Piperidine urea derivatives as soluble epoxide hydrolase inhibitors

Abstract

Described herein are novel piperidine urea derived compounds and pharmaceutical compositions thereof for the treatment of conditions and diseases mediated by soluble epoxide hydrolases.

Description

[Technical Field]

[0001] The subject matter disclosed herein is generally directed towards methods and compositions for the treatment of pain and neurodegenerative diseases, in particular, selective piperidine urea-derived compounds for the treatment of neuropathic pain and neurodegenerative diseases, as well as methods for the treatment of conditions and diseases mediated by soluble epoxide hydrolases. [Background technology]

[0002] The epoxidation of arachidonic acid by cytochrome P450 enzymes during inflammation and injury yields epoxyeicosatrienoic acid (EET). EET has a variety of biological effects, including modulation of inflammation, endothelial function, and neuronal cell survival. EET levels are regulated by soluble epoxide hydrolase (sEH), the main enzyme responsible for their degradation and conversion to inactive dihydroxyeicosatrienoic acid (DHET). sEH thereby limits many of the biological effects of EET. EET produces important biological effects, particularly in the vascular and nervous systems. Inhibition of sEH increases the half-life of EET, which then translates into beneficial therapeutic effects.

[0003] sEH inhibitors may be useful in the treatment of neuropathic and inflammatory pain, neurodegenerative diseases, acute respiratory distress syndrome (ARDS), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and Crohn's disease [Non-Patent Literature 1; Non-Patent Literature 2, Non-Patent Literature 3; Non-Patent Literature 4; Non-Patent Literature 5; Non-Patent Literature 6; Non-Patent Literature 7; Non-Patent Literature 8, Non-Patent Literature 9, Non-Patent Literature 10; Non-Patent Literature 11; Non-Patent Literature 12, Non-Patent Literature 13, Non-Patent Literature 14, Non-Patent Literature 15; Non-Patent Literature 16; Non-Patent Literature 17]. sEH inhibitors reduce the expression of inflammatory genes and show potential usefulness in inflammatory diseases (Non-Patent Literature 10). 14,15-EET is about 35 times more potent than morphine and stimulates met-enkaphline in the brain, suggesting potential usefulness for analgesia (Non-Patent Literature 18).

[0004] Several studies have verified that EET and sEH inhibition possess neuroprotective properties. sEH is highly expressed in the brain, and EET production and metabolism in the brain extend to many regions, including peripheral and central neurons, astrocytes and oligodendrocytes, vascular endothelial cells, and smooth muscle cells [Non-Patent Literature 19, 20, 21, 22]. Studies have shown that inhibition of EET or sEH i) prevents cytokine and oxidant-mediated injury in neuronal cells; ii) prevents endoplasmic reticulum (ER) stress, a key contributor to dopaminergic neuron loss; iii) increases astrocyte release of vascular endothelial growth factor and neuronal recovery after oxygen-glucose depletion; and iv) promotes axonal growth [Non-Patent Literature 23, 24, 25, 26, 27, 28, 29, 30, and 31]. sEH deficiency attenuates dopaminergic neuronal cell loss in a paraquat-induced mouse model of Parkinson's disease [Non-Patent Literature 32]. Inhibition of sEH reduces neuropathy and neuropathic pain, including diabetic neuropathic pain, in multiple animal models [Non-Patent Literature 33, 34, 35, 36, 37]. sEH levels are elevated in cortical brain tissue from subjects with cognitive impairment, and sEH inhibition prevents H2O2-induced hyperphosphorylation of tau protein, a key factor in the pathogenesis of Alzheimer's disease [Non-Patent Literature 38, 39]. sEH inhibition is protective in rodent models of ischemic and diabetic stroke [Non-Patent Literature 40, 41, 42, 43].

[0005] Therefore, an object of this disclosure is to provide methods and novel compositions for the treatment of pain and neurodegenerative diseases, in particular selective piperidine urea-derived compounds for the treatment of neuropathic pain and Parkinson's disease, as well as methods for the treatment of conditions and diseases mediated by soluble epoxide hydrolase.

[0006] Any reference or identification of any document in this application does not constitute an endorsement that such document is available as prior art to this disclosure. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International Publication No. 2013 / 057322 [Non-patent literature]

[0008] [Non-Patent Document 1] Biomolecules (2020), 10, 703-724 [Non-Patent Document 2] Proc. Natl. Acad. Sciences. (2018), 115, E5815-E5823 [Non-Patent Document 3] Neurotherapeutics. (2020), 17(3), 900-916 [Non-Patent Document 4] Proc. Natl. Acad. Sciences. (2008),105 (48), 18901-18906 [Non-Patent Document 5] Pharmacology & Therapeutics 180 (2017) 62-76 [Non-Patent Document 6] Nat. Rev. Drug. Discov. (2009), 8(10), 794-805 [Non-Patent Document 7] Cardiovasc. Hematol. Agents Med. Chem. (2012), Sep, 10(3), 212-22 [Non-Patent Document 8] Prostaglandins and Other Lipid Mediators 140 (2019) 31-39 [Non-Patent Document 9] Progress in Neurobiology, (2019), 172, 23-39

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-licensed Document 14

Non-licensed Document 15

Non-licensed Document 16

Non-licensed Document 17

Non-licensed Document 18

Non-licensed Document 19

Non-licensed Document 20

Non-licensed Document 21

Non-licensed Document 22

Non-licensed Document 36

Non-licensed Document 37

Non-licensed Document 38

Non-licensed Document 39

Non-licensed Document 40

Non-licensed Document 41

Non-licensed Document 42

Non-licensed Document 43

Non-licensed Document 44

Non-licensed Document 45

Non-licensed Document 46

Non-licensed Document 47

Non-licensed Document 48

Non-Patent Document 49

Non-Patent Document 50

Summary of the Invention

[0009] In the first embodiment, the above object is achieved in accordance with the present disclosure by providing a composition that may include at least one of a compound of formula I:

[0010] <000​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Selected from the group consisting of, R 5 This is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine. R 6 The group is selected from alkyl, cycloalkyl, aryl, or heteroaryl. The aryl or heteroaryl may be optionally substituted once or more times with a group or substituent, such as alkyl, hydroxy, halogen, or haloalkyl. X is selected from O, (CH2)p, NH; p is selected from 0 to 2, and Y1-Y2 is selected from CH2-CH2, CH2-O, or CH=CH; if Y1-Y2 is CH2-O, then X is selected from O or NH; or R 1 It is not hydrogen, Y3 is selected from H or Me.

[0012] In further embodiments, the composition, Formula II:

[0013] [ka]

[0014] They may also be provided according to their stereoisomers or pharmaceutically acceptable salts; During the ceremony, R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and R 1 This refers to a group or substituent, such as alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 COR 3 It may be optionally replaced once or multiple times, R 2 This is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl. R 3This is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy. R 4 These include hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, and SO2R. 5 COR 3 Selected from the group consisting of, R 5 This is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine. R 6 The group is selected from alkyl, cycloalkyl, aryl, or heteroaryl. The aryl or heteroaryl may be optionally substituted once or more times with a group or substituent, such as alkyl, hydroxy, halogen, or haloalkyl. X is selected from O, (CH2)p, NH; p is selected from 0 to 2, and Y1-Y2 is selected from CH2-CH2, CH2-O, or CH=CH; however, if Y1-Y2 is CH2-O, then X is selected from O or NH, or R 1 It is not hydrogen.

[0015] In a further embodiment, the composition is Formula III:

[0016] [ka]

[0017] They may also be provided according to their stereoisomers or pharmaceutically acceptable salts; During the ceremony, R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and R 1 This refers to a group or substituent, such as alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 SO2NHR 2COR 3 It may be optionally replaced once or multiple times, R 2 This is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl. R 3 This is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy. R 4 These include hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, and SO2R. 5 COR 3 Selected from the group consisting of, R 5 This is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine. R 6 The group is selected from alkyl, cycloalkyl, aryl, or heteroaryl. The aryl or heteroaryl may be optionally substituted once or more times with a group or substituent, such as alkyl, hydroxy, halogen, or haloalkyl. X is selected from O, (CH2)p, and NH; p is selected from 0 to 2.

[0018] In a further embodiment, the composition is formula IV:

[0019] [ka]

[0020] They may also be provided as compositions of the stereoisomer or pharmaceutically acceptable salt thereof; During the ceremony, R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and R 1 This refers to a group or substituent, such as alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R5 SO2NHR 2 COR 3 It may be optionally replaced once or multiple times, R 2 This is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl. R 3 This is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy. R 4 These include hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, and SO2R. 5 COR 3 Selected from the group consisting of, R 5 This is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine. R 6 The group is selected from alkyl, cycloalkyl, aryl, or heteroaryl. The aryl or heteroaryl may be optionally substituted once or more times with a group or substituent, such as alkyl, hydroxy, halogen, or haloalkyl. X is selected from O, (CH2)p, and NH; p is selected from 0 to 2.

[0021] Furthermore, the composition may contain one or more of the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0022] [ka]

[0023] [ka]

[0024] [ka]

[0025] Furthermore, this disclosure may provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound as shown herein.

[0026] In a further embodiment, a method for performing treatment on a subject requiring treatment for pain or neurodegenerative disease or other inflammatory disease, wherein the subject is given a therapeutically effective amount of Formula I:

[0027] [ka]

[0028] A method may be provided that involves administering at least one compound of the stereoisomer or a pharmaceutically acceptable salt thereof.

[0029] Furthermore, the method is Formula II for the treatment of pain or neurodegenerative diseases in a therapeutically effective amount:

[0030] [ka]

[0031] This may include administering at least one of the compounds, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0032] Furthermore, the method involves formula III for the treatment of pain or neurodegenerative diseases in a therapeutically effective amount for the subject:

[0033] [ka]

[0034] This may include administering at least one of the compounds, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0035] Furthermore, the method involves formula IV for the treatment of pain or neurodegenerative diseases in a therapeutically effective amount for the subject:

[0036] [ka]

[0037] This may include administering at least one of the compounds, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0038] Furthermore, the method may include administering a therapeutically effective dose of at least one compound, selected from one or more of the following, for the treatment of pain or neurodegenerative disease:

[0039] [ka]

[0040] [ka]

[0041] [ka]

[0042] Furthermore, the Disclosure may provide a method for providing treatment to a subject requiring treatment for neuropathic pain or inflammatory pain, comprising administering to the subject a therapeutically effective amount of one of the compositions described herein.

[0043] Furthermore, a method may be provided for performing treatment on a subject requiring treatment for Parkinson's disease, comprising administering to the subject a therapeutically effective amount of the composition described herein.

[0044] These and other aspects, purposes, features, and advantages of the exemplary embodiments will become apparent to those skilled in the art, considering the following detailed description of the exemplary embodiments.

[0045] An understanding of the features and advantages of this disclosure can be obtained by referring to the following detailed description illustrating exemplary embodiments in which the principles of this disclosure may be utilized, and to the accompanying drawings. [Brief explanation of the drawing]

[0046] [Figure 1] Figure 1 shows the soluble epoxide hydrolase inhibitory activity of the compounds of formula I, as shown in Table 1. [Figure 2] Figure 2 shows the soluble epoxide hydrolase inhibitory activity of the compound of formula I, as shown in Table 1 (continued). [Figure 3] Figure 3 shows the efficacy of the compound of formula I in a neuropathic pain model. [Figure 4] Figure 4 shows the efficacy of compound A of formula I in a model of diabetic peripheral neuropathy. [Figure 5] Figure 5 shows the efficacy of compound B of formula I in a Parkinson's disease model (improvement in spontaneous motor activity). [Figure 6] Figure 6 shows the neuroprotective effects of compound B of formula I in a Parkinson's disease model. [Figure 7] Figure 7 shows the efficacy of compound B of formula I (improvement in spontaneous motor activity) in a rodent model of Parkinson's disease. [Modes for carrying out the invention]

[0047] The drawings in this application are for illustrative purposes only and are not necessarily drawn to scale.

[0048] Detailed description of exemplary embodiments Before this disclosure is described in more detail, it should be understood that this disclosure is not limited to the specific embodiments described and is therefore naturally subject to change. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0049] Unless otherwise explicitly stated, the terms and phrases used in this document, as well as their variations, should be interpreted as open-ended rather than restrictive. Similarly, groups of items linked with the conjunction "and" should not be read as requiring the existence of each and every one of those items in the group, but rather as "and / or" unless otherwise explicitly stated. Likewise, groups of items linked with the conjunction "or" should not be read as requiring mutual exclusivity within the group, but rather as "and / or" unless otherwise explicitly stated.

[0050] Furthermore, while the items, elements, or components of this disclosure may be described or claimed singly, unless explicitly stated to be singular, it is assumed that they may encompass multiple terms. The presence of phrases such as “one or more,” “at least,” “but not limited to,” or other similar phrases in some cases should not be interpreted as meaning that a narrower case is intended or required in cases where such broader phrases may not be present.

[0051] Unless otherwise defined, all scientific and technical terms used herein have the same meanings as those commonly understood by those skilled in the art to which this disclosure pertains. Any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of this disclosure, but preferred methods and materials are described herein.

[0052] All publications and patents referenced herein are referenced to disclose and describe methods and / or materials in the context in which they are referenced. All such publications and patents are incorporated herein by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. Such incorporation by reference is expressly limited to the methods and / or materials described in the referenced publications and patents and does not extend to any lexicographical definitions from the referenced publications and patents. Any lexicographical definitions in the referenced publications and patents that are not expressly repeated in this application should not be treated as such and should not be read as defining any term appearing in the accompanying claims. Any reference to any publication is to its disclosure prior to the filing date and this disclosure should not be construed as an acknowledgment that there is no prior right to such publication on the grounds of prior disclosure. Furthermore, the dates of publications provided may differ from the actual publication dates, and the actual publication dates may need to be independently verified.

[0053] As will be apparent to those skilled in the art by reading this disclosure, each of the individual embodiments described and illustrated in this application has separate components and features that can be readily separated or combined with respect to the features of any of several other embodiments without deviating from the scope or spirit of this disclosure. Any described method may be performed in the order of the described events, or in any other logically possible order.

[0054] Where a range is expressed, further embodiments include those from one specific value and / or to another specific value. A numerical range description by endpoints includes the endpoints described, as well as all the numbers and ratios contained within each range. Where a range of values ​​is provided, it is understood that each intervening value between the upper and lower limits of that range, up to one-tenth of the lower limit unit unless the context otherwise explicitly specifies, and any other described or intervening values ​​within that described range are included in this disclosure. The upper and lower limits of these smaller ranges may be independently contained within and also included in this disclosure and subject to any particularly excluded limits within the described range. Where a described range includes one or both limits, the range excluding either or both of those included limits is also included in this disclosure. For example, if a described range includes one or both of the limits, the range excluding either or both of those limits is also included in this disclosure. For example, the phrase "x~y" includes the range from "x" to "y," as well as the range greater than "x" and less than "y." A range can also be expressed as an upper limit, for example, "about x, y, z, or less," which should be interpreted as including the ranges "less than x," "less than y," and "less than z," in addition to the specific ranges of "about x," "about y," and "about z." Similarly, the phrase "about x, y, z, or greater than" should be interpreted as including the ranges "greater than x," "greater than y," and "greater than z," in addition to the specific ranges of "about x," "about y," and "about z." Additionally, the phrase "about "x"~"y"" (where "x" and "y" are numerical values) includes "about "x"~"."

[0055] It should be noted that ratios, concentrations, quantities, and other numerical data may be expressed herein in the form of ranges. It will be further understood that each endpoint of a range has significance both with respect to and independently of the other endpoints. It will also be understood that a number of values ​​will be disclosed herein, and that each value will also be disclosed herein not only as the value itself but also as "about" that particular value. For example, if the value "10" is disclosed, "about 10" is also disclosed. Ranges may be expressed herein as "about" one particular value and / or "about" another particular value. Similarly, it will be understood that if a value is expressed as approximate by the use of the preceding word "about," that particular value forms further aspects. For example, if the value "about 10" is disclosed, "10" is also disclosed.

[0056] Such range formats are used for convenience and conciseness, and therefore should be understood to be interpreted flexibly to include not only the numerical value explicitly stated as the limit of the range, but also all individual numerical values ​​or sub-ranges contained within that range, as if each numerical value and sub-range were explicitly stated. For example, the numerical range "approximately 0.1% to 5%" should be interpreted to include not only the explicitly stated value of approximately 0.1% to approximately 5%, but also the individual values ​​within the indicated range (e.g., approximately 1%, approximately 2%, approximately 3%, and approximately 4%) as well as sub-ranges (e.g., approximately 0.5% to approximately 1.1%; approximately 5% to approximately 2.4%; approximately 0.5% to approximately 3.2%; and approximately 0.5% to approximately 4.4%, and other possible sub-ranges).

[0057] As used herein, the singular forms "a," "an," and "the" include both singular and plural references unless the context otherwise explicitly specifies.

[0058] As used herein, “about,” “approximately,” and “substantially,” when used in connection with measurable variables such as parameters, quantities, and temporal lengths, mean to include variations of a specified value and its deviations from that value, such as variations of + / -10% or less, + / -5% or less, + / -1% or less, and + / -0.1% or less from the specified value, including those within experimental error (which may be determined, for example, by a given dataset, by standards accepted in the art, and / or by a given confidence interval, for example, a 90%, 95%, or higher % confidence interval from the mean), provided that such variations are appropriate for the practices described herein. As used herein, the terms “about,” “approximately,” “…or about…,” and “substantially” may mean that the quantity or value in question may be an exact value or a value that provides results or effects equivalent to those described in the claims or taught herein. That is, quantities, sizes, formulations, parameters, and other quantities and characteristics are not and do not need to be exact, and may be approximate and / or greater or less, if desired, to reflect tolerances, conversion factors, rounding, and measurement errors, and other factors known to those skilled in the art, so as to yield equivalent results or effects. In some circumstances, it is not reasonably possible to determine values ​​that will yield equivalent results or effects. In general, quantities, sizes, formulations, parameters, or other quantities or characteristics are “about,” “approximately,” or “…or about…,” whether explicitly stated as such. When “about,” “approximately,” or “…or about…” is used before a quantitative value, it is understood that the parameter also includes a specific quantitative value itself, unless otherwise specifically stated.

[0059] As used herein, “biological sample” may contain whole cells and / or living cells and / or cell debris. A biological sample may contain (or be derived from) “body fluids.” This disclosure includes amniotic fluid, aqueous humor, vitreous fluid, bile, serum, and maternal fluid. This includes embodiments selected from milk, cerebrospinal fluid, earwax, chyle, porridge, endolymph, perilymph, exudate, feces, female ejaculate, gastric acid, gastric juice, lymph, mucus (including nasal mucus and sputum), pericardial fluid, peritoneal fluid, pleural fluid, pus, mucosal secretions, saliva, sebum (skin oil), semen, sputum, synovial fluid, sweat, tears, urine, vaginal secretions, vomit, and one or more mixtures thereof. Biological samples include cell cultures, body fluids, and cell cultures from body fluids. Body fluids may be obtained from mammalian organisms, for example, by puncture or other collection or extraction procedures.

[0060] As used herein, “agent” refers to any substance, compound, and molecule, etc., that can be administered to an agent. An agent may be inert. An agent may be an activator. An agent may be a primary activator, or in other words, a component of a composition to which all or part of the effect of the composition is attributed. An agent may be a secondary agent, or in other words, a component of a composition to which additional part and / or other effects of the composition are attributed.

[0061] As used herein, “activator” or “active ingredient” means a substance, compound, or molecule that is biologically active or otherwise induces a biological or physiological effect in the subject to which it is administered. In other words, “activator” or “active ingredient” means one or more components of a composition to which all or part of the effect of the composition is attributable.

[0062] As used herein, “administration” means any suitable administration for the delivery of the agent and / or for a subject to be given the agent, and can be oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, ventricular, intraosseous, intraocular, intracranial, intraperitoneal, intrafocal, intranasal, cardiac, intra-articular, intracavitary, intramedullary, intravitreous, intracerebral, ventricular, tympanic, cochlear, rectal, vaginal, by inhalation, by catheter, stent, or via an implanted reservoir or other device that administers the composition into the perivascular space and adventitia, either actively or passively (e.g., by diffusion). For example, a medical device, such as a stent, may contain a composition or formulation disposed on its surface, which can then be dissolved or otherwise distributed to surrounding tissues and cells. The term "parenteral" can include subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intrafocal, and intracranial injection or infusion techniques.The routes of administration include, for example, the auricle (ear), buccal side, conjunctiva, skin, teeth, electroosmosis, intracervix, endosinusial, intratracheal, intestinal, epidural, extraamniotic, extracorporeal, hemodialysis, infiltration, interstitium, intraabdomen, intraamniotic, intraarterial, intraarticular, intrabiliary, intrabronchial, intrabursal, intracardiac, intracartilage, intrasacral, intracavitary, intracerebral, cisterna magna, and cornea. Internal, within the tooth crown, within the corona, within the corpus cavernosum, within the skin, within the disc, within the glandular duct, within the duodenum, within the dura mater, within the epithelium, within the esophagus, within the stomach, within the gingiva, within the ileum, within the lesion, intraluminal, within the lymph, within the medullary, within the meninges, within the muscle, within the eye, within the ovary, within the pericardium, within the abdominal cavity, within the pleura, within the prostate, within the lung, within the sinus, within the spinal cord, within the synovial sac, within the tendon, within the testis, within the medullary cavity, chest Administration can be intracavitary, intratubular, intratumoral, intratympanic, intrauterine, intravascular, intravenous, intravenous bolus, intravenous infusion, intraventricular, intravesical, intravitreous, iontophoresis, irrigation, larynx, transnasal, transnasogastric, obstructive dressing techniques, ophthalmic, oral, oropharyngeal, other, parenteral, percutaneous, periarticular, peridural, perineurial, periodontal, rectal, respiratory (inhalation), retrobulbar, soft tissue, subarachnoid, subconjunctival, subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transplacental, transtracheal, transtympanic, ureter, urethra, and / or vaginal administration, 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.

[0063] As used herein, “control” may refer to an alternative subject or sample used in an experiment for comparative purposes and included to minimize or distinguish the effects of variables other than the independent variable.

[0064] The term "optional" or "optional" means that the subsequent events, situations, or substituents may or may not be present, and that the description includes both instances where the events or situations are present and instances where they are not.

[0065] As used herein, “dose,” “unit dose,” or “dosage” may refer to physically separate units suitable for use in a subject, each unit containing a predetermined amount of a pharmaceutical preparation calculated to produce one or more desired responses in relation to its administration.

[0066] As used herein, the term "molecular weight" may generally refer to the mass or average mass of a material.

[0067] The terms “subject,” “individual,” and “patient” are used interchangeably herein to refer to vertebrates, preferably mammals, more preferably humans. Mammals include, but are not limited to, rodents, apes, humans, farm animals, sports animals, and companion animals. Tissues, cells, and their offspring of biological entities obtained in vivo or cultured in vitro are also included in the term “subject.”

[0068] As used herein, “substantially pure” can mean that the species of interest is the dominant species present (i.e., based on molar concentration, it is more abundant than any other individual species in the composition), and preferably, a substantially purified fraction is a composition in which the species of interest constitutes about 50 percent of all species present. Generally, a substantially pure composition constitutes more than about 80 percent of all species present in the composition, more preferably about 85%, 90%, 95%, and 99%. Most preferably, the species of interest is purified to an essential homogeneity (impurity species cannot be detected in the composition by conventional detection methods), and the composition is essentially composed of a single species.

[0069] Where used interchangeably in this specification, the terms “sufficient” and “effective” may refer to the amount (e.g., mass, volume, dosage, concentration, and / or duration) required to achieve one or more desired and / or described results. For example, a therapeutically effective dose refers to the amount required to achieve one or more therapeutic effects.

[0070] As used herein, “tangible medium” means a physically tangible or accessible medium that is not merely abstract thought or unrecorded spoken words. “Tangible medium” includes, but is not limited to, words on cellulose or plastic material, or data stored in a suitable computer-readable storage form. The data may be stored on a unit device, such as flash memory or a CD-ROM, or on a server that can be accessed by a user, for example, via a web interface.

[0071] As used herein, the terms “to treat” and “treatment” can generally mean obtaining a desired pharmacological and / or physiological effect. The effect may be, but not necessarily, preventive in terms of preventing or partially preventing a disease, its symptoms or condition, such as cancer and / or indirect radiation injury. The effect may be therapeutic in terms of the partial or complete cure of a disease, condition, symptom or adverse effect attributable to a disease, disorder, or condition. As used herein, the term “treatment” covers any treatment of cancer and / or indirect radiation injury in a subject, particularly in humans and / or companion animals, and may include any one or more of the following: (a) preventing a disease or injury from occurring in a subject that may have a predisposition to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., stopping its onset; and (c) alleviating the disease, i.e., reducing or relieving the disease and / or its symptoms or condition. When used herein, the term “treatment” may refer to a therapeutic treatment alone, a preventive treatment alone, or both a therapeutic and preventive treatment. Those who require treatment (the subjects requiring it) may include those who already have a disability and / or those for whom disability should be prevented. When used herein, the term “to treat” may include inhibiting a disease, disability, or condition, e.g., preventing its progression; and alleviating a disease, disability, or condition, e.g., causing regression of the disease, disability, and / or condition. Treating a disease, disability, or condition may include relieving at least one symptom of a particular disease, disability, or condition, even if the underlying pathophysiology is not affected, e.g., treating pain in a subject by administering an analgesic, even if such an analgesic does not treat the cause of the pain.

[0072] Where used herein, the terms “weight percent,” “wt%,” and “wt.%” are interchangeable, unless otherwise specified, refer to the weight percentage of a given component based on the total weight of the composition in 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 ​​for 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 components in the composition, it should be understood that the sum of the wt% values ​​for a specified component in the disclosed composition or formulation is equal to 100.

[0073] "Halogen or halo" refers to fluorine, chlorine, bromine, or iodine.

[0074] The "alkyl" group refers to a linear or branched alkyl group. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl, heptyl, and octyl. Unless otherwise specified, alkyl groups typically have about 1 to about 10 carbon atoms.

[0075] The term "cycloalkyl" refers to a cyclic alkyl group, which may be monocyclic or bicyclic. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise specified, cycloalkyl groups typically have about 3 to about 10 carbon atoms.

[0076] A "haloalkyl" group refers to a linear or branched alkyl group in which at least one hydrogen atom is replaced by a halogen or halo group. Examples of haloalkyl groups include trifluoromethyl, chloroethyl, difluoromethyl, and difluoroethyl.

[0077] The "hydroxyalkyl" group refers to a linear monovalent hydrocarbon radical of 1 to 3 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 5 carbon atoms substituted with one or two hydroxyl groups, provided that if two hydroxyl groups are present, they are not both located on the same carbon atom. Typical examples include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, and 3-hydroxypropyl.

[0078] "Alkoxyalkyl" means a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms substituted with an alkoxy group, such as methoxymethyl, 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl.

[0079] "Heterocycloalkyl" means a non-aromatic monocyclic or polycyclic ring containing carbon and hydrogen atoms and at least one heteroatom, preferably 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. Heterocycloalkyl groups may have one or more carbon-carbon double bonds or carbon-heteroatom double bonds in the ring, provided that the ring is not made aromatic by their presence. Examples of heterocycloalkyl groups include pyrrolidinyl pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, tetrahydrofuranyl, tetrahydropyranyl, and pyranyl.

[0080] "Alkoxy" refers to an -O (alkyl) group, where alkyl is defined above. Exemplary alkoxyl groups include methoxy, ethoxy, propoxy, butoxy, iso-propoxy, and iso-butoxy. Unless otherwise specified, alkoxy groups typically have 1 to about 10 carbon atoms.

[0081] "Amine" refers to a primary, secondary, or tertiary amino group. Secondary and tertiary amines may contain alkyl, cycloalkyl, or aryl substitutions. Some examples of amines include NH2, NHMe, and NMe2NH(cyclopropyl). Unless otherwise specified, the alkyl or cycloalkyl group on the amine typically has 1 to about 8 carbon atoms.

[0082] "Aryl" refers to a monocyclic or polycyclic aromatic ring system in which approximately 6 to approximately 14 carbon atoms are optionally substituted. Exemplary aryl groups include phenyl and naphthyl. Unless otherwise specified, aryl groups typically have 6 to approximately 14 carbon atoms.

[0083] "Heteroaryl" means an aromatic monocyclic or polycyclic ring system of about 4 to about 12 carbon atoms having at least one heteroatom or heterogroup selected from -O-, -N-, -S-, -SO2, or -CO. Exemplary heteroaryl groups include one or more of pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, imidazolyl, triazolyl, pyridadinyl, thienopyrimidyl, furanyl, indolyl, isoindolyl, benzo[1,3]dioxolyl, benzimidazolyl, 1,3-benzoxathiolyl, pyrrolidine, 2,4-dionyl, quinazolinyl, pyridyl, pyrimidinyl, and thiophenyl. Unless otherwise specified, heteroaryl groups typically have 4 to about 10 carbon atoms.

[0084] A "5-6 membered heteroaryl" is an aromatic monocyclic ring system of 5 or 6 ring atoms having at least one heteroatom or heterogroup selected from -O-, -N-, -S-, -SO2, or -CO. Exemplary "5-6 membered heteroaryl" groups include one or more such groups as pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, pyridadinyl, pyridyl, thienopyrimidyl, tetrazolyl, imidazolyl, triazolyl, and furanyl.

[0085] "Optionally substituted" means that the substitution is optional, and therefore the specified atom or molecule can be unsubstituted. If a substitution is desired, such a substitution means that any number of hydrogens on the specified atom are replaced with those selected from the indicated group, provided that the number of hydrogens does not exceed the normal valency of the specified atom, and the substitution results in a compound that is sufficiently stable for use.

[0086] "Salt" means any acid or base salt, pharmaceutically acceptable solvate, or any compound of a compound that, when administered to a recipient, has the ability to provide (directly or indirectly) the compound described herein. However, it should be understood that pharmaceutically acceptable salts also fall within the scope of this disclosure. Preparation of salts can be carried out using known methods. For example, pharmaceutically acceptable salts of compounds assumed herein to be useful may be synthesized by conventional chemical methods using a parent compound containing base or acid functionality. Generally, such salts may be prepared, for example, by preparing a free acid or base form of the compound and reacting it with a stoichiometric amount of a suitable base or acid in water or an organic solvent, or in a mixture of the two. Generally, non-aqueous media, such as solvents, one or more of which may be used, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Examples of acid addition salts include mineral acid addition salts, such as one or more hydrochlorides, hydrobroms, hydroiodides, sulfates, and phosphates, as well as one or more organic acid addition salts, such as one or more acetates, maleates, fumarates, citrates, oxalates, succinates, tartrates, malates, mandelates, methanesulfons, and p-toluenesulfons. Examples of base addition salts include inorganic salts, such as one or more sodium, potassium, calcium, ammonium, magnesium, and lithium salts, as well as one or more organic base salts, such as ethylenediamine, ethanolamine, N,N-dialkyl-ethanolamine, triethanolamine, and basic amino acid salts.

[0087] The term "therapeutably effective" refers to the ability of an agent or combination to prevent a disorder or improve its severity while generally avoiding adverse side effects that would discourage a patient from taking the administered agent. A therapeutically effective composition of the present disclosure may contain the compound of the present disclosure in doses of about 10 to about 3000 mg. The exact dosage may be determined based on a number of factors, including the patient's characteristics and the degree of treatment required.

[0088] Where used herein, “therapeutic dose” means the dose or amount and frequency of administration of the compound of this disclosure administered to a subject to result in any therapeutic response. The dose or effective dose to be administered to a subject and the frequency of administration to the subject can be readily determined by those skilled in the art by the use of known techniques and by observing results obtained under similar circumstances. In determining the effective dose or dosage, a number of factors may be considered by the diagnosing physician, 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; the sex, age, weight, overall health status and individual responsiveness of the subject to be treated; and other relevant circumstances.

[0089] The compounds described herein may be administered in the form of a pharmaceutical composition in mixture with one or more pharmaceutically acceptable excipients or carriers. A “composition” may contain one compound or a mixture of compounds. A “pharmaceutical composition” is any composition that is useful or potentially useful in generating a physiological response in a subject to which such a pharmaceutical composition is administered.

[0090] The term "pharmaceutically acceptable" is used with respect to excipients to define non-toxic substances that are generally suitable for use in human or animal pharmaceutical products. Pharmaceutical compositions may be in commonly used forms, such as tablets, capsules, powders, syrups, solutions, and suspensions. Pharmaceutical compositions may contain fragrances, sweeteners, etc., in a suitable solid or liquid carrier or diluent, or in a suitable sterile medium for forming an injectable solution or suspension. Such compositions typically contain about 0.1 to about 50% by weight, and some of the active ingredients. In its application form, the composition contains approximately 1-20% of the active compound, with the remainder being a pharmaceutically acceptable carrier, diluent, or solvent.

[0091] Various embodiments are described herein hereafter. It should be noted that specific embodiments are not intended to be exhaustive or to be a limitation to broader embodiments discussed herein. One embodiment described in conjunction with a particular embodiment is not necessarily limited to that embodiment and may be implemented in conjunction with any other embodiment. Throughout this specification, references to “one embodiment,” “one embodiment,” and “exemplary embodiment” mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of this disclosure. Thus, occurrences of the phrases “in one embodiment,” “in one embodiment,” or “exemplary embodiment” in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, a particular feature, structure, or characteristic may be combined in one or more embodiments in any preferred manner, as will be apparent to those skilled in the art from this disclosure. Furthermore, some embodiments described herein include some features included in other embodiments but not others, but combinations of features from different embodiments are within the scope of this disclosure. For example, in the appended claims, any of the claimed embodiments may be used in any combination.

[0092] All patents, patent applications, published applications, and publications, databases, websites, and other published materials referenced herein are incorporated by reference to the same extent as each individual publication, published patent document, or patent application is incorporated by reference, particularly and individually.

[0093] kit Any of the compounds and / or formulations described herein may be provided as a combination kit. Where used herein, the terms “combination kit” or “kit of parts” refer to any additional components used to package, sell, market, deliver, and / or administer a compound, composition, formulation, particle, cell, and any combination or single element contained therein, such as an active ingredient. Such additional components include, but are not limited to, packaging, syringes, blister packaging, and bottles. If one or more of the compounds, compositions, formulations, particles, or cells described herein, or a combination thereof (e.g., a drug), contained in a kit are administered simultaneously, the combination kit may contain the active ingredient in a single formulation, such as a pharmaceutical formulation (e.g., a tablet, liquid preparation, dehydrated preparation, etc.), or in separate formulations. If the compounds, compositions, formulations, particles, and cells described herein, or a combination thereof and / or kit components, are not administered simultaneously, the combination kit may contain each drug or other component in separate pharmaceutical formulations. Separate kit components may be contained in a single package within the kit or in separate packages.

[0094] In some embodiments, the combination kit also includes instructions printed on a tangible medium or otherwise contained therein. The instructions may provide information regarding the content of the compound and / or formulation, safety information regarding the content of the compound and formulation (e.g., pharmaceutical formulation), dosage information, instructions for use, and / or recommended treatment regimens for the compound and / or pharmaceutical formulation contained therein. In some embodiments, the instructions may provide instructions and protocols for administering the compound and / or formulation described herein to subjects requiring it. In some embodiments, the instructions may provide one or more embodiments of methods for administering the pharmaceutical formulation, for example, methods described in more detail elsewhere herein.

[0095] Detailed explanation of this disclosure Embodiments of the present disclosure are described in detail below, with one or more examples being provided below. Each example is provided as a description of the present disclosure, not as an limitation of the present disclosure. In fact, it will be apparent to those skilled in the art that various modifications can be made in the present disclosure without departing from the scope or spirit of the present disclosure. For example, a feature illustrated or described as part of one embodiment may be used in another embodiment to bring about a further embodiment. Therefore, the present disclosure is intended to cover such modifications and variations as falling within the scope of the appended claims and their equivalents. Other objects, features, and aspects of the present disclosure are disclosed in the following detailed description or are obvious from that description.

[0096] For ease of reference, this disclosure is written in terms of administration to human subjects. However, it should be understood that such description is not limited to administration to humans and includes administration to other animals unless otherwise explicitly stated.

[0097] The anticipated derivatives are those that can improve the solubility of the compounds of this disclosure or increase their bioavailability when administered to a subject (for example, by making orally administered compounds more readily absorbable). The compounds of formula I may be amorphous, semicrystalline, or crystalline, and may be given as the parent compound, its salt, and / or solvated form. The solvates may be partial or surface associations of the crystal lattice. All of these forms are intended to be within the scope of this disclosure. Methods of solvation are generally known in the art. A preferred solvate is a pharmaceutically acceptable solvate. In one embodiment, the solvate is a hydrate.

[0098] In one embodiment, this disclosure relates to Formula I:

[0099] [ka]

[0100] This is directed towards novel compounds, their stereoisomers, or pharmaceutically acceptable salts; During the ceremony, R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and R 1 This refers to a group or substituent, such as alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 COR 3 It may be optionally replaced once or multiple times, R 2 This is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl. R 3 This is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy. R 4These include hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, and alkoxy. SO2R 5 COR 3 Selected from the group consisting of, R 5 This is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine. R 6 The group is selected from alkyl, cycloalkyl, aryl, or heteroaryl. The aryl or heteroaryl may be optionally substituted once or more times with a group or substituent, such as alkyl, hydroxy, halogen, or haloalkyl. X is selected from O, (CH2)p, NH; p is selected from 0 to 2, and Y1-Y2 is selected from CH2-CH2, CH2-O, or CH=CH; if Y1-Y2 is CH2-O, then X is selected from O or NH, and R 1 It is not hydrogen, Y3 is selected from H or Me.

[0101] In another embodiment, this disclosure relates to Formula II:

[0102] [ka]

[0103] This is directed towards novel compounds, their stereoisomers, or pharmaceutically acceptable salts; During the ceremony, R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and R 1 This refers to a group or substituent, such as alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 COR 3 It may be optionally replaced once or multiple times, R2 This is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl. R 3 This is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy. R 4 These include hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, and SO2R. 5 COR 3 Selected from the group consisting of, R 5 This is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine. R 6 The group is selected from alkyl, cycloalkyl, aryl, or heteroaryl. The aryl or heteroaryl may be optionally substituted once or more times with a group or substituent, such as alkyl, hydroxy, halogen, or haloalkyl. X is selected from O, (CH2)p, NH; p is selected from 0 to 2, and Y1-Y2 is selected from CH2-CH2, CH2-O, or CH=CH; if Y1-Y2 is CH2-O, then X is selected from O or NH, and R 1 It is not hydrogen.

[0104] In another embodiment, this disclosure relates to Formula III:

[0105] [ka]

[0106] This is directed towards novel compounds, their stereoisomers, or pharmaceutically acceptable salts; During the ceremony, R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and R 1This refers to a group or substituent, such as alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 SO2NHR 2 COR 3 It may be optionally replaced once or multiple times, R 2 This is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl. R 3 This is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy. R 4 These include hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, and SO2R. 5 COR 3 Selected from the group consisting of, R 5 This is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine. R 6 The group is selected from alkyl, cycloalkyl, aryl, or heteroaryl. The aryl or heteroaryl may be optionally substituted once or more times with a group or substituent, such as alkyl, hydroxy, halogen, or haloalkyl. X is selected from O, (CH2)p, and NH; p is selected from 0 to 2.

[0107] In another embodiment, the present invention relates to formula IV:

[0108] [ka]

[0109] This is directed to novel compounds of the same, their stereoisomers, or their pharmaceutically acceptable salts; During the ceremony, R 1is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and R 1 is a group or substituent, for example alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 SO2NHR 2 COR 3 once or may be optionally substituted one or more times, R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl, R 3 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy, R 4 is selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 COR 3 and is selected from the group consisting of, R 5 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine, R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl. Aryl or heteroaryl may be optionally substituted one or more times with a group or substituent, for example alkyl, hydroxy, halogen, haloalkyl, X is selected from O, (CH2)p, NH; p is selected from 0 to 2.

[0110] Furthermore, the composition may comprise one or more of the following compounds, their stereoisomers or their pharmaceutically acceptable salts;

[0111]

Chemical formula

[0112]

Chemical formula

[0113] [ka]

[0114] In yet another embodiment, the disclosure is directed to novel compounds of formula I, their stereoisomers, their tautomers and / or pharmaceutically acceptable salts thereof, which may be used as inhibitors of soluble epoxide hydrolase (sEH).

[0115] In another embodiment, the Disclosure is directed to a method for performing prevention and / or treatment in subjects requiring prevention and / or treatment of pain, neurodegenerative diseases and inflammatory disorders, comprising administering to a subject a therapeutically effective amount of a compound of formula I, its stereoisomers and / or pharmaceutically acceptable salts thereof. Furthermore, a compound of formula I, its stereoisomers and / or pharmaceutically acceptable salts may be used for the prevention or treatment of diabetic peripheral neuropathy, chemotherapy-induced neuropathy, postherpetic neuralgia, trigeminal neuralgia, fibromyalgia and other neuropathic pain or inflammatory pain conditions.

[0116] Furthermore, the compound of formula I may be optionally combined with one or more anti-inflammatory or analgesic drugs, such as a cox-2 inhibitor, an NSAID, pregabalin, gabapentin, or an opioid, and administered to a subject for the treatment of an inflammatory and / or painful condition.

[0117] In another embodiment, stereoisomers and / or pharmaceutically acceptable salts of formula I may be used for the treatment of neurodegenerative diseases, such as Parkinson's disease.

[0118] For ease of reference, the present disclosure is described from the perspective of administration to a human subject. However, such description is not limited to administration to humans and it will be understood that administration to other animals is also included if not otherwise explicitly stated.

[0119] The derivatives contemplated are those which can improve the dissolution of such compounds or increase their bioavailability when the compounds of the present disclosure are administered to a subject (e.g., by making a compound administered orally more readily absorbed). The compounds of Formula I may be amorphous, semi-crystalline, or crystalline and may be provided as either the parent compound, its salts, and / or its solvated forms. Solvates may be those that are partially or superficially associated with the crystal lattice. It is intended that all of these forms should be within the scope of the present disclosure. Methods of solvation are generally known in the art. Preferred solvates are pharmaceutically acceptable solvates. In one embodiment, the solvate is a hydrate.

[0120] In one embodiment, the compounds of the present disclosure (compounds of Formula I) are useful for the treatment of inflammatory pain, neuropathic pain, rheumatoid arthritis, osteoarthritis, diabetic nephropathy, hypertension, diabetes, and / or metabolic syndrome. The compounds of Formula I may be useful for raising epoxyeicosatrienoic acid (EET) levels in a subject to prevent and treat inflammatory and / or pain conditions.

[0121] The compounds of Formula I, their pharmaceutically acceptable salts, and / or their solvates can therefore be used in the prevention and / or treatment of the diseases or conditions discussed herein. A pharmaceutical composition containing a therapeutically effective amount of a compound of Formula I, its pharmaceutically acceptable salt, and / or its solvate, optionally together with a pharmaceutically acceptable excipient, is a further aspect of the present disclosure.

[0122] The compounds of formula I that must be administered, the therapeutically effective doses of their pharmaceutically acceptable salts and / or solvates, and the dosages for treating a pathological condition with the compounds depend on a number of factors, including the patient's age, condition, the severity of the disease, the route and frequency of administration, and the modulator compounds used.

[0123] Suitable pharmaceutically acceptable carriers may include solid fillers or diluents and sterile aqueous or organic solutions. The active ingredient may be present in such a pharmaceutical composition in an amount sufficient to provide the desired dosage within the range described above. For oral administration, the active ingredient may be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, and suspensions, etc. For parenteral administration, the active ingredient may be combined with a sterile aqueous or organic medium to form an injectable solution or suspension. For example, aqueous solutions of water-soluble pharmaceutically acceptable acid addition salts or salts of compounds with bases may be used, in addition to solutions such as sesame or peanut oil and aqueous propylene glycol. Aqueous solutions containing the active ingredient dissolved in a pharmaceutically acceptable solvent, such as polyhydroxylated castor oil, may also be used for injectable solutions. Injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration generally preferred for humans.

[0124] The following embodiments describe exemplary embodiments of the present disclosure. Other embodiments within the scope of the claims of this application will be apparent to those skilled in the art from consideration of this specification or from the practice of the disclosures disclosed herein. This specification, together with the embodiments, is intended to be considered exemplary only, and the scope and spirit of this disclosure are indicated by the claims following the embodiments.

[0125] General synthesis procedure The compounds of this disclosure may be synthesized by following the procedures outlined in Schemes I to VIII. The suggested methodologies are not intended to be limiting. Variations of these synthetic methodologies or methodologies reported in the literature may be employed to synthesize compounds within the scope of this disclosure.

[0126] [ka]

[0127] Scheme I shows a method for synthesizing compound 7 of formula I of this disclosure. In the first step, substituted benzyl halide 1 (Z=Cl, Br) is reacted with a trialkyl phosphate to obtain substituted benzyl phosphonate 2. This reaction may be carried out by heating 1 with the trialkyl phosphate at 120-150°C for 10-20 hours with or without a solvent, e.g., dimethylacetamide. A ylide is generated from intermediate 2 and reacted with substituted piperidone 3 to synthesize substituted alkene 4. The formation of the ylide from 2 may be carried out in the presence of a crown ether, in a solvent, e.g., THF, dimethoxyethane, or diethyl ether, using a base, e.g., sodium hydride or potassium hydride. This reaction may be started at a low temperature (0±5°C), followed by heating of the reaction mixture to about 20°C and further stirring for 20-60 minutes. The reaction of the ylide produced from 2 with 3 may be carried out by initiating the reaction at a low temperature (0±5°C) in a solvent, e.g., THF, dimethoxyethane, diethyl ether, or toluene, followed by heating the reaction mixture to about 20–40°C and stirring for 8–20 hours. Deprotection of the carbamate from 4 in the presence of an acid yields piperidine intermediate 5. This reaction may be carried out by stirring the reaction mixture at a temperature of 0–25°C for 20–90 minutes using an acid, e.g., trifluoroacetic acid, in a solvent, e.g., dichloromethane or dichloroethane. The reaction of 5 with the substituted cyclopropanecarbamate intermediate 6 yields the target compound 7. This reaction may be carried out by heating the reaction components at 40–60°C for a period of 3–6 hours using a solvent, e.g., dimethyl sulfoxide or dimethylacetamide, and a base, e.g., triethylamine, diisopropylethylamine.

[0128] The substituted cyclopropanecarbamate 6 may be synthesized from the corresponding cyclopropylamine 8 by reacting it with an aryl chloroformate (R=Ph, or Ar) using a solvent, e.g., dichloromethane, and a base, e.g., diisopropylethylamine. The reaction may be initiated at a low temperature (0±5°C), followed by heating of the reaction mixture to about 20-30°C and stirring for 20-40 minutes. The substituted benzyl halide 1 and substituted piperidone 3 used may be commercially purchased or synthesized from readily available reagents.

[0129] [ka]

[0130] Scheme II illustrates a method for synthesizing compound 11 of formula I of the present disclosure. In the first step, compound 4 is synthesized using the method described in Scheme I and hydrogenated to obtain saturated compound 9. This reaction may be carried out using catalytic hydrogenation (e.g., using Pd / C or Pt / C) in a solvent, e.g., methanol or ethanol, in a Parr hydrogenator. Deprotection of carbamate 9 in the presence of an acid yields piperidine intermediate 10. This reaction may be carried out by stirring the reaction mixture at a temperature of 0–25°C for 20–90 minutes using an acid, e.g., trifluoroacetic acid, in a solvent, e.g., dichloromethane or dichloroethane. Reaction of 10 with the substituted cyclopropanecarbamate intermediate 6 yields target compound 11. This reaction may be carried out by heating the reaction components at 40–60°C for a period of 3–6 hours using a solvent, e.g., dimethyl sulfoxide or dimethylacetamide and a base, e.g., triethylamine, diisopropylethylamine.

[0131] [ka]

[0132] Scheme III shows the synthesis methods for compounds 18 and 19 of the present disclosure. In the first step, compound 12 containing a heteroaryl ring A (e.g., pyridine, pyrimidine, pyrazine) is reacted with substituted phenol 13 to obtain 14. This reaction may be carried out by heating the reaction mixture at 80-120°C for 3-6 hours in a solvent, e.g., dimethylacetamide or dimethylformamide, using a base, e.g., potassium carbonate, sodium carbonate, or cesium carbonate. The resulting substituted benzyl alcohol is converted to the corresponding benzyl halide 15 by reaction with thionyl chloride. This reaction may be carried out by treating with thionyl chloride at 0-25°C for 1-3 hours using a solvent, e.g., dichloromethane. The substituted benzyl halide 15 is reacted with a trialkyl phosphate to obtain substituted benzyl phosphonate 16. This reaction may be carried out by heating 15 with the trialkyl phosphate at 120-150°C for 10-20 hours with or without a solvent, e.g., dimethylacetamide. The substituted alkene 17 is synthesized by generating an ylide from intermediate 16 and reacting it with substituted piperidone 3. The formation of the ylide from 16 may be carried out in the presence of a crown ether, in a solvent, e.g., THF, dimethoxyethane, or diethyl ether, using a base, e.g., sodium hydride or potassium hydride. The reaction may be initiated at a low temperature (0±5°C), followed by heating of the reaction mixture to about 20°C and stirring for a further 20-60 minutes. The reaction of the ylide generated from 16 with 3 may be carried out in a solvent, e.g., THF, dimethoxyethane, diethyl ether, or toluene, initiated at a low temperature (0±5°C), followed by heating of the reaction mixture to about 20-40°C and stirring for 8-20 hours. The conversion of 17 to 18 is carried out by deprotection of the carbamate in the presence of an acid and the substituted cyclopropanecarbamate intermediate 6 as described in Scheme I. The reaction may be carried out according to the steps of the reaction. The conversion of 17 to 19 may be achieved using a sequential process involving hydrogenation, deprotection of the carbamate, and reaction with the substituted cyclopropanecarbamate intermediate 6, as described in Scheme II.

[0133] [ka]

[0134] Scheme IV shows the synthetic methods of Compounds 26 and 27 of the present disclosure. In the first step, Compound 20 is reacted with a substituted phenol 21 to obtain 22. This reaction may be carried out by heating the reaction mixture at 80 - 120 °C for 3 - 8 hours using a base, such as cesium carbonate, in a solvent, such as dimethylacetamide or dimethylformamide. The obtained substituted benzyl alcohol is converted to the corresponding benzyl halide 23 by reaction with thionyl chloride. This reaction may be carried out by treating with thionyl chloride at 0 - 25 °C for 1 - 3 hours using a solvent, such as dichloromethane. The substituted benzyl halide 23 is reacted with a trialkyl phosphate to obtain a substituted benzyl phosphonate 24. This reaction may be carried out by heating 23 with the trialkyl phosphate at 120 - 150 °C for 10 - 20 hours with or without a solvent, such as dimethylacetamide. An ylide is generated from the intermediate 24 and reacted with a substituted piperidone 3 to synthesize a substituted alkene 25. The formation of the ylide from 24 may be carried out using a base, such as sodium hydride or potassium hydride, in a solvent, such as THF, dimethoxyethane, or diethyl ether, in the presence of a crown ether. The reaction may be initiated at a low temperature (0 ± 5 °C), followed by warming of the reaction mixture to about 20 °C and further stirring for 20 - 60 minutes. The reaction of the ylide generated from 24 with 3 may be carried out by initiating the reaction at a low temperature (0 ± 5 °C) in a solvent, such as THF, dimethoxyethane, diethyl ether or toluene, followed by warming of the reaction mixture to about 20 - 40 °C and stirring for 8 - 20 hours. The conversion of 25 to 26 may be carried out according to the steps of deprotection of the carbamate in the presence of an acid and reaction with a substituted cyclopropanecarbamate intermediate 6 as described in Scheme I. The conversion of 25 to 27 may be achieved using sequential steps involving hydrogenation, deprotection of the carbamate and reaction with a substituted cyclopropanecarbamate intermediate 6 as described in Scheme II.

[0135]

Chemical Structure

[0136] Scheme V shows a method for synthesizing compounds 33 and 34 of the present disclosure. In the first step, substituted benzyl halide 28 is reacted with a trialkyl phosphate to obtain substituted benzyl phosphonate 29. This reaction may be carried out by heating 28 with the trialkyl phosphate at 120–150°C for 10–20 hours with or without a solvent, e.g., dimethylacetamide. A ylide is generated from intermediate 29 and reacted with substituted piperidone 3 to synthesize substituted alkene 30. The formation of the ylide from 29 may be carried out in the presence of a crown ether, in a solvent, e.g., THF, dimethoxyethane, or diethyl ether, using a base, e.g., sodium hydride or potassium hydride. The reaction may be started at a low temperature (0±5°C), followed by heating of the reaction mixture to about 20°C and further stirring for 20–60 minutes. The reaction of the ylide produced from 29 with 3 may be carried out by initiating the reaction at a low temperature (0±5°C) in a solvent, e.g., THF, dimethoxyethane, diethyl ether, or toluene, followed by heating of the reaction mixture to about 20–40°C and stirring for 8–20 hours. Intermediate 31 containing heterocyclyl ring A is synthesized from 30 by reacting with the corresponding heterocycle, e.g., pyrrolidine, morpholine, or piperidine. This reaction may be carried out by treating 30 with heterocycle ring A using cesium carbonate and a catalyst, e.g., palladium acetate and 2,2'-bis(diphenylphosphin)-1,1'-binaphthyl (BINAP). The reaction may also be carried out by treating the reaction mixture at 20–100°C for 5–20 hours using a solvent, e.g., 1,4-dioxane. The conversion of 31 to 33 may be carried out according to the steps of deprotection of the carbamate in the presence of an acid and reaction with the substituted cyclopropanecarbamate intermediate 6, as described in Scheme I.

[0137] The conversion of 31 to 32 may be achieved using catalytic hydrogenation (Pd / C, H2) as described in Scheme II. Similarly, the conversion of 32 to 34 may be carried out according to a methodology involving deprotection of the carbamate and reaction with the substituted cyclopropanecarbamate intermediate 6 as described in Scheme II.

[0138] [ka]

[0139] Scheme VI shows a method for synthesizing compound 40 of the present disclosure. In the first step, compound 35 containing a heteroaryl ring A (e.g., pyridine, pyrimidine, pyrazine) is reacted with substituted phenol 36 to obtain 37. This reaction may be carried out by heating the reaction mixture at 80-120°C for 3-8 hours in a solvent, e.g., dimethylacetamide or dimethylformamide, using a base, e.g., potassium carbonate, sodium carbonate, or cesium carbonate. The substituted phenol 37 is reacted with piperidine mesylate 38 to obtain 39. This reaction may be carried out by heating the reaction mixture at 60-80°C for 6-8 hours in a solvent, e.g., dimethylacetamide or dimethylformamide, using a base, e.g., potassium carbonate, sodium carbonate, or cesium carbonate. The conversion of 39 to 40 may be carried out according to the steps of deprotection of the carbamate in the presence of an acid and reaction with substituted cyclopropanecarbamate intermediate 6, as described in Scheme I.

[0140] [ka]

[0141] Scheme VII shows a method for synthesizing the compounds of formulas 45 and 46 of this disclosure. In the first step, compound 41 containing a heteroaryl boronate is reacted with an aryl halide 42 to obtain 43. This reaction may be carried out by treating 41 and 42 for 12 to 18 hours at an ambient temperature of 20 to 25°C using a solvent, such as dimethylacetamide, dimethylformamide, a 2N sodium carbonate solution, and tetrakis(triphenylphosphine)palladium(0). The conversion of 43 to 45 may be carried out according to the steps of deprotection of the carbamate in the presence of an acid and reaction with a substituted cyclopropanecarbamate intermediate 6, as described in Scheme I.

[0142] The conversion of 43 to 44 may be achieved using catalytic hydrogenation (Pd / C, H2) as described in Scheme II. Similarly, the conversion of 44 to 46 may be carried out according to a methodology involving deprotection of the carbamate and reaction with the substituted cyclopropanecarbamate intermediate 6 as described in Scheme II.

[0143] [ka]

[0144] Scheme VIII shows a method for synthesizing the compound of Formula 54 of the present disclosure. In the first step, substituted benzyl halide 47 is reacted with a trialkyl phosphate to obtain substituted benzyl phosphonate 48. This reaction may be carried out by heating 47 with the trialkyl phosphate at 120-150°C for 10-20 hours. An ylide is generated from intermediate 48 and reacted with substituted piperidone 3 to synthesize substituted alkene 49. The formation of the ylide from 48 may be carried out in the presence of a crown ether, in a solvent such as THF, dimethoxyethane, or diethyl ether, using a base such as sodium hydride or potassium hydride. The reaction may be started at a low temperature (0±5°C), followed by heating of the reaction mixture to about 20°C and further stirring for 20-60 minutes. The reaction of the ylide produced from 48 with 3 may be carried out by initiating the reaction at a low temperature (0±5°C) in a solvent, e.g., THF, dimethoxyethane, diethyl ether, or toluene, followed by heating of the reaction mixture to about 20–40°C and stirring for 8–20 hours. The conversion of 49 to 50 may be achieved using catalytic hydrogenation (Pd / C, H2). This reaction may be carried out using catalytic hydrogenation (e.g., using Pd / C or Pt / C) in a solvent, e.g., methanol or ethanol, in a Parr hydrogenator. In the next step, the synthesis of 52 is achieved by reacting 50 with the substituted 1-fluoro-2-nitrobenzene 51 in a substitution reaction. This reaction may be carried out by treating 50 with 51 in a solvent, e.g., dimethylformamide, and heating the reaction mixture at 80–120°C for 10–20 hours in the presence of cesium carbonate. The synthesis of benzimidazole compound 53 may be achieved 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 may be carried out by treatment with the substituted cyclopropanecarbamate intermediate 6, as described in Scheme II. [Examples]

[0145] One embodiment of the present disclosure provides the preparation of novel compounds of Formula I using the procedures described in the following examples. Those skilled in the art will understand that these compounds can be prepared using the conditions of the following preparation procedures and known variations of the processes. Further, by utilizing the procedures described herein, those skilled in the art can prepare additional compounds of the present disclosure claimed in this application.

[0146] Example 1 - Synthesis of 4-(3-methoxy-benzylidene)-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0147]

Chemical formula

[0148] Step 1 - Thionyl chloride (74 mL, 1.01 mol) was added dropwise to a mixture of (3-methoxy-phenyl)-methanol (20.0 g, 0.14 mol) and pyridine (5.8 mL, 0.72 mol) in benzene (120 mL) while stirring the reaction solution in an ice bath. After removal of the ice bath, the reaction mixture was stirred at room temperature for a period of 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 by evaporation of the volatiles was purified by passing it through a silica gel (230 - 400) column (5% ethyl acetate in petroleum ether) to give the product 2 as a yellow oil 20.01 g (88%). 1 1H 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).

[0149] Step 2 - A solution of 2 (20 g, 0.12 mol) in triethyl phosphate (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 by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (20% ethyl acetate in petroleum ether) to obtain product 3 as a colorless oily substance of 27.0 g (81%). 1 H NMR(300MHz,CDCl3) δ (ppm): 1.26(t,J=7.2Hz,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).

[0150] 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 mixture was cooled (in an ice bath), and NaH (580 mg, 24.2 mmol) was added in small amounts. The reaction mixture was stirred at room temperature for 30 minutes and then recooled using an ice bath. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 4 (8.5 g, 43.0 mmol) in THF (44 mL) was added to the above reaction mixture at ice temperature, and the mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (100 mL), extracted with ethyl acetate, and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (25% ethyl acetate in petroleum ether) to obtain product 5 as 7.0 g (54%) of a yellow oily substance. 1 H NMR(300MHz,CDCl3) δ (ppm):1.49(s,9H), 2.32-2.36(m,2H), 2.44-2.50(m,2H), 3.42(t,J=5.7Hz,2H), 3. 52(t,J=5.7Hz,2H), 3.84(s,3H), 6.35(s,1H), 6.75-6.81(m,3H), 7.25-7.25(m,1H).

[0151] Step 4 - Trifluoroacetic acid (4.25 mL, 4.25 vol) was added to a solution of 5 (1.0 g, 3.2 mmol) in dichloromethane (8.0 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 1 hour. The crude product obtained by evaporation of volatiles was washed with diethyl ether to obtain 6 as a white solid (600 mg, 89%). 1 H NMR(300MHz,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=7.8Hz,1H), 8.79(bs,2H).

[0152] Step 5 - 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) at ice bath temperature. The ice bath was then 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 on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (10% ethyl acetate in petroleum ether) to obtain product 7 as a white solid of 2.6 g (50%). mp: 113.6-115.3°C. 1 H NMR (300MHz, 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).

[0153] Step 6: To a solution of amine 6 (300 mg, 0.94 mmol) in dimethyl sulfoxide (6 mL), diisopropylethylamine (0.5 mL, 2.82 mmol) and carbamate 7 (238 mg, 0.94 mmol) were added at 25°C. The reaction mixture was stirred at 55°C for 4 hours. The resulting reaction mixture was diluted with ethyl acetate (250 mL), washed with water (4 × 75 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to obtain product 8 as a white solid of 226 mg (65%). mp: 104.7-106.4°C. 1 H NMR(300MHz,CDCl3) δ (ppm):1.15-1.27(m,2H), 2.02-2.09(m,1H), 2.40(t,J=5.7Hz,2H), 2.54(t,J=5.7Hz,2H), 2.8 7(bs,1H), 3.39(t,J=5.7Hz,2H), 3.49(t,J=5.7Hz,2H), 3.82(s,3H), 4.87(s,1H,-CONH-, interchangeable 1 H), 6.37(s,1H), 6.75-6.81(m,3H), 7.18-7.30(m,6H). 13 ¹³C NMR (75MHz, 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)

[0154] Example 2 - Synthesis of 4-[3-(pyridine-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide

[0155] [ka]

[0156] Step 1 - 3-hydroxyphenyl-methanol (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) at room temperature. The reaction mixture was stirred at 100 °C for 5 hours. Next, 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 on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (30% ethyl acetate in petroleum ether) to obtain Product 2 as 34.5 g (71%) of a pale yellow oily substance. 1 H NMR(300MHz,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).

[0157] Step 2 - To a solution of 2 (34.5 g, 0.17 mol) in dichloromethane (345 mL), thionyl chloride (13.9 mL, 0.18 mol) was added dropwise while stirring the reaction mixture in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. Next, the volatiles were evaporated under reduced pressure, diluted with toluene (25 mL), and the toluene was evaporated under reduced pressure. This azeotropic process was repeated three times to obtain product 3 as a brown oily substance (36.8 g, 98%). 1 H NMR(300MHz,DMSO-d6) δ (ppm):4.77(s,2H), 7.04-7.20(m,4H), 7.27-7.29(m,1H), 7.42(t,J=8.4Hz,1H), 7.84-7.90(m,1H), 8.14-8.16(m,1H).

[0158] Step 3 - A solution of 3 (36.7 g, 0.16 mol) in triethyl phosphate (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 by evaporation of volatile matter was purified by passing it through a silica gel (230-400) column (60% ethyl acetate in petroleum ether) to obtain product 4 as a colorless oily substance of 41.33 g. The product contained unused triethyl phosphate and was used in the next step without further purification.

[0159] Step 4 - 15-crown ether (0.41 g, 1.8 mmol) was added to a solution of [3-(pyridine-2-yloxy)-benzyl]phosphonate diethyl ester 4 (30.0 g, 93.0 mmol) in THF (120 mL). The reaction mixture was cooled (in an ice bath), and NaH (3.35 g, 0.14 mol) was added in small amounts. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. To the above reaction mixture, a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 5 (18.6 g, 93.0 mmol) in THF (120 mL) was added 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 on sodium sulfate. The crude product obtained by evaporation of volatile substances was purified by passing it through a silica gel (230-400) column (3% ethyl acetate in petroleum ether) to obtain product 6 as 24.3 g (71%) of a yellow oily substance. 1 H NMR(300MHz,CDCl3) δ (ppm):1.41(s,9H), 2.27(t,J=5.4Hz,2H), 2.40(t,J=5.4Hz,2H), 3.33(bs,2H), 3.40(t,J=5.4Hz, 2H), 6.37(s,1H), 6.95-7.15(m,4H), 7.37(t,J=7.8Hz,2H), 7.83-7.88(m,1H), 8.14-8.16(m,1H).

[0160] Step 5 - Trifluoroacetic acid (51 mL) was added at ice temperature to a solution of 4-[3-(pyridine-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester 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 oily substance 7 (13.7 g, 85%) obtained by evaporation of volatile matter was used in the next step (13.7 g, 85%) without further purification. 1 H NMR(300MHz,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=7.5Hz,1H), 7.83-7.88(m,1H), 8.14-8.16(m,1H).

[0161] Step 6 - To a solution of amine 7 (15.0 g, 26.0 mmol) in dimethyl sulfoxide (150 mL), diisopropylethylamine (13.6 mL, 78.0 mmol) and the product from Step 5 of Example 1 (6.7 g, 26.0 mmol) were added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (1.2 L), washed with water (3 × 150 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to obtain product 8 as a pale yellow solid of 9.1 g (81%). mp: 52.3-54.1°C. 1 H NMR(300MHz,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-, interchangeable 1 H), 6.95-7.40(m,10H), 7.86(t,J=6.3Hz,1H), 8.14-8.16(m,2H). 13 ¹³C NMR (75MHz, 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)

[0162] Example 3 - Synthesis of 4-[3-(5-trifluoromethylpyridine-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide

[0163] [ka]

[0164] Step 1 - 3-hydroxyphenyl-methanol (17.4 g, 0.13 mol) and potassium carbonate (26.3 g, 0.19 mol) were added at room temperature to a solution of 5-trifluoromethyl-2-chloropyridine (23.0 g, 0.12 mol) in DMF (230 mL). The reaction mixture was stirred at 100 °C for 5 hours. Next, the resulting mixture was allowed to reach 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 by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (12% ethyl acetate in petroleum ether) to obtain Product 2 as 28.1 g (82%) of a pale yellow oily substance. 1 H NMR(300MHz,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=7.8Hz,1H), 7.90-7.94(m,1H), 8.45(s,1H).

[0165] Step 2 - To a solution of 2 (28.0 g, 0.10 mol) of product 2 in dichloromethane (280 mL), thionyl chloride (8.5 mL, 0.11 mol) was added dropwise while stirring the reaction mixture in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. Next, the volatiles were evaporated under reduced pressure, the mixture was diluted with toluene (15 mL), and the toluene was evaporated under reduced pressure. This azeotropic process was repeated three times to obtain product 3 as a red oily substance (29.6 g, 99%). 1 H NMR(300MHz,CDCl3) δ (ppm):4.62(s,2H), 7.05(d,J=8.7Hz,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).

[0166] Step 3 - A solution of 3 (29.0 g, 0.10 mol) in triethyl phosphate (26.2 mL, 0.15 mol) was heated at 150°C for 6 hours. The reaction mixture was allowed to reach room temperature, and the mixture was added to n-heptane (150 mL) to obtain a light orange precipitate. The precipitate was filtered and dried under vacuum to obtain product 4 as a white solid (30.8 g, 94%), which was used in the next step without further purification. 1 H NMR(300MHz,DMSO-d6) δ (ppm):1.16(t,J=6.9Hz,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=8.7Hz,1H), 8.23-8.26(m,1H), 8.55(s,1H).

[0167] Step 4 - 15-crown ether (0.28 g, 1.3 mmol) was added to a solution of ester 4 (25.0 g, 64.0 mmol) in THF (100 mL). The reaction mixture was cooled (in an ice bath), and NaH (2.3 g, 96.0 mmol) was added in small amounts over a period of 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, a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 5 (12.81 g, 64.0 mmol) in THF (100 mL) was added at ice temperature, and the mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water to obtain a white precipitate. The precipitate was filtered and dried to obtain product 6 as a white solid (24.4 g, 87%). 1 H NMR(300MHz,CD3OD) δ (ppm):1.48(s,9H), 2.36(t,J=5.1Hz,2H), 2.49(t,J=5.4Hz,2H), 3.43(t,J=5.7Hz,2H), 3.52(t,J=5.7Hz,2H) ), 6.43(s,1H), 7.01-7.03(m,2H), 7.14(d,J=8.4Hz,2H), 7.38-7.44(m,1H), 8.09-8.12(m,1H), 8.44(bs,1H).

[0168] Step 5 - Trifluoroacetic acid (42.5 mL) was added at ice temperature 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. Next, volatile matter was removed under reduced pressure to obtain the product as a red oily substance (10.7 g, 83%). Crude product 7 was used for the next step without further purification. 1 H NMR(300MHz,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=8.1Hz,1H), 8.21-8.23(m,1H), 8.56(s,1H), 8.76(bs,1H).

[0169] Step 6 - To a solution of amine 7 (10.5 g, 18.7 mmol) in dimethyl sulfoxide (10 mL), diisopropylethylamine (9.8 mL, 56.1 mmol) and the product from Step 5 of Example 1 (4.74 g, 18.7 mmol) were added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (1.0 L), washed with water (3 × 150 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (40% ethyl acetate in petroleum ether) to obtain product 8 as a white solid of 7.0 g (76%). mp: 98.9-101.5°C. 1 H NMR(300MHz,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, exchangeable with D2O) 1 H), 7.04-7.24(m,9H), 7.41(t,J=7.8Hz,1H), 8.22-8.25(m,1H), 8.58(s,1H). 13 C NMR(75MHz,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, 1 26.15, 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).

[0170] Example 4 - Synthesis of 4-[3-(pyridine-2-yloxy)-benzyl]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0171] [ka]

[0172] Step 1 - 10% Pd / C (900 mg) was added to a solution of product (6) from Step 4 of Example 2 in methanol (17 mL) at room temperature. The reaction mixture was stirred under hydrogen balloon pressure for 1 hour. The resulting reaction mixture was filtered through a Celite bed, and the filtrate was concentrated under reduced pressure to obtain product 7 as a yellow oily substance (850 mg, 66%). 1 H NMR(300MHz,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).

[0173] Step 2 - Trifluoroacetic acid (3.4 mL, 4.25 vol) was added at ice temperature to a solution of ester 7 (800 mg, 2.17 mmol) in dichloromethane (8 mL), and the reaction mixture was stirred at room temperature for 1 hour. Next, volatile matter was removed under reduced pressure to obtain the product as a brown oily substance (800 mg, 74%). Crude product 8 was used in the next step without further purification.

[0174] Step 3 - Diisopropylethylamine (0.5 mL, 2.82 mmol) and the product from Step 5 of Example 1 (256 mg, 1.0 mmol) were added at 25°C to a solution of crude amine 8 (500 mg, 1.0 mmol) in dimethyl sulfoxide (10 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 (4 × 75 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (60% ethyl acetate in petroleum ether) to obtain product 9 as a white solid of 230 mg (53%). mp: 126.8-128.6°C. 1H NMR(300MHz,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=6.6Hz,2H), 2. 73(t,J=11.4Hz,2H), 2.82-2.86(m,1H), 3.92(d,J=13.5Hz,2H), 4.84(s,1H,-CONH-, replaceable 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). 13 ¹³C NMR (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)

[0175] Example 5 - Chiral separation of the racemic product from Example 2 Prior to compound elution, a mobile phase (n-hexane:isopropyl alcohol; 80:20 v / v) was used for 15 column volumes on a chiral column (CHIRALPACK IA). A 250 mm × 10 mm (5 μm) column was equilibrated. Next, 500 μL of stock solution, prepared by dissolving 500 mg of the product from Example 2 in 5 mL of n-hexane and isopropyl alcohol (8:2), was injected, and fractions were collected based on the separation observed in the chromatogram. Fraction F1 was the first fraction eluted from the chiral column (retention time: 11.5 min to 13.00 min), and F2 was the second fraction eluted (retention time: 13.50 min to 15.50 min). Injection was repeated until complete separation of the residual (4.5 mL) stock solution was achieved. The solvents of F-1 and F-2 were then removed separately under reduced pressure to obtain chiral products 5A (entA) (140 mg) and 5B (entB) (150 mg), respectively.

[0176] 5A 4-[3-(pyridine-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid{(1S,2R)-2-phenyl-cyclopropyl)}-amide - HPLC: 99.98% (chiral purity: 98.55%). mp: 45.0~47.1℃. 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=7.8Hz,1H), 7.83-7.85(m,1H), 8.14-8.16(m,1H). MS:426(M+H).

[0177] 5B 4-[3-(pyridine-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid{(1R,2S)-2-phenyl-cyclopropyl)}-amide - HPLC: 99.89% (chiral purity: 98.93%). mp: 51.0~54.3℃. 1 H NMR(300MHz,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=7.8Hz,1H), 7.83-7.85(m,1H), 8.14-8.16(m,1H) MS:426(M+H).

[0178] [ka]

[0179] Example 6 - Synthesis of 4-[3-(pyrimidine-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide

[0180] [ka]

[0181] Step 1 - 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) at room temperature. The reaction mixture was stirred at 100 °C for 5 hours. Next, the resulting reaction mixture was cooled to room temperature, filtered to remove cesium carbonate, diluted with water (50 mL), extracted with ethyl acetate (100 mL), and the organic layer was dried over sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to obtain Product 1 as a pale yellow oily substance of 440 mg (54%). 1 H NMR (300MHz, DMSO-d6) δ (ppm): 4.52 (s, 2H), 5.28 (bs, 1H), 7.03-7.99 (m, 5H), 8.63 (d, J = 1.2Hz, 2H).

[0182] Step 2 - To a solution of 1 (440 mg, 2.1 mmol) in dichloromethane (8 mL), thionyl chloride (0.19 mL, 2.6 mmol) was added dropwise while the reaction mixture was stirred in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was quenched with ice-cold water (10 mL), extracted with ethyl acetate (100 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (25% ethyl acetate in petroleum ether) to obtain Product 2 as a pale pink solid of 400 mg (83%). 1 H NMR (300MHz, 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 = 4.5Hz, 2H).

[0183] Step 3 - A solution of 2-(3-chloromethyl-phenoxy)-pyrimidine 2 (400 mg, 1.8 mmol) in triethyl phosphate (0.45 mL, 2.7 mmol) was heated at 150°C for 6 hours. The reaction mixture was allowed to reach room temperature, and the crude product obtained by evaporation of volatile matter was purified by passing it through a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to obtain Product 3 as a white solid of 400 mg (69%). 1 H NMR(300MHz,DMSO-d6) δ (ppm):1.16(t,J=6.9Hz,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=7.5Hz,1H), 8.64(d,J=4.8Hz,2H).

[0184] 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 mixture was cooled (in an ice bath), and NaH (44 mg, 1.8 mmol) was added in small amounts. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. To the above reaction mixture, a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (250 mg, 1.2 mmol) in THF (2.5 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 (10 mL), extracted with ethyl acetate (100 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (25% ethyl acetate in petroleum ether) to obtain product 4 as a white solid of 360 mg (80%). 1 H NMR(300MHz,DMSO-d6) δ (ppm):1.41(s,9H), 2.28(t,J=5.4Hz,2H), 2.41(t,J=5.7Hz,2H), 3.33-3.41(m,4H), 6.38(s ,1H), 7.03-7.13(m,3H), 7.26(t,J=4.8Hz,1H), 7.39(t,J=7.8Hz,1H), 8.65(d,J=4.8Hz,2H).

[0185] Step 5 - Trifluoroacetic acid (1.7 mL) was added to a solution of 4 (360 mg, 0.97 mmol) in dichloromethane (4.0 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 1 hour. The crude product obtained by evaporation of the solvent was washed with diethyl ether to obtain product 5 as an off-white solid of 0.31 g (83%), which was used next without further purification.

[0186] Step 6 - To a solution of amine 5 (310 mg, 0.6 mmol) in dimethyl sulfoxide (4.0 mL), diisopropylethylamine (0.5 mL, 3.1 mmol) and the product from Step 5 of Example 1 (0.58 g, 2.4 mmol) were added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (100 mL), washed with water (3 × 50 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (60% ethyl acetate in petroleum ether) to obtain product 6 as a white solid of 210 mg (77%). mp: 52.7-57.6°C. 1 H NMR(300MHz,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( Exchangeable with bs,2H), 2.70-2.71(m,1H), 3.32-3.39(m,4H), 6.37(s,1H), 6.85(bs,1H,CONH) 1 H), 7.03-7.15(m,6H), 7.22-7.28(m,3H), 7.39(t,J=7.8Hz,1H), 8.65(d,J=7.8Hz,2H). 13 ¹³C NMR (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).

[0187] Example 7 - Synthesis of 4-{3-[1-(2-phenyl-cyclopropylcarbamoyl)-piperidine-4-ylidenemethyl]-phenoxy}-methyl benzoate:

[0188] [ka]

[0189] Step 1 - 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) at room temperature. The reaction mixture was stirred at 100 °C for 5 hours. Next, the resulting reaction mixture was allowed to reach room temperature and filtered to remove the cesium carbonate. The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 × 250 mL), and the organic layer was dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (30% ethyl acetate in petroleum ether) to obtain product 3 as 3.2 g (31%) of a pale yellow oily substance. 1 H NMR(300MHz,DMSO-d6) δ (ppm): 3.81(s,3H), 4.51(d,J=5.7Hz,2H), 5.28(t,J=5.7Hz,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).

[0190] Step 2 - To a solution of alcohol 3 (3.2 g, 12.3 mmol) in dichloromethane (50 mL), thionyl chloride (1.7 mL, 14.8 mmol) was added dropwise while the reaction mixture was stirred in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was quenched with ice-cold water (50 mL), extracted with ethyl acetate (250 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (5% ethyl acetate in petroleum ether) to obtain product 4 as a colorless oily substance of 2.3 g (67%). 1 H NMR(300MHz,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=8.7Hz,2H).

[0191] Step 3 - A solution of compound 4 (2.3 g, 7.9 mmol) in triethyl phosphate (2.3 mL, 11.9 mmol) was heated at 150°C for 6 hours. The reaction mixture was allowed to reach room temperature, and the crude product obtained by evaporation of volatile substances was purified by passing it through a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to obtain product 5 as 3.5 g (91%) of a pale yellow oily substance. 1 H NMR(300MHz,DMSO-d6) δ (ppm):1.15(t,J=6.9Hz,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=7.8Hz,1H), 7.97(d,J=8.7Hz,2H).

[0192] Step 4 - 15-crown 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 mixture was cooled (in an ice bath), and NaH (560 mg, 13.8 mmol) was added in small portions. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. To the above reaction mixture, a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 6 (1.9 g, 9.2 mmol) in THF (15 mL) was added at ice temperature, and the mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was quenched with saturated ammonium chloride (50 mL), extracted with ethyl acetate (500 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (10% ethyl acetate in petroleum ether) to obtain product 7 as a white solid of 1.8 g (46%). 1 H NMR(300MHz,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=8.7Hz,2H).

[0193] Step 5 - Trifluoroacetic acid (9.0 mL) was added at ice temperature 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 by evaporation of the solvent was washed with n-hexane to obtain product 8 as a dark black liquid of 1.5 g (83%). 1 H NMR(300MHz,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=8.1Hz,1H), 8.03(t,J=8.4Hz,2H).

[0194] Step 6 - To a solution of amine 8 (1.5 g, 3.4 mmol) in dimethyl sulfoxide (15.0 mL), diisopropylethylamine (2.0 mL, 10.2 mmol) and the product from Step 5 of Example 1 (0.86 g, 3.4 mmol) were added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (250 mL), washed with water (2 × 100 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (25% ethyl acetate in petroleum ether) to obtain product 9 as a white solid of 0.9 g (54%). mp: 48.5-53.2°C. 1 H NMR(300MHz,DMSO-d6) δ (ppm):1.10-1.20(m,2H), 1.88(bs,1H), 2.26(bs,2H), 2.37(bs,2H), 2.70-2.7 1(m,1H), 3.31-3.38(m,4H), 3.83(s,3H), 6.36(s,1H), 6.84(bs,1H,CONH) 1 H), 6.94-7.26(m,10H), 7.42(t,J=7.8Hz,1H), 7.97(d,J=8.4Hz,2H). 13 ¹³C 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).

[0195] Example 8 - Synthesis of 4-{3-[1-(2-phenyl-cyclopropylcarbamoyl)-piperidine-4-ylidenemethyl]-phenoxy}benzoic acid:

[0196] [ka]

[0197] A solution of the product from step 6 of Example 7 (0.5 g, 1.03 mmol) in methanol (3.0 mL) was added to a solution of sodium hydroxide (120 mg, 3.1 mmol) in water (2.0 mL) at 25°C. The reaction mixture was stirred at 55°C for 16 hours. The crude product obtained by evaporation of the solvent was diluted with water (20.0 mL), and the aqueous layer was washed with ethyl acetate (2 × 20 mL). Next, the aqueous layer was 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 obtain 350 mg (72%) of the product as a white solid. mp: 99.4~102.5°C. 1 H 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) 1 H), 6.93-7.44(m,11H), 7.95(d,J=8.4Hz,2H), 12.83(bs,1H). 13 ¹³C NMR (75MHz, 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 (MHz).

[0198] Example 9 - Synthesis of 4-(3-pyrrolidine-1-ylbenzyl)-piperidine-1-carboxylic acid-(2-phenylcyclopropyl)amide:

[0199] [ka]

[0200] Step 1 - A solution of 3-bromobenzyl bromide (6.0 g, 24.0 mmol) in triethyl phosphate (6.2 mL, 36.0 mmol) was heated at 130°C for 16 hours. The reaction mixture was cooled to room temperature, and the crude product obtained by evaporation of volatile substances was purified by passing it through a silica gel (230-400) column (30% ethyl acetate in petroleum ether) to obtain Product 2 as 6.5 g (89%) of a colorless oil. 1 H NMR (300MHz, DMSO-d6) δ (ppm): 1.17(t,J=7.2Hz,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).

[0201] 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 mixture was cooled (in an ice bath), and NaH (0.58 g, 14.6 mmol) was added in small amounts. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. To the above reaction mixture, a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.95 g, 9.7 mmol) in THF (10 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 (100 mL), extracted with ethyl acetate (3 × 100 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (5% ethyl acetate in petroleum ether) to obtain product 3 as 1.8 g (53%) of a yellow oily substance. 1 H NMR (300MHz, 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).

[0202] Step 3 - To a solution of compound 3 (2.0 g, 7.0 mmol) in 1,4-dioxane (20.0 mL), 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 at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 30 minutes, followed by stirring under reflux for 16 hours. The resulting reaction product 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 on sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (15% ethyl acetate in petroleum ether) to obtain product 4 as 0.6 g (32%) of a pale yellow oily substance. 1 H NMR(300MHz,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=8.1Hz,1H). MS:343.7(M+H).

[0203] 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). The reaction mixture was then heated at room temperature under a hydrogen gas pressure (1 kg / cm²). 2 The mixture was stirred under hydrogen pressure for 2 hours. After the hydrogen pressure was released, the reaction mixture was filtered through a Celite pad, washed with tetrahydrofuran, and the filtrate was concentrated to obtain product 5 as a pale yellow liquid (0.6 g). The crude product was used in the next step without further purification. 1H NMR(300MHz,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=6.9Hz,2H), 2.65(t,J=12.3Hz,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=7.8Hz,1H). MS:345.7(M+H).

[0204] Step 5 - Trifluoroacetic acid (3 mL) was added at ice temperature 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 oily substance 6 (0.6 g) obtained by evaporation of volatile matter was used in the next step without further purification.

[0205] Step 6 - To a solution of amine 6 (600 mg, 1.9 mmol) in dimethyl sulfoxide (6.0 mL), N,N-diisopropylethylamine (1.1 mL, 5.8 mmol) and the product from Step 5 of Example 1 (0.5 g, 1.9 mmol) were added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3 × 100 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (40% ethyl acetate in petroleum ether) and by preparative HPLC (phenomenex® 250 × 221.20 mm, 10 μM, 0.1% TFA in water and acetonitrile mobile phase) to obtain product 7 as 160 mg (23%) of pale yellow solid. mp: 145.6°C~151.5°C. IR: 3334, 2842, 1620, 1600, 1545, 1252 and 752 cm -1 . 11H NMR: (300MHz, 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=12.9Hz,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).

[0206] Example 10 - Synthesis of 4-(3-morpholine-4-yl-benzyl)-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)amide:

[0207] [ka]

[0208] Step 1 - 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) were added to a solution of the product from Step 2 of Example 9 (1.5 g, 4.2 mmol) in 1,4-dioxane (15.0 mL) under an argon atmosphere at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, followed by stirring under reflux for 16 hours. The resulting reaction mixture was cooled, filtered through a Celite pad, and washed with ethyl acetate (250 mL). The ethyl acetate layer was washed with water (2 × 100 mL), the organic layer was dried over sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (15% ethyl acetate in petroleum ether) to obtain crude product 2 as 0.35 g of a pale yellow oily substance.

[0209] Step 2 - 10% Pd / C (350 mg) was added to a solution of compound 2 (0.85 g, 2.37 mmol) in tetrahydrofuran (10.0 mL). The reaction mixture was then heated at room temperature under a hydrogen gas pressure (1 kg / cm²). 2 The mixture was stirred under hydrogen pressure for 2 hours. After the hydrogen pressure was released, the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain product 3 as a pale yellow liquid (0.8 g). The product was used in the next step without further purification.

[0210] Step 3 - Trifluoroacetic acid (4 mL) was added at ice temperature 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 oily substance 4 (0.8 g) obtained by evaporation of volatile matter was used in the next step without further purification.

[0211] To a solution of amine 4 (800 mg, 2.3 mmol) in dimethyl sulfoxide (8.0 mL), diisopropylethylamine (1.3 mL, 7.0 mmol) and the product from step 5 of Example 1 (0.6 g, 2.3 mmol) were added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3 × 100 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to obtain product 5 as a pale yellow solid of 420 mg. mp: 182.3°C-186.0°C. IR: 3330, 2841, 1620, 1600, 1545, 1247 and 756 cm⁻¹ -1 . 1 H NMR(300MHz,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=4.5Hz,4H), 3.74(t,J=4.5Hz,4H), 3.90(d,J=12.6Hz,2H), 6.61(d,J=7.2Hz,1H), 6.70-6.76(m,3H,11 H can be replaced with D2O), 7.07-7.15 (m, 4H), 7.22-7.27 (m, 2H). 13 C NMR(75MHz,DMSO-d6) δ (ppm):16.01, 24.75, 32.08, 34.56, 37.96, 43.17, 43.98, 49.00, 66.61, 113.09, 1 16.43, 120.52, 125.77, 126.29, 128.53, 129.12, 141.31, 142.51, 151.50, 158.28. MS:420.2(M+H).

[0212] Example 11 - Synthesis of 4-[3-(pyridine-2-yloxy)-phenoxy]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0213] [ka]

[0214] Step 1 - To a solution of 1,3-dihydroxybenzene (1.0 g, 9.0 mmol) in DMF (10.0 mL), Cs2CO3 (5.92 g, 18.0 mmol) and 2-fluoropyridine (0.8 mL, 9.0 mmol) were added. The reaction mixture was heated at 100°C for 16 hours. Next, 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 on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (10% ethyl acetate in petroleum ether) to obtain Product 3 as 400 mg (23%) of a pale yellow oily substance. 1 H NMR(300MHz,DMSO-d6) δ (ppm):6.20(s,1H), 6.48-6.53(m,1H), 6.61(d,J=8.1Hz,1H), 6.98(d,J=8.1Hz,1 Interchangeable with H), 7.11-7.21(m,2H), 7.84(t,J=8.1Hz,1H), 8.18(bs,1H), 9.61(s,1H,D2O) 1 H). MS: 187.9 (M+H).

[0215] Step 2 - To a solution of compound 3 (400 mg, 2.14 mmol) in DMF (8.0 mL), Cs2CO3 (1.4 g, 4.2 mmol) was added at room temperature. The reaction mixture was stirred for 5 minutes, then compound 4 (600 mg, 2.14 mmol) in DMF (2.0 mL) was added to the reaction mixture at room temperature, and the reaction mixture was stirred at 65°C for 8 hours. The reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3 × 50 mL), and the ethyl acetate layer was dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to obtain product 5 as a pale yellow oily substance of 540 mg (67%). 1 H NMR(300MHz,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), 6.7 5(s,1H), 6.80-6.84(m,1H), 6.99-7.02(m,1H), 7.14(d,J=5.1Hz,1H), 7.29(t,J=7.8Hz,1H), 7.85(t,J=7.5Hz,1H), 8.17(d,J=5.1Hz,1H). MS: 371.4 (M+H).

[0216] Step 3 - Trifluoroacetic acid (2.0 mL) was added at ice temperature 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 oily substance 6 obtained by evaporation of volatiles was used in the next step without further purification.

[0217] To a solution of amine 6 (390 mg, 0.78 mmol) in dimethyl sulfoxide (5.0 mL), diisopropylethylamine (0.67 mL, 3.9 mmol) and the product from step 5 of Example 1 (198 mg, 0.78 mmol) were added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (250 mL), washed with water (3 × 10 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatile matter was purified by passing it through a silica gel (230-400) column (70% ethyl acetate in petroleum ether) to obtain the product as an off-white, low-melting solid. The obtained product was further purified by preparative HPLC to obtain product 7 as 200 mg of off-white, low-melting solid. mp: 43.9°C-46.8°C. IR: 3313, 1621, 1586, 1423 and 1235 cm⁻¹ -1 . 1 H NMR(300MHz,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 Interchangeable with 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) 1 H), 7.00(d,J=8.0Hz,1H), 7.08-7.14(m,4H), 7.21-7.31(m,3H), 8.82(t,J=7.2Hz,2H), 8.16(d,J=5.1Hz,1H). MS:430.4(M+H).

[0218] Example 12 - Synthesis of 4-[3-(1H-pyrazole-4-yl)-benzyl]-piperidine-1-carboxylic acid (-2-phenyl-cyclopropyl)-amide:

[0219] [ka]

[0220] 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), 4-dimethylaminopyridine (0.25 g, 2.0 mmol) and di-tert-butyl dicarbonate (3.0 mL, 15.4 mmol) were added. The resulting reaction was stirred at room temperature for 12 hours. The reaction mixture was quenched with water (50.0 mL) and extracted with ethyl acetate (200 mL). The ethyl acetate layer was dried on anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (15% ethyl acetate in petroleum ether) to obtain Product 2 as 1.25 g (40%) of off-white solid. 1 H NMR (300MHz, 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).

[0221] Step 2 - Compound 2 (1.9 g, 5.6 mmol) and 2N sodium carbonate solution (4.3 mL, 8.5 mmol) were added to a solution of the compound product from Step 2 of Example 9 (1.0 g, 2.8 mmol) in DMF (10 mL) at room temperature. The reaction mixture was stirred under an argon atmosphere for 10 minutes. Next, tetrakis(triphenylphosphine)palladium(0) (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 hours. The reaction mixture was quenched with water (100 mL), extracted with ethyl acetate (500 mL), and washed with water (2 × 250 mL) and brine (100 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The crude product obtained by evaporation of the solvent under reduced pressure was purified by silica gel column chromatography (40% ethyl acetate in petroleum ether) to obtain product 3 as 550 mg (57%) of off-white solid. 1H NMR(300MHz,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=7.5Hz,1H), 7.31(t,J=7.5Hz,1H), 7.44-7.47(m,2H), 7.92(s,1H), 8.19(s,1H), 12.94(s,1H). MS:338.1(MH).

[0222] Step 3 - To a solution of compound 3 (0.5 g, 1.4 mmol) in 20% methanol in chloroform (10.0 mL), 10% Pd / C (200 mg) was added. The reaction mixture was heated at room temperature under a hydrogen gas pressure (1 kg / cm²). 2 The mixture was stirred under low heat for 24 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain product 4 as a pale yellow liquid (0.5 g). The crude product was used for the next step without further purification.

[0223] Step 4 - Trifluoroacetic acid (2.5 mL) was added at ice temperature 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 hour. The brown oily substance 5 (0.5 g) obtained by evaporation of volatile matter was used in the next step without further purification.

[0224] Step 5 - To a solution of amine 5 (500 mg, 1.0 mmol) in dimethyl sulfoxide (5.0 mL), N,N-diisopropylethylamine (0.8 mL, 4.2 mmol) and the product from Step 5 of Example 1 (270 mg, 1.0 mmol) were added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3 × 100 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (3% methanol in chloroform) to obtain product 6 as 210 mg of off-white solid. mp: 157.4°C~163.4°C. IR: 3330, 1619, 1545, 1475 and 753 cm⁻¹ -1 .1 H NMR(300MHz,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=12.6Hz,2H), 6.71(d,J=2.7Hz,1H,D2O exchangeable) 1 H), 6.98 (d, J=7.5Hz, 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, replaceable with D2O) 1 H). 13 C NMR(75MHz,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:40 1.3 (M+H).

[0225] Example 13 - Synthesis of 4-[3-(1-methyl-1H-pyrazole-4-yl)-benzyl]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0226] [ka]

[0227] 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 of Example 12 in THF (25 mL). The resulting reaction 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 on anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to obtain Product 1 as 600 mg (83%) of off-white solid. 1 H NMR(300MHz,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=7.5Hz,1H), 7.39-7.43(m,2H), 7.85(s,1H), 8.14(s,1H). MS:298.0(Mt-Butyl+H).

[0228] Step 2 - Compound 1 (0.6 g, 1.7 mmol) was dissolved in 20% methanol in chloroform (10.0 mL) and 10% Pd / C (240 mg) was added. The reaction mixture was heated at room temperature under a hydrogen gas pressure (1 kg / cm²). 2 The mixture was stirred under conditions of 16 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain Product 2 as a pale yellow liquid (0.6 g, 98%). The obtained product was used in the next step without further purification. 1H NMR(300MHz,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=7.2Hz,1H), 7.25(t,J=7.5Hz,1H), 7.36(s,2H), 7.83(s,1H), 8.11(s,1H). MS:300.2(M - t-Butyl + H).

[0229] Step 3 - Trifluoroacetic acid (3.0 mL) was added at ice temperature 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 hour. The brown oily substance 3 (0.6 g) obtained by evaporation of volatile matter was used in the next step without further purification.

[0230] Step 4 - To a solution of amine 3 (600 mg, 1.6 mmol) in dimethyl sulfoxide (6.0 mL), diisopropylethylamine (1.2 mL, 6.4 mmol) and the product from Step 5 of Example 1 (370 mg, 1.4 mmol) were added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3 × 100 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (3% methanol in chloroform) to obtain product 4 as 350 mg (53%) of off-white solid. mp: 158.4°C-160.3°C. IR: 3353, 1619, 1544, 1473 and 752 cm⁻¹ -1 . 1 H NMR(300MHz,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=13.2Hz,2H), 6.71(d,J=2.7Hz,1H,D2O)1 H), 6.98(d,J=7.5Hz,1H), 7.07-7.15(m,3H), 7.21-7.27(m,3H), 7.36-7.38(m,2H), 7.83(s,1H), 8.11(s,1H). 13 C NMR(75MHz,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).

[0231] Example 14 - Synthesis of 4-(3-benzimidazole-1-ylbenzyl)-piperidine-1-carboxylic acid (2-phenylcyclopropyl)amide:

[0232] [ka]

[0233] Step 1 - Compound 1 in triethyl phosphate (5.9 mL, 37.7 mmol) A solution of (5.0 g, 23.14 mmol) was heated at 130°C for 16 hours. The reaction mixture was cooled to room temperature, and the crude product obtained by evaporation of volatile substances was purified by passing it through a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to obtain Product 2 as 4.9 g (89%) of a pale yellow oily substance. 1 H NMR(300MHz,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).

[0234] Step 2 - 15-crown ether (0.08 mL, 0.04 mmol) was added to a solution of compound 2 (4.9 g, 20.3 mmol) in THF (50 mL). The reaction mixture was cooled (in an ice bath), and NaH (1.22 g, 30.5 mmol) was added in small amounts. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. To the above reaction mixture, a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.05 g, 20.3 mmol) in THF (10 mL) was added at ice temperature, and 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 on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (5% ethyl acetate in petroleum ether) to obtain product 3 as 4.0 g (62%) of a yellow oily substance. 1 H NMR(300MHz,DMSO-d6) δ (ppm):1.42(s,9H), 2.33(t,J=5.7Hz,2H), 2.41(t,J=5.7Hz,2H), 3.38-3.41(m,2H), 3 .44(t,J=5.7Hz,2H), 6.50(s,1H), 7.61-7.71(m,2H), 8.02(s,1H), 8.07-8.10(m,1H). MS: 219.2 (M-BOC+H), 263.1 (Mt-Butyl+1).

[0235] Step 3 - To a solution of compound 3 (4.0 g, 12.5 mmol) in 90% methanol in dichloromethane (40.0 mL), 10% Pd / C (3.0 g) was added. The reactants were then heated at room temperature under a hydrogen gas pressure (1 kg / cm²). 2 The mixture was stirred under conditions of 20 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain product 4 as a pale yellow liquid (1.5 g, 41%). The product was used in the next step without further purification. 1H NMR(300MHz,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), 2.60-2.7 2(m,1H), 3.90(t,J=12.6Hz,2H)4.92(s,2H), 6.28-6.38(m,3H), 6.90(t,J=12.6Hz,1H). MS:191.1(M-BOC+1).

[0236] Step 4 - Cs2CO3 (8.9 g, 25.7 mmol) was added at room temperature 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 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 on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (7% ethyl acetate in petroleum ether) to obtain product 5 as 500 mg (35%) of a reddish-yellow oily substance. 1 H NMR(300MHz,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=12.9Hz,2H), 6 .87(t,J=7.5Hz,1H), 7.01(d,J=7.8Hz,1H), 7.13-7.20(m,3H), 7.30-7.35(m,1H), 7.50(t,J=6.6Hz,1H), 8.11(d,J=7.5Hz,1H), 9.35(s,1H). MS: 410.0 (MH).

[0237] Step 5 - 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) at room temperature (25°C). The reaction mixture was then stirred at 110°C for 18 hours. The reaction mixture was cooled to room temperature and then filtered through Celite with the help of 20 mL of formic acid. The crude product obtained by evaporation of volatiles was dissolved in 5% methanol in dichloromethane (50 mL) and filtered to remove inorganic salts. The filtrate was concentrated to obtain product 6 as an off-white solid (350 mg). The crude product was then used without purification.

[0238] Step 6 - To a solution of amine 6 (350 mg, 1.2 mmol) in dimethyl sulfoxide (5.0 mL), diisopropylethylamine (1.03 mL, 6.0 mmol) and the product from Step 5 of Example 1 (186 mg, 1.2 mmol) were added at 25°C. 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 × 50 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (1.5% methanol in dichloromethane) to obtain product 7 as an off-white solid of 170 mg (31%). mp: 72.5°C~76.4°C. IR: 3347, 2931, 16161, 1542, and 742 cm⁻¹ -1 . 1 H NMR(300MHz,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=12.9Hz,2H), 6.72(d,J=2.7Hz,1H,D2O) 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).

[0239] Example 15 - Synthesis of 4-(3-pyrrolidine-1-yl-benzylidene)-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0240] [ka]

[0241] Step 1 - To a solution of the product from Step 2 of Example 9 (2.0 g, 7.0 mmol) in 1,4-dioxane (20.0 mL), 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 at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 30 minutes, followed by stirring under reflux for 16 hours. The resulting reaction product 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 on sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (15% ethyl acetate in petroleum ether) to obtain Product 2 as 0.6 g (32%) of a pale yellow oily substance. 1 H NMR(300MHz,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=8.1Hz,1H). MS:343.7(M+1).

[0242] Step 2 - Trifluoroacetic acid (3 mL) was added at ice temperature 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 oily substance 3 (0.6 g) obtained by evaporation of volatile matter was used in the next step without further purification.

[0243] Step 3 - To a solution of amine 3 (600 mg, 1.9 mmol) in dimethyl sulfoxide (6.0 mL), diisopropylethylamine (1.1 mL, 5.8 mmol) and the product from Step 5 of Example 1 (0.5 g, 1.9 mmol) were added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3 × 100 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (40% ethyl acetate in petroleum ether) to obtain product 4 as 300 mg (42%) of off-white solid. mp: 145.7°C-147.4°C. IR: 3292, 2963, 1626, 1533, 1263 and 746 cm⁻¹ -1 . 1 H NMR(300MHz,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( Exchangeable with bs,1H), 3.30(bs,4H), 3.36-3.40(m,2H), 3.47-3.51(m,2H), 4.87(bs,1H,D2O) 1 H), 6.38-6.52(m,3H), 7.19-7.46(m,7H). 13 C NMR(75MHz,CDCl3) δ (ppm):16.01, 24.75, 32.08, 34.56, 37.96, 43.17, 43.98, 49.00, 66.61, 113.09, 1 16.43, 120.52, 125.77, 126.29, 128.53, 129.12, 141.31, 142.51, 151.50, 158.28. MS:402.7(M+H).

[0244] Example 16 - Synthesis of phenyl N-[(1R,2S)-2-phenylcyclopropyl]carbamate:

[0245] [ka]

[0246] The above chiral intermediate was synthesized using the general methodology described in the literature (Patent Document 1).

[0247] Step 1 - A suspension of trans-2-phenyl-cyclopropylamine hydrochloride (100 g, 0.59 mol) in water (500 mL) was basicized to pH > 7 by adding saturated sodium bicarbonate solution over 20 minutes at 0-5°C. The reaction mixture was stirred at 25-30°C for 2 hours. The reaction mixture was extracted with dichloromethane (3 × 700 mL), and the separated organic phase was dried over sodium sulfate and concentrated to obtain 2-phenyl-cyclopropylamine as off-white solid 2 (71.2 g, 92%).

[0248] Step 2 - To a solution of trans-2-phenylcyclopropylamine (70 g, 0.52 mol) in ethanol (700 mL), L(+) tartaric acid (79 g, 0.52 mol) was added at 0-5°C and the mixture was stirred at 25-30°C for 1 hour. After the reaction was complete, the solid was filtered and dried to obtain 2-phenylcyclopropylamine as 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 hours. The reaction mixture was cooled to room temperature for 1 hour. The separated solid was collected by filtration to obtain (1R,2S)-N-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-2-phenylcyclopropane-1-aminium (3) as a white solid (60 g, 90%).

[0249] Step 3 - To a solution of (1R,2S)-N-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-2-phenylcyclopropane-1-aminium(3) (60 g, 0.19 mol) in water (200 mL), 1.0 M sodium hydroxide (194 mL, 0.19 mol) was added over 20 minutes at 0-5°C, and the mixture was stirred for 1 hour. The aqueous phase was extracted with ethyl acetate (2 × 700 mL). The combined extracts were washed with water (2 × 400 mL) and brine (400 mL), dried on sodium sulfate, and concentrated under reduced pressure to obtain (1R,2S)-2-phenyl-cyclopropylamine as a pale yellow solid 4 (25 g, 87%).

[0250] Step 4 - 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) at ice bath temperature. The ice bath was then removed, and the reaction mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was diluted with ethyl acetate (1.0 L), washed with water (2 × 200 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatile matter was purified by passing it through a silica gel (230-400) column (10% ethyl acetate in petroleum ether) to obtain product 5 as a white solid of 16.0 g (71%). 1 H NMR (400MHz, 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.

[0251] Step 5 - To a stirred solution of (1R,2S)-2-phenyl-cyclopropylamine 4 (25.0 g, 0.19 mol) in diethyl ether (150 mL), 2.0 M HCl in ether (140 mL, 0.28 mol) was added at 0-5°C. The reaction mixture was stirred at 20-25°C for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting reaction product was washed with diethyl ether (2 × 100 mL) to obtain product 6, (1R,2S)-2-phenyl-cyclopropylamine hydrochloride, as an off-white solid of 30.0 g (95%). mp: 179.2-180.1°C; IR: 3643, 3054, 1979, 1501, 1160, 799, 743, 696 cm -1 . 1 ¹H NMR (400MHz, 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 a confirmatory sample, (1R,2S)-2-phenylcyclopropylamine hydrochloride purchased from Sigma-Aldrich.

[0252] Example 17 - Synthesis of 4-[3-(5-trifluoromethylpyridine-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid [(1S,2R)-2-phenyl-cyclopropyl)]amide:

[0253] [ka]

[0254] Step 1 - 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) at ice bath temperature. The ice bath was then removed, and the reaction mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was diluted with ethyl acetate (1.0 L), washed with water (2 × 200 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (10% ethyl acetate in petroleum ether) to obtain product 3 as a white solid of 500 mg (71%). 1 H NMR (400MHz, 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.

[0255] Step 2 - To a solution of the product from Step 5 of Example 3 (1.0 g, 2.2 mmol) in dimethyl sulfoxide (10 mL), diisopropylethylamine (1.2 mL, 6.6 mmol) and 3 (556 mg, 2.2 mmol) were added at 25°C. The reaction mixture was stirred at 60°C for 4 hours. The resulting reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3 × 100 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (40% ethyl acetate in petroleum ether) to obtain product 4 as a white solid of 770 mg (70%). mp: 100.2°C~101.0°C. IR: 3329, 1622, 1531, 1487, 1329, 1076 cm⁻¹ -1 . 1H NMR(400MHz,DMSO-d6) δ (ppm):1.08-1.18(m,2H), 1.85-1.90(m,1H), 2.27(t,J=5.6Hz,2H), 2.40(t,J=5.2Hz,2H), 2.69-2.72(m,1H), 3.32(t,J=6 .0Hz,2H), 3.38(t,J=6.0Hz,1H), 6.37(s,1H), 6.85(d,J=3.2Hz,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%.

[0256] Example 18 - Synthesis of 4-[3-(5-trifluoromethylpyridine-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid [(1R,2S)-2-phenyl-cyclopropyl)]amide:

[0257] [ka]

[0258] Step 1 - Triethylamine (1.21 mL, 8.85 mol) and phenyl chloroformate 1 (0.41 mL, 3.3 mol) were added to a suspension of (1R,2S)-2-phenyl-cyclopropylamine 2 (500 mg, 2.95 mmol) in dichloromethane (5.0 mL) at ice bath temperature. The ice bath was then removed, and the reaction mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was diluted with ethyl acetate (250 mL), washed with water (2 × 100 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (10% ethyl acetate in petroleum ether) to obtain product 3 as a white solid of 495 mg (70%). 1 H NMR (400MHz, 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.

[0259] Step 2 - Diisopropylethylamine (1.2 mL, 6.6 mmol) and 3 (556 mg, 2.2 mmol) were added at 25°C to a solution of the product from Step 5 of Example 3 (1.0 g, 2.2 mmol) in dimethyl sulfoxide (10 mL). The reaction mixture was stirred at 60°C for 4 hours. The resulting reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3 × 100 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (40% ethyl acetate in petroleum ether) to obtain product 4 as a white solid of 715 mg (65%). mp: 101.8°C~103.2°C. IR: 3329, 1623, 1531, 1388, 1329, 1076, 697 cm⁻¹ -1 . 1 H NMR(400MHz,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=6.0Hz,2H) ), 3.38(t,J=5.6Hz,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%.

[0260] Example 19 - Synthesis of 4-({3-[(5-methylpyridine-2-yl)oxy]phenyl}methylidene)-N-[2-phenylcyclopropyl]piperidine-1-carboxamide:

[0261] [ka]

[0262] Step 1 - 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-methylpyridine 1 (14.76 g, 0.13 mol) in DMF (150 mL) at room temperature. The reaction mixture was stirred at 100 °C for 5 hours. Next, 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 on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (30% ethyl acetate in petroleum ether) to obtain Product 2 as 6.0 g (23%) of a pale yellow oily substance. 1 H NMR(300MHz,DMSO-d6) δ (ppm):2.25(s,3H), 4.40(d,J=6.0Hz,2H), 5.22(t,J=6.0Hz,1H), 6.91-6.94(m,2H), 7.01(s ,1H), 7.11(d,J=7.5Hz,1H), 7.34(t,J=7.5Hz,1H), 7.66-7.69(m,1H), 7.98(d,J=2.1Hz,1H). MS:(M+H)216.2.

[0263] Step 2 - To a solution of [3-(5-methylpyridine-2-yloxy)-phenyl]methanol 2 (6.0 g, 0.027 mol) in dichloromethane (60 mL), thionyl chloride (2.3 mL, 0.03 mol) was added dropwise while the reaction mixture was stirred in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. Next, the volatiles were evaporated under reduced pressure, diluted with toluene (25 mL), and the toluene was evaporated under reduced pressure. This azeotropic process was repeated three times to obtain product 3 as a light brown oily substance (6.2 g, 95%). 1 H NMR(300MHz,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.

[0264] Step 3 - A solution of 2-(3-chloromethyl-phenoxy)-5-methylpyridine (6.2 g, 0.026 mol) in triethyl phosphate (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 by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (60% ethyl acetate in petroleum ether) to obtain Product 4 as 8.3 g of a pale yellow oily substance. The product contained unused triethyl phosphate and was used in the next step without further purification. did. 1 H NMR(300MHz,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=7.4Hz,1H), 7.32(t,J=8.1Hz,1H), 7.66-7.69(m,1H), 7.98-8.32(m,1H). MS:(M+H)336.1.

[0265] Step 4 - 15-crown ether (0.1 g, 0.48 mmol) was added to a solution of [3-(5-methylpyridine-2-yloxy)-benzyl]phosphonate diethyl ester 4 (8.3 g, 0.024 mol) in THF (40 mL). The reaction mixture was cooled (in an ice bath), and NaH (1.44 g, 0.036 mol) was added in small amounts. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. To the above reaction mixture, a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.9 g, 0.024 mol) in THF (40 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 (250 mL), extracted with ethyl acetate (3 × 500 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatile substances was purified by passing it through a silica gel (230-400) column (3% ethyl acetate in petroleum ether) to obtain product 5 as a pale yellow oily substance (6.7 g, 76%). 1H NMR(300MHz,CDCl3) δ (ppm):1.41(s,9H), 2.25-2.29(m,5H), 2.39(t,J=6.0Hz,2H), 3.36-3.42(m,4H), 6.36(s,1H), 6.9 0-6.95(m,3H), 7.02-7.05(m,1H), 7.35(t,J=7.8Hz,1H), 7.66-7.70(m,1H), 7.98(d,J=2.4Hz,1H). MS:(M+H)381.2.

[0266] Step 5 - Trifluoroacetic acid (27 mL) was added at ice temperature to a solution of 4-[3-(5-methylpyridine-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester 5 (6.7 g, 0.017 mol) in dichloromethane (67.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. Product 6 (6.96 g) obtained by evaporation of volatile matter was used in the next step without further purification. 1 H NMR(300MHz,DMSO-d6) δ (ppm):2.24(s,3H), 2.61(t,J=6.1Hz,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=7.8Hz,1H), 7.66-7.70(m,1H), 7.98(d,J=2.4Hz,1H), 8.70(bs,2H). MS:(M+H)281.3.

[0267] Step 6 - To a solution of amine 6 (3.0 g, 7.0 mmol) in dimethyl sulfoxide (30 mL), diisopropylethylamine (4.2 mL, 22.0 mmol) and the product from Step 5 of Example 1 (1.93 g, 7.0 mmol) were added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3 × 150 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to obtain product 7 as 2.33 g (70%) of off-white solid. mp: 87.8°C~91.0°C. IR: 3250, 2895, 1624, 1425, 1263, 848, 774 cm⁻¹ -1 . 1 1H NMR (300MHz, 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=5.1Hz,2H), 2.71(m,1H), 3.31(t,J=5.5Hz,2H), 3.38(t,J=5.5Hz,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=7.9,2.0Hz,1H), 7.70(dt,J=8.3,2.5Hz,1H), 7.99(bs,1H). MS: (M+H) 440.5.

[0268] Example 20 - Synthesis of 4-[3-(pyridine-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid [2-(4-methyl)phenyl-cyclopropyl]amide:

[0269] [ka]

[0270] Step 1 - Ammonium acetate (13.4 g, 0.17 mol) was added to acetic acid (100 mL) and stirred until completely dissolved. Next, 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 aqueous 2 M sodium hydroxide solution (pH=7), extracted with ethyl acetate (2 × 300 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was washed with hexane to obtain product 2 as a yellow solid (10 g, 74%). 1 H NMR (300MHz, DMSO-d6) δ (ppm): 2.361 (s, 3H), 7.303 (d, 2H), 7.755 (d, 2H), 8.072-8.213 (m, 2H). MS(MH)162.9.

[0271] Step 2 - Trimethyloxosulfonium iodide (6.7 g, 0.03 mol) was added to a solution of a 60% sodium hydride dispersion in mineral oil (0.98 g, 0.024 mol) in dimethyl sulfoxide (10 mL), and the mixture was stirred at room temperature for 30 minutes. Next, product 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 on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400 mesh) column (2% ethyl acetate in hexane) to obtain product 3 as a pale yellow oily substance (300 mg, 14%). 1 H NMR(300MHz,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.

[0272] Step 3 - To a solution of 3 (0.3 g, 0.0016 mol) in isopropyl alcohol (12 mL), hydrochloric acid (6.2 mL of 2.7 N solution, 0.0169 mol), followed by zinc powder (1.1 g, 0.0169 mol), was added in small portions. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized with 10% sodium hydroxide solution and filtered through a Celite bed. The filtrate was diluted with ethyl acetate (150 mL), washed with water (50 mL) and brine solution (50 mL), dried on sodium sulfate, and concentrated under reduced pressure. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400 mesh) column (2% methanol in chloroform) to obtain product 4 as a yellow oily substance (150 mg, 60%). 1 H NMR (300MHz, 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.

[0273] Step 4 - Triethylamine (0.17 mL, 0.0012 mol) and phenyl chloroformate (115 mg, 0.0007 mol) were added at 0°C to a solution of 4 (90 mg, 0.0006 mol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was diluted with ethyl acetate (150 mL), washed with water (50 mL), dried on sodium sulfate, and concentrated under reduced pressure. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400 mesh) column (10% ethyl acetate in hexane) to obtain product 5 as a white solid (30 mg, 18%). 1 H NMR (300MHz, 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.

[0274] Step 5 - Trifluoroacetic acid (4 mL) was added at 0°C to a solution of the product from Step 4 of Example 2 (1.0 g, 0.002 mol) in dichloromethane (10 mL), and the reaction mixture was stirred at room temperature for 1 hour. Product 7 (1.3 g, 97%) obtained by evaporation of volatiles was used for the next step without further purification.

[0275] Step 6 - To a solution of 7 (0.29 g, 0.0006 mol) in dimethyl sulfoxide (3 mL), diisopropylethylamine (0.59 mL, 0.0034 mol) and 5 (0.16 g, 0.0006 mol) were added at room temperature. The reaction mixture was stirred at 60 °C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (200 mL), washed with water (3 × 50 mL), dried on sodium sulfate, and concentrated under reduced pressure. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400 mesh) column (40% ethyl acetate in hexane) to obtain product 8 as an off-white solid (180 mg, 69%). mp: 87.8-91.0 °C. IR: 3250, 3013, 1624, 1573, 1425, 1263, 1117, 775 cm⁻¹ -1 . 1 1H NMR (300MHz, 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.

[0276] Example 21 - Synthesis of 4-[3-(pyrimidine-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid [(1R,2S)-2-phenyl-cyclopropyl]amide:

[0277] [ka]

[0278] Step 1 - Diisopropylethylamine (4.13 mL, 23.6 mmol) and the product from Step 4 of Example 16 (2.0 g, 7.89 mmol) were added at 25°C to a solution of amine 1 and the product from Step 5 of Example 6 (3.02 g, 7.89 mmol) in dimethyl sulfoxide (30.0 mL). The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3 × 150 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (60% ethyl acetate in petroleum ether) to obtain product 3 as a white solid of 2.3 g (70%). mp: 62.8-65.2°C. IR:3627, 3310, 1732, 1629, 1570, 1526, 1310, 1249, 1148, 753, 696cm -1 . 1 1H NMR (400MHz, DMSO-d6) δ (ppm):1.04-1.18(m,2H), 1.85-1.88(m,1H), 2.27(t,J=5.7Hz,2H), 2.39 (t,J=5.8Hz,2H), 2.71(dt,J=7.4,3.7Hz,1H), 3.31(d,J=5.9Hz,2H), 3.3 9(d,J=5.9Hz,2H), 6.37(s,1H), 6.84(d,J=3.1Hz,1H), 7.03-7.12(m,6H) , 7.20-7.30(m,3H), 7.39(t,J=4.7Hz,1H), 8.64(dd,J=4.7Hz,1.1Hz,2H). MS:427.4(M+H). HPLC purity: 99.79%. Chiral HPLC purity: 99.92%. Optical rotation: -1.190. Specific optical rotation: -111.71.

[0279] Example 22 - Synthesis of 4-[3-(5-methylpyridine-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)amide:

[0280] [ka]

[0281] Step 1 - Diisopropylethylamine (4.2 mL, 22.0 mmol) and the product from Step 4 of Example 16 (1.93 g, 7.0 mmol) were added at 25°C to a solution of Amine 1 in dimethyl sulfoxide (30 mL) and the product from Step 5 of Example 19 (3.0 g, 7.0 mmol). 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 on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to obtain Product 3 as a pale yellow solid of 2.7 g (81%). mp: 53.1-53.9°C. IR: 3321, 3024, 1628, 1526, 1475, 1249, 752, 695 cm⁻¹ -1 . 1 1H NMR (300MHz, 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 =5.6Hz,2H), 2.71(m,1H), 3.31(t,J=5.5Hz,2H), 3.38(t,J=5.5Hz,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=7.9,2.0Hz,1H), 7.70(dt,J=8.3,2.5Hz,1H), 7.99(d,J=2.8Hz,1H). MS(M+H) 440.5. HPLC purity: 98.5%. Chiral HPLC purity: 100%.

[0282] Example 23 - Synthesis of 4-[3-(pyrimidine-2-yloxy)-benzylidene]-piperidine-1-carboxylate methyl-((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0283] [ka]

[0284] Step 1 - 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 from Example 21 (150 mg, 7.89 mmol) in dimethylformamide (30.0 mL) at 0-5°C. 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 on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (25% ethyl acetate in petroleum ether) to obtain 77 mg (50%) of a pale yellow solid. 1 H NMR(300MHz,DMSO-d6) δ (ppm):1.24(dt,J=7.8Hz,5.9Hz,2H), 2.02-2.07(m,1H), 2.27(q,J=5.9Hz,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=7.9Hz,1H), 8.65(d,J=4.8Hz,2H). MS:441.5(M+H). HPLC purity: 98.1%.

[0285] Example 24 - Synthesis of 4-[3-(5-methylpyrazine-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)amide:

[0286] [ka]

[0287] Step 1 - 3-hydroxyphenyl-methanol (11.6 g, 0.094 mol) and cesium carbonate (76.0 g, 0.23 mol) were added at room temperature to a solution of 2-chloro-5-methylpyrazine (10 g, 0.078 mol) in DMF (100 mL). The reaction mixture was stirred at 100 °C for 5 hours. Next, 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 on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (30% ethyl acetate in petroleum ether) to obtain Product 1 as 6.8 g (40%) of a pale yellow oily substance. 1 H NMR(300MHz,DMSO-d6) δ (ppm): 2.45(s,3H), 4.50(d,J=4.5Hz,2H), 5.26(t,J=5.26Hz,1H), 7.0-7.18(m,3H), 7.37(t,J=7.5Hz,1H), 8.1(s,1H), 8.4(d,J=1.2Hz,1H). MS(M+H)217.2.

[0288] Step 2 - To a solution of 1 (6.0 g, 0.027 mol) in dichloromethane (60 mL), thionyl chloride (2.3 mL, 0.03 mol) was added dropwise while stirring the reaction mixture in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. Next, the volatiles were evaporated under reduced pressure, diluted with toluene (25 mL), and the toluene was evaporated under reduced pressure. This azeotropic process was repeated three times to obtain product 2 as a light brown oily substance (6.2 g). The crude product was used for the next step without further purification. MS(M+H) 235.3.

[0289] Step 3 - A solution of 2 (6.2 g, 0.026 mol) in triethyl phosphate (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 by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (60% ethyl acetate in petroleum ether) to obtain product 3 as 8.3 g of a pale yellow oily substance. The product contained unused triethyl phosphate and was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6) δ (ppm):1.16(t,J=7.0Hz,6H), 2.45(s,3H), 3.23(s,1H), 3.23(s,1H), 3.94(dq,J=8.2Hz,7.0Hz,4H), 7.0-7 .12(m,2H), 7.13-7.15(m,1H), 7.36(t,J=7.8Hz,1H), 8.09(dd,J=1.4Hz,0.7Hz,1H), 8.39(d,J=1.4Hz,1H). MS(M+H)337.1.

[0290] Step 4 - 15-crown ether (0.1 g, 0.48 mmol) was added to a solution of 3 (8.3 g, 0.024 mol) in THF (40 mL). The reaction mixture was cooled (in an ice bath), and NaH (1.44 g, 0.036 mol) was added in small amounts. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. To the above reaction mixture, a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 5 (4.9 g, 0.024 mol) in THF (40 mL) was added at ice temperature, and 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 on sodium sulfate. Product 4 was obtained as a pale yellow oily substance (6.7 g) from the crude product obtained by evaporation of volatiles. MS(M+H) 382.3. Product 4 was used in the next step without further purification.

[0291] Step 5 - Trifluoroacetic acid (27 mL, 4V) was added to a solution of 4 (6.7 g, 0.017 mol) in dichloromethane (67.0 mL) at ice-cold temperature, and the reaction mixture was stirred at room temperature for 1 hour. Product 6 (6.96 g, 90%) obtained by evaporation of volatiles was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6) δ (ppm):2.45(s,3H), 2.60-2.67(m,4H), 3.10-3.17(m,4H), 6.46(s,1H), 7.04-7.1 2(m,4H), 7.38(t,J=7.8Hz,1H), 8.09(s,1H), 8.40(d,J=4.4Hz,1H), 8.61(bs,2H). MS(M+H)282.3.

[0292] Step 6 - Diisopropylethylamine (1.4 mL, 7.5 mmol) and the carbamate product from Step 4 of Example 16 (0.7 g, 2.75 mmol) were added at 25°C to a solution of amine 6 (1.0 g, 2.5 mmol) in dimethyl sulfoxide (30 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 × 150 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatile matter was purified by passing it through a silica gel (230-400) column (60% ethyl acetate in petroleum ether) to obtain product 7 as 0.7 g (68%) of a pale yellow solid. mp: 50.8°C. IR: 3305, 2923, 1627, 1528, 1473, 1337, 1266, 695 cm⁻¹ -1 . 1 H NMR(300MHz,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%.

[0293] Example 25 - Synthesis of 4-[3-(5-chloropyridine-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)amide

[0294] [ka]

[0295] Step 1 - 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) at room temperature. The reaction mixture was stirred at 100 °C for 6 hours. The reaction was monitored by TLC. The resulting mixture was cooled to room temperature, 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 by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (12% ethyl acetate in petroleum ether) to obtain Product 1 as 12.0 g (67%) of a pale yellow oily substance. 1 H NMR(400MHz,DMSO-d6) δ (ppm):8.17(t,J=2.4Hz,1H), 7.94-7.91(m,1H), 7.33(t,J=8.0Hz,1H), 7.14-7.1(m,1 H), 7.06-7.03(m,2H), 6.98-6.95(m,1H), 5.22(t,J=5.6Hz,1H), 4.48(d,J=5.6Hz,2H). MS m / z(M+H):236.0

[0296] Step 2: To a solution of 1 (12.0 g, 0.0509 mol) in dichloromethane (120 mL), thionyl chloride (4.1 mL, 0.0560 mol) was added dropwise while stirring the reaction mixture in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. After complete consumption of the starting materials, 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. Crude product 2 obtained by evaporation was used directly in the next step without further purification (12.5 g, 96%). 1 H NMR(400MHz,DMSO-d6) δ (ppm):8.20(d,J=2.4Hz,1H), 8.19-7.95(m,1H), 7.42(t,J=7.6Hz,1H), 7. 29(d,J=8.0Hz,1H), 7.21(t,J=2.0Hz,1H), 7.12-7.09(m,2H), 4.75(s,1H). MS m / z(M+H):254.1

[0297] Step 3: A solution of 2 (12.5 g, 0.0494 mol) in triethyl phosphate (20.0 mL, 0.1235 mol) was heated at 150°C for 6 hours. The reaction mixture was allowed to reach room temperature, and after removing volatiles, the resulting crude product was added to n-heptane (150 mL) to obtain a light orange precipitate. The precipitate was filtered and dried under vacuum to obtain product 3 as an off-white solid (16.5 g, 91%), which was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6) δ (ppm):8.19-8.18(m,1H), 7.97-7.94(m,1H), 7.34(t,J=7.6Hz,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=4.4Hz,6H). MS m / z(M+H):356.2

[0298] Step 4: To a solution of 3 (15.5 g, 0.0435 mol) in THF (100 mL), 15-crown ether (0.19 g, 0.87 mmol) was added. The reaction mixture was cooled (in an ice bath), and NaH (2.07 g, 0.0870 mol) was added in small amounts over a period of 5 minutes. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 5 (8.66 g, 0.0435 mol) in THF (50 mL) was added at ice temperature, and the mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried on anhydrous sodium sulfate and concentrated. After evaporation of volatiles, the crude product was purified by silica gel column chromatography to obtain product 4 as a pale yellow liquid (13.1 g, 75%). 1 H NMR(400MHz,DMSO-d6) δ (ppm):8.19(d,J=2.0Hz,1H), 7.96-7.93(m,1H), 7.36(t,J=7.6Hz,1H), 7.09-7.06(m,2H), 6.99-6.9 6(m,2H), 6.35(s,1H), 3.40-3.32(m,4H), 2.38(t,J=5.2Hz,2H), 2.26(t,J=6.0Hz,2H), 1.39(s,9H). MS m / z(M+Na):423.2

[0299] Step 5: Trifluoroacetic acid (52.0 mL) was added at ice temperature to a solution of 4 (13.0 g, 0.0325 mol) in dichloromethane (130 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After complete consumption of the starting materials, volatiles were removed under reduced pressure to obtain the product as a light brown oily substance. The crude product was washed with ether (3 × 50 mL) to obtain 6 as a light brown, concentrated liquid (13.8 g of crude product). 1H NMR(400MHz,DMSO-d6) δ (ppm):8.82(bs,2H), 8.19(d,J=2.8Hz,1H), 7.96-7.93(m,1H), 7.38(t,J=8.0Hz,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=5.6Hz,2H), 2.53-2.48(m,2H). MS m / z(M+H):301.2

[0300] Step 6: To a solution of 6 (15.8 g, 0.0381 mol) in dimethyl sulfoxide (78 mL), diisopropyl-ethyl-amine (20.34 mL, 0.1149 mol) and the carbamate product from Step 4 of Example 16 (10.62 g, 0.0419 mol) were added at 25°C. The reaction mixture was stirred at 60°C for 6 hours. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3 × 200 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (40% ethyl acetate in petroleum ether) to obtain product 7 as a pale yellow, fuzzy solid (11.6 g, 66%). Melting range (MR): 44.8-62.6°C 1 1H NMR (400MHz, DMSO-d6) δ (ppm):8.18(d,J=2.4Hz,1H), 7.94-7.91(m,1H), 7.35(t,J=7.6Hz,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=5.2Hz,2H), 2.24-2.22(t ,J=5.6Hz,2H), 1.85(m,1H), 1.13(d,J=4.8Hz,1H), 1.04(d,J=7.6Hz,1H). 13¹³C NMR (100MHz, 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%.

[0301] Example 26 - Synthesis of 4-[3-(5-fluoropyridine-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)amide

[0302] [ka]

[0303] Step 1: To a solution of 2,5-difluoropyridine (8.2 g, 0.0719 mol) in DMSO (80 mL), 3-hydroxyphenyl-methanol (8.9 g, 0.0719 mol) and cesium carbonate (28.12 g, 0.0863 mol) were added at room temperature, and the reaction mixture was stirred at 85 °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 (3 × 400 mL), and the organic layer was dried over sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (12% ethyl acetate in petroleum ether) to obtain Product 1 as 4.3 g (28%) of a pale yellow oily substance. 1 H NMR(400MHz,DMSO-d6) δ (ppm):8.17(t,J=2.4Hz,1H), 7.84-7.78(m,1H), 7.35(t,J=10.4Hz,1H), 7.15-6.95(m,4H), 5.25(t,J=7.6Hz,1H), 4.50(d,J=7.6Hz,2H). MS m / z(M+H):220.0

[0304] Step 2: To a solution of 1 (6.5 g, 0.0296 mol) in dichloromethane (65 mL), thionyl chloride (2.4 mL, 0.0326 mol) was added dropwise while the reaction mixture was stirred in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 2 hours. 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. Crude product 2 obtained by evaporation was used directly in the next step without further purification (6.7 g, 95%). 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.15(d,J=2.4Hz,1H), 7.83-7.80(m,1H), 7.40(t,J=7.6Hz,1H), 7.27-7.25(m,1H), 7.19-7.06(m,3H), 4.75(s,1H). MS m / z(M+H):238.0

[0305] Step 3: A solution of 2 (6.5 g, 0.0274 mol) in triethyl phosphate (12.6 mL, 0.0685 mol) was heated at 150°C for 6 hours. The reaction mixture was cooled to room temperature, and after evaporation of volatiles, the resulting mixture was purified by silica gel (230-400) column chromatography to obtain product 3 as a pale yellow liquid (9.0 g, 95%). 1 H NMR(400MHz,DMSO-d6) δ (ppm):8.15(d,J=4.0Hz,1H), 7.86-7.80(m,1H), 7.34(t,J=10.4Hz,1H), 7.12 -6.97(m,4H), 4.02-3.89(m,4H), 3.28 and 3.21(2s,2H), 1.15(t,J=9.2Hz,6H). MS m / z(M+H):340.2

[0306] Step 4: To a solution of 3 (9.0 g, 0.0256 mol) in THF (60 mL), 15-crown ether (0.12 g, 0.53 mmol) was added. The reaction mixture was cooled (in an ice bath), and 60% NaH (1.26 g, 0.0530 mol) was added in small amounts over a period of 5 minutes. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 5 (5.28 g, 0.0256 mol) in THF (30 mL) was added at ice temperature, and the mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried on anhydrous sodium sulfate and concentrated. After evaporation of volatiles, the crude product was purified by silica gel column chromatography to obtain product 4 as a pale yellow solid (8.0 g, 78%). 1 H NMR(400MHz,DMSO-d6) δ (ppm):8.15(d,J=3.2Hz,1H), 7.84-7.79(m,1H), 7.35(t,J=8.0Hz,1H), 7.12-7.04(m,2H), 6.96-6.9 2(m,2H), 6.35(s,1H), 3.40-3.32(m,4H), 2.37(t,J=5.6Hz,2H), 2.25(t,J=5.2Hz,2H), 1.39(s,9H). M.S. m / z(M+Na):407.2

[0307] Step 5: Trifluoroacetic acid (32.5 mL) was added at ice temperature to a solution of 4 (8.2 g, 0.0213 mol) in dichloromethane (82 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 materials, volatiles were removed under reduced pressure to obtain the product as a red oil. The crude product was washed with ether (3 × 50 mL) to obtain 6 as a dark brown oil (9.0 g of crude product). 1H NMR(300MHz,DMSO-d6) δ (ppm):8.73(bs,2H), 8.15(d,J=3.2Hz,1H), 7.84-7.79(m,1H), 7.37(t,J=8.0Hz,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=6.0Hz,2H), 2.49-2.48(m,2H). MS m / z(M+H):285.4

[0308] Step 6: To a solution of 6 (8.4 g, 0.021 mol) in dimethyl sulfoxide (42 mL), diisopropyl-ethyl-amine (11.1 mL, 0.063 mol) and the carbamate product from Step 4 of Example 16 (5.8 g, 0.023 mol) were added at 25°C. 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 on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (40% ethyl acetate in petroleum ether) to obtain product 7 as a pale yellow, fuzzy solid (7.15 g, 66%). 1 H NMR(400MHz,DMSO-d6) δ (ppm):8.15(d,J=2.4Hz,1H), 7.82-7.80(m,1H), 7.35(t,J=8.0Hz,1H), 7.24 -7.21(m,2H), 7.14-7.04(m,5H), 6.96-6.94(m,2H), 6.84(d,J=2.8Hz,1H), 6 .34(s,1H), 3.38-3.28(m,4H), 2.71-2.69(m,1H), 2.34(t,J=5.2Hz,2H), 2.2 3(t,J=4.8Hz,2H), 1.86(m,1H), 1.13(d,J=4.8Hz,1H), 1.04(d,J=7.6Hz,1H). 13C NMR:(100MHz,DMSO-d6):δ 159.15, 157.57, 156.01(d,J=244.7Hz), 154.08, 141.99, 139.69, 138.76, 134.13(d,J=26.3Hz), 129.54, 128.09, 127.85(d ,J=20.9Hz), 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%.

[0309] Example 27: Synthesis of 6-{3-[1-((1R,2S)-2-phenyl-cyclopropylcarbamoyl)-piperidine-4-ylidenemethyl]-phenoxy}-nicotinate methyl ester

[0310] [ka]

[0311] Step 1: To a solution of methyl 6-chloropyridine-3-carboxylate (50.0 g, 0.29 mol) in dimethyl acetamide (500 mL), 3-hydroxyphenyl-methanol (39.79 g, 0.32 mol) and potassium carbonate (60.4 g, 0.43 mol) were added at room temperature. The reaction mixture was stirred at 100 °C for 6 hours. The reaction was monitored by TLC. The resulting mixture was cooled to room temperature and diluted with water (300 mL). The mixture was then extracted with ethyl acetate (2 × 500 mL), and the organic layer was dried on sodium sulfate. The crude product obtained by evaporation of volatile substances was purified by passing it through a silica gel (230-400) column (12% ethyl acetate in petroleum ether) to obtain Product 1 as a pale yellow oily substance (30.0 g, 40%). 1H NMR(400MHz,DMSO-d6) δ (ppm):8.82(d,J=2.0Hz,1H), 8.30-8.27(m,1H), 7.42(t,J=8.0Hz,1H), 7.27-7.19( m,2H), 7.09-7.07(m,1H), 6.96(d,J=8.8Hz,1H), 4.73(s,2H), 3.93(d,J=3.6Hz,3H). MS m / z(M+H):259.8

[0312] Step 2: To a solution of 1 (30.0 g, 0.115 mol) in dichloromethane (300 mL), thionyl chloride (9.4 mL, 0.127 mol) was added dropwise while stirring the reaction mixture in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 2 hours. After complete consumption of the starting materials, the volatiles were evaporated under reduced pressure and diluted with ethyl acetate (500 mL). The organic layer was washed with saturated sodium bicarbonate solution (200 mL) and water. The organic layer was dried on anhydrous sodium sulfate and concentrated. The crude product obtained by evaporation was purified by silica gel (230-400) column chromatography to obtain product 2 as a pale yellow liquid (28.0 g, 87%). 1 H NMR(400MHz,DMSO-d6) δ (ppm):8.82(d,J=0.8Hz,1H), 8.31-8.28(m,1H), 7.43(t,J=8.0Hz,1H), 7.29-7.27(m,1H) ), 7.21(t,J=2.0Hz,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

[0313] Step 3: A solution of 2 (28.0 g, 0.10 mol) in triethyl phosphate (41.0 mL, 0.25 mol) was heated at 150°C for 6 hours. The reaction mixture was cooled to room temperature, and after evaporation of volatiles, the resulting mixture was purified by silica gel column chromatography to obtain 3 as a pale yellow liquid (32.0 g, 84%). 1H NMR(400MHz,DMSO-d6) δ (ppm):8.65-8.64(m,1H), 8.30-8.27(m,1H), 7.35(t,J=8.0Hz,1H), 7.16-7.03( m,4H), 3.96-3.88(m,4H), 3.82(s,3H), 3.27 and 3.21(2s,2H), 1.15-1.11(m,6H). MS m / z(M+H):380.2

[0314] Step 4: To a solution of 3 (35.5 g, 0.093 mol) in THF (200 mL), 15-crown ether (0.41 g, 1.8 mmol) was added. The reaction mixture was cooled (in an ice bath), and 60% NaH (5.5 g, 0.14 mol) was added in small amounts over a period of 5 minutes. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 5 (18.7 g, 0.093 mol) in THF (150 mL) was added at ice temperature, and the mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried on anhydrous sodium sulfate and concentrated. After evaporation of volatiles, the crude product (30.0 g) obtained was dissolved in methanol (300 mL), and aqueous lithium hydroxide solution (3.0 g, 0.0707 mol) was added at ice temperature. The resulting reaction mixture was stirred at 50°C for 2 hours. The reaction was monitored by TLC. After evaporation of volatiles, the crude product was dissolved in water (200 mL) and washed with methyl tert-butyl ether (2 × 200 mL). The aqueous layer was acidified to pH 2.0 using a 1.0 N aqueous HCl solution. The precipitated product was filtered and dried to obtain compound 4 as an off-white solid (23.0 g, 61%). 1 H NMR(400MHz,DMSO-d6) δ (ppm):13.19(bs,1H), 8.66-8.65(m,1H), 8.28-8.25(m,1H), 7.39(t,J=8.0Hz,1H), 7.11-7.00(m,4H), 6.37(s,1H), 3.4 0-3.32(m,4H), 2.39(t,J=5.6Hz,2H), 2.27(t,J=5.2Hz,2H), 1.39(s,9H). MS m / z(M+H):433.2

[0315] Step 5: Trimethylsilyl chloride (8.9 mL, 0.0697 mol) was added to a solution of 4 (13.0 g, 0.0317 mol) in methanol (130 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 12 hours and monitored by TLC. After complete consumption of the starting materials, volatiles were removed under reduced pressure. The resulting crude product was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, dried on anhydrous sodium sulfate, filtered, and concentrated. After evaporation of volatiles, the resulting crude product was purified by silica gel (230-400) column chromatography to obtain product 6 as a pale yellow liquid (5.2 g, 51%). 1 H NMR(400MHz,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), 6.2 4(s,1H), 3.84(s,3H), 2.78-2.65(m,4H), 2.34(t,J=5.2Hz,2H), 2.21(t,J=5.2Hz,2H). MS m / z(M+H):325.3

[0316] Step 6: To a solution of 6 (5.2 g, 0.016 mol) in dimethyl sulfoxide (52 mL, 10V), diisopropylethylamine (8.9 mL, 0.048 mol) and the carbamate product from Step 4 of Example 16 (4.0 g, 0.016 mol) were added at 25°C. The reaction mixture was stirred at 60°C for 6 hours. The reaction was monitored by TLC. The resulting reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3 × 100 mL), and dried on anhydrous sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (40% ethyl acetate in petroleum ether) to obtain product 7 as a pale yellow, fuzzy solid (5.0 g, 65%). Melting point range (MR): 52.6-72.8°C. 11H NMR (400MHz, DMSO-d6) δ (ppm):8.68(d,J=2.0Hz,1H), 8.31-8.28(m,1H), 7.38(t,J=8.0Hz,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=5.2Hz,2H), 2.25( t,J=5.2Hz,2H), 1.86(m,1H), 1.15(d,J=4.8Hz,1H), 1.05(d,J=6.0Hz,1H). 13 ¹³C NMR (100MHz, 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%

[0317] Example 28: Synthesis of 6-{3-[1-((1R,2S)-2-phenyl-cyclopropylcarbamoyl)-piperidine-4-ylidenemethyl]-phenoxy}nicotinic acid

[0318] [ka]

[0319] 1. Product of Example 27 (1.8 g, 0.0038 mol) in methanol (18 mL) 0.32 g, 0.0076 mol aqueous lithium hydroxide was added dropwise to the solution of ) at ice temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC. After evaporation of volatiles, the crude product obtained 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 obtain 1.52 g (87%) of off-white solid. Melting range (MR) 141-159°C. 1 1H NMR (400MHz, 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. 0Hz,1H), 7.24-7.21(m,2H), 7.13-7.01(m,7H), 6.83(d,J=3.2Hz,1H), 6.35 (s,1H), 3.38-3.28(m,4H), 2.71-2.69(m,1H), 2.37(t,J=5.2Hz,2H), 2.25( t,J=5.2Hz,2H), 1.86(m,1H), 1.15(d,J=4.4Hz,1H), 1.05(d,J=7.6Hz,1H). 13 ¹³C NMR (100MHz, 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%.

[0320] Example 29: Synthesis of 4-[3-(5-hydroxymethylpyridine-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)amide

[0321] [ka]

[0322] Step 1: To a solution of product 1 from Step 4 of Example 27 (3.6 g, 0.0085 mol) in dimethoxyethane (35 mL), N-methylmorpholine (1.4 mL, 0.0128 mol) and isobutyl chloroformate (1.21 mL, 0.0093 mol) were added at ice temperature, and the reaction mixture was stirred at room temperature for 30 minutes. Sodium borohydride (1.9 g, 0.0512 mol) was added to the reaction mixture in small amounts, and the mixture was stirred for 12 hours. The reaction was monitored by TLC. After the complete consumption of starting material 1, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (300 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel (230-400) column chromatography to obtain product 2 as an off-white solid (3.2 g, 92%). 1 H NMR(400MHz,DMSO-d6) δ (ppm):8.06(m,1H), 7.79-7.76(m,1H), 7.34(t,J=8.0Hz,1H), 7.05-6.95(m,4H), 6.35(s,1H), 5.24(t,J=6.0 Hz,1H), 4.45(d,J=5.6Hz,1H), 3.40-3.32(m,4H), 2.38(t,J=5.6Hz,2H), 2.25(t,J=5.2Hz,2H), 1.39(s,9H). MS m / z(M+H):397.3

[0323] Step 2: Trifluoroacetic acid (12.8 mL) was added at ice temperature to a solution of 2 (3.2 g, 0.08 mol) in dichloromethane (32 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 materials, volatiles were removed under reduced pressure to obtain the crude product as a reddish-brown oily substance. The obtained crude product was washed with ether (3 × 50 mL) to obtain 3 as an off-white solid (3.3 g of crude product). MS m / z(M+H): 297.17

[0324] Step 3: To a solution of 3 (3.3 g, 0.08 mmol) in dimethyl sulfoxide (30 mL), diisopropylethylamine (4.2 mL, 0.024 mol) and the carbamate product from Step 4 of Example 16 (2.0 g, 0.08 mmol) were added at 25 °C. The reaction mixture was stirred at 60 °C for 6 hours. The resulting reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3 × 100 mL), and dried on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (40% ethyl acetate in petroleum ether) to obtain 4 as a pale yellow, fuzzy solid (1.82 g, 58%). Melting range (MR): 51-65 °C. 1 1H NMR (400MHz, DMSO-d6) δ (ppm):8.07(d,J=2.0Hz,1H), 7.80-7.77(m,1H), 7.34(t,J=8.0Hz,1H), 7 .26-6.92(m,7H), 6.83(d,J=3.2Hz,1H), 6.35(s,1H), 5.25(t,J=6.0Hz,1H ), 4.45(d,J=7.2Hz,1H), 3.40-3.32(m,4H), 2.38(t,J=5.6Hz,2H), 2.25(t ,J=5.2Hz,2H), 1.87(m,1H), 1.16(d,J=6.0Hz,1H), 1.05(d,J=7.6Hz,1H). 13 ¹³C NMR (100MHz, 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%.

[0325] Example 30: Synthesis of 4-[3-(5-methoxymethylpyridine-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)amide

[0326] [ka]

[0327] Step 1: To a solution of the product from Step 1 of Example 29 (3.2 g, 8.0 mmol) in tetrahydrofuran (32 mL), 60% NaH (0.97 g, 0.024 mol) was added at ice temperature, 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 mixture at the same ice temperature, and stirring was continued for 12 hours. The reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture 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 on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel (230-400) column chromatography to obtain product 2 as an off-white solid (2.6 g, 78%). 1 H NMR(400MHz,DMSO-d6) δ (ppm):8.08(d,J=2.0Hz,1H), 7.80-7.78(m,1H), 7.35(t,J=8.0Hz,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=5.6Hz,2H), 2.25(t,J=5.6Hz,2H), 1.39(s,9H). MS m / z(M+H):411.3

[0328] Step 2: Trifluoroacetic acid (10.4 mL) was added to a solution of 2 (2.6 g, 6.3 mmol) of 2 in dichloromethane (26.0 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After complete consumption of the starting materials, volatiles were removed under reduced pressure to obtain the product as a reddish-brown oil (brow red oil). The crude product was washed with ether (3 × 50 mL) to obtain 3 as a pale yellow concentrated liquid (2.9 g of crude product). 1H NMR(400MHz,DMSO-d6) δ (ppm):8.69(bs,2H), 8.09-8.08(m,1H), 7.81-7.78(m,1H), 7.38(t,J=7.6Hz,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=5.6Hz,2H), 2.45(t,J=5.6Hz,2H). MS m / z(M+H):311.3

[0329] Step 3: To a solution of 3 (2.9 g, 6.8 mmol) in dimethyl sulfoxide (30 mL, 10V), diisopropylethylamine (3.5 mL, 0.0205 mol) and carbamate product 5 (1.7 g, 6.8 mmol) from Step 4 of Example 16 were added at 25°C. 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 on sodium sulfate. The crude product obtained by evaporation of volatiles was purified by passing it through a silica gel (230-400) column (30% ethyl acetate in n-hexane) to obtain product 4 as a pale yellow rubbery solid (2.6 g, 86%). 1 H NMR(400MHz,DMSO-d6) δ (ppm):8.08(d,J=2.0Hz,1H), 7.81-7.78(m,1H), 7.33(t,J=7.6Hz,1H), 7.25- 7.21(m,2H), 7.09-6.93(m,7H), 6.83(d,J=3.2Hz,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=5.6Hz,2H), 2. 25(t,J=5.6Hz,2H), 1.85(m,1H), 1.13(d,J=4.8Hz,1H), 1.04(d,J=7.6Hz,1H). 13¹³C NMR (100MHz, 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 H PLC: 99.60%.

[0330] Example 31 - Soluble epoxide hydrolase (sEH) inhibition assay: An sEH enzyme inhibition assay was performed using a commercially available kit (Cayman catalog number 10011671) from Cayman Chemical Company in Ann Arbor, Michigan. The assay used 3-phenyl-cyano(6-methoxy-2-naphthalenyl)-methyl ester-2-oxiranacetic acid as the substrate for sEH. Hydrolysis of the substrate yielded highly fluorescent products that could be monitored at excitation and emission wavelengths of 330 and 465 nm, respectively. The assay mixture consisted of 185–190 μL of assay buffer and 5 μL of sEH enzyme in a 96-well plate. The reaction was initiated by adding 5 μL of substrate to compound at different concentrations (in 5 μL of DMSO) or DMSO alone (as the medium). The plate was incubated at 25°C for 15 minutes. Data analysis was performed to determine the inhibition percentage.

[0331] Concentration less than 10 μM (IC 50 Compounds that inhibit soluble epoxide hydrolase are considered to be active. The inhibitory activity of compounds of formula I is given in Table 1 (see Figures 1 and 2).

[0332] The efficacy of compounds of general formula I in neuropathic pain and inflammatory pain can be evaluated using animal models known in the literature (Non-Patent Literature 44).

[0333] Example 32 - The model described below (partial ligation of the sciatic nerve) can be used to evaluate the potential of the compound of Formula 1 for treating neuropathic pain.

[0334] Rats were anesthetized with 100 mg / kg of ketamine hydrochloride injection (Aneket, obtained from Neon Laboratories Ltd., Mumbai, India) mixed in a 10:1 ratio, and 10 mg / kg of xylazine hydrochloride injection (Xylazine, obtained from Indian Immunologicals Ltd., Hyderabad, India). The right sciatic nerve was exposed in the proximal femoral region. The posterior aspect of the nerve was carefully released from the surrounding connective tissue near the trochanter, just distal to the point where the posterior biceps semitendinosus (PBST) nerve branches off from the common sciatic nerve. The nerve was fixed in place by pinching the epineurium on its posterior side, taking care not to compress the nerve against the underlying structures. 5-0 Mersilk (Ethicon®, available from Johnson & Johnson Company) was inserted into the nerve using a 3 / 8-inch curved inverted triangular minineedle and tightly ligated so that the dorsal one-third to one-half of the nerve's thickness was captured by the ligature. The muscle was closed with 3-0 Vicryl absorbable suture, and the skin was also closed with skin staples. Sulfanilamide (Negasunt from Bayer) dust was applied to the muscle after suturing. Siamese controls underwent each surgery by exposing the nerve without ligation, and the wound was closed in the same manner as described above. After the completion of the surgery, the animals were individually housed in cages under warm conditions until they recovered from anesthesia. On day 6, paw withdrawal latency was measured and randomized. After weighing and a minimum of 15 minutes of acclimatization to the treatment room, the animals were administered the test item (compound C or compound D of formula I, 25 mg / kg / day, orally); the reference item gabapentin (30 mg / kg / day, ip) or the medium in a time-delayed manner as planned in the study. The volume of the administered dose was based on the animal's body weight.

[0335] Limb withdrawal latency (PWL) of both hind limbs in all rats was measured once before administration and twice after administration (on days 6 and 12, 1 hour and 3 hours after treatment, respectively) using a Hargreaves Plantar apparatus (obtained from Ugo Basile in Comerio, Italy). At each time point, and based on an acceptable threshold (> -25 DS %), the mean of the two closest observations out of a total of three observations per limb was analyzed. This was considered for the following reasons. Two sequential readings for the same limb were maintained at approximately 5-minute intervals. The percentage difference score (%DS) in PWL between the operated and unoperated limbs at each time point was used as an indicator of hyperalgesia.

[0336] %DS = 100 × (PWL for the operated limb - PWL for the unoperated limb) / PWL for the unoperated limb

[0337] Compounds showing a significant percentage difference score compared to the media-treated group are considered active. Figure 3 shows the anti-hyperalgesic efficacy of compounds C and D of formula I in a neuropathic pain model.

[0338] Example 33 - The model described below (streptozotocin-induced diabetic neuropathy) can be used to evaluate the potential of the compound of Formula 1 to treat peripheral diabetic neuropathy.

[0339] The study was conducted according to the published protocol, and all procedures / measurements were performed in a blinded manner (Non-Patent Literature 45; Non-Patent Literature 46). A single dose of streptozotocin (55 mg / kg, iv) was used to induce type 1 diabetes in rats. Animals were significantly diabetic (maximum glucose level of 600 mg / dl) by day 4 and remained diabetic until the end of the study. Limb withdrawal threshold (PWT) was measured (baseline value) the day before streptozotocin injection using a manual von Frey filament, and animals were stratified based on PWT values. For acute studies, on day 10, animals were given a medium, pregabalin (30 mg / kg), or compound A of formula I. PWT was assessed 1, 2, 4, and 6 hours after administration and compared with sham and diabetic control (pathological control) animals. For chronic studies, compound A (3 mg / kg / day) and media or pregabalin administration were continued for an additional 5 days, and PWT was assessed on day 15 at 1, 2, 4, and 6 hours after the last dose, compared to the sham and diabetic control groups. Two-way ANOVA statistical analysis was performed for blood glucose and PWT, and one-way ANOVA for AUC (0-6), followed by Dunnett's multiple comparison test with a 95% confidence interval (alpha 0.05) compared to the diabetic control group.

[0340] Figure 4 shows the efficacy (pain regulation) of compound A compared to diabetic and sham control animals in a streptozotocin-induced diabetic peripheral neuropathy model.

[0341] Example 34 - The potential of the compound of Formula 1 to treat Parkinson's disease can be evaluated using the model described below (MPTP-induced parkinsonism in zebrafish).

[0342] Parkinsonism in zebrafish was studied using the methodology described by Bretaud et al (Non-Patent Document 47). For MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced parkinsonism, 3 μl of 60 μg / g MPTP was injected into adult zebrafish as an intramuscular injection along the lateral muscle.

[0343] Compound B of formula I or L-DOPA was administered orally by mixing with fish feed pellets. Fish were conditioned to consume 3 pellets per day. To prepare feed containing 1 ng of compound B of formula I, a 1 ng / μl stock of compound B was diluted in 10 μl of Ringer's solution and divided into 3 fish feed pellets (approximately 3.3 μl per pellet). Before adding compound B, the fish feed pellets were dried at 37°C for 1 hour to remove moisture. After adding the compound B solution and absorption by the pellets, the pellets were stored at 4°C. To prepare fish feed pellets containing L-DOPA, 4 μl of 1 ng / μl L-DOPA stock solution was mixed. The liquid was divided into three fish feed pellets (approximately 1.3 μl / pellet). Fish were fed three pellets per day. The concentration of the administered compound was controlled by the number of pellets and the amount of compound per pellet. Feed pellets containing the medium but without the drug were used as a placebo or control.

[0344] Spontaneous motility activity: The observation tank was divided into four sections by drawing three vertical lines of equal length (6.25 cm per section). The number of lines crossed by adult zebrafish over a 5-minute period was counted. The fish were allowed to acclimate to the measurement tank for 30 minutes before taking measurements. Measurements were separated for only 4 hours before compound administration or MPTP challenge.

[0345] Brain pathology: Fish were anesthetized in 15°C water and sacrificed by excision between the brain and spinal cord. The brain was dissected, and the midbrain portion was removed with pins and a knife. Brain tissue was smeared on glass slides and stained with hematoxylin and eosin for 2 minutes each, followed by washing with water. Slides were observed at 45× magnification using a Labomed LX 400 microscope. The number of degenerated neurons was counted for three fields per smear. Degenerated neurons were characterized by relatively faint staining accompanied by loss of cellular structure, cell hypertrophy or shrinkage, irregularly shaped cell membranes, and a high rate of cell lysis during smear preparation, as described in established protocols (Non-Patent Literature 48; Non-Patent Literature 49; Non-Patent Literature 50).

[0346] Statistical Analysis: Statistical comparisons were performed using GraphPad. Student's t-tests with 95% confidence intervals were performed using a two-way ANOVA with alpha = 0.05 (95% confidence interval), and Tukey's multiple comparison post-hoc test was used to compare the means of each column. Significance is indicated by asterisks: ns - not significant, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

[0347] Figure 5 shows that treatment with compound B completely mitigated MPTP-induced changes in spontaneous motor activity. However, continued treatment with L-DOPA (beyond day 3) resulted in increased motor behavior that may reflect L-DOPA-induced dyskinesia, similar to that observed in humans.

[0348] Figure 6 reveals a significant increase in neurodegenerative cells in the MPTP-treated group (treated on days 6 and 8), along with abnormal cellular structure, disordered cellular composition, easily disintegrating cells under smear, and lightly stained cells. In the L-DOPA-treated group, brain pathology showed a similar visual field to the MPTP-treated group, i.e., neurodegeneration with altered cellular structure, indicating that L-DOPA did not have a significant effect in reducing MPTP-induced toxicity in neuronal cells. On the other hand, brain smears from the compound B-treated group mainly showed strong staining characteristics with intact cellular structure indicating normal cells. Overall, the number of neurodegenerative cells was significantly reduced in the compound B-treated group compared to the MPTP-treated group (>80%). The L-DOPA-treated group showed a non-significant decrease in the number of neurodegenerative cells on day 8 compared to the MPTP group.

[0349] Example 35 - The potential of the compound of Formula 1 to treat Parkinson's disease can be evaluated using the model described below (MPTP-induced parkinsonism in mice). Parkinson's disease was induced in all animals by subcutaneous injection of MPTP (20 mg / kg) over a period of 5 days. The control group did not receive MPTP.

[0350] For five consecutive days, compound B of formula I was orally administered once daily at a dose of 15 mg (or 30 mg / kg) 30 minutes before each MPTP injection. After five days of treatment, the mice were subjected to a behavioral (beamwalk) test.

[0351] Beam Walk Test - Prior to MPTP injection, mice were trained to cross a narrow 100 cm long beam in bright light (20 lux) to reach a closed escape platform, creating an aversive stimulus. This encouraged the mice to cross the beam and go to a dark, closed target box. Individual mice were tested 48 hours after the first MPTP injection. The time taken to cross the beam and reach the closed escape platform, and the number of slips were recorded. Latency to reach the platform was used as an indicator of motor function and coordination, and the number of slip errors was used to assess balance.

[0352] Figure 7 shows that treatment with compound B of formula I significantly reduced the time required to cross the beam compared to the MPTP group animals.

[0353] Various modifications and variations of the methods, pharmaceutical compositions, and kits described herein will be apparent to those skilled in the art without deviating from the scope and spirit of the disclosure. While the disclosure is described in connection with specific embodiments, it will be understood that further modifications are possible and that the claimed disclosure should not be unduly limited to such specific embodiments. Indeed, various modifications of the described embodiments for performing the disclosure which are obvious to those skilled in the art are intended to be within the scope of the disclosure. This application is intended to cover any modifications, uses, or adaptations of the disclosure, including deviations from the disclosure, that generally adhere to the principles of the disclosure, fall within the scope of customary practices known in the art relating to the disclosure, and are applicable to the essential features set forth herein.

Claims

1. The following compounds, their stereoisomers, or pharmaceutically acceptable salts. 【Chemistry 1】 【Chemistry 2】 【Transformation 3】

2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition according to claim 2 for treating pain, neurodegenerative disease, or inflammatory disease in a subject, A pharmaceutical composition comprising administering to a subject a therapeutically effective amount of at least one of the compounds, its stereoisomer, or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition according to claim 2 for treating neuropathic pain or inflammatory pain in a subject, A pharmaceutical composition in which a therapeutically effective amount of the pharmaceutical composition is administered to the subject.

5. A pharmaceutical composition according to claim 2 for treating Parkinson's disease in a subject, A pharmaceutical composition in which a therapeutically effective amount of the pharmaceutical composition is administered to the subject.

6. A pharmaceutical composition according to claim 2 for treating diabetic peripheral neuropathy in a subject, A pharmaceutical composition in which a therapeutically effective amount of the pharmaceutical composition is administered to the subject.

7. The pharmaceutical composition according to claim 4, wherein the neuropathic pain is peripheral neuropathic pain.

8. The pharmaceutical composition according to claim 4, wherein the neuropathic pain is selected from the group consisting of postherpetic neuralgia, trigeminal neuralgia, focal peripheral nerve injury, painful loss of sensation central pain, spinal cord injury, multiple sclerosis, peripheral neuropathy, HIV, or chemotherapy-induced pain.

Images