184] R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein R 1 may be optionally substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 、SO2NHR 2 、COR 3 ;

[0185] R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl;

[0186] R 3 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy;

[0187] R 4 is selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 、COR 3 ;

[0188] R 5 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine;

[0189] R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl. The aryl or heteroaryl may be optionally substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl;

[0190] X is selected from O, (CH2)p, NH; where p is selected from 0 - 2, provided that when p = 0, R 1 is not aryl;

[0191] In addition, the composition may comprise one or more of the following compounds, their stereoisomers or their pharmaceutically acceptable salts;

[0192]

[0193]

[0194]

[0195] In one embodiment, the present invention may include a compound of Formula I, wherein the compound is an inhibitor of soluble epoxide hydrolase (sEH) that is greater than 10-fold selective relative to fatty acid amide hydrolase (FAAH (SEQ ID NO:5)).

[0196] In an embodiment, the present invention may include a compound of Formula I, wherein the compound may inhibit soluble epoxide hydrolase, IC 50 is <100 nM and has >10-fold selectivity relative to fatty acid amide hydrolase (IC50, FAAH (SEQ ID NO:5)).

[0197] In another embodiment, the compound of Formula I may inhibit soluble epoxide hydrolase, IC 50 is ≤100 nM and inhibits fatty acid amide hydrolase (FAAH (SEQ ID NO:5)), IC 50 is >1000 nM.

[0198] In another embodiment, the compound of Formula I may inhibit soluble epoxide hydrolase, IC 50 is <50 nM and inhibits fatty acid amide hydrolase (FAAH (SEQ ID NO:5)), IC 50 is >1000 nM.

[0199] In another embodiment, the compound of Formula I may inhibit soluble epoxide hydrolase, IC 50 is <20 nM and inhibits fatty acid amide hydrolase (FAAH (SEQ ID NO:5)), IC 50 is >1000 nM.

[0200] In other embodiments, the therapeutically effective amount of the compound of Formula I may be from about 0.5 mg / day to about 3,000 mg / day. In an embodiment, the therapeutically effective amount of the compound of Formula I may be from about 1 mg / day to about 2,000 mg / day. In an embodiment, the therapeutically effective amount of the compound of Formula I may be from about 2 mg / day to about 1000 mg / day. In an embodiment, the therapeutically effective amount of the compound of Formula I may be from 3 mg / day to about 700 mg / day. In an embodiment, the therapeutically effective amount of the compound of Formula I may be from 4 mg / day to about 500 mg / day. In an embodiment, the therapeutically effective amount of the compound of Formula I may be from 3 mg / day to about 400 mg / day. In an embodiment, the therapeutically effective amount of the compound of Formula I may be from 10 mg / day to about 300 mg / day.

[0201] In some embodiments, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 2 mg to about 1,500 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 4 mg to about 750 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 6 mg to about 600 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 10 mg to about 500 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 20 mg to about 400 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 20 mg to about 300 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 20 mg to about 200 mg per day.

[0202] In other embodiments, a therapeutically effective amount of the compound of Formula I for adult subjects can be from about 20 mg to about 120 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for adult subjects can be from about 20 mg to about 100 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for adult subjects can be from about 20 mg to about 75 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for adult subjects can be from about 20 mg to about 60 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for adult subjects can be from about 20 mg to about 50 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for adult subjects can be from about 20 mg to about 40 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for adult subjects can be from about 24 mg to about 40 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 0.1 mg to about 700 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 0.25 mg to about 350 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 0.5 mg to about 300 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 1 mg to about 200 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 2 mg to about 100 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 3 mg to about 80 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 4 mg to about 60 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 5 mg to about 80 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 6 mg to about 60 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 6 mg to about 50 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 6 mg to about 40 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 6 mg to about 30 mg per day. In an embodiment, a therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 7 mg to about 25 mg.

[0203] In other embodiments, a therapeutically effective amount of a compound of Formula I can be administered as a single dose or as a dose repeated one or several times at certain time intervals. In an embodiment, a therapeutically effective amount is administered once daily or once every two days or once every three days or once a week. The administration can be once, twice, or three times a day. In an embodiment, as long as the symptoms or disease are present, a therapeutically effective amount is administered daily or every other day for more than two weeks, ten weeks, thirty weeks, one year. In an embodiment, a therapeutically effective amount is administered daily or every other day for more than 30 weeks.

[0204] In addition, the present invention can provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound as shown in the present invention.

[0205] In some embodiments, the present invention provides a method for inhibiting or reducing the metastasis of a primary tumor in a cancer subject, the method comprising administering to the subject a regimen of a therapeutically effective amount of a compound of Formula I, with or without one or more chemotherapeutic agents and / or checkpoint inhibitors.

[0206] On the other hand, the present invention relates to novel compounds of Formula I, their stereoisomers, stable labeled (e.g., deuterated) variants, tautomers, and / or their pharmaceutically acceptable salts, which can be used as inhibitors of soluble epoxide hydrolase (sEH). On the other hand, the present invention relates to methods for preventing and / or treating pain, neurodegenerative diseases, cancer, and inflammatory diseases in subjects in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I, its stereoisomers, and / or its pharmaceutically acceptable salts. In addition, the compound of Formula I, with or without its stereoisomers and / or pharmaceutically acceptable salts, can be used as a monotherapy or in combination therapy with one or more chemotherapeutic agents and / or immune checkpoint inhibitors for preventing or treating cancer.

[0207] In addition, the compound of Formula I, its stereoisomers, and / or its pharmaceutically acceptable salts can be used for preventing, inhibiting, or treating cancer in a subject, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound of Formula I, with or without one or more chemotherapeutic agents and / or immune checkpoint inhibitors.

[0208] In another embodiment, the stereoisomers and / or pharmaceutically acceptable salts of Formula I can be used in combination with an anti-inflammatory agent (NSAID or cox-2 (SEQ ID NO:4) inhibitor), one or more chemotherapeutic agents, and / or immune checkpoint inhibitors for treating cancer.

[0209] For ease of reference, the present invention will be described in terms of administration to human subjects. However, it should be understood that these descriptions are not limited to administration to humans unless otherwise explicitly stated, and also include administration to other animals.

[0210] The expected derivatives are those derivatives that can improve the dissolution of the compounds of the present invention or increase their bioavailability when the compounds of the present invention are administered to a subject (e.g., by making the orally administered compounds more readily absorbable). The compounds of formula I can be amorphous, semi-crystalline or crystalline, and can be given as the parent compound, its salts and / or solvated forms. The solvate can be part of the lattice or surface associated. All these forms should be within the scope of the present invention. Solvation methods are well known in the art. Suitable solvates are pharmaceutically acceptable solvates. In one embodiment, the solvate is a hydrate.

[0211] In one embodiment, the compounds of the present invention (compounds of formula I) can be used for the treatment of inflammatory pain, neuropathic pain, rheumatoid arthritis, osteoarthritis, diabetic nephropathy, hypertension, diabetes and / or metabolic syndrome. The compounds of formula I can be used to increase the levels of epoxyeicosatrienoic acids (EETs) in a subject to prevent and treat inflammatory and / or pain conditions.

[0212] Accordingly, the compounds of formula I, their pharmaceutically acceptable salts and / or their solvates can be used for the prevention and / or treatment of the diseases or conditions discussed in the present invention. Further aspects of the present invention relate to pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I, its pharmaceutically acceptable salt and / or its solvate, which may also include pharmaceutically acceptable excipients.

[0213] The therapeutically effective amount of the compounds of formula I, their pharmaceutically acceptable salts and / or solvates that must be administered, as well as the dosage for treating a pathological condition with said compounds, will depend on many factors, including age, the condition of the patient, the severity of the disease, the route and frequency of administration, the modulating compounds used, etc.

[0214] Suitable pharmaceutically acceptable carriers can include solid fillers or diluents and sterile aqueous or organic solutions. The active ingredient can be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the above range. Thus, for oral administration, the active ingredient can be combined with suitable solid or liquid carriers or diluents to form capsules, tablets, powders, syrups, solutions, suspensions, etc. For parenteral administration, the active ingredient can be combined with a sterile aqueous or organic medium to form an injectable solution or suspension. For example, solutions in sesame oil or peanut oil, aqueous propylene glycol solutions, etc., as well as aqueous solutions of water-soluble pharmaceutically acceptable acid addition salts or salts with bases of the compound can be used. Solutions in which the active ingredient is dissolved in a pharmaceutically acceptable solvent such as an aqueous solution of polyhydroxylated castor oil can also be used for injection solutions. The injectable solutions prepared in this way can then be administered intravenously, intraperitoneally, subcutaneously or intramuscularly, with intramuscular administration generally being preferred for humans.

[0215] The following examples describe exemplary embodiments of the present invention. Other embodiments within the scope of the claims of the present invention will be apparent to those skilled in the art upon consideration of the specification or practice of the invention disclosed herein. The specification, together with the examples, is to be considered merely exemplary, and the scope and spirit of the present invention are indicated by the claims that follow the examples.

[0216] Conventional synthetic procedures

[0217] The compounds of the present invention can be synthesized according to the procedures outlined in Schemes I - VIII. The proposed methods are not restrictive. Variations of these synthetic methods or methods reported in the literature can be employed to synthesize compounds within the scope of the present invention.

[0218] Scheme I

[0219]

[0220] R 1 = alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl heterocycloalkyl

[0221] R 4 = alkyl, halogen, haloalkyl, alkoxy, SO2R5, COR3

[0222] R 6 = alkyl, cycloalkyl, aryl or heteroaryl

[0223] X = O, (CH2) p , p = 0.-2

[0224] Scheme I shows the synthetic method of the compound 7 of formula I of the present invention. In the first step, the substituted benzyl halide 1 (Z = Cl, Br) reacts with trialkyl phosphate to form the substituted benzyl phosphonate 2. This reaction can be carried out by heating 1 with trialkyl phosphate at 120 - 150 °C for 10 - 20 hours in the presence or absence of a solvent (such as dimethylacetamide). The substituted olefin 4 is synthesized by generating an ylid from the intermediate 2 and reacting it with the substituted piperidone 3. In a solvent (such as THF, dimethoxyethane or ether), in the presence of a crown ether, an ylid is generated from 2 using a base (such as sodium hydride or potassium hydride). This reaction can be initiated at low temperature (0 + 5 °C), and then the reaction mixture is heated to about 20 °C and stirred for another 20 - 60 minutes. The reaction between the ylid generated from 2 and 3 can be carried out in a solvent such as THF, dimethoxyethane, ether or toluene, and the reaction is initiated at low temperature (0 °C + 5 °C), and then the reaction mixture is heated to about 20 - 40 °C and stirred for 8 - 20 hours. In the presence of an acid, the carbamate is deprotected from 4 to obtain the piperidine intermediate 5. This reaction can be carried out by stirring the reaction mixture in a solvent (such as dichloromethane or dichloroethane) and using an acid (such as trifluoroacetic acid) at a temperature of 0 - 25 °C for 20 - 90 minutes. 5 reacts with the substituted cyclopropane carbamate intermediate 6 to obtain the target compound 7. This reaction can be carried out by using a solvent (such as dimethyl sulfoxide or dimethylacetamide) and a base (such as triethylamine, diisopropylethylamine), and heating the reaction components at 40 - 60 °C for 3 - 6 hours.

[0225] The substituted cyclopropane carbamate 6 can be synthesized from the corresponding cyclopropylamine 8 by reacting with an aryl chloroformate (R = Ph or Ar) using a solvent such as dichloromethane and a base such as diisopropylethylamine. The reaction can be initiated at low temperature (0 ± 5 °C), and then the reaction mixture is heated to about 20 - 30 °C and stirred for 20 - 40 minutes. The substituted benzyl halide 1 and the substituted piperidone 3 used in Scheme I can be commercially available or synthesized from readily available reagents.

[0226] Scheme II

[0227]

[0228] R 1 = alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl

[0229] R 4 = alkyl, halogen, halo, alkoxy, SO2R5, COR3

[0230] R 6 = alkyl, cycloalkyl, aryl or heteroaryl

[0231] X = O, (CH2) p, p = 0.-2

[0232] Scheme II shows the synthesis method of the compound 11 of formula I of the present invention. In the first step, the compound 4 is synthesized using the method described in Scheme I, and it is hydrogenated to obtain the saturated compound 9. This reaction can be carried out using catalytic hydrogenation (using, for example, Pd / C or Pt / C) in a solvent such as methanol or ethanol in a Parr hydrogenation apparatus. In the presence of an acid, the carbamate 9 is deprotected to obtain the piperidine intermediate 10. This reaction can be carried out by stirring the reaction mixture in a solvent (such as dichloromethane or dichloroethane) and using an acid (such as trifluoroacetic acid) at a temperature of 0 - 25 °C for 20 - 90 minutes. 10 reacts with the substituted cyclopropane carbamate intermediate 6 to obtain the target compound 11. This reaction can be carried out by heating the reaction components in a solvent (such as dimethyl sulfoxide or dimethylacetamide) and a base (such as triethylamine, diisopropylethylamine) at 40 - 60 °C for 3 - 6 hours.

[0233] Scheme III

[0234]

[0235] R 1 = heteroaryl, substituted or unsubstituted

[0236] R 4 = alkyl, halogen, haloalkyl, alkoxy, SO2R5, COR3

[0237] R 6 = alkyl, cycloalkyl, aryl or heteroaryl

[0238] R 7 = alkyl, haloalkyl, alkoxy, SO2R5, COR3

[0239] Scheme III shows the synthetic methods of Compounds 18 and 19 of the present invention. In the first step, Compound 12 containing a heteroaromatic ring A (such as pyridine, pyrimidine, pyrazine) reacts with a substituted phenol 13 to obtain 14. 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), and heating the reaction mixture at 80 - 120 °C for 3 - 6 hours. The obtained substituted benzyl alcohol is converted to the corresponding benzyl halide 15 by reacting with thionyl chloride. This reaction can be carried out using a solvent such as dichloromethane and treating with thionyl chloride at 0 - 25 °C for 1 - 3 hours. The substituted benzyl halide 15 reacts with trialkyl phosphite to form a substituted benzyl phosphonate 16. This reaction can be carried out by heating 15 with trialkyl phosphite at 120 - 150 °C for 10 - 20 hours, with or without a solvent (such as dimethylacetamide). The substituted olefin 17 is synthesized by generating a ylide from intermediate 16 and reacting it with a substituted piperidone 3. In a solvent (such as THF, dimethoxyethane or ether), in the presence of a crown ether, a ylide is generated from 16 using a base (such as sodium hydride or potassium hydride). The reaction can be initiated at a low temperature (0 °C + 5 °C), and then the reaction mixture is heated to about 20 °C and stirred for another 20 - 60 minutes. The reaction between the ylide generated from 16 and 3 can be carried out in a solvent such as THF, dimethoxyethane, ether or toluene, and the reaction is initiated at a low temperature (0 + 5 °C), and then the reaction mixture is heated to about 20 - 40 °C and stirred for 8 - 20 hours. The conversion of 17 to 18 can be carried out after the following steps: deprotecting the carbamate in the presence of an acid and reacting with a substituted cyclopropane carbamate intermediate 6 as described in Scheme I. The conversion of 17 to 19 can be completed using a series of steps including hydrogenation, deprotection of the carbamate and reaction with a substituted cyclopropane carbamate intermediate 6, as described in Scheme II.

[0240] Scheme IV

[0241]

[0242] R 13 = CO2R (R = H, alkyl, NH2, NHMe), CH2OR,

[0243] R 4 = alkyl, halogen, haloalkyl, alkoxy, SO2R5, COR3

[0244] R 6 = alkyl, cycloalkyl, aryl or heteroaryl

[0245] Scheme IV shows the synthetic methods of compounds 26 and 27 of the present invention. In the first step, compound 20 reacts with substituted phenol 21 to obtain 22. This reaction can be carried out by heating the reaction mixture in a solvent (such as dimethylacetamide or dimethylformamide), using a base (such as cesium carbonate), at 80 - 120 °C for 3 - 8 hours. The obtained substituted benzyl alcohol is converted to the corresponding benzyl halide 23 by reacting with thionyl chloride. This reaction can be carried out using a solvent such as dichloromethane and treating it with thionyl chloride at 0 - 25 °C for 1 - 3 hours. The substituted benzyl halide 23 reacts with trialkyl phosphite to form substituted benzyl phosphonate 24. This reaction can be carried out by heating 23 and trialkyl phosphite at 120 - 150 °C for 10 - 20 hours in the presence or absence of a solvent such as dimethylacetamide. The substituted olefin 25 is synthesized by generating a ylide from intermediate 24 and reacting it with substituted piperidone 3. In a solvent such as THF, dimethoxyethane or ether, in the presence of a crown ether, a ylide is generated from 24 using a base such as sodium hydride or potassium hydride. The reaction can be initiated at low temperature (0 °C + 5 °C), and then the reaction mixture is heated to about 20 °C and stirred for another 20 - 60 minutes. The reaction between the ylide generated from 24 and 3 can be carried out in a solvent such as THF, dimethoxyethane, ether or toluene, and initiated at low temperature (0 + 5 °C), and then the reaction mixture is heated to about 20 - 40 °C and stirred for 8 - 20 hours. The conversion from 25 to 26 can be carried out after the following steps: deprotecting the carbamate in the presence of an acid and reacting it with the substituted cyclopropane carbamate intermediate 6 as described in Scheme I. The conversion from 25 to 27 can be completed using a series of steps including hydrogenation, deprotection of the carbamate and reaction with the substituted cyclopropane carbamate intermediate 6, as described in Scheme II.

[0246] Scheme V

[0247]

[0248] R 4 = alkyl, halogen, haloalkyl, alkoxy, SO2R5, COR3

[0249] R 6 = alkyl, cycloalkyl, aryl or heteroaryl

[0250] Ring A - heterocyclic group

[0251] Scheme V shows the synthetic methods of compounds 33 and 34 of the present invention. In the first step, the substituted benzyl halide 28 reacts with trialkyl phosphite to generate the substituted benzyl phosphonate 29. This reaction can be carried out by heating 28 and trialkyl phosphite at 120 - 150 °C for 10 - 20 hours with or without a solvent (such as dimethylacetamide). The substituted olefin 30 is synthesized by generating a ylide from the intermediate 29 and reacting it with the substituted piperidone 3. In a solvent (such as THF, dimethoxyethane or ether), in the presence of a crown ether, a base (such as sodium hydride or potassium hydride) is used to generate a ylide from 29. The reaction can be initiated at low temperature (0 °C + 5 °C), and then the reaction mixture is heated to about 20 °C and stirred for another 20 - 60 minutes. The reaction between the ylide generated from 29 and 3 can be carried out in a solvent such as THF, dimethoxyethane, ether or toluene, and the reaction is initiated at low temperature (0 + 5 °C), and then the reaction mixture is heated to about 20 - 40 °C and stirred for 8 - 20 hours. The intermediate 31 containing the heterocyclic ring A is synthesized by reacting 30 with the corresponding heterocycles such as pyrrolidine, morpholine, piperidine. This reaction can be carried out by treating 30 with a heterocycle of ring A using cesium carbonate and a catalyst such as palladium acetate and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP). The reaction can be carried out by treating the reaction mixture at 20 - 100 °C for 5 - 20 hours using a solvent such as 1,4-dioxane. The conversion from 31 to 33 can be carried out after the following steps: deprotecting the carbamate in the presence of an acid and reacting it with the substituted cyclopropane carbamate intermediate 6 as described in Scheme I.

[0252] The conversion from 31 to 32 can be completed using catalytic hydrogenation ((Pd / C, H2) as described in Scheme II. Similarly, the conversion from 32 to 34 can be carried out according to the method including deprotecting the carbamate and reacting it with the substituted cyclopropane carbamate intermediate 6, as described in Scheme II.

[0253] Scheme VI

[0254]

[0255] R 4 = alkyl, halogen, haloalkyl, alkoxy, SO2R5, COR3

[0256] R 6 = alkyl, cycloalkyl, aryl or heteroaryl

[0257] R 7 = alkyl, haloalkyl, SO2R5, COR3

[0258] Scheme VI shows the synthetic method of Compound 40 of the present invention. In the first step, Compound 35 containing a heteroaromatic ring A (such as pyridine, pyrimidine, pyrazine) reacts with substituted phenol 36 to obtain 37. This reaction can be carried out by heating the reaction mixture in a solvent (such as dimethylacetamide or dimethylformamide), using a base (such as potassium carbonate, sodium carbonate or cesium carbonate), at 80 - 120 °C for 3 - 8 hours. Substituted phenol 37 reacts with piperidine methanesulfonate 38 to obtain 39. This reaction can be carried out in a solvent (such as dimethylacetamide or dimethylformamide), using a base (such as potassium carbonate, sodium carbonate, cesium carbonate), and heating the reaction mixture at 60 - 80 °C for 6 - 8 hours. The conversion from 39 to 40 can be carried out in the following steps: deprotecting the carbamate in the presence of an acid and reacting with the substituted cyclopropane carbamate intermediate 6 as described in Scheme I.

[0259] Scheme VII

[0260]

[0261] Scheme VII shows the synthetic methods of Compounds 45 and 46 of the present invention. In the first step, Compound 41 containing a heteroaryl borate reacts with aryl halide 42 to obtain 43. This reaction can be carried out by treating 41 and 42 in a solvent such as dimethylacetamide, dimethylformamide with 2N sodium carbonate solution and tetrakis(triphenylphosphine)palladium(0) at ambient temperature 20 - 25 °C for 12 - 18 hours. The conversion from 43 to 45 can be carried out after the following steps: deprotecting the carbamate in the presence of an acid and reacting with the substituted cyclopropane carbamate intermediate 6 as described in Scheme I.

[0262] As described in Scheme II, 43 can be converted to 44 using catalytic hydrogenation (Pd / C, H2). Similarly, the conversion from 44 to 46 can be carried out according to the method including deprotection of the carbamate and reaction with the substituted cyclopropane carbamate intermediate 6, as described in Scheme II.

[0263] Scheme VIII

[0264]

[0265] R4 = alkyl, hydrogen, halogen, alkoxy

[0266] R6 = alkyl, aryl, cycloalkyl

[0267] Scheme VIII shows the synthetic method of the compound of formula 54 of the present invention. In the first step, the substituted benzyl halide 47 reacts with trialkyl phosphite to generate the substituted benzyl phosphonate 48. This reaction can be carried out by heating 47 with trialkyl phosphite at 120 - 150 °C for 10 - 20 hours. The substituted olefin 49 is synthesized by generating a ylide from the intermediate 48 and reacting it with the substituted piperidone 3. In a solvent (such as THF, dimethoxyethane or ether), in the presence of a crown ether, a base (such as sodium hydride or potassium hydride) is used to generate the ylide from 48. The reaction can be initiated at low temperature (0 + 5 °C), and then the reaction mixture is heated to about 20 °C and stirred for another 20 - 60 minutes. The reaction between the ylide generated from 48 and 3 can be carried out in a solvent such as THF, dimethoxyethane, ether or toluene, and initiated at low temperature (0 + 5 °C), and then the reaction mixture is heated to about 20 - 40 °C and stirred for 8 - 20 hours. The conversion of 49 to 50 can be completed using catalytic hydrogenation (Pd / C, H2). This reaction can be carried out using catalytic hydrogenation (using, for example; Pd / C or Pt / C) in a solvent such as methanol or ethanol in a Parr hydrogenation apparatus. In the next step, the synthesis of 52 is completed by reacting 50 with the substituted 1 - fluoro - 2 - nitrobenzene 51 in a substitution reaction. This reaction can be carried out by treating 50 with 51 in a solvent such as dimethylformamide and heating the reaction mixture at 80 - 120 °C for 10 - 20 hours in the presence of cesium carbonate. The synthesis of the benzimidazole compound 53 can be completed by treating 52 with formic acid and sodium formate in the presence of Pd / C at about 25 °C and heating the mixture at about 100 - 120 °C for 12 - 20 hours. The conversion of 53 to 54 can be carried out by treating with the substituted cyclopropane carbamate intermediate 6 as described in Scheme II.

[0268] Example

[0269] Examples of the present invention provide methods for preparing the novel compounds of formula I using the methods described in the following examples. Those skilled in the art will understand that known variations of the conditions and methods of the following preparation procedures can be used to prepare these compounds. In addition, by utilizing the methods described in the present invention, those of ordinary skill in the art can prepare other compounds of the present invention claimed herein.

[0270] Example 1: Synthesis of 4-(3 - methoxy - benzylidene)-piperidine - 1 - carboxylic acid (2 - phenyl - cyclopropyl)-amide:

[0271]

[0272] Step 1 - Thionyl chloride (74 mL, 1.01 mol) was added dropwise to a mixture of (3-methoxyphenyl)methanol (20.0 g, 0.14 mol) and pyridine (5.8 mL, 0.72 mol) in benzene (120 mL) while stirring the reaction in an ice bath. After removing the ice, the reaction mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was quenched with saturated sodium bicarbonate solution (100 ml), extracted with ethyl acetate (2 × 300 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 solution of 5% ethyl acetate) to give 20.01 g (88%) of the yellow oily product 2. 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).

[0273] Step 2 - A solution of 2 (20 g, 0.12 mol) in triethyl phosphite (29.0 mL, 0.16 mol) was heated at 150 °C for 17 hours. The reaction mixture was cooled to room temperature, and the crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 20% ethyl acetate) 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).

[0274] Step 3 - 15-Crown ether (0.2 mL, 0.9 mmol) was added to a solution of 3 (11.0 g, 43.0 mmol) in THF (44 mL). 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 cooled again using an ice bath. A solution of tert-butyl 4-oxopiperidine-1-carboxylate 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 by silica gel (230 - 400) column (petroleum ether solution of 25% ethyl acetate) to give the yellow oily product 5, 7.0 g (54%). 11H 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).

[0275] Step 4 - At ice temperature, trifluoroacetic acid (4.25 mL, 4.25 volumes) was added to a solution of 5 (1.0 g, 3.2 mmol) in dichloromethane (8.0 mL). The reaction mixture was stirred at room temperature for 1 hour. The crude product obtained after evaporation of the volatiles was washed with diethyl ether to give white solid 6 (600 mg, 89%). 1 1H 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).

[0276] Step 5 - At ice bath temperature, triethylamine (0.06 mol) and phenyl chloroformate 1A (4.8 g, 0.03 mol) were added to a suspension of trans-2-phenylcyclopropylamine 2A (3.5 g, 0.02 mol) in dichloromethane (35 mL). Then the ice bath was removed and the reaction mixture was stirred at room temperature for 30 minutes. The resulting reaction mixture was diluted with ethyl acetate (200 ml), washed with water (2 × 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 solution of 10% ethyl acetate) to give white solid product 7, 2.6 g (50%). Melting point: 113.6–115.3 °C. 1 1H 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).

[0277] Step 6: At 25 °C, to a solution of amine 6 (mg, 0.94 mmol) in dimethyl sulfoxide (6 mL) was added diisopropylethylamine (0.56 mL, 2.82 mmol) and carbamate 7 (238 mg, 0.94 mmol). The reaction mixture was stirred at 55 °C for 4 h. The resulting reaction mixture was diluted with ethyl acetate (250 ml), washed with water (4 × 75 ml) and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by column (silica gel (230 - 400), petroleum ether solution of 50% ethyl acetate) to give product 8 as a white solid, 226 mg (65%). Melting point: 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-, exchangeable 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 and 159.53. MS: 363 (M + H).

[0278] Example 2: Synthesis of 4-[3-(pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid (2-phenylcyclopropyl)-amide:

[0279]

[0280] Step 1 - At room temperature, 3 - hydroxyphenylmethanol (30.0 g, 0.24 mol) and cesium carbonate (117.3 g, 0.36 mol) were added to a solution of 2 - fluoropyridine (25.8 g, 0.27 mol) in DMF (300 mL). The reaction mixture was stirred at 100 °C for 5 hours. Then the resulting mixture was allowed to reach 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 by silica gel (230 - 400) column (petroleum ether solution of 30% ethyl acetate) to give product 2 as a pale yellow oil, 34.5 g (71%). 1 1H 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).

[0281] Step 2 - Thionyl chloride (13.9 mL, 0.18 mol) was added dropwise to a solution of 2 (34.5 g, 0.17 mol) in dichloromethane (345 mL) while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. Then the volatiles were evaporated under reduced pressure and diluted with toluene (25 ml), and toluene was evaporated under reduced pressure. This azeotropic process was repeated 3 times to obtain product 3 as a brown oil (36.8 g, 98%). 1 1H 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).

[0282] Step 3 - A solution of 3 (36.7 g, 0.16 mol) in triethyl phosphite (41.6 mL, 0.26 mol) was heated at 150 °C for 6 hours. The reaction mixture was allowed to reach room temperature, and the crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 60% ethyl acetate) to give 41.33 g of product 4 as a colorless oil. The product contained unreacted triethyl phosphite and was used in the next step without further purification.

[0283] Step 4 - To a solution of diethyl [3-(pyridin-2-yloxy)-benzyl]phosphonate 4 (30.0 g, 93.0 mmol) in THF (120 mL) was added 15-crown ether (0.41 g, 1.8 mmol). The reaction was cooled (ice bath) and NaH (3.35 g, 0.14 mol) was added portionwise. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. To the above reaction mixture at ice temperature was added a solution of tert-butyl 4-oxopiperidine-1-carboxylate 5 (18.6 g, 93.0 mmol) in THF (120 mL), and the mixture was 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 by silica gel (230 - 400) column (petroleum ether solution of 3% ethyl acetate) to give 24.3 g (71%) of the product 6 as a yellow oil. 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).

[0284] Step 5 - At ice temperature, trifluoroacetic acid (51 mL) was added to a solution of tert-butyl 4-[3-(pyridin-2-yloxy)-benzylidene]piperidine-1-carboxylate 6 (12.0 g, 33.0 mmol) in dichloromethane (120.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. The brown oil 7 (13.7 g, 85%) obtained after evaporation of the volatiles was used for the next step (13.7 g, 85%) without further purification. 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).

[0285] Step 6 - At 25 °C, diisopropylethylamine (13.6 mL, 78.0 mmol) and the product of Step 5, Example 1 (6.7 g, 26.0 mmol) were added to a solution of amine 7 (15.0 g, 26.0 mmol) in dimethyl sulfoxide (150 mL). The reaction mixture was stirred at 60 °C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (1.2 L), washed with water (3 × 150 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 solution of 50% ethyl acetate) to give 9.1 g (81%) of a light yellow solid product 8. Melting point: 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-, exchangeable 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).

[0286] Example 3: Synthesis of 4-[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0287]

[0288] Step 1 - At room temperature, add 3-hydroxyphenyl-methanol (17.4 g, 0.13 mol) and potassium carbonate (26.3 g, 0.19 mol) to a solution of 5-trifluoromethyl-2-chloropyridine (23.0 g, 0.12 mol) in DMF (230 mL). Stir the reaction mixture at 100 °C for 5 hours. Then allow the resulting mixture to reach room temperature, dilute with water (200 ml), extract with ethyl acetate (3 × 400 ml), and dry the organic layer over sodium sulfate. The crude product obtained after evaporation of the volatiles is purified by silica gel (230 - 400) column (petroleum ether solution of 12% ethyl acetate) to give 28.1 g (82%) of the product 2 as a pale yellow oil. 1 H 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).

[0289] Step 2 - Dropwise add thionyl chloride (8.5 mL, 0.11 mol) to a solution of 2 (28.0 g, 0.10 mol) in dichloromethane (280 mL) while stirring the reaction in an ice bath. After removing the ice bath, stir the reaction mixture at room temperature for 1 hour. Then evaporate the volatiles under reduced pressure, dilute with toluene (15 ml), and evaporate toluene under reduced pressure. Repeat this azeotropic process 3 times to obtain 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).

[0290] Step 3 - Heat a solution of 3 (29.0 g, 0.10 mol) in triethyl phosphite (26.2 mL, 0.15 mol) at 150 °C for 6 hours. Allow the reaction mixture to reach room temperature, add the mixture to n-heptane (150 ml) to obtain a pale orange precipitate. Filter the resulting precipitate and dry it under vacuum to obtain the product 4 as a white solid (30.8 g, 94%), which is used for the next step without further purification. 11H 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).

[0291] 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). The reaction was cooled (ice bath) and NaH (2.3 g, 96.0 mmol) was added portionwise over 5 minutes. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. To the above reaction mixture at ice temperature was added a solution of tert-butyl 4-oxopiperidine-1-carboxylate 5 (12.81 g, 64.0 mmol) in THF (100 mL), and the mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water to give a white precipitate. The precipitate was filtered and dried to give product 6 as a white solid (24.4 g, 87%). 1 1H 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).

[0292] Step 5 - At ice temperature, trifluoroacetic acid (42.5 mL) was added to a solution of 6 (10.0 g, 23.0 mmol) in dichloromethane (100 mL), and the reaction mixture was stirred at room temperature for 1 hour. Then the volatiles were removed under reduced pressure to give a red oily product (10.7 g, 83%). The crude product 7 was used in the next step without further purification. 1 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).

[0293] Step 6 - At 25 °C, diisopropylethylamine (9.8 mL, 56.1 mmol) and the product of Step 5, Example 1 (4.74 g, 18.7 mmol) were added to a solution of amine 7 (10.5 g, 18.7 mmol) in dimethyl sulfoxide (10 mL). The 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 (3 × 150 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 solution of 40% ethyl acetate) to give 7.0 g (76%) of the white solid product 8. Melting point: 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 exchangeable 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). 13 C 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).

[0294] Example 4: Synthesis of 4-[3-(pyridin-2-yloxy)-benzyl]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0295]

[0296] Step 1 - At room temperature, 10% Pd / C (900 mg) was added to a methanol (17 mL) solution of the product of Step 4, Example 2(6), and the reaction mixture was stirred for 1 hour under the pressure of a hydrogen balloon. The resulting reaction mixture was filtered through a bed of diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the product 7 (850 mg, 66%) as a yellow oil. 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).

[0297] Step 2 - At ice temperature, trifluoroacetic acid (3.4 mL, 4.25 volumes) was added to a dichloromethane (8 mL) solution of ester 7 (800 mg, 2.17 mmol), and the reaction mixture was stirred at room temperature for 1 hour. Then the volatiles were removed under reduced pressure to give the product (800 mg, 74%) as a brown oil. The crude product 8 was used in the next step without further purification.

[0298] Step 3 - At 25 °C, diisopropylethylamine (0.5 mL, 2.82 mmol) and the product of Step 5, Example 1 (256 mg, 1.0 mmol) were added to a solution of the crude amine 8 (500 mg, 1.0 mmol) in dimethyl sulfoxide (10 mL). The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (250 ml), washed with water (4 × 75 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 solution of 60% ethyl acetate) to give 230 mg (53%) of the white solid product 9. Melting point: 126.8 - 128.6 °C. 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-, exchangeable 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). 13CNMR(75MHz,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).

[0299] Example 5: Chiral Separation of the Racemic Product of Example 2

[0300] The chiral column (CHIRALPACK IA 250 mm×10 mm 5 μm) was equilibrated with 15 column volumes of the mobile phase (n-hexane: isopropanol; 80:20 v / v) before elution of the compound. Then, 500 μL of the stock solution (prepared by dissolving 500 mg of the product of Example 2 in 5 ml of n-hexane and isopropanol (8:2)) was injected, and the fractions were collected according to the separation seen in the chromatogram. Fraction F1 was the first eluted fraction from the chiral column (retention time: 11.5 minutes to 13.00 minutes), and fraction F2 was the second eluted fraction from the chiral column (retention time: 13.50 minutes to 15.50 minutes). Repeated injections were performed to complete the separation of the remaining (4.5 ml) stock solution. Then, the solvents of F-1 and F-2 were removed under reduced pressure to obtain the chiral products 5A (entA) (140 mg) and 5B (entB) (150 mg), respectively.

[0301] 5A 4-[3-(Pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid {(1S,2R)-2-phenyl-cyclopropyl}-amide - HPLC: 99.98% (chiral purity: 98.55%). Melting point: 45.0 - 47.1 °C. mp: 45.0 - 47.1 °C. 1 H NMR(300MHz,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).

[0302] 5B 4-[3-(Pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid{(1R,2S)-2-phenyl-cyclopropyl}-amide - HPLC: 99.89% (Chiral purity: 98.93%). Melting point: 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).

[0303]

[0304] Example 6: Synthesis of 4-[3-(Pyrimidin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid (2-phenylcyclopropyl)-amide:

[0305]

[0306] Step 1 - At room temperature, cesium carbonate (2.6 g, 8.0 mmol) and 2-chloropyrimidine (680 mg, 6.0 mmol) were added to a solution of 3-hydroxyphenyl-methanol (500 mg, 4.0 mmol) in DMF (5 mL). The reaction mixture was stirred at 100 °C for 5 hours. Then the resulting reaction mixture was cooled to room temperature, cesium carbonate was filtered off, the filtrate was diluted with water (50 ml), extracted with ethyl acetate (100 ml), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 50% ethyl acetate) to give Product 1 as a pale yellow oil, 440 mg (54%). 1 H 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).

[0307] Step 2 - Thionyl chloride (0.19 mL, 2.6 mmol) was added dropwise to a solution of 1 (440 mg, 2.1 mmol) in dichloromethane (8 mL) 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 resulting reaction mixture was quenched with ice 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 by silica gel (230 - 400) column (petroleum ether solution of 25% ethyl acetate) to give 400 mg (83%) of the pale pink solid product 2. 1 H 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).

[0308] 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 reaction mixture was allowed to reach room temperature, and the crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 50% ethyl acetate) to give 400 mg (69%) of the white solid product 3. 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).

[0309] Step 4 - 15-Crown ether (5 μL, 0.02 mmol) was added to a solution of ester 3 (400 mg, 1.2 mmol) in THF (2.5 mL). The reaction was cooled (ice bath) and NaH (44 mg, 1.8 mmol) was added in portions. The reaction mixture was stirred at room temperature for 30 min and cooled again to ice temperature. A solution of tert-butyl 4-oxo-piperidine-1-carboxylate (250 mg, 1.2 mmol) in THF (2.5 mL) was added to the above reaction mixture at ice temperature and stirred at room temperature for 16 h. The resulting reaction mixture was diluted with 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 by silica gel (230 - 400) column (petroleum ether solution of 25% ethyl acetate) to give 360 mg (80%) of the white solid product 4.1 1H 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).

[0310] Step 5 - At ice temperature, trifluoroacetic acid (1.7 mL) was added to a solution of 4 (360 mg, 0.97 mmol) in dichloromethane (4.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. The crude product obtained after evaporating the solvent was washed with diethyl ether to give the off-white solid product 5, 0.31 g (83%), which was carried on to the next step without further purification.

[0311] Step 6 - At 25 °C, diisopropylethylamine (0.5 mL, 3.1 mmol) and the product of Step 5, Example 1 (0.58 g, 2.4 mmol) were added to a solution of amine 5 (310 mg, 0.6 mmol) in dimethyl sulfoxide (4.0 mL). The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (100 ml), washed with water (3 × 50 ml), and dried over sodium sulfate. The crude product obtained after evaporating the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 60% ethyl acetate) to give 210 mg (77%) of the white solid product 6. Melting point: 52.7–57.6 °C. 1 1H 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 exchangeable 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). 13CNMR(75MHz, 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).

[0312] Example 7: Synthesis of methyl 4-{3-[1-(2-phenyl-cyclopropylcarbamoyl)-piperidin-4-ylidene-methyl]-phenoxy}-benzoate:

[0313]

[0314] Step 1 - At room temperature, cesium carbonate (26.2 g, 80.5 mmol) and ester 1 (7.5 g, 48.3 mmol) were added to a solution of 3-hydroxyphenyl-methanol 2 (5.0 g, 40.2 mmol) in DMF (50 mL). The reaction mixture was stirred at 100 °C for 5 h. Then the resulting reaction mixture was allowed to reach room temperature and filtered to remove cesium carbonate. The filtrate was diluted with water (200 ml), extracted with ethyl acetate (2 × 250 ml), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 30% ethyl acetate) to give a pale yellow oily product 3, 3.2 g (31%). 1 H NMR(300MHz, 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).

[0315] Step 2 - Thionyl chloride (1.7 mL, 14.8 mmol) was added dropwise to a solution of alcohol 3 (3.2 g, 12.3 mmol) in dichloromethane (50 mL) 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 resulting reaction mixture was quenched with ice 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 by silica gel (230 - 400) column (petroleum ether solution of 5% ethyl acetate) to give a colorless oily product 4, 2.3 g (67%). 11H 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).

[0316] Step 3 - A solution of compound 4 (2.3 g, 7.9 mmol) in triethyl phosphite (2.3 mL, 11.9 mmol) was heated at 150 °C for 6 h. The reaction mixture was allowed to reach room temperature, and the crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 50% ethyl acetate) to give 3.5 g (91%) of product 5 as a pale yellow oil. 1 1H 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).

[0317] Step 4 - 15-Crown-5 ether (40 μL, 0.18 mmol) was added to a solution of 5 (3.5 g, 9.2 mmol) in THF (20 mL). The reaction was cooled (ice bath) and NaH (560 mg, 13.8 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 30 min and then cooled again to ice temperature. A solution of tert-butyl 4-oxopiperidine-1-carboxylate 6 (1.9 g, 9.2 mmol) in THF (15 mL) was added to the above reaction mixture at ice temperature and the mixture was stirred at room temperature for 16 h. The resulting reaction mixture was quenched with saturated ammonium chloride (50 ml), extracted with ethyl acetate (500 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 solution of 10% ethyl acetate) to give 1.8 g (46%) of product 7 as a white solid. 1 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).

[0318] Step 5 - At ice temperature, trifluoroacetic acid (9.0 mL) was added to a solution of tert-butyl ester 7 (1.8 g, 4.2 mmol) in dichloromethane (18.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. The crude product obtained after evaporating the solvent was washed with n-hexane to give product 8 as a viscous 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).

[0319] Step 6 - At 25 °C, diisopropylethylamine (2.0 mL, 10.2 mmol) and the product of Step 5, Example 1 (0.86 g, 3.4 mmol) were added to a solution of amine 8 (1.5 g, 3.4 mmol) in dimethyl sulfoxide (15.0 mL). The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (250 ml), washed with water (2 × 100 ml), and dried over sodium sulfate. The crude product obtained after evaporating the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 25% ethyl acetate) to give product 9 as a white solid, 0.9 g (54%). Melting point: 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), 6.36 (s, 1H), 6.84 (bs, 1H, CONH exchangeable 1 H), 6.94 - 7.26 (m, 10H), 7.42 (t, J = 7.8 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H). 1313C NMR(75MHz, 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).

[0320] Example 8: Synthesis of 4-{3-[1-(2-phenyl-cyclopropylcarbamoyl)-piperidin-4-ylidene-methyl]-phenoxy}-benzoic acid:

[0321]

[0322] At 25 °C, an aqueous solution of sodium hydroxide (120 mg, 3.1 mmol) in water (2.0 mL) was added to a solution of the product of Step 6, Example 7 (0.5 g, 1.03 mmol) in methanol (3.0 mL). The reaction mixture was stirred at 55 °C for 16 h. The crude product obtained after evaporation of the solvent was diluted with water (20.0 ml), and the aqueous layer was washed with ethyl acetate (2 × 20 ml). The aqueous layer was then acidified (pH = 2, 1.0 N HCl), saturated with solid 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 350 mg (72%) of the product as a white solid. Melting point: 99.4 - 102.5 °C. 1 1H NMR(300MHz, 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 exchangeable 1 H), 6.93 - 7.44 (m, 11H), 7.95 (d, J = 8.4 Hz, 2H), 12.83 (bs, 1H). 1313C 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).

[0323] Example 9: Synthesis of 4-(3-pyrrolidin-1-yl-benzyl)-piperidine-1-carboxylic acid-(2-phenyl-cyclopropyl)-amide:

[0324]

[0325] 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 and brought to room temperature. The crude product obtained after evaporation of the volatiles was purified by column chromatography on silica gel (230 - 400) (petroleum ether solution of 30% ethyl acetate) to give 6.5 g (89%) of the product 2 as a colorless oil. 1 1H 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).

[0326] Step 2 - 15-Crown ether (0.04 mL, 0.19 mmol) was added to a solution of 2 (3.0 g, 9.7 mmol) in THF (20 mL). 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 min and then cooled again to ice temperature. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.95 g, 9.7 mmol) in THF (10 mL) was added to the above reaction mixture at ice temperature and the mixture was stirred at room temperature for 16 h. The resulting reaction mixture was diluted with water (100 ml), extracted with ethyl acetate (3 × 100 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by column chromatography on silica gel (230 - 400) (petroleum ether solution of 5% ethyl acetate) to give 1.8 g (53%) of the product 3 as a yellow oil. 11H 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).

[0327] Step 3 - Under an argon atmosphere and at room temperature, pyrrolidine (0.9 mL, 10.6 mmol), cesium carbonate (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 to a solution of compound 3 (2.0 g, 7.0 mmol) in 1,4 - dioxane (20.0 mL). The reaction mixture was stirred at room temperature for 30 minutes and then at reflux for 16 hours. The resulting reaction mixture was filtered through a Celite pad 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 (petroleum ether solution of 15% ethyl acetate) to give 0.6 g (32%) of product 4 as a pale yellow oil. 1 1H 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).

[0328] Step 4 - 10% Pd / C (240 mg) was added to a solution of compound 4 (0.6 g, 1.7 mmol) in tetrahydrofuran (10.0 mL). At room temperature, under a hydrogen pressure of 1 kg / cm 2 ) the reaction mixture was stirred for 2 hours. After releasing the hydrogen pressure, the reaction mixture was filtered through a Celite pad, washed with tetrahydrofuran, and the filtrate was concentrated to give 0.6 g of product 5 as a pale yellow liquid. 11H 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).

[0329] Step 5 - At ice temperature, trifluoroacetic acid (3 mL) was added to a solution of compound 5 (0.6 g, 1.7 mmol) in dichloromethane (6.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. The brown oil 6 (0.6 g) obtained after evaporating the volatiles was used in the next step without further purification.

[0330] Step 6 - At 25 °C, N,N-diisopropylethylamine (1.1 mL, 5.8 mmol) and the product of Step 5, Example 1 (0.5 g, 1.9 mmol) were added to a solution of amine 6 (600 mg, 1.9 mmol) in dimethyl sulfoxide (6.0 mL). 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 evaporating the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 40% ethyl acetate) and preparative HPLC (Phenomenex 250 × 22 1.20 mm, 10 μm, mobile phase solution of water and acetonitrile with 0.1% TFA) to give a pale yellow solid product 7, 160 mg (23%). Melting point: 145.6 °C – 151.5 °C. IR: 3334, 2842, 1620, 1600, 1545, 1252 and 752 cm -1 。 11H 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), 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).

[0331] Example 10: Synthesis of (2-Phenyl-cyclopropyl)-4-(3-morpholin-4-yl-benzyl)-piperidine-1-carboxamide:

[0332]

[0333] Step 1 - Under an argon atmosphere, at room temperature, to a solution of the product from Step 2, 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 (4.1 g, 12.6 mmol), racemic BINAP (0.52 g, 0.84 mmol) and palladium acetate (0.56 g, 0.84 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then under reflux for 16 hours. The resulting reaction mass was cooled and filtered through a pad of diatomaceous earth, 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 (petroleum ether solution of 15% ethyl acetate) to give 0.35 g of a crude product 2 as a pale yellow oil.

[0334] Step 2 - To a solution of compound 2 (0.85 g, 2.37 mmol) in tetrahydrofuran (10.0 mL) was added 10% Pd / C (350 mg). The reaction mass was stirred at room temperature under a hydrogen pressure (1 kg / cm 2 ) for 2 hours. After releasing the hydrogen pressure, the reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated to give a pale yellow liquid product 3 (0.8 g). The product was carried on to the next step without further purification.

[0335] Step 3 - Under cryogenic temperature, trifluoroacetic acid (4 mL) was added to a solution of crude compound 3 (0.8 g, 2.2 mmol) in dichloromethane (8.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. The brown oil 4 (0.8 g) obtained after evaporating the volatiles was carried on to the next step without further purification.

[0336] At 25 °C, diisopropylethylamine (1.3 mL, 7.0 mmol) and the product of Step 5, Example 1 (0.6 g, 2.3 mmol) were added to a solution of amine 4 (800 mg, 2.3 mmol) in dimethyl sulfoxide (8.0 mL). 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 (3 × 100 mL), and dried over sodium sulfate. The crude product obtained after evaporating the volatiles was purified by column chromatography on silica gel (230 - 400) (petroleum ether solution of 50% ethyl acetate) to give 420 mg of a light yellow solid product 5. Melting point: 182.3 °C - 186.0 °C. IR: 3330, 2841, 1620, 1600, 1545, 1247 and 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 D2O exchangeable), 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).

[0337] Example 11: Synthesis of 4-[3-(pyridin-2-yloxy)-phenoxy]-piperidine-1-carboxylic acid (2-phenylcyclopropyl)-amide:

[0338]

[0339] Step 1 - To a solution of 1,3-dihydroxybenzene (1.0 g, 9.0 mmol) in DMF (10.0 mL) were added Cs2CO3 (5.92 g, 18.0 mmol) and 2-fluoropyridine (0.8 mL, 9.0 mmol). The reaction mixture was heated to 100 °C for 16 h. Then the resulting mixture was allowed to reach 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 by silica gel (230 - 400) column (petroleum ether solution of 10% ethyl acetate) to give the product as a pale yellow oil, 400 mg (23%). 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 6.20 (s, 1H), 6.48 - 6.53 (m, 1H), 6.61 (d, J = 8.1 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 7.11 - 7.21 (m, 2H), 7.84 (t, J = 8.1 Hz, 1H), 8.18 (bs, 1H), 9.61 (s, 1H, D2O-exchangeable 1 H). MS: 187.9 (M+H).

[0340] Step 2 - At room temperature, 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). The reaction mixture was stirred for 5 min, then a solution of 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 h. The reaction mixture was diluted with ethyl acetate (300 ml), washed with water (3 × 50 ml), and the ethyl acetate layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 50% ethyl acetate) to give the product as a pale yellow oil, 540 mg (67%). 11H 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).

[0341] Step 3 - At ice temperature, trifluoroacetic acid (2.0 mL) was added to a solution of compound 5 (0.4 g, 0.8 mmol) in dichloromethane (8.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. The brown oil 6 obtained after evaporating the volatiles was used in the next step without further purification.

[0342] At 25 °C, diisopropylethylamine (0.67 mL, 3.9 mmol) and the product of Step 5, Example 1 (198 mg, 0.78 mmol) were added to a solution of amine 6 (390 mg, 0.78 mmol) in dimethyl sulfoxide (5.0 mL). 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 (3 × 10 mL), and dried over sodium sulfate. The crude product obtained after evaporating the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 70% ethyl acetate) to obtain an off-white low melting point solid product. The obtained product was further purified by preparative HPLC to obtain product 7 as an off-white low melting point solid, 200 mg. Melting point: 43.9 °C–46.8 °C. IR: 3313, 1621, 1586, 1423 and 1235 cm -1 . 1 1H 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 1H), 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).

[0343] Example 12: Synthesis of 4-[3-(1H-pyrazol-4-yl)-benzyl]-piperidine-1-carboxylic acid (-2-phenylcyclopropyl)-amide:

[0344]

[0345] 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). The resulting reaction mixture was stirred at room temperature for 12 h. 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 crude product obtained was purified by silica gel column chromatography (petroleum ether solution of 15% ethyl acetate) to give a pale gray solid product 2, 1.25 g (40%). 1 1H 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).

[0346] Step 2 - At room temperature, to a solution of the compound product of Step 2, Example 9 (1.0 g, 2.8 mmol) in DMF (10 mL) was added Compound 2 (1.9 g, 5.6 mmol) and 2N sodium carbonate solution (4.3 mL, 8.5 mmol). The reaction mixture was stirred for 10 min under an argon atmosphere. Then, palladium(0) tetrakis(triphenylphosphine) (0.33 g, 0.28 mmol) was added to the reaction mixture under argon. The resulting reaction mixture was stirred at room temperature for 16 h. 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 with sodium sulfate and concentrated. The crude product obtained after evaporating the solvent under reduced pressure was purified by silica gel column chromatography (petroleum ether solution of 40% ethyl acetate) to give a pale gray solid product 3, 550 mg (57%). 11H 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 = 7.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.44 - 7.47 (m, 2H), 7.92 (s, 1H), 8.19 (s, 1H), 12.94 (s, 1H). MS: 338.1 (M-H).

[0347] Step 3 - To a solution of compound 3 (0.5 g, 1.4 mmol) in chloroform (10.0 mL) containing 20% methanol was added 10% Pd / C (200 mg). The reaction mixture was stirred at room temperature under a hydrogen pressure of 1 kg / cm 2 2) for 24 h. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated to give a pale yellow liquid product 4 (0.5 g). The crude product was used in the next step without further purification.

[0348] Step 4 - At ice temperature, trifluoroacetic acid (2.5 mL) was added to a solution of compound 4 (0.5 g, 1.6 mmol) in dichloromethane (5.0 mL), and the reaction mixture was stirred at room temperature for 1 h. The brown oil 5 (0.5 g) obtained after evaporation of the volatiles was used in the next step without additional purification.

[0349] Step 5 - At 25 °C, N,N-diisopropylethylamine (0.8 mL, 4.2 mmol) and the product of Step 5, Example 1 (270 mg, 1.0 mmol) were added to a solution of amine 5 (500 mg, 1.0 mmol) in dimethyl sulfoxide (5.0 mL). 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 (chloroform solution containing 3% methanol) to give product 6 as an off-white solid, 210 mg. Melting point: 157.4 °C – 163.4 °C. IR: 3330, 1619, 1545, 1475 and 753 cm -1 . 1 1H 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 = 2.7 Hz, 1H, D2O exchangeable 1H), 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, exchangeable with D2O 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).

[0350] Example 13: Synthesis of 4-[3-(1-Methyl-1H-pyrazol-4-yl)-benzyl]-piperidine-1-carboxylic acid (2-phenylcyclopropyl)-amide:

[0351]

[0352] Step 1 - Sodium hydride (0.25 g, 6.1 mmol) and methyl iodide (0.4 mL, 6.1 mmol) were added to a cooled (0 - 5 °C) solution of the product from Step 2, Example 12 (0.7 g, 2.0 mmol) in THF (25 mL). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (100 ml) and 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 (petroleum ether solution of 20% ethyl acetate) 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 (M - t-butyl + H).

[0353] Step 2 - To a solution of Compound 1 (0.6 g, 1.7 mmol) in chloroform (10.0 mL) containing 20% methanol was added 10% Pd / C (240 mg). At room temperature, under a hydrogen pressure (1 kg / cm 2 ), the reaction mixture was stirred for 16 h. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated to give Product 2 as a pale yellow liquid (0.6 g, 98%). The resulting product was carried on 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 (M - t-butyl + H).

[0354] Step 3 - At ice temperature, trifluoroacetic acid (3.0 mL) was added to a solution of Compound 2 (0.6 g, 1.6 mmol) in dichloromethane (6.0 mL), and the reaction mixture was stirred at room temperature for 1 h. The brown oil 3 (0.6 g) obtained after evaporation of the volatiles was used for the next step without additional purification.

[0355] Step 4 - At 25 °C, diisopropylethylamine (1.2 mL, 6.4 mmol) and the product of Step 5, Example 1 (370 mg, 1.4 mmol) were added to a solution of Amine 3 (600 mg, 1.6 mmol) in dimethyl sulfoxide (6.0 mL). 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 (chloroform solution containing 3% methanol) to give the off-white solid Product 4, 350 mg (53%). Melting point: 158.4 °C – 160.3 °C. IR: 3353, 1619, 1544, 1473 and 752 cm -1 . 11H 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), 3.90 (d, J = 13.2 Hz, 2H), 6.71 (d, J = 2.7 Hz, 1H, exchangeable with D2O 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 13C 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).

[0356] Example 14: Synthesis of 4-(3-benzimidazol-1-yl-benzyl)-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0357]

[0358] 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 crude product obtained after evaporation of the volatiles was purified by column chromatography on silica gel (230 - 400) (petroleum ether solution of 50% ethyl acetate) to give 4.9 g (89%) of product 2 as a pale yellow oil. 1 1H 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).

[0359] 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 portionwise. The reaction mixture was stirred at room temperature for 30 minutes and cooled again to ice temperature. To the above reaction mixture at ice temperature was added a solution of tert-butyl 4-oxopiperidine-1-carboxylate (4.05 g, 20.3 mmol) in THF (10 mL), and the mixture was 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 crude product obtained after evaporation of the volatiles was purified by column (silica gel (230 - 400), petroleum ether solution of 5% ethyl acetate) to give 4.0 g (62%) of the product 3 as a yellow oil. 1 HNMR (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 (M - t-Butyl + 1).

[0360] Step 3 - To a solution of Compound 3 (4.0 g, 12.5 mmol) in dichloromethane (40.0 mL) containing 90% methanol was added 10% Pd / C (3.0 g). The reaction mass was stirred at room temperature under a hydrogen pressure (1 kg / cm 2 ) for 20 hours. The reaction mass was filtered through a diatomaceous earth pad, and the filtrate was concentrated to give the product 4 as a light yellow liquid (1.5 g, 41%). The 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).

[0361] Step 4 - At room temperature, Cs2CO3 (8.9 g, 25.7 mmol) was added to a solution of compound 4 (1.5 g, 3.4 mmol) in DMF (8.0 mL). The reaction mixture was stirred for 5 minutes, and then a solution of 1-fluoro-2-nitrobenzene (0.8 g, 3.7 mmol) in DMF (2.0 mL) was added to the reaction mixture at room temperature. The mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with water (3 × 100 mL). The ethyl acetate layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 7% ethyl acetate) to give product 5 as a red-yellow oil, 500 mg (35%). 1 H 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 (M-H).

[0362] Step 5 - At room temperature of 25 °C, sodium formate (290 mg, 4.3 mmol) and Pd / C (10 mol%, 120 mg, 0.01 mmol) were added to a solution of compound 5 (500 mg, 1.2 mmol) in formic acid (10 mL). Then the reaction mixture was stirred at 110 °C for 18 hours. The reaction mixture was cooled to room temperature and then filtered through diatomaceous earth with the help of 20 ml of formic acid. The crude product obtained after evaporation of the volatiles was dissolved in dichloromethane (50 ml) with 5% methanol, and the inorganic salts were removed by filtration. The filtrate was concentrated to give product 6 as an off-white solid (350 mg). The crude product was sent directly to the next step without purification.

[0363] Step 6 - At 25 °C, diisopropylethylamine (1.03 mL, 6.0 mmol) and the product of Step 5, Example 1 (186 mg, 1.2 mmol) were added to a solution of amine 6 (350 mg, 1.2 mmol) in dimethyl sulfoxide (5.0 mL). 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 after evaporation of the volatiles was purified by silica gel (230 - 400) column (dichloromethane solution of 1.5% methanol) to give product 7 as an off-white solid, 170 mg (31%). Melting point: 72.5 °C – 76.4 °C. IR: 3347, 2931, 16161, 1542 and 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 = 2.7 Hz, 1H, D2O exchangeable 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).

[0364] Example 15: Synthesis of 4-(3-pyrrolidin-1-yl-benzylidene)-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0365]

[0366] Step 1 - Under an argon atmosphere at room temperature, pyrrolidine (0.9 mL, 10.6 mmol), cesium carbonate (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 to a solution of the product of Step 2, Example 9 (2.0 g, 7.0 mmol) in 1,4-dioxane (20.0 mL). The reaction mixture was stirred at room temperature for 30 minutes and then under reflux for 16 hours. The resulting reaction mass was filtered through a celite pad 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 (petroleum ether solution of 15% ethyl acetate) to obtain the product 2 as a pale yellow oil, 0.6 g (32%). 1 1H 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).

[0367] Step 2 - At ice temperature, trifluoroacetic acid (3 mL) was added to a solution of compound 2 (0.6 g, 1.7 mmol) in dichloromethane (6.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. The brown oil 3 (0.6 g) obtained after evaporation of the volatiles was used for the next step without further purification.

[0368] Step 3 - At 25 °C, diisopropylethylamine (1.1 mL, 5.8 mmol) and the product of Step 5, Example 1 (0.5 g, 1.9 mmol) were added to a solution of amine 3 (600 mg, 1.9 mmol) in dimethyl sulfoxide (6.0 mL). 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 solution of 40% ethyl acetate) to obtain the product 4 as an off-white solid, 300 mg (42%). Melting point: 145.7 °C – 147.4 °C. IR: 3292, 2963, 1626, 1533, 1263, and 746 cm -1 . 11H 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), 2.88 (bs, 1H), 3.30 (bs, 4H), 3.36 - 3.40 (m, 2H), 3.47 - 3.51 (m, 2H), 4.87 (bs, 1H, exchangeable with D2O 1 H), 6.38 - 6.52 (m, 3H), 7.19 - 7.46 (m, 7H). 13 13C 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).

[0369] Example 16: Synthesis of phenyl N-[(1R,2S)-2-phenylcyclopropyl]carbamate:

[0370]

[0371] The above chiral intermediate was synthesized using the conventional method described in the literature (WO 2013 / 057322).

[0372] Step 1 - At 0 - 5 °C, saturated sodium bicarbonate solution was added to a suspension of trans-2-phenyl-cyclopropylamine hydrochloride (100 g, 0.59 mol) in water (500 mL) over 20 minutes and the mixture was basified to pH > 7. The reaction mixture was stirred at 25 - 30 °C for 2 hours. The reaction mixture was extracted with dichloromethane (3 × 700 ml), 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%).

[0373] Step 2 - At 0 - 5 °C, L-(+)-tartaric acid (79 g, 0.52 mol) was added to a solution of trans-2-phenyl-cyclopropylamine (70 g, 0.52 mol) in ethanol (700 mL), and the mixture was stirred at 25 - 30 °C for 1 h. After the reaction was completed, the solid was filtered and dried to obtain 2-phenyl-cyclopropylamine in the form of tartrate (133 g). Isopropanol:water (3:1) (1.3 L) was added to the above salt (130 g), and the mixture was stirred at 70 °C for 2 h. The reaction mixture was cooled to room temperature within 1 h. The separated solid was collected by filtration to obtain the white solid (1R,2S)-N-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-2-phenylcyclopropan-1-ammonium (3) (60 g, 90%).

[0374] Step 3 - At 0 - 5 °C, 1.0 M sodium hydroxide (194 mL, 0.19 mol) was added to a solution of (1R,2S)-N-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-2-phenylcyclopropan-1-ammonium (3) (60 g, 0.19 mol) in water (200 mL) within 20 min, and the mixture was stirred for 1 h. 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 obtain (1R,2S)-2-phenyl-cyclopropylamine as a light yellow solid 4 (25 g, 87%).

[0375] Step 4 - At ice bath temperature, triethylamine (36.0 mL, 0.26 mol) and phenyl chloroformate (20.7 g, 0.13 mol) were added to a suspension of amine 4 (15.0 g, 88.0 mmol) in dichloromethane (150 mL). Then the ice bath was removed, and the reaction mixture was stirred at room temperature for 1 h. 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 by silica gel (230 - 400) column (petroleum ether solution of 10% ethyl acetate) to obtain 16.0 g (71%) of white solid product 5. 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.

[0376] Step 5 - At 0 - 5 °C, 2.0 M HCl in diethyl ether solution (140 mL, 0.28 mol) was added to a stirred solution of (1R,2S)-2-phenyl-cyclopropylamine 4 (25.0 g, 0.19 mol) in diethyl ether (150 mL). The reaction mixture was stirred at 20 - 25 °C for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting reaction mass was washed with diethyl ether (2 × 100 ml) to give the product 6, the hydrochloride salt of (1R,2S)-2-phenyl-cyclopropylamine, as an off-white solid, 30.0 g (95%). Melting point: 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 further confirmed by matching the analytical and spectral data with an authentic sample of (1R,2S)-2-phenylcyclopropylamine hydrochloride purchased from Sigma-Aldrich.

[0377] Example 17: Synthesis of 4-[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid [(1S,2R)-2-phenyl-cyclopropyl]-amide:

[0378]

[0379] Step 1 - At ice bath temperature, triethylamine (1.21 mL, 8.85 mol) and phenyl chloroformate 1 (0.41 mL, 3.3 mol) were added to a suspension of (1S,2R)-2-phenylcyclopropan-1-amine 2 (500 mg, 2.95 mmol) in dichloromethane (5.0 mL). Then the ice bath was 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 (2 × 200 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 solution of 10% ethyl acetate) to give 500 mg (71%) of the white solid product 3. 11H 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.

[0380] Step 2 - At 25 °C, diisopropylethylamine (1.2 mL, 6.6 mmol) and 3 (556 mg, 2.2 mmol) were added to a solution of the product of Step 5, Example 3 (1.0 g, 2.2 mmol) in dimethyl sulfoxide (10 mL). The reaction mixture was stirred at 60 °C for 4 h. The resulting reaction mixture was diluted with ethyl acetate (300 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 solution of 40% ethyl acetate) to give 770 mg (70%) of the white solid product 4. Melting point: 100.2 °C - 101.0 °C. IR: 3329, 1622, 1531, 1487, 1329, 1076 cm -1 . 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 = 5.2 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%.

[0381] Example 18: Synthesis of 4-[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid [(1R,2S)-2-phenyl-cyclopropyl)]-amide:

[0382]

[0383] Step 1 - At an ice bath temperature, add triethylamine (1.21 mL, 8.85 mmol) and phenyl chloroformate 1 (0.41 mL, 3.3 mmol) to a suspension of (1R,2S)-2-phenyl-cyclopropylamine 2 (500 mg, 2.95 mmol) in dichloromethane (5.0 mL). Then remove the ice bath and stir the reaction mixture at room temperature for 1 hour. The resulting reaction mixture is diluted with ethyl acetate (250 ml), washed with water (2 × 100 ml), and dried over sodium sulfate. The crude product obtained after evaporating the volatiles is purified by a silica gel (230 - 400) column (petroleum ether solution of 10% ethyl acetate) to obtain 495 mg (70%) of a white solid product 3. 1 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.

[0384] Step 2 - At 25 °C, add diisopropylethylamine (1.2 mL, 6.6 mmol) and 3 (556 mg, 2.2 mmol) to a solution of the product of Step 5, Example 3 (1.0 g, 2.2 mmol) in dimethyl sulfoxide (10 mL). Stir the reaction mixture at 60 °C for 4 h. The resulting reaction mixture is diluted with ethyl acetate (300 ml), washed with water (3 × 100 ml), and dried over sodium sulfate. The crude product obtained after evaporating the volatiles is purified by a silica gel (230 - 400) column (petroleum ether solution of 40% ethyl acetate) to obtain 715 mg (65%) of a white solid product 4. Melting point: 101.8 °C - 103.2 °C. IR: 3329, 1623, 1531, 1388, 1329, 1076, 697 cm -1 。 1 1H 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), 2.69 - 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%.

[0385] Example 19: Synthesis of 4-({3-[(5-methylpyridin-2-yl)oxy]phenyl}methylene)-N-[2-phenylcyclopropyl]piperidine-1-carboxamide:

[0386]

[0387] Step 1 - At room temperature, 3-hydroxyphenyl-methanol (15.0 g, 0.12 mol) and cesium carbonate (59.0 g, 0.18 mol) were added to a solution of 2-fluoro-5-methyl-pyridine 1 (14.76 g, 0.13 mol) in DMF (150 mL). The reaction mixture was stirred at 100 °C for 5 h. Then the resulting 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 by silica gel (230 - 400) column (petroleum ether solution of 30% ethyl acetate) to give the product 2 as a pale yellow oil, 6.0 g (23%). 1 1H 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, J = 7.5 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.66–7.69 (m, 1H), 7.98 (d, J = 2.1 Hz, 1H). MS: (M + H) 216.2.

[0388] Step 2 - Thionyl chloride (2.3 mL, 0.03 mol) was added dropwise to a solution of [3-(5-methyl-pyridin-2-yloxy)-phenyl]-methanol 2 (6.0 g, 0.027 mol) in dichloromethane (60 mL) while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 h. Then the volatiles were evaporated under reduced pressure and diluted with toluene (25 ml), and toluene was evaporated under reduced pressure. This azeotropic process was repeated 3 times to give the product 3 as a light brown oil (6.2 g, 95%). 1 1H 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.

[0389] 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 reach room temperature, and the crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 60% ethyl acetate) to give 8.3 g of the product as a light yellow oil. The product contained unreacted triethyl phosphate and was used in the next step without further purification. 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.

[0390] Step 4 - 15-Crown ether (0.1 g, 0.48 mmol) was added to a solution of diethyl [3-(5-methyl-pyridin-2-yloxy)-benzyl]-phosphonate 4 (8.3 g, 0.024 mol) in THF (40 mL). 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 then cooled again to ice temperature. A solution of tert-butyl 4-oxo-piperidine-1-carboxylate (4.9 g, 0.024 mol) in THF (40 ml) was added to the above reaction mixture at ice temperature and the mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (250 ml), extracted with ethyl acetate (3 × 500 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 solution of 3% ethyl acetate) to give 6.7 g (76%) of the product as a light yellow oil. 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.

[0391] Step 5 - At ice temperature, trifluoroacetic acid (27 mL) was added to a solution of tert-butyl 4-[3-(5-methylpyridin-2-yloxy)benzylidene]piperidine-1-carboxylate 5 (6.7 g, 0.017 mol) in dichloromethane (67.0 mL), and the reaction mixture was stirred at room temperature for 1 h. The product 6 (6.96 g) obtained after evaporation of the volatiles was used in the next step without further purification. 1 HNMR (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.

[0392] Step 6 - At 25 °C, diisopropylethylamine (4.2 mL, 22.0 mmol) and the product of Step 5, Example 1 (1.93 g, 7.0 mmol) were added to a solution of amine 6 (3.0 g, 7.0 mmol) in dimethyl sulfoxide (30 mL). 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 silica gel (230 - 400) column (petroleum ether solution of 50% ethyl acetate) to give the off-white solid product 7, 2.33 g (70%). Melting point: 87.8 °C - 91.0 °C. IR: 3250, 2895, 1624, 1425, 1263, 848, 774 cm -1 . 1 H 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.

[0393] Example 20: Synthesis of 4-[3-(pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid [2-(4-methyl)phenyl-cyclopropyl]-amide:

[0394]

[0395] Step 1 - Ammonium acetate (13.4 g, 0.17 mol) was added to acetic acid (100 mL) and stirred until completely dissolved. Then nitromethane (30.46 g, 0.49 mol) was added to the reaction mixture, followed by 4-methylbenzaldehyde (9.82 mL, 0.083 mol). The reaction mixture was refluxed at 100 °C for 6 hours. The reaction mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was quenched with 2 M aqueous sodium hydroxide (pH = 7) and extracted with ethyl acetate (2 × 300 ml), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was washed with hexane to give the yellow solid product 2 (10 g, 74%). 1 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 (M - H) 162.9.

[0396] Step 2 - Trimethyloxosulfonium iodide (6.7 g, 0.03 mol) was added to a solution of 60% dispersion of sodium hydride in mineral oil (0.98 g, 0.024 mol) in dimethyl sulfoxide (10 mL) and stirred at room temperature for 30 minutes. Then a solution of 2 (2 g, 0.012 mol) in dimethyl sulfoxide (10 ml) was added and the reaction mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was quenched with water (100 ml), extracted with ethyl acetate (2 × 300 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by column (230 - 400 mesh) of silica gel (hexane solution of 2% ethyl acetate) to give the light yellow oily product 3 (300 mg, 14%). 1 1H 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.

[0397] Step 3 - Hydrochloric acid (6.2 mL of 2.7 N solution, 0.0169 mol) was added to a solution of 3 (0.3 g, 0.0016 mol) in isopropanol (12 mL), and then zinc powder (1.1 g, 0.0169 mol) was added in portions. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was neutralized with 10% sodium hydroxide solution and filtered through a bed of diatomaceous earth. The filtrate was diluted with ethyl acetate (150 ml), washed with water (50 ml) and brine solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400 mesh) column (chloroform solution of 2% methanol) to give the yellow oily product 4 (150 mg, 60%). 1 1H 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.

[0398] Step 4 - Triethylamine (0.17 mL, 0.0012 mol) and phenyl chloroformate (115 mg, 0.0007 mol) were added to a solution of 4 (90 mg, 0.0006 mol) in dichloromethane (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The resulting reaction mixture 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 the volatiles was purified by silica gel (230 - 400 mesh) column (hexane solution of 10% ethyl acetate) to give the white solid product 5 (30 mg, 18%). 1 1H 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.

[0399] Step 5 - Trifluoroacetic acid (4 mL) was added to a solution of the product of Step 4, Example 2 (1.0 g, 0.002 mol) in dichloromethane (10 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The product 7 (1.3 g, 97%) obtained after evaporation of the volatiles was used for the next step without further purification.

[0400] Step 6 - At room temperature, diisopropylethylamine (0.59 mL, 0.0034 mol) and 5 (0.16 g, 0.0006 mol) were added to a solution of 7 (0.29 g, 0.0006 mol) in dimethyl sulfoxide (3 mL). The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture 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 by silica gel (230 - 400 mesh) column (hexane solution of 40% ethyl acetate) to give an off-white solid product 8 (180 mg, 69%). Melting point: 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。

[0401] Example 21: Synthesis of 4-[3-(pyrimidin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid [(1R,2S)-2-phenyl-cyclopropyl]-amide:

[0402]

[0403] Step 1 - At 25 °C, add diisopropylethylamine (4.13 mL, 23.6 mmol) and 2 (the product of Step 4 of Example 16 (2.0 g, 7.89 mmol)) to a solution of Amine 1 (the product of Step 5 of Example 6 (3.02 g, 7.89 mmol)) in dimethyl sulfoxide (30.0 mL). Stir the reaction mixture at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (300 ml), washed with water (3 × 150 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 solution of 60% ethyl acetate) to give 2.3 g (70%) of a white solid product 3. Melting point: 62.8 - 65.2 °C. IR: 3627, 3310, 1732, 1629, 1570, 1526, 1310, 1249, 1148, 753, 696 cm -1 . 1 H 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, J = 7.4, 3.7 Hz, 1H), 3.31 (d, J = 5.9 Hz, 2H), 3.39 (d, J = 5.9 Hz, 2H), 6.37 (s, 1H), 6.84 (d, J = 3.1 Hz, 1H), 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 purity: 99.79%. Chiral HPLC purity: 99.92%. Optical rotation: -1.190. Specific rotation: -111.71.

[0404] Example 22: Synthesis of 4-[3-(5-methyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0405]

[0406] Step 1 - At 25 °C, to a solution of Amine 1, the product of Step 5, Example 19 (3.0 g, 7.0 mmol) in dimethyl sulfoxide (30 mL), diisopropylethylamine (4.2 mL, 22.0 mmol) and the product of Step 4, Example 16 (1.93 g, 7.0 mmol) were added. 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 silica gel (230 - 400) column (petroleum ether solution of 50% ethyl acetate) to give 2.7 g (81%) of a pale yellow solid product 3. Melting point: 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%.

[0407] Example 23: Synthesis of 4-[3-(pyrimidin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid methyl-((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0408]

[0409] Step 1 - At 0 - 5 °C, sodium hydride (4.13 mL, 23.6 mmol) and methyl iodide (2.0 g, 7.89 mmol) were added to a solution of the product of 1 and Example 21 (150 mg, 7.89 mmol) in dimethylformamide (30.0 mL). The reaction mixture was stirred at 25 - 30 °C for 1 hour. The resulting reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (2 × 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 solution of 25% ethyl acetate) to give 77 mg (50%) of a pale yellow solid 2. 1 1H 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), 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%.

[0410] Example 24: Synthesis of 4-[3-(5-methyl-pyrazin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0411]

[0412] Step 1 - At room temperature, 3-hydroxybenzyl alcohol (11.6 g, 0.094 mol) and cesium carbonate (76.0 g, 0.23 mol) were added to a solution of 2-chloro-5-methyl-pyrazine (10 g, 0.078 mol) in DMF (100 mL). The reaction mixture was stirred at 100 °C for 5 hours. Then the resulting mixture was allowed to reach 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 by silica gel (230 - 400) column (petroleum ether solution of 30% ethyl acetate) to give 6.8 g (40%) of a pale yellow oily product 1. 11H 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.

[0413] Step 2 - In an ice bath, thionyl chloride (2.3 mL, 0.03 mol) was added dropwise to a solution of 1 (6.0 g, 0.027 mol) in dichloromethane (60 mL) while stirring the reaction mixture. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. Then the volatiles were evaporated under reduced pressure and the residue was diluted with toluene (25 ml), and the toluene was evaporated under reduced pressure. This azeotropic process was repeated 3 times to obtain the product 2 (6.2 g) as a light brown oil. The crude product was used in the next step without further purification. MS (M+H) 235.3.

[0414] Step 3 - A solution of 2 (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 cooled to room temperature, and the crude product obtained after evaporation of the volatiles was purified by column chromatography on silica gel (230 - 400) (petroleum ether solution of 60% ethyl acetate) to obtain the product 3, 8.3 g as a light yellow oil. 1 1H 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, 2H), 7.13 - 7.15 (m, 1H), 7.36 (t, J = 7.8 Hz, 1H), 8.09 (dd, J = 1.4 Hz, 0.7 Hz, 1H), 8.39 (d, J = 1.4 Hz, 1H). MS (M+H) 337.1.

[0415] Step 4 - Add 15-crown ether (0.1 g, 0.48 mmol) to a solution of 3 (8.3 g, 0.024 mol) in THF (40 mL). Cool the reaction (ice bath) and add NaH (1.44 g, 0.036 mol) portionwise. Stir the reaction mixture at room temperature for 30 minutes and cool again to ice temperature. Add a solution of tert-butyl 4-oxopiperidine-1-carboxylate 5 (4.9 g, 0.024 mol) in THF (40 mL) to the above reaction mixture at ice temperature and stir at room temperature for 16 hours. Dilute the resulting reaction mixture with water (250 ml), extract with ethyl acetate (3 × 500 ml), and dry over sodium sulfate. Evaporate the volatiles to obtain the crude product, giving a pale yellow oily product 4 (6.7 g). MS (M+H) 382.3. Product 4 is used in the next step without further purification.

[0416] Step 5 - At ice-cold temperature, add trifluoroacetic acid (27 mL, 4V) to a solution of 4 (6.7 g, 0.017 mol) in dichloromethane (67.0 mL). Stir the reaction mixture at room temperature for 1 hour. Evaporate the volatiles to obtain product 6 (6.96 g, 90%) for use in the next step without additional purification. 1 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.

[0417] Step 6 - At 25 °C, add diisopropylethylamine (1.4 mL, 7.5 mmol) and the carbamate product of Step 4, Example 16 (0.7 g, 2.75 mmol) to a solution of amine 6 (1.0 g, 2.5 mmol) in dimethyl sulfoxide (30 mL). Stir the reaction mixture at 60 °C for 5 h. Dilute the resulting reaction mixture with ethyl acetate (500 ml), wash with water (3 × 150 ml), and dry over sodium sulfate. Purify the crude product obtained after evaporation of the volatiles by silica gel (230 - 400) column (petroleum ether solution of 60% ethyl acetate) to give a pale yellow solid product 7, 0.7 g (68%). Melting point: 50.8 °C. IR: 3305, 2923, 1627, 1528, 1473, 1337, 1266, 695 cm -1 . 11H 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), 2.60–2.70 (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%.

[0418] Example 25: Synthesis of 4 - [3 - (pyrazin - 2 - yloxy) - benzylidene] - piperidine - 1 - carboxylic acid ((1R,2S) - 2 - phenyl - cyclopropyl) - amide:

[0419]

[0420] According to the synthesis method described in the product of Example 24, 2 - chloro - pyrazine was used instead of 2 - chloro - 5 - methyl - pyrazine described in Example 24 to prepare the target compound 7.

[0421] Example 26: Synthesis of 4 - [5 - methyl - 3 - (pyrimidin - 2 - yloxy) - benzylidene] - piperidine - 1 - carboxylic acid (2 - phenyl - cyclopropyl) - amide:

[0422]

[0423] According to the synthesis method described in the product of Example 6, 2 - chloro - 5 - methyl - pyrimidine was used instead of 2 - chloro - pyrimidine described in Example 6 to prepare the target compound 6.

[0424] Example 27: Synthesis of 4 - [3 - (5 - chloro - pyridin - 2 - yloxy) - benzylidene] - piperidine - 1 - carboxylic acid ((1R,2S) - 2 - phenyl - cyclopropyl) - amide:

[0425]

[0426] Step 1 - At room temperature, 3-hydroxyphenyl-methanol (9.42 g, 0.0760 mol) and cesium carbonate (29.72 g, 0.0912 mol) were added to a solution of 5-chloro-2-fluoropyridine (10.0 g, 0.0760 mol) in DMSO (100 mL). 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 (2 × 400 ml), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 12% ethyl acetate) to give the product 1 as a pale yellow oil, 12.0 g (67%). 1 1H 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.

[0427] Step 2: While stirring the reaction in an ice bath, thionyl chloride (4.1 mL, 0.0560 mol) was added dropwise to a solution of 1 (12.0 g, 0.0509 mol) in dichloromethane (120 mL). After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. After complete consumption of the starting material, the volatiles were evaporated under reduced pressure, diluted with ethyl acetate (250 ml), and the organic layer was washed with saturated sodium bicarbonate solution and water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product 2 obtained after evaporation was used directly in the next step without further purification (12.5 g, 96%). 1 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.

[0428] Step 3: A solution of 2 (12.5 g, 0.0494 mol) in triethyl phosphite (20.0 mL, 0.1235 mol) was heated at 150 °C for 6 h. The reaction mixture was allowed to reach room temperature, and the crude product obtained after removal of volatiles was added to n-heptane (150 ml) to give a pale orange precipitate. The precipitate obtained was filtered and dried under vacuum to give a grayish-white solid product 3 (16.5 g, 91%), which was used in the next step without further purification. 1 1H 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.

[0429] Step 4: 15-Crown-5 ether (0.19 g, 0.87 mmol) was added to a solution of 3 (15.5 g, 0.0435 mol) in THF (100 mL). 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 again to ice temperature. A solution of tert-butyl 4-oxopiperidine-1-carboxylate 5 (8.66 g, 0.0435 mol) in THF (50 mL) was added at ice temperature and the mixture was 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 volatiles was purified by silica gel column chromatography to give a pale yellow liquid product 4 (13.1 g, 75%). 1 1H 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, 2H), 6.35 (s, 1H), 3.40 - 3.32 (m, 4H), 2.38 (t, J = 5.2 Hz, 2H), 2.26 (t, J = 6.0 Hz, 2H), 1.39 (s, 9H). MS m / z (M + Na): 423.2.

[0430] Step 5: At ice temperature, trifluoroacetic acid (52.0 ml) was added to a solution of 4 (13.0 g, 0.0325 mol) in dichloromethane (130 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After complete consumption of the starting material, the volatiles were removed under reduced pressure to give a light brown oily product. The obtained crude product was washed with ether (3 × 50 ml) to give a light brown viscous liquid 6 (13.8 g of crude product). 1 1H 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.

[0431] Step 6: At 25 °C, diisopropyl-ethylamine (20.34 ml, 0.1149 mol) and the carbamate product of Step 4, Example 16 (10.62 g, 0.0419 mol) were added to a solution of 6 (15.8 g, 0.0381 mol) in dimethyl sulfoxide (78 mL). 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 (3 × 200 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 solution of 40% ethyl acetate) to give a light yellow fluffy solid product 7 (11.6 g, 66%). Melting range (MR): 44.8 - 62.6 °C. 1 1H 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). 1313C 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%.

[0432] Example 28: Synthesis of 4-[3-(5-Fluoro-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0433]

[0434] Step 1: At room temperature, cesium carbonate (28.12 g, 0.0863 mol) and 3-hydroxyphenyl-methanol (8.9 g, 0.0719 mol) were added to a solution of 2,5-difluoropyridine (8.2 g, 0.0719 mol) in DMSO (80 mL). 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 by column chromatography on silica gel (230 - 400) (petroleum ether solution of 12% ethyl acetate) to give 4.3 g (28%) of product 1 as a pale yellow oil. 1 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.

[0435] Step 2: While stirring the reaction in an ice bath, thionyl chloride (2.4 mL, 0.0326 mol) was added dropwise to a solution of 1 (6.5 g, 0.0296 mol) in dichloromethane (65 mL). After removing the ice bath, the reaction mixture was stirred at room temperature for 2 h. After complete consumption of the starting materials, the volatiles were evaporated under reduced pressure, diluted with ethyl acetate (200 mL), and the organic layer was washed with saturated sodium bicarbonate solution and water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product 2 obtained after evaporation was used directly in the next step without further purification (6.7 g, 95%). 1 1H 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.

[0436] 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 the volatiles was purified by column chromatography on silica gel (230 - 400) to give the light yellow liquid product 3 (9.0 g, 95%). 1 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.

[0437] Step 4: 15-Crown ether (0.12 g, 0.53 mmol) was added to a solution of 3 (9.0 g, 0.0256 mol) in THF (60 mL). The reaction was cooled (ice bath) and 60% NaH (1.26 g, 0.0530 mol) was added portionwise over 5 min. The reaction mixture was stirred at room temperature for 30 min and then cooled again to ice temperature. A solution of tert-butyl 4-oxopiperidine-1-carboxylate 5 (5.28 g, 0.0256 mol) in THF (30 mL) was added at ice temperature, and the mixture was 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 give the light yellow solid product 4 (8.0 g, 78%). 11H 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.

[0438] Step 5: At ice temperature, trifluoroacetic acid (32.5 mL) was added to a solution of 4 (8.2 g, 0.0213 mol) in dichloromethane (82 mL). 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 to obtain the product as a red oil. The resulting crude product was washed with diethyl ether (3 × 50 ml) to give a thick brown oily product 6 (9.0 g of crude product). 1 1H 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.

[0439] Step 6: At 25 °C, diisopropyl-ethyl-amine (11.1 ml, 0.063 mol) and the carbamate product of Step 4, Example 16 (5.8 g, 0.023 mol) were added to a solution of 6 (8.4 g, 0.021 mol) in dimethyl sulfoxide (42 ml). The reaction mixture was stirred at 60 °C for 6 hours. The resulting reaction mixture was diluted with ethyl acetate (400 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 solution of 40% ethyl acetate) to give product 7 as a light yellow fluffy solid (7.15 g, 66%). 11H 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 13C 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%.

[0440] Example 29: Synthesis of methyl 6-{3-[1-((1R,2S)-2-phenyl-cyclopropylcarbamoyl)-piperidin-4-ylidene-methyl]-phenoxy}-nicotinate:

[0441]

[0442] Step 1: At room temperature, 3-hydroxyphenylmethanol (39.79 g, 0.32 mol) and potassium carbonate (60.4 g, 0.43 mol) were added to a solution of methyl 6-chloropyridine-3-carboxylate (50.0 g, 0.29 mol) in dimethylacetamide (500 ml). 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 (300 ml), extracted with ethyl acetate (2 × 500 ml), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 12% ethyl acetate) to give the product 1 as a pale yellow oil (30.0 g, 40%). 11H 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.

[0443] Step 2: While stirring the reaction in an ice bath, thionyl chloride (9.4 mL, 0.127 mol) was added dropwise to a solution of 1 (30.0 g, 0.115 mol) in dichloromethane (300 mL). After removing the ice bath, the reaction mixture was stirred at room temperature for 2 h. After complete consumption of the starting materials, the volatiles were evaporated under reduced pressure, diluted with ethyl acetate (500 ml), and the organic layer was washed with saturated sodium bicarbonate (200 ml) solution and water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product obtained after evaporation was purified by silica gel (230 - 400) column chromatography to give the light yellow liquid product 2 (28.0 g, 87%). 1 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 Hz, 1H), 7.14 - 7.11 (m, 1H), 6.98 - 6.96 (m, 1H), 4.61 (s, 2H), 3.93 (s, 3H). MS m / z (M+H): 278.0.

[0444] Step 3: A solution of 2 (28.0 g, 0.10 mol) in triethyl phosphite (41.0 mL, 0.25 mol) was heated at 150 °C for 6 h. 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 light yellow liquid (32.0 g, 84%). 1 1H 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, mass spectrum m / Z (M+H): 380.2

[0445] Step 4: Add 15-crown ether (0.41 g, 1.8 mmol) to a solution of 3 (35.5 g, 0.093 mol) in THF (200 mL). Cool the reaction (ice bath) and add 60% NaH (5.5 g, 0.14 mol) portionwise over 5 minutes. Stir the reaction mixture at room temperature for 30 minutes and cool again to ice temperature. Add a solution of tert-butyl 4-oxopiperidine-1-carboxylate 5 (18.7 g, 0.093 mol) in THF (150 mL) at ice temperature and stir at room temperature for 16 hours. Quench the resulting reaction mixture with saturated ammonium chloride and extract with ethyl acetate. Dry the organic layer over anhydrous sodium sulfate and concentrate. Dissolve the crude product (30.0 g) obtained after evaporation of the volatiles in methanol (300 ml) and add aqueous lithium hydroxide (3.0 g, 0.0707 mol) at ice temperature. Stir the resulting reaction mass at 50 °C for 2 hours. Monitor the reaction by TLC. Dissolve the crude product obtained after evaporation of the volatiles in water (200 ml) and wash with methyl tert-butyl ether (2 × 200 ml). Acidify the aqueous layer to pH 2.0 with 1.0 N HCl aqueous solution. Filter and dry the precipitated product to give a off-white solid 4 (23.0 g, 61%). 1 1H 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.

[0446] Step 5: At ice temperature, add trimethylsilyl chloride (8.9 ml, 0.0697 mol) to a solution of 4 (13.0 g, 0.0317 mol) in methanol (130 ml). Stir the reaction mixture at room temperature for 12 hours and monitor by TLC. After complete consumption of the starting material, remove the volatiles under reduced pressure. Dilute the resulting crude product with saturated sodium bicarbonate solution and extract with ethyl acetate. Wash the organic layer with water, dry over anhydrous sodium sulfate, filter and concentrate. Purify the crude product obtained after evaporation of the volatiles by silica gel (230 - 400) column chromatography to give product 6 as a pale yellow liquid (5.2 g, 51%). 11H 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.

[0447] Step 6: At 25 °C, diisopropylethylamine (8.9 mL, 0.048 mol) and the carbamate product of Step 4, Example 16 (4.0 g, 0.016 mol) were added to a solution of 6 (5.2 g, 0.016 mol) in dimethyl sulfoxide (52 mL, 10V). The reaction mixture was stirred at 60 °C for 6 hours. The reaction was monitored by TLC. The resulting 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 after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 40% ethyl acetate) to give product 7 as a pale yellow fluffy solid (5.0 g, 65%). Melting point range (Mr): 52.6 - 72.8 °C. 1 1H 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). 1313C NMR: (100 MHz, DMSO-d6): 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%.

[0448] Example 30: Synthesis of 6-{3-[1-((1R,2S)-2-phenyl-cyclopropylcarbamoyl)-piperidin-4-ylidene-methyl]-phenoxy}-nicotinic acid:

[0449]

[0450] At ice temperature, an aqueous lithium hydroxide solution (0.32 g, 0.0076 mol) was added dropwise to a solution of the product of Example 27 (1.8 g, 0.0038 mol) in methanol (18 ml). The reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC. The crude product obtained after evaporation of the volatiles was diluted with water (10 ml), and the aqueous layer was washed with methyl tert-butyl ether. The resulting aqueous layer was acidified to pH 2 with 1.5 N HCl. The precipitated product was filtered and dried to give 1.52 g (87%) of an off-white solid 2. Melting range (MR) 141 - 159 °C. 1 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). 1313C 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%,

[0451] Example 31: Synthesis of 4-[3-(5-Hydroxymethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0452]

[0453] Step 1: At ice temperature, N-methylmorpholine (1.4 ml, 0.0128 mol) and isobutyl chloroformate (1.21 ml, 0.0093 mol) were added to a solution of Product 1 (3.6 g, 0.0085 mol) from Step 4 of Example 27 in 1,2-dimethoxyethane (35 ml). The reaction mixture was stirred at room temperature for 30 minutes. Sodium borohydride (1.9 g, 0.0512 mol) was added portionwise to the reaction mass and stirred for 12 hours. The reaction was monitored by TLC. After complete consumption of the 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 column chromatography on silica gel (230 - 400) to give Product 2 as an off-white solid (3.2 g, 92%). 1 1H 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, J = 5.6 Hz, 2H), 2.25 (t, J = 5.2 Hz, 2H), 1.39 (s, 9H). MS m / z (M+H): 397.3.

[0454] Step 2: At ice temperature, trifluoroacetic acid (12.8 ml) was added to a solution of 2 (3.2 g, 0.08 mol) in dichloromethane (32 ml). 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 to give a crude product as a brownish-red oil. The obtained crude product was washed with diethyl ether (3 × 50 ml) to give 3 as an off-white solid (3.3 g of crude product). Mass spectrometry m / z (M + H): 297.17.

[0455] Step 3: At 25 °C, diisopropyl-ethylamine (4.2 ml, 0.024 mol) and the carbamate product of Step 4, Example 16 (2.0 g, 0.08 mmol) were added to a solution of 3 (3.3 g, 0.08 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was stirred at 60 °C for 6 hours. The resulting reaction mixture was diluted with ethyl acetate (300 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 solution of 40% ethyl acetate) to give a light yellow fluffy solid 4 (1.82 g, 58%). Melting range (MR): 51 - 65 °C. 1 1H 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 13C NMR: (100 MHz, DMSO-d6): 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%.

[0456] Example 32: Synthesis of 4-[3-(5-methoxymethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0457]

[0458] Step 1: At ice temperature, 60% NaH (0.97 g, 0.024 mol) was added to a solution of product 1 (3.2 g, 8.0 mmol) from Step 1 of Example 29 in tetrahydrofuran (32 ml), and the reaction mixture was stirred at room temperature for 10 minutes. Methyl iodide (1.56 mL, 0.024 mol) was added to the reaction material at the same ice temperature, and stirring was continued for 12 hours. The reaction was monitored by TLC. After the raw materials were completely consumed, the reaction was quenched with saturated ammonium chloride solution (100 ml) and extracted with ethyl acetate (300 ml). The organic layer was further washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by silica gel (230 - 400) column chromatography to obtain a grayish-white solid product 2 (2.6 g, 78%). 1 1H 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.

[0459] Step 2: At ice temperature, trifluoroacetic acid (10.4 ml) was added to a solution of 2 (2.6 g, 6.3 mmol) in dichloromethane (26.0 ml), and the reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After the raw materials were completely consumed, the volatiles were removed under reduced pressure to obtain a brownish-red oily product. The obtained crude product was washed with ether (3 × 50 ml) to obtain a light yellow viscous liquid 3 (2.9 g of crude product). 11H 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.

[0460] Step 3: At 25 °C, to a solution of 3 (2.9 g, 6.8 mmol) in dimethyl sulfoxide (30 mL, 10V) was added diisopropyl-ethylamine (3.5 mL, 0.0205 mol) and the carbamate product 5 (1.7 g, 6.8 mmol) of Step 4, Example 16. The reaction mixture was stirred at 60 °C for 6 hours. The reaction was monitored by TLC. The resulting reaction mixture was diluted with ethyl acetate (300 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 (hexane solution of 30% ethyl acetate) to give the product 4 as a pale yellow gummy solid (2.6 g, 86%). 1 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). 1313C NMR: (100 MHz, DMSO-d6): δ 162.60, 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%.

[0461] Example 33: Synthesis of 4-({3-[(5-methylpyrimidin-2-yl)oxy]phenyl}methylene)-N-[(1R,2S)-2-phenylcyclopropyl]piperidine-1-carboxamide:

[0462]

[0463] Step 1 - At room temperature, 3-(hydroxymethyl)phenol (31.86 g, 0.256 mol) and cesium carbonate (100.36 g, 0.308 mol) were added to a solution of 2-chloro-5-methylpyrimidine 1 (33.0 g, 0.256 mol) in DMF (330 mL). The reaction mixture was stirred at 100 °C for 5 h. Then the resulting mixture was cooled to room temperature, diluted with dichloromethane (330 ml), washed with water (2 × 330 ml), 1N KOH solution (2 × 165 ml), brine, and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (hexane solution of 8% ethyl acetate) to give the white solid product 2 (22.0 g, 40%). 1 1H 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.

[0464] Step 2 - Thionyl chloride (8.1 mL, 0.111 mol) was added dropwise to a solution of {3-[(5-methylpyrimidin-2-yl)oxy]phenyl}methanol 2 (22.0 g, 0.101 mol) in dichloromethane (220 mL) 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 (220 ml). The organic layer was washed with saturated sodium bicarbonate solution (110 ml) and water (2 × 220 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the white solid product 3 (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 = 7.6 Hz, 1H), 7.2 (t, J = 2 Hz, 1H), 7.13 - 7.10 (m, 1H), 4.75 (s, 2H), 2.18 (s, 3H). MS m / z (M + H): 235.3.

[0465] 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 hours. The reaction mixture was allowed to reach room temperature, and the crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (hexane solution of 86% ethyl acetate) to give the light green oily product 4 (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.

[0466] Step 4 - At room temperature, 15-crown-5 ether (0.275 g, 0.0012 mol) was added to a solution of diethyl ({3-[(5-methylpyrimidin-2-yl)oxy]phenyl}methyl)phosphonate 4 (21.0 g, 0.062 mol) in THF (147 mL). The reaction was cooled (ice bath) and 60% NaH (3.73 g, 0.093 mol) was added portionwise. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (12.4 g, 0.0624 mol) in THF (63 mL) was added at ice temperature and the mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with ethyl acetate (210 ml), washed with water (3 × 210 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (hexane solution of 15% ethyl acetate) to give the white solid product 5 (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.

[0467] Step 5 - At ice temperature, trifluoroacetic acid (68.0 mL) was added to a solution of tert-butyl 4-({3-[(5-methylpyrimidin-2-yl)oxy]phenyl}methylene)piperidine-1-carboxylate 5 (17.0 g, 0.0445 mol) in dichloromethane (170 mL). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was evaporated to dryness under reduced pressure to give a crude product as a yellow oil. The crude product obtained was washed with ether (3 × 50 ml) to give product 6 as an off-white solid (15.8 g, crude). 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), 7.02 (m, 2H), 6.43 (s, 1H), 3.11 (d, J = 24 Hz, 4H), 2.59 (t, J = 5.6 Hz, 2H), 2.18 (s, 3H). MS m / z (M + H): 282.33.

[0468] Step 6 - At 25 - 30 °C, add diisopropylethylamine (20.0 mL, 0.113 mol) and the carbamate product 5 of Step 4, Example 16 (10.57 g, 0.0417 mol) to a solution of trifluoroacetate of 5 - methyl - 2 - {3 - [(piperidin - 4 - yl)methyl]phenoxy}pyrimidine 6 (15.0 g, 0.0379 mol) in dimethyl sulfoxide (150 mL). Stir the reaction mixture at 60 °C for 5 hours. The resulting reaction mixture is 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 is purified by silica gel (230 - 400) column (hexane solution of 70% ethyl acetate) to give a light yellow solid product 7 (12.0 g, 72%). Melting point range: 58 °C - 67.5 °C. 1 1H 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%.

[0469] Example 34: Synthesis of N - [(2S) - 2 - phenylcyclopropyl] - 4 - {[3 - (pyrazin - 2 - yloxy)phenyl]methylene}piperidine - 1 - carboxamide:

[0470]

[0471] Step 1: At room temperature, add 3 - (hydroxymethyl)phenol (16.25 g, 0.130 mol) and cesium carbonate (51.2 g, 0.157 mol) to a solution of 2 - chloropyrazine 1 (15.0 g, 0.130 mol) in DMF (150 ml). Stir the reaction mixture at 100 °C for 5 hours. Then allow the resulting mixture to reach room temperature, dilute with water (250 ml), extract with ethyl acetate (3 × 500 ml), wash the resulting organic layer with 1N KOH (2 × 250 ml) solution, and dry the separated organic layer over sodium sulfate. The crude product obtained after evaporation of the volatiles is purified by silica gel (230 - 400) column (hexane solution of 10% ethyl acetate) to give an off - white solid product 2 (9.3 g, 35%). 11H 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 = 7.6 Hz, 1H), 7.1 (s, 1H), 7.03 (dd, J = 6 Hz, J = 2 Hz, 1H), 5.25 (t, J = 5.6 Hz, 1H), 4.49 (d, J = 6 Hz, 2H). MS m / z (M+1): 203.2.

[0472] Step 2: Thionyl chloride (3.94 mL, 0.054 mol) was added dropwise to a solution of {3-[(pyrazin-2-yl)oxy]phenyl}methanol 2 (10.0 g, 0.049 mol) in dichloromethane (100 mL) 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 (250 mL). The organic layer was washed with saturated sodium bicarbonate solution (150 mL) and water (2 × 200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the yellow solid product 3 (9.0 g, 82%). 1 1H 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.

[0473] Step 3: A solution of 2-[3-(chloromethyl)phenoxy]pyrazine 3 (10.0 g, 0.045 mol) in triethyl phosphite (12.3 mL, 0.072 mol) was heated at 130 °C for 6 hours. The reaction mixture was allowed to reach room temperature, and the crude product obtained after evaporating the volatiles was purified by silica gel (230 - 400) column (hexane solution of 60% ethyl acetate) to give the colorless oily product 4 (9.49 g, 64.5%). 1 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.

[0474] Step 4: At room temperature, 15-crown-5 ether (136 mg, 0.62 mmol) was added to a solution of diethyl {[3-(pyrazin-2-yloxy)phenyl]methyl}phosphonate 4 (10.0 g, 0.031 mol) in THF (70 mL). At 0 - 5 °C, 60% NaH (1.86 g, 0.046 mol) was added portionwise to the above reaction mixture. The reaction mixture was stirred at room temperature for 30 minutes and then cooled to ice temperature 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 the mixture was 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 by column (silica gel (230 - 400), hexane solution of 15% ethyl acetate) to give product 5 as an off-white solid (9.1 g, 80%). 1 H 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.

[0475] Step 5: At ice temperature, trifluoroacetic acid (40 mL) was added to a solution of tert-butyl 4-{[3-(pyrazin-2-yloxy)phenyl]methylene}piperidine-1-carboxylate 5 (10.0 g, 0.027 mol) in dichloromethane (100 mL). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was evaporated to dryness under reduced pressure to give a crude product as an oily red substance. The obtained crude product 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.

[0476] Step 6: At 25 - 30 °C, to a solution of the trifluoroacetate of 2-[3-(piperidin-4-ylmethyl)phenoxy]pyrazine 6 (10.0 g, 0.026 mol) in dimethyl sulfoxide (100 ml, 10V) was added diisopropylethylamine (13.7 ml, 0.078 mol) and the carbamate product 5 from Example 16, Step 4 (7.3 g, 0.028 mol). 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 (3 × 150 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (hexane solution of 50% ethyl acetate) to give product 7 as a light yellow solid (8.0 g, 71%). Melting range: 41.7 °C – 52.6 °C; 1 1H 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%.

[0477] Example 35: Synthesis of 4-[3-(5-Hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0478]

[0479] Step 1: At room temperature, 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). The reaction mixture was stirred at 100 °C for 8 hours. Then the resulting mixture was allowed to reach room temperature, diluted with water (70 ml), and extracted with ethyl acetate (3 × 100 ml). The combined organic layers were dried over sodium sulfate and the solvent was evaporated under reduced pressure using a rotary evaporator. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (n-hexane solution of 30% ethyl acetate) to give product 2 as a light yellow oil (7.1 g, 63% yield).1 1H NMR (400 MHz, CDCl3) δ 8.19 (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, 0.9 Hz, 1H), 7.13 (d, 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.

[0480] Step 2: Thionyl chloride (2.43 g, 20.4 mmol) was added dropwise to a solution of {3-[(5-bromopyridin-2-yl)oxy]phenyl}methanol 2 (5.2 g, 18.57 mmol) in dichloromethane (52 mL) 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 (80 ml). The organic layer was washed with saturated sodium bicarbonate solution (25 ml) and water (25 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the product 3 as a white solid (4.12 g, 75% yield). 1 1H NMR (400 MHz, CDCl3) δ 8.22 (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 = 2.1 Hz, 1H), 7.08 (m, 1H), 6.86 (dd, J = 8.8, 0.6 Hz, 1H), 4.59 (s, 2H). MS m / z (M+2): 299.9.

[0481] Step 3: A solution of triethyl phosphite (5.78 mL, 33.7 mmol) in 5-bromo-2-[3-(chloromethyl)phenoxy]pyridine 3 (4 g, 13.5 mmol) was heated at 150 °C for 6 h. The reaction mixture was allowed to reach room temperature, and the crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 60% ethyl acetate) to give 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.

[0482] Step 4: 15-Crown ether (41 mg, 0.190 mmol) was added 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). The reaction was cooled (ice bath) and 60% NaH (342 mg, 14.2 mol) was added portionwise. The reaction mixture was stirred at room temperature for 30 min and cooled again to ice temperature. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.9 g, 9.52 mmol) in THF (19 mL) was added at ice temperature and the reaction mixture was stirred at room temperature for 16 h. 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 by silica gel (230 - 400) column (n-hexane solution of 5% ethyl acetate) to give product 5 as a white solid (2.58 g, 61% yield). 1 1H NMR (400 MHz, CDCl3) δ 8.22 (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, 1.7, 0.8 Hz, 1H), 7.01–6.92 (m, 2H), 6.84 (dd, J = 8.7, 0.7 Hz, 1H), 6.34 (s, 1H), 3.45 (m, 4H), 2.39 (m, 4H), 1.47 (s, 9H). MS m / z (M+Na): 469.21.

[0483] Step 5: Experiments were carried out using the method reported in the literature (Reference: J. Am. Chem. Soc. 2016, 138, 13493 - 13496). LiOH·H2O (396 mg, 9.43 mmol), ligand L-1 (110 mg, 0.337 mmol), and Cu(acac)2 (88 mg, 0.337 mmol) were successively added to a degassed solution of 4-[3-(5-bromo-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester 5 (2 g, 4.49 mmol) in DMSO (40 mL) and water (2 mL), and degassing was continued for 10 minutes. The resulting reaction mixture was heated at 85 °C for 48 hours. The reaction progress was monitored by TLC. The reaction mixture was cooled to ambient temperature, quenched by adding 5% aqueous NH4Cl solution (12 mL), and then 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 obtain the crude product. The obtained crude product was further purified by flash column chromatography on silica gel using a hexane solution of 40 - 45% ethyl acetate to obtain 4-[3-(5-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester (6) as a light brown solid (738 mg, 43% yield). 1 1H NMR (400 MHz, CDCl3) δ 9.69 (bs, 1H), 7.83 (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.

[0484] Step 6: At ice temperature, trifluoroacetic acid (2.4 mL) was added to a solution of 6 (600 mg, 1.57 mmol) in dichloromethane (6 mL), 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 to obtain the crude product 7 as an oily red substance. The obtained crude product was washed with diethyl ether (3 × 5 mL) to obtain the trifluoroacetate of 6-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyridin-3-ol as a brown oil (400 mg of crude product). MS m / z (M + 1): 283.21.

[0485] Step 7: At 25 °C, diisopropylethylamine (1.48 mL, 8.51 mmol) and the carbamate product 5 (269 mg, 1.06 mmol) from Step 4, Example 16 were added to a solution of 7 (300 mg, 1.06 mmol) in dimethyl sulfoxide (3 mL). 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), washed with water (3 × 20 mL), and dried over anhydrous sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by reverse-phase HPLC, the collected fractions were concentrated, and the resulting residue was lyophilized to give product 8 as an off-white solid (93 mg, 20%). 1 HNMR (400 MHz, DMSO-d6) δ 9.70 (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%.

[0486] Example 36: Synthesis of 4-[3-(4-Hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0487]

[0488] Step 1: At room temperature, 3-hydroxymethylphenol (5 g, 40.3 mmol) and cesium carbonate (15.75 g, 48.3 mmol) were added to a solution of 4-bromo-2-fluoropyridine 1 (7.72 g, 44.3 mmol) in DMSO (40 ml, 8V). The reaction mixture was stirred at 100 °C for 8 h. Then the resulting mixture was allowed to reach room temperature, diluted with water (70 ml), extracted with ethyl acetate (3 × 100 ml), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230-400) column (30% ethyl acetate in hexane solution) to give product 2 as a pale yellow oil (4.8 g, 43% yield). 11H NMR (400 MHz, CDCl3) δ 8.00 (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.

[0489] Step 2: Thionyl chloride (2.24 g, 18.8 mmol) was added dropwise to a solution of {3-[(4-bromopyridin-2-yl)oxy]phenyl}methanol 2 (4.8 g, 17.1 mmol) in dichloromethane (48 mL) 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 the residue was diluted with ethyl acetate (80 ml). The organic layer was washed with saturated sodium bicarbonate solution (25 ml) and water (25 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the product 3 as a white solid (4.05 g, 80% yield). 1 1H 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.

[0490] 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 hours. The reaction mixture was allowed to reach room temperature and the crude product obtained after evaporation of the volatiles was purified by silica gel (230-400) column (petroleum ether solution of 60% ethyl acetate) to give the product 4 as a colorless oil (3.88 g, 72% yield). 1 1H 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.

[0491] Step 4: Add 15-crown ether (41 mg, 0.190 mmol) to a solution of 4 (3.8 g, 9.52 mmol) in THF (19 mL). Cool the reaction (ice bath) and add 60% NaH (342 mg, 14.2 mmol) portionwise. Stir the reaction mixture at room temperature for 30 minutes and cool again to ice temperature. Add a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.9 g, 9.52 mmol) in THF (19 mL) at ice temperature and stir at room temperature for 16 hours. Dilute the resulting reaction mixture with water (50 ml), extract with ethyl acetate (3 × 40 ml), and dry over anhydrous sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by column (silica gel, 230 - 400 mesh, hexane solution of 5% ethyl acetate) to give product 5 as a white solid (2.75 g, 65% yield). 1 1H NMR (400 MHz, CDCl3) 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+Na): 467.6。

[0492] Step 5: Add LiOH·H2O (396 mg, 9.43 mmol), ligand L-1 (110 mg, 0.337 mmol) and Cu(acac)2 (88 mg, 0.337 mmol) successively to a degassed solution of 5 (2 g, 4.49 mmol) in DMSO (40 mL) and water (2 mL, 1V), and continue degassing for 10 minutes. Heat the resulting reaction mixture at 85 °C for 48 hours. Monitor the reaction progress using TLC. Cool the above reaction mixture to ambient temperature, quench by adding 5% aqueous NH4Cl solution (12 mL, 20V), and then dilute with ethyl acetate (25 mL). Separate the organic phase, wash with brine (15 mL), dry over Na2SO4, and concentrate under reduced pressure to obtain a crude product. The crude product obtained was further purified by flash chromatography on silica gel using a hexane solution of 40 - 45% ethyl acetate to give tert-butyl 4-[3-(5-hydroxypyridin-2-yloxy)benzylidene]piperidine-1-carboxylate (6) as a light brown solid (686 mg, 40% yield). 11H 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.

[0493] Step 6: At ice temperature, trifluoroacetic acid (1.2 ml) was added to a solution of tert-butyl 4-[3-(4-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylate 6 (400 mg, 1.04 mmol) in dichloromethane (4 ml). 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 to give the product 7 as an oily red residue. The crude product obtained was washed with diethyl ether (3 × 50 ml) to give the trifluoroacetate of 6-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyridin-3-ol as a brown oil (400 mg of crude product). MS m / z (M+1): 283.2.

[0494] Step 7: Diisopropylethylamine (1.38 ml, 7.94 mmol) and the carbamate product 5 of Step 4, Example 16 (251 mg, 0.992 mmol) were added to a solution of the trifluoroacetate of 6-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyridin-3-ol 7 (280 mg, 0.992 mmol) in dimethyl sulfoxide (2.8 mL, 10V). 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 (3 × 20 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by reverse-phase HPLC to give the product 8 as an off-white solid (137 mg, 32%). 11H 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, 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%.

[0495] Example 37: Synthesis of 4-[3-(6-Hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0496]

[0497] Step 1: At room temperature, 3-Hydroxymethylphenol (2.64 g, 21.3 mmol) and cesium carbonate (5.55 g, 17.0 mmol) were added to a solution of 2-Bromo-6-fluoropyridine 1 (2.5 g, 14.2 mmol) in DMF (25 mL, 10V). The reaction mixture was stirred at 100 °C for 8 hours. Then the resulting mixture was allowed to reach room temperature, diluted with water (50 mL), extracted with ethyl acetate (3 × 50 mL), and the organic layer was dried over anhydrous sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230-400) column (hexane solution of 30% ethyl acetate) to give product 2 as a pale yellow oil (2.48 g, 62% yield). 11H 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), 7.09 (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.

[0498] Step 2: Thionyl chloride (0.7 mL, 9.7 mmol) was added dropwise to a solution of {3-[(6-bromopyridin-2-yl)oxy]phenyl}methanol 2 (2.48 g, 8.85 mmol) in dichloromethane (25 mL) 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 sodium bicarbonate solution (25 ml) and water (25 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the product 3 as a brown oil (2.56 g, 86%). 1 1H 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.

[0499] Step 3: A solution of triethyl phosphite (3.67 mL, 21.0 mmol) of 2-bromo-6-[3-(chloromethyl)phenoxy]pyridine 3 (2.55 g, 8.50 mmol) was heated at 150 °C for 6 hours. The reaction mixture was brought to room temperature, and the crude product obtained after evaporation of the volatiles was purified by silica gel (230-400) column (petroleum ether solution of 60% ethyl acetate) to give the product 4 as a light brown oil (2.97 g, crude product). 1 1H 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.

[0500] 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 portionwise. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.76 g, 8.86 mmol) in THF (15 mL) was added at ice temperature and 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 by silica gel (230 - 400) column (hexane solution of 5% ethyl acetate) to give the product 5 as a yellow oil (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.

[0501] Step 5: To a degassed solution of tert-butyl 4-[3-(6-bromo-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylate 5 (1.8 g, 4.04 mmol) in DMSO (36 mL, 20V) and water (1.8 mL) was added LiOH·H2O (356 mg, 8.49 mmol), ligand L-1 (99.6 mg, 0.303 mmol) and Cu(acac)2 (79 mg, 0.303 mmol) and degassing was continued for 10 minutes. The resulting reaction mixture was heated at 100 °C under MW irradiation for 4 hours. The progress of the reaction was monitored using TLC. The above reaction mixture was cooled to ambient temperature, quenched by addition of 5% aqueous NH4Cl solution (12 mL), and then diluted with ethyl acetate (25 mL). The organic phase was separated, washed with brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product obtained was further purified by flash chromatography on silica gel using a hexane solution of 40 - 45% ethyl acetate to give tert-butyl 4-[3-(6-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylate (6) as a light brown solid (730 mg, 47% yield). 11H 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, 2H), 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。

[0502] Step 6: At ice temperature, trifluoroacetic acid (1.44 mL) was added to a solution of tert-butyl 4-[3-(6-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylate 6 (720 mg, 1.88 mmol) in dichloromethane (5.6 mL). 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 to obtain an oily product. The resulting crude product was washed with ether (3 × 5 ml) to give the trifluoroacetate salt of 6-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyridin-2-ol 7 as a brown oil (750 mg of crude product). 1 1H 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 (m, 5H), 6.46 (s, 1H), 6.35 (dd, J = 7.8, 3.7 Hz, 2H), 3.36 - 3.08 (m, 4H), 2.60 (t, J = 6.0 Hz, 2H, 2.39 (t, J = 6.0 Hz, 2H). MS m / z (M+H): 283.33。

[0503] Step 7: At 25 °C, diisopropylethylamine (1.9 ml, 12.9 mmol) and the carbamate product 5 of Step 4, Example 16 (570 mg, 2.25 mmol) were added to a solution of the trifluoroacetate salt of 2-bromo-6-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyridine 7 (730 mg, 2.5 mmol) in dimethyl sulfoxide (7.3 ml). The reaction mixture was stirred at 60 °C for 5 hours. The reaction was monitored by TLC. The resulting reaction mixture was diluted with ethyl acetate (70 ml), washed with water (3 × 20 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by reverse-phase HPLC twice to give the product 8 as an off-white solid (120 mg, 11%). 11H 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), 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 (ddd, 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 (ddd, 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%.

[0504] Example 38: Soluble epoxide hydrolase (sEH) inhibition assay:

[0505] The sEH enzyme inhibition assay was performed using a kit (Cayman Cat. No. 10011671) available from Cayman Chemical Company of Ann Arbor, Michigan. The assay used 3-phenyl-cyano(6-methoxy-2-naphthyl)-methyl ester-2-oxirane acetic acid as the substrate for sEH. Hydrolysis of the substrate produces a highly fluorescent product that can 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 the compound (in 5 μL of DMSO) or DMSO alone (vehicle) were added, and the reaction was initiated by adding 5 μL of the substrate. The plate was incubated at 25 °C for 15 minutes. Data analysis was performed and the percentage of inhibition was determined.

[0506] Example 39: Fatty acid amide hydrolase (FAAH (SEQ ID NO: 3)) inhibition assay:

[0507] The FAAH enzyme inhibition assay was performed using a kit (Cayman Cat. No. 10010183) available from Cayman Chemical Company of Ann Arbor, Michigan. The assay used AMC arachidonoyl amide (7-amino-4-methyl-2H-1-benzopyran-2-one-5Z,8Z,11Z,14Z-eicosatetraenamide, Cayman Chemical Cat# 10005098) as the substrate for FAAH. FAAH hydrolyzes AMC arachidonoyl amide, releasing the fluorescent product 7-amino-4-methylcoumarin (AMC). The fluorophore can be easily analyzed using an excitation wavelength of 340 - 360 nm and an emission wavelength of 450 - 465 nm. Different concentrations of the compound (in DMSO) or DMSO alone (vehicle) were added. After adding FAAH, the plate was incubated at ambient temperature for 20 minutes. The assay was initiated by the rapid addition of AMC arachidonoyl amide, and the reaction was carried out at ambient temperature for 60 minutes, during which the release of AMC was monitored by the accompanying increase in fluorescence intensity (excitation wavelength 340 - 360 nm, emission wavelength 450 - 465 nm). Fluorescence intensity measurements were made kinetically, and the reaction rate was calculated from the linear portion of the reaction using linear regression analysis.

[0508] % Initial Activity = (Inhibited Fluorescence / 100% Active Fluorescence) * 100

[0509] % Inhibition = 100 – (% Initial Activity)

[0510] Concentration (IC 50 ) Compounds that inhibit soluble epoxide hydrolase when less than 10 μM. The inhibitory activities of the compounds of formula I against sEH and FAAH enzymes are given in Table 1, see Figure 1 . The selectivity of sEH inhibition was determined by calculating the ratio of the inhibitory potencies of FAAH to sEH [IC 50 FAAH / IC 50 , sEH].

[0511] Animal models known in the literature can be used to evaluate the efficacy of compounds of general formula I as a single therapy and in combination with other agents in cancer.

[0512] Example 40 - Evaluation of the Potential of Compounds of Formula 1 to Treat Melanoma Cancer Using the B16F10 Syngeneic Mouse Tumor Model

[0513] The syngeneic mouse melanoma cell line B16F10 obtained from ATCC For this study. B16F10 cells stored in liquid nitrogen were thawed and resuscitated according to the recommended method. The cells were cultured and expanded in complete DMEM growth medium. Sub-confluent monolayers were harvested, pelleted and re-suspended in growth medium before counting on a hemocytometer by trypan blue exclusion. A cell suspension with 98% viability was prepared in 1X HBSS (pH 7.4) and kept on ice until implantation. A 0.1 ml cell suspension containing 0.2×10 6 cells was subcutaneously implanted into the flank region of the animals using a 22-gauge needle. After cell implantation, the mice were randomly divided into different treatment groups (n = 8 animals / group) according to body weight.

[0514] Control animals were administered the vehicle alone, while the treatment groups were administered test compound A or checkpoint inhibitors (anti-CTLA4 or anti-PD-1) as monotherapy or as combination therapy of compound A with checkpoint inhibitors (anti-CTLA4 or anti-PD-1 antibody). Compound A was orally administered at 5 mg / kg once daily for 0 - 21 days, while the anti-PD1 or anti-CTLA4 antibody was administered at 10 mg / kg by intraperitoneal (IP) injection on days 4, 7, 10, 13, and 16. Tumor growth was measured using a digital vernier caliper.

[0515] All animals were observed once daily for clinical symptoms, and mortality and morbidity were observed twice daily (morning and evening). Individual animal body weights were recorded three times a week at the time of tumor measurement. Humane endpoints were determined considering the visible size of the tumor, ulcerated or necrotic tumors, and animal health criteria. According to pre-determined criteria such as tumor size (~1500 mm 3 ), weight loss (≥20%), loss of ability to walk, dyspnea, or inability to drink or eat, the animals were euthanized when they were moribund.

[0516] Mouse anti-nuclear antibody (IgG) ELISA kit from CUSABIO (Cat.No.CSB-E12912m) was used to analyze anti-nuclear antibody (IgG). Sandwich enzyme-linked immunosorbent assay (ELISA) was used to detect anti-nuclear antibody (ANA) in mouse serum. ANA in the sample binds to a plate coated with anti-mouse IgG antibody, and the detection is completed using a detection antibody conjugated to an enzyme and 3,3',5,5'-tetramethylbenzidine (TMB) used as a substrate. The enzyme reaction produces a blue product, which turns yellow when the stop solution is added. The absorbance of each well was measured at 450 nm using a microplate reader (Thermo Scientific, ). The ANA concentration in the serum samples was determined by plotting a standard curve of known ANA concentrations according to the manufacturer's instructions.

[0517] Compared to the vehicle-treated control animal group, compound A showed significant tumor growth inhibitory effects (Figure 2 and Figure 3 ). The combination of Compound A with an anti-CTLA4 antibody ( Figure 2 ) or an anti-PD1 antibody ( Figure 3 ) shows better tumor growth inhibition than single treatment with checkpoint inhibitors (anti-CTLA4 or anti-PD1). The response rates of animals showing at least 40% tumor growth inhibition were compared between treatment groups relative to a control group. In this melanoma model, treatment with Compound A (as a single therapy or in combination with an anti-CTLA4 antibody) showed improved responses ( Figure 4 ) compared to animals treated with an anti-CTLA4 antibody. Treatment with Compound A (as a single therapy or in combination with an anti-CTLA4 antibody) also led to lower serum ANA levels ( Figure 5 ) compared to single therapy with an anti-CTLA4 antibody.

[0518] Example 41 - 4T1 evaluated the potential of a Compound of Formula 1 for treating breast cancer using a syngeneic murine tumor model.

[0519] The murine breast cancer cell line 4T1 obtained from the ATCC was used for this study. Cells stored in liquid nitrogen were thawed and resuscitated according to the recommended method. Cells were cultured and expanded in complete RPMI - 1640 growth medium. Subconfluent monolayer cells were harvested, pelleted and resuspended in growth medium, then counted on a hemocytometer by trypan blue exclusion. A cell suspension with a viability >96% was prepared in 1X HBSS (pH 7.4) mixed with ice-cold in a 1:1 ratio and kept on ice until implantation. 50 μL of the cell suspension containing 0.1×10 6 cells was implanted into the mammary fat pad (day 0) using a 22-gauge needle. Tumor volume was measured using digital calipers and animals were selected based on tumor size criteria of 50 to 80 mm 3 and an average tumor size of approximately 50 mm. Tumor-bearing mice were randomly divided into different groups (N = 8 animals / group) based on tumor size.

[0520] Animals in the control group were administered vehicle alone, while treatment groups were administered test Compound A or checkpoint inhibitors (anti-CTLA4 or anti-PD - 1) as single therapies or as combination therapies of Compound A with anti-CTLA4 ± anti-PD1 antibodies. Compound A was administered orally once daily at 5 mg / kg for 0 - 21 days, while anti-PD1 or anti-CTLA4 antibodies were administered at 10 mg / kg via the intraperitoneal (IP) route on days 0, 3, and 6. The anti-tumor efficacy of Compound A and its combinations with checkpoint inhibitors was evaluated by monitoring tumor growth kinetics, lung metastases, and survival. Tumor growth inhibition was evaluated by comparing tumor volumes between treatment groups and the control group.

[0521] Clinical symptoms, mortality, and morbidity of all animals were observed daily. During tumor measurement, the body weights of individual animals were recorded three times a week. The humane endpoint was determined considering the visible size of the tumor, ulcerated or necrotic tumors, and animal health criteria. According to pre-determined criteria such as tumor size (~2000 mm 3 ), weight loss (≥20%), loss of locomotion, dyspnea, or inability to drink or eat, animals were euthanized when moribund.

[0522] Lung metastasis - Three animals were euthanized on day 21 for lung metastasis determination. The three animals were from the vehicle control group, the treatment group with compound A as monotherapy, and the combination treatment group with checkpoint inhibitors (anti-CTLA4 + anti-PD1). Animals were euthanized by CO2 euthanasia, and lung tissues were isolated for assessment of metastasis. Lungs were excised and metastatic cancer cell colonies were observed macroscopically. Lungs were fixed in Bouin's solution, and surface lung nodules were counted. All lung specimens were stored in 10% NBF.

[0523] Compared to the vehicle-treated control animal group, compound A showed significant tumor growth inhibition (p < 0.0001)( Figure 6 ). The combination of compound A with anti-CTLA4 + anti-PD1 antibodies ( Figure 6 ) also showed significant tumor growth inhibition compared to monotherapy with compound A ( Figure 6 ).

[0524] Compared to the control group, the compound A treatment group showed significantly lower numbers of metastatic nodules in the lungs, showing a 37% reduction (p < 0.001)( Figure 7 ). Compared to the control group, the combination of compound A with checkpoint inhibitors (anti-CTLA-4 + anti-PD-1 antibodies) resulted in an 85% reduction in lung nodules (p < 0.0001)( Figure 7 ).

[0525] Example 42 - The potential of a compound of formula 1 for the treatment of brain cancer (glioblastoma) was evaluated using the G261 syngeneic mouse tumor model.

[0526] The mouse glioma GL261 (Luc2) tumor cell line was cultured in vitro according to the provider's specifications: DMEM supplemented with 10% FBS, 1% penicillin-streptomycin, 1 mM HEPES, and 200 μg / ml of G418 under selective pressure. The mycoplasma-free status of the cells was first checked and verified. Before inoculating mice, cell viability was evaluated by flow cytometry and live cell gating. Cell suspensions were prepared based on live cell counts.

[0527] Mouse glioma cells (GL261(luc2)) were stereotactically implanted into the brains of immunocompetent C57BL / 6J mice (in situ). On the day of inoculation, an analgesic regimen was performed by intraperitoneal injection of 0.1 mg / kg buprenorphine. The mice were induced with 4% isoflurane and maintained with 2% isoflurane. The scalp was shaved and incised to visualize the skull, especially the bregma. The mice were then attached to a stereotactic apparatus. To implant the cells, they were resuspended in sterile PBS and the required volume (25,000 cells / 1 μL) was aspirated with a Hamilton syringe. The syringe was fixed to the stereotactic apparatus and placed according to the appropriate injection site. The skull was opened with a 26G needle 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. Before suturing the skin, the injection site was cleaned with iodophor gauze. The anesthetized mice were placed on a warming blanket and monitored until they woke up. On day 6 after tumor inoculation, based on the first bioluminescence imaging (BLI), the mice were randomly assigned to different pharmacological groups, performed before any treatment, to confirm tumor implantation. Thereafter, BLI was performed weekly for a total of 5 weeks at days 14, 21, 28, 35, and 42 (a total of 6 BLI measurements) according to the survival rate of the mice within the group.

[0528] Animals in the control group were administered the vehicle alone, while the treatment groups were administered test compound A or anti-PD-1 antibody as monotherapy or as combination therapy (compound A ± anti-PD1). From day 6 to day 37 after tumor inoculation, compound A was administered by oral gavage at 5 mg / kg once daily and then every other day until day 41. The anti-PD1 antibody was administered intraperitoneally at 5 mg / kg once daily on days 6, 9, 12, and 15 after tumor inoculation.

[0529] From day 6 after tumor cell inoculation, tumor growth of all mice was monitored by bioluminescence imaging, and body weight and survival rate were monitored by considering the endpoint / sacrifice time, represented by Kaplan–Meier curves. To respect ethical laws, animals were sacrificed when they showed reliable clinical symptoms such as respiratory distress, hunched posture, or loss of >15% body weight.

[0530] As shown by bioluminescence imaging (BLI) measurements from day 6 to day 28 after tumor cell inoculation, appropriate tumor implantation was achieved in all inoculated animals. The animals showed appropriate tumor growth, as visible by BLI values measured over time, which showed kinetic evolution.

[0531] When administered as monotherapy, compound A showed an antitumor effect, with improved survival / life span compared to the control group ( Figure 8)。One of the 10 animals treated with compound A showed complete tumor rejection (confirmed by a significant decrease in bioluminescence imaging values and the absence of tumors in brain autopsy).

[0532] Example 43: Method for evaluating the potential of a compound of formula 1 to reduce or block chemotherapy-induced peripheral neuropathy - The potential of a compound of formula 1 to reduce or block chemotherapy-induced neuronal damage was evaluated using the animal (zebrafish) model described below and in the literature (Lisse TS et al PNAS113(15)E2189-E2198).

[0533] To induce peripheral neuropathy in adult zebrafish, zebrafish with an average body weight of about 200 mg were injected with 3 μL of a solution of 10 μM paclitaxel in 0.15% DMSO using a 33-gauge Hamilton syringe. The fish were treated with the vehicle alone or paclitaxel for 4 consecutive days (days 2-5) or with paclitaxel and compound A (10 - or 30 ng). Compound A was administered orally by mixing it with fish feed pellets. The fish were required to eat three pellets per day. The feed injected with the test compound was given in the morning, and then the regular non-compound feed was given in the afternoon and evening. To prepare the pellets injected with the test compound, a known amount of the compound was mixed with a known amount of feed powder and extruded into 4 mg pellets, each containing the required dose for administration. The concentration of the test compound administered to each fish was controlled by the number of pellets and the amount of the compound in each pellet. Feed pellets without the test compound but containing the excipient were used as placebo controls.

[0534] To determine peripheral nerve injury, the fish were wrapped in plastic foil until calm and the distal tail fin was stimulated with an insect pin until twitching of the fish was observed. The number of stimuli that caused twitching was recorded. Paclitaxel caused significant nerve injury as shown by an increase in the number of stimuli required ( Figure 9 ). The compound A + paclitaxel treatment group showed a rescue effect on paclitaxel-induced nerve injury. Four days after paclitaxel administration in the treatment regime, treatment with compound A (30 ng) also resulted in the rescue or reversal of paclitaxel-induced neuronal loss ( Figure 9 ).

[0535] Example 44 – CT26 syngeneic mouse tumor model was used to evaluate the potential of a compound of formula 1 to treat colon cancer.

[0536] CT26 cells were cultured in complete DMEM growth medium ( CRL-2638TM). Harvest the sub-confluent cell monolayer and prepare a cell suspension containing >97% viable cells in Hank's balanced salt solution (pH 7.4). Subcutaneously implant 0.1 ml of the cell suspension containing 50,000 cells into the flank region of the animal in anesthetized female BALB / c mice at 6 - 8 weeks of age.

[0537] After implanting the cells, randomly assign the mice to different treatment groups (N = 10). Monitor the animals three times a week during the period between inoculation and palpable (measurable) tumor growth. On the day of tumor inoculation, administer the test compound A to one group of mice (Group G2) by oral gavage at a dose of 5 mg / kg body weight. The control group (G1) is given only the vehicle. When the tumor size reaches 25 - 50 mm 3 , initiate the treatment with test compound A (Group G4) or anti-CTLA4 (Group G3). The test compound A (Group G4) is administered by oral gavage at a dose of 5 mg / kg body weight. Administer anti-mouse CTLA-4 (CD152, Clone 9H10, Bio X cell, West Lebanon, NH) once every three days via the intraperitoneal route at a dose of 2.5 mg / kg body weight, equivalent to 50 μg per mouse. When the tumor size reaches 25 - 50 mm 3 , also initiate the combination treatment of compound A (5 mg / kg, oral, once daily) and anti-mouse CTLA-4 antibody (2.5 mg / kg, intraperitoneal route, once every 3 days) (Group G5) in the mice. Administer compound A orally using a formulation consisting of 5% (v / v) ethanol + 50% (v / v) PEG 400 + 20% (v / v) propylene glycol + 25% (v / v) sterile water for injection. Dilute the CTLA-4 antibody in an appropriate dilution buffer at pH 7.0. Measure the tumor size three times a week using a digital vernier caliper and calculate the tumor volume as [length (L) × width (W) 2 / 2, where the length (L) and width (W) refer to the maximum and minimum diameters of the tumor. Monitor the tumor size, body weight, clinical symptoms, and survival rate of the animals until the tumor size reaches the predetermined endpoint criterion of approximately 1500 mm 3 , and then euthanize the animals based on ethical considerations.

[0538] Evaluate the anti-tumor efficacy of the test compound A as a single therapy and in combination with anti-CTLA4 by monitoring tumor growth kinetics, tumor growth delay, and survival. Evaluate the tumor growth inhibitory effect by comparing the tumor volumes of the treatment groups and the control group on day 30. Subsequently, perform survival analysis using the Kaplan-Meier method.

[0539] Compared with the control animal group G1 treated with the vehicle, compound A (groups G2 and G4) showed significant tumor growth inhibitory effects (p < 0.0001)( Figure 10 ). The combination of compound A with anti-CTLA4 antibody (group G5, Figure 10 ) also showed significant tumor growth inhibitory effects, which were improved compared with the single therapy of compound A in group G4 ( Figure 10 ). Compared with the control group G1, compound A (groups G2 and G4) showed a significant improvement in survival time ( Figure 11 ). The combination of compound A with anti-CTLA4 antibody (group G5, Figure 11 ) also showed a significant increase in survival rate ( Figure 11 ).

[0540] A therapeutically effective amount of the compound of formula I can be administered as a single dose or in repeated doses one or more times at intervals over a period of time. As previously mentioned, the attending physician may consider many factors in dose selection, including but not limited to: the potency 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 status and individual reactivity of the subject to be treated, as well as other relevant circumstances. The therapeutic dose for human subjects can be estimated based on data from animal studies and taking into account factors such as body surface area, pharmacokinetic profiles and related parameters. Allometric scaling and related methods described in the literature [e.g.; J Basic Clin Pharm. March 2016-May 2016; 7(2):27–31] can be used to estimate the human equivalent dose.

[0541] The therapeutically effective composition of the present invention for treating neurodegenerative diseases in a subject can include a compound of formula I administered at a dose of from about 0.5 mg / day to about 3000 mg / day.

[0542] Sequence Listing XML Consolidation Statement

[0543] The Sequence Listing XML provided herein is hereby incorporated by reference. The name of the XML file is NeuroPnCancerTherapy.XML, the creation date is September 29, 2023, and the size is 7 kilobytes.

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Claims

1. A method for treating cancer, comprising: administering to a subject a therapeutically effective amount of at least one compound of formula I: wherein R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; R 2 selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl; R 3 selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ; R 5 selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X is selected from O, (CH2)p, NH, and p is 0 - 2; Y1 - Y2 is selected from CH-CH2, CH-O or C=CH, provided that when Y1 - Y2 is CH-O, X is selected from O or NH or R 1 is not hydrogen; and Y3 is selected from H or Me, its stereoisomers or its pharmaceutically acceptable salts.

2. A method for treating cancer, comprising administering to a subject a therapeutically effective amount of at least one compound of formula I: wherein R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted with alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; R 2 selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl; R 3 selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ; R 5 selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X is selected from O, (CH2)p, NH, and p is 0 - 2, provided that when p = 0, Y1 - Y2 is not CH - CH2 or CH - O, and R 1 is not aryl; Y1 - Y2 is selected from CH - CH2, CH - O or C = CH, provided that when Y1 - Y2 is CH - O, X is selected from O or NH, and R 1 is not hydrogen or alkyl; and Y3 is selected from H or Me, its stereoisomers or its pharmaceutically acceptable salts.

3. The method according to claim 1, wherein Y3 is H, and the compound is a compound according to formula II: wherein R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted with alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; R 2 selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl; R 3 selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ; R 5 selected from the group consisting of an alkyl group, a haloalkyl group, a cycloalkyl group, an aryl group or an amine; R 6 selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X is selected from O, (CH2)p, NH, and p is 0 - 2; Y1 - Y2 is selected from CH - CH2, CH - O or C = CH, provided that when Y1 - Y2 is CH - O, X is selected from O or NH or R 1 which is not hydrogen; and Y3 is selected from H or Me, its stereoisomers or its pharmaceutically acceptable salts.

4. The method according to claim 2, wherein Y3 is H, and the compound is a compound according to formula II: wherein R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; R 2 selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl; R 3 selected from the group consisting of an alkyl group, a cycloalkyl group, a hydroxyl group, an amine, an alkylamine or an alkoxy group; R 4 selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ; R 5 selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X is selected from O, (CH2)p, NH, and p is from 0 to 2, provided that when p = 0, Y1 - Y2 is not CH - CH2 or CHO, and R 1 is not aryl; and Y1 - Y2 is selected from CH - CH2, CH - O or C=CH, provided that when Y1 - Y2 is CH - O, X is selected from O or NH, and R 1 is not hydrogen or alkyl, its stereoisomers or its pharmaceutically acceptable salts.

5. The method according to claim 1, wherein Y3 is H, Y1 - Y2 is C=CH, and the compound is a compound according to formula III: wherein R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 , SO2NHR 2 or COR 3 ; R 2 selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl; R 3 selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , SO2NHR 2 , COR 3 ; R 5 selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl; and X is selected from O, (CH2)p, NH, and p is 0 - 2, its stereoisomers or its pharmaceutically acceptable salts.

6. The method according to claim 1, wherein Y3 is H, Y1 - Y2 is CH - CH2, and the compound is a compound according to formula IV: wherein R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 , SO2NHR 2 , COR 3 ; R 2 selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl; R 3 selected from the group consisting of an alkyl group, a cycloalkyl group, a hydroxyl group, an amine, an alkylamine or an alkoxy group; R 4 selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , COR 3 ; R 5 selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl, the aryl or heteroaryl being optionally substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl; and X is selected from O, (CH2)p, NH, and p is 0 - 2, its stereoisomers or its pharmaceutically acceptable salts.

7. The method according to claim 2, wherein Y3 is H, Y1 - Y2 is CH - CH2, and the compound is a compound according to formula IV: wherein R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 , SO2NHR 2 , COR 3 ; R 2 selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl; R 3 selected from the group consisting of an alkyl group, a cycloalkyl group, a hydroxyl group, an amine, an alkylamine or an alkoxy group; R 4 selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , COR 3 ; R 5 selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl; X is selected from O, (CH2)p, NH; where p is 0 - 2, provided that when p = 0, R 1 is not an aryl group, its stereoisomers or its pharmaceutically acceptable salts.

8. The method according to claim 1, wherein, The compound of formula 1 is one or more of the following compounds: its stereoisomers or its pharmaceutically acceptable salts.

9. The method according to claim 1, wherein The compound of formula I is one of the following compounds: its stereoisomers or its pharmaceutically acceptable salts.

10. The method according to claim 1, wherein, The compound of formula I is one or more of the following compounds: its stereoisomers or its pharmaceutically acceptable salts.

11. The method according to claim 1, wherein The compound inhibits soluble epoxide hydrolase at a concentration (IC 50 ) of less than 10 μM.

12. The method according to claim 1, wherein, The compound inhibits soluble epoxide hydrolase at a concentration (IC 50 ) of less than 100 nM.

13. The method according to claim 1, wherein The compound inhibits soluble epoxide hydrolase at a concentration (IC 50 ) of less than 100 nM and has at least 10-fold selectivity in its inhibition relative to fatty acid amide hydrolase (IC 50 , FAAH (SEQ ID NO:5)).

14. The method according to claim 1, wherein, The compound inhibits soluble epoxide hydrolase at a concentration (IC 50 ) of less than 100 nM and inhibits fatty acid amide hydrolase (FAAH (SEQ ID NO: 5)) at a concentration (IC 50 ) of greater than 1000 nM.

15. 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 cancer, bladder cancer, gastrointestinal cancer, kidney cancer, breast cancer, gastric cardia 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, genital cancer, colon cancer, colorectal cancer, testicular cancer, laryngeal cancer or a combination of the above cancers.

16. The method according to claim 1, wherein, The cancer is selected from the group consisting of glioblastoma, melanoma, breast cancer, colon cancer or a combination of the above cancers.

17. The method according to claim 1, wherein, Administering the compound to reduce tumor size and / or inhibit tumor growth.

18. The method according to claim 1, wherein Administering the compound to inhibit metastasis of the primary tumor.

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

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

21. The method according to claim 1, further comprising administering at least one additional compound, the at least one additional compound being selected from at least one chemotherapeutic agent, at least one immune checkpoint inhibitor, at least one anti - inflammatory agent or a combination of the above.

22. The method according to 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. The method according to 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. The method according to claim 21, wherein The immune checkpoint inhibitor is selected from the group consisting of: pembrolizumab, nivolumab, cemiplimab, ipilimumab, atezolizumab, avelumab, durvalumab, or a combination of the foregoing.

25. The method according to claim 21, wherein The at least one anti-inflammatory agent is selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase-2 (cox-2) (SEQ ID NO:4) inhibitors, ω-3 fatty acids, or a combination of the foregoing.

26. The method according to 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 a combination of the foregoing.

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

28. A method of reducing toxicity and / or adverse side effects experienced by a patient administered one or more chemotherapeutic agents or checkpoint inhibitors, the method comprising administering to a subject at least one compound of Formula I: Wherein, R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; R 2 selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl; R 3 selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ; R 5 selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X is selected from O, (CH2)p, NH, and p is 0-2; Y1 - Y2 is selected from CH - CH2, CH - O or C=CH, provided that when Y1 - Y2 is CH - O, X is selected from O or NH or R 1 is not hydrogen; and Y3 may be selected from H or Me, Its stereoisomers or pharmaceutically acceptable salts thereof.

29. A method of reducing toxicity and / or adverse side effects experienced by a patient administered one or more chemotherapeutic agents or checkpoint inhibitors, the method comprising administering to a subject at least one compound of Formula I: Wherein R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; R 2 selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl; R 3 selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ; R 5 selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X is selected from O, (CH2)p, NH, and p is 0 - 2; however, when p = 0, Y1 - Y2 is not CH - CH2 or CH - O, and R 1 is not aryl; Y1 - Y2 is 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 which is not hydrogen or alkyl; and Y3 may be selected from H or Me, Its stereoisomers or pharmaceutically acceptable salts thereof.

30. The method according to claim 28 or 29, wherein, The compound of Formula I reduces nerve damage caused by administering the one or more chemotherapeutic agents.

31. A method of treating cancer, comprising administering to a subject a therapeutically effective amount of a soluble epoxide hydrolase inhibitor.

32. A method of treating cancer, comprising administering to a subject a therapeutically effective amount of a soluble epoxide hydrolase inhibitor and a therapeutically effective amount of one or more immune checkpoint inhibitors.

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

34. A compound of Formula I: Wherein R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; R 2 selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl; R 3 selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ; R 5 selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X is selected from O, (CH2)p, NH, and p is 0-2; Y1 - Y2 is selected from CH-CH2, CH-O or C=CH, provided that when Y1 - Y2 is CH-O, X is selected from O or NH or R 1 which is not hydrogen; and Y3 may be selected from H or Me, Its stereoisomers or pharmaceutically acceptable salts thereof, for treating cancer.

35. A compound of Formula I, comprising: Wherein, R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted with alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; R 2 selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl; R 3 selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ; R 5 selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X is selected from O, (CH2)p, NH, and p is 0 - 2, provided that when p = 0, Y1 - Y2 is not CH - CH2 or CH - O, and R 1 is not aryl; Y1 - Y2 is selected from CH-CH2, CH-O or C=CH, provided that when Y1 - Y2 is CH-O, X is selected from O or NH and R 1 is not hydrogen or alkyl; and Y3 may be selected from H or Me, Its stereoisomers or pharmaceutically acceptable salts thereof, for treating cancer.

36. A soluble epoxide hydrolase inhibitor for reducing toxicity and / or adverse side effects experienced by a patient administered one or more chemotherapeutic agents or checkpoint inhibitors.

37. A soluble epoxide hydrolase inhibitor for treating cancer.

38. A composition comprising a soluble epoxide hydrolase and an immune checkpoint inhibitor for treating cancer or reducing the side effects of an immune checkpoint inhibitor.

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