Piperidine urea derivatives for treatment of neurodegenerative diseases

Abstract

The present invention describes novel piperidine urea derivative compounds and pharmaceutical compositions thereof for the treatment of neurodegenerative disorders and diseases mediated by soluble epoxide hydrolases.

Description

Technical Field

[0001] The subject matter disclosed herein generally relates to methods and compositions for treating neurodegenerative diseases and diseases associated with synucleinopathies, particularly selected piperidine urea-derived compounds for treating neurodegenerative diseases, and methods for treating conditions and diseases mediated by soluble epoxide hydrolase. Background Art

[0002] Epoxyeicosatrienoic acids (EETs) are produced by the cytochrome P450 enzyme epoxidation of arachidonic acid during inflammation and injury and have potent anti-inflammatory properties. In addition, recent literature has shown that EETs reduce endoplasmic reticulum (ER) and mitochondrial stress in neurons and other cells. By reducing inflammation and ER / mitochondrial stress, EETs promote neuronal healing and survival. EET levels are regulated by soluble epoxide hydrolase (sEH), the main enzyme responsible for its degradation and conversion to inactive or weakly active dihydroxyeicosatrienoic acids (DHETs). Thus, SEH limits many of the biological actions of EETs. Inhibiting sEH can extend the half-life of EETs, which in turn translates into beneficial therapeutic effects.

[0003] sEH inhibitors can be used to treat neuropathic and inflammatory pain, neurodegenerative diseases, diseases associated with synucleinopathies, acute respiratory distress syndrome (ARDS), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and Crohn's disease [Biomolecules (2020), 10, 703-724; Proc. Natl. Acad. Sciences. (2018), 115, E5815–E5823, Neurotherapeutics. (2020), 17(3), 900-916; Proc. Natl. Acad. Sciences. (2008), 105(48), 18901–18906; Pharmacology & Therapeutics 180(2017) 62–76; Nat.Rev.Drug.Discov .(2009), 8(10), 794-805; Cardiovasc.Hematol.AgentsMed.Chem .(2012), Sep, 10(3), 212-22; Prostaglandinsand OtherLipidMediators 140(2019) 31–39, ProgressinNeurobiology ,(2019), 172, 23-39, Inflamm.Allergy Drug Targets (2012) Apr, 11(2), 143-58; Mol.Pain (2011), 4, 7-78; Drug Discov Today. 2015 Nov; 20(11): 1382-90, Biomolecules.May 1, 2020; 10(5):703, Prostaglandins Other Lipid Mediat .(2011), 96, 76 - 83, Pharmacology & Therapeutics 180(2017)62–76; Pharmacol Ther .Jun 19, 2017, S0163 - 7258(17)30154 - 7]; Biochimie 159(2019)59 - 65. sEH inhibitors reduced the expression of inflammatory genes and showed potential utility in inflammatory diseases (inflammation). Inflamm. Allergy Drug Targets (2012)Apr, 11(2):143 - 58). The potency of 14,15 - EET is about 35 times that of morphine and stimulates methionine enkephalin in the brain, indicating its potential analgesic utility. J Pharmacol Exp. Ther. (2008), Aug, 326(2), 614 - 22).

[0004] Synuclein is a family of small, highly charged proteins that are mainly expressed in neurons. Synuclein. A neuronal protein that regulates synaptic vesicle transport is abundantly expressed in different regions of the brain. One of these proteins, α - synuclein (α - Syn), appears to be associated with many neurodegenerative diseases. These diseases include Parkinson's disease (PD), dementia with Lewy bodies (DLB), rapid - eye - movement sleep behavior disorder (RBD), Lewy - body variant Alzheimer's disease (LBAD), neurodegeneration with brain iron accumulation (NBAI - 1), and pure autonomic failure (PAF), collectively referred to as α - synucleinopathies. In addition, Gaucher disease (GD), the most common lysosomal storage disease, caused by a deficiency of glucocerebrosidase (GBA1) (SEQ ID NO:1) and subsequent accumulation of toxic lipid substrates, has recently been recognized as the highest genetic risk factor for the development of α - synuclein aggregation diseases (synucleinopathies, including PD and DLB). GBA mutations result in three clinical manifestations. Type 1 Gaucher disease (GD) occurs in children and adults and mainly affects non - neural organs, while type 2 and type 3 Gaucher diseases present in childhood and adolescence and exhibit neurological deficits. A typical parkinsonian syndrome is one of the neurological complications of Gaucher disease (including type 1). The neuropathology of the Gaucher disease brain includes typical features of Parkinson's disease, such as cortical and brainstem Lewy bodies.

[0005] All synucleinopathies are characterized by the abnormal fibrillization and accumulation of proteinaceous, insoluble α-synuclein inclusions in neurons and glial cells, suggesting a common cellular pathology in the handling and clearance of α-synuclein. The mechanisms underlying synuclein aggregation and pathology are not fully understood, but processes such as neuronal inflammation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress may be involved in the pathology. Mutations that cause mitochondrial dysfunction and synucleinopathies include PINK1 (SEQ ID NO:2), which encodes PTEN-induced putative serine / threonine kinase 1. Thus, improving mitochondrial function and reducing ER stress and neuroinflammation may have a positive impact on diseases associated with synucleinopathies.

[0006] Several studies have confirmed that EETs and sEH inhibition have neuroprotective properties. sEH is highly expressed in the brain, and the production and metabolism of EETs in the brain span many regions and extend to peripheral and central neurons, astrocytes and oligodendrocytes, vascular endothelial cells, and smooth muscle cells J Histochem Cytochem. 2008 Jun;56(6):551-9, Am J Physiol 263:H519–25 1992, J Neurochem 61:150–9 1993 Prostaglandins Other Lipid Mediat. 91:68–84 2010]. Studies have shown that EETs or sEH inhibition - i) prevents cytokine- and oxidant-mediated neuronal cell damage; ii) prevents endoplasmic reticulum (ER) stress, which is a key factor in dopaminergic neuron loss; iii) increases the release of vascular endothelial growth factor by astrocytes and neuronal recovery after oxygen-glucose deprivation; and iv) promotes axon growth Am J Physiol Heart Circ Physiol 296:H1352-63,2009, Expert Rev Mol Med 13:7-12 2011, Expert Rev Mol Med 13:7-12,1998, Expert Rev Mol Med 13:7-12,2014, Neuropathol Appl Neurobiol. 42:607-620,2016, Proc Natl Acad Sci USA. 112:9082–9087 2015, J Neurosci 27:4642-9 2007, J Neurochem. 117:632-422011and Neuroscience 223:68-76 2012]. In multiple animal models of Parkinson's disease, sEH deficiency reduces the loss of dopaminergic neurons Mol Neurobiol. 52(1):187-95 2015]. In multiple animal models, inhibition of sEH reduces disease symptoms and promotes neuronal healing, including diabetic neuropathic painProc Natl Acad Sci USA. December 2, 2008; 105(48):18901-6, Eur J Pharmacol. January 30, 2013; 700(1-3):93-101, J Pain. September 2014; 15(9):907-14, Proc Natl Acad Sci USA. July 21, 2015; 112(29):9082-7, Behav Brain Res. May 30, 2017; 326:69-76]. The sEH level is elevated in the cortical brain tissue of cognitively impaired subjects, and sEH inhibition can prevent H2O2-induced hyperphosphorylation of tau protein, which is a key factor in the pathogenesis of Alzheimer's disease Prostaglandins Other Lipid Mediat. October 2014; 113-115:30-7, J Huazhong Univ Sci Technolog Med Sci. December 2016; 36(6):785-790]. sEH inhibition has a protective effect in rodent models of ischemic and diabetic stroke Future Neurol. March 1, 2009; 4(2):179-199, Am JPathol. June 2009; 174(6):2086-95, PLoS One. May 13, 2014; 9(5):e97529, Am J Physiol Heart Circ Physiol. December 1, 2013; 305(11):H1605-13].

[0007] Several studies have confirmed that sEH inhibition can provide therapeutic utility in the treatment of a variety of neurodegenerative diseases, such as Alzheimer's disease [Sci Transl Med. 2020 Dec 9; 12(573): eabb1206, Journal of Neuroscience, 2020(42): 8188–8203, Journal of Neuroinflammation 16, Article 267(2019) Neurotherapeutics volume 17, 1825–1835(2020)], depression and related disorders, schizophrenia, stroke, subarachnoid hemorrhage, traumatic brain injury, and multiple system atrophy (MSA) [Progress in Neurobiology 172(2019) 23–39, J Affect Disord. 2020 June 01; 270: 131–134, Proc Natl Acad Sci U SA. 2016 Mar 29; 113(13): E1944-52, J Cereb Blood Flow Metab, 35(2)(2015), pp. 267-276, J Neurosurg, 121(6)(2014), 1359-1366, Neurocritical Care volume 22, 306–319(2015), Brain Hemorrhages May 2022, Neurocrit Care(2021), J AtherosclerThromb. 2017 Dec 1; 24(12): 1258–1266].

[0008] Accordingly, it is an object of the present invention to provide methods and compositions for treating neurodegenerative diseases and diseases associated with synucleinopathies, including but not limited to dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), multiple system atrophy (MSA), and Gaucher's disease (GD). Selected piperidine urea-derived compounds are provided for the treatment of dementia with Lewy bodies and Gaucher's disease, as well as methods for treating conditions and diseases mediated by neurodegeneration and synucleinopathies.

[0009] The citation or identification of any document in this invention is not an admission that such document is available as prior art to this invention. Summary of the Invention

[0010] According to the present invention, the above object is achieved by providing, in one embodiment, a method for treating neurodegenerative diseases or diseases associated with synucleinopathies (excluding Parkinson's disease). The method may comprise administering to a subject a therapeutically effective amount of at least one compound of formula I, its stereoisomers or its pharmaceutically acceptable salts:

[0011]

[0012] wherein R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ;

[0013] R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl;

[0014] R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy;

[0015] R 4 may be selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ;

[0016] R 5 may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine;

[0017] R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl;

[0018] X may be selected from O, (CH2)p, NH, and p is 0-2;

[0019] Y1-Y2 may be selected from CH-CH2, CH-O or C=CH, but when Y1-Y2 is CH-O, X is selected from O or NH or R 1 is not hydrogen; and

[0020] Y3 may be selected from H or Me;

[0021] its stereoisomers or its pharmaceutically acceptable salts.

[0022] In another embodiment, a method of treating a neurodegenerative disease or a disease associated with synucleinopathy (excluding Parkinson's disease) is provided. The method may include administering to a subject a therapeutically effective amount of at least one compound of formula I, its stereoisomers or its pharmaceutically acceptable salts

[0023]

[0024] wherein,

[0025] R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ;

[0026] R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl;

[0027] R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy;

[0028] R 4 may be selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ;

[0029] R 5 may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine;

[0030] R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl;

[0031] X may be selected from O, (CH2)p, NH and p is 0 - 2, provided that when p = 0, Y1 - Y2 is not CH - CH2 or CH - O, and R 1 is not aryl;

[0032] Y1 - Y2 may be selected from CH - CH2, CH - O or C = CH, provided that when Y1 - Y2 is CH - O, X is selected from O or NH, and R 1 is not hydrogen or alkyl; and

[0033] Y3 may be selected from H or Me;

[0034] its stereoisomers or its pharmaceutically acceptable salts.

[0035] In addition, Y3 can be H, and the compound is a compound according to Formula II:

[0036]

[0037] Wherein,

[0038] R 1 is optionally selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ;

[0039] R 2 can be selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl;

[0040] R 3 can be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy;

[0041] R 4 can be selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , COR 3 ;

[0042] R 5 can be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine;

[0043] R 6 can be selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl;

[0044] X can be selected from O, (CH2)p, NH, and p is 0 - 2;

[0045] Y1 - Y2 can be selected from CH - CH2, CH - O or C═CH, but when Y1 - Y2 is CH - O, X is selected from O or NH or R 1 is not hydrogen; its stereoisomers or its pharmaceutically acceptable salts.

[0046] Furthermore, Y3 is H and the compound is a compound according to Formula II:

[0047]

[0048] Wherein

[0049] R 1Optionally selected from the group consisting of free alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ;

[0050] R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl;

[0051] R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy;

[0052] R 4 may be selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , COR 3 ;

[0053] R 5 may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine;

[0054] R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl;

[0055] X is optionally selected from O, (CH2)p, NH and p is 0-2, provided that when p = 0, Y1-Y2 is not CH-CH2 or CHO, and R 1 is not aryl;

[0056] Y1-Y2 may be selected from CH-CH2, CH-O or C=CH, provided that when Y1-Y2 is CH-O, X is selected from O or NH, and R 1 is not hydrogen or alkyl,

[0057] its stereoisomers or its pharmaceutically acceptable salts.

[0058] Furthermore, wherein Y3 is H, Y1-Y2 is C=CH, and the compound is a compound according to formula III,

[0059]

[0060] wherein

[0061] R 1 is optionally selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R1 unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 、SO2NHR 2 or COR 3 ;

[0062] R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl;

[0063] R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy;

[0064] R 4 may be selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 、SO2NHR 2 、COR 3 ;

[0065] R 5 may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine;

[0066] R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl; and

[0067] X may be selected from O, (CH2)p, NH, and p is 0 - 2,

[0068] its stereoisomers or its pharmaceutically acceptable salts.

[0069] The method according to claim 1, wherein Y3 is H, Y1 - Y2 is CH - CH2, and the compound is a compound according to formula IV,

[0070]

[0071] wherein

[0072] R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 、SO2NHR 2 、COR 3 ;

[0073] R 2may be selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl;

[0074] R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy;

[0075] R 4 may be selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 、COR 3 ;

[0076] R 5 may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine;

[0077] R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl. The aryl or heteroaryl may be optionally substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl; and

[0078] X may be selected from O, (CH2)p, NH; where p is selected from 0 - 2,

[0079] its stereoisomers or its pharmaceutically acceptable salts.

[0080] In addition, Y3 may be H, Y1 - Y2 is CH - CH2, and the compound is a compound according to formula IV

[0081]

[0082] where

[0083] R 1 may be optionally selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, where when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 、SO2NHR 2 、COR 3 ;

[0084] R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl;

[0085] R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy;

[0086] R 4may be selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , COR 3 ;

[0087] R 5 may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine;

[0088] R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl. The aryl or heteroaryl may be optionally substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl; and

[0089] X may be selected from O, (CH2)p, NH; where p is selected from 0 - 2, provided that when p = 0, R 1 is not aryl,

[0090] its stereoisomers or its pharmaceutically acceptable salts.

[0091] Furthermore, the compound of formula 1 may be one or more of the following compounds

[0092]

[0093]

[0094]

[0095] its stereoisomers or its pharmaceutically acceptable salts.

[0096] In addition, the compound of formula 1 may be one of the following compounds:

[0097]

[0098] its stereoisomers or its pharmaceutically acceptable salts.

[0099] Still further, the compound of formula 1 may be one or more of the following compounds, :

[0100]

[0101] its stereoisomers or its pharmaceutically acceptable salts.

[0102] Similarly, the compound may inhibit soluble epoxide hydrolase at a concentration of < 10 μM (IC 50 ).

[0103] In addition, the compound may inhibit soluble epoxide hydrolase at a concentration of < 100 nM (IC 50 ).

[0104] In addition, the compound can inhibit soluble epoxide hydrolase at a concentration of < 100 nM (IC 50 ), and has at least 10-fold selectivity relative to the inhibition of fatty acid amide hydrolase (IC 50 , (FAAH (SEQ ID NO:3)).

[0105] In addition, the compound can inhibit soluble epoxide hydrolase at a concentration of < 100 nM (IC 50 ), and can inhibit fatty acid amide hydrolase (FAAH (SEQ ID NO:3)) at a concentration of > 1000 nM (IC 50 ).

[0106] In addition, the disease can be selected from Gaucher's disease, Lewy body dementia, and Alzheimer's disease.

[0107] In addition, the compound can be administered at a dose of about 1 mg / day to about 1,000 mg / day.

[0108] Once again, the compound can be administered at a dose of about 5 mg / day to about 500 mg / day.

[0109] In addition, the compound can be used to treat one or more of neuronal loss, neuroinflammation, α-synuclein aggregation, and / or Lewy body formation.

[0110] In addition, the compound can be administered to treat impaired motor activity and other motor and non-motor related symptoms.

[0111] In addition, the compound can be used to treat cognitive dysfunction or dementia.

[0112] In addition, the present invention can provide a method for treating Parkinson's disease with dementia (PDD), familial Parkinson's disease associated with a PINK-1 (SEQ ID NO:2) mutation, or familial Parkinson's disease associated with a mutation in the glucocerebrosidase (GBA) gene, the method comprising:

[0113] administering to a subject a therapeutically effective amount of at least one compound of formula I:

[0114]

[0115] wherein,

[0116] wherein R 1 is optionally selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein when R 1 is aryl, heteroaryl, or heterocycloalkyl, R 1Unsubstituted or substituted with alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ;

[0117] R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl;

[0118] R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy;

[0119] R 4 may be selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ;

[0120] R 5 may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine;

[0121] R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl;

[0122] X may be selected from O, (CH2)p, NH, and p is 0 - 2;

[0123] Y1 - Y2 may be selected from CH - CH2, CH - O or C = CH, provided that when Y1 - Y2 is CH - O, X is selected from O or NH or R 1 is not hydrogen; and

[0124] Y3 may be selected from H or Me,

[0125] its stereoisomers or its pharmaceutically acceptable salts.

[0126] In addition, the present invention may provide a method for treating Parkinson's disease with dementia (PDD), familial Parkinson's disease associated with PINK - 1 (SEQ ID NO:2) mutation or familial Parkinson's disease associated with mutation in glucocerebrosidase (GBA) gene, the method comprising:

[0127] administering to a subject a therapeutically effective amount of at least one compound of formula I:

[0128]

[0129] wherein

[0130] R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1When R is an aryl, heteroaryl or heterocycloalkyl, 1 it is unsubstituted or substituted by an alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ;

[0131] R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl;

[0132] R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy;

[0133] R 4 may be selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ;

[0134] R 5 may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine;

[0135] R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl;

[0136] X may be selected from O, (CH2)p, NH and p is 0 - 2, provided that when p = 0, Y1 - Y2 is not CH - CH2 or CH - O, and R 1 is not aryl;

[0137] Y1 - Y2 may be selected from CH - CH2, CH - O or C = CH, provided that when Y1 - Y2 is CH - O, X is selected from O or NH, and R 1 is not hydrogen or alkyl; and

[0138] Y3 may be selected from H or Me,

[0139] its stereoisomers or its pharmaceutically acceptable salts.

[0140] Furthermore, the present invention may provide a method for treating Gaucher's disease, Parkinson's disease with dementia (PDD), familial Parkinson's disease associated with a PINK - 1 (SEQ ID NO:2) mutation or familial Parkinson's disease associated with a mutation in the glucocerebrosidase (GBA) gene, the method comprising administering to a subject a therapeutically effective amount of a soluble epoxide hydrolase inhibitor.

[0141] Compound of formula I:

[0142]

[0143] Wherein

[0144] R 1 is optionally selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ;

[0145] R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl;

[0146] R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy;

[0147] R 4 may be selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ;

[0148] R 5 may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine;

[0149] R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl;

[0150] X may be selected from O, (CH2)p, NH, and p is 0 - 2;

[0151] Y1 - Y2 may be selected from CH - CH2, CH - O or C = CH, provided that when Y1 - Y2 is CH - O, X is selected from O or NH or R 1 is not hydrogen; and

[0152] Y3 may be selected from H or Me;

[0153] its stereoisomers or its pharmaceutically acceptable salts.

[0154] The present invention may also provide a method for treating neurodegenerative diseases or diseases associated with synucleinopathies other than for treating Parkinson's disease.

[0155] Compound of formula I:

[0156]

[0157] wherein

[0158] R 1may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ;

[0159] R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl;

[0160] R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy;

[0161] R 4 may be selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ;

[0162] R 5 may be selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine;

[0163] R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl;

[0164] X may be selected from O, (CH2)p, NH and p is 0 - 2, provided that when p = 0, Y1 - Y2 is not CH - CH2 or CH - O, and R 1 is not aryl;

[0165] Y1 - Y2 may be selected from CH - CH2, CH - O or C = CH, provided that when Y1 - Y2 is CH - O, X is selected from O or NH, and R 1 is not hydrogen or alkyl; and

[0166] Y3 may be selected from H or Me,

[0167] its stereoisomers or its pharmaceutically acceptable salts.

[0168] Furthermore, methods for treating neurodegenerative diseases or diseases associated with synucleinopathies but not for treating Parkinson's disease may be provided.

[0169] In addition, the present invention can provide a soluble epoxide hydrolase inhibitor for treating Gaucher disease, Parkinson's disease with dementia (PDD), familial Parkinson's disease associated with mutations in PINK-1 (SEQ ID NO:2), or familial Parkinson's disease associated with mutations in the glucocerebrosidase (GBA) gene.

[0170] Based on the following detailed description of exemplary embodiments, these and other aspects, objects, features, and advantages of the exemplary embodiments will become apparent to those of ordinary skill in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[0171] By reference to the following detailed description and the drawings, an understanding of the features and advantages of the present invention will be obtained, the detailed description setting forth illustrative embodiments in which the principles of the present invention can be utilized, wherein:

[0172] Figure 1 Table 1 showing the soluble epoxide hydrolase inhibitory potency of the compounds of formula I is presented.

[0173] Figure 2 Showing the neuroprotective effect of compound A of formula I in synucleinopathy-induced neuronal loss in cultured dopamine neurons.

[0174] Figure 3 Showing the efficacy (improvement in motor activity) of compound A and compound B of formula I in synucleinopathy-induced motor deficits in a rodent model (α-syn+GBA1 (SEQ ID NO:1) inhibition).

[0175] Figure 4 Showing the efficacy of compound A and compound B of formula I in blocking α-Syn aggregation in a rodent model of synucleinopathy (α-syn+GBA1 (SEQ ID NO:1) inhibition).

[0176] Figure 5 Showing the neuroprotective effect of compound A and compound B of formula I in a rodent model of synucleinopathy.

[0177] Figure 6 Showing the efficacy (blocking neuroinflammation) of compound A and compound B of formula I in a rodent model of synucleinopathy.

[0178] Figure 7 Showing the efficacy (improvement in motor activity, bradykinesia) of compound A and compound B of formula I in a zebrafish model of synucleinopathy.

[0179] Figure 8 Showing the efficacy (improvement in dementia) of compound A and compound B of formula I in a zebrafish model of synucleinopathy.

[0180] Figure 9 It shows the efficacy (improvement of motor activity) of compound A of formula I in MPTP-induced Parkinson's syndrome in a zebrafish model.

[0181] Figure 10 It shows the efficacy (blocking of neurodegeneration) of compound A of formula I in MPTP-induced Parkinson's syndrome in a zebrafish model.

[0182] Figure 11 It shows the neuroprotective effect (TH+ neurons) of compound A of formula I in MPTP-induced Parkinson's syndrome in a zebrafish model.

[0183] The drawings are for illustrative purposes only and are not necessarily drawn to scale. Detailed Description

[0184] Before describing the present invention in more detail, it should be understood that the present invention is not limited to the specific embodiments described and can of course be changed. It should also be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to be limiting.

[0185] Unless otherwise specified, the terms and phrases and their variants used in the present invention, unless otherwise clearly stated, should be construed as open-ended rather than restrictive. Similarly, a group of items connected by the conjunction "and" should not be understood as requiring each of these items to be present in the group, but rather should be understood as "and / or", unless otherwise clearly stated. Similarly, a group of items linked by the conjunction "or" should not be understood as requiring mutual exclusivity between the groups, but should also be understood as "and / or", unless otherwise clearly stated.

[0186] In addition, although the items, elements or components of the present invention may be described or claimed in the singular, the plural form is also considered to be within the scope of the present invention unless explicitly stated to be limited to the singular form. In some cases, the presence of expansive words and phrases such as "one or more", "at least", "but not limited to" or other similar phrases should not be construed as meaning that a narrower case is intended or required in the absence of such expansive phrases.

[0187] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention pertains. Although any methods and materials similar or equivalent to those described in the present invention may also be used in the practice or testing of the present invention, the preferred methods and materials are now described.

[0188] All publications and patents cited in this specification are for the purpose of disclosing and describing the methods and / or materials related to the cited publications. All such publications and patents are hereby incorporated 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 cited publications and patents and does not extend to any dictionary definitions from the cited publications and patents. Any dictionary definitions not expressly repeated in this application from the cited publications and patents should not be so treated and should not be construed as defining any term appearing in the appended claims. The citation of any publication is only for the purpose of indicating that its publication date is earlier than the filing date of this application and should not be regarded as an admission that this disclosure does not have the right to be earlier than such publication due to prior disclosure. In addition, the provided publication date may be different from the actual publication date that needs to be independently confirmed.

[0189] As will be apparent to those skilled in the art upon reading the present disclosure, each of the various embodiments described and illustrated herein has discrete components and features that can be readily separated from or combined with the features of any one of several other embodiments without departing from the scope or spirit of the present disclosure. Any of the described methods can be performed in the order of the recited events or in any other order that is logically possible.

[0190] In the case of representing a range, another embodiment includes from a specific value and / or to another specific value. A numerical range recited by endpoints includes all numbers and fractions contained within the respective ranges, as well as the recited endpoints. In the case of providing a numerical range, it should be understood that unless the context clearly dictates otherwise, each intermediate value between the upper and lower limits of the range, down to one-tenth of the unit of the lower limit, and any other recited or intermediate value within the said range, is included in the present invention. The upper and lower limits of these smaller ranges may be independently included within the smaller ranges and are also included within the scope of the present invention, subject to any specific exclusions within the said range. In the case where the range includes one or both limits, a range excluding one or both of the included limits is also included in the present invention. For example, in the case where the range includes one or both limits, a range excluding one or both of these included limits is also included in the present invention, such as the phrase "x to y" includes the range from "x" to "y" and the range greater than "x" and less than "y". The range may also be expressed as an upper limit, such as "about x, y, z or less", and should be interpreted as including the specific ranges of "about x", "about y", and "about z" and the ranges "less than x", "less than y", and "less than z". Similarly, the phrase "about x, y, z or greater" should be interpreted as including the specific ranges of "about x", "about y", and "about z" and the ranges "greater than x", "greater than y", and "greater than z". In addition, the phrase "about 'x' to 'y' (where 'x' and 'y' are numerical values) includes "about 'x' to about 'y'".

[0191] It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed in the form of ranges in the present invention. It should also be understood that each endpoint of a range is significant relative to and independent of the other endpoint. It should also be understood that the present invention discloses multiple values, and in addition to the values themselves, each value is also disclosed in the present invention as "about" that specific value. For example, if the value "10" is disclosed, then "about 10" is also disclosed. A range may be expressed in the present invention as from "about" one specific value, and / or to "about" another specific value. Similarly, when a value is expressed as an approximation by using the antecedent "about", it will be understood that the specific value forms another aspect. For example, if the value "about 10" is disclosed, then "10" is also disclosed.

[0192] It should be understood that this range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the values explicitly recited as the limits of the range, but also all individual values or sub-ranges included within the range, as if each value and sub-range were explicitly recited. By way of illustration, the numerical range of "about 0.1% to 5%" should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also each individual value (e.g., about 1%, about 2%, about 3%, and about 4%) and sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4% and other possible sub-ranges).

[0193] As used in the present invention, the singular forms "a", "an", and "the" include both singular and plural referents unless the context clearly dictates otherwise.

[0194] As used in the present invention, terms such as "about", "approximately", "substantially", etc., when used in conjunction with measurable variables such as parameters, amounts, time durations, etc., are intended to cover variations of the specified value and variations outside the specified value, including variations within experimental error (which can be determined, for example, by a given data set, standards recognized in the art, and / or by using, for example, a given confidence interval (e.g., 90%, 95%, or a greater confidence interval), such as variations of the specified value + / - 10% or less, + / - 5% or less, + / - 1% or less, and + / - 0.1% or less, as long as such variations are suitable for implementation in the present invention. As used in the present invention, the terms "about", "approximately", "at or about", and "substantially" may indicate that the quantity or value being discussed can be an exact value or a value that provides an equivalent result or effect as recited in the claims or taught by the present invention. That is, it should be understood that quantities, dimensions, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and / or larger or smaller as needed, reflecting tolerances, conversion factors, rounding, measurement errors, etc., and other factors known to those skilled in the art, so as to obtain equivalent results or effects. In some cases, it is not reasonable to determine the value that provides an equivalent result or effect. Generally, a quantity, dimension, formulation, parameter, or other quantity or characteristic is "about", "approximately", or "at or about", whether or not explicitly stated. It should be understood that when "about", "approximately", or "equal to or about" is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless otherwise stated.

[0195] As used herein, "biological sample" can include whole cells and / or living cells and / or cell debris. A biological sample can contain (or be derived from) "body fluid". The present invention includes embodiments in which the body fluid is selected from amniotic fluid, aqueous humor, vitreous humor, bile, serum, breast milk, cerebrospinal fluid, cerumen (ear wax), chyle, chyme, endolymph, perilymph, exudate, feces, female ejaculate, gastric acid, gastric juice, lymph fluid, mucus (including nasal fluid and sputum), pericardial fluid, peritoneal fluid, pleural fluid, pus, rheum, saliva, sebum (skin oil), semen, sputum, synovial fluid, sweat, tears, urine, vaginal secretions, vomit, and one or more mixtures thereof. Biological samples include cell cultures, body fluids, and cell cultures derived from body fluids. Body fluids can be obtained from a mammalian organism, for example, by puncture or other collection or sampling procedures.

[0196] As used herein, "reagent" refers to any substance, compound, molecule, etc., that can be administered to the subject to which it is administered. A reagent can be inert. A reagent can be an active reagent. A reagent can be the primary active agent, or in other words, a component of a composition, the whole or part of the effect of which is attributed to that component. A reagent can be a secondary reagent, or in other words, a component of a composition, the additional part and / or other effect of which is attributed to that component.

[0197] As used herein, "active reagent" or "active component" refers to a substance, compound, or molecule having biological activity, or a substance, compound, or molecule that induces a biological or physiological effect on the subject to which it is administered. In other words, "active reagent" or "active component" refers to a component of a composition, the whole or part of the effect of which is attributed to that component.

[0198] As used herein, "administering" refers to any suitable mode of administering an agent being delivered and / or a subject receiving said agent, which can be oral, topical, intravenous, subcutaneous, transdermal, percutaneous, intramuscular, intra-articular, parenteral, intra-arterial, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intra-articular, intracorporal, intrathecal, intravenous, intracerebral, and intraventricular, intratympanic, intracochlear, rectal, vaginal, by inhalation, by catheter, stent or other devices for delivering the composition to the perivascular space and adventitia, either actively or passively (e.g., by diffusion). For example, a medical device such as a stent can contain a composition or formulation disposed on its surface, which can then dissolve or otherwise distribute into the surrounding tissue and cells. The term "parenteral" can include subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. The route of administration can be, for example, auricular (ear), oral, conjunctival, cutaneous, dental, iontophoretic, intracervical, intranasal sinus, intratracheal, enteral, epidural, extra-amniotic, extracorporeal, hemodialysis, osmotic, interstitial, intraperitoneal, intra-amniotic, intra-arterial, intra-articular, intra-biliary, intra-bronchial, intra-capsular, intracardiac, intra-cartilaginous, intra-coccygeal, intracorporal, intracavitary, intracerebral, intracisternal, intracatheter, intracorneal, intracoronal (dental), intracoronary, intracorporal, intradermal, intradiscal, intracatheter, intra-duodenal, intradural, intraepidermal, intra-esophageal, intragastric, intragingival, intra-ileal, intralesional, intraluminal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intra-ovarian, intra-pericardial, intraperitoneal, intra-pleural, intra-prostatic, intrapulmonary, intranasal, intraspinal, intrasynovial, intratendinous, intra-testicular, intra-capsular, intrathoracic, intratubular, intratumoral, intratympanic, intrauterine, intravascular, intravenous, intravenous bolus, intravenous drip, intraventricular, intravesical, intravitreal, iontophoresis, irrigation, laryngeal, nasal, nasogastric tube, occlusive dressing technique (possibly referring to an operation mode for local drug penetration), ophthalmic, oral, oropharyngeal, other routes of administration, parenteral (such as non-gastrointestinal routes like vein, muscle, etc.), transdermal, periaricular, epidural, perineural, periodontal, rectal, respiratory (inhalation), retrobulbar, soft tissue, subarachnoid, subconjunctival, subcutaneous, sublingual, submucosal, topical, transdermal, mucosal, transplacental, transtracheal, trans-tympanic, ureteral, urethral, and / or vaginal, and / or any combination of the above routes of administration, which typically depends on the disease to be treated, the subject being treated, and / or the agent being administered.

[0199] As used herein, "control" can refer to an alternative subject or sample used for comparison purposes in an experiment and is included to minimize or distinguish the effects of variables other than the independent variable.

[0200] The term "optional" or "optionally" means that the subsequent described event, circumstance or substituent may or may not occur, and the description includes the case where the event or circumstance occurs and the case where it does not occur.

[0201] As used in the present invention, "dose", "unit dose" or "dosage" may refer to a physically discrete unit suitable for a subject, each unit containing a predetermined amount of a pharmaceutical preparation, the predetermined amount being calculated to produce the desired response associated with its administration.

[0202] The term "molecular weight" as used in the present invention generally refers to the mass or average mass of a material.

[0203] The terms "subject", "individual" and "patient" are used interchangeably in the present invention and refer to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, rodents, primates, humans, farm animals, sport animals and pets. The term "subject" also includes tissues, cells and progeny of biological entities obtained in vivo or cultured in vitro.

[0204] As used in the present invention, "substantially pure" may mean that the target species is the major species present (i.e., more abundant on a molar basis than any other single species in the composition), and preferably, a substantially purified fraction is a composition in which the target species accounts for about 50% of all species present. Generally, a substantially pure composition will contain more than about 80% of all substances present in the composition, more preferably about 85%, 90%, 95% and more than 99%. Most preferably, the target species is purified to substantially homogeneous (contaminants cannot be detected in the composition by conventional detection methods), where the composition consists essentially of a single substance.

[0205] As used interchangeably in the present invention, the terms "sufficient" and "effective" may refer to the amount (e.g., mass, volume, dose, concentration and / or time) required to achieve one or more desired and / or specified results. For example, a therapeutically effective amount refers to the amount required to achieve one or more therapeutic effects.

[0206] As used in the present invention, "tangible medium of expression" refers to a physically tangible or accessible medium, rather than just an abstract idea or an unrecorded spoken word. "Tangible medium of expression" includes, but is not limited to, words on a cellulose or plastic material, or data stored in a suitable computer-readable memory. The data may be stored on a unit device such as a flash memory or a CD-ROM, or stored on a server accessible by a user via, for example, a web interface.

[0207] As used in the present invention, the terms "treatment" and "treating" can generally refer to obtaining the desired pharmacological and / or physiological effect. In terms of preventing or partially preventing a disease, its symptoms or disorders (such as cancer and / or indirect radiation damage), the effect can be, but does not necessarily have to be, prophylactic. In terms of partially or completely curing a disease, disorder, symptom or side effect attributable to a disease, disorder or condition, the effect can be therapeutic. The term "treatment" as used in the present invention encompasses any treatment of cancer and / or indirect radiation damage in a subject, particularly a human and / or a pet, and can include any one or more of the following: (a) preventing the occurrence of a disease or injury in a subject who may be susceptible to the disease but has not been diagnosed with the disease; (B) inhibiting the disease, i.e., preventing its development; and (C) alleviating the disease, i.e., reducing or improving the disease and / or its symptoms or conditions. The term "treatment" as used in the present invention can refer to a therapeutic treatment alone, a prophylactic treatment alone, or a therapeutic and prophylactic treatment. A patient in need of treatment (a subject in need of treatment) can include a patient who already has the disease and / or a patient who needs to prevent the disease. As used in the present invention, the term "treatment" can include inhibiting a disease, disorder or condition, such as preventing its progression; and alleviating the disease, disorder or condition, such as causing regression of the disease, disorder and / or condition. Treating a disease, disorder or condition can include improving at least one symptom of a particular disease, disorder or condition, even if the underlying pathophysiology is not affected, such as treating a subject's pain by administering an analgesic, even if such an agent does not treat the cause of the pain.

[0208] Unless otherwise specified, the terms "weight percentage", "wt%", and "wt.%", as used in the present invention, are used interchangeably and represent the weight percentage of a given component based on the total weight of the composition of which it is a component. That is, unless otherwise specified, all wt% values are based on the total weight of the composition. It should be understood that the sum of the wt% values of all components in the disclosed composition or formulation is equal to 100. Alternatively, if the wt% values are based on the total weight of a subset of components in the composition, it should be understood that the sum of the wt% values of the specified components in the disclosed composition or formulation is equal to 100.

[0209] "Halo" refers to fluorine, chlorine, bromine or iodine.

[0210] An "alkyl" group refers to a straight-chain or branched-chain alkyl group. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl, etc. Unless otherwise specified, an alkyl group generally has from about 1 to about 10 carbon atoms.

[0211] The term "cycloalkyl" refers to a cycloalkyl group that can be monocyclic or bicyclic. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Unless otherwise specified, cycloalkyl groups generally have from about 3 to about 10 carbon atoms.

[0212] "Haloalkyl" refers to a straight-chain or branched-chain alkyl group in which at least one hydrogen is replaced by a halogen or halo group. Exemplary haloalkyl groups include trifluoromethyl, chloroethyl, difluoromethyl, difluoroethyl, and the like.

[0213] Hydroxyalkyl refers to a straight-chain monovalent hydrocarbon group of 1-3 carbon atoms or a branched-chain monovalent hydrocarbon group of 3-5 carbon atoms substituted by one or two hydroxy groups, provided that if two hydroxy groups are present, they are not both on the same carbon atom. Representative examples include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl.

[0214] "Alkoxyalkyl" refers to a straight-chain monovalent hydrocarbon group of 1-6 carbon atoms or a branched-chain monovalent hydrocarbon group of 3-6 carbon atoms substituted by an alkoxy group as defined above, such as methoxymethyl, 2-methoxyethyl, 1-, 2- or 3-methoxypropyl.

[0215] "Heterocycloalkyl" refers to a non-aromatic monocyclic or polycyclic ring containing carbon and hydrogen atoms and at least one heteroatom, preferably 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl ring may have one or more carbon-carbon double bonds or carbon-heteroatom double bonds in the ring, provided that the ring does not become aromatic due to their presence. Examples of heterocycloalkyl groups include: pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, tetrahydrofuryl, tetrahydropyranyl, and pyranyl.

[0216] The term "alkoxy" "alkyl" refers to an -O(alkyl) group, where alkyl is as defined above. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, and the like. Unless otherwise specified, alkoxy groups generally have 1 to about 10 carbon atoms.

[0217] The term "amine" "amino" refers to a primary, secondary, or tertiary amino group. Secondary and tertiary amines may contain alkyl, cycloalkyl, or aryl substituents. Some examples of amines include NH2, NHMe, NMe2NH(cyclopropyl). Unless otherwise specified, the alkyl or cycloalkyl groups on the amine generally have 1 to about 8 carbon atoms.

[0218] The term "monocyclic" for "aryl" refers to an optionally substituted monocyclic or polycyclic aromatic ring system having from about 6 to about 14 carbon atoms. Exemplary aryls include phenyl, naphthyl, etc. Unless otherwise specified, aryl generally has 6 to about 14 carbon atoms.

[0219] The term "heteroatom" for "heteroaryl" refers to an aromatic monocyclic or polycyclic system having from about 4 to about 12 carbon atoms and having at least one heteroatom or hetero group selected from -O-, -N-, -S-, -SO2 or -CO. Exemplary heteroaryls include one or more of pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, imidazolyl, triazolyl, pyridazinyl, thienopyrimidinyl, furanyl, indolyl, isoindolyl, benzo[1,3]dioxolyl, benzimidazolyl, 1,3-benzoxathiolyl, pyrrolidine-2,4-dioneyl, quinazolinyl, pyridyl, pyrimidinyl, thienyl, etc. Unless otherwise specified, heteroaryl generally has 4 to about 10 carbon atoms.

[0220] "5- to 6-membered heteroaryl" is an aromatic monocyclic system of 5 or 6 ring atoms having at least one heteroatom or hetero group selected from -O-, -N-, -S-, -SO2 or -CO. Exemplary "5- to 6-membered heteroaryl" groups include one or more of pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, pyridazinyl, pyridyl, thienopyrimidinyl, tetrazolyl, imidazolyl, triazolyl, furanyl, etc.

[0221] "Optionally substituted" means that the substitution is optional, so the specified atom or molecule may be unsubstituted. In cases where substitution is required, such substitution means that any number of hydrogens on the specified atom are replaced by the selected specified group, provided that the normal valence of the specified atom is not exceeded and the substitution results in a sufficiently stable compound for use.

[0222] "Salt" means any acid or base salt, pharmaceutically acceptable solvate or any complex of a compound which, when administered to a recipient, is capable of providing (directly or indirectly) the compound described in the present invention. However, it should be understood that pharmaceutically unacceptable salts are also within the scope of the present invention. The preparation of salts can be carried out by known methods. For example, useful pharmaceutically acceptable salts of the compounds contemplated by the present invention can be synthesized by conventional chemical methods using a parent compound containing a basic or acidic functional group. Generally, such salts can be prepared, for example, by preparing the compound in free acid or base form and reacting it with a stoichiometric amount of a suitable base or acid in water or in an organic solvent or in a mixture of both. Generally, a non-aqueous medium can be used, such as one or more solvents, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Examples of acid addition salts include one or more inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, and one or more organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, mesylate and tosylate. Examples of base addition salts include one or more inorganic salts such as sodium salt, potassium salt, calcium salt, ammonium salt, magnesium salt and lithium salt, and one or more organic base salts such as ethylenediamine, ethanolamine, N,N-dialkylethanolamine, triethanolamine and basic amino acid salts.

[0223] The phrase "therapeutically effective" means the ability of an agent or combination to prevent or reduce the severity of the symptoms of a disorder or disease while generally avoiding adverse side effects. The therapeutically effective compositions of the present invention can include a dose of the compound of the present invention from about 1 to about 3000 mg.

[0224] The terms "effective amount" or "therapeutically effective amount" or "dose" as used in the present invention refer to the dose or amount of the compound of the present invention administered to a subject and the frequency of administration that results in a certain therapeutic response. A person of ordinary skill in the art can readily determine the dose or effective amount to be administered to a subject and the frequency of administration to the subject by using known techniques and by observing the results obtained in similar situations. In determining the effective amount or dose, the attending physician can consider a number of factors, including but not limited to the potency and duration of action of the compound used; the nature and severity of the disease to be treated, and the sex, age, weight, general health and individual reactivity of the subject to be treated, as well as other relevant circumstances.

[0225] The compounds described in the present invention can be administered in admixture with one or more pharmaceutically acceptable excipients or carriers in the form of a pharmaceutical composition. A "composition" can contain one compound or a mixture of compounds. A "pharmaceutical composition" means any composition that can be used or may be used to produce a physiological response in a subject to which the pharmaceutical composition is administered.

[0226] The term "pharmaceutically acceptable" with respect to excipients is used to define non-toxic substances that are generally suitable for human or animal pharmaceutical products. The pharmaceutical composition can be in a commonly used form, such as tablets, capsules, powders, syrups, solutions, suspensions, etc. The pharmaceutical composition can contain edible flavors, sweeteners, etc. in a suitable solid or liquid carrier or diluent, or in a suitable sterile medium to form an injectable solution or suspension. Such compositions generally contain from about 0.1% to about 50% by weight, and in some embodiments from about 1% to about 20% by weight, of the active compound, the remainder of the composition being a pharmaceutically acceptable carrier, diluent or solvent.

[0227] Various embodiments are described below. It should be noted that the specific embodiments are not intended as an exhaustive description or as a limitation on the broader aspects discussed in the present invention. An aspect described in connection with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment. References throughout this specification to "one embodiment", "an embodiment", "exemplary embodiment" mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the phrases "in one embodiment", "in an embodiment", or "exemplary embodiment" appearing throughout the specification do not necessarily all refer to the same embodiment, but may also refer to the same embodiment. Additionally, in one or more embodiments, the particular features, structures, or characteristics may be combined in any suitable manner, which will be apparent to those skilled in the art from the present invention. Moreover, although some embodiments described herein include some features that are not included in other embodiments, the combination of features of different embodiments is meant to be within the scope of the present invention. For example, in the appended claims, any of the claimed embodiments can be used in any combination.

[0228] All patents, patent applications, published applications and publications, databases, websites, and other publicly available materials cited in this invention are hereby incorporated by reference in their entirety, with the same effect as if each individual publication, published patent document, or patent application was specifically and individually indicated to be incorporated by reference.

[0229] Kit

[0230] Any compound and / or formulation described in the present invention can be provided as a combination kit. As used in the present invention, the term "combination kit" or "active ingredient" refers to a compound, composition, formulation, granule, unit, and any additional component for packaging, selling, marketing, delivering, and / or administering a combination or single component (such as an active ingredient) contained therein. These additional components include, but are not limited to, packaging, syringes, blister packs, bottles, etc. When one or more compounds, compositions, formulations, granules, units, or combinations thereof (e.g., reagents) described in the present invention contained in the kit are administered simultaneously, the combination kit can contain the active agent in a single formulation (such as a pharmaceutical formulation) or in separate formulations, e.g., tablets, liquid formulations, dehydrated formulations, etc. When the compounds, compositions, formulations, granules, and units or combinations thereof and / or kit components described in the present invention are not administered simultaneously, the combination kit can contain each reagent or other component in a separate pharmaceutical formulation. The separate kit components can be contained in a single package or in separate packages within the kit.

[0231] In some embodiments, the combination kit further includes instructions printed on or otherwise contained in a tangible expression medium. The instructions can provide information about the content of the compound and / or formulation, safety information about the content of the compound and formulation (such as a pharmaceutical formulation), information about dosage, indication of use, and / or recommended treatment regimens of the compound and / or pH Detailed Description

[0233] Reference will now be made in detail to embodiments of the present invention, one or more of which are set forth below. Each embodiment is provided by way of explanation of the present invention, and not as a limitation thereof. In fact, it will be apparent to those skilled in the art that various modifications can be made to the present invention without departing from the scope or spirit thereof. For example, features shown or described as part of one embodiment can be used in another embodiment to yield yet another embodiment. Accordingly, the present invention is intended to cover modifications and variations that fall within the scope of the appended claims and their equivalents. Other objects, features, and aspects of the present invention are disclosed in the following detailed description or are apparent from the following detailed description.

[0234] For ease of reference, the present invention will be described in terms of administration to human subjects. However, it should be understood that these descriptions are not limited to administration to humans unless otherwise expressly stated, and also include administration to other animals.

[0235] The expected derivatives are those derivatives that can improve the solubility of the compounds of the present invention or increase their bioavailability when the compounds of the present invention are administered to a subject (e.g., by making the orally administered compounds more readily absorbable). The compounds of formula I can be amorphous, semi-crystalline or crystalline, and can be given as the parent compound, its salts and / or solvated forms. The solvate can be part of the lattice or surface associated. All such forms are intended to be within the scope of the present invention. Solvation methods are well known in the art. Suitable solvates are pharmaceutically acceptable solvates. In one embodiment, the solvate is a hydrate.

[0236] In one aspect, the present invention relates to novel compounds of formula I:

[0237]

[0238] their stereoisomers, stable isotopes (e.g., deuterated variants) or their pharmaceutically acceptable salts;

[0239] wherein

[0240] R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein R 1 may optionally be substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , COR 3 ;

[0241] R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl;

[0242] R 3 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy;

[0243] R 4 is selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , COR 3 ;

[0244] R 5 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine;

[0245] R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl. The aryl or heteroaryl may optionally be substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl;

[0246] X is selected from the group consisting of O, (CH2)p, and NH; where p is selected from 0 - 2, provided that when p = 0, Y1 - Y2 is not CH - CH2 or CH - O, and R 1 is not aryl; and

[0247] Y1 - Y2 is selected from the group consisting of CH - CH2, CH2 - O, or C═CH; however, when Y1 - Y2 is CH2 - O, X is selected from O or NH, and R 1 is not hydrogen or alkyl;

[0248] Y3 is selected from H or Me.

[0249] On the other hand, the present invention relates to a new compound of formula II:

[0250]

[0251] its stereoisomers or its pharmaceutically acceptable salts;

[0252] wherein

[0253] R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 may be optionally substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 、COR 3 ;

[0254] R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl;

[0255] R 3 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy

[0256] R 4 is selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 、COR 3 ;

[0257] R 5 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine;

[0258] R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl. The aryl or heteroaryl may be optionally substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl;

[0259] X is selected from the group consisting of O, (CH2)p, and NH; where p is selected from 0 - 2, provided that when p = 0, Y1 - Y2 is not CH - CH2 or CH - O, and R 1 is not aryl; and

[0260] Y1 - Y2 is selected from CH - CH2, CH - O, or C═CH; however, when Y1 - Y2 is CH2 - O, X is selected from O or NH, and R 1 is not hydrogen or alkyl.

[0261] On the other hand, the present invention relates to novel compounds of formula III:

[0262]

[0263] their stereoisomers or their pharmaceutically acceptable salts;

[0264] wherein

[0265] R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; where R 1 may be optionally substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 , SO2NHR 2 , COR 3 ;

[0266] R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl;

[0267] R 3 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy;

[0268] R 4 is selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , COR 3 ;

[0269] R 5 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine;

[0270] R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl. The aryl or heteroaryl may be optionally substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl;

[0271] X is selected from O, (CH2)p, NH; where p is selected from 0 - 2;

[0272] On the other hand, the present invention relates to novel compounds of formula IV:

[0273]

[0274] their stereoisomers or their pharmaceutically acceptable salts;

[0275] wherein

[0276] R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein R 1 may optionally be substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 , SO2NHR 2 , COR 3 ;

[0277] R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl;

[0278] R 3 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy;

[0279] R 4 is selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 , COR 3 ;

[0280] R 5 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine;

[0281] R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl. The aryl or heteroaryl may optionally be substituted one or more times by groups or substituents such as alkyl, hydroxy, halogen, haloalkyl;

[0282] X is selected from O, (CH2)p, NH; where p is selected from 0 - 2, provided that when p = 0, R 1 is not aryl;

[0283] In addition, the composition may comprise one or more of the following compounds, their stereoisomers or their pharmaceutically acceptable salts;

[0284]

[0285]

[0286]

[0287] In an embodiment, the present invention may include a compound of Formula I, wherein the compound is an IC 50 soluble epoxide hydrolase (sEH) inhibitor with an IC value less than 10 μM.

[0288] In an embodiment, the present invention may include a compound of Formula I, wherein the compound is an inhibitor of soluble epoxide hydrolase (sEH) that has a selectivity greater than 10-fold relative to fatty acid amide hydrolase (FAAH (SEQ ID NO: 3)).

[0289] In another embodiment, the compound of Formula I may inhibit soluble epoxide hydrolase with an IC 50 value of < 100 nM, and inhibit fatty acid amide hydrolase (FAAH (SEQ ID NO: 3)) with an IC 50 value of > 1000 nM.

[0290] In another embodiment, the compound of Formula I may inhibit soluble epoxide hydrolase with an IC 50 value of < 50 nM, and inhibit fatty acid amide hydrolase (FAAH (SEQ ID NO: 3)) with an IC 50 value of > 1000 nM.

[0291] In another embodiment, the compound of Formula I may inhibit soluble epoxide hydrolase with an IC 50 value of < 20 nM, and inhibit fatty acid amide hydrolase (FAAH (SEQ ID NO: 3)) with an IC 50 value of > 1000 nM.

[0292] In some embodiments, the therapeutically effective amount of the compound of Formula I may be from about 0.5 mg / day to about 3,000 mg / day. In an embodiment, the therapeutically effective amount of the compound of Formula I may be from about 1 mg / day to about 2,000 mg / day. In an embodiment, the therapeutically effective amount of the compound of Formula I may be from about 2 mg / day to about 600 mg / day. In an embodiment, the therapeutically effective amount of the compound of Formula I may be from 3 mg / day to about 500 mg / day. In an embodiment, the therapeutically effective amount of the compound of Formula I may be from 4 mg / day to about 400 mg / day. In an embodiment, the therapeutically effective amount of the compound of Formula I may be from 3 mg / day to about 400 mg / day. In an embodiment, the therapeutically effective amount of the compound of Formula I may be from 10 mg / day to about 300 mg / day.

[0293] In some embodiments, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 2 mg to about 1,500 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 4 mg to about 750 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 6 mg to about 600 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 10 mg to about 500 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 20 mg to about 400 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 20 mg to about 300 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 20 mg to about 200 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 20 mg to about 120 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 20 mg to about 100 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 20 mg to about 75 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 20 mg to about 60 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 20 mg to about 50 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 20 mg to about 40 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for adult subjects can be from about 24 mg to about 40 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 0.1 mg to about 800 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 0.25 mg to about 350 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 0.5 mg to about 300 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 1 mg to about 200 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 2 mg to about 100 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 3 mg to about 80 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 4 mg to about 60 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 5 mg to about 80 mg per day. In an embodiment, the therapeutically effective amount of the compound of Formula I for non - adult subjects can be from about 6 mg to about 60 mg per day.In an embodiment, a therapeutically effective amount of a compound of formula I for a non - adult subject can be from about 6 mg to about 50 mg per day. In an embodiment, a therapeutically effective amount of a compound of formula I for a non - adult subject can be from about 6 mg to about 40 mg per day. In an embodiment, a therapeutically effective amount of a compound of formula I for a non - adult subject can be from about 6 mg to about 30 mg per day. In an embodiment, a therapeutically effective amount of a compound of formula I for a non - adult subject can be from about 7 mg to about 25 mg per day.

[0294] In some embodiments, a therapeutically effective amount of a compound of formula I can be administered as a single dose or as a dose repeated one or several times at regular time intervals. In an embodiment, a therapeutically effective amount is administered once a day, or once every two days, or once every three days, or once a week. The administration can be once, twice, or three times a day. In an embodiment, as long as the symptoms or the disease exist, a therapeutically effective amount is administered daily or every other day for more than two weeks, ten weeks, thirty weeks, one year. In an embodiment, a therapeutically effective amount is administered daily or every other day for more than 30 weeks.

[0295] On the other hand, the present invention relates to novel compounds of formula I, their stereoisomers, stable - labeled (e.g., deuterated) variants, tautomers, and / or their pharmaceutically acceptable salts, which can be used as inhibitors of soluble epoxide hydrolase (sEH).

[0296] On the other hand, the present invention relates to a method for preventing and / or treating pain, neurodegenerative diseases, diseases associated with synucleinopathies, and inflammatory diseases in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I, its stereoisomers, and / or its pharmaceutically acceptable salts. In addition, the compound of formula I, its stereoisomers, and / or pharmaceutically acceptable salts can be used for preventing or treating diseases associated with synucleinopathies, such as Lewy body dementia (LBD) and Gaucher's disease (GD), rapid - eye - movement sleep behavior disorder (RBD), Lewy body variant of Alzheimer's disease (LBAD), neurodegeneration with brain iron accumulation (NBAI - 1), and pure autonomic failure (PAF).

[0297] In addition, the compound of formula I, its stereoisomers, and / or pharmaceutically acceptable salts can be used for preventing or treating Alzheimer's disease, depression and related diseases, schizophrenia, stroke, subarachnoid hemorrhage, traumatic brain injury, and multiple system atrophy (MSA) in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of the composition of the present invention.

[0298] In another embodiment, the stereoisomers and / or pharmaceutically acceptable salts of formula I can be used for treating neurodegenerative diseases, such as Lewy body dementia (DLB) and Gaucher's disease.

[0299] For ease of reference, the present invention will be described in terms of administration to human subjects. However, it should be understood that these descriptions are not limited to administration to humans unless otherwise specifically stated, but also include administration to other animals.

[0300] Desired derivatives are those which, when the compounds of the present invention are administered to a subject (e.g., by making an orally administered compound more readily absorbed), can improve the solubility of the compounds of the present invention or increase their bioavailability. The compounds of formula I can be amorphous, semi-crystalline or crystalline, and can be given as the parent compound, its salts and / or solvated forms. Solvates can be part of the lattice or surface associated. All such forms are intended to be within the scope of the present invention. Solvation methods are well known in the art. Suitable solvates are pharmaceutically acceptable solvates. In one embodiment, the solvate is a hydrate.

[0301] In one embodiment, the compounds of the present invention (compounds of formula I) can be used to treat inflammatory pain, neuropathic pain, rheumatoid arthritis, osteoarthritis, diabetic nephropathy, hypertension, diabetes and / or metabolic syndrome. The compounds of formula I can be used to increase the levels of epoxyeicosatrienoic acids (EETs) in a subject to prevent and treat inflammatory and / or pain conditions.

[0302] Accordingly, the compounds of formula I, their pharmaceutically acceptable salts and / or their solvates can be used to prevent and / or treat the diseases or conditions discussed in the present invention. Further aspects of the present invention relate to pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I, its pharmaceutically acceptable salt and / or its solvate, which may also include pharmaceutically acceptable excipients.

[0303] The therapeutically effective amount of the compound of formula I, its pharmaceutically acceptable salt and / or solvate that must be administered, and the dosage for treating a pathological condition with said compound will depend on many factors, including age, the condition of the patient, the severity of the disease, the route and frequency of administration, the modulating compound used, etc.

[0304] Suitable pharmaceutically acceptable carriers may include solid fillers or diluents and sterile aqueous or organic solutions. The active ingredient may be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the above ranges. Thus, for oral administration, the active ingredient may be combined with suitable solid or liquid carriers or diluents to form capsules, tablets, powders, syrups, solutions, suspensions, etc. For parenteral administration, the active ingredient may be combined with a sterile aqueous or organic medium to form an injectable solution or suspension. For example, solutions in sesame oil or peanut oil, aqueous propylene glycol solutions, etc., as well as aqueous solutions of water-soluble pharmaceutically acceptable acid addition salts or salts with bases of the compounds, may be used. An aqueous solution in which the active ingredient is dissolved in a pharmaceutically acceptable solvent such as polyhydroxylated castor oil may also be used for injectable solutions. The injectable solutions thus prepared may be administered intravenously, intraperitoneally, subcutaneously or intramuscularly, with intramuscular administration generally being preferred for humans.

[0305] The following examples describe exemplary embodiments of the present invention. Other embodiments within the scope of the claims of the present invention will be apparent to those skilled in the art by considering the specification or practice of the invention disclosed herein. This specification, together with the examples, is considered to be merely exemplary, and the scope and spirit of the invention are indicated by the claims that follow the examples.

[0306] Conventional synthetic procedures

[0307] The compounds of the present invention may be synthesized according to the procedures outlined in Schemes I - VIII. The proposed methods are not restrictive. Variations of these synthetic methods or methods reported in the literature may be employed to synthesize the compounds within the scope of the present invention.

[0308] Scheme I

[0309]

[0310] R 1 = alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl

[0311] R 4 = alkyl, halogen, haloalkyl, alkoxy, SO2R5, COR3

[0312] R 6 = alkyl, cycloalkyl, aryl or heteroaryl

[0313] X = O, (CH2) p , p = 0.-2

[0314] Scheme I shows the synthetic method of the compound 7 of formula I of the present invention. In the first step, the substituted benzyl halide 1 (Z = Cl, Br) reacts with trialkyl phosphate to generate the substituted benzyl phosphonate 2. This reaction can be carried out by heating 1 with trialkyl phosphite at 120 - 150 °C for 10 - 20 hours in the presence or absence of a solvent (such as dimethylacetamide). The substituted olefin 4 is synthesized by generating an ylid from the intermediate 2 and reacting it with the substituted piperidone 3. In a solvent (such as THF, dimethoxyethane or ether), in the presence of a crown ether, an ylid is generated from 2 using a base (such as sodium hydride or potassium hydride). This reaction can be initiated at low temperature (0 + 5 °C), and then the reaction mixture is heated to about 20 °C and stirred for another 20 - 60 minutes. The reaction between the ylid generated from 2 and 3 can be carried out in a solvent such as THF, dimethoxyethane, ether or toluene, and the reaction is initiated at low temperature (0 °C + 5 °C), and then the reaction mixture is heated to about 20 - 40 °C and stirred for 8 - 20 hours. In the presence of an acid, the carbamate is deprotected from 4 to obtain the piperidine intermediate 5. This reaction can be carried out by stirring the reaction mixture in a solvent (such as dichloromethane or dichloroethane) and using an acid (such as trifluoroacetic acid) at a temperature of 0 - 25 °C for 20 - 90 minutes. 5 reacts with the substituted cyclopropane carbamate intermediate 6 to obtain the target compound 7. This reaction can be carried out using a solvent (such as dimethyl sulfoxide or dimethylacetamide) and a base (such as triethylamine, diisopropylethylamine), and heating the reaction components at 40 - 60 °C for 3 - 6 hours.

[0315] The substituted cyclopropane carbamate 6 can be synthesized from the corresponding cyclopropylamine 8 by reacting with an aryl chloroformate (R = Ph or Ar) using a solvent such as dichloromethane and a base such as diisopropylethylamine. The reaction can be initiated at low temperature (0 ± 5 °C), and then the reaction mixture is heated to about 20 - 30 °C and stirred for 20 - 40 minutes. The substituted benzyl halide 1 and the substituted piperidone 3 used in Scheme I can be commercially available or synthesized from readily available reagents.

[0316] Scheme II

[0317]

[0318] R 1 = alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl

[0319] R 4 = alkyl, halogen, haloalkyl, alkoxy, SO2R5, COR3

[0320] R 6 = alkyl, cycloalkyl, aryl or heteroaryl

[0321] X = O, (CH2) p.p = 0.-2

[0322] Scheme II shows the synthetic method of the compound 11 of formula I of the present invention. In the first step, compound 4 is synthesized using the method described in Scheme I, and it is hydrogenated to obtain the saturated compound 9. This reaction can be carried out using catalytic hydrogenation (using, for example, Pd / C or Pt / C) in a solvent such as methanol or ethanol in a Parr hydrogenation apparatus. In the presence of an acid, the carbamate 9 is deprotected to obtain the piperidine intermediate 10. This reaction can be carried out by stirring the reaction mixture in a solvent (such as dichloromethane or dichloroethane) and using an acid (such as trifluoroacetic acid) at a temperature of 0 - 25 °C for 20 - 90 minutes. 10 reacts with the substituted cyclopropane carbamate intermediate 6 to obtain the target compound 11. This reaction can be carried out by heating the reaction components in a solvent (such as dimethyl sulfoxide or dimethylacetamide) and a base (such as triethylamine, diisopropylethylamine) at 40 - 60 °C for 3 - 6 hours.

[0323] Scheme III

[0324]

[0325] R 1 = heteroaryl, substituted or unsubstituted

[0326] R 4 = alkyl, halogen, haloalkyl, alkoxy, SO2R5, COR3

[0327] R 6 = alkyl, cycloalkyl, aryl or heteroaryl

[0328] R 7 = alkyl, haloalkyl, alkoxy, SO2R5, COR3

[0329] Scheme III shows the synthetic methods of Compounds 18 and 19 of the present invention. In the first step, Compound 12 containing a heteroaromatic ring A (such as pyridine, pyrimidine, pyrazine) reacts with a substituted phenol 13 to obtain 14. This reaction can be carried out in a solvent (such as dimethylacetamide or dimethylformamide), using a base (such as potassium carbonate, sodium carbonate or cesium carbonate), and heating the reaction mixture at 80 - 120 °C for 3 - 6 hours. The obtained substituted benzyl alcohol is converted to the corresponding benzyl halide 15 by reacting with thionyl chloride. This reaction can be carried out using a solvent such as dichloromethane and treating it with thionyl chloride at 0 - 25 °C for 1 - 3 hours. The substituted benzyl halide 15 reacts with trialkyl phosphite to form a substituted benzyl phosphonate 16. This reaction can be carried out by heating 15 with trialkyl phosphite at 120 - 150 °C for 10 - 20 hours with or without a solvent (such as dimethylacetamide). The substituted olefin 17 is synthesized by generating a ylide from Intermediate 16 and reacting it with a substituted piperidone 3. In a solvent (such as THF, dimethoxyethane or ether), in the presence of a crown ether, a ylide is generated from 16 using a base (such as sodium hydride or potassium hydride). The reaction can be initiated at a low temperature (0 °C + 5 °C), and then the reaction mixture is heated to about 20 °C and stirred for another 20 - 60 minutes. The reaction between the ylide generated from 16 and 3 can be carried out in a solvent such as THF, dimethoxyethane, ether or toluene, and the reaction is initiated at a low temperature (0 + 5 °C), and then the reaction mixture is heated to about 20 - 40 °C and stirred for 8 - 20 hours. The conversion of 17 to 18 can be carried out after the following steps: deprotecting the carbamate in the presence of an acid and reacting it with a substituted cyclopropane carbamate intermediate 6 as described in Scheme I. The conversion of 17 to 19 can be completed using a series of steps including hydrogenation, deprotection of the carbamate and reaction with a substituted cyclopropane carbamate intermediate 6 as described in Scheme II.

[0330] Scheme IV

[0331]

[0332] R 13 = CO2R (R = H, alkyl, NH2, NHMe), CH2OR,

[0333] R 4 = alkyl, halogen, haloalkyl, alkoxy, SO2R5, COR3

[0334] R 6 = alkyl, cycloalkyl, aryl or heteroaryl

[0335] Scheme IV illustrates the synthetic methods of compounds 26 and 27 of the present invention. In the first step, compound 20 reacts with substituted phenol 21 to obtain 22. This reaction can be carried out by heating the reaction mixture in a solvent (such as dimethylacetamide or dimethylformamide), using a base (such as cesium carbonate), at 80 - 120 °C for 3 - 8 hours. The obtained substituted benzyl alcohol is converted to the corresponding benzyl halide 23 by reaction with thionyl chloride. This reaction can be carried out using a solvent such as dichloromethane and treating with thionyl chloride at 0 - 25 °C for 1 - 3 hours. The substituted benzyl halide 23 reacts with trialkyl phosphite to form substituted benzyl phosphonate 24. This reaction can be carried out by heating 23 and trialkyl phosphite at 120 - 150 °C for 10 - 20 hours with or without a solvent such as dimethylacetamide. The substituted olefin 25 is synthesized by generating a ylide from intermediate 24 and reacting it with substituted piperidone 3. In a solvent such as THF, dimethoxyethane or diethyl ether, in the presence of a crown ether, a ylide is generated from 24 using a base such as sodium hydride or potassium hydride. The reaction can be initiated at low temperature (0 °C + 5 °C), and then the reaction mixture is heated to about 20 °C and stirred for another 20 - 60 minutes. The reaction between the ylide generated from 24 and 3 can be carried out in a solvent such as THF, dimethoxyethane, diethyl ether or toluene, and initiated at low temperature (0 + 5 °C), and then the reaction mixture is heated to about 20 - 40 °C and stirred for 8 - 20 hours. The conversion from 25 to 26 can be carried out after the following steps: deprotecting the carbamate in the presence of an acid and reacting with the substituted cyclopropane carbamate intermediate 6 as described in Scheme I. The conversion from 25 to 27 can be completed using a series of steps including hydrogenation, deprotection of the carbamate and reaction with the substituted cyclopropane carbamate intermediate 6, as described in Scheme II.

[0336] Scheme V

[0337]

[0338] R 4 = alkyl, halogen, haloalkyl, alkoxy, SO2R5, COR3

[0339] R 6 = alkyl, cycloalkyl, aryl or heteroaryl

[0340] Ring A - heterocyclic group

[0341] Scheme V shows the synthetic methods of Compounds 33 and 34 of the present invention. In the first step, the substituted benzyl halide 28 reacts with trialkyl phosphite to generate the substituted benzyl phosphonate 29. This reaction can be carried out by heating 28 and trialkyl phosphite for 10 - 20 hours at 120 - 150 °C, with or without a solvent (such as dimethylacetamide). The substituted olefin 30 is synthesized by generating a ylide from the intermediate 29 and reacting it with the substituted piperidone 3. In a solvent (such as THF, dimethoxyethane, or diethyl ether), in the presence of a crown ether, a base (such as sodium hydride or potassium hydride) is used to generate the ylide from 29. The reaction can be initiated at low temperature (0 °C + 5 °C), and then the reaction mixture is heated to about 20 °C and stirred for another 20 - 60 minutes. The reaction between the ylide generated from 29 and 3 can be carried out in a solvent such as THF, dimethoxyethane, diethyl ether, or toluene, and the reaction is initiated at low temperature (0 + 5 °C), and then the reaction mixture is heated to about 20 - 40 °C and stirred for 8 - 20 hours. The intermediate 31 containing heterocycle A is synthesized by reacting 30 with the corresponding heterocycles such as pyrrolidine, morpholine, and piperidine. This reaction can be carried out by treating 30 with the A-ring heterocycle using cesium carbonate and a catalyst such as palladium acetate and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP). The reaction can be carried out by treating the reaction mixture at 20 - 100 °C for 5 - 20 hours using a solvent such as 1,4-dioxane. The conversion from 31 to 33 can be carried out after the following steps: deprotecting the carbamate in the presence of an acid and reacting it with the substituted cyclopropane carbamate intermediate 6 as described in Scheme I.

[0342] The conversion from 31 to 32 can be completed using catalytic hydrogenation ((Pd / C, H2) as described in Scheme II. Similarly, the conversion from 32 to 34 can be carried out according to the method including deprotecting the carbamate and reacting it with the substituted cyclopropane carbamate intermediate 6, as described in Scheme II.

[0343] Scheme VI

[0344]

[0345] R 4 = alkyl, halogen, haloalkyl, alkoxy, SO2R5, COR3

[0346] R 6 = alkyl, cycloalkyl, aryl or heteroaryl

[0347] R 7 = alkyl, haloalkyl, SO2R5, COR3

[0348] Scheme VI shows the synthesis method of compound 40 of the present invention. In the first step, compound 35 containing a heteroaromatic ring A (such as pyridine, pyrimidine, pyrazine) reacts with a substituted phenol 36 to obtain 37. This reaction can be carried out by heating the reaction mixture in a solvent (such as dimethylacetamide or dimethylformamide) using a base (such as potassium carbonate, sodium carbonate or cesium carbonate) at 80 - 120 °C for 3 - 8 hours. Substituted phenol 37 reacts with piperidine methanesulfonate 38 to obtain 39. This reaction can be carried out in a solvent (such as dimethylacetamide or dimethylformamide), using a base (such as potassium carbonate, sodium carbonate, cesium carbonate), and heating the reaction mixture at 60 - 80 °C for 6 - 8 hours. The conversion from 39 to 40 can be carried out in the following steps: deprotecting the carbamate in the presence of an acid and reacting with the substituted cyclopropane carbamate intermediate 6 as described in Scheme I.

[0349] Scheme VII

[0350]

[0351] Scheme VII shows the synthesis method of compounds 45 and 46 of the present invention. In the first step, compound 41 containing a heteroaryl borate reacts with an aryl halide 42 to obtain 43. This reaction can be carried out by treating 41 and 42 in a solvent such as dimethylacetamide, dimethylformamide with 2N sodium carbonate solution and tetrakis(triphenylphosphine)palladium(0) at ambient temperature 20 - 25 °C for 12 - 18 hours. The conversion from 43 to 45 can be carried out after the following steps: deprotecting the carbamate in the presence of an acid and reacting with the substituted cyclopropane carbamate intermediate 6 as described in Scheme I.

[0352] As described in Scheme II, 43 can be converted to 44 using catalytic hydrogenation (Pd / C, H2). Similarly, the conversion from 44 to 46 can be carried out according to a method including deprotection of the carbamate and reaction with the substituted cyclopropane carbamate intermediate 6 as described in Scheme II.

[0353] Scheme VIII

[0354]

[0355] R4 = alkyl, hydrogen, halogen, alkoxy

[0356] R6 = alkyl, aryl, cycloalkyl

[0357] Scheme VIII shows the synthetic method of the compound of formula 54 of the present invention. In the first step, the substituted benzyl halide 47 reacts with trialkyl phosphite to form the substituted benzyl phosphonate 48. This reaction can be carried out by heating 47 with trialkyl phosphite at 120 - 150 °C for 10 - 20 hours. The substituted olefin 49 is synthesized by generating a ylide from the intermediate 48 and reacting it with the substituted piperidone 3. In a solvent (such as THF, dimethoxyethane or ether), in the presence of a crown ether, a base (such as sodium hydride or potassium hydride) is used to generate the ylide from 48. The reaction can be initiated at low temperature (0 + 5 °C), and then the reaction mixture is heated to about 20 °C and stirred for another 20 - 60 minutes. The reaction between the ylide generated from 48 and 3 can be carried out in a solvent such as THF, dimethoxyethane, ether or toluene, and the reaction is initiated at low temperature (0 + 5 °C), and then the reaction mixture is heated to about 20 - 40 °C and stirred for 8 - 20 hours. The conversion of 49 to 50 can be completed using catalytic hydrogenation (Pd / C, H2). This reaction can be carried out using catalytic hydrogenation (using, for example, Pd / C or Pt / C) in a solvent such as methanol or ethanol in a Parr hydrogenation apparatus. In the next step, the synthesis of 52 is completed by reacting 50 with the substituted 1 - fluoro - 2 - nitrobenzene 51 in a substitution reaction. This reaction can be carried out by treating 50 with 51 in a solvent such as dimethylformamide and heating the reaction mixture at 80 - 120 °C for 10 - 20 hours in the presence of cesium carbonate. The synthesis of the benzimidazole compound 53 can be completed by treating 52 with formic acid and sodium formate in the presence of Pd / C at about 25 °C and heating the mixture at about 100 - 120 °C for 12 - 20 hours. The conversion of 53 to 54 can be carried out by treating with the substituted cyclopropane carbamate intermediate 6 as described in Scheme II.

[0358] Example

[0359] Examples of the present invention provide methods for preparing the novel compounds of formula I using the methods described in the following examples. Those skilled in the art will understand that known variations of the conditions and methods of the following preparation procedures can be used to prepare these compounds. In addition, by utilizing the methods described in the present invention, those of ordinary skill in the art can prepare other compounds of the present invention claimed herein.

[0360] Example 1: Synthesis of 4-(3 - methoxy - benzylidene)-piperidine - 1 - carboxylic acid (2 - phenyl - cyclopropyl)-amide:

[0361]

[0362] Step 1 - Thionyl chloride (74 mL, 1.01 mol) was added dropwise to a mixture of (3-methoxyphenyl)methanol (20.0 g, 0.14 mol) and pyridine (5.8 mL, 0.72 mol) in benzene (120 mL) while stirring the reaction in an ice bath. After removing the ice, the reaction mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was quenched with saturated sodium bicarbonate solution (100 ml), extracted with ethyl acetate (2 × 300 ml), and dried over sodium sulfate. The crude product obtained after evaporating the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 5% ethyl acetate) to give 20.01 g (88%) of yellow oily product 2. 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).

[0363] Step 2 - A solution of 2 (20 g, 0.12 mol) in triethyl phosphite (29.0 mL, 0.16 mol) was heated at 150 °C for 17 hours. The reaction mixture was cooled to room temperature, and the crude product obtained after evaporating the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 20% ethyl acetate) to give product 3 as a colorless oil, 27.0 g (81%). 1 1H NMR (300 MHz, CDCl3) δ (ppm): 1.26 (t, J = 7.2 Hz, 6H), 3.11 (s, 1H), 3.18 (s, 1H), 3.81 (s, 3H), 4.01 - 4.03 (m, 4H), 6.79 - 6.91 (m, 3H), 7.21 - 7.28 (m, 1H).

[0364] Step 3 - 15-Crown ether (0.2 mL, 0.9 mmol) was added to a solution of 3 (11.0 g, 43.0 mmol) in THF (44 mL). The reaction was cooled (ice bath) and NaH (580 mg, 24.2 mmol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and cooled again using an ice bath. A solution of tert-butyl 4-oxopiperidine-1-carboxylate 4 (8.5 g, 43.0 mmol) in THF (44 mL) was added to the above reaction mixture at ice temperature and stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (100 ml), extracted with ethyl acetate, and dried over sodium sulfate. The crude product obtained after evaporating the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 25% ethyl acetate) to give yellow oily product 5, 7.0 g (54%). 11H NMR (300 MHz, CDCl3) δ (ppm): 1.49 (s, 9H), 2.32 - 2.36 (m, 2H), 2.44 - 2.50 (m, 2H), 3.42 (t, J = 5.7 Hz, 2H), 3.52 (t, J = 5.7 Hz, 2H), 3.84 (s, 3H), 6.35 (s, 1H), 6.75 - 6.81 (m, 3H), 7.25 - 7.25 (m, 1H).

[0365] Step 4 - At ice temperature, trifluoroacetic acid (4.25 mL, 4.25 volumes) was added to a solution of 5 (1.0 g, 3.2 mmol) in dichloromethane (8.0 mL). The reaction mixture was stirred at room temperature for 1 hour. The crude product obtained after evaporating the volatiles was washed with diethyl ether to give white solid 6 (600 mg, 89%). 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.54 - 2.62 (m, 4H), 3.07 - 3.17 (m, 4H), 3.75 (s, 3H), 6.44 (s, 1H), 6.77 - 6.84 (m, 3H), 7.27 (t, J = 7.8 Hz, 1H), 8.79 (bs, 2H).

[0366] Step 5 - At ice bath temperature, triethylamine (0.06 mol) and phenyl chloroformate 1A (4.8 g, 0.03 mol) were added to a suspension of trans-2-phenylcyclopropylamine 2A (3.5 g, 0.02 mol) in dichloromethane (35 mL). Then the ice bath was removed and the reaction mixture was stirred at room temperature for 30 minutes. The resulting reaction mixture was diluted with ethyl acetate (200 ml), washed with water (2 × 100 ml), and dried over sodium sulfate. The crude product obtained after evaporating the volatiles was purified by column chromatography on silica gel (230 - 400) (petroleum ether solution of 10% ethyl acetate) to give white solid product 7, 2.6 g (50%). Melting point: 113.6–115.3 °C. 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.14 - 1.26 (m, 2H), 2.03 - 2.09 (m, 1H), 2.72 - 2.75 (m, 1H), 7.10 - 7.40 (m, 10H), 8.18 (bs, 1H). MS: 254 (M + H).

[0367] Step 6: At 25 °C, diisopropylethylamine (0.56 mL, 2.82 mmol) and carbamate 7 (238 mg, 0.94 mmol) were added to a solution of amine 6 (mg, 0.94 mmol) in dimethyl sulfoxide (6 mL). The reaction mixture was stirred at 55 °C for 4 h. The resulting reaction mixture was diluted with ethyl acetate (250 ml), washed with water (4 × 75 ml) and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by column chromatography on silica gel (230 - 400) (petroleum ether solution of 50% ethyl acetate) to give product 8 as a white solid, 226 mg (65%). Melting point: 104.7 - 106.4 °C. 1 H NMR (300 MHz, CDCl3) δ (ppm): 1.15 - 1.27 (m, 2H), 2.02 - 2.09 (m, 1H), 2.40 (t, J = 5.7 Hz, 2H), 2.54 (t, J = 5.7 Hz, 2H), 2.87 (bs, 1H), 3.39 (t, J = 5.7 Hz, 2H), 3.49 (t, J = 5.7 Hz, 2H), 3.82 (s, 3H), 4.87 (s, 1H, -CONH-, exchangeable 1 H), 6.37 (s, 1H), 6.75 - 6.81 (m, 3H), 7.18 - 7.30 (m, 6H). 13 C NMR (75 MHz, CDCl3) δ (ppm): 16.44, 25.10, 29.14, 33.19, 35.72, 44.60, 45.60, 55.18, 111.88, 114.60, 121.36, 124.76, 125.95, 126.65, 128.28, 129.16, 137.90, 138.70, 140.88, 157.95 and 159.53. MS: 363 (M + H).

[0368] Example 2: Synthesis of 4-[3-(pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid (2-phenylcyclopropyl)-amide:

[0369]

[0370] Step 1 - At room temperature, 3 - hydroxyphenylmethanol (30.0 g, 0.24 mol) and cesium carbonate (117.3 g, 0.36 mol) were added to a solution of 2 - fluoropyridine (25.8 g, 0.27 mol) in DMF (300 mL). The reaction mixture was stirred at 100 °C for 5 hours. Then the resulting mixture was allowed to reach room temperature, diluted with water (250 ml), extracted with ethyl acetate (3 × 500 ml), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 30% ethyl acetate) to give product 2 as a pale yellow oil, 34.5 g (71%). 1 1H NMR (300 MHz, DMSO - d6) δ (ppm): 4.49 - 4.51 (m, 2H), 5.24 - 5.30 (m, 1H), 6.98 - 7.15 (m, 5H), 7.33 - 7.40 (m, 1H), 7.82 - 7.89 (m, 1H), 8.14 - 8.16 (m, 1H).

[0371] Step 2 - Thionyl chloride (13.9 mL, 0.18 mol) was added dropwise to a solution of 2 (34.5 g, 0.17 mol) in dichloromethane (345 mL) while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. Then the volatiles were evaporated under reduced pressure and diluted with toluene (25 ml), and toluene was evaporated under reduced pressure. This azeotropic process was repeated 3 times to obtain product 3 as a brown oil (36.8 g, 98%). 1 1H NMR (300 MHz, DMSO - d6) δ (ppm): 4.77 (s, 2H), 7.04 - 7.20 (m, 4H), 7.27 - 7.29 (m, 1H), 7.42 (t, J = 8.4 Hz, 1H), 7.84 - 7.90 (m, 1H), 8.14 - 8.16 (m, 1H).

[0372] Step 3 - A solution of 3 (36.7 g, 0.16 mol) in triethyl phosphite (41.6 mL, 0.26 mol) was heated at 150 °C for 6 hours. The reaction mixture was allowed to reach room temperature, and the crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 60% ethyl acetate) to give 41.33 g of product 4 as a colorless oil. The product contained unreacted triethyl phosphite and was used in the next step without further purification.

[0373] Step 4 - To a solution of diethyl [3-(pyridin-2-yloxy)-benzyl]-phosphonate 4 (30.0 g, 93.0 mmol) in THF (120 mL) was added 15-crown ether (0.41 g, 1.8 mmol). The reaction was cooled (ice bath) and NaH (3.35 g, 0.14 mol) was added portionwise. The reaction mixture was stirred at room temperature for 30 minutes and cooled again to ice temperature. To the above reaction mixture at ice temperature was added a solution of tert-butyl 4-oxo-piperidine-1-carboxylate 5 (18.6 g, 93.0 mmol) in THF (120 mL), and the mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (500 ml), extracted with ethyl acetate (3×500 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 3% ethyl acetate) to give 24.3 g (71%) of the product 6 as a yellow oil. 1 H NMR (300 MHz, CDCl3) δ (ppm): 1.41 (s, 9H), 2.27 (t, J = 5.4 Hz, 2H), 2.40 (t, J = 5.4 Hz, 2H), 3.33 (bs, 2H), 3.40 (t, J = 5.4 Hz, 2H), 6.37 (s, 1H), 6.95 - 7.15 (m, 4H), 7.37 (t, J = 7.8 Hz, 2H), 7.83 - 7.88 (m, 1H), 8.14 - 8.16 (m, 1H).

[0374] Step 5 - At ice temperature, trifluoroacetic acid (51 mL) was added to a solution of tert-butyl 4-[3-(pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylate 6 (12.0 g, 33.0 mmol) in dichloromethane (120.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. The brown oil 7 (13.7 g, 85%) obtained after evaporation of the volatiles was used for the next step (13.7 g, 85%) without further purification. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 2.56 - 2.63 (m, 4H), 3.10 - 3.16 (m, 4H), 6.46 (s, 1H), 6.99 - 7.15 (m, 5H), 7.39 (t, J = 7.5 Hz, 1H), 7.83 - 7.88 (m, 1H), 8.14 - 8.16 (m, 1H).

[0375] Step 6 - At 25 °C, diisopropylethylamine (13.6 mL, 78.0 mmol) and the product of Step 5, Example 1 (6.7 g, 26.0 mmol) were added to a solution of amine 7 (15.0 g, 26.0 mmol) in dimethyl sulfoxide (150 mL). The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (1.2 L), washed with water (3 × 150 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by column (silica gel (230 - 400), petroleum ether solution of 50% ethyl acetate) to give 9.1 g (81%) of a light yellow solid product 8. Melting point: 52.3 - 54.1 °C. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.06 - 1.18 (m, 2H), 1.88 (bs, 1H), 2.26 (m, 2H), 2.28 (m, 2H), 2.69 - 2.72 (m, 1H), 3.29 - 3.38 (m, 4H), 6.36 (s, 1H), 6.85 - 6.86 (bs, 1H, -CONH-, exchangeable 1 H), 6.95 - 7.40 (m, 10H), 7.86 (t, J = 6.3 Hz, 1H), 8.14 - 8.16 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) δ (ppm): 15.99, 27.74, 29.40, 34.42, 36.08, 44.41, 45.47, 112.09, 119.31, 119.52, 121.60, 123.58, 125.24, 125.80, 126.41, 128.52, 129.88, 139.19, 140.09, 140.56, 142.42, 147.91, 154.42, 158.09 and 163.45. MS: 426 (M + H).

[0376] Example 3: Synthesis of 4-[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0377]

[0378] Step 1 - At room temperature, 3 - hydroxyphenyl - methanol (17.4 g, 0.13 mol) and potassium carbonate (26.3 g, 0.19 mol) were added to a solution of 5 - trifluoromethyl - 2 - chloro - pyridine (23.0 g, 0.12 mol) in DMF (230 mL). The reaction mixture was stirred at 100 °C for 5 hours. Then the resulting mixture was allowed to reach room temperature, diluted with water (200 ml), extracted with ethyl acetate (3 × 400 ml), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 12% ethyl acetate) to give 28.1 g (82%) of product 2 as a pale yellow oil. 1 H NMR (300 MHz, CDCl3) δ (ppm): 4.75 (s, 2H), 7.03 - 7.10 (m, 2H), 7.19 (s, 1H), 7.26 - 7.28 (m, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.90 - 7.94 (m, 1H), 8.45 (s, 1H).

[0379] Step 2 - Thionyl chloride (8.5 mL, 0.11 mol) was added dropwise to a solution of 2 (28.0 g, 0.10 mol) in dichloromethane (280 mL) while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. Then the volatiles were evaporated under reduced pressure, diluted with toluene (15 ml), and toluene was evaporated under reduced pressure. This azeotropic process was repeated 3 times to obtain product 3 as a red oil (29.6 g, 99%). 1 H NMR (300 MHz, CDCl3) δ (ppm): 4.62 (s, 2H), 7.05 (d, J = 8.7 Hz, 1H), 7.12 - 7.13 (m, 1H), 7.23 - 7.32 (m, 2H), 7.42 - 7.47 (m, 1H), 7.92 - 7.95 (m, 1H), 8.46 (s, 1H).

[0380] Step 3 - A solution of 3 (29.0 g, 0.10 mol) in triethyl phosphite (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 give a pale orange precipitate. The resulting precipitate was filtered and dried under vacuum to give product 4 as a white solid (30.8 g, 94%), which was used for the next step without further purification. 11H NMR (300 MHz, DMSO-d6) δ (ppm): 1.16 (t, J = 6.9 Hz, 6H), 3.24 and 3.31 (2s, 2H), 3.90 - 4.00 (m, 4H), 7.07 - 7.10 (m, 2H), 7.17 - 7.25 (m, 2H), 7.39 (d, J = 8.7 Hz, 1H), 8.23 - 8.26 (m, 1H), 8.55 (s, 1H).

[0381] Step 4 - To a solution of ester 4 (25.0 g, 64.0 mmol) in THF (100 mL) was added 15-crown ether (0.28 g, 1.3 mmol). The reaction was cooled (ice bath) and NaH (2.3 g, 96.0 mmol) was added portionwise over 5 minutes. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. To the above reaction mixture at ice temperature was added a solution of tert-butyl 4-oxopiperidine-1-carboxylate 5 (12.81 g, 64.0 mmol) in THF (100 mL), and the mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water to give a white precipitate. The precipitate was filtered and dried to give product 6 as a white solid (24.4 g, 87%). 1 1H NMR (300 MHz, CD3OD) δ (ppm): 1.48 (s, 9H), 2.36 (t, J = 5.1 Hz, 2H), 2.49 (t, J = 5.4 Hz, 2H), 3.43 (t, J = 5.7 Hz, 2H), 3.52 (t, J = 5.7 Hz, 2H), 6.43 (s, 1H), 7.01 - 7.03 (m, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.38 - 7.44 (m, 1H), 8.09 - 8.12 (m, 1H), 8.44 (bs, 1H).

[0382] Step 5 - At ice temperature, trifluoroacetic acid (42.5 mL) was added to a solution of 6 (10.0 g, 23.0 mmol) in dichloromethane (100 mL), and the reaction mixture was stirred at room temperature for 1 hour. Then the volatiles were removed under reduced pressure to give a red oily product (10.7 g, 83%). The crude product 7 was used in the next step without further purification. 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.60 - 2.64 (m, 4H), 3.11 - 3.17 (m, 4H), 6.47 (s, 1H), 7.08 - 7.26 (m, 4H), 7.43 (t, J = 8.1 Hz, 1H), 8.21 - 8.23 (m, 1H), 8.56 (s, 1H), 8.76 (bs, 1H).

[0383] Step 6 - At 25 °C, diisopropylethylamine (9.8 mL, 56.1 mmol) and the product of Step 5, Example 1 (4.74 g, 18.7 mmol) were added to a solution of amine 7 (10.5 g, 18.7 mmol) in dimethyl sulfoxide (10 mL). The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (1.0 L), washed with water (3 × 150 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by column chromatography on silica gel (230 - 400) (petroleum ether solution of 40% ethyl acetate) to give 7.0 g (76%) of the white solid product 8. Melting point: 98.9–101.5 °C. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.08 - 1.18 (m, 2H), 1.85 - 1.90 (m, 1H), 2.77 (bs, 2H), 2.39 (bs, 2H), 2.69 - 2.72 (m, 1H), 3.32 - 3.39 (m, 4H), 6.37 (s, 1H), 6.85 (s, 1H, exchangeable with D2O 1 H), 7.04 - 7.24 (m, 9H), 7.41 (t, J = 7.8 Hz, 1H), 8.22 - 8.25 (m, 1H), 8.58 (s, 1H). 13 C NMR (75 MHz, DMSO-d6) δ (ppm): 15.99, 24.74, 29.39, 34.44, 36.07, 44.37, 45.44, 112.25, 118.97, 119.81, 120.23, 120.66, 121.09, 121.53, 122.08, 122.57, 123.42, 125.79, 126.15, 126.38, 128.52, 129.76, 130.08, 137.98, 138.01, 139.42, 140.34, 142.42, 145.72, 145.77, 153.38, 158.08, 166.01. MS: 494 (M + H).

[0384] Example 4: Synthesis of 4-[3-(pyridin-2-yloxy)-benzyl]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0385]

[0386] Step 1 - At room temperature, 10% Pd / C (900 mg) was added to a methanol (17 mL) solution of the product of Step 4, Example 2(6), and the reaction mixture was stirred under a hydrogen balloon pressure for 1 h. The resulting reaction mixture was filtered through a diatomaceous earth bed, and the filtrate was concentrated under reduced pressure to give the product 7 (850 mg, 66%) as a yellow oil. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 0.98 - 1.04 (m, 2H), 1.37 (s, 9H), 1.43 - 1.56 (m, 3H), 2.60 (m, 4H), 3.88 - 3.92 (m, 2H), 6.91 - 7.02 (m, 2H), 7.10 - 7.17 (m, 2H), 7.25 - 7.31 (m, 2H), 7.84 - 7.89 (m, 1H), 8.14 - 8.16 (m, 1H).

[0387] Step 2 - At ice temperature, trifluoroacetic acid (3.4 mL, 4.25 volumes) was added to a dichloromethane (8 mL) solution of ester 7 (800 mg, 2.17 mmol), and the reaction mixture was stirred at room temperature for 1 h. Then the volatiles were removed under reduced pressure to give the product (800 mg, 74%) as a brown oil. The crude product 8 was used in the next step without further purification.

[0388] Step 3 - At 25 °C, diisopropylethylamine (0.5 mL, 2.82 mmol) and the product of Step 5, Example 1 (256 mg, 1.0 mmol) were added to a solution of the crude amine 8 (500 mg, 1.0 mmol) in dimethyl sulfoxide (10 mL). The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (250 ml), washed with water (4 × 75 ml) and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 60% ethyl acetate) to give 230 mg (53%) of the white solid product 9. Melting point: 126.8 - 128.6 °C. 1 H NMR (300 MHz, CDCl3) δ (ppm): 1.12 - 1.27 (m, 4H), 1.68 - 1.71 (m, 3H), 1.89 - 2.06 (m, 1H), 2.56 (d, J = 6.6 Hz, 2H), 2.73 (t, J = 11.4 Hz, 2H), 2.82 - 2.86 (m, 1H), 3.92 (d, J = 13.5 Hz, 2H), 4.84 (s, 1H, -CONH-, exchangeable 1 H), 6.90 - 7.03 (m, 5H), 7.15 - 7.35 (m, 6H), 7.68 - 7.74 (m, 1H), 8.21 - 8.23 (m, 2H). 13CNMR(75MHz,CDCl3)δ(ppm):16.45,25.06,29.65,31.82,33.18,37.88,42.86,44.24,111.61,118.48,118.61,121.66,125.36,125.88,126.66,128.24,129.40,139.37,141.02,141.99,147.80,154.28,158.21 and 163.73. MS: 428(M + H).

[0389] Example 5: Chiral Separation of the Racemic Product of Example 2

[0390] The chiral column (CHIRALPACK IA 250mm×10mm 5μm) was equilibrated with the mobile phase (n-hexane: isopropanol; 80:20 v / v) at 15 column volumes before eluting the compound. Then 500 μL of the stock solution (prepared by dissolving 500 mg of the product of Example 2 in 5 ml of n-hexane and isopropanol (8:2)) was injected, and the fractions were collected according to the separation seen in the chromatogram. Fraction F1 was the first eluted fraction from the chiral column (retention time: 11.5 minutes to 13.00 minutes), and fraction F2 was the second eluted fraction from the chiral column (retention time: 13.50 minutes to 15.50 minutes). Repeated injections were made to complete the separation of the remaining (4.5 ml) stock solution. Then the solvents of F-1 and F-2 were removed separately under reduced pressure to obtain the chiral products 5A (entA) (140 mg) and 5B (entB) (150 mg) respectively.

[0391] 5A 4-[3-(Pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid {(1S,2R)-2-phenyl-cyclopropyl}-amide - HPLC: 99.98% (chiral purity: 98.55%). Melting point: 45.0 - 47.1 °C. mp: 45.0 - 47.1 °C. 1 H NMR(300MHz,DMSO-d6)δ(ppm):1.06 - 1.10(m,1H),1.15 - 1.18(m,1H),1.87(m,1H),2.24 - 2.28(m,2H),2.38 - 2.40(m,2H),2.69 - 2.72(m,1H),3.29 - 3.40(m,4H),6.36(s,1H),6.85 - 6.86(m,1H),6.95 - 7.27(m,10H),7.37(t,J = 7.8Hz,1H),7.83 - 7.85(m,1H),8.14 - 8.16(m,1H). MS: 426(M + H).

[0392] 5B 4-[3-(Pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid {(1R,2S)-2-phenyl-cyclopropyl}-amide - HPLC: 99.89% (chiral purity: 98.93%). Melting point: 51.0 - 54.3 °C. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.06 - 1.08 (m, 1H), 1.15 - 1.18 (m, 1H), 1.87 (m, 1H), 2.24 - 2.26 (m, 2H), 2.38 - 2.40 (m, 2H), 2.69 - 2.72 (m, 1H), 3.29 - 3.40 (m, 4H), 6.36 (s, 1H), 6.84 - 6.85 (m, 1H), 6.95 - 7.27 (m, 10H), 7.37 (t, J = 7.8 Hz, 1H), 7.83 - 7.85 (m, 1H), 8.14 - 8.16 (m, 1H MS: 426 (M+H).

[0393]

[0394] Example 6: Synthesis of 4-[3-(Pyrimidin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid (2-phenylcyclopropyl)-amide:

[0395]

[0396] Step 1 - At room temperature, cesium carbonate (2.6 g, 8.0 mmol) and 2-chloropyrimidine (680 mg, 6.0 mmol) were added to a solution of 3-hydroxyphenyl-methanol (500 mg, 4.0 mmol) in DMF (5 mL). The reaction mixture was stirred at 100 °C for 5 hours. Then the resulting reaction mixture was cooled to room temperature, cesium carbonate was filtered off, the filtrate was diluted with water (50 ml), extracted with ethyl acetate (100 ml), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 50% ethyl acetate) to give Product 1 as a pale yellow oil, 440 mg (54%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 4.78 (s, 2H), 7.17 - 7.19 (m, 1H), 7.28 - 7.34 (m, 3H), 7.42 - 7.45 (m, 1H), 8.65 (d, J = 4.5 Hz, 2H).

[0397] Step 2 - Thionyl chloride (0.19 mL, 2.6 mmol) was added dropwise to a solution of 1 (440 mg, 2.1 mmol) in dichloromethane (8 mL) while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was quenched with ice water (10 ml), extracted with ethyl acetate (100 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 25% ethyl acetate) to give 400 mg (83%) of a pale pink solid product 2. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 4.78 (s, 2H), 7.17 - 7.19 (m, 1H), 7.28 - 7.34 (m, 3H), 7.42 - 7.45 (m, 1H), 8.65 (d, J = 4.5 Hz, 2H).

[0398] Step 3 - A solution of 2-(3-chloromethyl-phenoxy)-pyrimidine 2 (400 mg, 1.8 mmol) in triethyl phosphite (0.45 mL, 2.7 mmol) was heated at 150 °C for 6 hours. The reaction mixture was allowed to reach room temperature, and the crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 50% ethyl acetate) to give 400 mg (69%) of a white solid product 3. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.16 (t, J = 6.9 Hz, 6H), 3.23 (s, 1H), 3.30 (s, 1H), 3.90 - 4.00 (m, 4H), 7.06 - 7.09 (m, 2H), 7.16 - 7.18 (m, 1H), 7.25 - 7.28 (m, 1H), 7.37 (t, J = 7.5 Hz, 1H), 8.64 (d, J = 4.8 Hz, 2H).

[0399] Step 4 - 15-Crown ether (5 μL, 0.02 mmol) was added to a solution of ester 3 (400 mg, 1.2 mmol) in THF (2.5 mL). The reaction was cooled (ice bath) and NaH (44 mg, 1.8 mmol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. A solution of tert-butyl 4-oxo-piperidine-1-carboxylate (250 mg, 1.2 mmol) in THF (2.5 mL) was added to the above reaction mixture at ice temperature and stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (10 ml), extracted with ethyl acetate (100 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 25% ethyl acetate) to give 360 mg (80%) of a white solid product 4.1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.41 (s, 9H), 2.28 (t, J = 5.4 Hz, 2H), 2.41 (t, J = 5.7 Hz, 2H), 3.33 - 3.41 (m, 4H), 6.38 (s, 1H), 7.03 - 7.13 (m, 3H), 7.26 (t, J = 4.8 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 8.65 (d, J = 4.8 Hz, 2H).

[0400] Step 5 - At ice temperature, trifluoroacetic acid (1.7 mL) was added to a solution of 4 (360 mg, 0.97 mmol) in dichloromethane (4.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. The crude product obtained after evaporation of the solvent was washed with diethyl ether to give a grayish-white solid product 5, 0.31 g (83%), which was carried on to the next step without further purification.

[0401] Step 6 - At 25 °C, diisopropylethylamine (0.5 mL, 3.1 mmol) and the product of Step 5, Example 1 (0.58 g, 2.4 mmol) were added to a solution of amine 5 (310 mg, 0.6 mmol) in dimethyl sulfoxide (4.0 mL). The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (100 ml), washed with water (3 × 50 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 60% ethyl acetate) to give 210 mg (77%) of a white solid product 6. Melting point: 52.7–57.6 °C. 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.04 - 1.06 (m, 1H), 1.14 - 1.20 (m, 1H), 1.85 - 1.88 (m, 1H), 2.27 (bs, 2H), 2.39 (bs, 2H), 2.70 - 2.71 (m, 1H), 3.32 - 3.39 (m, 4H), 6.37 (s, 1H), 6.85 (bs, 1H, CONH exchangeable 1 H), 7.03 - 7.15 (m, 6H), 7.22 - 7.28 (m, 3H), 7.39 (t, J = 7.8 Hz, 1H), 8.65 (d, J = 7.8 Hz, 2H). 13CNMR (75 MHz, DMSO-d6) δ (ppm): 16.03, 24.76, 29.37, 34.50, 36.10, 44.37, 45.41, 117.37, 119.95, 122.23, 123.49, 125.80, 126.00, 126.34, 128.54, 129.91, 139.19, 140.21, 142.44, 153.20, 158.05, 160.47 and 165.21. MS: 427 (M+H).

[0402] Example 7: Synthesis of methyl 4-{3-[1-(2-phenyl-cyclopropylcarbamoyl)-piperidin-4-ylidene-methyl]-phenoxy}-benzoate:

[0403]

[0404] Step 1 - At room temperature, cesium carbonate (26.2 g, 80.5 mmol) and ester 1 (7.5 g, 48.3 mmol) were added to a solution of 3-hydroxyphenyl-methanol 2 (5.0 g, 40.2 mmol) in DMF (50 mL). The reaction mixture was stirred at 100 °C for 5 h. Then the resulting reaction mixture was allowed to reach room temperature and filtered to remove cesium carbonate. The filtrate was diluted with water (200 ml), extracted with ethyl acetate (2 × 250 ml), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 30% ethyl acetate) to give a pale yellow oily product 3, 3.2 g (31%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 3.81 (s, 3H), 4.51 (d, J = 5.7 Hz, 2H), 5.28 (t, J = 5.7 Hz, 1H), 6.98 - 7.06 (m, 4H), 7.17 - 7.19 (m, 1H), 7.38 - 7.40 (m, 1H), 7.95 - 7.98 (m, 2H).

[0405] Step 2 - Thionyl chloride (1.7 mL, 14.8 mmol) was added dropwise to a solution of alcohol 3 (3.2 g, 12.3 mmol) in dichloromethane (50 mL) while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 h. The resulting reaction mixture was quenched with ice water (50 ml), extracted with ethyl acetate (250 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 5% ethyl acetate) to give a colorless oily product 4, 2.3 g (67%). 11H NMR (300 MHz, DMSO-d6) δ (ppm): 3.83 (s, 3H), 4.78 (s, 2H), 7.06 - 7.12 (m, 3H), 7.21 (bs, 1H), 7.30 - 7.33 (m, 1H), 7.44 - 7.49 (m, 1H), 7.98 (d, J = 8.7 Hz, 2H).

[0406] Step 3 - A solution of compound 4 (2.3 g, 7.9 mmol) in triethyl phosphite (2.3 mL, 11.9 mmol) was heated at 150 °C for 6 h. The reaction mixture was allowed to reach room temperature, and the crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 50% ethyl acetate) to give 3.5 g (91%) of product 5 as a pale yellow oil. 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.15 (t, J = 6.9 Hz, 6H), 3.23 (s, 1H), 3.30 (s, 1H), 3.83 (s, 3H), 3.89 - 3.99 (m, 4H), 7.00 - 7.06 (m, 4H), 7.15 - 7.17 (m, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.97 (d, J = 8.7 Hz, 2H).

[0407] Step 4 - 15-Crown-5 ether (40 μL, 0.18 mmol) was added to a solution of 5 (3.5 g, 9.2 mmol) in THF (20 mL). The reaction was cooled (ice bath) and NaH (560 mg, 13.8 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 30 min and cooled again to ice temperature. A solution of tert-butyl 4-oxopiperidine-1-carboxylate 6 (1.9 g, 9.2 mmol) in THF (15 mL) was added to the above reaction mixture at ice temperature and stirred at room temperature for 16 h. The resulting reaction mixture was quenched with saturated ammonium chloride (50 ml), extracted with ethyl acetate (500 ml) and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 10% ethyl acetate) to give 1.8 g (46%) of product 7 as a white solid. 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.40 (s, 9H), 2.27 - 2.40 (m, 4H), 3.40 - 3.60 (m, 4H), 3.83 (s, 3H), 6.37 (s, 1H), 6.94 - 6.99 (m, 2H), 7.05 - 7.12 (m, 3H), 7.39 - 7.41 (m, 1H), 7.98 (d, J = 8.7 Hz, 2H).

[0408] Step 5 - At ice temperature, trifluoroacetic acid (9.0 mL) was added to a solution of tert-butyl ester 7 (1.8 g, 4.2 mmol) in dichloromethane (18.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. The crude product obtained after evaporating the solvent was washed with n-hexane to give product 8 as a viscous black liquid, 1.5 g (83%). 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.63 - 2.72 (m, 4H), 3.16 - 3.28 (m, 4H), 3.91 (s, 3H), 6.49 (s, 1H), 6.86 (s, 1H), 6.95 - 7.02 (m, 4H), 7.36 (t, J = 8.1 Hz, 1H), 8.03 (t, J = 8.4 Hz, 2H).

[0409] Step 6 - At 25 °C, diisopropylethylamine (2.0 mL, 10.2 mmol) and the product of Step 5, Example 1 (0.86 g, 3.4 mmol) were added to a solution of amine 8 (1.5 g, 3.4 mmol) in dimethyl sulfoxide (15.0 mL). The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (250 ml), washed with water (2 × 100 ml), and dried over sodium sulfate. The crude product obtained after evaporating the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 25% ethyl acetate) to give product 9 as a white solid, 0.9 g (54%). Melting point: 48.5 - 53.2 °C. 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.10 - 1.20 (m, 2H), 1.88 (bs, 1H), 2.26 (bs, 2H), 2.37 (bs, 2H), 2.70 - 2.71 (m, 1H), 3.31 - 3.38 (m, 4H), 3.83 (s, 3H), 6.36 (s, 1H), 6.84 (bs, 1H, CONH exchangeable 1 H), 6.94 - 7.26 (m, 10H), 7.42 (t, J = 7.8 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H). 1313C NMR (75 MHz, DMSO-d6) δ (ppm): 16.02, 24.76, 29.40, 34.49, 36.07, 44.32, 45.38, 52.44, 117.81, 118.27, 120.49, 123.40, 124.51, 125.61, 125.79, 126.33, 128.53, 130.59, 132.02, 139.85, 140.45, 142.43, 155.40, 158.04, 161.73 and 166.11. MS: 483 (M+H).

[0410] Example 8: Synthesis of 4-{3-[1-(2-Phenyl-cyclopropylcarbamoyl)-piperidin-4-ylidene-methyl]-phenoxy}-benzoic acid:

[0411]

[0412] At 25 °C, an aqueous solution of sodium hydroxide (120 mg, 3.1 mmol) in water (2.0 mL) was added to a solution of the product from Step 6, Example 7 (0.5 g, 1.03 mmol) in methanol (3.0 mL). The reaction mixture was stirred at 55 °C for 16 h. The crude product obtained after evaporation of the solvent was diluted with water (20.0 ml), and the aqueous layer was washed with ethyl acetate (2 × 20 ml). The aqueous layer was then acidified (pH = 2, 1.0 N HCl), saturated with solid NaCl, and the product was extracted with ethyl acetate (2 × 150 ml). The combined organic layers were dried over sodium sulfate and concentrated to give 350 mg (72%) of a white solid product. Melting point: 99.4 - 102.5 °C. 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.15 - 1.29 (m, 2H), 1.88 (bs, 1H), 2.26 (bs, 2H), 2.37 (bs, 2H), 2.71 (bs, 1H), 3.32 - 3.38 (m, 4H), 6.36 (s, 1H), 6.84 (bs, 1H, CONH exchangeable 1 H), 6.93 - 7.44 (m, 11H), 7.95 (d, J = 8.4 Hz, 2H), 12.83 (bs, 1H). 1313C NMR (75 MHz, DMSO-d6) δ (ppm): 16.02, 24.75, 29.40, 34.51, 36.07, 44.31, 45.37, 117.76, 118.17, 120.38, 123.43, 125.47, 125.79, 126.32, 128.54, 130.57, 132.13, 139.81, 140.41, 144.44, 155.59, 158.03, 163.36 and 167.22. MS: 467 (M-H).

[0413] Example 9: Synthesis of 4-(3-pyrrolidin-1-yl-benzyl)-piperidine-1-carboxylic acid-(2-phenyl-cyclopropyl)-amide:

[0414]

[0415] Step 1 - A solution of 3-bromobenzyl bromide (6.0 g, 24.0 mmol) in triethyl phosphite (6.2 mL, 36.0 mmol) was heated at 130 °C for 16 h. The reaction mixture was cooled and brought to room temperature. The crude product obtained after evaporation of the volatiles was purified by column chromatography on silica gel (230 - 400) (petroleum ether solution of 30% ethyl acetate) to give 6.5 g (89%) of the product 2 as a colorless oil. 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.17 (t, J = 7.2 Hz, 6H), 3.24 (s, 1H), 3.31 (s, 1H), 3.91 - 4.01 (m, 4H), 7.28 - 7.29 (m, 2H), 7.43 - 7.50 (m, 2H). MS: 307.0 (M+) and 309.0 (M+2).

[0416] Step 2 - 15-Crown ether (0.04 mL, 0.19 mmol) was added to a solution of 2 (3.0 g, 9.7 mmol) in THF (20 mL). The reaction was cooled (ice bath) and NaH (0.58 g, 14.6 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 30 min and cooled again to ice temperature. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.95 g, 9.7 mmol) in THF (10 mL) was added to the above reaction mixture at ice temperature and the mixture was stirred at room temperature for 16 h. The resulting reaction mixture was diluted with water (100 ml), extracted with ethyl acetate (3 × 100 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by column chromatography on silica gel (230 - 400) (petroleum ether solution of 5% ethyl acetate) to give 1.8 g (53%) of the product 3 as a yellow oil. 11H NMR (300 MHz, DMSO-d6) δ (ppm): 1.41 (s, 9H), 2.28 (bs, 2H), 2.38 (bs, 2H), 3.34 - 3.41 (m, 4H), 6.36 (s, 1H), 7.25 - 7.30 (m, 2H), 7.41 - 7.43 (m, 2H). MS: 252.0 (M - BOC).

[0417] Step 3 - Under an argon atmosphere and at room temperature, pyrrolidine (0.9 mL, 10.6 mmol), cesium carbonate (7.0 g, 21.2 mmol), racemic BINAP (0.9 g, 1.4 mmol), and palladium acetate (0.95 g, 1.4 mmol) were added to a solution of compound 3 (2.0 g, 7.0 mmol) in 1,4-dioxane (20.0 mL). The reaction mixture was stirred at room temperature for 30 minutes and then under reflux for 16 hours. The resulting reaction mixture was filtered through a pad of diatomaceous earth and washed with ethyl acetate (250 mL). The ethyl acetate layer was washed with water (2 × 100 mL), dried over sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether solution of 15% ethyl acetate) to give 0.6 g (32%) of product 4 as a pale yellow oil. 1 1H NMR (300 MHz, CDCl3) δ (ppm): 1.49 (s, 9H), 2.01 (bs, 4H), 2.33 - 2.35 (m, 2H), 2.50 - 2.53 (m, 2H), 3.27 - 3.29 (m, 4H), 3.39 - 3.49 (m, 2H), 3.50 - 3.54 (m, 2H), 6.36 - 6.53 (m, 4H), 7.19 (t, J = 8.1 Hz, 1H). MS: 343.7 (M + H).

[0418] Step 4 - 10% Pd / C (240 mg) was added to a solution of compound 4 (0.6 g, 1.7 mmol) in tetrahydrofuran (10.0 mL). At room temperature, 2 under a hydrogen pressure of 1 kg / cm 11H NMR (300 MHz, DMSO-d6) δ (ppm): 1.10 - 1.21 (m, 2H), 1.49 (s, 9H), 1.64 - 1.72 (m, 3H), 1.98 - 2.03 (m, 4H), 2.49 (d, J = 6.9 Hz, 2H), 2.65 (t, J = 12.3 Hz, 2H). 3.27 - 3.31 (m, 2H), 4.07 - 4.15 (m, 2H), 6.35 (s, 1H), 6.42 - 6.47 (m, 2H), 7.14 (t, J = 7.8 Hz, 1H). MS: 345.7 (M + H).

[0419] Step 5 - At ice temperature, trifluoroacetic acid (3 mL) was added to a solution of compound 5 (0.6 g, 1.7 mmol) in dichloromethane (6.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. The brown oil 6 (0.6 g) obtained after evaporating the volatiles was used for the next step without further purification.

[0420] Step 6 - At 25 °C, N,N-diisopropylethylamine (1.1 mL, 5.8 mmol) and the product of Step 5, Example 1 (0.5 g, 1.9 mmol) were added to a solution of amine 6 (600 mg, 1.9 mmol) in dimethyl sulfoxide (6.0 mL). The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (500 ml), washed with water (3 × 100 ml), and dried over sodium sulfate. The crude product obtained after evaporating the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 40% ethyl acetate) and preparative HPLC (Phenomenex 250 × 22 1.20 mm, 10 μm, mobile phase solution of water and acetonitrile with 0.1% TFA) to give a pale yellow solid product 7, 160 mg (23%). Melting point: 145.6 °C – 151.5 °C. IR: 3334, 2842, 1620, 1600, 1545, 1252 and 752 cm -1 。 11H NMR: (300 MHz, DMSO-d6) δ (ppm): 0.95 - 1.19 (m, 3H), 1.13 - 1.17 (m, 1H), 1.50 - 1.55 (m, 2H), 1.63 - 1.66 (m, 1H), 1.81 - 1.87 (m, 1H), 1.93 (bs, 4H), 2.40 - 2.42 (m, 2H), 2.56 - 2.60 (m, 2H), 2.67 - 2.68 (m, 1H), 3.19 (bs, 4H), 3.90 (d, J = 12.9 Hz, 2H), 6.32 - 6.40 (m, 3H), 6.71 (bs, 1H), 7.02 - 7.15 (m, 4H), 7.21 - 7.26 (m, 2H). MS: 404.5 (M+H).

[0421] Example 10: Synthesis of 4-(3-Morpholin-4-yl-benzyl)-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0422]

[0423] Step 1 - Under an argon atmosphere and at room temperature, to a solution of the product of Step 2, Example 9 (1.5 g, 4.2 mmol) in 1,4-dioxane (15.0 mL) was added morpholine (0.45 mL, 5.1 mmol), cesium carbonate (4.1 g, 12.6 mmol), racemic BINAP (0.52 g, 0.84 mmol), and palladium acetate (0.56 g, 0.84 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then at reflux for 16 hours. The resulting reaction mass was cooled and filtered through a pad of diatomaceous earth, and washed with ethyl acetate (250 mL). The ethyl acetate layer was washed with water (2 × 100 ml), and the organic layer was dried over sodium sulfate and concentrated. The crude product obtained was purified by silica gel column chromatography (petroleum ether solution of 15% ethyl acetate) to give 0.35 g of a crude product 2 as a pale yellow oil.

[0424] Step 2 - To a solution of compound 2 (0.85 g, 2.37 mmol) in tetrahydrofuran (10.0 mL) was added 10% Pd / C (350 mg). The reaction mass was stirred at room temperature under a hydrogen pressure (1 kg / cm 2 ) for 2 hours. After releasing the hydrogen pressure, the reaction mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated to give a pale yellow liquid product 3 (0.8 g). The product was carried on to the next step without further purification.

[0425] Step 3 - At ice temperature, trifluoroacetic acid (4 mL) was added to a solution of crude compound 3 (0.8 g, 2.2 mmol) in dichloromethane (8.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. The brown oil 4 (0.8 g) obtained after evaporating the volatiles was carried on to the next step without further purification.

[0426] At 25 °C, diisopropylethylamine (1.3 mL, 7.0 mmol) and the product of Step 5, Example 1 (0.6 g, 2.3 mmol) were added to a solution of amine 4 (800 mg, 2.3 mmol) in dimethyl sulfoxide (8.0 mL). The reaction mixture was stirred at 60 °C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3 × 100 mL), and dried over sodium sulfate. The crude product obtained after evaporating the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 50% ethyl acetate) to give 420 mg of a light yellow solid product 5. Melting point: 182.3 °C - 186.0 °C. IR: 3330, 2841, 1620, 1600, 1545, 1247 and 756 cm -1 。 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 0.95 - 1.08 (m, 3H), 1.11 - 1.18 (m, 1H), 1.49 - 1.53 (m, 2H), 1.61 - 1.67 (m, 1H), 1.85 - 1.88 (m, 1H), 2.43 - 2.61 (m, 4H), 2.67 - 2.68 (m, 1H), 3.08 (t, J = 4.5 Hz, 4H), 3.74 (t, J = 4.5 Hz, 4H), 3.90 (d, J = 12.6 Hz, 2H), 6.61 (d, J = 7.2 Hz, 1H), 6.70 - 6.76 (m, 3H, one 1 H is D2O exchangeable), 7.07 - 7.15 (m, 4H), 7.22 - 7.27 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) δ (ppm): 16.01, 24.75, 32.08, 34.56, 37.96, 43.17, 43.98, 49.00, 66.61, 113.09, 116.43, 120.52, 125.77, 126.29, 128.53, 129.12, 141.31, 142.51, 151.50, 158.28. MS: 420.2 (M + H).

[0427] Example 11: Synthesis of 4-[3-(pyridin-2-yloxy)-phenoxy]-piperidine-1-carboxylic acid (2-phenylcyclopropyl)-amide:

[0428]

[0429] Step 1 - To a solution of 1,3-dihydroxybenzene (1.0 g, 9.0 mmol) in DMF (10.0 mL) was added Cs2CO3 (5.92 g, 18.0 mmol) and 2-fluoropyridine (0.8 mL, 9.0 mmol). The reaction mixture was heated to 100 °C for 16 h. Then the resulting mixture was allowed to reach room temperature, diluted with water (250 ml), extracted with ethyl acetate (3 × 500 ml), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 10% ethyl acetate) to give a pale yellow oily product 3, 400 mg (23%). 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 6.20 (s, 1H), 6.48 - 6.53 (m, 1H), 6.61 (d, J = 8.1 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 7.11 - 7.21 (m, 2H), 7.84 (t, J = 8.1 Hz, 1H), 8.18 (bs, 1H), 9.61 (s, 1H, D2O-exchangeable 1 H). MS: 187.9 (M + H).

[0430] Step 2 - At room temperature, Cs2CO3 (1.4 g, 4.2 mmol) was added to a solution of compound 3 (400 mg, 2.14 mmol) in DMF (8.0 mL). The reaction mixture was stirred for 5 min, then a solution of compound 4 (600 mg, 2.14 mmol) in DMF (2.0 mL) was added to the reaction mixture at room temperature, and the reaction mixture was stirred at 65 °C for 8 h. The reaction mixture was diluted with ethyl acetate (300 ml), washed with water (3 × 50 ml), and the ethyl acetate layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 50% ethyl acetate) to give a pale yellow oily product 5, 540 mg (67%). 11H NMR (300 MHz, DMSO-d6) δ (ppm): 1.40 (s, 9H), 1.48 - 1.51 (m, 2H), 1.89 - 1.92 (m, 2H), 3.14 - 3.16 (m, 2H), 3.63 - 3.68 (m, 2H), 4.56 - 4.58 (m, 1H), 6.65 - 6.68 (m, 1H), 6.75 (s, 1H), 6.80 - 6.84 (m, 1H), 6.99 - 7.02 (m, 1H), 7.14 (d, J = 5.1 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.85 (t, J = 7.5 Hz, 1H), 8.17 (d, J = 5.1 Hz, 1H). MS: 371.4 (M+H).

[0431] Step 3 - Under cryogenic temperature, trifluoroacetic acid (2.0 mL) was added to a solution of compound 5 (0.4 g, 0.8 mmol) in dichloromethane (8.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. The brown oil 6 obtained after evaporating the volatiles was used for the next step without further purification.

[0432] At 25 °C, diisopropylethylamine (0.67 mL, 3.9 mmol) and the product of Step 5, Example 1 (198 mg, 0.78 mmol) were added to a solution of amine 6 (390 mg, 0.78 mmol) in dimethyl sulfoxide (5.0 mL). The reaction mixture was stirred at 60 °C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (250 mL), washed with water (3 × 10 mL), and dried over sodium sulfate. The crude product obtained after evaporating the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 70% ethyl acetate) to obtain an off-white low melting point solid product. The obtained product was further purified by preparative HPLC to obtain product 7 as an off-white low melting point solid, 200 mg. Melting point: 43.9 °C–46.8 °C. IR: 3313, 1621, 1586, 1423 and 1235 cm -1 . 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.07 - 1.09 (m, 1H), 1.14 - 1.18 (m, 1H), 1.46 - 1.49 (m, 2H), 1.86 (bs, 3H), 2.68 - 2.69 (m, 1H), 3.08 (t, J = 9.6 Hz, 2H), 3.64 - 3.68 (m, 2H), 4.53 (bs, 1H), 6.64 - 6.67 (m, 1H), 6.74 (bs, 1H), 6.80 (bs, 1H), 6.83 (bs, 1H, D2O exchangeable 1H), 7.00 (d, J = 8.0 Hz, 1H), 7.08 - 7.14 (m, 4H), 7.21 - 7.31 (m, 3H), 8.82 (t, J = 7.2 Hz, 2H), 8.16 (d, J = 5.1 Hz, 1H). MS: 430.4 (M + H).

[0433] Example 12: Synthesis of 4-[3-(1H-pyrazol-4-yl)-benzyl]-piperidine-1-carboxylic acid (-2-phenylcyclopropyl)-amide:

[0434]

[0435] Step 1 - To a cooled (0 - 5 °C) solution of Compound 1 (2.0 g, 10.3 mmol, Sigma Aldrich) in dimethylformamide (20.0 mL) was added 4-dimethylaminopyridine (0.25 g, 2.0 mmol) and di-tert-butyl dicarbonate (3.0 mL, 15.4 mmol). The resulting reaction mixture was stirred at room temperature for 12 hours. The reaction was quenched with water (50.0 ml) and extracted with ethyl acetate (200 ml). The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (petroleum ether solution of 15% ethyl acetate) to give the off-white solid product 2, 1.25 g (40%). 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.27 (s, 12H), 1.58 (s, 9H), 7.87 (s, 1H), 8.37 (s, 1H). MS: 195.3 (M - BOC + H).

[0436] Step 2 - At room temperature, to a solution of the compound product (1.0 g, 2.8 mmol) from Step 2, Example 9 in DMF (10 mL) was added Compound 2 (1.9 g, 5.6 mmol) and 2N sodium carbonate solution (4.3 mL, 8.5 mmol). The reaction mixture was stirred under an argon atmosphere for 10 minutes. Then, under argon, tetrakis(triphenylphosphine)palladium(0) (0.33 g, 0.28 mmol) was added to the reaction mixture. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 ml) and extracted with ethyl acetate (500 ml), 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 after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography (petroleum ether solution of 40% ethyl acetate) to give the off-white solid product 3, 550 mg (57%). 11H NMR (300 MHz, DMSO-d6) δ (ppm): 1.42 (s, 9H), 2.28 - 2.31 (m, 2H), 2.42 - 2.44 (m, 2H), 3.34 - 3.44 (m, 4H), 6.39 (s, 1H), 7.03 (d, J = 7.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.44 - 7.47 (m, 2H), 7.92 (s, 1H), 8.19 (s, 1H), 12.94 (s, 1H). MS: 338.1 (M-H).

[0437] Step 3 - To a solution of compound 3 (0.5 g, 1.4 mmol) in chloroform (10.0 mL) containing 20% methanol was added 10% Pd / C (200 mg). The reaction mixture was stirred at room temperature under a hydrogen pressure (1 kg / cm 2 ) for 24 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated to give a pale yellow liquid product 4 (0.5 g). The crude product was used in the next step without further purification.

[0438] Step 4 - At ice temperature, trifluoroacetic acid (2.5 mL) was added to a solution of compound 4 (0.5 g, 1.6 mmol) in dichloromethane (5.0 mL), and the reaction mixture was stirred at room temperature for 1 h. The brown oil 5 (0.5 g) obtained after evaporation of the volatiles was used in the next step without additional purification.

[0439] Step 5 - At 25 °C, N,N-diisopropylethylamine (0.8 mL, 4.2 mmol) and the product of Step 5, Example 1 (270 mg, 1.0 mmol) were added to a solution of amine 5 (500 mg, 1.0 mmol) in dimethyl sulfoxide (5.0 mL). The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (500 ml), washed with water (3 × 100 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (chloroform solution containing 3% methanol) to give product 6 as an off-white solid, 210 mg. Melting point: 157.4 °C – 163.4 °C. IR: 3330, 1619, 1545, 1475 and 753 cm -1 . 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.01 - 1.17 (m, 4H), 1.51 - 1.55 (m, 2H), 1.82 (bs, 1H), 1.83 - 1.85 (m, 1H), 2.54 - 2.68 (m, 5H), 3.90 (d, J = 12.6 Hz, 2H), 6.71 (d, J = 2.7 Hz, 1H, exchangeable with D2O 1H), 6.98 (d, J = 7.5 Hz, 1H), 7.07 - 7.15 (m, 3H), 7.21 - 7.27 (m, 3H), 7.41 - 7.43 (m, 2H), 7.90 (s, 1H), 8.17 (s, 1H), 12.91 (s, 1H, exchangeable with D2O 1 H). 13 C NMR (75 MHz, DMSO-d6) δ (ppm): 16.00, 24.74, 32.06, 34.53, 37.88, 42.81, 43.98, 121.69, 123.17, 125.77, 126.31, 127.05, 128.52, 128.99, 133.22, 141.06, 142.50, 158.22. MS: 401.3 (M + H).

[0440] Example 13: Synthesis of 4-[3-(1-methyl-1H-pyrazol-4-yl)-benzyl]-piperidine-1-carboxylic acid (2-phenylcyclopropyl)-amide:

[0441]

[0442] Step 1 - Sodium hydride (0.25 g, 6.1 mmol) and methyl iodide (0.4 mL, 6.1 mmol) were added to a cooled (0 - 5 °C) solution of the product from Step 2, Example 12 (0.7 g, 2.0 mmol) in THF (25 mL). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (100 ml) and extracted with ethyl acetate (500 ml). The organic layer was washed with water (2 × 250 ml) and brine (100 ml). The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether solution of 20% ethyl acetate) to give Product 1 as an off-white solid, 600 mg (83%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.45 (s, 9H), 2.30 - 2.31 (m, 2H), 2.42 - 2.44 (m, 2H), 3.35 - 3.44 (m, 4H), 3.89 (s, 3H), 6.39 (s, 1H), 7.02 - 7.05 (m, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.39 - 7.43 (m, 2H), 7.85 (s, 1H), 8.14 (s, 1H). MS: 298.0 (M - t-butyl + H).

[0443] Step 2 - To a solution of Compound 1 (0.6 g, 1.7 mmol) in chloroform (10.0 mL) containing 20% methanol was added 10% Pd / C (240 mg). At room temperature, under a hydrogen pressure (1 kg / cm 2 ), the reaction mixture was stirred for 16 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated to give Product 2 as a pale yellow liquid (0.6 g, 98%). The product obtained was carried on to the next step without further purification. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.02 - 1.09 (m, 2H), 1.38 (s, 9H), 1.54 - 1.58 (m, 2H), 1.68 - 1.70 (m, 1H), 2.50 - 2.52 (m, 1H), 2.62 - 2.73 (m, 2H), 3.85 - 3.93 (m, 2H), 3.89 (s, 3H), 6.98 (d, J = 7.2 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 7.36 (s, 2H), 7.83 (s, 1H), 8.11 (s, 1H). MS: 300.2 (M-t-butyl + H).

[0444] Step 3 - At ice temperature, trifluoroacetic acid (3.0 mL) was added to a solution of Compound 2 (0.6 g, 1.6 mmol) in dichloromethane (6.0 mL), and the reaction mixture was stirred at room temperature for 1 h. The brown oil 3 (0.6 g) obtained after evaporation of the volatiles was used for the next step without additional purification.

[0445] Step 4 - At 25 °C, diisopropylethylamine (1.2 mL, 6.4 mmol) and the product of Step 5, Example 1 (370 mg, 1.4 mmol) were added to a solution of Amine 3 (600 mg, 1.6 mmol) in dimethyl sulfoxide (6.0 mL). The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (500 ml), washed with water (3 × 100 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (chloroform solution containing 3% methanol) to give the off-white solid Product 4, 350 mg (53%). Melting point: 158.4 °C – 160.3 °C. IR: 3353, 1619, 1544, 1473 and 752 cm -1 . 11H NMR (300 MHz, DMSO-d6) δ (ppm): 1.01 - 1.15 (m, 4H), 1.51 - 1.55 (m, 2H), 1.82 - 1.83 (m, 1H), 1.84 - 1.86 (m, 1H), 2.57 - 2.68 (m, 4H), 3.34 - 3.37 (m, 1H), 3.85 (s, 3H), 3.90 (d, J = 13.2 Hz, 2H), 6.71 (d, J = 2.7 Hz, 1H, exchangeable with D2O 1 H), 6.98 (d, J = 7.5 Hz, 1H), 7.07 - 7.15 (m, 3H), 7.21 - 7.27 (m, 3H), 7.36 - 7.38 (m, 2H), 7.83 (s, 1H), 8.11 (s, 1H). 13 13C NMR (75 MHz, DMSO-d6) δ (ppm): 16.00, 24.74, 32.05, 34.53, 37.89, 42.79, 43.99, 122.44, 122.97, 125.77, 126.10, 126.31, 127.15, 128.19, 128.52, 129.05, 132.91, 136.43, 141.11, 142.50, 158.21. MS: 415.0 (M + H).

[0446] Example 14: Synthesis of 4-(3-benzimidazol-1-yl-benzyl)-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0447]

[0448] Step 1 - A solution of compound 1 (5.0 g, 23.14 mmol) in triethyl phosphite (5.9 mL, 37.7 mmol) was heated at 130 °C for 16 h. The reaction mixture was cooled to room temperature, and the crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 50% ethyl acetate) to give product 2 as a light yellow oil, 4.9 g (89%). 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.09 - 1.21 (m, 6H), 3.44 (s, 1H), 3.51 (s, 1H), 3.93 - 4.07 (m, 4H), 7.60 - 7.66 (m, 1H), 7.73 - 7.76 (m, 1H), 8.11 - 8.14 (m, 1H), 8.19 (s, 1H). MS: 274.1 (M + 1).

[0449] Step 2 - Add 15-crown ether (0.08 mL, 0.04 mmol) to a solution of compound 2 (4.9 g, 20.3 mmol) in THF (50 mL). Cool the reaction (ice bath) and add NaH (1.22 g, 30.5 mmol) portionwise. Stir the reaction mixture at room temperature for 30 minutes and cool it again to ice temperature. Add a solution of tert-butyl 4-oxopiperidine-1-carboxylate (4.05 g, 20.3 mmol) in THF (10 mL) to the above reaction mixture at ice temperature and stir at room temperature for 4 hours. Dilute the resulting reaction mixture with water (100 ml), extract with ethyl acetate (3 × 250 ml), and dry over sodium sulfate. The crude product obtained after evaporation of the volatiles is purified by silica gel (230 - 400) column (petroleum ether solution of 5% ethyl acetate) to give 4.0 g (62%) of product 3 as a yellow oil. 1 HNMR(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(M-t-Butyl+1).

[0450] Step 3 - Add 10% Pd / C (3.0 g) to a solution of compound 3 (4.0 g, 12.5 mmol) in dichloromethane (40.0 mL) with 90% methanol. Stir the reaction material at room temperature under hydrogen pressure (1 kg / cm 2 ) for 20 hours. Filter the reaction material through a diatomaceous earth pad and concentrate the filtrate to give product 4 as a light yellow liquid (1.5 g, 41%). The product is carried on to the next step without further purification. 1 H 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),2.60-2.72(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).

[0451] Step 4 - At room temperature, Cs2CO3 (8.9 g, 25.7 mmol) was added to a solution of compound 4 (1.5 g, 3.4 mmol) in DMF (8.0 mL). The reaction mixture was stirred for 5 minutes, and then a solution of 1-fluoro-2-nitrobenzene (0.8 g, 3.7 mmol) in DMF (2.0 mL) was added to the reaction mixture at room temperature. The mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with water (3 × 100 mL). The ethyl acetate layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 7% ethyl acetate) to give product 5 as a red-yellow oil, 500 mg (35%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 0.97 - 1.08 (m, 2H), 1.38 (s, 9H), 1.54 - 1.58 (m, 2H), 1.65 - 1.68 (m, 1H), 2.40 - 2.52 (m, 2H), 2.64 - 2.73 (m, 2H), 3.91 (d, J = 12.9 Hz, 2H), 6.87 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 7.13 - 7.20 (m, 3H), 7.30 - 7.35 (m, 1H), 7.50 (t, J = 6.6 Hz, 1H), 8.11 (d, J = 7.5 Hz, 1H), 9.35 (s, 1H). MS: 410.0 (M - H).

[0452] Step 5 - At room temperature of 25 °C, sodium formate (290 mg, 4.3 mmol) and Pd / C (10 mol%, 120 mg, 0.01 mmol) were added to a solution of compound 5 (500 mg, 1.2 mmol) in formic acid (10 mL). Then the reaction mixture was stirred at 110 °C for 18 hours. The reaction mixture was cooled to room temperature and then filtered through diatomaceous earth with the help of 20 ml formic acid. The crude product obtained after evaporation of the volatiles was dissolved in dichloromethane (50 ml) with 5% methanol, and the inorganic salts were filtered off. The filtrate was concentrated to give product 6 as an off-white solid (350 mg). The crude product was sent directly to the next step without purification.

[0453] Step 6 - At 25 °C, add diisopropylethylamine (1.03 mL, 6.0 mmol) and the product of Step 5, Example 1 (186 mg, 1.2 mmol) to a solution of amine 6 (350 mg, 1.2 mmol) in dimethyl sulfoxide (5.0 mL). Stir the reaction mixture at 60 °C for 6 h. Dilute the resulting reaction mixture with ethyl acetate (300 ml), wash with water (3 × 50 ml), and dry over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (dichloromethane solution of 1.5% methanol) to give product 7 as an off-white solid, 170 mg (31%). Melting point: 72.5 °C – 76.4 °C. IR: 3347, 2931, 16161, 1542 and 742 cm -1 . 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.00 - 1.14 (m, 4H), 1.54 - 1.57 (m, 2H), 1.71 - 1.79 (m, 1H), 1.80 - 1.84 (m, 1H), 2.48 - 2.65 (m, 5H), 3.92 (d, J = 12.9 Hz, 2H), 6.72 (d, J = 2.7 Hz, 1H, D2O exchangeable 1 H), 7.07 - 7.15 (m, 3H), 7.21 - 7.26 (m, 3H), 7.30 - 7.35 (m, 3H), 7.50 - 7.54 (m, 3H), 7.60 - 7.62 (m, 1H), 7.77 - 7.79 (m, 1H), 8.55 (s, 1H). MS: 451.0 (M+H).

[0454] Example 15: Synthesis of 4-(3-pyrrolidin-1-yl-benzylidene)-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0455]

[0456] Step 1 - Under an argon atmosphere and at room temperature, pyrrolidine (0.9 mL, 10.6 mmol), cesium carbonate (7.0 g, 21.2 mmol), racemic BINAP (0.9 g, 1.4 mmol), and palladium acetate (0.95 g, 1.4 mmol) were added to a solution of the product of Step 2, Example 9 (2.0 g, 7.0 mmol) in 1,4 - dioxane (20.0 mL). The reaction mixture was stirred at room temperature for 30 minutes and then under reflux for 16 hours. The resulting reaction mass was filtered through a celite pad and washed with ethyl acetate (250 mL). The ethyl acetate layer was washed with water (2 × 100 mL), dried over sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether solution of 15% ethyl acetate) to obtain the product 2 as a pale yellow oil, 0.6 g (32%). 1 1H NMR (300 MHz, CDCl3) δ (ppm): 1.49 (s, 9H), 2.01 (bs, 4H), 2.33 - 2.35 (m, 2H), 2.50 - 2.53 (m, 2H), 3.27 - 3.29 (m, 4H), 3.39 - 3.49 (m, 2H), 3.50 - 3.54 (m, 2H), 6.36 - 6.53 (m, 4H), 7.19 (t, J = 8.1 Hz, 1H). MS: 343.7 (M + 1).

[0457] Step 2 - At ice - temperature, trifluoroacetic acid (3 mL) was added to a solution of compound 2 (0.6 g, 1.7 mmol) in dichloromethane (6.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. The brown oil 3 (0.6 g) obtained after evaporating the volatiles was used for the next step without further purification.

[0458] Step 3 - At 25 °C, diisopropylethylamine (1.1 mL, 5.8 mmol) and the product of Step 5, Example 1 (0.5 g, 1.9 mmol) were added to a solution of amine 3 (600 mg, 1.9 mmol) in dimethyl sulfoxide (6.0 mL). The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3 × 100 mL), and dried over sodium sulfate. The crude product obtained after evaporating the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 40% ethyl acetate) to obtain the product 4 as an off - white solid, 300 mg (42%). Melting point: 145.7 °C – 147.4 °C. IR: 3292, 2963, 1626, 1533, 1263, and 746 cm -1 . 11H NMR (300 MHz, CDCl3) δ (ppm): 1.22 - 1.26 (m, 2H), 2.02 (bs, 5H), 2.38 - 2.41 (m, 2H), 2.56 - 2.59 (m, 2H), 2.88 (bs, 1H), 3.30 (bs, 4H), 3.36 - 3.40 (m, 2H), 3.47 - 3.51 (m, 2H), 4.87 (bs, 1H, exchangeable with D2O 1 H), 6.38 - 6.52 (m, 3H), 7.19 - 7.46 (m, 7H). 13 13C NMR (75 MHz, CDCl3) δ (ppm): 16.01, 24.75, 32.08, 34.56, 37.96, 43.17, 43.98, 49.00, 66.61, 113.09, 116.43, 120.52, 125.77, 126.29, 128.53, 129.12, 141.31, 142.51, 151.50, 158.28. MS: 402.7 (M + H).

[0459] Example 16: Synthesis of phenyl N - [(1R,2S) - 2 - phenylcyclopropyl]carbamate:

[0460]

[0461] The above - mentioned chiral intermediate was synthesized using the conventional method described in the literature (WO 2013 / 057322).

[0462] Step 1 - At 0 - 5 °C, saturated sodium bicarbonate solution was added to a suspension of trans - 2 - phenyl - cyclopropylamine hydrochloride (100 g, 0.59 mol) in water (500 mL) within 20 minutes, and the mixture was alkalized to pH > 7. The reaction mixture was stirred at 25 - 30 °C for 2 hours. The reaction mixture was extracted with dichloromethane (3 × 700 ml), and the separated organic phase was dried over sodium sulfate and concentrated to give 2 - phenyl - cyclopropylamine as an off - white solid 2 (71.2 g, 92%).

[0463] Step 2 - At 0 - 5 °C, L(+)-tartaric acid (79 g, 0.52 mol) was added to a solution of trans-2-phenyl-cyclopropylamine (70 g, 0.52 mol) in ethanol (700 mL), and the mixture was stirred at 25 - 30 °C for 1 h. After completion of the reaction, the solid was filtered and dried to obtain 2-phenyl-cyclopropylamine in the form of tartrate (133 g). Isopropanol: water (3:1) (1.3 L) was added to the above salt (130 g), and the mixture was stirred at 70 °C for 2 h. The reaction mixture was cooled to room temperature within 1 h. The separated solid was collected by filtration to obtain the white solid (1R,2S)-N-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-2-phenylcyclopropan-1-ammonium (3) (60 g, 90%).

[0464] Step 3 - At 0 - 5 °C, 1.0 M sodium hydroxide (194 mL, 0.19 mol) was added to a solution of (1R,2S)-N-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-2-phenylcyclopropane-1-ammonium (3) (60 g, 0.19 mol) in water (200 mL) over 20 min, and the mixture was stirred for 1 h. The aqueous phase was extracted with ethyl acetate (2 × 700 ml). The combined extracts were washed with water (2 × 400 ml), brine (400 ml), dried over sodium sulfate and concentrated under reduced pressure to obtain (1R,2S)-2-phenyl-cyclopropylamine as a pale yellow solid 4 (25 g, 87%).

[0465] Step 4 - At ice bath temperature, triethylamine (36.0 mL, 0.26 mol) and phenyl chloroformate (20.7 g, 0.13 mol) were added to a suspension of amine 4 (15.0 g, 88.0 mmol) in dichloromethane (150 mL). Then the ice bath was removed, and the reaction mixture was stirred at room temperature for 1 h. The resulting reaction mixture was diluted with ethyl acetate (1.0 L), washed with water (2 × 200 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 10% ethyl acetate) to obtain 16.0 g (71%) of white solid product 5. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 1.15 - 1.25 (m, 2H), 2.04 - 2.08 (m, 1H), 2.72 - 2.75 (m, 1H), 7.10 - 7.40 (m, 10H), 8.17 (bs, 1H). MS (M + H) 254.3.

[0466] Step 5 - At 0 - 5 °C, 2.0 M HCl in diethyl ether solution (140 mL, 0.28 mol) was added to a stirred solution of (1R,2S)-2-phenyl-cyclopropylamine 4 (25.0 g, 0.19 mol) in diethyl ether (150 mL). The reaction mixture was stirred at 20 - 25 °C for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting reaction mass was washed with diethyl ether (2 × 100 ml) to give the product 6, the hydrochloride salt of (1R,2S)-2-phenyl-cyclopropylamine, as an off-white solid, 30.0 g (95%). Melting point: 179.2 - 180.1 °C; IR: 3643, 3054, 1979, 1501, 1160, 799, 743, 696 cm -1 . 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 1.14 - 1.19 (m, 1H), 1.43–1.48 (m, 1H), 2.38 - 2.43 (m, 1H), 2.72 - 2.76 (m, 1H), 7.09 - 7.24 (m, 3H), 7.22 - 7.33 (m, 2H), 8.81 (bs, 3H). MS (M+H) 134.3. Chiral HPLC purity: 100%. The chirality of 6 was further confirmed by matching the analytical and spectral data with an authentic sample of (1R,2S)-2-phenylcyclopropylamine hydrochloride purchased from Sigma-Aldrich.

[0467] Example 17: Synthesis of 4-[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid [(1S,2R)-2-phenyl-cyclopropyl]-amide:

[0468]

[0469] Step 1 - At ice-bath temperature, triethylamine (1.21 mL, 8.85 mmol) and phenyl chloroformate 1 (0.41 mL, 3.3 mmol) were added to a suspension of (1S,2R)-2-phenylcyclopropan-1-amine 2 (500 mg, 2.95 mmol) in dichloromethane (5.0 mL). Then the ice-bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was diluted with ethyl acetate (1.0 L), washed with water (2 × 200 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 10% ethyl acetate) to give 500 mg (71%) of the white solid product 3. 11H NMR (400 MHz, DMSO-d6) δ (ppm): 1.19 - 1.26 (m, 2H), 2.05 - 2.08 (m, 1H), 2.72 - 2.75 (m, 1H), 7.11 - 7.38 (m, 10H), 8.18 (bs, 1H). MS (M+H) 254.5.

[0470] Step 2 - At 25 °C, diisopropylethylamine (1.2 mL, 6.6 mmol) and 3 (556 mg, 2.2 mmol) were added to a solution of the product of Step 5, Example 3 (1.0 g, 2.2 mmol) in dimethyl sulfoxide (10 mL). The reaction mixture was stirred at 60 °C for 4 h. The resulting reaction mixture was diluted with ethyl acetate (300 ml), washed with water (3 × 100 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 40% ethyl acetate) to give 770 mg (70%) of the white solid product 4. Melting point: 100.2 °C - 101.0 °C. IR: 3329, 1622, 1531, 1487, 1329, 1076 cm -1 . 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.08 - 1.18 (m, 2H), 1.85 - 1.90 (m, 1H), 2.27 (t, J = 5.6 Hz, 2H), 2.40 (t, J = 5.2 Hz, 2H), 2.69 - 2.72 (m, 1H), 3.32 (t, J = 6.0 Hz, 2H), 3.38 (t, J = 6.0 Hz, 1H), 6.37 (s, 1H), 6.85 (d, J = 3.2 Hz, 1H), 7.04 - 7.41 (m, 10H), 8.22 - 8.25 (m, 1H), 8.58 (bs, 1H). MS: 494.3 (M+H). HPLC purity: 99.78%. Chiral HPLC purity: 100%.

[0471] Example 18: Synthesis of 4-[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid [(1R,2S)-2-phenyl-cyclopropyl)]-amide:

[0472]

[0473] Step 1 - At an ice bath temperature, add triethylamine (1.21 mL, 8.85 mmol) and phenyl chloroformate 1 (0.41 mL, 3.3 mmol) to a suspension of (1R,2S)-2-phenyl-cyclopropylamine 2 (500 mg, 2.95 mmol) in dichloromethane (5.0 mL). Then remove the ice bath and stir the reaction mixture at room temperature for 1 hour. The resulting reaction mixture is diluted with ethyl acetate (250 ml), washed with water (2 × 100 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles is purified by silica gel (230 - 400) column (petroleum ether solution of 10% ethyl acetate) to obtain 495 mg (70%) of the white solid product 3. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.15 - 1.25 (m, 2H), 2.04 - 2.08 (m, 1H), 2.72 - 2.75 (m, 1H), 7.10 - 7.40 (m, 10H), 8.17 (bs, 1H). MS (M+H) 254.3.

[0474] Step 2 - At 25 °C, add diisopropylethylamine (1.2 mL, 6.6 mmol) and 3 (556 mg, 2.2 mmol) to a solution of the product of Step 5, Example 3 (1.0 g, 2.2 mmol) in dimethyl sulfoxide (10 mL). Stir the reaction mixture at 60 °C for 4 h. The resulting reaction mixture is diluted with ethyl acetate (300 ml), washed with water (3 × 100 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles is purified by silica gel (230 - 400) column (petroleum ether solution of 40% ethyl acetate) to obtain 715 mg (65%) of the white solid product 4. Melting point: 101.8 °C - 103.2 °C. IR: 3329, 1623, 1531, 1388, 1329, 1076, 697 cm -1 。 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.07 - 1.18 (m, 2H), 1.85 - 1.90 (m, 1H), 2.25–2.40 (m, 4H), 2.67–2.75 (m, 2H), 2.69 - 2.72 (m, 1H), 3.31 (t, J = 6.0 Hz, 2H), 3.38 (t, J = 5.6 Hz, 1H), 6.36 (s, 1H), 6.85 (s, 1H), 7.04 - 7.15 (m, 6H), 7.22 - 7.41 (m, 4H), 8.22 - 8.24 (m, 1H), 8.58 (bs, 1H). MS: 494.3 (M+H). HPLC purity: 99.96%. Chiral HPLC purity: 100%.

[0475] Example 19: Synthesis of 4-({3-[(5-methylpyridin-2-yl)oxy]phenyl}methylene)-N-[2-phenylcyclopropyl]piperidine-1-carboxamide:

[0476]

[0477] Step 1 - At room temperature, 3-hydroxybenzyl alcohol (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). The reaction mixture was stirred at 100 °C for 5 h. The resulting mixture was then cooled to room temperature, diluted with water (250 ml), extracted with ethyl acetate (3 × 500 ml), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by column chromatography on silica gel (230 - 400) (petroleum ether solution of 30% ethyl acetate) to give the product 2 as a pale yellow oil, 6.0 g (23%). 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.25 (s, 3H), 4.40 (d, J = 6.0 Hz, 2H), 5.22 (t, J = 6.0 Hz, 1H), 6.91 - 6.94 (m, 2H), 7.01 (s, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.66–7.69 (m, 1H), 7.98 (d, J = 2.1 Hz, 1H). MS: (M+H) 216.2.

[0478] Step 2 - Thionyl chloride (2.3 mL, 0.03 mol) was added dropwise to a solution of [3-(5-methylpyridin-2-yloxy)phenyl]methanol 2 (6.0 g, 0.027 mol) in dichloromethane (60 mL) while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 h. Then the volatiles were evaporated under reduced pressure and the residue was diluted with toluene (25 ml), and toluene was evaporated under reduced pressure. This azeotropic process was repeated 3 times to give the product 3 as a light brown oil (6.2 g, 95%). 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.25 (s, 3H), 4.76 (s, 2H), 6.95–6.98 (m, 2H), 7.15–7.26 (m, 2H), 7.38–7.40 (m, 1H), 7.66–7.69 (m, 1H), 7.99–8.0 (m, 1H). MS: (M+H) 234.3.

[0479] Step 3 - A solution of 2-(3-chloromethyl-phenoxy)-5-methyl-pyridine (6.2 g, 0.026 mol) in triethyl phosphite (7.3 mL, 0.042 mol) was heated at 150 °C for 6 hours. The reaction mixture was allowed to reach room temperature, and the volatile components were evaporated. The crude product obtained was purified by silica gel (230 - 400) column (petroleum ether solution of 60% ethyl acetate) to give 8.3 g of a light yellow oily product 4. The product contained unreacted triethyl phosphate and was used for the next step without further purification. 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.13–1.23 (m, 6H), 2.25 (s, 3H), 3.20–3.27 (m, 2H), 3.89–3.99 (m, 4H), 6.91 - 6.99 (m, 3H), 7.09 (d, J = 7.4 Hz, 1H), 7.32 (t, J = 8.1 Hz, 1H), 7.66–7.69 (m, 1H), 7.98–8.32 (m, 1H). MS: (M+H) 336.1.

[0480] Step 4 - 15-Crown ether (0.1 g, 0.48 mmol) was added to a solution of diethyl [3-(5-methyl-pyridin-2-yloxy)-benzyl]-phosphonate 4 (8.3 g, 0.024 mol) in THF (40 mL). The reaction was cooled (ice bath) and NaH (1.44 g, 0.036 mol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. A solution of tert-butyl 4-oxo-piperidine-1-carboxylate (4.9 g, 0.024 mol) in THF (40 ml) was added to the above reaction mixture at ice temperature and stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (250 ml), extracted with ethyl acetate (3×500 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatile components was purified by silica gel (230 - 400) column (petroleum ether solution of 3% ethyl acetate) to give 6.7 g (76%) of a light yellow oily product 5. 1 1H NMR (300 MHz, CDCl3) δ (ppm): 1.41 (s, 9H), 2.25–2.29 (m, 5H), 2.39 (t, J = 6.0 Hz, 2H), 3.36–3.42 (m, 4H), 6.36 (s, 1H), 6.90–6.95 (m, 3H), 7.02 - 7.05 (m, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.66 - 7.70 (m, 1H), 7.98 (d, J = 2.4 Hz, 1H). MS:

[0481] (M+H) 381.2.

[0482] Step 5 - At ice temperature, trifluoroacetic acid (27 mL) was added to a solution of tert-butyl 4-[3-(5-methylpyridin-2-yl)oxy]benzylidene piperidine-1-carboxylate 5 (6.7 g, 0.017 mol) in dichloromethane (67.0 mL), and the reaction mixture was stirred at room temperature for 1 h. The product 6 (6.96 g) obtained after evaporating the volatiles was used for the next step without further purification. 1 HNMR (300 MHz, DMSO-d6) δ (ppm): 2.24 (s, 3H), 2.61 (t, J = 6.1 Hz, 2H), 3.10–3.30 (m, 4H), 6.36 (s, 1H), 6.90–6.95 (m, 3H), 7.02 -7.05 (m, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.66 -7.70 (m, 1H), 7.98 (d, J = 2.4 Hz, 1H), 8.70 (bs, 2H). MS: (M+H) 281.3.

[0483] Step 6 - At 25 °C, diisopropylethylamine (4.2 mL, 22.0 mmol) and the product of Step 5, Example 1 (1.93 g, 7.0 mmol) were added to a solution of amine 6 (3.0 g, 7.0 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (500 ml), washed with water (3 × 150 ml), and dried over sodium sulfate. The crude product obtained after evaporating the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 50% ethyl acetate) to obtain a grayish-white solid product 7, 2.33 g (70%). Melting point: 87.8 °C - 91.0 °C. IR: 3250, 2895, 1624, 1425, 1263, 848, 774 cm -1 . 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.05-1.18 (m, 2H), 1.80–1.95 (m, 1H), 2.23–2.33 (m, 5H), 2.40 (t, J = 5.1 Hz, 2H), 2.71 (m, 1H), 3.31 (t, J = 5.5 Hz, 2H), 3.38 (t, J = 5.5 Hz, 2H), 6.37 (s, 1H), 6.86-6.97 (m, 4H), 7.04 -7.22 (m, 3H), 7.23–7.33 (m, 3H), 7.40 (td, J = 7.9, 2.0 Hz, 1H), 7.70 (dt, J = 8.3, 2.5 Hz, 1H), 7.99 (bs, 1H). MS:

[0484] (M+H) 440.5.

[0485] Example 20: Synthesis of 4-[3-(pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid [2-(4-methyl)phenyl-cyclopropyl]-amide:

[0486]

[0487] Step 1 - Ammonium acetate (13.4 g, 0.17 mol) was added to acetic acid (100 mL) and stirred until completely dissolved. Then nitromethane (30.46 g, 0.49 mol) was added to the reaction mixture, followed by 4-methylbenzaldehyde (9.82 mL, 0.083 mol). The reaction mixture was refluxed at 100 °C for 6 hours. The reaction mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was quenched with 2 M aqueous sodium hydroxide (pH = 7) and extracted with ethyl acetate (2 × 300 ml), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was washed with hexane to give the yellow solid product 2 (10 g, 74%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 2.361 (s, 3H), 7.303 (d, 2H), 7.755 (d, 2H), 8.072 - 8.213 (m, 2H). MS (M-H) 162.9.

[0488] Step 2 - Trimethylsulfoxonium iodide (6.7 g, 0.03 mol) was added to a solution of 60% dispersion of sodium hydride in mineral oil (0.98 g, 0.024 mol) in dimethyl sulfoxide (10 mL) and stirred at room temperature for 30 minutes. Then a solution of 2 (2 g, 0.012 mol) in dimethyl sulfoxide (10 ml) was added and the reaction mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was quenched with water (100 ml), extracted with ethyl acetate (2 × 300 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by column chromatography on silica gel (230 - 400 mesh) (hexane solution of 2% ethyl acetate) to give the light yellow oily product 3 (300 mg, 14%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.653 - 1.704 (m, 1H), 2.203 - 2.273 (m, 1H), 2.353 (s, 3H), 3.112 - 3.157 (m, 1H), 4.370 - 4.417 (m, 1H), 7.015 - 7.042 (d, 2H), 7.14 - 7.166 (d, 2H). MS (M+H) 178.1.

[0489] Step 3 - Hydrochloric acid (6.2 mL of 2.7 N solution, 0.0169 mol) was added to a solution of 3 (0.3 g, 0.0016 mol) in isopropanol (12 mL), and then zinc powder (1.1 g, 0.0169 mol) was added in portions. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was neutralized with 10% sodium hydroxide solution and filtered through a bed of diatomaceous earth. The filtrate was diluted with ethyl acetate (150 ml), washed with water (50 ml) and brine solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained after evaporation of the volatiles was purified by column chromatography on silica gel (230 - 400 mesh) (chloroform solution with 2% methanol) to give the product 4 as a yellow oil (150 mg, 60%). 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 0.879 (m, 2H), 1.667 (m, 1H), 2.229 (s, 3H), 2.293 - 2.331 (m, 1H), 7.018 (d, J = 8.1, 2H), 6.879 (d, J = 8.1, 2H). MS (M+H) 148.2.

[0490] Step 4 - Triethylamine (0.17 mL, 0.0012 mol) and phenyl chloroformate (115 mg, 0.0007 mol) were added to a solution of 4 (90 mg, 0.0006 mol) in dichloromethane (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The resulting reaction mixture was diluted with ethyl acetate (150 ml), washed with water (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained after evaporation of the volatiles was purified by column chromatography on silica gel (230 - 400 mesh) (hexane solution with 10% ethyl acetate) to give the product 5 as a white solid (30 mg, 18%). 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.115 - 1.123 (m, 2H), 2.245 (s, 3H), 7.000 - 7.120 (m, 6H), 7.181 - 7.356 (m, 1H), 7.361 - 7.395 (m, 2H). MS (M+H) 268.3.

[0491] Step 5 - Trifluoroacetic acid (4 mL) was added to a solution of the product of Step 4, Example 2 (1.0 g, 0.002 mol) in dichloromethane (10 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The product 7 (1.3 g, 97%) obtained after evaporation of the volatiles was used for the next step without further purification.

[0492] Step 6 - At room temperature, diisopropylethylamine (0.59 mL, 0.0034 mol) and 5 (0.16 g, 0.0006 mol) were added to a solution of 7 (0.29 g, 0.0006 mol) in dimethyl sulfoxide (3 mL). The reaction mixture was stirred at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (200 mL), washed with water (3 × 50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400 mesh) column (hexane solution of 40% ethyl acetate) to give the off-white solid product 8 (180 mg, 69%). Melting point: 87.8 - 91.0 °C. IR: 3250, 3013, 1624, 1573, 1425, 1263, 1117, 775 cm -1 . 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.001 - 1.046 (m, 1H), 1.085 - 1.133 (m, 1H), 1.836 - 1.845 (m, 1H), 2.249 (s, 5H), 2.382 - 2.44 (m, 2H), 2.643 - 2.665 (m, 1H), 3.29 - 3.326 (m, 2H), 3.365 - 3.401 (m, 2H), 6.360 (s, 1H), 6.952 - 7.082 (m, 8H), 7.117 - 7.157 (m, 1H), 7.348 - 7.401 (m, 1H), 7.830 - 7.888 (m, 1H), 8.156 - 8.166 (m, 1H). MS (M+H) 440.4.

[0493] Example 21: Synthesis of 4-[3-(pyrimidin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid [(1R,2S)-2-phenyl-cyclopropyl]-amide:

[0494]

[0495] Step 1 - At 25 °C, add diisopropylethylamine (4.13 mL, 23.6 mmol) and 2 (the product of Step 4 of Example 16 (2.0 g, 7.89 mmol)) to a solution of Amine 1 (the product of Step 5 of Example 6 (3.02 g, 7.89 mmol)) in dimethyl sulfoxide (30.0 mL). Stir the reaction mixture at 60 °C for 5 h. The resulting reaction mixture was diluted with ethyl acetate (300 ml), washed with water (3 × 150 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 60% ethyl acetate) to give 2.3 g (70%) of the white solid product 3. Melting point: 62.8 - 65.2 °C. IR: 3627, 3310, 1732, 1629, 1570, 1526, 1310, 1249, 1148, 753, 696 cm -1 . 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 1.04 - 1.18 (m, 2H), 1.85–1.88 (m, 1H), 2.27 (t, J = 5.7 Hz, 2H), 2.39 (t, J = 5.8 Hz, 2H), 2.71 (dt, J = 7.4, 3.7 Hz, 1H), 3.31 (d, J = 5.9 Hz, 2H), 3.39 (d, J = 5.9 Hz, 2H), 6.37 (s, 1H), 6.84 (d, J = 3.1 Hz, 1H), 7.03 - 7.12 (m, 6H), 7.20 - 7.30 (m, 3H), 7.39 (t, J = 4.7 Hz, 1H), 8.64 (dd, J = 4.7 Hz, 1.1 Hz, 2H). MS: 427.4 (M+H). HPLC purity: 99.79%. Chiral HPLC purity: 99.92%. Optical rotation: -1.190. Specific rotation: -111.71.

[0496] Example 22: Synthesis of 4-[3-(5-methyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0497]

[0498] Step 1 - At 25 °C, to a solution of Amine 1, the product of Step 5, Example 19 (3.0 g, 7.0 mmol) in dimethyl sulfoxide (30 mL), add diisopropylethylamine (4.2 mL, 22.0 mmol) and the product of Step 4, Example 16 (1.93 g, 7.0 mmol). Stir the reaction mixture at 60 °C for 5 h. Dilute the resulting reaction mixture with ethyl acetate (500 ml), wash with water (3 × 150 ml), and dry over sodium sulfate. The crude product obtained after evaporation of the volatiles is purified by silica gel (230 - 400) column (petroleum ether solution of 50% ethyl acetate) to give 2.7 g (81%) of a light yellow solid product 3. Melting point: 53.1 - 53.9 °C. IR: 3321, 3024, 1628, 1526, 1475, 1249, 752, 695 cm -1 。 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.06 - 1.21 (m, 2H), 1.80–1.95 (m, 1H), 2.23–2.33 (m, 5H), 2.40 (t, J = 5.6 Hz, 2H), 2.71 (m, 1H), 3.31 (t, J = 5.5 Hz, 2H), 3.38 (t, J = 5.5 Hz, 2H), 6.37 (s, 1H), 6.86 - 6.97 (m, 4H), 7.04 - 7.22 (m, 3H), 7.23–7.33 (m, 3H), 7.40 (td, J = 7.9, 2.0 Hz, 1H), 7.70 (dt, J = 8.3, 2.5 Hz, 1H), 7.99 (d, J = 2.8 Hz, 1H). MS (M+H) 440.5. HPLC purity: 98.5%. Chiral HPLC purity: 100%.

[0499] Example 23: Synthesis of 4-[3-(pyrimidin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid methyl-((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0500]

[0501] Step 1 - At 0 - 5 °C, sodium hydride (4.13 mL, 23.6 mmol) and methyl iodide (2.0 g, 7.89 mmol) were added to a solution of the product of 1 and Example 21 (150 mg, 7.89 mmol) in dimethylformamide (30.0 mL). The reaction mixture was stirred at 25 - 30 °C for 1 hour. The resulting reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (2 × 100 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 25% ethyl acetate) to give 77 mg (50%) of pale yellow solid 2. 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.24 (dt, J = 7.8 Hz, 5.9 Hz, 2H), 2.02–2.07 (m, 1H), 2.27 (q, J = 5.9 Hz, 2H), 2.38–2.41 (m, 2H), 2.79 (s, 4H), 3.12 - 3.33 (m, 4H), 6.34 (s, 1H), 6.97 - 7.21 (m, 6H), 7.20 - 7.31 (m, 3H), 7.39 (t, J = 7.9 Hz, 1H), 8.65 (d, J = 4.8 Hz, 2H). MS: 441.5 (M + H). HPLC purity: 98.1%.

[0502] Example 24: Synthesis of 4-[3-(5-methyl-pyrazin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0503]

[0504] Step 1 - At room temperature, 3-hydroxybenzyl alcohol (11.6 g, 0.094 mol) and cesium carbonate (76.0 g, 0.23 mol) were added to a solution of 2-chloro-5-methyl-pyrazine (10 g, 0.078 mol) in DMF (100 mL). The reaction mixture was stirred at 100 °C for 5 hours. Then the resulting mixture was allowed to reach room temperature, diluted with water (250 ml), extracted with ethyl acetate (3 × 500 ml), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 30% ethyl acetate) to give 6.8 g (40%) of the product 1 as a pale yellow oil. 11H NMR (300 MHz, DMSO-d6) δ (ppm): 2.45 (s, 3H), 4.50 (d, J = 4.5 Hz, 2H), 5.26 (t, J = 5.26 Hz, 1H), 7.0–7.18 (m, 3H), 7.37 (t, J = 7.5 Hz, 1H), 8.1 (s, 1H), 8.4 (d, J = 1.2 Hz, 1H). MS (M+H) 217.2.

[0505] Step 2 - In an ice bath, thionyl chloride (2.3 mL, 0.03 mol) was added dropwise to a solution of 1 (6.0 g, 0.027 mol) in dichloromethane (60 mL) while stirring the reaction mixture. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. Then the volatiles were evaporated under reduced pressure and the residue was diluted with toluene (25 ml), and the toluene was evaporated under reduced pressure. This azeotropic process was repeated 3 times to obtain the product 2 (6.2 g) as a light brown oil. The crude product was used in the next step without further purification. MS (M+H) 235.3.

[0506] Step 3 - A solution of 2 (6.2 g, 0.026 mol) in triethyl phosphite (7.3 mL, 0.042 mol) was heated at 150 °C for 6 hours. The reaction mixture was cooled to room temperature, and the crude product obtained after evaporation of the volatiles was purified by column chromatography on silica gel (230 - 400) (petroleum ether solution of 60% ethyl acetate) to obtain the product 3, 8.3 g, as a light yellow oil. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.16 (t, J = 7.0 Hz, 6H), 2.45 (s, 3H), 3.23 (s, 1H), 3.23 (s, 1H), 3.94 (dq, J = 8.2 Hz, 7.0 Hz, 4H), 7.0 - 7.12 (m, 2H), 7.13 - 7.15 (m, 1H), 7.36 (t, J = 7.8 Hz, 1H), 8.09 (dd, J = 1.4 Hz, 0.7 Hz, 1H), 8.39 (d, J = 1.4 Hz, 1H). MS (M+H) 337.1.

[0507] Step 4 - Add 15-crown ether (0.1 g, 0.48 mmol) to a solution of 3 (8.3 g, 0.024 mol) in THF (40 mL). Cool the reaction (ice bath) and add NaH (1.44 g, 0.036 mol) portionwise. Stir the reaction mixture at room temperature for 30 minutes and cool again to ice temperature. Add a solution of tert-butyl 4-oxopiperidine-1-carboxylate 5 (4.9 g, 0.024 mol) in THF (40 mL) to the above reaction mixture at ice temperature and stir at room temperature for 16 hours. Dilute the resulting reaction mixture with water (250 ml), extract with ethyl acetate (3 × 500 ml), and dry over sodium sulfate. Evaporate the volatiles to obtain the crude product, giving a pale yellow oily product 4 (6.7 g). MS (M+H) 382.3. Product 4 is used in the next step without further purification.

[0508] Step 5 - At ice-cold temperature, add trifluoroacetic acid (27 mL, 4V) to a solution of 4 (6.7 g, 0.017 mol) in dichloromethane (67.0 mL). Stir the reaction mixture at room temperature for 1 hour. Evaporate the volatiles to obtain product 6 (6.96 g, 90%) for use in the next step without additional purification. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 2.45 (s, 3H), 2.60–2.67 (m, 4H), 3.10–3.17 (m, 4H), 6.46 (s, 1H), 7.04 -7.12 (m, 4H), 7.38 (t, J = 7.8 Hz, 1H), 8.09 (s, 1H), 8.40 (d, J = 4.4 Hz, 1H), 8.61 (bs, 2H). MS (M+H) 282.3.

[0509] Step 6 - At 25 °C, add diisopropylethylamine (1.4 mL, 7.5 mmol) and the carbamate product of Step 4, Example 16 (0.7 g, 2.75 mmol) to a solution of amine 6 (1.0 g, 2.5 mmol) in dimethyl sulfoxide (30 mL). Stir the reaction mixture at 60 °C for 5 h. Dilute the resulting reaction mixture with ethyl acetate (500 ml), wash with water (3 × 150 ml), and dry over sodium sulfate. Purify the crude product obtained after evaporation of the volatiles by silica gel (230-400) column (petroleum ether solution of 60% ethyl acetate) to obtain a pale yellow solid product 7, 0.7 g (68%). Melting point: 50.8 °C. IR: 3305, 2923, 1627, 1528, 1473, 1337, 1266, 695 cm -1 . 11H NMR (300 MHz, DMSO-d6) δ (ppm): 1.02 - 1.20 (m, 2H), 1.82–1.84 (m, 1H), 2.21–2.41 (m, 4H), 2.46 (s, 3H), 2.60–2.70 (m, 1H), 3.26–3.34 (m, 4H), 6.32 (s, 1H), 6.80–7.22 (m, 9H), 7.35 (t, J = 7.6, 1H), 8.06 (bs, 1H), 8.37 (bs, J = 8.3, 1H). MS: 441.4 (M+H). HPLC: 99.91%.

[0510] Example 25: Synthesis of 4 - [3 - (pyrazin - 2 - yloxy) - benzylidene] - piperidine - 1 - carboxylic acid ((1R,2S) - 2 - phenyl - cyclopropyl) - amide:

[0511]

[0512] According to the synthesis method described in the product of Example 24, 2 - chloro - pyrazine was used instead of 2 - chloro - 5 - methyl - pyrazine described in Example 24 to prepare the target compound 7.

[0513] Example 26: Synthesis of 4 - [5 - methyl - 3 - (pyrimidin - 2 - yloxy) - benzylidene] - piperidine - 1 - carboxylic acid (2 - phenyl - cyclopropyl) - amide:

[0514]

[0515] According to the synthesis method described in the product of Example 6, 2 - chloro - 5 - methyl - pyrimidine was used instead of 2 - chloro - pyrimidine described in Example 6 to prepare the target compound 6.

[0516] Example 27: Synthesis of 4 - [3 - (5 - chloro - pyridin - 2 - yloxy) - benzylidene] - piperidine - 1 - carboxylic acid ((1R,2S) - 2 - phenyl - cyclopropyl) - amide:

[0517]

[0518] Step 1 - At room temperature, 3-hydroxyphenyl-methanol (9.42 g, 0.0760 mol) and cesium carbonate (29.72 g, 0.0912 mol) were added to a solution of 5-chloro-2-fluoropyridine (10.0 g, 0.0760 mol) in DMSO (100 mL). The reaction mixture was stirred at 100 °C for 6 hours. The reaction was monitored by TLC. The resulting mixture was cooled to room temperature, diluted with water (200 ml), extracted with ethyl acetate (2 × 400 ml), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 12% ethyl acetate) to give the product 1 as a pale yellow oil, 12.0 g (67%). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.17 (t, J = 2.4 Hz, 1H), 7.94 - 7.91 (m, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.14 - 7.1 (m, 1H), 7.06 - 7.03 (m, 2H), 6.98–6.95 (m, 1H), 5.22 (t, J = 5.6 Hz, 1H), 4.48 (d, J = 5.6 Hz, 2H). MS m / z (M+H): 236.0.

[0519] Step 2: While stirring the reaction in an ice bath, thionyl chloride (4.1 mL, 0.0560 mol) was added dropwise to a solution of 1 (12.0 g, 0.0509 mol) in dichloromethane (120 mL). After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. After complete consumption of the starting material, the volatiles were evaporated under reduced pressure, diluted with ethyl acetate (250 ml), and the organic layer was washed with saturated sodium bicarbonate solution and water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product 2 obtained after evaporation was used directly in the next step without further purification (12.5 g, 96%). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.20 (d, J = 2.4 Hz, 1H), 8.19 - 7.95 (m, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 2.0 Hz, 1H), 7.12 - 7.09 (m, 2H), 4.75 (s, 1H). MS m / z (M+H): 254.1.

[0520] Step 3: A solution of 2 (12.5 g, 0.0494 mol) in triethyl phosphite (20.0 mL, 0.1235 mol) was heated at 150 °C for 6 h. The reaction mixture was allowed to reach room temperature, and the crude product obtained after removal of volatiles was added to n-heptane (150 ml) to give a pale orange precipitate. The precipitate obtained was filtered and dried under vacuum to give a grayish-white solid product 3 (16.5 g, 91%), which was used in the next step without further purification. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.19 - 8.18 (m, 1H), 7.97 - 7.94 (m, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.13 - 7.06 (m, 1H), 7.03 - 6.99 (m, 3H), 3.95 (m, 4H), 3.27 and 3.21 (2s, 2H), 1.15 (t, J = 4.4 Hz, 6H). MS m / z (M+H): 356.2.

[0521] Step 4: 15-Crown-5 ether (0.19 g, 0.87 mmol) was added to a solution of 3 (15.5 g, 0.0435 mol) in THF (100 mL). The reaction was cooled (ice bath) and NaH (2.07 g, 0.0870 mol) was added portionwise over 5 min. The reaction mixture was stirred at room temperature for 30 min and cooled again to ice temperature. A solution of tert-butyl 4-oxopiperidine-1-carboxylate 5 (8.66 g, 0.0435 mol) in THF (50 mL) was added at ice temperature and the mixture was stirred at room temperature for 16 h. The resulting reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product obtained after evaporation of volatiles was purified by silica gel column chromatography to give a pale yellow liquid product 4 (13.1 g, 75%). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.19 (d, J = 2.0 Hz, 1H), 7.96 - 7.93 (m, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.09 - 7.06 (m, 2H), 6.99 - 6.96 (m, 2H), 6.35 (s, 1H), 3.40 - 3.32 (m, 4H), 2.38 (t, J = 5.2 Hz, 2H), 2.26 (t, J = 6.0 Hz, 2H), 1.39 (s, 9H). MS m / z (M+Na): 423.2.

[0522] Step 5: At ice temperature, trifluoroacetic acid (52.0 ml) was added to a solution of 4 (13.0 g, 0.0325 mol) in dichloromethane (130 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After complete consumption of the starting material, the volatiles were removed under reduced pressure to give a light brown oily product. The obtained crude product was washed with diethyl ether (3 × 50 ml) to give a light brown viscous liquid 6 (13.8 g of crude product). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.82 (bs, 2H), 8.19 (d, J = 2.8 Hz, 1H), 7.96 - 7.93 (m, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 7.02 - 7.00 (m, 2H), 6.44 (s, 1H), 3.38 - 3.33 (m, 4H), 2.60 (t, J = 5.6 Hz, 2H), 2.53 - 2.48 (m, 2H). MS m / z (M + H): 301.2.

[0523] Step 6: At 25 °C, diisopropyl-ethylamine (20.34 ml, 0.1149 mol) and the carbamate product of Step 4, Example 16 (10.62 g, 0.0419 mol) were added to a solution of 6 (15.8 g, 0.0381 mol) in dimethyl sulfoxide (78 mL). The reaction mixture was stirred at 60 °C for 6 hours. The resulting reaction mixture was diluted with ethyl acetate (500 ml), washed with water (3 × 200 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 40% ethyl acetate) to give a light yellow fluffy solid product 7 (11.6 g, 66%). Melting range (MR): 44.8 - 62.6 °C. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.18 (d, J = 2.4 Hz, 1H), 7.94 - 7.91 (m, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.23 - 7.19 (m, 2H), 7.12 - 7.05 (m, 5H), 6.95 - 6.82 (m, 2H), 6.32 (s, 1H), 3.37 - 3.26 (m, 4H), 2.71 - 2.69 (m, 1H), 2.36 - 2.33 (t, J = 5.2 Hz, 2H), 2.24 - 2.22 (t, J = 5.6 Hz, 2H), 1.85 (m, 1H), 1.13 (d, J = 4.8 Hz, 1H), 1.04 (d, J = 7.6 Hz, 1H). 1313C NMR: (100 MHz, DMSO-d6): δ 161.69, 157.57, 153.49, 145.56, 141.99, 139.92, 139.75, 138.80, 129.56, 128.08, 125.85, 125.34, 125.21, 123.04, 121.29, 119.02, 113.05, 44.93, 43.89, 35.63, 34.07, 28.91, 24.32 and 15.58. MS m / z (M+H): 460.32, HPLC purity: 99.36%, chiral purity: 99.71%.

[0524] Example 28: Synthesis of 4-[3-(5-fluoro-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0525]

[0526] Step 1: At room temperature, 3-hydroxybenzyl alcohol (8.9 g, 0.0719 mol) and cesium carbonate (28.12 g, 0.0863 mol) were added to a solution of 2,5-difluoropyridine (8.2 g, 0.0719 mol) in DMSO (80 mL). The reaction mixture was stirred at 85 °C for 6 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 after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 12% ethyl acetate) to give 4.3 g (28%) of product 1 as a pale yellow oil. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.17 (t, J = 2.4 Hz, 1H), 7.84 - 7.78 (m, 1H), 7.35 (t, J = 10.4 Hz, 1H), 7.15 - 6.95 (m, 4H), 5.25 (t, J = 7.6 Hz, 1H), 4.50 (d, J = 7.6 Hz, 2H). MS m / z (M+H): 220.0.

[0527] Step 2: While stirring the reaction in an ice bath, thionyl chloride (2.4 mL, 0.0326 mol) was added dropwise to a solution of 1 (6.5 g, 0.0296 mol) in dichloromethane (65 mL). After removing the ice bath, the reaction mixture was stirred at room temperature for 2 h. After complete consumption of the starting materials, the volatiles were evaporated under reduced pressure, diluted with ethyl acetate (200 mL), and the organic layer was washed with saturated sodium bicarbonate solution and water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product 2 obtained after evaporation was used directly in the next step without further purification (6.7 g, 95%). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.15 (d, J = 2.4 Hz, 1H), 7.83 - 7.80 (m, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.27 - 7.25 (m, 1H), 7.19 - 7.06 (m, 3H), 4.75 (s, 1H). MS m / z (M + H): 238.0.

[0528] Step 3: A solution of 2 (6.5 g, 0.0274 mol) in triethyl phosphite (12.6 mL, 0.0685 mol) was heated at 150 °C for 6 h. The reaction mixture was cooled to room temperature, and the mixture obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column chromatography to give the light yellow liquid product 3 (9.0 g, 95%). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.15 (d, J = 4.0 Hz, 1H), 7.86 - 7.80 (m, 1H), 7.34 (t, J = 10.4 Hz, 1H), 7.12 - 6.97 (m, 4H), 4.02 - 3.89 (m, 4H), 3.28 and 3.21 (2s, 2H), 1.15 (t, J = 9.2 Hz, 6H). MS m / z (M + H): 340.2.

[0529] Step 4: 15-Crown ether (0.12 g, 0.53 mmol) was added to a solution of 3 (9.0 g, 0.0256 mol) in THF (60 mL). The reaction was cooled (ice bath) and 60% NaH (1.26 g, 0.0530 mol) was added portionwise over 5 min. The reaction mixture was stirred at room temperature for 30 min and then cooled again to ice temperature. A solution of tert-butyl 4-oxopiperidine-1-carboxylate 5 (5.28 g, 0.0256 mol) in THF (30 mL) was added at ice temperature, and the mixture was stirred at room temperature for 16 h. The resulting reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product obtained after evaporation of the volatiles was purified by silica gel column chromatography to give the light yellow solid product 4 (8.0 g, 78%). 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.15 (d, J = 3.2 Hz, 1H), 7.84 - 7.79 (m, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.12 - 7.04 (m, 2H), 6.96 - 6.92 (m, 2H), 6.35 (s, 1H), 3.40 - 3.32 (m, 4H), 2.37 (t, J = 5.6 Hz, 2H), 2.25 (t, J = 5.2 Hz, 2H), 1.39 (s, 9H). MS m / z (M+Na): 407.2.

[0530] Step 5: At ice temperature, trifluoroacetic acid (32.5 mL) was added to a solution of 4 (8.2 g, 0.0213 mol) in dichloromethane (82 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the raw materials were completely consumed, the volatiles were removed under reduced pressure to obtain the product as a red oil. The obtained crude product was washed with ether (3 × 50 ml) to obtain a thick brown oily product 6 (9.0 g of crude product). 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.73 (bs, 2H), 8.15 (d, J = 3.2 Hz, 1H), 7.84 - 7.79 (m, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.12 - 7.06 (m, 2H), 7.00 - 6.96 (m, 2H), 6.44 (s, 1H), 3.15 - 3.09 (m, 4H), 2.59 (t, J = 6.0 Hz, 2H), 2.49 - 2.48 (m, 2H). MS m / z (M+H): 285.4.

[0531] Step 6: At 25 °C, diisopropyl-ethyl-amine (11.1 ml, 0.063 mol) and the carbamate product of Step 4, Example 16 (5.8 g, 0.023 mol) were added to a solution of 6 (8.4 g, 0.021 mol) in dimethyl sulfoxide (42 ml). The reaction mixture was stirred at 60 °C for 6 hours. The obtained reaction mixture was diluted with ethyl acetate (400 ml), washed with water (3 × 100 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 40% ethyl acetate) to obtain product 7 as a light yellow fluffy solid (7.15 g, 66%). 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.15 (d, J = 2.4 Hz, 1H), 7.82 - 7.80 (m, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.24 - 7.21 (m, 2H), 7.14 - 7.04 (m, 5H), 6.96 - 6.94 (m, 2H), 6.84 (d, J = 2.8 Hz, 1H), 6.34 (s, 1H), 3.38 - 3.28 (m, 4H), 2.71 - 2.69 (m, 1H), 2.34 (t, J = 5.2 Hz, 2H), 2.23 (t, J = 4.8 Hz, 2H), 1.86 (m, 1H), 1.13 (d, J = 4.8 Hz, 1H), 1.04 (d, J = 7.6 Hz, 1H). 13 13C NMR: (100 MHz, DMSO-d6): δ 159.15, 157.57, 156.01 (d, J = 244.7 Hz), 154.08, 141.99, 139.69, 138.76, 134.13 (d, J = 26.3 Hz), 129.54, 128.09, 127.85 (d, J = 20.9 Hz), 125.86, 125.35, 124.91, 123.09, 120.97, 118.71, 113.01, 44.94, 43.90, 35.63, 34.07, 28.91, 24.32 and 15.58. MS m / z (M+H): 444.3, HPLC purity: 99.21%, chiral HPLC: 99.37%.

[0532] Example 29: Synthesis of methyl 6-{3-[1-((1R,2S)-2-phenyl-cyclopropylcarbamoyl)-piperidin-4-ylidene-methyl]-phenoxy}-nicotinate:

[0533]

[0534] Step 1: At room temperature, 3-hydroxyphenylmethanol (39.79 g, 0.32 mol) and potassium carbonate (60.4 g, 0.43 mol) were added to a solution of methyl 6-chloropyridine-3-carboxylate (50.0 g, 0.29 mol) in dimethylacetamide (500 ml). The reaction mixture was stirred at 100 °C for 6 hours. The reaction was monitored by TLC. The resulting mixture was cooled to room temperature, diluted with water (300 ml), extracted with ethyl acetate (2 × 500 ml), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 12% ethyl acetate) to give the product 1 as a pale yellow oil (30.0 g, 40%). 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.82 (d, J = 2.0 Hz, 1H), 8.30 - 8.27 (m, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.27 - 7.19 (m, 2H), 7.09 - 7.07 (m, 1H), 6.96 (d, J = 8.8 Hz, 1H), 4.73 (s, 2H), 3.93 (d, J = 3.6 Hz, 3H). MS m / z (M+H): 259.8.

[0535] Step 2: While stirring the reaction in an ice bath, thionyl chloride (9.4 mL, 0.127 mol) was added dropwise to a solution of 1 (30.0 g, 0.115 mol) in dichloromethane (300 mL). After removing the ice bath, the reaction mixture was stirred at room temperature for 2 hours. After the raw materials were completely consumed, the volatiles were evaporated under reduced pressure, diluted with ethyl acetate (500 ml), and the organic layer was washed with saturated sodium bicarbonate (200 ml) solution and water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product obtained after evaporation was purified by silica gel (230 - 400) column chromatography to obtain the light yellow liquid product 2 (28.0 g, 87%). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.82 (d, J = 0.8 Hz, 1H), 8.31 - 8.28 (m, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.29 - 7.27 (m, 1H), 7.21 (t, J = 2.0 Hz, 1H), 7.14 - 7.11 (m, 1H), 6.98 - 6.96 (m, 1H), 4.61 (s, 2H), 3.93 (s, 3H). MS m / z (M+H): 278.0.

[0536] Step 3: A solution of 2 (28.0 g, 0.10 mol) in triethyl phosphite (41.0 mL, 0.25 mol) was heated at 150 °C for 6 hours. The reaction mixture was cooled to room temperature, and the mixture obtained after evaporating the volatiles was purified by silica gel column chromatography to obtain 3 as a light yellow liquid (32.0 g, 84%). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.65 - 8.64 (M, 1H), 8.30 - 8.27 (M, 1H), 7.35 (T, J = 8.0 Hz, 1H), 7.16 - 7.03 (M, 4H), 3.96 - 3.88 (M, 4H), 3.82 (S, 3H), 3.27 and 3.21 (2S, 2H), 1.15 - 1.11 (M, mass spectrum m / Z (M+H): 380.2

[0537] Step 4: Add 15-crown ether (0.41 g, 1.8 mmol) to a solution of 3 (35.5 g, 0.093 mol) in THF (200 mL). Cool the reaction (ice bath) and add 60% NaH (5.5 g, 0.14 mol) portionwise over 5 minutes. Stir the reaction mixture at room temperature for 30 minutes and cool again to ice temperature. Add a solution of tert-butyl 4-oxopiperidine-1-carboxylate 5 (18.7 g, 0.093 mol) in THF (150 mL) at ice temperature and stir at room temperature for 16 hours. Quench the resulting reaction mixture with saturated ammonium chloride and extract with ethyl acetate. Dry the organic layer over anhydrous sodium sulfate and concentrate. Dissolve the crude product (30.0 g) obtained after evaporation of the volatiles in methanol (300 ml) and add aqueous lithium hydroxide (3.0 g, 0.0707 mol) at ice temperature. Stir the resulting reaction mass at 50 °C for 2 hours. Monitor the reaction by TLC. Dissolve the crude product obtained after evaporation of the volatiles in water (200 ml) and wash with methyl tert-butyl ether (2 × 200 ml). Acidify the aqueous layer to pH 2.0 with 1.0 N HCl aqueous solution. Filter and dry the precipitated product to give a off-white solid 4 (23.0 g, 61%). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 13.19 (bs, 1H), 8.66 - 8.65 (m, 1H), 8.28 - 8.25 (m, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.11 - 7.00 (m, 4H), 6.37 (s, 1H), 3.40 - 3.32 (m, 4H), 2.39 (t, J = 5.6 Hz, 2H), 2.27 (t, J = 5.2 Hz, 2H), 1.39 (s, 9H). MS m / z (M + H): 433.2.

[0538] Step 5: At ice temperature, add trimethylsilyl chloride (8.9 ml, 0.0697 mol) to a solution of 4 (13.0 g, 0.0317 mol) in methanol (130 ml). Stir the reaction mixture at room temperature for 12 hours and monitor by TLC. After complete consumption of the starting material, remove the volatiles under reduced pressure. Dilute the resulting crude product with saturated sodium bicarbonate solution and extract with ethyl acetate. Wash the organic layer with water, dry over anhydrous sodium sulfate, filter and concentrate. Purify the crude product obtained after evaporation of the volatiles by silica gel (230 - 400) column chromatography to give product 6 as a pale yellow liquid (5.2 g, 51%). 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.68 - 8.67 (m, 1H), 8.31 - 8.28 (m, 1H), 7.39 - 7.36 (m, 1H), 7.13 - 6.97 (m, 4H), 6.24 (s, 1H), 3.84 (s, 3H), 2.78 - 2.65 (m, 4H), 2.34 (t, J = 5.2 Hz, 2H), 2.21 (t, J = 5.2 Hz, 2H). MS m / z (M+H): 325.3.

[0539] Step 6: At 25 °C, to a solution of 6 (5.2 g, 0.016 mol) in dimethyl sulfoxide (52 mL, 10V) was added diisopropyl-ethylamine (8.9 mL, 0.048 mol) and the carbamate product of Step 4, Example 16 (4.0 g, 0.016 mol). The reaction mixture was stirred at 60 °C for 6 hours. The reaction was monitored by TLC. The resulting reaction mixture was diluted with ethyl acetate (300 ml), washed with water (3 × 100 ml), and dried over anhydrous sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 40% ethyl acetate) to give Product 7 as a light yellow fluffy solid (5.0 g, 65%). Melting point range (Mr): 52.6 - 72.8 °C. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.68 (d, J = 2.0 Hz, 1H), 8.31 - 8.28 (m, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.24 - 7.20 (m, 2H), 7.13 - 7.01 (m, 7H), 6.84 - 6.83 (m, 1H), 6.35 (s, 1H), 3.84 (s, 3H), 3.38 - 3.30 (m, 4H), 2.71 - 2.69 (m, 1H), 2.37 (t, J = 5.2 Hz, 2H), 2.25 (t, J = 5.2 Hz, 2H), 1.86 (m, 1H), 1.15 (d, J = 4.8 Hz, 1H), 1.05 (d, J = 6.0 Hz, 1H). 1313C NMR: (100 MHz, DMSO-d6): δ 165.87, 164.78, 157.57, 152.92, 149.45, 141.99, 140.87, 139.87, 138.88, 129.66, 128.08, 125.85, 125.67, 125.34, 122.97, 121.66, 120.97, 119.39, 111.21, 52.23, 44.92, 43.88, 35.63, 34.07, 28.90, 24.31 and 15.57, MS m / z (M+H): 484.3, HPLC purity: 98.65%, chiral HPLC: 99.08%.

[0540] Example 30: Synthesis of 6-{3-[1-((1R,2S)-2-phenyl-cyclopropylcarbamoyl)-piperidin-4-ylidene-methyl]-phenoxy}-nicotinic acid:

[0541]

[0542] Under ice temperature, an aqueous lithium hydroxide solution (0.32 g, 0.0076 mol) was added dropwise to a solution of 1. the product of Example 27 (1.8 g, 0.0038 mol) in methanol (18 ml). The reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC. The crude product obtained after evaporation of the volatiles was diluted with water (10 ml), and the aqueous layer was washed with methyl tert-butyl ether. The resulting aqueous layer was acidified to pH 2 with 1.5 N HCl. The precipitated product was filtered and dried to obtain 1.52 g (87%) of an off-white solid 2. Melting range (MR) 141 - 159 °C. 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 13.19 (bs, 1H), 8.66 - 8.65 (m, 1H), 8.28 - 8.26 (m, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.24 - 7.21 (m, 2H), 7.13 - 7.01 (m, 7H), 6.83 (d, J = 3.2 Hz, 1H), 6.35 (s, 1H), 3.38 - 3.28 (m, 4H), 2.71 - 2.69 (m, 1H), 2.37 (t, J = 5.2 Hz, 2H), 2.25 (t, J = 5.2 Hz, 2H), 1.86 (m, 1H), 1.15 (d, J = 4.4 Hz, 1H), 1.05 (d, J = 7.6 Hz, 1H). 1313C NMR: (100 MHz, DMSO-d6): δ 165.84, 165.69, 157.57, 153.03, 149.57, 142.0, 141.05, 139.84, 138.86, 129.64, 128.09, 125.85, 125.59, 125.34, 123.0, 122.02, 121.66, 119.40, 111.06, 44.92, 43.89, 35.64, 34.08, 28.91, 24.30 and 15.57. MS m / z (M+H): 470.3, HPLC purity: 99.88%, chiral HPLC: 99.50%,

[0543] Example 31: Synthesis of 4-[3-(5-Hydroxymethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0544]

[0545] Step 1: At ice temperature, N-methylmorpholine (1.4 ml, 0.0128 mol) and isobutyl chloroformate (1.21 ml, 0.0093 mol) were added to a solution of product 1 (3.6 g, 0.0085 mol) from step 4 of Example 27 in 1,2-dimethoxyethane (35 ml). The reaction mixture was stirred at room temperature for 30 minutes. Sodium borohydride (1.9 g, 0.0512 mol) was added portionwise to the reaction mass and stirred for 12 hours. The reaction was monitored by TLC. After complete consumption of starting material 1, the reaction mass was quenched with water (100 ml) and extracted with ethyl acetate (300 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by column chromatography on silica gel (230 - 400) to give product 2 as an off-white solid (3.2 g, 92%). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.06 (m, 1H), 7.79 - 7.76 (m, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.05 - 6.95 (m, 4H), 6.35 (s, 1H), 5.24 (t, J = 6.0 Hz, 1H), 4.45 (d, J = 5.6 Hz, 1H), 3.40 - 3.32 (m, 4H), 2.38 (t, J = 5.6 Hz, 2H), 2.25 (t, J = 5.2 Hz, 2H), 1.39 (s, 9H). MS m / z (M+H): 397.3.

[0546] Step 2: At ice temperature, trifluoroacetic acid (12.8 ml) was added to a solution of 2 (3.2 g, 0.08 mol) in dichloromethane (32 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After complete consumption of the starting material, the volatiles were removed under reduced pressure to give a crude product as a brownish-red oil. The obtained crude product was washed with diethyl ether (3 × 50 ml) to give 3 as an off-white solid (3.3 g of crude product). Mass spectrometry m / Z (M+H): 297.17.

[0547] Step 3: At 25 °C, diisopropyl-ethylamine (4.2 ml, 0.024 mol) and the carbamate product of Step 4, Example 16 (2.0 g, 0.08 mmol) were added to a solution of 3 (3.3 g, 0.08 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was stirred at 60 °C for 6 hours. The resulting reaction mixture was diluted with ethyl acetate (300 ml), washed with water (3 × 100 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 40% ethyl acetate) to give a light yellow fluffy solid 4 (1.82 g, 58%). Melting range (MR): 51 - 65 °C. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.07 (d, J = 2.0 Hz, 1H), 7.80 - 7.77 (m, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.26 - 6.92 (m, 7H), 6.83 (d, J = 3.2 Hz, 1H), 6.35 (s, 1H), 5.25 (t, J = 6.0 Hz, 1H), 4.45 (d, J = 7.2 Hz, 1H), 3.40 - 3.32 (m, 4H), 2.38 (t, J = 5.6 Hz, 2H), 2.25 (t, J = 5.2 Hz, 2H), 1.87 (m, 1H), 1.16 (d, J = 6.0 Hz, 1H), 1.05 (d, J = 7.6 Hz, 1H). 13 C NMR: (100 MHz, DMSO-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%.

[0548] Example 32: Synthesis of ((1R,2S)-2-phenyl-cyclopropyl)-amide of 4-[3-(5-methoxymethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid:

[0549]

[0550] Step 1: At ice temperature, 60% NaH (0.97 g, 0.024 mol) was added to a solution of product 1 (3.2 g, 8.0 mmol) from Step 1 of Example 29 in tetrahydrofuran (32 ml), and the reaction mixture was stirred at room temperature for 10 minutes. Methyl iodide (1.56 mL, 0.024 mol) was added to the reaction material at the same ice temperature, and stirring was continued for 12 hours. The reaction was monitored by TLC. After the raw materials were completely consumed, the reaction was quenched with saturated ammonium chloride solution (100 ml) and extracted with ethyl acetate (300 ml). The organic layer was further washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by silica gel (230 - 400) column chromatography to obtain a grayish-white solid product 2 (2.6 g, 78%). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.08 (d, J = 2.0 Hz, 1H), 7.80 - 7.78 (m, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.06 - 6.93 (m, 4H), 6.35 (s, 1H), 4.37 (s, 2H), 3.40 - 3.32 (m, 4H), 3.26 (s, 3H), 2.38 (t, J = 5.6 Hz, 2H), 2.25 (t, J = 5.6 Hz, 2H), 1.39 (s, 9H). MS m / z (M + H): 411.3.

[0551] Step 2: At ice temperature, trifluoroacetic acid (10.4 ml) was added to a solution of 2 (2.6 g, 6.3 mmol) in dichloromethane (26.0 ml), and the reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After the raw materials were completely consumed, the volatiles were removed under reduced pressure to obtain a brownish-red oily product. The obtained crude product was washed with ether (3 × 50 ml) to obtain a light yellow viscous liquid 3 (2.9 g of crude product). 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.69 (bs, 2H), 8.09 - 8.08 (m, 1H), 7.81 - 7.78 (m, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.08 - 6.97 (m, 4H), 6.45 (s, 1H), 4.37 (s, 2H), 3.27 (s, 3H), 3.15 - 3.09 (m, 4H), 2.60 (t, J = 5.6 Hz, 2H), 2.45 (t, J = 5.6 Hz, 2H). MS m / z (M+H): 311.3.

[0552] Step 3: At 25 °C, to a solution of 3 (2.9 g, 6.8 mmol) in dimethyl sulfoxide (30 mL, 10V) was added diisopropyl-ethylamine (3.5 mL, 0.0205 mol) and the carbamate product 5 of Step 4, Example 16 (1.7 g, 6.8 mmol). The reaction mixture was stirred at 60 °C for 6 hours. The reaction was monitored by TLC. The resulting reaction mixture was diluted with ethyl acetate (300 ml), washed with water (3 × 100 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (hexane solution of 30% ethyl acetate) to give the product 4 as a pale yellow gummy solid (2.6 g, 86%). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.08 (d, J = 2.0 Hz, 1H), 7.81 - 7.78 (m, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.25 - 7.21 (m, 2H), 7.09 - 6.93 (m, 7H), 6.83 (d, J = 3.2 Hz, 1H), 6.34 (s, 1H), 4.37 (s, 2H), 3.38 - 3.28 (m, 4H), 3.27 (s, 3H), 2.71 - 2.69 (m, 1H), 2.36 (t, J = 5.6 Hz, 2H), 2.25 (t, J = 5.6 Hz, 2H), 1.85 (m, 1H), 1.13 (d, J = 4.8 Hz, 1H), 1.04 (d, J = 7.6 Hz, 1H). 1313C NMR: (100 MHz, DMSO-d6): δ 162.60, 157.57, 153.87, 146.76, 142.00, 140.15, 139.65, 138.71, 129.52, 128.87, 128.10, 125.86, 125.35, 124.90, 123.12, 121.21, 118.96, 111.26, 70.58, 57.49, 44.94, 43.90, 35.63, 34.08, 28.92, 24.31 and 15.57. MS m / z (M+H): 470.3, HPLC purity: 99.57%, chiral HPLC: 99.60%.

[0553] Example 33: Synthesis of 4-({3-[(5-methylpyrimidin-2-yl)oxy]phenyl}methylene)-N-[(1R,2S)-2-phenylcyclopropyl]piperidine-1-carboxamide:

[0554]

[0555] Step 1 - At room temperature, 3-(hydroxymethyl)phenol (31.86 g, 0.256 mol) and cesium carbonate (100.36 g, 0.308 mol) were added to a solution of 2-chloro-5-methylpyrimidine 1 (33.0 g, 0.256 mol) in DMF (330 mL). The reaction mixture was stirred at 100 °C for 5 h. The resulting mixture was then cooled to room temperature, diluted with dichloromethane (330 ml), washed with water (2 × 330 ml), 1N KOH solution (2 × 165 ml), brine, and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (hexane solution of 8% ethyl acetate) to give the white solid product 2 (22.0 g, 40%). 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.4 (s, 2H), 7.3 (t, J = 8.1 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.07 (s, 1H), 7.0 (d, J = 7.5 Hz, 1H), 5.26 (m, 1H), 4.49 (d, J = 5.4, 2H), 2.19 (s, 3H). MS m / z (M+H): 217.1.

[0556] Step 2 - Thionyl chloride (8.1 mL, 0.111 mol) was added dropwise to a solution of {3-[(5-methylpyrimidin-2-yl)oxy]phenyl}methanol 2 (22.0 g, 0.101 mol) in dichloromethane (220 mL) while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated under reduced pressure and diluted with ethyl acetate (220 ml). The organic layer was washed with saturated sodium bicarbonate solution (110 ml) and water (2 × 220 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the white solid product 3 (21.5 g, 90%). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.45 (s, 2H), 7.4 (t, J = 8 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.2 (t, J = 2 Hz, 1H), 7.13 - 7.10 (m, 1H), 4.75 (s, 2H), 2.18 (s, 3H). MS m / z (M + H): 235.3.

[0557] Step 3 - A solution of 2-[3-(chloromethyl)phenoxy]-5-methylpyrimidine 3 (21.0 g, 0.0894 mol) in triethyl phosphite (25.0 ml, 0.143 mol) was heated at 130 °C for 16 hours. The reaction mixture was allowed to reach room temperature, and the crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (hexane solution of 86% ethyl acetate) to give the light green oily product 4 (21.6 g, 72%). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.44 (s, 2H), 7.3 (t, J = 8 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 7.02 (t, J = 8 Hz, 2H), 3.95 - 3.88 (m, 4H), 3.31 - 3.20 (m, 2H), 2.18 (s, 3H), 1.15 - 1.11 (m, 6H). MS m / z (M + H): 337.3.

[0558] Step 4 - At room temperature, 15-crown-5 ether (0.275 g, 0.0012 mol) was added to a solution of diethyl ({3-[(5-methylpyrimidin-2-yl)oxy]phenyl}methyl)phosphonate 4 (21.0 g, 0.062 mol) in THF (147 mL). The reaction was cooled (ice bath) and 60% NaH (3.73 g, 0.093 mol) was added portionwise. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (12.4 g, 0.0624 mol) in THF (63 mL) was added at ice temperature and the mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with ethyl acetate (210 ml), washed with water (3 × 210 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by column (silica gel (230 - 400), hexane solution of 15% ethyl acetate) to give the white solid product 5 (17.0 g, 72%). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.44 (s, 2H), 7.34 (t, J = 8 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.99 - 6.97 (m, 2H), 6.34 (s, 1H), 3.38 (t, J = 5.6 Hz, 2H), 2.37 (t, J = 5.6 Hz, 2H), 2.24 (t, J = 5.6 Hz, 2H), 2.18 (s, 3H), 1.38 (s, 9H). MS m / z (M + H): 382.3.

[0559] Step 5 - At ice temperature, trifluoroacetic acid (68.0 mL) was added to a solution of tert-butyl 4-({3-[(5-methylpyrimidin-2-yl)oxy]phenyl}methylene)piperidine-1-carboxylate 5 (17.0 g, 0.0445 mol) in dichloromethane (170 mL). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was evaporated to dryness under reduced pressure to give a crude product as a yellow oil. The crude product obtained was washed with ether (3 × 50 ml) to give product 6 as an off-white solid (15.8 g, crude). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.83 (bs, 2H), 8.45 (s, 2H), 7.37 (t, J = 8.4 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.02 (m, 2H), 6.43 (s, 1H), 3.11 (d, J = 24 Hz, 4H), 2.59 (t, J = 5.6 Hz, 2H), 2.18 (s, 3H). MS m / z (M + H): 282.33.

[0560] Step 6 - At 25 - 30 °C, to a solution of trifluoroacetate of 5 - methyl - 2 - {3 - [(piperidin - 4 - yl)methyl]phenoxy}pyrimidine 6 (15.0 g, 0.0379 mol) in dimethyl sulfoxide (150 mL) was added diisopropylethylamine (20.0 mL, 0.113 mol) and the carbamate product 5 of Step 4, Example 16 (10.57 g, 0.0417 mol). The reaction mixture was stirred at 60 °C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (150 ml), washed with water (3 × 150 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (hexane solution of 70% ethyl acetate) to give the light yellow solid product 7 (12.0 g, 72%). Melting point range: 58 °C - 67.5 °C. 1 1H NMR (400 MHz, DMSO - d6) δ (ppm): 8.4 (s, 2H), 7.3 (t, J = 7.6 Hz, 1H), 7.23 - 7.19 (m, 2H), 7.12 - 7.06 (m, 4H), 6.9 (d, J = 8 Hz, 2H), 6.8 (s, 1H), 6.3 (s, 1H), 3.36 - 3.29 (m, 4H), 2.6 (s, 2H), 2.3 (s, 2H), 2.2 - 2.1 (m, 5H), 1.87 - 1.84 (m, 1H), 1.16 - 1.06 (m, 2H). MS m / z (M + H): 441.4, HPLC purity: 99.67%

[0561] Example 34: Synthesis of N - [(2S) - 2 - phenylcyclopropyl] - 4 - {[3 - (pyrazin - 2 - yloxy)phenyl]methylene}piperidine - 1 - carboxamide:

[0562]

[0563] Step 1: At room temperature, to a solution of 2 - chloropyrazine 1 (15.0 g, 0.130 mol) in DMF (150 ml) was added 3 - (hydroxymethyl)phenol (16.25 g, 0.130 mol) and cesium carbonate (51.2 g, 0.157 mol). The reaction mixture was stirred at 100 °C for 5 hours. Then the resulting mixture was allowed to reach room temperature, diluted with water (250 ml), extracted with ethyl acetate (3 × 500 ml), the resulting organic layer was washed with 1N KOH (2 × 250 ml) solution, and the separated organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (hexane solution of 10% ethyl acetate) to give the off - white solid product 2 (9.3 g, 35%). 11H NMR (400 MHz, DMSO-d6) δ (ppm): 8.50 (d, J = 1.2 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.18 - 8.17 (m, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.1 (s, 1H), 7.03 (dd, J = 6 Hz, J = 2 Hz, 1H), 5.25 (t, J = 5.6 Hz, 1H), 4.49 (d, J = 6 Hz, 2H). MS m / z (M+1): 203.2.

[0564] Step 2: Thionyl chloride (3.94 mL, 0.054 mol) was added dropwise to a solution of {3-[(pyrazin-2-yl)oxy]phenyl}methanol 2 (10.0 g, 0.049 mol) in dichloromethane (100 mL, 10V) while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated under reduced pressure and diluted with ethyl acetate (250 mL). The organic layer was washed with saturated sodium bicarbonate solution (150 mL) and water (2 × 200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the yellow solid product 3 (9.0 g, 82%). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.54 - 8.54 (m, 1H), 8.36 (d, J = 2.8, 1H), 8.19 - 8.18 (m, 1H), 7.43 (t, J = 7.6, 1H), 7.31 - 7.14 (m, 3H), 4.75 (s, 2H). MS m / z (M+1): 221.2.

[0565] Step 3: A solution of 2-[3-(chloromethyl)phenoxy]pyrazine 3 (10.0 g, 0.045 mol) in triethyl phosphite (12.3 mL, 0.072 mol) was heated at 130 °C for 6 hours. The reaction mixture was allowed to reach room temperature, and the crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (hexane solution of 60% ethyl acetate) to give the colorless oil product 4 (9.49 g, 64.5%). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.51 (d, J = 1.6 Hz, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.18 - 8.17 (m, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.08 - 7.05 (m, 2H), 3.95 - 3.88 (m, 4H), 3.26 (2s, 2H), 1.13 (t, J = 3.2 Hz, 6H). MS m / z (M+1): 323.2.

[0566] Step 4: At room temperature, 15-crown-5 ether (136 mg, 0.62 mmol) was added to a solution of diethyl {[3-(pyrazin-2-yloxy)phenyl]methyl}phosphonate 4 (10.0 g, 0.031 mol) in THF (70 mL). At 0 - 5 °C, 60% NaH (1.86 g, 0.046 mol) was added portionwise to the above reaction mixture. The reaction mixture was stirred at room temperature for 30 minutes and then cooled again to ice temperature. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (6.18 g, 0.031 mol) in THF (30 mL) was added at ice temperature, and the mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (500 ml), extracted with ethyl acetate (3 × 500 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by column (silica gel (230 - 400), hexane solution of 15% ethyl acetate) to give product 5 as an off-white solid (9.1 g, 80%). 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.51 (d, J = 1.2 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.18 - 8.17 (m, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.04 - 7.02 (m, 3H), 6.34 (s, 1H), 3.37 (t, J = 5.2 Hz, 2H), 3.32 - 3.29 (m, 2H), 2.37 (t, J = 5.6 Hz, 2H), 2.24 (t, J = 5.6 Hz, 2H), 1.37 (s, 9H). MS m / z (M + 1): 368.4.

[0567] Step 5: At ice temperature, trifluoroacetic acid (40 mL) was added to a solution of tert-butyl 4-{[3-(pyrazin-2-yloxy)phenyl]methylene}piperidine-1-carboxylate 5 (10.0 g, 0.027 mol) in dichloromethane (100 mL). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was evaporated to dryness under reduced pressure to give a crude product as an oily red substance. The obtained crude product was washed with ether (3 × 50 ml) to give 6 as an off-white solid (9.5 g, 92%). 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.72 (bs, 2H), 8.52 (d, J = 1.6 Hz, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.18 - 8.17 (m, 1H), 7.42 - 7.38 (m, 1H), 7.12 - 7.06 (m, 3H), 6.44 (s, 1H), 3.13 - 3.07 (m, 4H), 2.58 (t, J = 5.6 Hz, 2H). MS m / z (M + 1): 268.3.

[0568] Step 6: At 25 - 30 °C, to a solution of the trifluoroacetate of 2-[3-(piperidin-4-ylmethyl)phenoxy]pyrazine 6 (10.0 g, 0.026 mol) in dimethyl sulfoxide (100 ml, 10V) was added diisopropylethylamine (13.7 ml, 0.078 mol) and the carbamate product 5 from Example 16, Step 4 (7.3 g, 0.028 mol). The reaction mixture was stirred at 60 °C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (500 ml), washed with water (3 × 150 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (hexane solution of 50% ethyl acetate) to give product 7 as a light yellow solid (8.0 g, 71%). Melting range: 41.7 °C - 52.6 °C; 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.52 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 1.2 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 7.6 Hz, 2H), 7.12 - 7.01 (m, 6H), 6.83 (d, J = 2.4 Hz, 1H), 6.33 (s, 1H) 3.37 - 3.27 (m, 4H), 2.67 (d, J = 3.2 Hz, 1H), 2.35 (s, 1H), 2.23 (s, 1H), 1.87 - 1.82 (m, 1H), 1.16 - 1.01 (m, 2H). MS m / z (M+1): 427.4. HPLC purity: 99.49%.

[0569] Example 35: Synthesis of 4-[3-(5-Hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0570]

[0571] Step 1: At room temperature, to a solution of 5-bromo-2-fluoropyridine 1 (7.72 g, 44.3 mmol) in DMSO (40 mL, 8V) was added 3-hydroxymethylphenol (5 g, 40.3 mmol) and cesium carbonate (15.75 g, 48.3 mmol). The reaction mixture was stirred at 100 °C for 8 hours. Then the resulting mixture was allowed to reach room temperature, diluted with water (70 ml), and extracted with ethyl acetate (3 × 100 ml). The combined organic layers were dried over sodium sulfate and the solvent was evaporated under reduced pressure using a rotary evaporator. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (hexane solution of 30% ethyl acetate) to give product 2 as a light yellow oil (7.1 g, 63% yield).1 1H NMR (400 MHz, CDCl3) δ 8.19 (dd, J = 2.6, 0.6 Hz, 1H), 7.77 (dd, J = 8.7, 2.6 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.20 (ddd, J = 7.6, 1.7, 0.9 Hz, 1H), 7.13 (d, J = 2.1 Hz, 1H), 7.03 (ddd, J = 8.1, 2.5, 1.0 Hz, 1H), 6.84 (dd, J = 8.7, 0.7 Hz, 1H), 4.68 (s, 2H). MS m / z (M): 280.21.

[0572] Step 2: Thionyl chloride (2.43 g, 20.4 mmol) was added dropwise to a solution of {3-[(5-bromopyridin-2-yl)oxy]phenyl}methanol 2 (5.2 g, 18.57 mmol) in dichloromethane (52 mL) while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated under reduced pressure and diluted with ethyl acetate (80 ml). The organic layer was washed with saturated sodium bicarbonate solution (25 ml) and water (25 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to give product 3 as a white solid (4.12 g, 75% yield). 1 1H NMR (400 MHz, CDCl3) δ 8.22 (dd, J = 2.6, 0.7 Hz, 1H), 7.79 (dd, J = 8.7, 2.6 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.29–7.21 (m, 2H), 7.17 (t, J = 2.1 Hz, 1H), 7.08 (m, 1H), 6.86 (dd, J = 8.8, 0.6 Hz, 1H), 4.59 (s, 2H). MS m / z (M+2): 299.9.

[0573] Step 3: A solution of triethyl phosphite (5.78 mL, 33.7 mmol) in 5-bromo-2-[3-(chloromethyl)phenoxy]pyridine 3 (4 g, 13.5 mmol) was heated at 150 °C for 6 h. The reaction mixture was allowed to reach room temperature, and the crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (petroleum ether solution of 60% ethyl acetate) to give product 4 as a colorless oil (3.88 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J = 2.6, 0.7 Hz, 1H), 7.76 (dd, J = 8.7, 2.6 Hz, 1H), 7.40–7.29 (m, 1H), 7.16 (dt, J = 7.3, 1.7 Hz, 1H), 7.07 (q, J = 2.3 Hz, 1H), 7.02 (dtd, J = 8.1, 2.3, 1.0 Hz, 1H), 6.83 (dd, J = 8.7, 0.7 Hz, 1H), 4.03 (dqd, J = 8.7, 7.1, 1.6 Hz, 4H), 3.16 (d, J = 21.6 Hz, 2H), 1.25 (t, J = 7.1 Hz, 6H). MS m / z (M + 1): 401.

[0574] Step 4: 15-Crown ether (41 mg, 0.190 mmol) was added to a solution of diethyl ({3-[(5-bromopyridin-2-yl)oxy]phenyl}methyl)phosphonate 4 (3.8 g, 9.52 mmol) in THF (19 mL). The reaction was cooled (ice bath) and 60% NaH (342 mg, 14.2 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 30 min and cooled again to ice temperature. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.9 g, 9.52 mmol) in THF (19 mL) was added at ice temperature and the mixture was stirred at room temperature for 16 h. The resulting reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (3 × 40 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (n-hexane solution of 5% ethyl acetate) to give product 5 as a white solid (2.58 g, 61% yield). 1 1H NMR (400 MHz, CDCl3) δ 8.22 (dd, J = 2.6, 0.7 Hz, 1H), 7.77 (dd, J = 8.7, 2.6 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.04 (ddt, J = 7.7, 1.7, 0.8 Hz, 1H), 7.01–6.92 (m, 2H), 6.84 (dd, J = 8.7, 0.7 Hz, 1H), 6.34 (s, 1H), 3.45 (m, 4H), 2.39 (m, 4H), 1.47 (s, 9H). MS m / z (M + Na): 469.21.

[0575] Step 5: The experiment was carried out using the method reported in the literature (Reference: J. Am. Chem. Soc. 2016, 138, 13493 - 13496). LiOH·H2O (396 mg, 9.43 mmol), ligand L-1 (110 mg, 0.337 mmol), and Cu(acac)2 (88 mg, 0.337 mmol) were successively added to a degassed solution of 4-[3-(5-bromo-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester 5 (2 g, 4.49 mmol) in DMSO (40 mL) and water (2 mL), and degassing was continued for 10 minutes. The resulting reaction mixture was heated at 85 °C for 48 hours. The reaction progress was monitored by TLC. The reaction mixture was cooled to ambient temperature, quenched by adding 5% aqueous NH4Cl solution (12 mL), and then diluted with ethyl acetate (25 mL). The organic layer was separated, washed with brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was further purified by flash chromatography on silica gel using a hexane solution of 40 - 45% ethyl acetate to obtain 4-[3-(5-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester (6) as a light brown solid (738 mg, 43% yield). 1 1H NMR (400 MHz, CDCl3) δ 9.69 (bs, 1H), 7.83 (s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 4.9 Hz, 1H), 6.92 (d, J = 7.8 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 6.30 (s, 1H), 3.48 (t, J = 5.7 Hz, 2H), 3.35 (t, J = 5.9 Hz, 2H), 2.41 (t, J = 5.9 Hz, 2H), 2.29 (t, J = 5.8 Hz, 2H), 1.47 (s, 9H). MS m / z (M+Na): 405.44.

[0576] Step 6: At ice temperature, trifluoroacetic acid (2.4 ml) was added to a solution of 6 (600 mg, 1.57 mmol) in dichloromethane (6 ml), and the reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After complete consumption of the starting material, the volatiles were removed under reduced pressure to obtain the crude product 7 as an oily red substance. The obtained crude product was washed with diethyl ether (3 × 5 ml) to obtain the trifluoroacetate of 6-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyridin-3-ol as a brown oil (400 mg of crude product). MS m / z (M+1): 283.21.

[0577] Step 7: At 25 °C, to a solution of 7 (300 mg, 1.06 mmol) in dimethyl sulfoxide (3 mL) was added diisopropylethylamine (1.48 mL, 8.51 mmol) and the carbamate product 5 (269 mg, 1.06 mmol) from Step 4, Example 16. The reaction mixture was stirred at 60 °C for 4 h. The reaction was monitored by TLC. The resulting reaction mixture was diluted with ethyl acetate (20 mL), washed with water (3 × 20 mL), and dried over anhydrous sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by reverse-phase HPLC, the collected fractions were concentrated, and the resulting residue was lyophilized to give product 8 as an off-white solid (93 mg, 20%). 1 HNMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.77–7.67 (m, 1H), 7.37–7.15 (m, 4H), 7.17–7.07 (m, 3H), 6.98 (d, J = 7.6 Hz, 1H), 6.93–6.79 (m, 4H), 6.33 (s, 1H), 3.37 (d, J = 6.0 Hz, 2H), 3.32–3.25 (m, 2H), 2.75–2.61 (m, 1H), 2.30 (dt, J = 42.8, 5.8 Hz, 4H), 1.88 (ddd, J = 9.4, 6.1, 3.2 Hz, 1H), 1.16 (dt, J = 9.6, 5.1 Hz, 1H), 1.09–1.02 (m, 1H). MS m / z (M+1): 442.4; HPLC purity: 96.70%; chiral HPLC purity: 96.0%.

[0578] Example 36: Synthesis of 4-[3-(4-Hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0579]

[0580] Step 1: At room temperature, to a solution of 4-bromo-2-fluoropyridine 1 (7.72 g, 44.3 mmol) in DMSO (40 ml) was added 3-(hydroxymethyl)phenol (5 g, 40.3 mmol) and cesium carbonate (15.75 g, 48.3 mmol). The reaction mixture was stirred at 100 °C for 8 h. Then the resulting mixture was allowed to reach room temperature, diluted with water (70 ml), extracted with ethyl acetate (3 × 100 ml), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230-400) column (30% ethyl acetate in hexane) to give product 2 as a pale yellow oil (4.8 g, 43% yield). 11H NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 5.4, 1.8 Hz, 1H), 7.40 (td, J = 7.8, 1.8 Hz, 1H), 7.28–7.22 (m, 1H), 7.15 (dt, J = 5.3, 2.0 Hz, 2H), 7.11 (d, J = 1.8 Hz, 1H), 7.05 (dd, J = 8.0, 2.3 Hz, 1H), 4.72 (s, 2H). MS m / z (M+2): 281.9.

[0581] Step 2: Thionyl chloride (2.24 g, 18.8 mmol) was added dropwise to a solution of {3-[(4-bromopyridin-2-yl)oxy]phenyl}methanol 2 (4.8 g, 17.1 mmol) in dichloromethane (48 mL) while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated under reduced pressure and diluted with ethyl acetate (80 ml). The organic layer was washed with saturated sodium bicarbonate solution (25 ml) and water (25 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to give product 3 as a white solid (4.05 g, 80% yield). 1 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 5.5 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.25 (q, J = 2.0, 1.3 Hz, 1H), 7.21–7.14 (m, 2H), 7.13–7.05 (m, 2H), 4.59 (s, 2H). MS m / z (M+2): 299.9.

[0582] Step 3: A solution of 3 (4 g, 13.5 mmol) in triethyl phosphite (5.78 mL, 33.7 mmol) was heated at 150 °C for 6 hours. The reaction mixture was brought to room temperature and the crude product obtained after evaporation of the volatiles was purified by silica gel (230-400) column (petroleum ether solution of 60% ethyl acetate) to give product 4 as a colorless oil (3.88 g, 72% yield). 1 1H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J = 5.4 Hz, 1H), 7.36 (m, 1H), 7.20–7.13 (m, 2H), 7.07 (t, J = 1.9 Hz, 2H), 7.03 (m, 1H), 4.03 (m, 4H), 3.16 (d, J = 21.7 Hz, 2H), 1.25 (t, J = 7.1 Hz, 6H). MS m / z (M+H): 401.20.

[0583] Step 4: To a solution of 4 (3.8 g, 9.52 mmol) in THF (19 mL) was added 15-crown ether (41 mg, 0.190 mmol). The reaction was cooled (ice bath) and 60% NaH (342 mg, 14.2 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 30 minutes and cooled again to ice temperature. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.9 g, 9.52 mmol) in THF (19 mL) was added at ice temperature and the mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (3 × 40 mL), and dried over anhydrous sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by column chromatography on silica gel (230 - 400 mesh) (hexane solution of 5% ethyl acetate) to give product 5 as a white solid (2.75 g, 65% yield). 1 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 5.4 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.15 (dd, J = 5.4, 1.6 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 7.00–6.93 (m, 2H), 6.34 (s, 1H), 3.45 (dt, J = 40.2, 5.9 Hz, 5H), 2.50–2.27 (m, 4H), 1.47 (s, 9H). MS m / z (M+Na): 467.6.

[0584] Step 5: To a degassed solution of 5 (2 g, 4.49 mmol) in DMSO (40 mL) and water (2 mL) were successively added LiOH·H2O (396 mg, 9.43 mmol), ligand L-1 (110 mg, 0.337 mmol), and Cu(acac)2 (88 mg, 0.337 mmol), and degassing was continued for 10 minutes. The resulting reaction mixture was heated at 85 °C for 48 hours. The progress of the reaction was monitored by TLC. The above reaction mixture was cooled to ambient temperature, quenched by the addition of 5% aqueous NH4Cl solution (12 mL), and then diluted with ethyl acetate (25 mL). The organic phase was separated, washed with brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure to give a crude product. The crude product obtained was further purified by flash chromatography on silica gel using a hexane solution of 40 - 45% ethyl acetate to give tert-butyl 4-[3-(5-hydroxypyridin-2-yloxy)benzylidene]piperidine-1-carboxylate (6) as a light brown solid (686 mg, 40% yield). 11H NMR (400 MHz, chloroform-d) δ 8.02 (d, J = 5.4 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.15 (dd, J = 5.4, 1.6 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 7.00–6.93 (m, 2H), 6.34 (s, 1H), 3.45 (dt, J = 40.2, 5.9 Hz, 5H), 2.50–2.27 (m, 4H), 1.47 (s, 9H). MS m / z (M+1): 383.2.

[0585] Step 6: At ice temperature, trifluoroacetic acid (1.2 ml) was added to a solution of tert-butyl 4-[3-(4-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylate 6 (400 mg, 1.04 mmol) in dichloromethane (4 ml). The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. After complete consumption of the starting material, the volatiles were removed under reduced pressure to afford the product 7 as an oily red residue. The crude product obtained was washed with diethyl ether (3 × 50 ml) to give the trifluoroacetate salt of 6-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyridin-3-ol as a brown oil (400 mg crude product). MS m / z (M+1): 283.2.

[0586] Step 7: Diisopropylethylamine (1.38 ml, 7.94 mmol) and the carbamate product 5 of Step 4, Example 16 (251 mg, 0.992 mmol) were added to a solution of the trifluoroacetate salt of 6-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyridin-3-ol 7 (280 mg, 0.992 mmol) in dimethyl sulfoxide (2.8 mL, 10V). The reaction mixture was stirred at 60 °C for 4 h. The reaction was monitored by TLC. The resulting reaction mixture was diluted with ethyl acetate (20 ml), washed with water (3 × 20 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by reverse phase HPLC to give the product 8 as an off-white solid (137 mg, 32%). 11H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.24 (tt, J = 7.9, 1.3 Hz, 2H), 7.15–7.08 (m, 3H), 7.04 (d, J = 7.7 Hz, 1H), 6.95–6.88 (m, 2H), 6.83 (d, J = 3.2 Hz, 1H), 6.55 (dd, J = 5.7, 2.1 Hz, 1H), 6.35 (s, 1H), 6.28 (d, J = 2.0 Hz, 1H), 3.38 (t, J = 5.8 Hz, 2H), 3.32 (m, 2H), 2.70 (tt, J = 6.9, 3.6 Hz, 1H), 2.37 (t, J = 5.8 Hz, 2H), 2.29–2.22 (m, 2H), 1.88 (ddd, J = 9.4, 6.1, 3.2 Hz, 1H), 1.16 (dt, J = 9.6, 5.1 Hz, 1H), 1.07 (dt, J = 7.6, 5.8 Hz, 1H). MS m / z (M+H): 442.19, HPLC purity: 98.50%; chiral HPLC purity: 97.9%.

[0587] Example 37: Synthesis of 4-[3-(6-Hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0588]

[0589] Step 1: At room temperature, 3-Hydroxymethylphenol (2.64 g, 21.3 mmol) and cesium carbonate (5.55 g, 17.0 mmol) were added to a solution of 2-Bromo-6-fluoropyridine 1 (2.5 g, 14.2 mmol) in DMF (25 mL, 10V). The reaction mixture was stirred at 100 °C for 8 h. Then the resulting mixture was allowed to reach room temperature, diluted with water (50 mL), extracted with ethyl acetate (3 × 50 mL), and the organic layer was dried over anhydrous sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (hexane solution of 30% ethyl acetate) to give Product 2 as a pale yellow oil (2.48 g, 62% yield). 11H NMR (400 MHz, DMSO-d6) δ (ppm): 7.79 (t, J = 7.9 Hz, 1H), 7.39 (t, J = 7.9 Hz, 2H), 7.19 (dt, J = 7.7, 1.2 Hz, 1H), 7.09 (t, J = 1.9 Hz, 1H), 7.04–6.97 (m, 2H), 5.29 (t, J = 5.8 Hz, 1H), 4.52 (d, J = 5.8 Hz, 2H). MS m / z (M): 280.

[0590] Step 2: Thionyl chloride (0.7 mL, 9.7 mmol) was added dropwise to a solution of {3-[(6-bromopyridin-2-yl)oxy]phenyl}methanol 2 (2.48 g, 8.85 mmol) in dichloromethane (25 mL) while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 h. The volatiles were evaporated under reduced pressure and diluted with ethyl acetate (60 ml). The organic layer was washed with saturated sodium bicarbonate solution (25 ml) and water (25 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to give product 3 as a brown oil (2.56 g, 86%). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.86–7.76 (m, 1H), 7.50–7.36 (m, 2H), 7.33 (dt, J = 7.7, 1.3 Hz, 1H), 7.25 (t, J = 2.1 Hz, 1H), 7.161–7.071 (m, J = 8.1, 2.4, 1.1 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 4.79 (s, 2H). MS m / z (M): 298.19.

[0591] Step 3: A solution of triethyl phosphite (3.67 mL, 21.0 mmol) and 2-bromo-6-[3-(chloromethyl)phenoxy]pyridine 3 (2.55 g, 8.50 mmol) was heated at 150 °C for 6 h. The reaction mixture was allowed to reach room temperature and the crude product obtained after evaporation of the volatiles was purified by silica gel (230–400) column (petroleum ether solution of 60% ethyl acetate) to give product 4 as a light brown oil (2.97 g, crude product). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.88–7.72 (m, 1H), 7.52–6.96 (m, 6H), 4.011–3.90 (m, J = 14.7, 7.3, 4.0 Hz, 4H), 1.16 (tt, J = 7.7, 5.3 Hz, 6H). MS m / z (M+Na): 422.5.

[0592] Step 4: To a solution of diethyl ({3-[(6-bromopyridin-2-yl)oxy]phenyl}methyl)phosphonate 4 (2.96 g, 7.39 mmol) in THF (20 mL) was added 15-crown ether (32 mg, 0.147 mmol). The reaction was cooled (ice bath) and 60% NaH (266 mg, 11.0 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 30 minutes and cooled again to ice temperature. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.76 g, 8.86 mmol) in THF (15 mL) was added at ice temperature and the mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (3 × 40 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230 - 400) column (hexane solution of 5% ethyl acetate) to give the product 5 as a yellow oil (2.11 g, 65% yield). 1 H NMR (400 MHz, DMSO) δ (ppm): 7.84–7.77 (m, 1H), 7.44–7.35 (m, 2H), 7.14–6.99 (m, 4H), 6.39 (s, 1H), 3.47–3.36 (m, 3H), 3.35 (s, 2H), 2.42 (t, J = 5.8 Hz, 2H), 2.30–2.24 (m, 2H), 1.40 (s, 9H). MS m / z (M+Na): 467.6.

[0593] Step 5: To a degassed solution of tert-butyl 4-[3-(6-bromo-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylate 5 (1.8 g, 4.04 mmol) in DMSO (36 mL, 20V) and water (1.8 mL) were added LiOH·H2O (356 mg, 8.49 mmol), ligand L-1 (99.6 mg, 0.303 mmol), and Cu(acac)2 (79 mg, 0.303 mmol) and degassing was continued for 10 minutes. The resulting reaction mixture was heated at 100 °C under MW irradiation for 4 hours. The progress of the reaction was monitored using TLC. The above reaction mixture was cooled to ambient temperature, quenched by addition of 5% aqueous NH4Cl solution (12 mL), and then diluted with ethyl acetate (25 mL). The organic phase was separated, washed with brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product obtained was further purified by flash chromatography on silica gel using a hexane solution of 40 - 45% ethyl acetate to give tert-butyl 4-[3-(6-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylate (6) as a light brown solid (730 mg, 47% yield). 11H NMR (400 MHz, DMSO-d6) δ (ppm): 10.80 (bs, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.96–6.90 (m, 2H), 6.36–6.33 (m, 3H), 3.40 (t, J = 5.2 Hz, 1H), 3.38–3.31 (m, 2H), 2.39 (t, J = 5.6 Hz, 2H), 2.27 (t, J = 5.6 Hz, 2H), 1.45 (s, 9H), MS m / z (M+Na): 405.17。

[0594] Step 6: At ice temperature, trifluoroacetic acid (1.44 mL) was added to a solution of tert-butyl 4-[3-(6-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylate 6 (720 mg, 1.88 mmol) in dichloromethane (5.6 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After complete consumption of the starting material, the volatiles were removed under reduced pressure to give an oily product. The resulting crude product was washed with diethyl ether (3 × 5 ml) to give the trifluoroacetate salt of 6-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyridin-2-ol 7 as a brown oil (750 mg of crude product). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.64 (s, 2H), 7.65 (t, J = 7.9 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.29–6.89 (m, 5H), 6.46 (s, 1H), 6.35 (dd, J = 7.8, 3.7 Hz, 2H), 3.36 - 3.08 (m, 4H), 2.60 (t, J = 6.0 Hz, 2H, 2.39 (t, J = 6.0 Hz, 2H). MS m / z (M+H): 283.33。

[0595] Step 7: At 25 °C, diisopropylethylamine (1.9 ml, 12.9 mmol) and the carbamate product 5 of Step 4, Example 16 (570 mg, 2.25 mmol) were added to a solution of the trifluoroacetate salt of 2-bromo-6-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyridine 7 (730 mg, 2.5 mmol) in dimethyl sulfoxide (7.3 ml). The reaction mixture was stirred at 60 °C for 5 hours. The reaction was monitored by TLC. The resulting reaction mixture was diluted with ethyl acetate (70 ml), washed with water (3 × 20 ml), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by reverse-phase HPLC twice to give the product 8 as an off-white solid (120 mg, 11%). 11H NMR (400 MHz, DMSO-d6) δ (ppm): 10.83 (s, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.24 (dd, J = 8.2, 6.9 Hz, 2H), 7.17–7.00 (m, 4H), 6.99–6.81 (m, 3H), 6.35 (s, 3H), 3.38 (t, J = 5.7 Hz, 3H), 3.30 (t, J = 5.9 Hz, 2H), 2.70 (ddd, J = 7.9, 5.5, 2.4 Hz, 1H), 2.37 (t, J = 5.8 Hz, 2H), 2.26 (t, J = 5.7 Hz, 2H), 1.88 (ddd, J = 9.4, 6.1, 3.2 Hz, 1H), 1.16 (m, 1H), 1.07 (m, 1H). MS m / z (M+H): 442.7, HPLC purity: 98.48%; chiral HPLC: 98.6%.

[0596] Example 38: Soluble epoxide hydrolase (sEH) inhibition assay:

[0597] The sEH enzyme inhibition assay was performed using a kit (Cayman Cat. No. 10011671) available from Cayman Chemical Company of Ann Arbor, Michigan. The assay used 3-phenyl-cyano(6-methoxy-2-naphthyl)-methyl ester-2-oxirane acetic acid as the substrate for sEH. Hydrolysis of the substrate produces a highly fluorescent product that can be monitored at excitation and emission wavelengths of 330 and 465 nm, respectively. The assay mixture consisted of 185 - 190 μl of assay buffer and 5 μl of sEH enzyme in a 96-well plate. Different concentrations of the compound (in 5 μL of DMSO) or DMSO alone (vehicle) were added, and the reaction was initiated by adding 5 μL of the substrate. The plate was incubated at 25 °C for 15 minutes. Data analysis was performed and the percentage of inhibition was determined.

[0598] Example 39: Fatty acid amide hydrolase (FAAH (SEQ ID NO:3)) inhibition assay:

[0599] The FAAH enzyme inhibition assay was performed using a kit (Cayman Cat. No. 10010183) available from Cayman Chemical Company of Ann Arbor, Michigan. The assay used AMC arachidonoyl amide (7-amino-4-methyl-2H-1-benzopyran-2-one-5Z,8Z,11Z,14Z-eicosatetraenamide, Cayman Chemical Cat#10005098) as a substrate for FAAH. FAAH hydrolyzes AMC arachidonoyl amide, releasing the fluorescent product 7-amino-4-methylcoumarin (AMC). The fluorophore can be easily analyzed using an excitation wavelength of 340 - 360 nm and an emission wavelength of 450 - 465 nm. Different concentrations of the compound (in DMSO) or DMSO alone (vehicle) were added. After adding FAAH, the plate was incubated at ambient temperature for 20 minutes. The assay was initiated by the rapid addition of AMC arachidonoyl amide, and the reaction was carried out at ambient temperature for 60 minutes, during which the release of AMC was monitored by the accompanying increase in fluorescence intensity (excitation wavelength 340 - 360 nm, emission wavelength 450 - 465 nm). Fluorescence intensity measurements were made kinetically, and the reaction rate was calculated from the linear portion of the reaction using linear regression analysis.

[0600] % Initial Activity = (Inhibited Fluorescence / 100% Active Fluorescence) * 100

[0601] % Inhibition = 100 – (% Initial Activity)

[0602] Concentration (IC 50 ) Compounds that inhibit soluble epoxide hydrolase at less than 10 μM are considered active sEH inhibitors. The inhibitory activities of the compounds of formula I against sEH and FAAH enzymes are given in Table 1, see Figure 1 . The selectivity of sEH inhibition was determined by calculating the ratio of the inhibitory potencies of FAAH to sEH [IC 50 FAAH / IC 50 , sEH].

[0603] The efficacy of the compounds of general formula I in neurodegenerative diseases can be evaluated using animal models known in the literature.

[0604] Example 40 - The method described below (in vitro model of GBA1 (SEQ ID NO:1) inhibition) can be used to evaluate the potential of the compounds of formula 1 for neuroprotection and blocking α-synuclein aggregation associated with synucleinopathies, including Gaucher's disease, see Figure 2 .

[0605] In this in vitro model, dopaminergic neurons were isolated from the rat midbrain and cultured as described in the literature (FASEB J. 2008; 22(7): 2488-97). To mimic synucleinopathy, the cells were damaged by α-syn fibrils and Conduritol B epoxide (CBE, 20 μM) - a covalent inhibitor of GBA1 (SEQ ID NO: 1). This model reproduced the basic neuropathological features of synucleinopathy (e.g., the loss of dopaminergic neurons and axonal networks was evaluated by staining with tyrosine hydroxylase (TH), a marker of dopaminergic neurons in the nervous system).

[0606] Treatment with the test compound (Compound A) - On day 6 of culture, Compound A was dissolved in DMSO (100%, stock solution) and then diluted with the culture medium to obtain the desired concentration. Compound A was added to the culture for 1 hour 2 hours before CBE and 2 hours before α-syn application.

[0607] Treatment with CBE: On day 6 of culture, Conduritol B epoxide (CBE, 20 μM) was added to the culture for 1 hour before α-syn damage (to be confirmed / altered).

[0608] Treatment with α-Syn: On day 3, human α-syn was stirred at 37 °C for 3 days to generate fibrils (Lin et al., Elife. 2020 Jun 26; 9: e54726). On day 6, α-syn (250 nM) was directly applied to the cells in the presence of CBE. On day 8, in the continued presence of the test compound, the damage was extended for an additional 48 hours.

[0609] Treatment of neurons with CBE and α-syn induced a significant reduction in neuronal survival and axonal networks. Treatment with Compound A resulted in a large neuroprotective effect from 50 nM to 500 nM. At a concentration of 500 nM, Compound A completely prevented the loss of dopaminergic neurons and completely preserved the axonal network (evaluated by TH staining).

[0610] Example 41: An animal model of GBA1 (SEQ ID NO: 1) inhibition and synucleinopathy to evaluate the potential of compounds of formula 1 to treat synucleinopathy-related diseases including Gaucher disease.

[0611] Aged mice (18 months) were used as models of age-related neurodegenerative diseases and Parkinson's disease. α-Synuclein (α-syn) oligomer / fibril lesions (precisely characterized by western blot) were induced by intranigral (substantia nigra, pars compacta, SNPC) injection. These animals were treated with CBE with or without compound A or compound B for 4 weeks. Chronic inhibition of GBA1 (SEQ ID NO:1) (CBE) and α-Syn fibrils mediate toxic effects through multiple intracellular mechanisms such as mitochondrial and endoplasmic reticulum (ER) stress and impaired autophagy-lysosomal pathway function (Callizot et al., PlosOne. https: / / doi.org / 10.1371 / journal.pone.0215277).

[0612] The synucleinopathy-induced motor deficits were evaluated by the pole test ( Figure 3 ) - Three weeks after surgery, the motor coordination of the mice was evaluated by the pole test. The principle of this test is based on the ability of the mice to cross a horizontal pole connected to a platform (18 mm in diameter, 60 cm long). The test requires good coordination between the forelimbs and hindlimbs, as well as good balance. The mice were placed at one end of the pole and needed to reach the platform located on the other side of the pole. Motor coordination was studied after two training sessions (one day and two days) before the test. The sessions were recorded by a video camera system. The time taken to cross the pole, the number of steps, and the number of failed steps were measured.

[0613] As Figure 3 shown, in the mice treated with CBE and α-syn, the time taken to reach the platform in the pole test was significantly increased (compared to the control group without compounds). Treatment with compound A or compound B normalized the behavior to the control level.

[0614] Tissue collection and immunostaining - At the end of the experiment (28 days after surgery), mice were deeply anesthetized and perfused with cold PBS (3 minutes) and then with cold 4% paraformaldehyde (PFA) in PBS (3 minutes). Brains were dissected and further fixed in 4% PFA overnight at 4°C. Subsequently, the brains were placed in a solution of 30% sucrose in Tris-buffered saline (TBS) at 4°C. Coronal sections 40 μm thick (including the SNpc) were cut using a cryostat (4 sections per mouse, spaced 100 mm apart). For immunostaining, free-floating sections were incubated in TBS containing 0.25% bovine serum albumin, 0.3% Triton X-100, and 1% goat serum for 1 hour at room temperature. This incubation blocked non-specific binding sites and permeabilized the tissue. A selected number of sections from each animal were processed and incubated with the selected antibodies for 24 hours at 4°C or for 2 hours at room temperature: TH: chicken polyclonal antibody against tyrosine hydroxylase (1 / 1000); α-syn: rabbit polyclonal antibody against α-synuclein (1 / 200); IBA1: goat polyclonal antibody against IBA1 (1 / 200). These antibodies were visualized with Alexa Fluor 488 anti-rabbit IgG and Alexa Fluor 568 anti-chicken IgG, at a dilution of 1 / 500, in TBS containing 0.25% donkey serum albumin, 0.3% Triton X-100, and 1% goat serum. Images were obtained using a confocal laser scanning microscope.

[0615] The following readings were evaluated: Aggregation of α–syn in the SNpc ( Figure 4 ) - Treatment with CBE and α–syn (no compound vs. control) significantly increased α–syn aggregation (control vs. no compound). Treatment with the sEH inhibitor compound B significantly reduced α–syn aggregation.

[0616] The number of TH-positive cells in the SNpc ( Figure 5 ) - α-syn / / CBE-induced synuclein aggregation was associated with a significant loss of TH(+) neurons in the SNpc, which was associated with strong neuroinflammation (Ib1+, Figure 6 ).

[0617] Treatment with compound A or compound B reduced neurodegeneration and prevented neuronal death. Figure 5 . Additionally, a significant reduction in Iba1+ microglia was observed, indicating a positive effect of the molecule on neuroinflammation. Figure 6 .

[0618] Treatment with compound A or compound B showed a strong protective effect on dopaminergic neurons (survival and α-syn aggregation) and completely prevented neuroinflammation. Additionally, complete prevention of dyskinesia was observed.

[0619] Example 42: Use of the PINK1 (SEQ ID NO:2)-null / α-syn zebrafish model of synucleinopathy to evaluate the potential of a compound of formula 1 to treat diseases associated with mutations in PINK1 (SEQ ID NO:2) (PTEN-induced putative kinase), which is associated with familial Parkinson's disease. Mitochondrial quality control is important in neurological diseases, and mutations in PINK lead to reduced autophagy and mitophagy, which are associated with aging and age-related diseases such as PD. Mutations in PINK1 (SEQ ID NO:2) cause autosomal recessive PD, and certain clinical features are more common in patients with PINK1 (SEQ ID NO:2) mutations, such as an age of onset of approximately 30 years in this case.

[0620] A genetic approach according to Solnica-Kreze et al., Development. 1996 Dec;123:37-46. PMID:9007227 was used to generate PINK-null zebrafish. Adult male zebrafish were treated with 5 mM of the ENU chemical mutagen to induce random mutagenesis, and cognitive and motor deficits were screened. Genotyping was performed by fin-clipping, and PINK1+ / - mutants were identified. (Gene ID: 30214). F1 mutants carrying the PINK1+ / - mutation were inbred, and the resulting F2 embryos (hereinafter referred to as PINK1- / -) were used for research purposes. α-Synuclein was delivered to PINK-null zebrafish larvae by intracranial microinjection. Seven days after the α-synuclein challenge, behavioral changes induced by synucleinopathy were monitored by evaluating swimming speed (bradykinesia - Figure 7 ) and dementia (predator avoidance test - Figure 8 ). Total swimming speed was derived from video recording and data analysis, including the time and distance that the zebrafish swam.

[0621] Compared with wild-type (WT), the swimming speed of PINK1- / - mutant fish was significantly reduced (p<0.0001), confirming the presence of bradykinesia ( Figure 7 - wild-type vs vehicle group). The group treated with the sEH inhibitor (Compound A of formula I) showed a significant increase in swimming speed, thereby indicating rescue of bradykinesia.

[0622] In the memory test, compared with the PINK1- / -α-syn model group, the wild-type group showed spatial memory, where 100% of wild-type zebrafish avoided the predator. Treatment with Compound A restored memory to the wild-type zebrafish level ( Figure 8 ).

[0623] Example 43 - The potential of the compounds of formula I to treat motor activity deficits and rescue neuronal damage was evaluated using MPTP-induced Parkinson's disease in a zebrafish model.

[0624] The study was conducted according to the protocol published by Bretaud et al. (Neurotoxicol Teratol. 2004 Nov-Dec; 26(6), 857-64). For MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced Parkinson's disease, adult zebrafish were injected with 3 μl of 60 μg / g of MPTP, administered by intramuscular injection along the lateral muscle. The fish were sedated with ice water to limit movement during injection. The injection was maintained at 40° at the injection site, and the corresponding volume of MPTP was delivered by intramuscular injection. The test compounds were administered orally by mixing with fish feed pellets. The fish were trained to eat three pellets per day. The test compound A was evaluated in preventive and therapeutic modes (5 days after MPTP treatment). The MPTP-induced behavioral changes and nerve damage were monitored by: I) assessing the distance of tracking motor activity; II) assessing peripheral nerve damage by the twitch response; III) assessing brain neuronal damage by brain pathology.

[0625] Motor activity: The observation pool was divided into four regions by drawing three vertical lines at equal distances, each region being 6.25 cm in length. The number of lines crossed by adult zebrafish within 5 minutes was calculated. The fish were allowed to acclimatize in the measurement pool for 30 minutes before reading the readings. The measurement intervals were 4 hours before administration or induction could be carried out.

[0626] The twitch response was measured as described by Lisse TS et al. (1). The fish were placed intact on a moist sponge foil until calm, and the distal tail fin was stimulated with an insect pin until a twitch of the fish was observed. The number of stimuli that caused a twitch was recorded. The twitch response was recorded once every evening, at intervals of approximately 4-6 hours, starting from the morning of administration, for 8 days.

[0627] Brain pathology: Study fish samples were collected on day 8. Before collecting the samples, the zebrafish in each group were euthanized by rapid cooling. The whole fish was used intact and fixed in 10% NBF solution as the primary fixative for 24 hours, and then fixed in Davidson's fixative for 12 hours. In addition, the tissues were processed according to the protocol mentioned in the ZIRC (Zebrafish International Resource Center) manual. 5% trichloroacetic acid (TCA) was used as a decalcifying agent, and then the tissues were dehydrated using increasing concentrations of ethanol, and cleared using chloroform and xylene. After cleaning, the tissues were infiltrated with paraffin wax containing wax and embedded in a histological model.

[0628] Compared with the control group animals, the MPTP-treated animals showed a significant decrease in motor activity (p < 0.0001), which gradually deteriorated during the treatment (Figure 9 )。The group treated with the sEH inhibitor (Compound A of Formula I) showed rescue from MPTP-induced abnormal movements and exhibited behavior similar to that of the control animal group. As Figure 9 shown, 5 days after daily MPTP challenge, treatment with Compound A rescued the motor dysfunction of the animals.

[0629] Neural injury (twitch response) - Selective loss of cutaneous fine fibers and axons projecting along the bony rays within the distal fin region results in a significant temporal change in the tactile response, as demonstrated by the need for significantly more stimulation with an insect pin at the distal fin in MPTP-treated animals before an evoked twitch response can be elicited. Treatment with Compound A (given as a prophylactic or therapeutic model) demonstrated substantial rescue of the peripheral nerve injury induced by MPTP treatment ( Figure 10 ).

[0630] Dopaminergic neurons. The MPTP-treated group showed a significant decrease in the number of TH+ cells. The Compound A-treated group showed dose-dependent rescue activity by preventing the loss of TH+ cells ( Figure 11 ). Compound A administered in the treatment mode (treatment on day 5) also showed a protective effect against neuronal degeneration.

[0631] A therapeutically effective amount of the compound of Formula I can be administered in a single dose or in doses repeated one or several times at certain time intervals. As previously mentioned, the attending physician can consider many factors in dose selection, including but not limited to: the potency and duration of action of the compound used; the nature and severity of the disease to be treated, and the sex, age, weight, general health status, and individual reactivity of the subject to be treated, as well as other relevant circumstances. The therapeutic dose for human subjects can be estimated based on data from animal studies and taking into account factors such as body surface area, pharmacokinetic profiles, and related parameters. Allometric scaling and related methods described in the literature [e.g., J Basic Clin Pharm. March 2016-May 2016; 7(2):27–31] can be used to estimate the human equivalent dose.

[0632] The therapeutically effective composition of the present invention for treating a neurodegenerative disease in a subject can comprise a compound of Formula I administered at a dose of from about 0.5 mg / day to about 3000 mg / day.

[0633] According to literature reports, mutations in the GBA gene are associated with Parkinson's disease and Gaucher's disease - the link between the GBA gene and Parkinson's syndrome. Lancet Neurol. 2012 Nov; 11(11):986 - 98. doi:10.1016 / S1474 - 4422(12)70190 - 4. PMID:23079555; PMCID:PMC4141416; GBA gene: Parkinson's disease and Gaucher's disease, https: / / www.gaucherdisease.org / blog / gaucher - disease - and - parkinsons - what - to - know - now / ; GBA variants in Parkinson's disease, Movement Disorders, 35(12), 2201 - 2210, https: / / doi.org / 10.1002 / mds.28225.

[0634] Mutations in the human kinase PINK1 are associated with Parkinson's disease (PD), see for example, Structure of PINK1 and mechanisms of Parkinson's disease - associated mutations, https: / / doi.org / 10.7554 / eLife.29985; PINK1 mutations in Parkinson's disease lead to reduced complex I activity and synaptic function defects. EMBO Mol Med. 2009 May; 1(2):99 - 111. doi:10.1002 / emmm.200900006. PMID:20049710; PMCID:PMC3378121.

[0635] Sequence Listing XML Consolidation Statement

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Claims

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

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

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

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

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

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

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

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

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

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

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

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

13. The method according to claim 1, wherein The compound inhibits soluble epoxide hydrolase at a concentration (IC 50 ) of less than 100 nM and has at least 10-fold selectivity for inhibition relative to fatty acid amide hydrolase (IC 50 , (FAAH (SEQ ID NO:3)).

14. The method according to claim 1, wherein The compound inhibits soluble epoxide hydrolase at a concentration (IC 50 ) of less than 100 nM and inhibits fatty acid amide hydrolase (FAAH (SEQ ID NO: 3)) at a concentration (IC 50 ) of greater than 1000 nM.

15. The method according to claim 1, wherein The diseases are selected from Gaucher's disease, dementia with Lewy bodies, and Alzheimer's disease.

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

17. The method according to claim 1, wherein, The compound is administered at a dose of about 5 mg / day to about 500 mg / day.

18. The method according to claim 1, wherein, The compound is administered to treat one or more of neuronal loss, neuroinflammation, α - synuclein aggregation, and / or Lewy body formation.

19. The method according to claim 1, wherein The compound is administered to treat impaired motor activity and other motor and non - motor related symptoms.

20. The method according to claim 1, wherein The compound is administered to treat cognitive dysfunction or dementia.

21. A method for treating Parkinson's disease with dementia (PDD), familial Parkinson's disease associated with a PINK - 1 (SEQ ID NO:2) mutation, or familial Parkinson's disease associated with a mutation in the glucocerebrosidase (GBA) gene, comprising: administering to a subject a therapeutically effective amount of at least one compound of formula I: wherein R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; R 2 selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl; R 3 selected from the group consisting of an alkyl group, a cycloalkyl group, a hydroxyl group, an amine, an alkylamine or an alkoxy group; R 4 selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ; R 5 selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X is selected from O, (CH2)p, NH, and p is 0 - 2; Y1 - Y2 is selected from CH - CH2, CH - O or C=CH, but when Y1 - Y2 is CH - O, X is selected from O or NH or R 1 not hydrogen; and Y3 is selected from H or Me, its stereoisomers or its pharmaceutically acceptable salts.

22. A method for treating Parkinson's disease with dementia (PDD), familial Parkinson's disease associated with a PINK-1 (SEQ ID NO:2) mutation, or familial Parkinson's disease associated with a mutation in the glucocerebrosidase (GBA) gene, comprising: administering to a subject a therapeutically effective amount of at least one compound of formula I: wherein R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; R 2 selected from the group consisting of hydrogen, an alkyl group, a haloalkyl group or a cycloalkyl group; R 3 selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ; R 5 selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X is selected from O, (CH2)p, NH, and p is 0 - 2; Y1 - Y2 is selected from CH-CH2, CH-O or C=CH, provided that when Y1 - Y2 is CH-O, X is selected from O or NH or R 1 is not hydrogen; and Y3 is selected from H or Me, its stereoisomers or its pharmaceutically acceptable salts.

23. A method for treating Gaucher disease, Parkinson's disease with dementia (PDD), familial Parkinson's disease associated with a PINK-1 (SEQ ID NO:2) mutation, or familial Parkinson's disease associated with a mutation in the glucocerebrosidase (GBA) gene, comprising administering to a subject a therapeutically effective amount of a soluble epoxide hydrolase inhibitor.

24. A compound of formula I: wherein R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted by alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; R 2 selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl; R 3 selected from the group consisting of an alkyl group, a cycloalkyl group, a hydroxyl group, an amine, an alkylamine or an alkoxy group; R 4 selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ; R 5 selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X is selected from O, (CH2)p, NH and p is 0 - 2, provided that when p = 0, Y1 - Y2 is not CH - CH2 or CH - O, and R 1 is not aryl; Y1 - Y2 is selected from CH - CH2, CH - O or C = CH, but when Y1 - Y2 is CH - O, X is selected from O or NH, and R 1 is not hydrogen or alkyl; and Y3 is selected from H or Me, its stereoisomers or its pharmaceutically acceptable salts, for treating neurodegenerative diseases or diseases associated with synucleinopathies, but not for treating Parkinson's disease.

25. A compound of formula I: wherein R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein when R 1 is aryl, heteroaryl or heterocycloalkyl, R 1 is unsubstituted or substituted with alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 or COR 3 ; R 2 selected from the group consisting of hydrogen, alkyl, haloalkyl or cycloalkyl; R 3 selected from the group consisting of an alkyl group, a cycloalkyl group, a hydroxyl group, an amine, an alkylamine or an alkoxy group; R 4 selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy, SO2R 5 or COR 3 ; R 5 selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine; R 6 selected from the group consisting of alkyl, cycloalkyl, aryl or heteroaryl; X is selected from O, (CH2)p, NH and p is from 0 to 2, provided that when p = 0, Y1 - Y2 is not CH-CH2 or CH-O, and R 1 is not aryl; Y1 - Y2 is selected from CH - CH2, CH - O or C = CH, but when Y1 - Y2 is CH - O, X is selected from O or NH, and R 1 is not hydrogen or alkyl; and Y3 is selected from H or Me, its stereoisomers or its pharmaceutically acceptable salts, for treating neurodegenerative diseases or diseases associated with synucleinopathies, but not for treating Parkinson's disease.

26. A soluble epoxide hydrolase inhibitor for treating Gaucher disease, Parkinson's disease with dementia (PDD), familial Parkinson's disease associated with a PINK-1 (SEQ ID NO:2) mutation, or familial Parkinson's disease associated with a mutation in the glucocerebrosidase (GBA) gene.

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