Piperidine urea derivatives for the treatment of neurodegenerative diseases

Abstract

Described herein are 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 relates generally to methods and compositions for the treatment of neurodegenerative diseases and diseases associated with synucleinopathy, specifically to selective piperidine urea-derived compounds for the treatment of neurodegenerative diseases, and methods for the treatment of conditions and diseases mediated by soluble epoxide hydrolases. [Background technology]

[0002] Epoxyeicosatrienoic acids (EETs) are produced by epoxidation of arachidonic acid by cytochrome P450 enzymes during inflammation and injury and have potent anti-inflammatory properties. Furthermore, recent literature has shown that EETs can inhibit endoplasmic reticulum stress and mitochondrial stress in neurons and other cells. It has been suggested that reducing inflammation and endoplasmic reticulum / mitochondrial stress may By doing so, EETs promote neuronal healing and survival. Their concentrations are regulated by soluble epoxide hydrolase (sEH), the primary enzyme responsible for the degradation of EETs, converting them to inactive or weakly active dihydroxyeicosatrienoic acids (DHETs). Inhibiting sEH increases the half-life of EETs, leading to therapeutic effects.

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

[0004] Synucleins are a family of small, highly charged proteins that are primarily expressed in neurons. Synucleins, neuronal proteins that regulate synaptic vesicle trafficking, are abundantly expressed in various parts of the brain. One of these proteins, α-synuclein (α-syn), It appears to be involved in many neurodegenerative diseases, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), rapid eye movement sleep behavior disorder (RBD), Alzheimer's disease with Lewy bodies (LBAD), neurodegeneration with brain iron accumulation (NBAI-1), and pure autonomic failure (PAF). These diseases are collectively called α-synucleinopathies. Gaucher disease (GD), the most common lysosomal storage disease caused by a deficiency of the enzyme GBA1 (SEQ ID NO: 1) and the subsequent accumulation of toxic lipid substrates, has recently been identified as a lysosomal storage disorder characterized by the α-synthase Highest genetic risk factors for developing synuclein aggregation disorders (synucleinopathies including PD and DLB) Mutations in GBA cause three clinical syndromes: type 1 Gaucher disease (GD) occurs in children and adults and primarily affects non-neurological organs, while types 2 and 3 Gaucher disease and Parkinson's disease occur in childhood and adolescence, respectively, and are characterized by neurological disorders. Neuropathy is one of the neurological complications of Gaucher disease (including type 1). Pathology includes classic features of Parkinson's disease, such as cortical and brainstem Lewy bodies.

[0005] All synucleinopathies exhibit abnormal fibrillation and the accumulation of insoluble proteinaceous α-synuclein inclusions in neurons and glia, sharing a common cellular pathology in the processing and clearance of α-synuclein. The mechanisms leading to synuclein aggregation and pathology are not fully understood, but several processes, such as neuronal inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress, may be involved in the pathogenesis. Mutations associated with mitochondrial dysfunction and synucleinopathies include the PTEN-induced serine-threonine kinase 1 gene, which encodes the PTEN-induced serine-threonine kinase 1 gene. Therefore, it is thought that PINK1 (SEQ ID NO: 2) improves mitochondrial function and promotes endoplasmic reticulum storage. Reducing neuronal inflammation and neuronal damage may have a beneficial effect on the disorders associated with synucleinopathy.

[0006] sEH is highly expressed in the brain, and the production and metabolism of EETs in the brain extend to many areas, and are transmitted to peripheral nerves. These effects extend to neuronal cells, central neurons, astroglia, oligodendrocytes, vascular endothelial cells, and smooth muscle cells [J Histochem Cytochem.2008 Jun; 56(6):551-9, Am J Physiol 263: H519-25 1992, J Neurochem 61: 150-9 1993 Prostaglandins Other Lipid Mediat.91: 68-84 2010]. Studies have shown that inhibition of EETs or sEH i) prevents cytokine- and oxidant-mediated injury in neurons, ii) prevents endoplasmic reticulum (ER) stress, which is a major contributor to the loss of dopaminergic neurons, and iii) inhibits the upregulation of vascular endothelial growth factor (VEGF). enhancing strocytic release and neuronal recovery after oxygen-glucose deprivation; iv) It has been shown to promote axonal growth [Am J Physiol Heart Circ Physiol 296:H1352-63, 2009, Expert Rev Mol Med 13: 7-12 2011, Expert Rev Mol Med 13: 7-12, 1998, Expert Rev Mol Med 13: 7-12, 2014, Neuropathol Appl Neurobiol.42:607-620, 2016, Proc Natl Acad Sci US A. 112: 9082-9087 2015, J Neurosci 27: 4642-9 2007, J Neurochem.117: 632-42 2011 and Neuroscience 223: 68-76 2012]. Deficiency of sEH attenuates the loss of dopaminergic neurons in multiple animal models of Parkinson's disease [Mol Neurobiol. In multiple animal models, inhibition of sEH ameliorates disease symptoms and improves diabetic neuropathy. It promotes neuronal healing, including that associated with noxious pain [Proc Natl Acad Sci US A. 2008 Dec 2;105(48):18901-6, Eur J Pharmacol.2013 Jan 30;700(1-3):93-101, J Pain.2014 Sep; 15(9):907-14, Proc Natl Acad Sci US A. 2015 Jul 21;112(29):9082-7, Behav Brain Res. 2017 May 30;326:69-76]. sEH levels are significantly elevated in the cortical brain tissue of subjects with cognitive impairment. sEH inhibition is thought to be a key factor in the development of Alzheimer's disease, leading to increased levels of tau. Prevents H2O2-induced increased protein phosphorylation [Prostaglandins Other Lipid Mediat.2014 Oct; 113-115:30-7, J Huazhong Univ Sci Technolog Med Sci. 2016 Dec; 36(6):785-790]. sEH inhibition protects in rodent models of ischemic and diabetic stroke. 2013 Dec 1;305(11):H1605-13].

[0007] Several studies have demonstrated that sEH inhibition may be beneficial in the treatment of multiple neurodegenerative diseases, including Alzheimer's disease. It has been verified that it may provide therapeutic benefits [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, multiple system atrophy (MSA) [Progress in Neurobiology 172 (2019) 23-39, J Affect Disord. 2020 June 01; 270: 131-134, Proc Natl Acad Sci USA. 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), Cerebral hemorrhage May 2022 issue, Neurocri t Care (2021), J Atheroscler Thromb.2017 Dec 1; 24(12):1258-1266].

[0008] Thus, synucleinopathies, including but not limited to dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), multiple system atrophy (MSA), and Gaucher disease (GD), are also contemplated. It is an object of the present disclosure to provide methods and compositions for the treatment of neurodegenerative diseases and disorders associated with Lewy body dementia and Gaucher disease, as well as conditions and disorders mediated by neurodegeneration and synucleinopathy. Selected piperidine urea-derived compounds have been disclosed as methods for the treatment of dementia with Lewy bodies and Gaucher disease, as well as conditions and disorders mediated by neurodegeneration and synucleinopathy.

[0009] Citation or identification of any document in this application is not an admission that such document is available as prior art to the present disclosure. Summary of the Invention

[0010] The above objects are achieved, according to the present disclosure, by providing, by way of example, a method for treating a neurodegenerative disease or a disease associated with a synucleinopathy, excluding Parkinson's disease, comprising administering to a subject at least one compound of Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof. This can include administering to the subject a therapeutically effective amount of a salt.

[0011] [ka]

[0012] where R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , or COR 3 is replaced by; R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , SO2R 5 , or COR 3 may be selected from the group consisting of: R 5is a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine may be selected from; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X is selected from O, (CH2)p, and NH, where p is 0 to 2; Y1-Y2 may be selected from CH-CH2, CH-O or C=CH, but Y1-Y2 When CH—O, X is selected from O or NH, or R 1 is not hydrogen; and Y3 can be selected from H or Me.

[0013] In a further embodiment, a method for treating a neurodegenerative disease or a disease associated with a synucleinopathy, excluding Parkinson's disease, is provided, the method comprising administering a therapeutically effective amount of at least one compound of Formula I administering to a subject one of the compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. may include:

[0014] [ka]

[0015] R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , or COR 3 is replaced by; R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , SO2R 5 , or COR 3 may be selected from the group consisting of: R 5 is a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine may be selected from; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X can be selected from O, (CH2)p, and NH, where p is 0 to 2, but when p=0, Y1-Y2 are not CH-CH2 or CH-O, and R 1 is not aryl; Y1-Y2 may be selected from CH-CH2, CH-O or C=CH, provided that when Y1-Y2 are CH-O, X is selected from O or NH, and R 1 is not hydrogen or alkyl and Y3 can be selected from H or Me.

[0016] Additionally, Y3 can be H and the compound is a compound according to Formula II, a stereoisomer or a pharmaceutically acceptable salt thereof.

[0017] [ka]

[0018] R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxy Alkyl, alkoxy, amine, SO2NHR 2 , or COR 3 is replaced by; R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , SO2R 5 , C.O.R. 3 may be selected from the group consisting of: R 5 is a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine may be selected from; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X is selected from O, (CH2)p, and NH, where p is 0 to 2; Y1-Y2 may be selected from CH-CH2, CH-O or C=CH, provided that when Y1-Y2 is CH-O, X is selected from O or NH, or R 1 is not hydrogen.

[0019] Nevertheless, when Y3 is H, the compound is a compound according to formula II, a stereoisomer thereof or a pharmaceutical If the salt is acceptable for:

[0020] [ka]

[0021] R 1may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , or COR 3 is replaced by; R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , SO2R 5 , C.O.R. 3 may be selected from the group consisting of: R 5 is a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine may be selected from; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X can be selected from O, (CH2)p, and NH, where p is 0 to 2, but when p=0, Y1-Y2 are not CH-CH2 or CH-O, and R 1 is not aryl; Y1-Y2 is CH-CH 2, CH-O , or C=CH, provided that when Y1-Y2 are CH-O, X is selected from O or NH, and R 1 is not hydrogen or alkyl.

[0022] Furthermore, Y3 is H and Y1-Y2 are C=CH and the compound is a compound according to formula III , a stereoisomer or a pharmaceutically acceptable salt thereof;

[0023] [ka]

[0024] R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 , SO2NHR 2 , or COR 3 is replaced by; R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , SO2R 5 , SO2NHR 2 , C.O.R. 3 may be selected from the group consisting of: R 5 is a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine may be selected from; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; and X is selected from O, (CH2)p, and NH, where p is 0-2.

[0025] Y3 is H, Y1-Y2 are CH-CH2, and the compound is a compound according to formula IV, 10. The method of claim 1, wherein the compound is an isomer or a pharmaceutically acceptable salt.

[0026] [ka]

[0027] R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 , SO2NHR 2 , C.O.R. 3 is replaced by; R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , SO2R 5 , C.O.R. 3 may be selected from the group consisting of: R 5 is a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine may be selected from; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl, where the aryl or heteroaryl may be optionally substituted one or more times with a group or substituent such as alkyl, hydroxy, halogen, haloalkyl, and the like; and X may be selected from O, (CH2)p, NH; where p is selected from 0-2.

[0028] Additionally, Y3 may be H and Y1-Y2 are CH-CH2, and the compound is according to formula IV The compound, a stereoisomer or a pharmaceutically acceptable salt thereof.

[0029] [ka]

[0030] R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 , SO2NHR 2 , C.O.R. 3 is replaced by; R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , SO2R 5 , C.O.R. 3 may be selected from the group consisting of: R 5 is a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine may be selected from; R 6may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl, where the aryl or heteroaryl may be optionally substituted one or more times with a group or substituent such as alkyl, hydroxy, halogen, haloalkyl, and the like; and X may be selected from O, (CH2)p, and NH; where p is selected from 0 to 2, but when p=0, R 1 is not aryl.

[0031] Additionally, the compound of formula 1 may be one or more of the following compounds, stereoisomers or pharmaceutically acceptable salts thereof:

[0032] [ka]

[0033] [ka]

[0034] [ka]

[0035] Additionally, the compound of formula 1 may be one of the following compounds, a stereoisomer or a pharmaceutically acceptable salt thereof:

[0036] [ka]

[0037] Furthermore, the compound of formula 1 may be one or more of the following compounds, stereoisomers or pharmaceutically acceptable salts thereof:

[0038] [ka]

[0039] Furthermore, this compound50 ) less than 10 μM and soluble epoxide hydrolase may be inhibited.

[0040] Furthermore, this compound 50 ) inhibits soluble epoxide hydrolase at less than 100 nM. It may harm.

[0041] Furthermore, compounds were measured at a concentration (IC 50 ) inhibits soluble epoxide hydrolase at less than 100 nM. and inhibiting fatty acid amide hydrolase (IC 50 , (FAAH (SEQ ID NO: 3)) Both can have a 10-fold selectivity.

[0042] Furthermore, this compound 50 ) inhibits soluble epoxide hydrolase at less than 100 nM. Concentration (IC 50 ) may inhibit fatty acid amide hydrolase (FAAH (SEQ ID NO: 3)) at levels greater than 1000 nM.

[0043] Additionally, the disease may be selected from Gaucher's disease, dementia with Lewy bodies, and Alzheimer's disease.

[0044] Furthermore, the compounds can be administered in doses of from about 1 mg / day to about 1,000 mg / day. Furthermore, the compound can be administered at a dose of about 5 mg / day to about 500 mg / day.

[0045] Additionally, the compounds may inhibit neuronal loss, neuroinflammation, α-synchrony aggregation, and / or can be administered to treat one or more of the following: Lewy body formation.

[0046] Additionally, the compounds can be administered to treat locomotor activity disorders and other movement and non-movement related conditions.

[0047] Additionally, the compounds can be administered to treat cognitive impairment and dementia.

[0048] Additionally, the present disclosure provides a method for treating Parkinson's disease with dementia (PDD), familial Parkinson's disease associated with PINK-1 (SEQ ID NO: 2) mutations, or mutations in the glucocerebrosidase (GBA) gene. 1. A method for treating familial Parkinson's disease associated with Therapeutic use of at least one compound of formula I, its stereoisomers or pharmaceutically acceptable salts The method may include administering an effective amount to a subject.

[0049] [ka]

[0050] R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , or COR 3 is replaced by; R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , SO2R 5 , or COR 3 may be selected from the group consisting of: R5 is a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine may be selected from; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X is selected from O, (CH2)p, and NH, where p is 0 to 2; Y1-Y2 may be selected from CH-CH2, CH-O or C=CH, provided that when Y1-Y2 is CH-O, X is selected from O or NH, or R 1 is not hydrogen; and Y3 can be selected from H or Me.

[0051] Additionally, the present disclosure provides a method for treating Parkinson's disease with dementia (PDD), familial Parkinson's disease associated with PINK-1 (SEQ ID NO: 2) mutations, or mutations in the glucocerebrosidase (GBA) gene. 1. A method for treating familial Parkinson's disease associated with A method can be provided that includes administering to a subject a therapeutically effective amount of at least one compound of Formula I, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0052] [ka]

[0053] R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , or COR 3 is replaced by; R 2may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , SO2R 5 , or COR 3 may be selected from the group consisting of: R 5 is a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine may be selected from; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X can be selected from O, (CH2)p, and NH, where p is 0 to 2, but when p=0, Y1-Y2 are not CH-CH2 or CH-O, and R 1 is not aryl; Y1-Y2 may be selected from CH-CH2, CH-O or C=CH, provided that when Y1-Y2 are CH-O, X is selected from O or NH, and R 1 is hydrogen or alkyl is not; and Y3 can be selected from H or Me.

[0054] Furthermore, the present disclosure provides a method for treating Gaucher disease, Parkinson's disease with dementia (PDD), and PINK-1 (sequence number PINK-1)-associated dementia, comprising administering to a subject a therapeutically effective amount of a soluble epoxide hydrolase inhibitor. Number: 2) A method for treating familial Parkinson's disease associated with a mutation in the glucocerebrosidase (GBA) gene or familial Parkinson's disease associated with a mutation in the glucocerebrosidase (GBA) gene may be provided.

[0055] A compound of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof:

[0056] [ka]

[0057] R 1 may be selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1 is either non-substituted or is alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , or COR 3 is replaced by; R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , SO2R 5 , or COR 3 may be selected from the group consisting of: R 5 is a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine may be selected from; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X is selected from O, (CH2)p, and NH, where p is 0 to 2; Y1-Y2 may be selected from CH-CH2, CH-O or C=CH, provided that when Y1-Y2 is CH-O, X is selected from O or NH, or R 1 is not hydrogen; and Y3 can be selected from H or Me.

[0058] The present disclosure may also provide methods for use in the treatment of neurodegenerative diseases or diseases associated with synucleinopathy, but which are not Parkinson's disease.

[0059] A compound of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof:

[0060] [ka]

[0061] R 1は , alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 When is aryl, heteroaryl, or heterocycloalkyl, R 1 is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , or COR 3 is replaced by; R 2 may be selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R 3 may be selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , SO2R 5 , or COR 3 may be selected from the group consisting of: R 5 is a group consisting of alkyl, haloalkyl, cycloalkyl, aryl or amine may be selected from; R 6 may be selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X can be selected from O, (CH2)p, and NH, where p is 0 to 2, but when p=0, Y1-Y2 are not CH-CH2 or CH-O, and R 1 is not aryl; Y1-Y2 may be selected from CH-CH2, CH-O or C=CH, is CH—O, X is selected from O or NH, and R 1 is not hydrogen or alkyl; and Y3 can be selected from H or Me.

[0062] Additionally, methods may be provided for use in treating diseases other than Parkinson's disease, but related to neurodegenerative or synucleinopathies.

[0063] Furthermore, the present disclosure provides methods for treating Gaucher disease, Parkinson's disease with dementia (PDD), PINK-1 (sequence Number: 2) Soluble epoxide hydrolase inhibitors for use in the treatment of familial Parkinson's disease associated with mutations in the glucocerebrosidase (GBA) gene or familial Parkinson's disease associated with mutations in the glucocerebrosidase (GBA) gene may be provided.

[0064] These and other aspects, objects, features, and advantages of the exemplary embodiments will become apparent to those skilled in the art upon consideration of the following detailed description of the exemplary embodiments.

[0065] An understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments in which the principles of the disclosure may be utilized, and the accompanying drawings of which: [Brief explanation of the drawings]

[0066] [Figure 1-1] FIG. 1 shows the soluble epoxide hydrolase inhibitory potency of compounds of formula I in Table 1. [Figure 1-2] FIG. 1 shows the soluble epoxide hydrolase inhibitory potency of compounds of formula I in Table 1. [Figure 1-3]FIG. 1 shows the soluble epoxide hydrolase inhibitory potency of compounds of formula I in Table 1. [Figure 2] FIG. 2 shows the neuroprotective effect of compound A of formula I in synucleinopathy-induced neuronal loss in cultured dopamine neurons. [Figure 3] FIG. 3 shows the efficacy (improvement of motor activity) of Compound A and Compound B of Formula I against synucleinopathy-induced motor impairment in a rodent model (α-syn+GBA1 (SEQ ID NO: 1) inhibition). [Figure 4] FIG. 4 shows the efficacy of Compound A and Compound B of Formula I in inhibiting α-syn aggregation in a rodent model of synucleinopathy (α-syn+GBA1 (SEQ ID NO: 1) inhibition). [Figure 5] FIG. 5 shows the neuroprotective effects of Compound A and Compound B of Formula I in a rodent model of synucleinopathy. [Figure 6] FIG. 6 shows the efficacy (blocking neuroinflammation) of Compound A and Compound B of Formula I in a rodent model of synucleinopathy. [Figure 7] FIG. 7 shows the efficacy (improvement of motor activity, bradycardia) of Compound A and Compound B of Formula I in a zebrafish model of synucleinopathy. [Figure 8] FIG. 8 shows the efficacy (amelioration of dementia) of Compound A and Compound B of Formula I in a zebrafish model of synucleinopathy. [Figure 9] FIG. 9 shows the efficacy (improvement of motor activity) of compound A of formula I against MPTP-induced parkinsonism in a zebrafish model. [Figure 10] FIG. 10 shows the efficacy of compound A of formula I against MPTP-induced parkinsonism in a zebrafish model (blocking neurodegeneration). [Figure 11] FIG. 11 shows the neuroprotection (TH+ neurons) of Compound A of Formula I in MPTP-induced parkinsonism in a zebrafish model. DETAILED DESCRIPTION OF THE INVENTION

[0067] The figures depicted herein are for illustrative purposes only and are not necessarily drawn to scale.

[0068] Before describing the present disclosure in more detail, it is to be understood that this disclosure is not limited to particular embodiments described, and as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0069] Unless otherwise expressly stated, terms and phrases used herein, and variations thereof, should be construed as open ended rather than limiting. Similarly, groups of items joined by the conjunction "and" should not be read as requiring the presence of every single one of those items in the group, but rather "and / or" unless expressly stated otherwise. Similarly, groups of items joined by the conjunction "or" should not be read as requiring mutual exclusivity between the groups, but rather "and / or" unless expressly stated otherwise.

[0070] Furthermore, although items, elements, or components of the disclosure may be described or claimed in the singular, the plural is intended to be within its scope unless limitation to the singular is expressly stated. In some cases, the terms "one or more," "at least," "but these" and "any" may be used interchangeably. The presence of a broader term, such as "but not limited to," or other similar term, shall not be read to imply that a narrower case is intended or required where such broader term may not be present.

[0071] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of this disclosure, the preferred methods and materials are now described.

[0072] All publications and patents cited herein are cited to disclose and describe the methods and / or materials in connection with which the publications are cited. All such publications and patents are incorporated by reference herein as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. Such incorporation by reference is expressly limited to the methods and / or materials described in the cited publications and patents and does not extend to dictionary definitions of the cited publications and patents. Lexical definitions in cited publications and patents that are not expressly repeated in this application should not be treated as such and should not be read as defining terms recited in the appended claims. The citation of publications is for their disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publications by prior disclosure. Further, the stated publication dates may differ from the actual publication dates, which may need to be independently confirmed.

[0073] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has distinct components and features that may be readily separated from, or combined with, the features of any of the other several embodiments without departing from the scope or spirit of the disclosure. Any described method can be carried out in the order of events described or in any other order that is logically possible.

[0074] When a range is expressed, a further embodiment includes from the one particular value and / or to the other particular value. The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within each range, as well as the recited endpoints. When a range of values ​​is provided, unless the context clearly dictates otherwise, each intervening value, to one-tenth of the unit of the lower limit, between the upper and lower limit of that range, and every other recited value within that recited range. or any intervening value is understood to be encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure. For example, if a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure. For example, the phrase "from x to y" includes not only a range from "x" to "y," but also a range greater than "x" but less than "y." Ranges can also be expressed as upper limits, e.g., "about x, y, z, or less." and should be interpreted to include the specific ranges of "about x," "about y," and "about z," as well as the ranges "less than x," "less than y," and "less than z." Similarly, the phrase "about x, y, z, or more" should be interpreted to include not only the specific ranges of "about x," "about y," and "about z," but also the ranges "greater than x," "greater than y," and "greater than z." Furthermore, the expression "about 'x' to 'y'" includes "about 'x' to 'about 'y'" when 'x' and 'y' are numerical values.

[0075] It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format. It is further understood that the endpoints of each range are significant in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values ​​disclosed herein, and that each value is herein disclosed as "about" that particular value in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Ranges can be expressed herein as from "about" one particular value and / or to "about" another particular value. Similarly, when values ​​are expressed as approximations, the use of the antecedent "about" will understand that the particular value forms a further aspect. For example, if the value "about 10" is disclosed, then "10" is also disclosed.

[0076] It should be understood that such range formats are used for convenience and brevity and, therefore, should be interpreted flexibly to include not only the numerical values ​​expressly recited as the limits of the range, but also all individual numerical values ​​or subranges subsumed within that range, as if each numerical value and subrange were expressly recited. As an example, a numerical range of "about 0.1% to about 5%" should be interpreted to include not only the explicitly recited numerical values ​​of about 0.1% to about 5%, but also individual numerical values ​​(e.g., about 1%, about 2%, about 3%, about 4%) and subranges (e.g., about 0.5% to about 1.1%, about 5% to about 2.4%, about 0.5% to about 3.2%, about 0.5% to about 4.4%, and other possible subranges) within the indicated range.

[0077] As used herein, the singular forms "a," "an," and "the" include both the singular and the plural referents unless the context clearly indicates otherwise.

[0078] As used herein, "about," "approximately," "substantially," and the like, when used in connection with a measurable variable, such as a parameter, amount, time duration, and the like, are meant to encompass variation of the specified value and variation from the specified value, including within experimental error (e.g., as may be determined by a given data set, an art-recognized standard, and / or, for example, a predetermined confidence interval (e.g., a 90%, 95% or greater confidence interval from the mean)). To the extent such variation is appropriate for practice in this disclosure, variations within experimental error (as may be determined by a given data set, an art-recognized standard, and / or, for example, a predetermined confidence interval (e.g., a 90%, 95% or greater confidence interval from the mean)) are intended to encompass variation within experimental error (as may be determined by a given data set, an art-recognized standard, and / or, for example, a predetermined confidence interval (e.g., a 90%, 95% or greater confidence interval from the mean)). These include variations within a dataset, art-recognized standards, and / or within a predetermined confidence interval, for example, which may be determined by a given confidence interval (e.g., a 90%, 95%, or greater confidence interval from the mean). As used herein, the terms "about," "approximate," "about," and "substantially" may mean that the amount or value in question may be the exact value, or a value that provides an equivalent result or effect as recited in the claims or taught herein. That is, amounts, sizes, formulations, parameters, and other quantities and characteristics are not exact and may be approximate. It is understood that values ​​need not be exact, but may be approximated and / or larger or smaller, as desired, to reflect tolerances, conversion factors, rounding, measurement error, and other factors known to those skilled in the art that would produce equivalent results or effects. In some circumstances, it may not be possible to reasonably determine a value that would produce equivalent results or effects. Generally, an amount, size, formulation, parameter, or other quantity or characteristic is "about," "approximate," or "about" whether or not expressly stated as such. When "about," "approximate," or "about" is used before a quantitative value, it is understood that the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0079] As used herein, a "biological sample" may include whole cells and / or viable cells and / or cell debris. A biological sample may include (or be derived from) a "body fluid." The present disclosure encompasses embodiments in which the body fluid is selected from amniotic fluid, aqueous humor, vitreous humor, bile, blood serum, breast milk, cerebrospinal fluid, earwax, chyle, chyme, endolymph, perilymph, exudate, feces, female ejaculate, gastric acid, gastric juice, lymph, mucus (including nasal secretions, sputum), pericardial fluid, peritoneal fluid, pleural fluid, pus, secretions, saliva, sebum (sebum), semen, sputum, synovial fluid, sweat, tears, urine, vaginal secretions, vomit, and mixtures of one or more of these. Biological samples include cell cultures, body fluids, and cell cultures from body fluids. Body fluids can be obtained from a mammalian organism, for example, by puncture or other withdrawal or sampling procedures.

[0080] As used herein, "agent" refers to any substance, compound, molecule, etc., that can be administered to a subject. An agent can be inactive. An agent can be an active agent. An agent can be a primary active agent, in other words, a component(s) of a composition to which all or part of the composition's effect is attributable. An agent can be a secondary agent, in other words, an additional part of the composition and / or a component(s) of a composition to which other effects of the composition are attributable.

[0081] As used herein, "active agent" or "active ingredient" refers to a substance, compound, or molecule that is biologically active or otherwise induces a biological or physiological effect in a subject to which it is administered. In other words, "active agent" or "active ingredient" refers to an ingredient or component of a composition to which all or part of the composition's effect is attributed.

[0082] As used herein, "administration" refers to any suitable administration to the agent being delivered and / or the subject receiving the agent, including oral, topical, intravenous, subcutaneous, transdermal, transcutaneous, intramuscular, intraarticular, parenteral, intraarterial, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, topical, intranasal, intracardiac, intraarticular, intracavernosal, intrathecal, intravenous, intracerebral, and intraventricular, intratympanic, intracochlear, intrarectal, intravaginal, by inhalation, via a catheter, a stent, or via an implanted reservoir or other device that actively or passively (e.g., by diffusion) administers the composition to the perivascular space and adventitia. For example, a medical device such as a stent can contain a composition or formulation disposed on its surface, which can then dissolve or otherwise distribute into surrounding tissues and cells. The term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intraserosal, and intracranial injection or infusion techniques. Routes of administration include, for example, auricular (ear), buccal, conjunctival, dermal, dental, electroosmotic, intracervical, intranasal, intratracheal, enteral, epidural, extra-amniotic, extracorporeal, hemodialysis, infiltrative, interstitial, intraperitoneal, intra-amniotic, intra-articular, intrabiliary, intrabronchial, intra-synovial, intracardiac, intra-articular, intracoccygeal, intracavernous, intracavity, intracerebral, intrathoracic, intracorneal, Intradental cavity, intracoronary artery, intracavernous, intradermal, intrabladder, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intracavity, intralymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intraovarian, intrapericardium, intraperitoneum, intrapleura, intrabladder, intrapulmonary, intraanus, intraspinal cord, intrasynovial, intratendon, intratesticular, intramedullary cavity, intrathoracic cavity, intraluminal, intratumoral, intrasternal, uterine intrauterine, intravascular, intravenous, bolus injection, intravenous infusion, intraventricular, intravesical, intravitreal, iontophoresis, perfusion, laryngeal, nasal, nasogastric, occlusive dressing, ophthalmic, buccal, oropharyngeal, other, parenteral, transdermal, periarticular, peridural, peridural, periodontal, rectal, respiratory (inhalation), retrobulbar, soft tissue, subarachnoid, subconjunctival, subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transplacental, transtracheal, transtympanic, ureteral, urethral, ​​and / or vaginal administration, and / or any combination of the above routes of administration, which typically depend on the disease being treated, the subject being treated, and / or the agent(s) being administered.

[0083] As used herein, a "control" can refer to a substitute subject or sample used in an experiment for comparison purposes and included to minimize or distinguish the effects of variables other than the independent variable.

[0084] The terms "optional" or "optionally" mean that the subsequently described event, circumstance, or substituent may or may not occur, and that the description includes instances in which the event or circumstance occurs and instances in which it does not occur.

[0085] As used herein, "dose," "unit dose," or "dosage" can refer to physically discrete units suitable for administration to a subject, each unit containing a predetermined quantity of a pharmaceutical formulation calculated to produce a desired response or reaction associated with its administration.

[0086] As used herein, the term "molecular weight" may generally refer to the mass or average mass of a substance.

[0087] As used herein, the terms "subject," "individual," and "patient" are used interchangeably to refer to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, rodents, apes, humans, farm animals, sport animals, and pets. Tissues, cells, and their progeny of biological entities obtained in vivo or cultured in vitro are also encompassed by the term "subject."

[0088] As used herein, "substantially pure" can mean that the target species is the predominant species present (i.e., more abundant than other individual species in the composition on a molar basis); preferably, a substantially purified fraction is one in which the target species constitutes about 50% of all species present. Generally, a substantially pure composition will constitute about 80% or more of all species present in the composition, more preferably about 85%, 90%, 95%, or 99% or more. Most preferably, the target species is purified to essential homogeneity (contaminating species cannot be detected in the composition by conventional detection methods), and the composition consists essentially of a single species.

[0089] When used interchangeably herein, the terms "sufficient" and "effective" refer to an amount (e.g., an amount) necessary to achieve one or more desired and / or described results. For example, a therapeutically effective amount can refer to the amount necessary to achieve one or more therapeutic effects.

[0090] As used herein, a "tangible medium of expression" refers to a medium that is physically tangible or accessible and is not merely an abstract thought or unrecorded spoken word. "Tangible media of expression" include, but are not limited to, words on a cellulosic or plastic material, or data stored in any suitable computer-readable memory form. The data may be stored on a unit device such as a flash memory or CD-ROM, or on a server accessible to a user, for example, via a web interface.

[0091] As used herein, the terms "therapy" and "treatment" refer to the desired pharmacological and "Treatment" can generally refer to obtaining a therapeutic and / or physiological effect. The effect may be, but need not necessarily be, prophylactic, in that it prevents or partially prevents a disease, symptom, or condition, such as cancer and / or indirect radiation damage. The effect may be therapeutic, in that it partially or completely cures a disease, condition, symptom, or side effects resulting from a disease, disorder, or condition. As used herein, the term "treatment" covers any treatment of cancer and / or indirect radiation damage in a subject, particularly a human and / or companion animal, and may include any one or more of the following: (a) a predisposition to suffer from a disease (b) preventing disease or injury from occurring in a subject who may have, but has not yet been diagnosed as having, the disease; (b) inhibiting the disease, i.e., preventing its onset. and (c) alleviating the disease, i.e., preventing the disease and / or its symptoms. Alleviating or ameliorating a disease, disorder, or condition. As used herein, the term "treatment" can refer to therapeutic treatment only, prophylactic treatment only, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and / or those in whom a disorder is to be prevented. As used herein, the term "treating" can include inhibiting a disease, disorder, or condition, e.g., preventing its progression; and alleviating a disease, disorder, or condition, e.g., causing regression of a disease, disorder, and / or condition. Treating a disease, disorder, or condition includes improving at least one symptom of a particular disease, disorder, or condition, even if the underlying pathophysiology is not affected. For example, treating a subject's pain by administering an analgesic may be included, even if such an analgesic does not treat the cause of the pain.

[0092] As used herein, the terms "weight %," "wt%," and "wt%" can be used interchangeably and, unless otherwise specified, refer to the weight percent 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. The sum of the wt% values ​​of all components in a disclosed composition or formulation should be understood to equal 100. Alternatively, wt% values ​​may be used to refer to the total weight of a subset of components in a composition. When based on weight, the sum of the wt% values ​​of the specified ingredients in a disclosed composition or formulation should be understood to equal 100.

[0093] "Halogen or halo" means fluorine, chlorine, bromine or iodine.

[0094] An "alkyl" group refers to a straight-chain or branched alkyl group. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl, and the like. Unless otherwise specified, alkyl groups typically have from about 1 to about 10 carbon atoms.

[0095] A "cycloalkyl" group refers to a cyclic alkyl group that may be monocyclic or bicyclic. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Unless otherwise specified, a cycloalkyl group typically has from about 3 to about 10 carbon atoms.

[0096] A "haloalkyl" group is an alkyl group in which at least one hydrogen has been replaced with a halogen or halo group. It refers to a straight or branched chain alkyl group. Exemplary haloalkyl groups include trifluoromethyl, chloroethyl, difluoromethyl, difluoroethyl, and the like.

[0097] A "hydroxyalkyl" group means a linear monovalent hydrocarbon radical of one to three carbon atoms or a branched monovalent hydrocarbon radical of three to five carbon atoms substituted by one or two hydroxy groups. Representative examples include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, and the like.

[0098] "Alkoxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms substituted with an alkoxy group, as defined above, such as methoxymethyl, 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl.

[0099] "Heterocycloalkyl" means a group consisting of carbon and hydrogen atoms and at least one heterocyclic group. A heterocycloalkyl group refers to a non-aromatic monocyclic or polycyclic ring consisting of one or more carbon-carbon double bonds or carbon-hetero groups in the ring, unless their presence renders the ring aromatic. Examples of heterocycloalkyl groups include pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, tetrahydrofuranyl, tetrahydropyranyl, pyranyl, and the like.

[0100] "Alkoxy" refers to the group -O(alkyl), where alkyl is as defined above. Exemplary alkoxyl groups include methoxy, ethoxy, propoxy, butoxy, iso-propoxy, iso-butoxy, and the like. Unless otherwise specified, alkoxy groups typically have from 1 to about 10 carbon atoms.

[0101] "Amine" refers to primary, secondary, and tertiary amino groups. Secondary and tertiary amines may contain alkyl, cycloalkyl, or aryl substitutions. Examples of amines include NH, NHMe, NMeNH (cyclopropyl), and the like. Unless otherwise specified, The alkyl or cycloalkyl group on the amine typically has from 1 to about 8 carbon atoms.

[0102] "Aryl" means an optionally substituted monocyclic or polycyclic aromatic ring having from about 6 to about 14 carbon atoms. "aryl" refers to an aromatic ring system. Exemplary aryl groups include phenyl, naphthyl, and the like. Unless otherwise specified, aryl groups typically have from 6 to about 14 carbon atoms.

[0103] "Heteroaryl" is selected from -O-, -N-, -S-, -SO2, or -CO-. "Heteroaryl" refers to an aromatic monocyclic or polycyclic ring system of about 4 to about 12 carbon atoms having at least one heteroatom or heterogroup. Exemplary heteroaryl groups include pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, imidazolyl, triazolyl, pyridazinyl, thienopyrimidinylfuranyl, indolyl, isoindolyl, benzo[1,3]dioxolyl, benzimidazolyl, 1,3-benzoxathiolyl, and pyrrolyl. Examples include quinazolinyl, pyridyl, pyrimidinyl, and thiophenyl. Unless otherwise specified, a heteroaryl group typically contains from 4 to about 10 carbon atoms. Has.

[0104] "5- to 6-membered heteroaryl" refers to an aromatic group of 5 or 6 ring atoms having at least one heteroatom or heterogroup 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, thienopyrimidyl, tetrazolyl, imidazolyl, triazolyl, furanyl, and the like. It can be obtained.

[0105] "Optionally substituted" means that substitution is optional, and thus the specified atom or molecule can be unsubstituted. If substitution is desired, such substitution may be made by replacing any number of hydrogens on the specified atom with a selection from the indicated group, provided that the number does not exceed the normal valence of the specified atom and the substitution results in a compound that is sufficiently stable for use. This means that

[0106] "Salt" refers to any acid or base salt, pharmaceutically acceptable solvate, or any complex of a compound that, when administered to a recipient, can provide (directly or indirectly) a compound as described herein. However, it should be understood that non-pharmaceutically acceptable salts are also within the scope of this disclosure. Salt preparation can be carried out using known methods. For example, pharmaceutically acceptable salts of compounds contemplated as useful herein can be synthesized by conventional chemical methods using a parent compound that contains a basic or acid functional group. Generally, such salts can be prepared, for example, by preparing the free acid or base form of the compound and reacting it with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixture thereof. Generally, non-aqueous media such as one or more solvents, such as ether, ethyl acetate, ethanol, isopropanol, acetonitrile, and the like, can be utilized. Examples of acid addition salts include one or more of mineral acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc., and organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, etc. Examples of base addition salts include one or more of inorganic salts such as sodium salt, potassium salt, calcium salt, ammonium salt, magnesium salt, lithium salt, etc., and organic base salts such as ethylenediamine salt, ethanolamine salt, N,N-dialkylethanolamine salt, triethanolamine salt, basic amino acid salt, etc.

[0107] The phrase "therapeutically effective" refers to the ability of an agent or combination to prevent or reduce the severity of symptoms of a disorder or disease, generally while avoiding side effects. Therapeutically effective compositions of the present disclosure may include a dose of about 1 to about 3000 mg of a compound of the present disclosure.

[0108] As used herein, "effective amount" or "therapeutically effective amount" refers to the dose or amount and frequency of administration of a compound of the present disclosure administered to a subject to produce a therapeutic response. The dose or effective amount to be administered to a subject and the frequency of administration to a subject can be easily determined by those skilled in the art using known techniques and observing the results obtained under similar circumstances. When determining the effective amount or dosage, the attending physician can take into account many factors, including, but not limited to, the potency and duration of action of the compound used, the nature and severity of the disease being treated, and the gender, age, weight, general health and individual responsiveness of the subject being treated, as well as other relevant circumstances.

[0109] The compounds described herein may be used in admixture with one or more pharmaceutically acceptable excipients or carriers. The compound or compounds can be administered in the form of a pharmaceutical composition. A "pharmaceutical composition" is a composition that is useful or potentially useful for producing a physiological response in a subject to which such pharmaceutical composition is administered.

[0110] The term "pharmaceutically acceptable" is used with respect to excipients to define a non-toxic substance generally suitable for use in human or veterinary medicine. Pharmaceutical compositions may be in commonly employed forms such as tablets, capsules, powders, syrups, solutions, suspensions, and the like. Pharmaceutical compositions may contain suitable solid or liquid carriers or diluents to form injectable solutions or suspensions, or flavoring agents, sweeteners, and the like, in a suitable sterile vehicle. Such compositions typically contain from about 0.1 to about 50% by weight of the active compound, some active ingredient, and / or some non-active ingredient. In this embodiment, it contains about 1 to about 20% by weight, and the remainder of the composition is a pharmaceutically acceptable carrier, diluent or or a solvent.

[0111] Various embodiments are described below. Certain embodiments are not intended to be exhaustive or to be limiting. It should be noted that these statements are not intended as limitations on the broad aspects discussed herein. An aspect described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment(s). Throughout this specification, references to "one embodiment," "one embodiment," or "exemplary embodiment" are intended to imply that the particular feature, structure, or characteristic described in connection with the embodiment is applicable to at least one embodiment of the present disclosure. Thus, the appearances of the phrases "in one embodiment," "in an embodiment," or "one exemplary embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment, and may. Furthermore, a particular feature, structure, or characteristic may be included in one or more embodiments of the present disclosure. The features of the present invention may be combined in any suitable manner, as would be apparent to one skilled in the art. Furthermore, although some embodiments described herein include some features but not other features included in other embodiments, it is intended that combinations of features from different embodiments are within the scope of the present disclosure. For example, in the appended claims, any of the claimed embodiments may be used in any combination.

[0112] All patents, patent applications, published applications, and publications, databases, websites, and other published materials cited herein are incorporated by reference to the same extent as if each individual publication, published patent document, or patent application was specifically and individually indicated to be incorporated by reference.

[0113] kit Any of the compounds and / or formulations described herein can be presented as a combination kit. As used herein, the term "combination kit" or "kit of parts" refers to any additional components used to package, sell, sell, deliver, and / or administer a compound, composition, formulation, particle, cell, or combination of elements or a single element, such as an active ingredient contained therein. Such additional components include, but are not limited to, packaging, syringes, blister packs, bottles, etc. When one or more of the compounds, compositions, formulations, particles, cells, or combinations thereof (e.g., drug(s)) contained in the kit described herein are administered simultaneously, the combination kit can be used in combination. The combination kit can include the active agent(s) in a single formulation, such as a pharmaceutical formulation (e.g., tablet, liquid formulation, dehydrated formulation, etc.), or in separate formulations. When the compounds, compositions, formulations, particles, and cells described herein, or combinations thereof and / or kit components are not administered simultaneously, the combination kit can include each agent or other component in a separate pharmaceutical formulation. Separate kit components can be included in a single package or in separate packages within the kit.

[0114] In some embodiments, the combination kit also includes instructions printed on or otherwise contained in a tangible medium. The instructions may provide information regarding the contents of the compound and / or formulation, safety information regarding the contents of the compound and formulation (e.g., pharmaceutical formulation), dosage of the compound and / or formulation, indications for use, and / or recommended treatment regime(s).

[0115] Detailed Description of the Disclosure Reference will now be made in detail to the embodiments of the present disclosure, one or more examples of which are set forth below. The examples are provided to illustrate, but not to limit, the disclosure. Indeed, it will be apparent to those skilled in the art that various modifications can be made in the disclosure without departing from the scope or spirit of the disclosure. For example, as part of one embodiment, The illustrated or described features can be used in other embodiments to yield further embodiments. Thus, the present disclosure is intended to cover such modifications and variations as come within the scope of the appended claims and their equivalents. Other objects, features, and aspects of the present disclosure are set forth in the appended claims. and aspects are disclosed in or apparent from the following detailed description.

[0116] For ease of reference, the present disclosure will be described in terms of administration to human subjects, however, it will be understood that such description is not limited to administration to humans and also includes administration to other animals unless expressly stated otherwise.

[0117] Contemplated derivatives are those that may improve the solubility or increase the bioavailability of the compounds of the present disclosure when such compounds are administered to a subject (e.g., by making an orally administered compound more easily absorbed). The compounds of Formula I may be amorphous, semi-crystalline, or crystalline and may be administered in the form of the parent compound, its salt, and / or solvate. The solvate may be part of the crystal lattice or may be superficially associated. All of these forms are intended to be within the scope of the present disclosure. Methods of solvation are generally known in the art. Suitable solvates are pharmaceutically acceptable solvates. In one embodiment, the solvate is a hydrate.

[0118] In one aspect, the present disclosure is directed to novel compounds of Formula I, a stereoisomer, stable label (eg, deuterated variant), or pharmaceutically acceptable salt thereof.

[0119] [ka]

[0120] where R 1is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 is alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , C.O.R. 3 and optionally substituted one or more times with a group or substituent such as It may also be used.

[0121] R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl R 3 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , SO2R 5 , C.O.R. 3 selected from the group consisting of R 5 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted one or more times with groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, etc.

[0122] X is selected from O, (CH2)p, and NH; where p is selected from 0 to 2, but p=0 When Y1-Y2 are not CH-CH2 or CH-O, and R 1 is an aryl without; and Y1-Y2 are selected from CH-CH2, CH2-O, or C=CH, provided that Y1-Y2 are C When R is H2-O, X is selected from O or NH; 1is not hydrogen or alkyl Y3 is selected from H or Me 。

[0123] In another aspect, the present disclosure is directed to novel compounds of Formula II, a stereoisomer or a pharmaceutically acceptable salt thereof:

[0124] [ka]

[0125] where R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 is alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2NHR 2 , C.O.R. 3 and optionally substituted one or more times with a group or substituent such as It may also be used.

[0126] R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl R 3 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , SO2R 5 , C.O.R. 3 Selected from the group consisting of R 5 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R 6is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted one or more times with groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, etc.

[0127] X is selected from O, (CH2)p, and NH; where p is selected from 0 to 2, but p=0 When Y1-Y2 are not CH-CH2 or CH-O, and R 1 is the aryl without; and Y1-Y2 are selected from CH-CH2, CH-O, or C=CH, provided that Y1-Y2 are C When R is H2-O, X is selected from O or NH; 1 is not hydrogen or alkyl.

[0128] In another aspect, the present disclosure provides novel compounds of formula III, their stereoisomers or pharmaceutically acceptable salts thereof: It is directed towards salt.

[0129] [ka]

[0130] where R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 is alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 , SO2NHR 2 , C.O.R. 3 and optionally 1 with a group or substituent such as It may be substituted more than once.

[0131] R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl R 3 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , SO2R 5 , C.O.R. 3 Selected from the group consisting of R 5 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted one or more times with groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, etc.

[0132] X is selected from O, (CH2)p, and NH; where p is selected from 0 to 2. In another aspect, the present invention is directed to novel compounds of formula IV, a stereoisomer or a pharmaceutically acceptable salt thereof:

[0133] [ka]

[0134] where R 1 is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where R 1 is alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO2R 5 , SO2NHR 2 , C.O.R. 3 and optionally 1 with a group or substituent such as may be substituted more than once R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl R 3 is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , SO2R 5 , C.O.R. 3 Selected from the group consisting of R 5 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R 6 is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl may be optionally substituted one or more times with groups or substituents such as alkyl, hydroxy, halogen, haloalkyl, etc.

[0135] X is selected from O, (CH2)p, and NH; where p is selected from 0 to 2, but not limited to p=0. When, R 1 is not aryl.

[0136] Additionally, the composition may include one or more of the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0137] [ka]

[0138] [ka]

[0139] [ka]

[0140] In one embodiment, the present disclosure provides a compound comprising: 50It may contain <10 uM of a compound of formula I that is an inhibitor of soluble epoxide hydrolase (sEH).

[0141] In one embodiment, the disclosure may include a compound of Formula I, wherein the compound is an inhibitor of soluble epoxide hydrolase (sEH) with greater than 10-fold selectivity over fatty acid amide hydrolase (FAAH (SEQ ID NO: 3)).

[0142] In another embodiment, compounds of formula I have an IC 50 Soluble epoxide hydrochloride Inhibits enzymes with IC > 1000 nM 50 can inhibit fatty acid amide hydrolase (FAAH (SEQ ID NO: 3)).

[0143] In a further embodiment, the compound of formula I is 50 Inhibits soluble epoxide hydrolase at <50 nM, IC 50 Inhibits fatty acid amide hydrolase (FAAH (SEQ ID NO: 3)) at >1000 nM It can harm.

[0144] In a further embodiment, the compound of formula I is 50 Inhibits soluble epoxide hydrolase at <20 nM, IC 50 Inhibits fatty acid amide hydrolase (FAAH (SEQ ID NO: 3)) at >1000 nM It can harm.

[0145] In some embodiments, a therapeutically effective amount of a compound of Formula I can be from about 0.5 mg / day to about 3,000 mg / day. In embodiments, a therapeutically effective amount of a compound of Formula I can be from about 1 mg / day to about 2,000 mg / day. In embodiments, a therapeutically effective amount of a compound of Formula I can be from about 2 mg / day to about 600 mg / day. In embodiments, a therapeutically effective amount of a compound of Formula I can be from 3 mg / day to about 600 mg / day. In embodiments, the therapeutically effective amount of the compound of Formula I may be 4 mg / day to about 400 mg / day. In embodiments, the therapeutically effective amount of the compound of Formula I may be In embodiments, the therapeutically effective amount of the compound of formula I may be from 10 mg / day to about 300 mg / day.

[0146] In some embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject is 1 In an embodiment, the compound of Formula I is administered to an adult subject in a dose of about 2 mg to about 1,500 mg per day. The therapeutically effective amount of the compound may be from about 4 mg to about 750 mg per day. A therapeutically effective amount of a compound of Formula I for an elephant may be from about 6 mg to about 600 mg per day. In some embodiments, the therapeutically effective amount of the compound of Formula I for an adult subject may be from about 10 mg to about 500 mg per day. In an embodiment, the dose of a compound of Formula I for an adult subject may be about 20 mg to about 400 mg. A therapeutically effective amount may be from about 20 mg to about 300 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 20 mg to about 200 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 20 mg to about 120 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 20 mg to about 100 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 20 mg to about 75 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 20 mg to about 120 mg per day. The therapeutically effective amount of the compound may be from about 20 mg to about 60 mg per day. A therapeutically effective amount of a compound of formula I for a human subject may be from about 20 mg to about 50 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 20 mg to about 40 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for an adult subject may be from about 24 mg to about 40 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for a non-adult subject may be from about 0.1 mg to about 800 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for a non-adult subject may be from about 0.1 mg to about 800 mg per day. A therapeutically effective amount of a compound of Formula I for a subject can be from about 0.25 mg to about 350 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for a non-adult subject can be from about 0.5 mg to about 300 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for a non-adult subject can be from about 0.5 mg to about 300 mg per day. The effective amount may be from about 1 mg to about 200 mg per day. A therapeutically effective amount of a compound of formula I may range from about 2 mg to about 100 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for a non-adult subject may be from about 3 mg to about 80 mg per day. In embodiments, the dose of a compound of Formula I to a non-adult subject may be about 4 mg to about 60 mg. A therapeutically effective amount of a compound of Formula I for a non-adult subject may be from about 5 mg to about 80 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for a non-adult subject may be from about 6 mg to about 60 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for a non-adult subject may be from about 6 mg to about 50 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for a non-adult subject may be from about 5 mg to about 80 mg per day. In embodiments, a therapeutically effective amount of a compound of Formula I for a non-adult subject may be from about 6 mg to about 50 mg per day. In embodiments, the administration of a compound of Formula I to a non-adult subject may be from about 6 mg to about 40 mg per dose. A therapeutically effective amount of the compound of Formula I for a non-adult subject may be from about 6 mg to about 30 mg per day. In embodiments, a therapeutically effective amount of the compound of Formula I for a non-adult subject may be from about 7 mg to about 25 mg per day.

[0147] In some embodiments, a therapeutically effective amount of a compound of formula I may be administered in a single dose or in one or several repeated doses after a certain time interval. A therapeutically effective amount is administered daily, or once every two or three days, or once a week. The dose may be once, twice, or three times daily. In embodiments, the therapeutically effective amount is administered daily or every other day for 2 weeks or more, 10 weeks or more, 30 weeks or more, 1 year or more, or as long as the symptoms or disease are present. In embodiments, the therapeutically effective amount is administered daily or every other day for 30 weeks or more.

[0148] In yet another aspect, the present disclosure provides inhibitors of soluble epoxide hydrolase (sEH). The present invention is directed to novel compounds of formula I, their stereoisomers, stably labeled (e.g., deuterated) variants, tautomers and / or pharmaceutically acceptable salts thereof, which can be used as

[0149] In another aspect, the present disclosure is directed to a method for the prevention and / or treatment of pain, neurodegenerative diseases, diseases associated with synucleinopathy, and inflammatory disorders in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, its stereoisomers, and / or pharmaceutically acceptable salts thereof, wherein the compound of Formula I, its stereoisomers, and / or pharmaceutically acceptable salts thereof are used for the prevention or treatment of diseases associated with synucleinopathy, such as Lewy body dementia (LBD) and Gaucher 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). It is possible.

[0150] Furthermore, the compounds of Formula I, their stereoisomers and / or pharmaceutically acceptable salts are useful for the prevention or treatment of Alzheimer's disease, depression and related disorders, schizophrenia, stroke, subarachnoid hemorrhage, traumatic brain injury, and multiple system atrophy (MSA) in subjects in need of such treatment. The compositions can be used in the treatment of various conditions, including rheumatoid arthritis, ... and rheumatoid arthritis, which methods include administering to a subject a therapeutically effective amount of a composition described herein.

[0151] In another embodiment, the stereoisomers and / or pharmaceutically acceptable salts of Formula I can be used to treat neurodegenerative diseases such as dementia with Lewy bodies (DLB) and Gaucher disease. do.

[0152] For ease of reference, the present disclosure will be described in terms of administration to human subjects, however, it will be understood that such description is not limited to administration to humans and also includes administration to other animals unless expressly stated otherwise.

[0153] The contemplated derivatives may improve the solubility or increase the bioavailability of the compounds of the present disclosure when such compounds are administered to a subject (e.g., by making orally administered compounds more easily absorbed). The compounds of Formula I may be amorphous, semi-crystalline, or crystalline, and may be administered in the form of the parent compound, its salt, and / or solvate. The solvate may be part of the crystal lattice or may be superficially associated. All of these forms are intended to be within the scope of the present disclosure. Solvation methods are generally known in the art. Suitable solvates are pharmaceutically acceptable solvates. In one embodiment, the solvate is a hydrate.

[0154] In one embodiment, the compounds of the present disclosure (compounds of Formula I) are useful for treating inflammatory pain, neuropathic pain, rheumatoid arthritis, osteoarthritis, diabetic nephropathy, hypertension, diabetes, and / or metabolic syndrome. Compounds of Formula I may be useful for increasing epoxyeicosatrienoic acid (EET) levels in a subject to prevent and treat inflammatory and / or painful conditions.

[0155] The compounds of formula I, their pharmaceutically acceptable salts, and / or solvates thereof may therefore be used in the prevention and / or treatment of the diseases or conditions discussed herein. Pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I, its pharmaceutically acceptable salts, and / or solvates thereof, optionally together with a pharmaceutically acceptable excipient, are a further aspect of the present disclosure.

[0156] The therapeutically effective amount of a compound of formula I, its pharmaceutically acceptable salts and / or solvates to be administered, and the dosage for treating a pathological condition with said compound, will depend on many factors, such as the age and condition of the patient, the severity of the disease, the route and frequency of administration, and the modulator compound used.

[0157] 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 in the range described above. Thus, for oral administration, the active ingredient may be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions, 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, sesame oil, peanut oil, aqueous propylene glycol, etc. may be used, as may aqueous solutions of water-soluble pharmaceutically acceptable acid addition salts or salts with bases of the compounds. Alternatively, the active ingredient may be combined with a pharmaceutical carrier such as polyhydroxylated castor oil. Alternatively, an aqueous solution of the compound dissolved in a physiologically acceptable solvent can be used as an injection. The injection solution thus prepared can be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration generally being preferred for humans.

[0158] The following examples describe exemplary embodiments of the present disclosure. Other embodiments within the scope of the claims herein will be apparent to those skilled in the art from consideration of the specification or examples of the present disclosure disclosed herein. It is intended that the specification, together with the examples, be considered exemplary, with the scope and spirit of the disclosure being indicated by the claims which follow the examples.

[0159] General synthetic procedure Compounds of the present disclosure can be synthesized according to the procedures outlined in Schemes I-VIII. The suggested methodologies are not intended to be limiting: variations on these synthetic methodologies or methodologies reported in the literature can be employed to synthesize compounds within the scope of this disclosure.

[0160] [ka]

[0161] Scheme I illustrates a method for synthesizing compound 7 of formula I of the present disclosure. In the first step, a substituted benzyl halide 1 (Z = Cl, Br) is reacted with a trialkyl phosphate to give a substituted benzyl phosphonate 2. This reaction can be carried out by heating 1 with a trialkyl phosphite at 120-150 °C for 10-20 hours, with or without a solvent such as dimethylacetamide. Substituted alkenes 4 can be obtained by generating ylides from intermediate 2 and reacting them with substituted piperidones 3. The synthesis of 3 with the ylide from 2 can be carried out in a solvent such as THF, dimethoxyethane, or diethyl ether in the presence of a crown ether using a base such as sodium hydride or potassium hydride. This reaction can be initiated at low temperatures (0±5°C), after which the reaction mixture is warmed to approximately 20°C and stirred for an additional 20-60 minutes. The reaction of 3 with the ylide from 2 can be carried out in a solvent such as THF, dimethoxyethane, diethyl ether, or toluene. The reaction is initiated at a low temperature (0±5°C), and then the reaction mixture is heated to about 20-40°C and stirred for 8-20 minutes. This reaction can be carried out by stirring for 20 hours at a temperature of 0 to 25°C using an acid such as trifluoroacetic acid in a solvent such as dichloromethane or dichloroethane. The reaction can be carried out by stirring for about 90 minutes. Reaction of intermediate 6 with dimethyl sulfoxide gives the desired compound 7. This can be accomplished by heating the reactants in a solvent such as methylacetamide and a base such as triethylamine or diisopropylethylamine at 40-60° C. for 3-6 hours.

[0162] Substituted cyclopropane carbamates 6 can be prepared in solvents such as dichloromethane and diisopropyl Reaction with allyl chloroformate (R=Ph or Ar) using a base such as ethylamine The reaction can be carried out by reacting the corresponding cyclopropylamine 8 with the The reaction mixture can be started at low temperature (0±5° C.), and then warmed to about 20-30° C. and stirred for 20-40 minutes. can be purchased commercially or synthesized from readily available reagents.

[0163] [ka]

[0164] Scheme II illustrates a method for synthesizing compound 11 of formula I of the present disclosure. In the first step, Scheme I Compound 4, synthesized using the methodology described above, is hydrogenated to give saturated compound 9. This reaction can be carried out using catalytic hydrogenation (e.g., using Pd / C or Pt / C) in a Parr hydrogenation apparatus in solvents such as methanol or ethanol. Deprotection of carbamate 9 in the presence of acid gives piperidine intermediate 10. This reaction can be carried out in solvents such as dichloromethane and dichloromethane. In a solvent such as chloroethane, an acid such as trifluoroacetic acid is used, and the reaction mixture is heated to a temperature of 0 to 25°C. The reaction can be carried out by stirring at 40°C for 20-90 minutes. The reaction of 10 with the substituted cyclopropane carbamate intermediate 6 gives the target compound 11. This reaction is carried out in the presence of dimethyl sulfoxide. The reaction can be carried out by heating the reactants at 40-60° C. for 3-6 hours using a solvent such as dimethylacetamide and a base such as triethylamine or diisopropylethylamine.

[0165] [ka]

[0166] Scheme III illustrates a method for synthesizing compounds 18 and 19 of the present disclosure. In the first step, hetero Compound 12 containing an aryl ring A (pyridine, pyrimidine, pyrazine, etc.) is reacted with substituted phenol 13 to give 14. This reaction can be carried out in a wide range of amides, such as dimethylacetamide, dimethylformamide, etc. The reaction mixture can be heated at 80-120°C for 3-6 hours in any solvent using a base such as potassium carbonate, sodium carbonate, or cesium carbonate. The alcohol is converted to the corresponding benzyl halide 15 by reaction with thionyl chloride. This reaction is carried out in a solvent such as dichloromethane with thionyl chloride at 0-25°C for 1-3 hours. The substituted benzyl halide 15 can be reacted with a trialkyl phosphite to give the substituted benzyl phosphonate 16. This reaction can be carried out by heating 15 with the trialkyl phosphite at 120-150°C for 10-20 hours, with or without a solvent such as dimethylacetamide. The ylide from intermediate 16 is then reacted with substituted piperidone 3 to give the substituted alkene 17. In solvents such as THF, dimethoxyethane, and diethyl ether, the presence of crown ethers The reaction can be carried out using a base such as sodium hydride or potassium hydride under reduced pressure. The reaction can be initiated at a low temperature (0±5°C), followed by warming the reaction mixture to about 20°C and stirring for an additional 20-60 minutes. The reaction of the ylide generated from 16 with 3 can be carried out in a solvent such as THF, dimethoxyethane, diethyl ether, or toluene by initiating the reaction at a low temperature (0±5°C), followed by warming the reaction mixture to about 20-40°C and stirring for 8-20 hours. 17 to 18 The conversion to HCl can be achieved by deprotecting the carbamate in the presence of acid, as described in Scheme I. This can be carried out after the step of reacting the substituted cyclopropane carbamate intermediate 6 with The conversion of 17 to 19 uses sequential steps including hydrogenation, carbamate deprotection, and reaction with the substituted cyclopropane carbamate intermediate 6, as described in Scheme II. This can be achieved by:

[0167] [ka]

[0168] Scheme IV illustrates a method for synthesizing compounds 26 and 27 of the present disclosure. In the first step, compound 20 is reacted with a substituted phenol 21 to give 22. This reaction can be carried out in a solvent such as dimethylacetamide or dimethylformamide using a base such as cesium carbonate and heating the reaction mixture at 80-120°C for 3-8 hours. The resulting substituted benzyl alcohol The benzyl halide 23 is converted to the corresponding benzyl halide 24 by reaction with thionyl chloride. This reaction is carried out in a solvent such as dichloromethane at 0-25°C for 1-3 hours. The reaction can be carried out by the following procedure. Substituted benzyl halide 23 is reacted with trialkyl phosphite to give substituted benzyl phosphonate 24. This reaction can be carried out by heating trialkyl phosphite and 23 at 120-150°C for 10-20 hours, with or without a solvent such as dimethylacetamide. Substituted alkenes 25 are synthesized by generating the ylide from intermediate 24 and reacting it with substituted piperidone 3. The generation of the ylide from 24 can be carried out using a base such as sodium hydride or potassium hydride in the presence of a crown ether in a solvent such as THF, dimethoxyethane, or diethyl ether. The reaction can be initiated at low temperature (0±5°C), after which the reaction mixture can be warmed to approximately 20°C and stirred for an additional 20-60 minutes. The reaction of the ylide generated from 24 with 3 can be carried out in a solvent such as THF, dimethoxyethane, diethyl ether, or toluene by initiating the reaction at low temperature (0±5°C) and then warming the reaction mixture to about 20-40°C and stirring for 8-20 hours. Conversion of 25 to 26 can be carried out after deprotection of the carbamate in the presence of acid and reaction with the substituted cyclopropane carbamate intermediate 6, as described in Scheme I. Conversion of 25 to 27 can be carried out by This can be achieved using sequential steps including hydrogenation, carbamate deprotection, and reaction with a substituted cyclopropane carbamate intermediate 6, as described in Scheme II. .

[0169] [ka]

[0170] Scheme V shows a method for synthesizing compounds 33 and 34 of the present disclosure. In the first step, a substituted benzoyl group is reacted with 34. The benzyl halide 28 is reacted with a trialkyl phosphite to give the substituted benzyl phosphonate 29. This reaction can be carried out by heating 28 with the trialkyl phosphite at 120-150 °C for 10-20 hours, with or without a solvent such as dimethylacetamide. The substituted alkene 30 can be obtained by generating the ylide from intermediate 29 and reacting it with the substituted piperidone 3. The synthesis of the ylide from 29 is carried out in THF, dimethoxyethane, diethyl ether, The reaction can be carried out in a solvent such as ethanol in the presence of a crown ether using a base such as sodium hydride or potassium hydride. The reaction can be initiated at a low temperature (0±5°C), and the reaction mixture can then be warmed to about 20°C and stirred for an additional 20-60 minutes. The reaction of the ylide generated from 29 with 3 can be carried out in a solvent such as ethanol in the presence of a crown ether using a base such as sodium hydride or potassium hydride. The reaction is carried out in a solvent such as THF, dimethoxyethane, diethyl ether or toluene at low The reaction mixture is then heated to about 20 to 40°C and stirred for 8 to 20 hours. Intermediate 31 containing heterocyclyl ring A can be prepared by stirring the mixture of pyrrolidine It can be synthesized from 30 by reacting with the corresponding heterocycle, such as morpholine or piperidine. This reaction is carried out with cesium carbonate and palladium acetate and 2,2'-bis(diphenyl)- The conversion of 31 to 33 can be achieved by treating 30 with the ring A heterocycle using a catalyst such as (1,1'-(2-phenylphosphino)-1,1'-binaphthyl (BINAP). The reaction can be carried out using a solvent such as 1,4-dioxane at 20-100°C for 5-20 hours. The conversion of 31 to 33 can be achieved by deprotection of the carbamate in the presence of acid, as described in Scheme I. and the reaction with the substituted cyclopropane carbamate intermediate 6. Cut.

[0171] Conversion of 31 to 32 can be achieved using catalytic hydrogenation (Pd / C, H), as described in Scheme II. Similarly, conversion of 32 to 34 can be achieved by carbamate deprotection and subsequent reaction with the substituted cyclopropane carbamate intermediate 6, as described in Scheme II. The reaction can be carried out according to the methodology comprising the reaction.

[0172] [ka]

[0173] Scheme VI illustrates a method for synthesizing compound 40 of the present disclosure. In the first step, compound 35 containing a heteroaryl ring A (pyridine, pyrimidine, pyrazine, etc.) is reacted with a substituted phenol 36. This reaction can be carried out in a solvent such as dimethylacetamide or dimethylformamide using a base such as potassium carbonate, sodium carbonate, or cesium carbonate by heating the reaction mixture at 80-120°C for 3-8 hours. Reaction of 39 with mesylate 38 gives 39. 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 60-80 °C for 6-8 hours. Conversion of 39 to 40 can be achieved by deprotecting the carbamate in the presence of acid and then cleaving the substituted silyl group, as described in Scheme I. This can be carried out after the step of reacting with chloropropane carbamate intermediate 6.

[0174] [ka]

[0175] Scheme VII illustrates a method for synthesizing compounds of formula 45 and 46 of the present disclosure. In the first step, The arylboronate-containing compound 41 is reacted with an aryl halide 42 to give 43. This reaction is carried out by reacting 41 and 42 in a solvent such as dimethylacetamide or dimethylformamide with 2N aqueous sodium carbonate and tetrakis(triphenylphosphine)palladium (0 ) at an ambient temperature of 20 to 25°C for 12 to 18 hours. The conversion of 43 to 45 can be achieved by the reaction of the carbamate in the presence of an acid, as described in Scheme I. and reacting with a substituted cyclopropane carbamate intermediate 6. It is possible.

[0176] Conversion of 43 to 44 can be achieved using catalytic hydrogenation (Pd / C, H), as described in Scheme II. Similarly, conversion of 44 to 46 can be achieved by deprotection of the carbamate and reaction with the substituted cyclopropane carbamate intermediate 6, as described in Scheme II. The method may be carried out according to a methodology including:

[0177] [ka]

[0178] Scheme VIII illustrates a method for synthesizing compounds of formula 54 of the present disclosure. In the first step, substituted benzyl halide 47 is reacted with a trialkyl phosphite to give substituted benzyl phosphonic acid 48. This reaction can be carried out by heating 47 with the trialkyl phosphite at 120-150°C for 10-20 hours. Substituted alkenes 49 are synthesized by generating the ylide from intermediate 48 and reacting it with substituted piperidone 3. The generation of the ylide from 48 can be carried out using a base such as sodium hydride or potassium hydride in the presence of a crown ether in a solvent such as THF, dimethoxyethane, or diethyl ether. The reaction can be initiated at a low temperature (0±5°C), after which the reaction mixture can be warmed to approximately 20°C and stirred for an additional 20-60 minutes. The reaction of the ylide generated from 48 with 3 can be carried out in a solvent such as THF, dimethoxyethane, diethyl ether, or toluene by initiating the reaction at low temperature (0±5°C) and then warming the reaction mixture to approximately 20-40°C and stirring for 8-20 hours. This reaction can be carried out using a Parr hydrogenation apparatus. In a solvent such as methanol or ethanol, catalytic hydrogenation (e.g., Pd / C or Pt In the next step, the substituted 1-fluoro-2-nitrobenzene 51 is subjected to a substitution reaction with 50 to synthesize 52. This reaction can be carried out by treating 50 with 51 in a solvent such as dimethylformamide and heating the reaction mixture in the presence of cesium carbonate at 80-120°C for 10-20 hours. The synthesis of benzimidazole compound 53 can be carried out using 52 was treated with formic acid and sodium formate in the presence of Pd / C at around 25°C, and the mixture was heated to 100-120°C. The conversion of 53 to 54 can be achieved by heating at around °C for 12-20 h. By treatment with substituted cyclopropane carbamate intermediate 6 as described It can be implemented. [Example]

[0179] One embodiment of the present disclosure provides the preparation of novel compounds of Formula I using the procedures described in the following examples. Those skilled in the art will understand that known variations of the conditions and steps of the following preparative procedures can be used to prepare these compounds. Moreover, by utilizing the procedures described herein, those skilled in the art can prepare additional compounds of the present disclosure claimed herein.

[0180] Example 1 - 4-(3-Methoxy-benzylidene)-piperidine-1-carboxylic acid (2-phenyl Synthesis of (cyclopropyl)-amide:

[0181] [ka]

[0182] Step 1 - To a mixture of (3-methoxy-phenyl)-methanol (20.0 g, 0.14 mol) and pyridine (5.8 mL, 0.72 mol) in benzene (120 mL) was added dropwise thionyl chloride (74 mL, 1.01 mol) while stirring in an ice bath. The resulting reaction mixture was diluted with saturated aqueous sodium bicarbonate (100 mL). The mixture was quenched with HCl, extracted with ethyl acetate (2×300 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (5% ethyl acetate in petroleum ether) to give the product 2 as a yellow oil, 20.01 g (88%). 1 H NMR (300 MHz, CDCl3) δ (ppm):3.84 (s, 3H), 4.58 (s, 2H), 6.86-6.90 (m, 1H), 6.95-7.00 (m, 2H), 7.26-7.32 (m, 1H).

[0183] Step 2 - A solution of 2 (20 g, 0.12 mol) in triethyl phosphite (29.0 mL, 0.16 mol) was added to 150 mL of ° The reaction mixture was cooled to room temperature and the volatiles were evaporated. The resulting crude product was purified on a silica gel (230-400) column (20% ethyl acetate in petroleum ether) to give product 3 as a colorless oil 27.0 g (81%). 1 H NMR (300 MHz, CDCl3) δ (ppm): 1.26 (t, J=7.2 Hz, 6H), 3.11 (s, 1H), 3.18 (s, 1H), 3.81 (s, 3H), 4.01-4.03 (m, 4H), 6.79-6.91 (m, 3H), 7.21-7.28 (m, 1H).

[0184] Step 3 - To a solution of 3 (11.0 g, 43.0 mmol) in THF (44 mL) was added 15-crown ether (0.2 mL, 0.9 mmol) was added. The reaction was cooled (ice bath) and NaH (580 mg, 24.2 mmol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and re-cooled using an ice bath. To the above reaction mixture was added 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 4 (8.5 mL) in THF (44 mL). A solution of 1,2-dimethyl-3,4-dichloro-2 ... The crude product obtained was purified by silica gel (230-400) column (25% ethyl acetate in petroleum ether). to give the product 5 as a yellow oil 7.0 g (54%). 1 H NMR (300 MHz, CDCl3) δ (ppm): 1.49 (s, 9H), 2.32-2.36 (m, 2H), 2.44-2.50 (m, 2H), 3.42 (t, J=5.7 Hz, 2H), 3.52 (t, J=5.7 Hz, 2H), 3.84 (s, 3H), 6.35 (s, 1H), 6.75-6.81 (m, 3H), 7.25-7.25 (m, 1H).

[0185] Step 4 - To a solution of 5 (1.0 g, 3.2 mmol) in dichloromethane (8.0 mL) was added trifluoroacetic acid (4.25 mL, 4.25 vol) at ice temperature, and the reaction mixture was stirred at room temperature for 1 hour. The crude product obtained by evaporation of the volatiles was washed with diethyl ether to give 6 as a white solid (600 mg, 89%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 2.54-2.62 (m, 4H), 3.07-3.17 (m, 4H), 3.75 (s, 3H), 6.44 (s, 1H), 6.77-6.84 (m, 3H), 7.27 (t, J=7.8 Hz, 1H), 8.79 (bs, 2H).

[0186] Step 5 - To a suspension of trans-2-phenylcyclopropylamine 2A (3.5 g, 0.02 mol) in dichloromethane (35 mL) was added triethylamine (0.06 mol) and phenyl chloroformate 1A (4.8 g, 0.03 mol) at ice bath temperature. The ice bath was then removed, and the reaction mixture was stirred at room temperature for 30 minutes. The resulting reaction mixture was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (10% ethyl acetate in petroleum ether) to give product 7 as a white solid (2.6 g, 50%): 113.6-115.3 °C. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.14-1.26 (m, 2H), 2.03-2.09 (m, 1H), 2.72-2.75 (m, 1H), 7.10-7.40 (m, 10H), 8.18 (bs, 1H).MS: 254 (M+H).

[0187] Step 6: To a solution of amine 6 (300 mg, 0.94 mmol) in dimethyl sulfoxide (6 mL) was added diisopropylethylamine (0.5 mL, 2.82 mmol) and carbamate 7 (238 mg, 0.94 mmol). The resulting reaction mixture was diluted with ethyl acetate (250 mL) and washed with water (4×75 mL). The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to give product 8 as a white solid, 226 mg (65%), 104.7-106.4 °C. 1 H NMR (300 MHz, CDCl3) δ (ppm): 1.15-1.27 (m, 2H), 2.02-2.09 (m, 1H), 2.40 (t, J=5.7 Hz, 2H), 2.54 (t, J=5.7 Hz, 2H), 2.87 (bs, 1H), 3.39 (t, J=5.7 Hz, 2H), 3.49 (t, J=5.7 Hz, 2H), 3.82 (s, 3H), 4.87 (s, 1H, -CONH-, interchangeable 1 H), 6.37 (s, 1H), 6.75-6.81 (m, 3H), 7.18-7.30 (m, 6H). 13 C NMR (75 MHz, CDCl3) δ (ppm): 16.44, 25.10, 29.14, 33.19, 35.72, 44.60, 45.60, 55.18, 111.88, 114.60, 121.36, 124.76, 125.95, 126.65, 128.28, 129.16, 137.90, 138.70, 140.88, 157.95, 159.53.MS: 363 (M+H)

[0188] Example 2 - Synthesis of 4-[3-(pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide

[0189] [ka]

[0190] Step 1 - To a solution of 2-fluoro-pyridine (25.8 g, 0.27 mol) in DMF (300 mL) was added 3-hydroxy- Hydroxyphenyl-methanol (30.0 g, 0.24 mol) and cesium carbonate (117.3 g, 0.36 mol) were added at room temperature. The reaction mixture was stirred at 100°C for 5 hours. The resulting mixture was allowed to cool to room temperature, diluted with water (250 mL), extracted with ethyl acetate (3 x 500 mL), and the organic layer was dried over sodium sulfate. The volatiles were evaporated and the crude product was purified by silica gel (230-400) column chromatography. The product 2 was purified in hexane (30% ethyl acetate in petroleum ether) to give 34.5 g (71%) of a pale yellow oil. was obtained as. 1 H NMR (300 MHz, DMSO-d6) δ (ppm):4.49-4.51 (m, 2H), 5.24-5.30 (m, 1H), 6.98-7.15 (m, 5H), 7.33-7.40 (m, 1H), 7.82-7.89 (m, 1H), 8.14-8.16 (m, 1H).

[0191] Step 2 - To a solution of 2 (34.5 g, 0.17 mol) in dichloromethane (345 mL), react in an ice bath. Thionyl chloride (13.9 mL, 0.18 mol) was added dropwise to the mixture while stirring. After removing the ice bath, the reaction The mixture was stirred at room temperature for 1 hour. The volatiles were then evaporated under reduced pressure, diluted with toluene (25 mL), and the toluene was evaporated under reduced pressure. This azeotropic step was repeated three times to give product 3 as a brown oil (36.8 g, 98%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm):4.77 (s, 2H), 7.04-7.20 (m, 4H), 7.27-7.29 (m, 1H), 7.42 (t, J=8.4 Hz, 1H), 7.84-7.90 (m, 1H), 8.14-8.16 (m, 1H). Step 3 - A solution of 3 (36.7 g, 0.16 mol) in triethyl phosphite (41.6 mL, 0.26 mol) was added to 150 mL of ° The reaction mixture was heated at 4°C for 6 hours. The reaction mixture was allowed to cool to room temperature, and the volatiles were evaporated to give a crude product, which was purified on a silica gel (230-400) column (60% ethyl acetate in petroleum ether). This gave product 4 as a colorless oil, 41.33 g, which contained unused triethyl phosphate and was used in the next step without further purification.

[0192] Step 4—To a solution of [3-(pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester 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 in portions. The reaction mixture was stirred at room temperature for 30 minutes and cooled to ice again. To the above reaction mixture was added 4- A solution of oxo-piperidine-1-carboxylic acid tert-butyl ester 5 (18.6 g, 93.0 mmol) was added to ice The mixture was added warm and stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (500 mL), extracted with ethyl acetate (3×500 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (3% ethyl acetate in petroleum ether) to give product 6 as a yellow oil, 24.3 g (71%). 1 H NMR (300 MHz, CDCl3) δ (ppm): 1.41 (s, 9H), 2.27 (t, J=5.4 Hz, 2H), 2.40 (t, J=5.4 Hz, 2H), 3.33 (bs, 2H), 3.40 (t, J=5.4 Hz, 2H), 6.37 (s, 1H), 6.95-7.15 (m, 4H), 7.37 (t, J=7.8 Hz, 2H), 7.83-7.88 (m, 1H), 8.14-8.16 (m, 1H).

[0193] Step 5 - 4-[3-(pyridin-2-yloxy)-benzylidene] in dichloromethane (120.0 mL) To a solution of 1-[(2-methyl-2-propanol)-piperidine-1-carboxylic acid tert-butyl ester 6 (12.0 g, 33.0 mmol) was added trifluoroacetic acid (51 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 1 h. Evaporation of the volatiles afforded a brown oil 7 (13.7 g, 85%), which was used in the next step without further purification. (13.7 g, 85%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 2.56-2.63 (m, 4H), 3.10-3.16 (m, 4H), 6.46 (s, 1H), 6.99-7.15 (m, 5H), 7.39 (t, J=7.5 Hz, 1H), 7.83-7.88 (m, 1H), 8.14-8.16 (m, 1H).

[0194] Step 6—To a solution of amine 7 (15.0 g, 26.0 mmol) in dimethyl sulfoxide (150 mL) was added diisopropylethylamine (13.6 mL, 78.0 mmol) and the product of Step 5 of Example 1 (6.7 g, 26.0 mmol) was added at 25° C. The resulting reaction mixture was stirred at 60° C. for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (1.2 L), washed with water (3x150 mL), and sodium sulfate was added. The crude product obtained by evaporation of the volatiles was then dried over silica gel (230-400). Purification with rum (50% ethyl acetate in petroleum ether) gave product 8 as a pale yellow solid 9.1 g (81%): 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-, interchangeable 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)

[0195] Example 3 - 4-[3-(5-trifluoromethyl-pyridin-2-yloxy)-benzylidene Synthesis of ]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide

[0196] [ka]

[0197] Step 1 - To a solution of 5-trifluoromethyl-2-chloro-pyridine (23.0 g, 0.12 mol) in DMF (230 mL) was added 3-hydroxyphenyl-methanol (17.4 g, 0.13 mol) and potassium carbonate (26.3 g, 0.19 mol) at room temperature. The resulting reaction mixture was stirred at 100 °C for 5 hours. The resulting mixture was cooled to room temperature, diluted with water (200 mL), extracted with ethyl acetate (3 x 400 mL), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (12% ethyl acetate in petroleum ether) to give product 2 as a pale yellow oil, 28.1 g (82%). 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).

[0198] Step 2 - To a solution of 2 (28.0 g, 0.10 mol) in dichloromethane (280 mL), add the reaction mixture in an ice bath. Thionyl chloride (8.5 mL, 0.11 mol) was added dropwise to the mixture while stirring. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. The volatiles were then evaporated under reduced pressure, diluted with toluene (15 mL), and the toluene was evaporated under reduced pressure. This azeotropic step was repeated three times to give 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).

[0199] Step 3 - A solution of 3 (29.0 g, 0.10 mol) in triethyl phosphite (26.2 mL, 0.15 mol) was added to 150 ° The reaction mixture was heated at 4°C for 6 hours. The reaction mixture was allowed to cool to 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. was obtained as a white solid (30.8 g, 94%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.16 (t, J=6.9 Hz, 6H), 3.24 and 3.31(2s, 2H), 3.90-4.00 (m, 4H), 7.07-7.10 (m, 2H), 7.17-7.25 (m, 2H), 7.39 (d, J=8.7 Hz, 1H), 8.23-8.26 (m, 1H), 8.55 (s, 1H).

[0200] 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 min. The reaction mixture was stirred at room temperature for 30 min and cooled to ice again. To the reaction mixture was added a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 5 (12.81 g, 64.0 mmol) in THF (100 mL) at ice temperature, and the mixture was stirred at room temperature for 16 hours. The precipitate was filtered. After filtration and drying, product 6 was obtained as a white solid (24.4 g, 87%). 1 H NMR (300 MHz, CD3OD) δ (ppm): 1.48 (s, 9H), 2.36 (t, J=5.1 Hz, 2H), 2.49 (t, J=5.4 Hz, 2H), 3.43 (t, J=5.7 Hz, 2H), 3.52 (t, J=5.7 Hz, 2H), 6.43 (s, 1H), 7.01-7.03 (m, 2H), 7.14 (d, J=8.4 Hz, 2H), 7.38-7.44 (m, 1H), 8.09-8.12 (m, 1H), 8.44 (bs, 1H).

[0201] Step 5 - To a solution of 6 (10.0 g, 23.0 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (42.5 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 1 h. The volatiles were then removed under reduced pressure to give the product as a red oil (10.7 g, 83%). The crude product 7 was used in the next step without further purification. 1 H 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).

[0202] Step 6—To a solution of amine 7 (10.5 g, 18.7 mmol) in dimethyl sulfoxide (10 mL), Diisopropylethylamine (9.8 mL, 56.1 mmol) and the product of Step 5 of Example 1 (4.74 g, 18.7 mmol) was added at 25° C. 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 was obtained by evaporation of the volatiles. The material was purified on a silica gel (230-400) column (40% ethyl acetate in petroleum ether) to give product 8 as a white solid 7.0 g (76%): 98.9-101.5 °C 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.08-1.18 (m, 2H), 1.85-1.90 (m, 1H), 2.77 (bs, 2H), 2.39 (bs, 2H), 2.69-2.72 (m, 1H), 3.32-3.39 (m, 4H), 6.37 (s, 1H), 6.85 (s, 1H, D2O exchangeable 1 H), 7.04-7.24 (m, 9H), 7.41 (t, J=7.8 Hz, 1H), 8.22-8.25 (m, 1H), 8.58 (s, 1H). 13 C NMR (75 MHz, DMSO-d6) δ (ppm): 15.99, 24.74, 29.39, 34.44, 36.07, 44.37, 45.44, 112.25, 118.97, 119.81, 120.23, 120.66, 121.09, 121.53, 122.08, 122.57, 123.42, 125.79, 126.15, 126.38, 128.52, 129.76, 130.08, 137.98, 138.01, 139.42, 140.34, 142.42, 145.72, 145.77, 153.38, 158.08, 166.01.MS: 494 (M+H).

[0203] Example 4 - Synthesis of 4-[3-(pyridin-2-yloxy)-benzyl]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0204] [ka]

[0205] Step 1 - To a solution of the product of Step 4 of Example 2(6) in methanol (17 mL) was added 10% Pd / C (900 mg) at room temperature, and the reaction mixture was stirred under hydrogen balloon pressure for 1 hour. The resulting reaction mixture was filtered through a celite bed and the filtrate was concentrated under reduced pressure to give product 7. was obtained as a yellow oil (850 mg, 66%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 0.98-1.04 (m, 2H), 1.37 (s, 9H), 1.43-1.56 (m, 3H), 2.60 (m, 4H), 3.88-3.92 (m, 2H), 6.91-7.02 (m, 2H), 7.10-7.17 (m, 2H), 7.25-7.31 (m, 2H), 7.84-7.89 (m, 1H), 8.14-8.16 (m, 1H).

[0206] Step 2 - Ester 7 (800 mg, 2.17 mmol) in dichloromethane (8 mL) was added at ice-temperature. Trifluoroacetic acid (3.4 mL, 4.25 vol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The volatiles were then removed under reduced pressure to give the product as a brown oil (800 mg, 74%). The crude product 8 was used in the next step without further purification.

[0207] Step 3 - To a solution of crude amine 8 (500 mg, 1.0 mmol) in dimethyl sulfoxide (10 mL) was added diisopropylethylamine (0.5 mL, 2.82 mmol) and the product of Step 5 of Example 1 (256 mg, 1.0 mmol) at 25 °C. The resulting reaction mixture was stirred at 60 °C for 5 h. The reaction mixture was diluted with ethyl acetate (250 mL), washed with water (4X75 mL), dried over sodium sulfate, and The crude product obtained by evaporating the volatiles was purified by silica gel (230-400) column (petroleum ether). Purification with 60% ethyl acetate in ether gave product 9 as a white solid in 230 mg (53%) at 126.8–128.6 °C. 1H NMR (300 MHz, CDCl3) δ (ppm): 1.12-1.27 (m, 4H), 1.68-1.71 (m, 3H), 1.89-2.06 (m, 1H), 2.56 (d, J=6.6 Hz, 2H), 2.73 (t, J=11.4 Hz, 2H), 2.82-2.86 (m, 1H), 3.92 (d, J=13.5 Hz, 2H), 4.84 (s, 1H, -CONH-, interchangeable 1 H), 6.90-7.03 (m, 5H), 7.15-7.35 (m, 6H), 7.68-7.74 (m, 1H), 8.21-8.23 (m, 2H). 13 C NMR (75 MHz, CDCl) 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)

[0208] Example 5 - Chiral separation of the racemate of Example 2 A chiral column (CHIRALPACK IA 250 mm x 10 mm 5 μm) was equilibrated with 15 column volumes of mobile phase (n-hexane:isopropyl alcohol; 80:20 v / v) prior to elution of the compound. 500 mg of the product of Example 2 was then eluted in 5 mL of n-hexane and isopropyl alcohol (8:2). A 500 μL stock solution prepared by dissolving in 500 μL of entA was injected, and fractions were collected based on the separation observed in the chromatogram. Fraction F1 was the first fraction to elute from the chiral column (retention time: 11.5 min - 13.00 min), and F2 was the second fraction to elute (retention time: 13.50 min - 15.50 min). The remaining stock solution (4.5 mL) was repeatedly injected to ensure complete separation. The solvents in F-1 and F-2 were then removed separately under reduced pressure to give the chiral products 5A (entA) (140 mg) and 5B (entB) (150 mg), respectively.

[0209] 5A 4-[3-(pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid {(1S,2R)-2-phenyl-cyclopropyl)}-amide - HPLC: 99.98% (chiral purity: 98.55%): 45.0 - 47.1 °C. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.06-1.10 (m, 1H), 1.15-1.18 (m, 1H), 1.87 (m, 1H), 2.24-2.28 (m, 2H), 2.38-2.40 (m, 2H), 2.69-2.72 (m, 1H), 3.29-3.40 (m, 4H), 6.36 (s, 1H), 6.85-6.86 (m, 1H), 6.95-7.27 (m, 10H), 7.37 (t, J=7.8 Hz, 1H), 7.83-7.85 (m, 1H), 8.14-8.16 (m, 1H).MS: 426 (M+H).

[0210] 5B 4-[3-(pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid {(1R,2S)-2-phenyl-cyclopropyl)}-amide - HPLC: 99.89% (chiral purity: 98.93%): 51.0 - 54.3 °C. 1H 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).

[0211] [ka]

[0212] Example 6 - Synthesis of 4-[3-(pyrimidin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide

[0213] [ka]

[0214] Step 1 - Dissolution of 3-hydroxyphenyl-methanol (500 mg, 4.0 mmol) in DMF (5 mL) The solution was added with cesium carbonate (2.6 g, 8.0 mmol) and 2-chloropyrimidine (680 mg, 6.0 mmol). The resulting reaction mixture was stirred at 100° C. for 5 hours, cooled to room temperature, filtered to remove cesium carbonate, and the filtrate was diluted with water (50 mL). Extraction with ethyl acetate (100 mL) was performed, and the organic layer was dried over sodium sulfate. The crude product obtained by evaporation of the volatiles was purified by silica gel (230-400) column (50% ethyl acetate in petroleum ether). ) to give the product 1 as a pale yellow oil, 440 mg (54%).1 H NMR (300 MHz, DMSO-d6) δ (ppm):4.52 (s, 2H), 5.28 (bs, 1H), 7.03-7.99 (m, 5H), 8.63 (d, J = 1.2 Hz, 2H).

[0215] Step 2 - To a solution of 1 (440 mg, 2.1 mmol) in dichloromethane (8 mL) was added 1,000 mL of 1,000 sulphite, and stirred in an ice bath. Thionyl chloride (0.19 mL, 2.6 mmol) was added dropwise while the mixture was stirred. After removing the ice bath, the reaction mixture was The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice-cold water (10 mL), extracted with ethyl acetate (100 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (25% ethyl acetate in petroleum ether) to give product 2 as a pale pink solid (400 mg, 83%). 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).

[0216] Step 3 - 2-(3-chloromethyl-phenoxy)-2-(2 ... A solution of 400 mg (1.8 mmol) of β-pyrimidine 2 was added to 150 mL of HCl. ° The reaction mixture was heated at 4°C for 6 hours. The mixture was returned to room temperature, and the volatiles were evaporated. The resulting crude product was then passed through a silica gel (230-400) column. (50% ethyl acetate in petroleum ether) to give product 3 as a white solid, 400 mg (69%). Got it. 1H 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).

[0217] Step 4 - To a solution of ester 3 (400 mg, 1.2 mmol) in THF (2.5 mL) was added 15-crown ether (5 μL, 0.02 mmol). The reaction was cooled (ice bath) and NaH (44 mg, 1.8 mmol) was added in portions. The reaction mixture was stirred at room temperature for 30 min and cooled to ice again. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (250 mg, 1.2 mmol) in THF (2.5 mL) was added to the reaction mixture at ice temperature, and the mixture was stirred at room temperature for 16 hours. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (25% ethyl acetate in petroleum ether). The product 4 was obtained as a white solid, 360 mg (80%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.41 (s, 9H), 2.28 (t, J = 5.4 Hz, 2H), 2.41 (t, J = 5.7 Hz, 2H), 3.33-3.41 (m, 4H), 6.38 (s, 1H), 7.03-7.13 (m, 3H), 7.26 (t, J = 4.8 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 8.65 (d, J = 4.8 Hz, 2H).

[0218] Step 5: To a solution of 4 (360 mg, 0.97 mmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.7 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated to give The crude product was washed with diethyl ether to give the product 5 as an off-white solid, 0.31 g (83%), which was carried on without further purification.

[0219] Step 6—To a solution of amine 5 (310 mg, 0.6 mmol) in dimethyl sulfoxide (4.0 mL), Diisopropylethylamine (0.5 mL, 3.1 mmol) and the product of Step 5 of Example 1 (0.58 g, 2.4 mmol) was added at 25° C. The resulting reaction mixture was stirred at 60° C. for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (100 mL), washed with water (3×50 mL), dried over sodium sulfate, and The crude product obtained by evaporating the volatiles was purified by silica gel (230-400) column (petroleum ether). Purification with 60% ethyl acetate in ether gave product 6 as a white solid in 210 mg (77%) at 52.7-57.6 °C. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.04-1.06 (m, 1H), 1.14-1.20 (m, 1H), 1.85-1.88 (m, 1H), 2.27 (bs, 2H), 2.39 (bs, 2H), 2.70-2.71 (m, 1H), 3.32-3.39 (m, 4H), 6.37 (s, 1H), 6.85 (bs, 1H, CONH 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). 13C NMR (75 MHz, DMSO-d6) δ (ppm): 16.03, 24.76, 29.37, 34.50, 36.10, 44.37, 45.41, 117.37, 119.95, 122.23, 123.49, 125.80, 126.00, 126.34, 128.54, 129.91, 139.19, 140.21, 142.44, 153.20, 158.05, 160.47, and 165.21. MS: 427 (M+H).

[0220] Example 7 - Synthesis of 4-{3-[1-(2-phenyl-cyclopropylcarbamoyl)-piperidin-4-ylidenemethyl]-phenoxy}-benzoic acid methyl ester

[0221] [ka]

[0222] Step 1 - To a solution of 3-hydroxyphenyl-methanol 2 (5.0 g, 40.2 mmol) in DMF (50 mL), cesium carbonate (26.2 g, 80.5 mmol) and ester 1 (7.5 g, 48.3 mmol) were added at room temperature. The resulting reaction mixture was stirred at 100°C for 5 hours. The resulting reaction mixture was allowed to cool to room temperature and filtered to remove cesium carbonate. The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (2 x 250 mL), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (30% ethyl acetate in petroleum ether) to give the crude product. Product 3 was obtained as a pale yellow oil, 3.2 g (31%). 1H 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).

[0223] Step 2 - To a solution of alcohol 3 (3.2 g, 12.3 mmol) in dichloromethane (50 mL) was added thionyl chloride (1.7 mL, 14.8 mmol) dropwise while stirring the reaction in an ice bath. The ice bath was removed. The reaction mixture was then stirred at room temperature for 1 hour. The resulting reaction mixture was quenched with ice-cold water (50 mL), extracted with ethyl acetate (250 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (5% ethyl acetate in petroleum ether) to give product 4 as a colorless oil (2.3 g, 67%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm):3.83 (s, 3H), 4.78 (s, 2H), 7.06-7.12 (m, 3H), 7.21 (bs, 1H), 7.30-7.33 (m, 1H), 7.44-7.49 (m, 1H), 7.98 (d, J = 8.7 Hz, 2H).

[0224] Step 3 - Compound 4 (2.3 g, 7.9 mmol) in triethyl phosphite (2.3 mL, 11.9 mmol) Solution 150 ° C for 6 h. The reaction mixture was allowed to cool to room temperature, and the volatiles were evaporated to give a crude product which was purified on a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to give product 5 as a pale yellow oil, 3.5 g (91%). 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).

[0225] Step 4 - To a solution of 5 (3.5 g, 9.2 mmol) in THF (20 mL) was added 15-crown ether (40 μL, 0.18 mmol). The reaction was cooled (ice bath) and NaH (560 mg, 13.8 mmol) was added in portions. The reaction mixture was stirred at room temperature for 30 min and cooled to ice again. To the above reaction mixture was added a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 6 (1.9 g, 9.2 mmol) in THF (15 mL) at ice temperature and stirred at room temperature for 16 h. The resulting reaction mixture was diluted with saturated ammonium chloride. The mixture was quenched with sodium ammonium chloride (50 mL), extracted with ethyl acetate (500 mL), dried over sodium sulfate, and The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (10% ethyl acetate in petroleum ether) to give the product 7 as a white solid 1.8 g (46%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.40 (s, 9H), 2.27-2.40 (m, 4H), 3.40-3.60 (m, 4H), 3.8 3 (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).

[0226] Step 5—To a solution of tert-butyl ester 7 (1.8 g, 4.2 mmol) in dichloromethane (18.0 mL) was added trifluoroacetic acid (9.0 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 1 h. The crude product obtained by evaporating the solvent was washed with n-hexane to give product 8 as a thick black liquid (1.5 g). (83%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 2.63-2.72 (m, 4H), 3.16-3.28 (m, 4H), 3.91 (s, 3H), 6.49 (s, 1H), 6.86 (s, 1H), 6.95-7.02 (m, 4H), 7.36 (t, J = 8.1 Hz, 1H), 8.03 (t, J = 8.4 Hz, 2H).

[0227] Step 6—To a solution of amine 8 (1.5 g, 3.4 mmol) in dimethyl sulfoxide (15.0 mL), Diisopropylethylamine (2.0 mL, 10.2 mmol) and the product of Step 5 of Example 1 (0.86 g, 3.4 mmol) were added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (250 mL), washed with water (2x100 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) and purified by HPLC. in 25% ethyl acetate) to give product 9 as a white solid 0.9 g (54%): 48.5 - 53.2 °C. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.10-1.20 (m, 2H), 1.88 (bs, 1H), 2.26 (bs, 2H), 2.37 (bs, 2H), 2.70-2.71 (m, 1H), 3.31-3.38 (m, 4H), 3.83 (s, 3H), 3.83 (s, 3H), 6.36 (s, 1H), 6.84 (bs, 1H, CONH exchangeable 1H), 6.94-7.26 (m, 10H), 7.42 (t, J = 7.8 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ (ppm): 16.02, 24.76, 29.40, 34.49, 36.07, 44.32, 45.38, 52.44, 117.81, 118.27, 120.49, 123.40, 124.51, 125.61, 125.79, 126.33, 128.53, 130.59, 132.02, 139.85, 140.45, 142.43, 155.40, 158.04, 161.73 and 166.11. MS: 483 (M+H).

[0228] Example 8 - Synthesis of 4-{3-[1-(2-phenyl-cyclopropylcarbamoyl)-piperidin-4-ylidenemethyl]-phenoxy}-benzoic acid:

[0229] [ka]

[0230] To a solution of the product of Step 6 of Example 7 (0.5 g, 1.03 mmol) in methanol (3.0 mL) was added a solution of sodium hydroxide (120 mg, 3.1 mmol) in water (2.0 mL) at 25° C. The reaction mixture was stirred at 55° C. for 16 hours. The crude product obtained by evaporation of the solvent was diluted with water (20.0 mL) and the resulting mixture was concentrated in water. The aqueous layer was then acidified (pH=2, 1.0N HCl) to remove the solid. The mixture was saturated with NaCl and the product was extracted with ethyl acetate (2X150 mL). The combined organic layers were dried over sodium sulfate and concentrated to give the product as a white solid, 350 mg (72%): 99.4 - 102.5 °C. 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). 13 C NMR (75 MHz, DMSO-d6) δ (ppm): 16.02, 24.75, 29.40, 34.51, 36.07, 44.31, 45.37, 117.76, 118.17, 120.38, 123.43, 125.47, 125.79, 126.32, 128.54, 130.57, 132.13, 139.81, 140.41, 144.44, 155.59, 158.03, 163.36, and 167.22. MS: 467 (MH).

[0231] Example 9 - 4-(3-pyrrolidin-1-yl-benzyl)-piperidine-1-carboxylic acid-(2- Synthesis of phenyl-cyclopropyl-amide:

[0232] [ka]

[0233] Step 1 - 3-Bromobenzyl bromide (6.0 g, 24.0 mmol) in triethyl phosphite (6.2 mL, 36.0 mmol) was dissolved in 130 ° The reaction mixture was then cooled to room temperature, and the volatiles were evaporated to give a crude product, which was purified by column chromatography on silica gel (230-400) (acetic acid in petroleum ether). Purification with ethyl acetate (30%) gave the product 2 as a colorless oil 6.5 g (89%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.17 (t, J = 7.2 Hz, 6H), 3.24 (s, 1H), 3.31 (s, 1H), 3.91-4.01 (m, 4H), 7.28-7.29 (m, 2H), 7.43-7.50 (m, 2H). MS: 307.0 (M+) and 309.0 (M+2).

[0234] Step 2 - To a solution of 2 (3.0 g, 9.7 mmol) in THF (20 mL) was added 15-crown ether (0.04 mL, 0.19 mmol). The reaction was cooled (ice bath) and NaH (0.58 g, 14.6 mmol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and cooled to ice temperature again. To the above reaction mixture, a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.95 g, 9.7 mmol) in THF (10 mL) was added at ice temperature and stirred at room temperature for 16 hours. The resulting reaction mixture The 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 silica gel (230-400) column (petroleum ether) Purification with 5% ethyl acetate in ethanol gave the product 3 as a yellow oil 1.8 g (53%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.41 (s, 9H), 2.28 (bs, 2H), 2.38 (bs, 2H), 3.34-3.41 (m, 4H), 6.36 (s, 1H), 7.25-7.30 (m, 2H), 7.41-7.43 (m, 2H).ms: 252.0 (m-boc).

[0235] Step 3 - To a solution of compound 3 (2.0 g, 7.0 mmol) in 1,4-dioxane (20.0 mL) at room temperature Under an argon atmosphere, pyrrolidine (0.9 mL, 10.6 mmol) and cesium carbonate (7.0 g, 21.2 mmol) To the resulting mixture, racemic BINAP (0.9 g, 1.4 mmol) and palladium acetate (0.95 g, 1.4 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes, followed by stirring under reflux for 16 hours. The resulting reaction mass was filtered through a pad of Celite and washed with ethyl acetate (250 mL). The ethyl acetate layer was washed with water (2×100 mL), dried over sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (15% ethyl acetate in petroleum ether) to give product 4 as a pale yellow oil, 0.6 g (32%). 1 H NMR (300 MHz, CDCl3) δ (ppm): 1.49 (s, 9H), 2.01 (bs, 4H), 2.33-2.35 (m, 2H), 2.50-2.53 (m, 2H), 3.27-3.29 (m, 4H), 3.39-3.49 (m, 2H), 3.50-3.54 (m, 2H), 6.36-6.53 (m, 4H), 7.19 (t, J= 8.1 Hz, 1H). MS: 343.7 (M+H).

[0236] Step 4 - To a solution of compound 4 (0.6 g, 1.7 mmol) in tetrahydrofuran (10.0 mL), 10% Pd / C (240 mg) was added. The mixture was heated under hydrogen gas pressure (1 kg / cm 2 ) and the reaction mass was stirred at room temperature for 2 hours. After releasing the hydrogen pressure, the reaction mixture was filtered through a pad of Celite and washed with tetrahydrofuran. The filtrate was concentrated to give the product 5 as a pale yellow liquid (0.6 g). The crude product was carried on to the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.10-1.21 (m, 2H), 1.49 (s, 9H), 1.64-1.72 (m, 3H), 1.98-2.03 (m, 4H), 2.49 (d, J= 6.9 Hz, 2H), 2.65 (t, J= 12.3 Hz, 2H).3.27-3.31 (m, 2H), 4.07-4.15 (m, 2H), 6.35 (s, 1H), 6.42-6.47 (m, 2H), 7.14 (t, J= 7.8 Hz, 1H). ms: 345.7 (m+h).

[0237] Step 5—To a solution of compound 5 (0.6 g, 1.7 mmol) in dichloromethane (6.0 mL) was added trifluoroacetic acid (3 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated to give The resulting brown oil 6 (0.6 g) was used in the next step without further purification.

[0238] Step 6—To a solution of amine 6 (600 mg, 1.9 mmol) in dimethyl sulfoxide (6.0 mL) was added N,N-diisopropylethylamine (1.1 mL, 5.8 mmol) and the product of Step 5 of Example 1 (0.5 g, 1.9 mmol) at 25° C. The reaction mixture was stirred at 60° C. for 5 h. The resulting reaction mixture was The mixture was diluted with ethyl acetate (500 mL), washed with water (3×100 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by column chromatography on silica gel (230-400) (petroleum ether). Purification by preparative HPLC (phenomenex 250x221.20 mm, 10 μM, 0.1% TFA in water and acetonitrile mobile phase) gave 160 mg (23%) of product 7 as a pale yellow solid: 145.6 °C - 151.5 °C. IR: 3334, 2842, 1620, 1600, 1545, 1252, 752 cm -1 . 1H NMR: (300 MHz, DMSO-d6) δ (ppm): 0.95-1.19 (m, 3H), 1.13-1.17 (m, 1H), 1.50-1.55 (m, 2H), 1.63-1.66 (m, 1H), 1.81-1.87 (m, 1H), 1.93 (bs, 4H).93 (bs, 4H), 2.40-2.42 (m, 2H), 2.56-2.60 (m, 2H), 2.67-2.68 (m, 1H), 3.19 (bs, 4H), 3.90 (d, J= 12.9 Hz, 2H), 6.32-6.40 (m, 3H), 6.71 (bs, 1H), 7.02-7.15 (m, 4H), 7.21-7.26 (m, 2H).MS: 404.5 (M+H).

[0239] Example 10 - Synthesis of 4-(3-morpholin-4-yl-benzyl)-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0240] [ka]

[0241] Step 1 - The product of Step 2 of Example 9 (1.5 g, 4.2 mmol) in 1,4-dioxane (15.0 mL) To the solution 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) at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 30 minutes, followed by stirring under reflux for 16 hours. The resulting reaction mass was cooled, filtered through a pad of Celite, and washed with ethyl acetate (250 mL). The ethyl acetate layer was washed with water (2X100 mL), and the organic layer was dried over sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (15% ethyl acetate in petroleum ether). The mixture was purified by HPLC to give crude product 2 as a pale yellow oil (0.35 g).

[0242] Step 2: To a solution of compound 2 (0.85 g, 2.37 mmol) in tetrahydrofuran (10.0 mL), 10% Pd / C (350 mg) was added. The mixture was heated under hydrogen gas pressure (1 kg / cm 2 The reaction mass was stirred at room temperature for 2 hours. After releasing the hydrogen pressure, the reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated to give the product. 3 was obtained as a pale yellow liquid (0.8 g), which was carried on to the next step without further purification.

[0243] Step 3—To a solution of crude compound 3 (0.8 g, 2.2 mmol) in dichloromethane (8.0 mL) was added trifluoroacetic acid (4 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated. The resulting brown oil 4 (0.8 g) was carried on to the next step without further purification.

[0244] To a solution of amine 4 (800 mg, 2.3 mmol) in dimethyl sulfoxide (8.0 mL) was added diisopropyl ether. Pyroethylamine (1.3 mL, 7.0 mmol) and the product of Step 5 of Example 1 (0.6 g, 2.3 mmol) were added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3x100 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230-400) column (50% ethyl acetate in petroleum ether). The product 5 was purified by HPLC (chill) to give 420 mg of a pale yellow solid: 182.3°C - 186.0°C. IR: 3330, 2841, 1620, 1600, 1545, 1247, 756 cm -1 . 1H 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, MS: 420.2 (M+H).

[0245] Example 11 - Synthesis of 4-[3-(pyridin-2-yloxy)-phenoxy]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0246] [ka]

[0247] Step 1 - To a solution of 1,3-dihydroxybenzene (1.0 g, 9.0 mmol) in DMF (10.0 mL) was added Cs2CO3 (5.92 g, 18.0 mmol) and 2-fluoropyridine (0.8 mL, 9.0 mmol). The mixture was stirred at 100° C. for 16 hours. The resulting mixture was cooled to room temperature, diluted with water (250 mL), and added with acetic acid. The crude product obtained by evaporation of the volatiles was purified by silica gel (230-400) column (10% ethyl acetate in petroleum ether). to give product 3 as a pale yellow oil in 400 mg (23%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 6.20 (s, 1H), 6.48-6.53 (m, 1H), 6.61 (d, J= 8.1 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).

[0248] Step 2 - To a solution of compound 3 (400 mg, 2.14 mmol) in DMF (8.0 mL) was added Cs2CO3 (1.4 g, 4.2 mmol) at room temperature. After stirring the reaction mixture for 5 minutes, compound 4 (600 mg, 2.14 mmol) in DMF (2.0 mL) was added to the reaction mixture at room temperature, and the reaction mixture was stirred at 65 °C for 8 hours. The resulting reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3 x 50 mL), and evaporated. The layer was dried over sodium sulfate, and the crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to give 540 mg (67%) of product 5 as a pale yellow oil. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.40 (s, 9H), 1.48-1.51 (m, 2H), 1.89-1.92 (m, 2H), 3.14-3.16 (m, 2H), 3.63-3.68 (m, 2H), 4.56-4.58 (m, 1H), 6.65-6.68 (m, 1H), 6.75 (s, 1H), 6.80-6.84 (m, 1H), 6.99-7.02 (m, 1H), 7.14 (d, J= 5.1 Hz, 1H), 7.29 (t, J= 7.8 Hz, 1H), 7.85 (t, J= 7.5 Hz, 1H), 8.17 (d, J= 5.1 Hz, 1H).MS: 371.4 (M+H).

[0249] Step 3 - Compound 5 (0.4 g, 0.8 mmol) in dichloromethane (8.0 mL) was added to a solution of 1,2-dichloromethane at ice temperature. Fluoroacetic acid (2.0 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated to give The resulting brown oil 6 was used in the next step without further purification.

[0250] To a solution of amine 6 (390 mg, 0.78 mmol) in dimethyl sulfoxide (5.0 mL) was added diisopropylethylamine (0.67 mL, 3.9 mmol) and the product of Step 5 of Example 1 (198 mg, 0.78 mmol). The reaction mixture was stirred at 60° C. for 5 hours. The resulting reaction mixture was diluted with acetic acid Diluted with ethyl acetate (250 mL), washed with water (3X10 mL) and dried over sodium sulfate. The crude product obtained by evaporation was then purified by silica gel (230-400) column (70% acetic acid in petroleum ether). The resulting product was further purified by preparative HPLC to give 200 mg of product 7 as an off-white, low-melting solid: 43.9 ℃ - 46.8℃. IR: 3313, 1621, 1586, 1423 and 1235 cm -1 . 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.07-1.09 (m, 1H), 1.14-1.18 (m, 1H), 1.46-1.49 (m, 2H), 1.86 (bs, 3H), 2.68-2.69 (m, 1H), 3.08 (t, J= 9.6 Hz, 2H), 3.64-3.68 (m, 2H), 4.53 (bs, 1H), 6.64-6.67 (m, 1H), 6.74 (bs, 1H), 6.80 (bs, 1H), 6.83 (bs, 1H, D2O exchangeable 1 H), 7.00 (d, J= 8.0 Hz, 1H), 7.08-7.14 (m, 4H), 7.21-7.31 (m, 3H), 8.82 (t, J= 7.2 Hz, 2H), 8.16 (d, J= 5.1 Hz, 1H). MS: 430.4 (M+H).

[0251] Example 12 - 4-[3-(1H-pyrazol-4-yl)-benzyl]-piperidine-1-carbo Synthesis of carboxylic acid (-2-phenyl-cyclopropyl)-amide:

[0252] [ka]

[0253] 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 and di-tert-butyl dicarbonate (3.0 mL, 15.4 mmol) were added. The resulting reaction mass was heated to room temperature. The reaction mixture was stirred at rt for 12 hours, and the reaction mixture was quenched with water (50.0 mL) and extracted with ethyl acetate (200 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (15% ethyl acetate in petroleum ether) to give product 2 as an off-white solid (1.25 g, 40%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.27 (s, 12H), 1.58 (s, 9H), 7.87 (s, 1H), 8.37 (s, 1H).ms: 195.3 (m-boc+h).

[0254] Step 2—A solution of the compound product of Step 2 of Example 9 (1.0 g, 2.8 mmol) in DMF (10 mL) Compound 2 (1.9 g, 5.6 mmol) and 2N sodium carbonate solution (4.3 mL, 8.5 mmol) were added to the mixture at room temperature. The reaction mixture was stirred under an argon atmosphere for 10 minutes. Then, tetrakis(triphenyl To the reaction mixture was added (0.33 g, 0.28 mmol) of methyl phosphine palladium(0) under an argon atmosphere. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL), extracted with ethyl acetate (500 mL), and washed with water (2×250 mL) and brine (100 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (40% ethyl acetate in petroleum ether) to give product 3 as an off-white solid, 550 mg (57%). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.42 (s, 9H), 2.28-2.31 (m, 2H), 2.42-2.44 (m, 2H), 3.34-3.44 (m, 4H), 6.39 (s, 1H), 7.03 (d, J= 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 (mh).

[0255] Step 3—To a solution of compound 3 (0.5 g, 1.4 mmol) in 20% methanol in chloroform (10.0 mL) was added 10% Pd / C (200 mg). The reaction was heated at room temperature under hydrogen gas pressure (1 kg / cm 2 ) below, 24 hours The reaction mass was filtered through a pad of celite and the filtrate was concentrated to give the product 4 as a pale yellow liquid (0.5 g). This crude product was used in the next step without further purification.

[0256] Step 4 - Compound 4 (0.5 g, 1.6 mmol) in dichloromethane (5.0 mL) was added to a solution of 1,000 sulphite at ice temperature. Fluoroacetic acid (2.5 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated to give The resulting brown oil 5 (0.5 g) was used in the next step without further purification.

[0257] Step 5—To a solution of amine 5 (500 mg, 1.0 mmol) in dimethyl sulfoxide (5.0 mL) was added N,N-diisopropylethylamine (0.8 mL, 4.2 mmol) and the product of Step 5 of Example 1 (270 mg, 1.0 mmol) at 25° C. The reaction mixture was stirred at 60° C. for 5 h. The resulting reaction The mixture was diluted with ethyl acetate (500 mL), washed with water (3×100 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230-400) column (chloroform). The product was purified with 3% methanol in hexane to give 210 mg of product 6 as an off-white solid: 157.4°C - 163.4°C. IR: 3330, 1619, 1545, 1475, 753 cm -1 . 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.01-1.17 (m, 4H), 1.51-1.55 (m, 2H), 1.82 (bs, 1H), 1.83-1.85 (m, 1H), 2.54-2.68 (m, 5H), 3.90 (d, J= 12.6 Hz, 2H), 6.71 (d, J= 2.7 Hz, 1H, D2O exchangeable 1 H), 6.98 (d, J= 7.5 Hz, 1H), 7.07-7.15 (m, 3H), 7.21-7.27 (m, 3H), 7.41-7.43 (m, 2H), 7.90 (s, 1H), 8.17 (s, 1H), 12.91 (s, 1H, D2O exchangeable 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).

[0258] Example 13 - Synthesis of 4-[3-(1-methyl-1H-pyrazol-4-yl)-benzyl]-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0259] [ka]

[0260] Step 1 - To a cooled (0-5°C) solution of the product of Step 2, Example 12 (0.7 g, 2.0 mmol) in THF (25 mL) was added sodium hydride (0.25 g, 6.1 mmol) and methyl iodide (0.4 mL, 6.1 mmol). The resulting reaction was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (500 mL). The organic layer was washed with water (2×250 mL) and brine (100 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to give product 1 as an off-white solid, 600 mg (83%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.45 (s, 9H), 2.30-2.31 (m, 2H), 2.42-2.44 (m, 2H), 3.35-3.44 (m, 4H), 3.89 (s, 3H), 6.39 (s, 1H), 7.02-7.05 (m, 1H), 7.30 (t, J= 7.5 Hz, 1H), 7.39-7.43 (m, 2H), 7.85 (s, 1H), 8.14 (s, 1H).MS: 298.0 (Mt-butyl+H).

[0261] Step 2 - Compound 1 (0.6 g, 1.7 mmol) in 20% chloroform (10.0 mL) methanol 10% Pd / C (240 mg) was added to the reaction mixture, and the reaction mixture was heated at room temperature under hydrogen gas pressure (1 kg / cm 2 ) and stirred for 16 hours. The reaction was filtered through a pad of Celite, and the filtrate was concentrated to give product 2 as a pale yellow liquid. The product obtained was carried to the next step without further purification. 1H 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).

[0262] Step 3: Compound 2 (0.6 g, 1.6 mmol) in dichloromethane (6.0 mL) was added to a solution of 1,2-dichloromethane (1.2 mL) at ice temperature. Fluoroacetic acid (3.0 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated to give The resulting brown oil 3 (0.6 g) was used in the next step without further purification.

[0263] Step 4—To a solution of amine 3 (600 mg, 1.6 mmol) in dimethyl sulfoxide (6.0 mL), Diisopropylethylamine (1.2 mL, 6.4 mmol) and the product of Step 5 of Example 1 (370 mg, 1.4 mmol) were added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3x100 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230-400) column (chloroform). The product 4 was purified by HPLC using a 3% methanol in HCl solution to give 350 mg (53%) of product 4 as an off-white solid: 158.4 °C - 160.3 °C. IR: 3353, 1619, 1544, 1473, 752 cm -1 . ( 1)H NMR (300 MHz, DMSO-d6) δ (ppm): 1.01-1.15 (m, 4H), 1.51-1.55 (m, 2H), 1.82-1.83 (m, 1H), 1.84-1.86 (m, 1H), 2.57-2.68 (m, 4H), 3.34-3.37 (m, 1H), 3.85 (s, 3H), 3.85 (s, 3H), 3.90 (d, J= 13.2 Hz, 2H), 6.71 (d, J= 2.7 Hz, 1H, D2O exchangeable 1 H), 6.98 (d, J= 7.5 Hz, 1H), 7.07-7.15 (m, 3H), 7.21-7.27 (m, 3H), 7.36-7.38 (m, 2H), 7.83 (s, 1H), 8.11 (s, 1H). 13 C NMR (75 MHz, DMSO-d6) δ (ppm): 16.00, 24.74, 32.05, 34.53, 37.89, 42.79, 43.99, 122.44, 122.97, 125.77, 126.10, 126.31, 127.15, 128.19, 128.52, 129.05, 132.91, 136.43, 141.11, 142.50, 158.21.MS: 415.0 (M+H) .

[0264] Example 14 - Synthesis of 4-(3-benzimidazol-1-yl-benzyl)-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0265] [ka]

[0266] Step 1 - Dissolution of compound 1 (5.0 g, 23.14 mmol) in triethyl phosphite (5.9 mL, 37.7 mmol) Liquid 130 o The reaction mixture was cooled to room temperature and the volatiles were evaporated. The resulting crude product was purified on a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to give product 2 as a pale yellow oil 4.9 g (89%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.09-1.21 (m, 6H), 3.44 (s, 1H), 3.51 (s, 1H), 3.93-4.07 (m, 4H), 7.60-7.66 (m, 1H), 7.73-7.76 (m, 1H), 8.11-8.14 (m, 1H), 8.19 (s, 1H).ms: 274.1 (m+1).

[0267] Step 2 - To a solution of compound 2 (4.9 g, 20.3 mmol) in THF (50 mL) was added 15-crown ether (0.08 mL, 0.04 mmol). The reaction was cooled (ice bath) and NaH (1.22 g, 30.5 mmol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and cooled to ice temperature again. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.05 g, 20.3 mmol) in THF (10 mL) was added to the above reaction mixture at ice temperature and stirred at room temperature for 4 hours. The resulting reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (3×250 mL), and dried over sodium sulfate. The volatiles were evaporated. The crude product obtained by evaporation was purified by silica gel (230-400) column (5% ethyl acetate in petroleum ether). to give the product 3 as a yellow oil 4.0 g (62%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.42 (s, 9H), 2.33 (t, J= 5.7 Hz, 2H), 2.41 (t, J= 5.7 Hz, 2H), 3.38-3.41 (m, 2H), 3.44 (t, J= 5.7 Hz, 2H), 6.50 (s, 1H), 7.61-7.71 (m, 2H), 8.02 (s, 1H), 8.07-8.10 (m, 1H).MS: 219.2 (M-BOC+H), 263.1 (Mt-Butyl+1).

[0268] Step 3—To a solution of compound 3 (4.0 g, 12.5 mmol) in 90% methanol in dichloromethane (40.0 mL) was added 10% Pd / C (3.0 g). The reaction was heated under hydrogen gas pressure (1 kg / cm 2 The reaction mixture was stirred at room temperature for 20 hours under 100°C for 1 hour. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated to give product 4 as a pale yellow liquid. This product was carried to the next step without further purification. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 0.81-1.00 (m, 2H), 1.38 (s, 9H), 1.77-1.80 (m, 2H), 2.28-2.34 (m, 2H), 2.60-2.72 (m, 1H), 3.90 (t, J= 12.6 Hz, 2H) 4.92 (s, 2H), 6.28-6.38 (m, 3H), 6.90 (t, J= 12.6 Hz, 1H). ms: 191.1 (m-boc+1).

[0269] Step 4 - To a solution of compound 4 (1.5 g, 3.4 mmol) in DMF (8.0 mL) was added Cs2CO3 (8.9 g, 25.7 mmol) was added. The reaction mixture was stirred for 5 minutes, and 1-fluoro-2-nitrobenzene (0.8 g, 3.7 mmol) in DMF (2.0 mL) was added to the reaction mixture at room temperature, and 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 on a silica gel (230-400) column (7% ethyl acetate in petroleum ether) to give product 5 as a red-yellow oil, 500 mg (35%). 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 (mh).

[0270] Step 5 - To a solution of compound 5 (500 mg, 1.2 mmol) in formic acid (10 mL) was added sodium formate (290 mg, 4.3 mmol) and Pd / C (10 mol %, 120 mg, 0.01 mmol) were added at room temperature (25°C). The reaction mixture was stirred at 110°C for 18 hours. After cooling to room temperature, the reaction mixture was filtered through Celite with the aid of 20 mL of formic acid. The crude product obtained after evaporation of the volatiles was dissolved in 5% methanol in dichloromethane (50 mL) and filtered to remove inorganic salts. The filtrate was concentrated to give product 6 as an off-white solid (350 mg). The crude product was carried on to the next step without further purification. Moved.

[0271] Step 6—To a solution of amine 6 (350 mg, 1.2 mmol) in dimethyl sulfoxide (5.0 mL), Diisopropylethylamine (1.03 mL, 6.0 mmol) and the product of Step 5 of Example 1 (186 mg, 1.2 mmol) were added at 25° C. The reaction mixture was stirred at 60° C. for 6 hours. The mixture was diluted with ethyl acetate (300 mL), washed with water (3X50 mL), dried over sodium sulfate, and The crude product obtained by evaporating the volatiles was then passed through a silica gel (230-400) column (dichloromethane). The product 7 was purified using a 1.5% methanol in hexanes solution to give 170 mg (31%) of product 7 as an off-white solid. %) obtained:IR: 3347, 2931, 16161, 1542, 742 cm -1 . 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.00-1.14 (m, 4H), 1.54-1.57 (m, 2H), 1.71-1.79 (m, 1H), 1.80-1.84 (m, 1H), 2.48-2.65 (m, 5H), 3.92 (d, J= 12.9 Hz, 2H), 6.72 (d, J= 2.7 Hz, 1H, D2O exchangeable Noh 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).

[0272] Example 15 - Synthesis of 4-(3-pyrrolidin-1-yl-benzylidene)-piperidine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide:

[0273] [ka]

[0274] Step 1 - The product of Step 2 of Example 9 (2.0 g, 7.0 mmol) in 1,4-dioxane (20.0 mL) To the solution was added 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) at room temperature under an argon atmosphere. 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 pad of Celite and washed with ethyl acetate (250 mL). The ethyl acetate layer was washed with water (2×100 mL), dried over sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (15% ethyl acetate in petroleum ether) to give product 2 as a pale yellow oil 0.6 g (32%). 1 H NMR (300 MHz, CDCl3) δ (ppm): 1.49 (s, 9H), 2.01 (bs, 4H), 2.33-2.35 (m, 2H), 2.50-2.53 (m, 2H), 3.27-3.29 (m, 4H), 3.39-3.49 (m, 2H), 3.50-3.54 (m, 2H), 6.36-6.53 (m, 4H), 7.19 (t, J= 8.1 Hz, 1H). ms: 343.7 (m+1).

[0275] Step 2: Compound 2 (0.6 g, 1.7 mmol) in dichloromethane (6.0 mL) was added to a solution of 1,2-dichloromethane at ice temperature. Fluoroacetic acid (3 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The resulting brown oil 3 (0.6 g) was used in the next step without further purification.

[0276] Step 3—To a solution of amine 3 (600 mg, 1.9 mmol) in dimethyl sulfoxide (6.0 mL), Diisopropylethylamine (1.1 mL, 5.8 mmol) and the product of Step 5 of Example 1 (0.5 mL) g, 1.9 mmol) was added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3X100 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (40% ethyl acetate in petroleum ether) to give product 4 as an off-white solid in 300 mg (42%): IR: 3292, 2963, 1626, 1533, 1263, 746 cm -1 . 1 H NMR (300 MHz, CDCl3) δ (ppm): 1.22-1.26 (m, 2H), 2.02 (bs, 5H), 2.38-2.41 (m, 2H), 2.56-2.59 (m, 2H), 2.56-2.59 (m, 2H), 2.88 (bs, 1H), 3.30 (bs, 4H), 3.36-3.40 (m, 2H), 3.47-3.51 (m, 2H), 4.87 (bs, 1H, D2O exchangeable 1 H), 6.38-6.52 (m, 3H), 7.19-7.46 (m, 7H). 13 C NMR (75 MHz, CDCl3) δ (ppm): 16.01, 24.75, 32.08, 34.56, 37.96, 43.17, 43.98, 49.00, 66.61, 113.09, 116.43, 120.52, 125.77, 126.29, 128.53, 129.12, 141.31, 142.51, 151.50, 158.28.MS: 402.7 (M+H).

[0277] Example 16 - Synthesis of phenyl N-[(1R,2S)-2-phenylcyclopropyl]carbamate:

[0278] [ka]

[0279] The chiral intermediates shown above were synthesized using general methodology described in the literature (WO 2013 / 057322).

[0280] Step 1 - To a suspension of trans-2-phenyl-cyclopropylamine hydrochloride (100 g, 0.59 mol) in water (500 mL) was added saturated aqueous sodium bicarbonate solution at 0-5°C over 20 minutes to basify to pH > 7. The reaction mixture was stirred at 25-30°C for 2 hours. The reaction mixture was extracted with dichloromethane (3X700 mL) and the separated organic phase was dried over sodium sulfate and concentrated to give 2-phenyl-cyclopropylamine as an off-white solid 2 (71.2 g, 92%).

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

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

[0283] Step 4 - To a suspension of amine 4 (15.0 g, 88.0 mmol) in dichloromethane (150 mL) was added triethylamine (36.0 mL, 0.26 mol), phenyl chloroformate (20.7 g, 0.13 mol) at ice bath temperature. The ice bath was then removed and the reaction mixture was stirred at room temperature for 1 hour. The residue was diluted with ethyl acetate (1.0 L), washed with water (2X200 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (10% ethyl acetate in petroleum ether) to give product 5 as a white solid, 16.0 g (71%). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 1.15-1.25 (m, 2H), 2.04-2.08 (m, 1H), 2.72-2.75 (m, 1H), 7.1 0-7.40 (m, 10H), 8.17 (bs, 1H). MS (M+H) 254.3.

[0284] Step 5—To a stirred solution of (1R,2S)-2-phenyl-cyclopropylamine 4 (25.0 g, 0.19 mol) in diethyl ether (150 mL) was added 2.0 M hydrochloric acid in ether (140 mL, 0.28 mol) at 0–5° C. The reaction mixture was stirred at 20-25°C for 30 minutes. The reaction mixture was concentrated under reduced pressure. The collected reaction mass was washed with diethyl ether (2X100 mL) to give product 6, the hydrochloride salt of (1R,2S)-2-phenyl-cyclopropylamine as an off-white solid 30.0 g (95%): 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 determined by authentic 6 purchased from Sigma-Aldrich. Further confirmation was achieved by matching analytical and spectral data with the sample, (1R,2S)-2-phenylcyclopropylamine hydrochloride.

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

[0286] [ka]

[0287] Step 1 - To a suspension of (1S,2R)-2-phenylcyclopropan-1-amine 2 (500 mg, 2.95 mmol) in dichloromethane (5.0 mL) was added triethylamine (1.21 mL, 8.85 mol) and phenyl chloroformate 1 (0.41 mL, 3.3 mol) at ice bath temperature. The ice bath was removed and the reaction mixture was heated to room temperature. The mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was diluted with ethyl acetate (1.0 L), washed with water (2×200 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (10% ethyl acetate in petroleum ether) to give product 3 as a white solid. The yield was 500 mg (71%) of the compound. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 1.19-1.26 (m, 2H), 2.05-2.08 (m, 1H), 2.72-2.75 (m, 1H), 7.11-7.38 (m, 10H), 8.18 (bs, 1H).MS (M+H) 254.5.

[0288] Step 2 - To a solution of the product of Step 5 of Example 3 (1.0 g, 2.2 mmol) in dimethyl sulfoxide (10 mL) was added diisopropylethylamine (1.2 mL, 6.6 mmol) and 3 (556 mg, 2.2 mmol) at 25 °C. The reaction mixture was stirred at 60 °C for 4 h. The resulting reaction mixture was diluted with ethyl acetate. The crude product obtained after evaporation of the volatiles was purified by column chromatography on a silica gel (230-400) column (40% acetic acid in petroleum ether). Purification with ethyl acetate gave product 4 as a white solid, 770 mg (70%): 100.2°C -101.0°C. IR: 3329, 1622, 1531, 1487, 1329, 1076 cm -1 . 1 H 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=5.2Hz, 2 H), 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%.

[0289] Example 18 - 4-[3-(5-trifluoromethyl-pyridin-2-yloxy)-benzylidene [(1R,2S)-2-phenyl-cyclopropyl]-amide Form:

[0290] [ka]

[0291] Step 1 - To a suspension of (1R,2S)-2-phenyl-cyclopropylamine 2 (500 mg, 2.95 mmol) in dichloromethane (5.0 mL) was added triethylamine (1.21 mL, 8.85 mol) and phenyl chloroformate 1 (0.41 mL, 3.3 mol) at ice bath temperature. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. The resulting reaction mixture was diluted with ethyl acetate (250 mL) and diluted with water (2x100 mL). The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (10% ethyl acetate in petroleum ether) to give product 3 as a white solid, 495 mg (70%). 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.

[0292] Step 2 - To a solution of the product of Step 5 of Example 3 (1.0 g, 2.2 mmol) in dimethyl sulfoxide (10 mL) was added diisopropylethylamine (1.2 mL, 6.6 mmol) and 3 (556 mg, 2.2 mmol) at 25 °C. The reaction mixture was stirred at 60 °C for 4 h. The resulting reaction mixture was diluted with ethyl acetate. The crude product obtained after evaporation of the volatiles was purified by column chromatography on a silica gel (230-400) column (40% acetic acid in petroleum ether). Purification with ethyl acetate gave product 4 as a white solid, 715 mg (65%): 101.8°C -103.2°C. IR: 3329, 1623, 1531, 1388, 1329, 1076, 697 cm -1 . 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 1.07-1.18 (m, 2H), 1.85-1.90 (m, 1H), 2.25 - 2.40 (m, 4H), 2.67 - 2.75 (m, 2H), 2.69-2.72 (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%.

[0293] Example 19 - 4-({3-[(5-methylpyridin-2-yl)oxy]phenyl}methyl Synthesis of (2-phenyl-)-N-[2-phenylcyclopropyl]piperidine-1-carboxamide:

[0294] [ka]

[0295] Step 1 - Dissolve 2-fluoro-5-methyl-pyridine 1 (14.76 g, 0.13 mol) in DMF (150 mL) To the solution, 3-hydroxyphenyl-methanol (15.0 g, 0.12 mol) and cesium carbonate (59.0 g, 0.18 mol) were added at room temperature. The reaction mixture was stirred for 100 minutes. ° The mixture was stirred at RT for 5 hours. The mixture was cooled to room temperature, diluted with water (250 mL), extracted with ethyl acetate (3×500 mL), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (30% ethyl acetate in petroleum ether) to give the product 2 as a pale yellow oil, 6.0 g (23%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 2.25 (s, 3H), 4.40 (d, J=6.0 Hz, 2H), 5.22 (t, J=6.0 Hz ,1H), 6.91- 6.94 (m, 2H), 7.01 (s, 1H), 7.11 (d, 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.

[0296] Step 2 - [3-(5-methyl-pyridin-2-yloxy)-phenyl] in dichloromethane (60 mL) To a solution of 2 (6.0 g, 0.027 mol) in 2-methyl-2-thiazolinone (2H2O), thionichloride was added while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. The volatiles were then evaporated under reduced pressure, diluted with toluene (25 mL), and the toluene was evaporated under reduced pressure. This azeotropic process was repeated three times to give product 3 as a light brown oil (6.2 g, 95%). 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.

[0297] Step 3 - 2-(3-chloromethyl-phenoxy)-2-(2 ... A solution of 150 ml of 5-methyl-pyridine (6.2 g, 0.026 mol) was added to 150 ml of ° The mixture was heated at 40°C for 6 hours. The reaction mixture was returned to room temperature, and the volatiles were evaporated. The resulting crude product was then separated onto a silica gel (230-400) column. Purification with hexane (60% ethyl acetate in petroleum ether) gave the product 4 as a pale yellow oil, 8.3 g. This product contained unused triethyl phosphate and was used in the next step without further purification. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.13 - 1.23 (m, 6H), 2.25 (s, 3H), 3.20 - 3.27 (m, 2H), 3.89 - 3.99 (m, 4H), 6.91 - 6.99 (m, 3H), 7.09 (d, J=7.4 Hz, 1H), 7.32 (t, J=8.1 Hz, 1H), 7.66 - 7.69 (m, 1H), 7.98 - 8.32 (m, 1H).MS: (M+H) 336.1.

[0298] Step 4 - To a solution of [3-(5-methyl-pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester 4 (8.3 g, 0.024 mol) in THF (40 mL) was added 15-crown ether (0.1 g, 0.48 mmol). The reaction was cooled (ice bath) and NaH (1.44 g, 0.036 mol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and then cooled to ice-cold temperature again. To the above reaction mixture, a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.9 g, 0.024 mol) in THF (40 mL) was added. The reaction mixture was diluted with water (250 mL) and stirred at room temperature for 16 hours. Extraction with ethyl acetate (3×500 mL) and drying over sodium sulfate were performed. Evaporation of the volatiles gave The crude product was purified on a silica gel (230-400) column (3% ethyl acetate in petroleum ether), The product 5 was obtained as a pale yellow oil (6.7 g, 76%). 1 H NMR (300 MHz, CDCl3) δ (ppm): 1.41 (s, 9H), 2.25 - 2.29 (m, 5H), 2.39 (t, J=6.0 Hz, 2H), 3.36 - 3.42 (m, 4H), 6.36 (s, 1H), 6.90 - 6.95 (m, 3H), 7.02 -7.05 (m, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.66 -7.70 (m, 1H), 7.98 (d, J=2.4 Hz, 1H).MS: (M+H) 381.2.

[0299] Step 5 - 4-[3-(5-methyl-pyridin-2-yloxy)-benzyl]-benzoate in dichloromethane (67.0 mL) Solution of 1-(2-phenylindylene)-piperidine-1-carboxylic acid tert-butyl ester 5 (6.7 g, 0.017 mol) Trifluoroacetic acid (27 mL) was added to the mixture at ice temperature, and the reaction mixture was stirred at room temperature for 1 h. The product 6 (6.96 g) obtained by evaporation of the volatiles was used in the next step without further purification. 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 2.24 (s, 3H), 2.61 (t, J = 6.1 Hz, 2H), 3.10 - 3.30 (m, 4H), 6.36 (s, 1H), 6.90 - 6.95 (m, 3H), 7.02 -7.05 (m, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.66 -7.70 (m, 1H), 7.98 (d, J=2.4 Hz, 1H), 8.70 (bs, 2H).MS: (M+H) 281.3.

[0300] Step 6 - To a solution of amine 6 (3.0 g, 7.0 mmol) in dimethyl sulfoxide (30 mL) was added dichloromethane. Isopropylethylamine (4.2 mL, 22.0 mmol) and the product of Step 5 of Example 1 (1.93 g, 7.0 mmol) was added at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3X150 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to give product 7 as an off-white solid, 2.33 g (70%): 87.8°C - 91.0°C. IR: 3250, 2895, 1624, 1425, 1263, 848, 774 cm -1 . 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.05-1.18 (m, 2H), 1.80 - 1.95 (m, 1H), 2.23 - 2.33 (m, 5H), 2.40 (t, J = 5.1 Hz, 2H), 2.71 (m, 1H), 3.31 (t, J = 5.5 Hz, 2H), 3.38 (t, J = 5.5 Hz, 2H), 6.37 (s, 1H), 6.86 - 6.97 (m, 4H), 7.04 -7.22 (m, 3H), 7.23 - 7.33 (m, 3H), 7.40 (td, J = 7.9, 2.0 Hz, 1H), 7.70 (dt, J = 8.3, 2.5 Hz, 1H), 7.99 (bs, 1H).MS: (M+H) 440.5.

[0301] Example 20 - Synthesis of 4-[3-(pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid [2-(4-methyl)phenyl-cyclopropyl]-amide:

[0302] [ka]

[0303] Step 1 - Add ammonium acetate (13.4 g, 0.17 mol) to acetic acid (100 mL) and dissolve completely. The mixture was stirred until the reaction mixture was dissolved. Nitromethane (30.46 g, 0.49 mol) was then added to the reaction mixture, followed by 4-methyl-benzaldehyde (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 2M aqueous sodium hydroxide solution (pH = 7), extracted with ethyl acetate (2×300 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude was washed with hexane to give product 2 as a yellow solid. (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 (MH) 162.9.

[0304] Step 2 - Sodium hydride 60% mineral oil dispersion (0.98 g, To a solution of 2 (0.024 mol), trimethyloxosulfonium iodide (6.7 g, 0.03 mol) was added and stirred at room temperature for 30 min. Then, 2 (2 g, 0.012 mol) in dimethyl sulfoxide (10 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was quenched with water (100 mL). The mixture was extracted with ethyl acetate (2×300 mL) and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400 mesh) column (2% ethyl acetate in hexane) to give product 3 as a pale yellow oil (300 mg, 14%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.653-1.704 (m, 1H), 2.203-2.273(m, 1H), 2.353(s, 3H), 3.112-3.157(m, 1H), 4.370-4.417 (m, 1H), 7.015-7.042 (d, 2H), 7.14-7.166 (d, 2H).MS (M+H) 178.1.

[0305] Step 3 - To a solution of 3 (0.3 g, 0.0016 mol) in isopropyl alcohol (12 mL) was added hydrochloric acid (6.2 mL of a 2.7 N solution, 0.0169 mol), followed by the portionwise addition of zinc dust (1.1 g, 0.0169 mol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized with 10% aqueous sodium hydroxide solution. The filtrate was filtered through a layer of Celite, diluted with ethyl acetate (150 mL), and diluted with water (50 mL) and sodium chloride. It was washed with water (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified on a silica gel (230-400 mesh) column (2% methanol in chloroform) to give product 4 as a yellow oil (150 mg, 60%). 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.

[0306] Step 4 - To a solution of 4 (90 mg, 0.0006 mol) in dichloromethane (2 mL), triethylamine (0.17 mL, 0.0012 mol) and phenyl chloroformate (115 mg, 0.0007 mol) were added at 0°C. The reaction mass was stirred at room temperature for 1 hour. The resulting reaction mass was diluted with ethyl acetate (150 mL) and water (50 The crude product obtained after evaporation of the volatiles was purified by silica gel (230-400 mesh) column (10% ethyl acetate in hexanes). Purification gave the product 5 as a white solid (30 mg, 18%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.115-1.123 (m, 2H), 2.245 (s, 3H), 7.000-7.120 (m, 6H), 7.181-7.356 (m, 1H), 7.361-7.395 (m, 2H).MS (M+H) 268.3.

[0307] Step 5—To a solution of the product of Step 4 of Example 2 (1.0 g, 0.002 mol) in dichloromethane (10 mL) was added trifluoroacetic acid (4 mL) at 0° C., and the reaction mixture was stirred at room temperature for 1 h. Evaporation of the volatiles afforded product 7 (1.3 g, 97%), which was used in the next step without further purification.

[0308] Step 6 - To a solution of 7 (0.29 g, 0.0006 mol) in dimethyl sulfoxide (3 mL) at room temperature Diisopropylethylamine (0.59 mL, 0.0034 mol) and 5 (0.16 g, 0.0006 mol) were added. The reaction was stirred at 60°C for 5 hours. The resulting reaction mass was diluted with ethyl acetate (200 mL), washed with water (3X50 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 (40% ethyl acetate in hexane). ) to give product 8 as an off-white solid (180 mg, 69%): 87.8-91.0°C. IR: 3250, 3013, 1624, 1573, 1425, 1263, 1117, 775cm -1 . 1 H NMR (300 MHz, DMSO-d 6) 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.

[0309] Example 21 - Synthesis of 4-[3-(pyrimidin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid [(1R,2S)-2-phenyl-cyclopropyl]-amide:

[0310] [ka]

[0311] Step 1 - 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) was added diisopropylethylamine (4.13 mL, 23.6 mmol) and 2, the product of Step 4 of Example 16 (2.0 g, 7.89 mmol) at 25°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (300 mL) and washed with water (3X150 mL). The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (60% ethyl acetate in petroleum ether) to give product 3 as a white solid, 2.3 g (70%): 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 pure Resolution: 99.79%. Chiral HPLC Purity: 99.92%. Optical Rotation Number: -1.190. Specific Rotation: -111.71.

[0312] Example 22 - Synthesis of 4-[3-(5-methyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0313] [ka]

[0314] Step 1 - To a solution of amine 1, the product of Step 5 of Example 19 (3.0 g, 7.0 mmol) in dimethyl sulfoxide (30 mL) was added diisopropylethylamine (4.2 mL, 22.0 mmol) and the product of Step 4 of Example 16 (1.93 g, 7.0 mmol) at 25°C. The reaction mixture was heated at 60°C for 5 h. The reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3×150 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (50% ethyl acetate in petroleum ether) to give product 3 as a pale yellow solid, 2.7 g (81%): 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%.

[0315] Example 23 - Synthesis of 4-[3-(pyrimidin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid methyl-((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0316] [ka]

[0317] Step 1—To a solution of 1, the product of Example 21 (150 mg, 7.89 mmol) in dimethylformamide (30.0 mL) was added sodium hydride (4.13 mL, 23.6 mmol) and methyl iodide (2.0 g, 7.89 mmol) was added. 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 (2x100 mL), and dried over sodium sulfate. The crude product obtained by evaporation of the volatiles was purified on a silica gel (230-400) column (25% ethyl acetate in petroleum ether) to give 2 as a pale yellow solid, 77 mg (50%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.24 (dt, J = 7.8 Hz, 5.9 Hz, 2H), 2.02 - 2.07 (m, 1H), 2.27 (q, J = 5.9 Hz, 2H), 2.38 - 2.41 (m, 2H), 2.79 (s, 4H), 2.79 (s, 4H), 3.12 - 3.33 (m, 4H), 6.34 (s, 1H), 6.97 -7.21 (m, 6H), 7.20-7.31 (m, 3H), 7.39 (t, J = 7.9 Hz, 1H), 8.65 (d, J = 4.8 Hz, 2H).MS: 441.5 (M+H). HPLC purity: 98.1%.

[0318] Example 24 - Synthesis of 4-[3-(5-methyl-pyrazin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0319] [ka]

[0320] Step 1 - To a solution of 2-chloro-5-methyl-pyrazine (10 g, 0.078 mol) in DMF (100 mL) To the resulting mixture, 3-hydroxyphenyl-methanol (11.6 g, 0.094 mol) and cesium carbonate (76.0 g, 0.23 mol) were added at room temperature. The reaction mixture was stirred at 100°C for 5 hours. The resulting mixture was cooled to room temperature, diluted with water (250 mL), extracted with ethyl acetate (3 x 500 mL), and the organic layer was dried over sodium sulfate. The volatiles were evaporated and the resulting crude product was purified by silica gel (230-400) column chromatography. (30% ethyl acetate in petroleum ether) to give the product 1 as a pale yellow oil 6.8 g (40%). 1 H 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.

[0321] Step 2 - To a solution of 1 (6.0 g, 0.027 mol) in dichloromethane (60 mL) was added thionyl chloride (2.3 mL, 0.03 mol) dropwise while stirring the reaction mixture in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 h. Volatiles were then evaporated under reduced pressure and the resulting solution was extracted with toluene. The mixture was diluted with toluene (25 mL) and the toluene was evaporated under reduced pressure. This azeotropic step was repeated three times to give product 2 as a light brown oil (6.2 g). This crude product was used in the next step without further purification. MS (M+H) 235.3.

[0322] Step 3 - A solution of 2 (6.2 g, 0.026 mol) in triethyl phosphite (7.3 mL, 0.042 mol) was added to 150 ° The reaction mixture was heated at 4°C for 6 hours. The reaction mixture was cooled to room temperature, and the volatiles were evaporated to give a crude product, which was purified on a silica gel (230-400) column (60% ethyl acetate in petroleum ether) to give 8.3 g of product 3 as a pale yellow oil. The product contained unused triethyl phosphate. was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 1.16 (t, J=7.0 Hz, 6H), 2.45 (s, 3H), 3.23 (s, 1H), 3.23 (s, 1H), 3.94 (dq, J=8.2 Hz, 7.0 Hz, 4H), 7.0 - 7.12 (m, 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.

[0323] Step 4 - To a solution of 3 (8.3 g, 0.024 mol) in THF (40 mL) was added 15-crown ether (0.1 g, 0.48 mmol). The reaction was cooled (ice bath) and NaH (1.44 g, 0.036 mol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and then cooled to ice temperature again. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 5 (4.9 g, 0.024 mol) in F (40 mL) was added at ice temperature and stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (250 mL). The mixture was extracted with ethyl acetate (3×500 mL) and dried over sodium sulfate. The volatiles were evaporated. The crude product obtained was used in the next step without further purification to give product 4 (6.7 g) as a pale yellow oil. MS (M+H) 382.3.

[0324] Step 5 - To a solution of 4 (6.7 g, 0.017 mol) in dichloromethane (67.0 mL) was added thiazolinone under ice cooling. Trifluoroacetic acid (27 mL, 4V) was added and the reaction mixture was stirred at room temperature for 1 h. Evaporation of the volatiles afforded product 6 (6.96 g, 90%), which was used in the next step without further 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.

[0325] Step 6 - To a solution of amine 6 (1.0 g, 2.5 mmol) in dimethyl sulfoxide (30 mL) was added dichloromethane. Isopropylethylamine (1.4 mL, 7.5 mmol) and the carbamate product of Step 4 of Example 16 (0.7 g, 2.75 mmol) were added at 25° C. The reaction mixture was stirred at 60° C. for 5 hours. The reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3×150 mL), and dried over sodium sulfate. The crude product obtained by evaporation of the volatiles was purified by silica gel (230-400) column ( Purification with 60% ethyl acetate in petroleum ether gave product 7 as a pale yellow solid 0.7 g (68%): 50.8 °C. IR: 3305, 2923, 1627, 1528, 1473, 1337, 1266, 695 cm -1 . 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 1.02-1.20 (m, 2H), 1.82 - 1.84 (m, 1H), 2.21 - 2.41 (m, 4H), 2.46 (s, 3H), 2.46 (s, 3H), 2.60 - 2.70 (m, 1H), 3.26 - 3.34 (m, 4H), 6.32 (s, 1H), 6.80 - 7.22 (m, 9H), 7.35 (t, J = 7.6, 1H), 8.06 (bs, 1H), 8.37 (bs, J = 8.3, 1H).MS: 441.4 (M+H). HPLC: 99.91%.

[0326] Example 25 - Synthesis of 4-[3-pyrazin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide

[0327] [ka]

[0328] The target compound 7 is prepared according to the synthetic method described for the product of Example 24, starting from 2-chloro-pyrazine instead of 2-chloro-5-methyl-pyrazine as described in Example 24.

[0329] Example 26 - 4-[5-methyl-3-(pyrimidin-2-yloxy)-benzylidene]-piperazine Synthesis of lysine-1-carboxylic acid (2-phenyl-cyclopropyl)-amide

[0330] [ka]

[0331] Target compound 6 is prepared according to the synthetic method described for the product of Example 6, starting from 2-chloro-5-methyl-pyrimidine instead of 2-chloro-pyrimidine as described in Example 6.

[0332] Example 27 - Synthesis of 4-[3-(5-chloro-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide.

[0333] [ka]

[0334] Step 1 - A solution of 5-chloro-2-fluoropyridine (10.0 g, 0.0760 mol) in DMSO (100 mL) was added with 3-hydroxyphenyl-methanol (9.42 g, 0.0760 mol) and cesium carbonate at room temperature. To the resulting solution was added ethanol (29.72 g, 0.0912 mol). The reaction mixture was stirred at 100°C for 6 hours. The reaction was monitored by TLC. The resulting mixture was cooled to room temperature, diluted with water (200 mL), extracted with ethyl acetate (2x400 mL), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (12% ethyl acetate in petroleum ether) to give the desired product. The product 1 was obtained as a pale yellow oil, 12.0 g (67%). 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

[0335] Step 2: To a solution of 1 (12.0 g, 0.0509 mol) in dichloromethane (120 mL), add the reaction mixture in an ice bath. Thionyl chloride (4.1 mL, 0.0560 mol) was added dropwise to the mixture while stirring. 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. The mixture was evaporated, diluted with ethyl acetate (250 mL), and the organic layer was washed with saturated aqueous sodium bicarbonate and water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product 2 obtained after evaporation was directly carried to the next step without further purification (12.5 g, 96%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.20 (d, J=2.4 Hz, 1H), 8.19-7.95 (m, 1H), 7.42 (t, MS m / z (M+H): 254.1

[0336] 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 resulting precipitate was filtered and dried under vacuum to give the product 3 as an off-white solid (16.5 g, 91%), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.19-8.18 (m, 1H), 7.97-7.94 (m, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.13-7.06 (m, 1H), 7.03-6.99 (m, 3H), 3.95 (m, 4H), 3.27 and 3.21(2s, 2H), 1.15 (t, J=4.4 Hz, 6H).MS m / z (M+H): 356.2

[0337] Step 4: To a solution of 3 (15.5 g, 0.0435 mol) in THF (100 mL) was added 15-crown ether (0.19 g, 0.87 mmol). The reaction was cooled (ice bath) and NaH (2.07 g, 0.0870 mol) was added portionwise over 5 min. The reaction mixture was stirred at room temperature for 30 min and cooled to ice again. THF (50 mL) A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 5 (8.66 g, 0.0435 mol) in The resulting mixture was added at ice temperature and stirred at room temperature for 16 hours. The resulting reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product obtained by evaporating the volatiles was purified by silica gel column chromatography to obtain product 4 as a pale yellow solid. Obtained as a liquid (13.1 g, 75%). 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, MS m / z (M+Na):423.2

[0338] Step 5: A solution of 4 (13.0 g, 0.0325 mol) in dichloromethane (130 mL) was added to triflate at ice temperature. Fluoroacetic acid (52.0 mL) was added and 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 the product as a light brown oil. The crude product was washed with ether (3×50 mL) to give 6 as a thick light brown liquid (13.8 g crude product). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.82 (bs, 2H), 8.19 (d, J=2.8 Hz, 1H), 7.96-7.93 (m, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.09 (d, J=8.8 Hz, MS m / z (M+H): 301.2

[0339] Step 6: To a solution of 6 (15.8 g, 0.0381 mol) in dimethyl sulfoxide (78 mL) was added diisopropyl ether. Propyl-ethyl-amine (20.34 mL, 0.1149 mol) and the carbamate product of Step 4 of Example 16 (10.62 g, 0.0419 mol) were added at 25°C. The reaction mixture was stirred at 60°C for 6 hours. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3X200 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified by silica gel (230-400) column chromatography. Purification by elution with hexane (40% ethyl acetate in petroleum ether) gave the product 7 as a pale yellow fluffy solid (11.6 g, 66%). Melting point range (MR): 44.8-62.6°C. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.18 (d, J=2.4 Hz, 1H), 7.94-7.91 (m, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.23-7.19 (m, 2H), 7.12-7.05 (m, 5H), 6.95-6.82 (m, 2H), 6.32 (s, 1H), 3.37-3.26 (m, 4H), 2.71-2.69 (m, 1H), 2.36-2.33 (t, J=5.2 Hz, 2H), 2.24-2.22 (t, J=5.6 Hz, 2H), 1.85 (m, 1H), 1.13 (d, J=4.8 Hz, 1H), 1.04 (d, J=7.6 Hz, 1H). 13 C NMR: (100 MHz, DMSO-d6):δ 161.69, 157.57, 153.49, 145.56, 141.99, 139.92, 139.75, 138.80, 129.56, 128.08, 125.85, 125.34, 125.21, 123.04, 121.29, 119.02, 113.05, 44.93, 43.89, 35.63, 34.07, 28.91, 24.32 and 15.58.MS m / z (M+H): 460.32, HPLC purity: 99.36%, Chiral purity: 99.71%.

[0340] Example 28 - Synthesis of 4-[3-(5-fluoro-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide

[0341] [ka]

[0342] Step 1: To a solution of 2,5-difluoropyridine (8.2 g, 0.0719 mol) in DMSO (80 mL) 3-Hydroxyphenyl-methanol (8.9 g, 0.0719 mol) and cesium carbonate (28.12 g, 0.0863 mol) were added under warm conditions, and the reaction mixture was stirred for 6 hours at 85° C. The reaction was monitored by TLC. The resulting mixture was cooled to room temperature, diluted with water (200 mL), extracted with ethyl acetate (3×400 mL), and the organic layer was dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (12% ethyl acetate in petroleum ether) to give product 1 as a pale yellow oil, 4.3 g (28%). 1 H 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

[0343] Step 2: To a solution of 1 (6.5 g, 0.0296 mol) in dichloromethane (65 mL), add the reaction mixture in an ice bath. Thionyl chloride (2.4 mL, 0.0326 mol) was added dropwise with stirring. After removing the ice bath, the reaction mixture was stirred at room temperature for 2 hours. After complete consumption of the starting material, the volatiles were evaporated under reduced pressure. The mixture was then diluted with ethyl acetate (200 mL), and the organic layer was washed with saturated aqueous sodium bicarbonate and water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product 2 obtained by evaporation was directly used in the next step without further purification (6.7 g, 95%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.15 (d, J=2.4 Hz, 1H), 7.83-7.80 (m, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.27-7.25 (m, 1H), 7.19-7.06 (m, 3H), 4.75 (s, 1H).MS m / z (M+H): 238.0

[0344] 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 volatiles were evaporated. The resulting mixture was purified by silica gel (230-400) column chromatography. Product 3 was obtained as a pale yellow liquid (9.0 g, 95%). 1 H 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

[0345] Step 4: To a solution of 3 (9.0 g, 0.0256 mol) in THF (60 mL) was added 15-crown ether (0.12 g, 0.53 mmol). The reaction was cooled (ice bath) and 60% NaH (1.26 g, 0.0530 mol) was added portionwise over 5 min. The reaction mixture was stirred at room temperature for 30 min and cooled to ice again. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 5 (5.28 g, 0.0256 mol) in THF (30 mL) was added at ice temperature and stirred at room temperature for 16 h. The resulting reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product obtained after evaporation of the volatiles was purified by silica gel column chromatography to give product 4 as a pale yellow solid. Obtained as a solid (8.0 g, 78%). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.15 (d, J=3.2 Hz, 1H), 7.84-7.79 (m, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.12-7.04 (m, 2H), 6.96-6.92 (m, MS m / z (M+Na):407.2

[0346] Step 5: A solution of 4 (8.2 g, 0.0213 mol) in dichloromethane (82 mL) was added to triflate at ice temperature. Oroacetic acid (32.5 mL) was added 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 give the product as a red oil. The crude product was washed with ether (3×50 mL) to give 6 as a dark brown oil (9.0 g Crude). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 8.73 (bs, 2H), 8.15 (d, J=3.2 Hz, 1H), 7.84-7.79 (m, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.12-7.06 (m, 2H), 7.00-6.96 (m, 2H), 6.44 (s, 1H), 3.15-3.09 (m, 4H), 2.59 (t, J=6.0 Hz, 2H), 2.49-2.48 (m, 2H).MS m / z (M+H): 285.4

[0347] Step 6: To a solution of 6 (8.4 g, 0.021 mol) in dimethyl sulfoxide (42 mL) was added diisopropyl-ethyl-amine (11.1 mL, 0.063 mol) and the carbamate product of Step 4 of Example 16 (5.8 g, 0.023 mol) at 25° C. The reaction mixture was stirred at 60° C. for 6 hours. The reaction mixture was diluted with ethyl acetate (400 mL), washed with water (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 Purification with 40% ethyl acetate in ether gave the product 7 as a pale yellow fluffy solid. (7.15 g, 66%). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.15 (d, J=2.4 Hz, 1H), 7.82-7.80 (m, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.24-7.21 (m, 2H), 7.14-7.04 (m, 5H), 6.96-6.94 (m, 2H), 6.84 (d, J=2.8 Hz, 1H), 6.34 (s, 1H), 3.38-3.28 (m, 4H), 2.71-2.69 (m, 1H), 2.34 (t, J=5.2 Hz, 2H), 2.23 (t, J=4.8 Hz, 2H), 1.86 (m, 1H), 1.13 (d, J=4.8 Hz, 1H), 1.04 (d, J=7.6 Hz, 1H). 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%.

[0348] Example 29: Synthesis of 6-{3-[1-((1R,2S)-2-phenyl-cyclopropylcarbamoyl)-piperidin-4-ylidenemethyl]-phenoxy}-nicotinic acid methyl ester

[0349] [ka]

[0350] Step 1: To a solution of methyl 6-chloropyridine-3-carboxylate (50.0 g, 0.29 mol) in dimethylacetamide (500 mL) was added 3-hydroxyphenylmethanol (39.79 g, 0.32 mol) and potassium carbonate (60.4 g, 0.43 mol) at room temperature. The reaction mixture was stirred at 100° C. for 6 hours. The reaction was monitored by TLC. The resulting mixture was cooled to room temperature and diluted with water (300 mL). The crude product obtained by evaporation of the volatiles was purified by column chromatography on silica gel (230-400) (12% ethyl acetate in petroleum ether). The product 1 was purified by HPLC (chill) to give the product 1 as a pale yellow oil (30.0 g, 40%). 1H 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

[0351] Step 2: To a solution of 1 (30.0 g, 0.115 mol) in dichloromethane (300 mL) was added thionyl chloride (9.4 mL, 0.127 mol) dropwise while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was The mixture was stirred at room temperature for 2 hours. After complete consumption of the starting material, the volatiles were evaporated under reduced pressure. The mixture was then diluted with ethyl acetate (500 mL), and the organic layer was washed with saturated sodium bicarbonate (200 mL) and water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product obtained after evaporation was purified by silica gel (230-400) column chromatography to give product 2 as a pale yellow liquid (28.0 g, 87%). 1 H 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

[0352] Step 3: A solution of 2 (28.0 g, 0.10 mol) in triethyl phosphite (41.0 mL, 0.25 mol) was stirred for 6 h. The reaction mixture was cooled to room temperature and the volatiles were evaporated. The resulting mixture was purified by silica gel column chromatography to give 3 as a pale yellow liquid. (32.0 g, 84%) 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.65-8.64 (m, 1H), 8.30-8.27 (m, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.16-7.03 (m, 4H), 3.96-3.88 (m, 4H), 3.82 (s, 3H), 3.27 and 3.21(2s, 2H), 1.15-1.11 (m, 6H).MS m / z (M+H): 380.2

[0353] Step 4: To a solution of 3 (35.5 g, 0.093 mol) in THF (200 mL) was added 15-crown ether (0.41 g, 1.8 mmol). The reaction was cooled (ice bath) and 60% NaH (5.5 g, 0.14 mol) was added over 5 min. The reaction mixture was stirred at room temperature for 30 min and cooled to ice again. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 5 (18.7 g, 0.093 mol) in THF (150 mL) was added in portions. The resulting mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product (30.0 g) obtained by evaporating the volatiles was dissolved in methanol (300 mL), and an aqueous solution of lithium hydroxide (3.0 g, 0.0707 mol) was added at ice temperature. The resulting reaction mixture was stirred at 50°C for 2 hours. The reaction was monitored by TLC. The crude product obtained by evaporating the volatiles was dissolved in water (200 mL). The aqueous layer was dissolved in 1.0 N aqueous hydrochloric acid and washed with methyl tert-butyl ether (2x200 mL). The mixture was acidified to pH 2.0 with HCl, and the precipitated product was filtered and dried to give 4 as an off-white solid (23.0 g, 61%). 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

[0354] Step 5: To a solution of 4 (13.0 g, 0.0317 mol) in methanol (130 mL) was added trimethylsilyl methyl methyl ester at ice temperature. Silyl chloride (8.9 mL, 0.0697 mol) was added and the reaction mixture was stirred at room temperature for 12 hours. After complete consumption of the starting material, the volatiles were removed under reduced pressure. The resulting crude product was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product obtained after evaporation of the volatiles was purified by silica gel (230-400) column chromatography to give product 6 as a pale yellow liquid (5.2 g, 51%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.68-8.67 (m, 1H), 8.31-8.28 (m, 1H), 7.39-7.36 (m, 1H), 7.13-6.97 (m, 4H), 6.24 (s, 1H), 3.84 (s, 3H), 2.78-2.65 (m, 4H), 2.34 (t, J=5.2 Hz, 2H), 2.21 (t, J=5.2 Hz, 2H). MS m / z (M+H): 325.3

[0355] Step 6: To a solution of 6 (5.2 g, 0.016 mol) in dimethyl sulfoxide (52 mL, 10 V) was added diisopropyl-ethyl-amine (8.9 mL, 0.048 mol) and the carbamethoxazole from Step 4 of Example 16. The ester product (4.0 g, 0.016 mol) was added at 25°C. The reaction mixture was stirred at 60°C for 6 hours. The reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3×100 mL), and dried over anhydrous sodium sulfate. The crude product obtained by evaporation of the volatiles was The product was purified on a silica gel (230-400) column (40% ethyl acetate in petroleum ether) to give product 7. Obtained as a pale yellow fluffy solid (5.0 g, 65%). Melting point range (MR): 52.6-72.8°C. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.68 (d, J=2.0 Hz, 1H), 8.31-8.28 (m, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.24-7.20 (m, 2H), 7.13-7.01 (m, 7H), 6.84-6.83 (m, 1H), 6.35 (s, 1H), 3.84 (s, 3H), 3.38-3.30 (m, 4H), 2.71-2.69 (m, 1H), 2.37 (t, J=5.2 Hz, 2H), 2.25 (t, J=5.2 Hz, 2H), 1.86 (m, 1H), 1.15 (d, J=4.8 Hz, 1H), 1.05 (d, J=6.0 Hz, 1H). 13 C 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.M (M+H): 484.3, HPLC purity: 98.65%, Chiral HPLC: 99.08

[0356] Example 30: 6-{3-[1-((1R,2S)-2-phenyl-cyclopropylcarbamoyl)-pyridinyl}- Synthesis of peridin-4-ylidenemethyl]-phenoxy}-nicotinic acid

[0357] [ka]

[0358] To a solution of 1, the product of Example 27 (1.8 g, 0.0038 mol) in methanol (18 mL) was added 1.0 mL of ... the product of Example 27 (1.8 g, 0.0038 mol) in methanol (18 mL) at ice temperature. Lithium hydroxide (0.32 g, 0.0076 mol) was added dropwise, and the reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC. The crude product obtained by 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 hydrochloric acid. The precipitated product was filtered and dried to give 2 as an off-white solid, 1.52 g (87%), melting point (MR) 141-159°C. 1 H 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). 13C 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%, Ki Ral HPLC: 99.50%,

[0359] Example 31: Synthesis of 4-[3-(5-hydroxymethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide

[0360] [ka]

[0361] Step 1: A solution of 1, the product of Step 4 of Example 27 (3.6 g, 0.0085 mol) in dimethoxyethane (35 mL) was added with N-methylmorpholine (1.4 mL, 0.0128 mol) and isochloroformate at ice temperature. Butyl borohydride (1.21 mL, 0.0093 mol) was added and the reaction mixture was stirred at room temperature for 30 minutes. Sodium hydroxide (1.9 g, 0.0512 mol) was added in portions 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 ethyl acetate was added. The resulting mixture was extracted with ethyl acetate (300 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel (230-400) column chromatography to give product 2 as an off-white solid (3.2 g, 92%). 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

[0362] Step 2: A solution of 2 (3.2 g, 0.08 mol) in dichloromethane (32 mL) was added with trifluoromethane at ice temperature. Acetic acid (12.8 mL) was added 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 give the crude product as a brown-red oil. The crude product was washed with ether (3×50 mL) to give 3 as an off-white solid (crude product 3.3 g). MS m / z (M+H): 297.17

[0363] Step 3: To a solution of 3 (3.3 g, 0.08 mmol) in dimethyl sulfoxide (30 mL) was added diisopropyl-ethyl-amine (4.2 mL, 0.024 mol) and the carbamate product from Step 4 of Example 16. The product (2.0 g, 0.08 mmol) was added at 25°C. The resulting reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3x100 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (40% ethyl acetate in petroleum ether). 4 was obtained as a pale yellow fluffy solid (1.82 g, 58%). Melting point (MR): 51-65 °C. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.07 (d, J=2.0 Hz, 1H), 7.80-7.77 (m, 1H), 7.34 (t, J=8.0 Hz, 1H), 7.26-6.92 (m, 7H), 6.83 (d, J=3.2 Hz, 1H), 6.35 (s, 1H), 5.25 (t, J=6.0 Hz, 1H), 4.45 (d, J=7.2 Hz, 1H), 3.40-3.32 (m, 4H), 2.38 (t, J=5.6 Hz, 2H), 2.25 (t, J=5.2 Hz, 2H), 1.87 (m, 1H), 1.16 (d, J=6.0 Hz, 1H), 1.05 (d, J=7.6 Hz, 1H). 13 C NMR: (100 MHz, DMSO-d6):δ162.03, 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%.

[0364] Example 32: Synthesis of 4-[3-(5-methoxymethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide

[0365] [ka]

[0366] Step 1: To a solution of the product of Step 1 of Example 29 (13.2 g, 8.0 mmol) in tetrahydrofuran (32 mL) was added 60% NaH (0.97 g, 0.024 mol) at ice temperature, and the reaction mixture was stirred at room temperature for 10 minutes. The mixture was stirred. Methyl iodide (1.56 mL, 0.024 mol) was added to the reaction mass at the same ice temperature, and stirring was continued for 12 hours. After complete consumption of the starting material, the reaction was quenched with saturated aqueous 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 give product 2 as an off-white solid (2.6 g, 78%). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.08 (d, J=2.0 Hz, 1H), 7.80-7.78 (m, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.06-6.93 (m, 4H), 6.35 (s, 1H), 4.37 (s, 2H), 3.40-3.32 (m, 4H), 3.26 (s, 3H), 2.38 (t, J=5.6 Hz, 2H), 2.25 (t, J=5.6 Hz, 2H), 1.39 (s, 9H). MS m / z (M+H): 411.3

[0367] Step 2: A solution of 2 (2.6 g, 6.3 mmol) in dichloromethane (26.0 mL) was added to trichloromethane at ice temperature. Fluoroacetic acid (10.4 mL) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was stirred at 60° C. for 6 hours. After complete consumption of the starting material, the volatiles were removed under reduced pressure to give the product. The crude product was washed with ether (3×50 mL) to give 3 as a pale yellow thick liquid (crude product 2.9 g). 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 8.69 (bs, 2H), 8.09-8.08 (m, 1H), 7.81-7.78 (m, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.08-6.97 (m, 4H), 6.45 (s, 1H), 4.37 (s, 2H), 3.27 (s, 3H), 3.15-3.09 (m, 4H), 2.60 (t, J=5.6 Hz, 2H), 2.45 (t, J=5.6 Hz, 2H).MS m / z (M+H): 311.3

[0368] Step 3: To a solution of 3 (2.9 g, 6.8 mmol) in dimethyl sulfoxide (30 mL, 10 V) was added diisopropyl ether. Isopropyl-ethyl-amine (3.5 mL, 0.0205 mol) and the carbamate product 5 (1.7 g, 6.8 mmol) from Step 4 of Example 16 were added at 25° C. The reaction mixture was stirred at 60° C. for 6 hours. The reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3×100 mL), and dried over sodium sulfate. The crude product obtained by evaporation of the volatiles was The product 4 was purified on a silica gel (230-400) column (30% ethyl acetate in n-hexane) to give a pale yellow gum. This was obtained as a crystalline solid (2.6 g, 86%). 1 H 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). 13C NMR: (100 MHz, DMSO-d6):δ162.60, 157.57, 153.87, 146.76, 142.00, 140.15, 139.65, 138.71, 129.52, 128.87, 128.10, 125.86, 125.35, 124.90, 123.12, 121.21, 118.96, 111.26, 70.58, 57.49, 44.94, 43.90, 35.63, 34.08, 28.92, 24.31 and 15.57.MS m / z (M+H): 470.3, HPLC purity: 99.57%, Chiral HPLC: 99.60%

[0369] Example 33. 4-({3-[(5-methylpyrimidin-2-yl)oxy]phenyl}methylide Synthesis of N-[(1R,2S)-2-phenylcyclopropyl]piperidine-1-carboxamide :

[0370] [ka]

[0371] Step 1—To a solution of 2-chloro-5-methylpyrimidine 1 (33.0 g, 0.256 mol) in DMF (330 mL) was added 3-(hydroxymethyl)phenol (31.86 g, 0.256 mol) and cesium carbonate (100.36 g, 0.308 mol) at room temperature. The reaction mixture was stirred at 100° C. for 5 hours. The resulting mixture was Cool to room temperature, dilute with dichloromethane (330 mL), wash with water (2×330 mL), 1N aqueous KOH (2×165 mL), brine, and dry the organic layer over sodium sulfate. Evaporate the volatiles. The resulting crude product was purified on a silica gel (230-400) column (8% ethyl acetate in hexane) to give product 2 as a white solid (22.0 g, 40%). 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

[0372] Step 2 - {3-[(5-methylpyrimidin-2-yl)oxy]fluoranhydride in dichloromethane (220 mL) To a solution of 22.0 g (0.101 mol) of phenylmethanol 2 (22.0 g, 0.101 mol) was added thiamine chloride while stirring the reaction in an ice bath. Onil (8.1 mL, 0.111 mol) was added dropwise. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated under reduced pressure and diluted with ethyl acetate (220 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (110 mL) and water (2X220 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give product 3 as a white solid (21.5 g, 90%). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.45 (s, 2H), 7.4 (t, J = 8 Hz, 1H), 7.28 (d, J = 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

[0373] Step 3 - 2-[3-(chloromethyl)phenoxy]phenoxyethanol in triethyl phosphite (25.0 mL, 0.143 mol) A solution of 21.0 g (0.0894 mol) of 5-methylpyrimidine 3 was added to 130 mL of oThe reaction mixture was heated at C for 16 h. The reaction mixture was allowed to cool to room temperature, and the volatiles were evaporated to give a crude product which was purified on a silica gel (230-400) column (86% ethyl acetate in hexane) to give product 4 as a pale green oil (21.6 g, 72%). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.44 (s, 2H), 7.3 (t, J = 8 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 7.02 (t, J = 8 Hz, 2H), 3.95-3.88 (m, 4H), 3.31-3.20 (m, 2H), 2.18 (s, 3H), 1.15-1.11 (m, 6H).MS m / z (M+H): 337.3

[0374] Step 4—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) was added 15-crown-5 ether (0.275 g, 0.0012 mol) at room temperature. The reaction was cooled (ice bath) and 60% NaH (3.73 g, 0.093 mol) was added. The reaction mixture was stirred at room temperature for 30 minutes and then cooled to ice-cold temperature again. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (12.4 g, 0.0624 mol) in water was added at ice temperature and stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with ethyl acetate (210 mL) and The crude product was washed with water (3×210 mL) and dried over sodium sulfate. The product was purified on a silica gel (230-400) column (15% ethyl acetate in hexane) to give product 5. This was obtained as a yellow solid (17.0 g, 72%). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.44 (s, 2H), 7.34 (t, J = 8 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.99-6.97 (m, 2H), 6.34 (s, 1H), 3.38 (t, J = 5.6 Hz, 2H), 2.37 (t, J = 5.6 Hz, 2H), 2.24 (t, J = 5.6 Hz, 2H), 2.18 (s, 3H), 1.38 (s, 9H). MS m / z (M+H): 382.3

[0375] Step 5 - To a solution of tert-butyl 4-({3-[(5-methylpyrimidin-2-yl)oxy]phenyl}methylidene)piperidine-1-carboxylate 5 (17.0 g, 0.0445 mol) in dichloromethane (170 mL) was added trifluoroacetic acid (68.0 mL) at ice temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was evaporated under reduced pressure to afford the crude product as a yellow oil. The resulting crude product was washed with diethyl 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), 7.08 (d, J = 7. 6 Hz, 1H).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

[0376] Step 6 - 5-Methyl-2-{3-[(piperidin-4-ylidene)-2-yl]methylpropional in dimethyl sulfoxide (150 mL) To a solution of the trifluoroacetate salt of {(methyl)phenoxy}pyrimidine 6 (15.0 g, 0.0379 mol) was added diisopropylethylamine (20.0 mL, 0.113 mol) and the carbamate product 5 (10.57 g, 0.0417 mol) from Step 4 of Example 16 at 25-30°C. The reaction mixture was heated at 60°C for 5 h. The reaction mixture was diluted with ethyl acetate (150 mL), washed with water (3×150 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (70% ethyl acetate in hexane) to give product 7 as a pale yellow solid. (12.0 g, 72%). Melting range: 58°C-67.5°C. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.4 (s, 2H), 7.3 (t, J = 7.6 Hz, 1H), 7.23-7.19 (m, 2H), 7.12-7.06 (m, 4H), 6.9 (d, J = 8 Hz, 2H), 6.8 MS m / z (M+H): 441.4, HPLC purity: 99.67

[0377] Example 34: N-[(2S)-2-phenylcyclopropyl]-4-{[3-(pyrazin-2-yl)methyl]-4-(phenylcyclopropyl)methyl]-4-[[3-(pyrazin-2-yl)methyl] ... Synthesis of {(2- ...

[0378] [ka]

[0379] Step 1: 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) at room temperature. The reaction mixture was stirred at 100° C. for 5 hours. The resulting mixture was then cooled to room temperature. The mixture was reconstituted, diluted with water (250 mL), extracted with ethyl acetate (3 x 500 mL), and the resulting organic layer was washed with 1N KOH (2 x 250 mL). The separated organic layer was dried over sodium sulfate. The crude product obtained by evaporation of the volatiles was purified by silica gel (230-400) column (10% ethyl acetate in hexane). Purification by HPLC gave the product 2 as an off-white solid (9.3 g, 35%). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.50 (d, J = 1.2 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.18-8.17 (m, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 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

[0380] Step 2: {3-[(pyrazin-2-yl)oxy]phenyl} in dichloromethane (100 mL, 10 V) To a solution of 2 (10.0 g, 0.049 mol) in methanol was added thionyl chloride (3.94 mL, 0.054 mol) dropwise while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 h. The volatiles were evaporated under reduced pressure and diluted with ethyl acetate (250 mL). The organic layer was washed with saturated charcoal. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the product 3 as a yellow solid (9.0 g, 82%). 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.

[0381] 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 added to 130 o The reaction mixture was then cooled to room temperature, and the volatiles were evaporated. The crude product was then purified by column chromatography on silica gel (230-400) (60% ethyl acetate in hexane). Purification by HPLC gave the product 4 as a colorless oil (9.49 g 64.5%). 1 H 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

[0382] Step 4: To a solution of diethyl {[3-(pyrazin-2-yloxy)phenyl]methyl}phosphonate 4 (10.0 g, 0.031 mol) in THF (70 mL) was added 15-crown-5 ether (136 mg, 0.62 mmol) at room temperature. 60% NaH (1.86 g, 0.046 mol) was added in portions to the above reaction mixture at 0-5 °C. The reaction mixture was stirred at room temperature for 30 minutes and cooled to ice again. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (6.18 g, 0.031 mol) in THF (30 mL) was added at ice temperature and stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (500 mL), extracted with ethyl acetate (3 × 500 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (15% ethyl acetate in hexane) to give the product 5 as an off-white solid (9.1 g, 80%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 8.51 (d, J = 1.2 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.18-8.17 (m, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.04-7.02 (m, 3H), 6.34 (s, 1H), 3.37 (t, J = MS m / z (M+1):368.4

[0383] Step 5: tert-Butyl 4-{[3-(pyrazin-2-yloxy)phenyl]phenyl]propanol in dichloromethane (100 mL) To a solution of 10.0 g (0.027 mol) of 1-[(2-methyl- ... Trifluoroacetic acid (40 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated from the reaction mixture under reduced pressure to give the crude product as a red oil, which was washed with ether (3×50 mL) to give 6 as an off-white solid (9.5 g, 92%). 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 8.72 (bs, 2H), 8.52 (d, J = 1.6 Hz, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.18-8.17 (m, 1H), 7.42-7.38 (m, 1H), 7.12-7.06 (m, 3H), 6.44 (s, 1H), 3.13-3.07 (m, 4H), 2.58 (t, J = 5.6 Hz, 2H).MS m / z (M+1):268.3

[0384] Step 6: To a solution of the trifluoroacetate salt of 2-[3-(piperidin-4-ylidenemethyl)phenoxy]pyrazine 6 (10.0 g, 0.026 mol) in dimethyl sulfoxide (100 mL, 10 V) was added diisopropyl Ethylamine (13.7 mL, 0.078 mol) and 7.3 g (0.028 mol) of the carbamate product 5 from Step 4 of Example 16 were added at 25-30°C. The reaction mixture was stirred at 60°C for 5 hours. The resulting reaction mixture was diluted with ethyl acetate (500 mL), washed with water (3 x 150 mL), and dried over sodium sulfate. The crude product obtained by evaporation of the volatiles was purified by silica gel (230-400) column (50% acetic acid in hexane). Purification with ethyl acetate gave product 7 as a pale yellow solid (8.0 g, 71%). Melting range: 41.7°C - 52.6°C; 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

[0385] Example 35: Synthesis of 4-[3-(5-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide

[0386] [ka]

[0387] Step 1: 5-Bromo-2-fluoropyridine 1 (7.72 g, 44.3 mmol) in DMSO (40 mL, 8 V) To the solution was added 3-hydroxymethylphenol (5 g, 40.3 mmol) and cesium carbonate (15.75 g, 48.3 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 8 hours. The resulting mixture was cooled to room temperature, diluted with water (70 mL), and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was washed with sulfuric acid. The crude product obtained after evaporation of the volatiles was purified by silica gel (230-400) column (30% ethyl acetate in n-hexane). Purification by HPLC gave product 2 as a pale yellow oil (7.1 g, 63% yield). 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, 0.6 Hz, 1H).6, 1.7, 0.9 Hz, 1H), 7.13 (ddd, J = 2.1 Hz, 1H), 7.03 (ddd, J = 8.1, 2.5, 1.0 Hz, 1H), 6.84 (dd, J = 8.7, 0.7 Hz, 1H), 4.68 (s, 2H).MS m / z (M): 280.21

[0388] Step 2: To a solution of {3-[(5-bromopyridin-2-yl)oxy]phenyl}methanol 2 (5.2 g, 18.57 mmol) in dichloromethane (52 mL) was added thionyl chloride (2.43 g, 20.4 mmol) dropwise while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 h. The volatiles were evaporated under reduced pressure and diluted with ethyl acetate (80 mL). The organic layer was washed with saturated bicarbonate and thionyl chloride (2.43 g, 20.4 mmol). The organic layer was dried over anhydrous sodium sulfate and concentrated to give product 3 as a white solid (4.12 g, 75% yield). 1 H NMR (400 MHz, CDCl3) 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

[0389] Step 3: A solution of 5-bromo-2-[3-(chloromethyl)phenoxy]pyridine 3 (4 g, 13.5 mmol) in triethyl phosphite (5.78 mL, 33.7 mmol) was added to 150 mL of HCl. o The reaction mixture was heated at 25°C for 6 hours. The reaction mixture was then cooled to room temperature, and the volatiles were evaporated. The crude product was then separated by column chromatography on silica gel (230-400). Purification with 60% ethyl acetate in ether gave product 4 as a colorless oil (3.88 g, yield rate 72%). 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 MS m / z (M+1):401

[0390] Step 4: To a solution of diethyl ({3-[(5-bromopyridin-2-yl)oxy]phenyl}methyl)phosphonate 4 (3.8 g, 9.52 mmol) in THF (19 mL) was added 15-crown ether (41 mg, 0.190 mmol). The reaction was cooled (ice bath) and 60% NaH (342 mg, 14.2 mol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and cooled to ice again. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.9 g, 9.52 mmol) in THF (19 mL) was added at ice temperature and stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (3×40 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (5% ethyl acetate in n-hexane) to give product 5 as a white solid (2.58 g, 61% yield). 1 H NMR (400 MHz, CDCl3) 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. 7.7, 1.7, MS m / z (M+Na):469.21

[0391] Step 5: Experiments were carried out using the methodology reported in the literature (Reference: J. Am. Chem. Soc. 2016, 138, 13493-13496). 4-[3-(5-bromo-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester was prepared in DMSO (40 mL) and water (2 mL). To a degassed solution of 5 (2 g, 4.49 mmol), LiOH.HO (396 mg, 9.43 mmol) and the ligands L-1 (110 mg, 0.337 mmol) and Cu(acac) (88 mg, 0.337 mmol) were added sequentially, and the degassing was continued for 10 min. The resulting reaction mixture was heated at 85°C for 48 hours. The progress of the reaction was monitored using TLC. The reaction mixture was cooled to ambient temperature, quenched by the addition of 5% aq NH4Cl (12 mL), and diluted with ethyl acetate (25 mL). The organic layer was separated, washed with brine (15 mL), and diluted with anhydrous sulfuric acid. The mixture was dried over sodium and concentrated under reduced pressure to give the crude product, which was further purified by silica gel flash chromatography using 40-45% ethyl acetate in hexanes to give 4-[3-(5-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carbox- one. The acid tert-butyl ester (6) was obtained as a light brown solid (738 mg, 43% yield). 1 H NMR (400 MHz, CDCl3) δ 9.69 (bs, 1H), .83 (s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 4.9 Hz, 1H), 6.92 (d, J = 7.8 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 6.30 (s, 1H), 3.48 (t, J = 5.7 Hz, 2H), 3.35 (t, J = 5.9 Hz, 2H), 2.41 (t, J = 5.9 Hz, 2H), 2.29 (t, J = 5.8 Hz, 2H), 1.47 (s, 9H).MS m / z (M+Na):405.44

[0392] Step 6: A solution of 6 (600 mg, 1.57 mmol) in dichloromethane (6 mL) was added to triflate at ice temperature. Oroacetic acid (2.4 mL) was added 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 give the crude product 7 as a red oil. The crude product was washed with ether (3 x 5 mL) to give the trifluoroacetate salt of 6-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyridin-3-ol as a brown oil (400 mg crude product). MS m / z (M+1): 283.21

[0393] Step 7: To a solution of 7 (300 mg, 1.06 mmol) in dimethyl sulfoxide (3 mL) was added diisopropyl propylethylamine (1.48 mL, 8.51 mmol) and the carbamate derivative from Step 4 of Example 16. Product 5 (269 mg, 1.06 mmol) was added at 25 °C. The reaction mixture was stirred at 60 °C for 4 hours. The reaction was monitored by TLC. The resulting reaction mixture was diluted with ethyl acetate (20 mL), washed with water (3 x 20 mL), and dried over anhydrous sodium sulfate. The crude product obtained by 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. Obtained as an off-white solid (93 mg, 20%). 1 H NMR (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

[0394] Example 36: Synthesis of 4-[3-(4-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0395] [ka]

[0396] Step 1: Solution of 4-bromo-2-fluoropyridine 1 (7.72 g, 44.3 mmol) in DMSO (40 mL) To the mixture was added 3-hydroxymethylphenol (5 g, 40.3 mmol) and cesium carbonate (15.75 g, 48.3 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 8 hours. The resulting mixture was cooled to room temperature, diluted with water (70 mL), extracted with ethyl acetate (3 x 100 mL), and the organic layer was washed with sodium sulfate. The crude product obtained by evaporating the volatiles was then purified by silica gel (230-400) column chromatography. (30% ethyl acetate in n-hexane) to give the product 2 as a pale yellow oil (4.8 g, 43% yield). 1 H 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

[0397] Step 2: To a solution of {3-[(4-bromopyridin-2-yl)oxy]phenyl}methanol 2 (4.8 g, 17.1 mmol) in dichloromethane (48 mL) was added thionyl chloride (2.24 g, 18.8 mmol) dropwise while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 h. The volatiles were evaporated under reduced pressure and diluted with ethyl acetate (80 mL). The organic layer was washed with saturated sodium bicarbonate and thionyl chloride (2.24 g, 18.8 mmol). 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 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 5.5 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.25 (q, J = 2.0, 1.3 Hz, 1H), 7.21 - 7.14 (m, 2H), 7.13 - 7.05 (m, 2H), 4.59 (s, 2H).MS m / z (M+2):299.9

[0398] Step 3: A solution of 3 (4 g, 13.5 mmol) in triethyl phosphite (5.78 mL, 33.7 mmol) was added to 150 o The reaction mixture was then heated at 4°C for 6 hours. The reaction mixture was then cooled to room temperature, and the volatiles were evaporated to give a crude product, which was purified on a silica gel (230-400) column (60% ethyl acetate in petroleum ether) to give product 4. Obtained as a colorless oil (3.88 g, 72% yield). 1 H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J = 5.4 Hz, 1H), 7.36 (m, 1H), 7.20 - 7.13 (m, 2H), 7.07 (t, J = 1.9 Hz, 2H), 7.03 (m, 1H), 4.03 (m, 4H), 3.16 (d, J = 21.7 Hz, 2H), 1.25 (t, J = 7.1 Hz, 6H).MS m / z (M+H): 401.20

[0399] Step 4: To a solution of 4 (3.8 g, 9.52 mmol) in THF (19 mL) was added 15-crown ether (41 mg The reaction was cooled (ice bath) and 60% NaH (342 mg, 14.2 mol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and then cooled to ice again. A solution of oxo-piperidine-1-carboxylic acid tert-butyl ester (1.9 g, 9.52 mmol) was added to ice bath. The mixture was added to the flask and stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (3 x 40 mL), and dried over anhydrous sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230 - 400 mesh) column (5% ethyl acetate in n-hexane) and purified. The product 5 was obtained as a white solid (2.75 g, 65% yield). 1 H 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

[0400] Step 5: To a degassed solution of 5 (2 g, 4.49 mmol) in DMSO (40 mL) and water (2 mL), LiOH.HO (396 mg, 9.43 mmol) and the ligands L-1 (110 mg, 0.337 mmol) and Cu(acac) (88 mg, 0.337 mmol) were added sequentially, and degassing was continued for 10 min. The resulting reaction mixture was heated at 85 °C for 48 h. The progress of the reaction was monitored using TLC. The above reaction mixture was cooled to ambient temperature, quenched by the addition of 5% aq. NH4Cl (12 mL), and diluted with ethyl acetate (25 mL). The organics were separated. The extract was washed with brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was further purified by silica gel flash chromatography using 40-45% ethyl acetate in hexane to give 4-[3-(5-hydroxy-pyridin-2-yloxy)-benzoyl]- [Iridene]-piperidine-1-carboxylic acid tert-butyl ester (6) was obtained as a light brown solid (686 mg, 40% yield). 1 H NMR (400 MHz, Chloroform-d) δ 8.02 (d, J = 5.4 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.15 (dd, J = 5.4, 1.6 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 7.00 - 6.93 (m, 2H), 6.34 (s, 1H), 3.45 (dt, J = 40.2, 5.9 Hz, 5H), 2.50 - 2.27 (m, 4H), 1.47 (s, 9H).MS m / z (M+1):383.2

[0401] Step 6: To a solution of 4-[3-(4-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester 6 (400 mg, 1.04 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1.2 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. After complete consumption of the starting material, the volatiles were removed under reduced pressure to give the product. 7 was obtained as a red oil. The crude product was washed with ether (3 x 50 mL) to give the trifluoroacetate salt of 6-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyridin-3-ol as a brown oil (400 mg crude product). MS m / z (M+1): 283.2

[0402] Step 7: Trifluoroacetate solution of 6-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyridin-3-ol 7 (280 mg, 0.992 mmol) in dimethyl sulfoxide (2.8 mL, 10 V) To this was added diisopropylethylamine (1.38 mL, 7.94 mmol) and the carbamate product 5 (251 mg, 0.992 mmol) from Step 4 of Example 16 at 25° C. The reaction mixture was stirred at 60° C. for 4 hours. The reaction was monitored by TLC. The resulting reaction mixture was diluted with ethyl acetate (20 mL), washed with water (3×20 mL), and dried over sodium sulfate. The crude product obtained by evaporation of the volatiles was The material was purified by reverse phase HPLC to give the product 8 as an off-white solid (137 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.24 (tt, J = 7.9, 1.3 Hz, 2H), 7.15 - 7.08 (m, 3H), 7.04 (d, J = 7.7 Hz, 1H), 6.95 - 6.88 (m, 2H), 6.83 (d, J = 3.2 Hz, 1H), 6.55 (dd, J = 5.7, 2.1 Hz, 1H), 6.35 (s, 1H), 6.28 (d, J = 2.0 Hz, 1H), 3.38 (t, J = 5.8 Hz, 2H), 3.32 (m, 2H), 2.70 (tt, J = 6. 9.9, 3.6 Hz, 1H), 2.37 (t, J = 5.8 Hz, 2H), 2.29 - 2.22 (m, 2H), 1.88 (ddd, J = 9.4, 6.1, 3.2 Hz, 1H), 1.16 (dt, J = 9.6, 5.1 Hz, 1H), 1.07 (dt, J = 7.6, 5.8 Hz, 1H).MS m / z (M+H): 442.19, HPLC purity: 98.50%; Chiral HPLC purity: 97.9%.

[0403] Example 37: Synthesis of 4-[3-(6-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid ((1R,2S)-2-phenyl-cyclopropyl)-amide:

[0404] [ka]

[0405] Step 1: A solution of 2-bromo-6-fluoropyridine 1 (2.5 g, 14.2 mmol) in DMF (25 mL, 10 V) was treated with 3-hydroxymethylphenol (2.64 g, 21.3 mmol) and cesium carbonate (5 mL) at room temperature. The reaction mixture was stirred at 100°C for 8 hours. The resulting mixture was allowed to cool to room temperature, diluted with water (50 mL), extracted with ethyl acetate (3 x 50 mL), and the organic layer was dried over anhydrous sodium sulfate. The volatiles were evaporated and the crude product was purified by silica gel (230-400). Purification by column (30% ethyl acetate in n-hexane) gave product 2 as a pale yellow oil (2.48 g, 62% yield). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.79 (t, J = 7.9 Hz, 1H), 7.39 (t, J = 7.9 Hz, 2H), 7.19 (dt, J = 7.7, 1. 2 Hz, 1H), 7.19 (dt, J = 7.7, 1. MS m / z (M): 280.

[0406] Step 2: To a solution of {3-[(6-bromopyridin-2-yl)oxy]phenyl}methanol 2 (2.48 g, 8.85 mmol) in dichloromethane (25 mL) was added thionyl chloride (0.7 mL, 9.7 mmol) dropwise while stirring the reaction in an ice bath. After removing the ice bath, the reaction mixture was stirred at room temperature for 1 h. The volatiles were evaporated under reduced pressure and diluted with ethyl acetate (60 mL). The organic layer was washed with saturated bicarbonate The organic layer was dried over anhydrous sodium sulfate and concentrated to give product 3 as a brown oil (2.56 g, 86%). 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

[0407] Step 3: A solution of 2-bromo-6-[3-(chloromethyl)phenoxy]pyridine 3 (2.55 g, 8.50 mmol) in triethyl phosphite (3.67 mL, 21.0 mmol) was added to 150 mL of HCl. o The reaction mixture was heated at 4°C for 6 hours. The mixture was returned to room temperature, and the volatiles were evaporated. The resulting crude product was then passed through a silica gel (230-400) column. (60% ethyl acetate in petroleum ether) to give product 4 as a light brown oil (2.97 g, crude). And got it. 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 7.88 - 7.72 (m, 1H), 7.52 - 6.96 (m, 6H), 4.011 - 3.90 (m, J = 14.7, 7.3, 4.0 Hz, 4H), 1.16 (tt, J = 7.7, 5.3 Hz, 6H).MS m / z (M+Na):422.5

[0408] Step 4: To a solution of diethyl ({3-[(6-bromopyridin-2-yl)oxy]phenyl}methyl)phosphonate 4 (2.96 g, 7.39 mmol) in THF (20 mL) was added 15-crown ether (32 mg, 0.147 mmol). The reaction was cooled (ice bath) and 60% NaH (266 mg, 11.0 mmol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and cooled to ice again. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.76 g, 8.86 mmol) in THF (15 mL) was added at ice temperature and stirred at room temperature for 16 hours. The resulting reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (3×40 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified on a silica gel (230-400) column (5% ethyl acetate in n-hexane) to give product 5 as a yellow 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

[0409] Step 5: 4-[3-(6-bromo-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylate To a degassed solution of tert-butyl carboxylic acid ester 5 (1.8 g, 4.04 mmol) in DMSO (36 mL, 20 V), water (1.8 mL), LiOH.HO (356 mg, 8.49 mmol), the ligand, L-1 (99.6 mg, 0.303 mmol), and Cu(acac) (79 mg, 0.303 mmol) were added sequentially, and the degassing was continued for 10 min. The resulting reaction mixture was subjected to MW irradiation. The reaction mixture was heated at 100°C for 4 hours under irradiation. The progress of the reaction was monitored by TLC. The mixture was cooled to ambient temperature and quenched with 5% aq NH4Cl (12 mL) and ethyl acetate (25 mL). The organics were separated, washed with brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure. Concentration gave the crude product, which was further purified by silica gel flash chromatography using 40-45% ethyl acetate in hexane to give 4-[3-(6-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester (6) as a pale brown solid. This was obtained as a yellow solid (730 mg, 47% yield). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.80 (bs, 1H), 7.64 (t, J =8.0 Hz, 1H), 7.53 (t, J =8.0 Hz, 1H), 7.03 (d, J =7.6 Hz, 1H), 6.96 - 6.90 (m, 2 H), 6.36 - 6.33 (m, 3H), 3.40 (t, J = 5.2 Hz, 1H), 3.38 - 3.31(m, 2H), 2.39 (t, J = 5.6 Hz, 2H), 2.27 (t, J = 5.6 Hz, 2H), 1.45 (s, 9H), MS m / z (M+Na):405.17

[0410] Step 6: To a solution of 4-[3-(6-hydroxy-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester 6 (720 mg, 1.88 mmol) in dichloromethane (5.6 mL) was added trifluoroacetic acid (1.44 mL) at ice temperature, and the reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After complete consumption of the starting material, the volatiles were removed under reduced pressure. The product was obtained as a red oil. The crude product was washed with ether (3×5 mL) and purified by elution with trifluoroacetate of 6-{3-[(piperidin-4-ylidene)methyl]phenoxy}pyridin-2-ol 7. The acid salt was obtained as a brown oil (750 mg crude). 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.64 (s, 2H), 7.65 (t, J = 7.9 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.29 - 6.89 (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

[0411] Step 7: 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) was added diisopropyl ether. Isopropylethylamine (1.9 mL, 12.9 mmol) and the carbamate from Step 4 of Example 16. The reaction mixture was stirred at 60°C for 5 hours. The reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (70 mL), washed with water (3x20 mL), and dried over sodium sulfate. The crude product obtained after evaporation of the volatiles was purified twice by reverse-phase HPLC to give product 8 as an off-white solid (120 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.83 (s, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.24 (dd, J = 8. 2, 6.9 Hz, 2H).2, 6.9 Hz, 2H), 7.17 - 7.00(m, 4H), 6.99 - 6.81(m, 3H), 6.35(s, 3H), 3.38(t, J = 5.7 Hz, 3H), 3.30(t, J = 5.9 Hz, 2H), 2.70(dd, J = 7.9, 5.5, 2.4Hz, 1H), 2.37(t, J = 5.8 Hz, 2H), 2.26(t, J = 5.7 Hz, 2H), 1.88(dd, J = 9.4, 6.1, 3.2 Hz, 1H), 1.16 (m, 1H), 1.07 (m, 1H).MS m / z (M+H): 442.7, HPLC purity: 98.48%; Chiral HPLC: 98.6

[0412] Example 38 - Soluble Epoxide Hydrolase (sEH) Inhibition Assay: The sEH enzyme inhibition assay was performed using a commercially available kit from Cayman Chemical Company, Ann Arbor, Michigan (Cayman Cat. No. 10011671). The substrate used was 3-phenyl-cyano(6-methoxy-2-naphthalenyl)-methyl ester-2-oxiraneacetic acid. Hydrolysis of the substrate yielded a highly fluorescent product that could be monitored at excitation and emission wavelengths of 330 and 465 nm, respectively. The assay mixture consisted of 185-190 μL of assay buffer and 5 μL of sEH enzyme in a 96-well plate. Different concentrations of the compound (in 5 μL of DMSO) or DMSO (vehicle) alone was added, and the reaction was initiated by adding 5 μL of substrate. The plate was incubated at 25° C. for 15 minutes. Data analysis was performed to determine the percent inhibition.

[0413] Example 39 - Fatty acid amide hydrolase (FAAH (SEQ ID NO: 3)) inhibition assay: The FAAH enzyme inhibition assay is commercially available from Cayman Chemical Company, Ann Arbor, Michigan. The assay was performed using a commercially available kit (Cayman Cat. No. 10010183). The assay uses AMC arachidonoylamide (7-amino-4-methyl-2H-1-benzopyran-2-one-5Z,8Z,11Z,14Z-eicosatetraenamide, Cayman Chemical Cat. No. 10005098) as a substrate for FAAH. FAAH hydrolyzes AMC arachidonoylamide to produce the fluorescent product, 7-amino-4-methylcoumarate. This fluorophore emits an amine (AMC) at an excitation wavelength of 340-360 nm and an emission wavelength of 450-465 nm. The assay can be performed in 24 hours. Different concentrations of compounds (in DMSO) or DMSO (vehicle) alone were added. After the addition of FAAH, the plate was incubated for 20 minutes at ambient temperature. The assay was performed using AMC amide The reaction was initiated by the rapid addition of arachidonoylamide and carried out at ambient temperature for 60 min, during which the release of AMC was monitored by the concomitant increase in fluorescence intensity (excitation wavelength 340-360). The fluorescence intensity was measured kinetically, and the reaction rate was calculated using linear regression. The linear part of the reaction was calculated using the analysis.

[0414] Initial activity = (inhibitory fluorescence / 100% active fluorescence)*100 Inhibition rate = 100 - (% initial activity)

[0415] Concentration (IC 50 Compounds that inhibit soluble epoxide hydrolase at a concentration of less than 10 μM are considered to be active. The inhibitory activity of the compounds of Formula I against the sEH and FAAH enzymes is shown in Table 1 (see Figure 1). The selectivity of sEH inhibition is measured by the inhibitory potency of FAAH versus sEH [IC 50 FAAH / IC 50sEH ] is determined by dividing

[0416] The efficacy of compounds of general formula I in neurodegenerative diseases can be assessed using animal models known in the literature.

[0417] Example 40 - Methods described below (In vitro model of GBA1 (SEQ ID NO: 1) inhibition) to evaluate the potential of the compound of Formula 1 for neuroprotection and for the treatment of rheumatoid arthritis, including Gaucher disease. It can be used to block α-syn aggregation associated with nucleinopathies (see Figure 2). In this in vitro model, dopaminergic neurons were isolated from rat midbrain and cultured as previously described (FASEB J. 2008; 22(7):2488-97). To mimic synucleinopathy, cells were injured with conduritol B epoxide (CBE, 20 μM), a covalent inhibitor of α-syn fibrils and GBA1 (SEQ ID NO: 1). This model mimics synucleinopathies. The essential neuropathological features of the disease (e.g., loss of dopaminergic neurons and neurite networks as assessed by staining with tyrosine hydroxylase (TH), a marker of dopaminergic neurons in the nervous system) are reproduced.

[0418] Treatment with test compound (Compound A) - On day 6 of culture, Compound A was added to the cells in DMSO (100%, stock solution). Compound A was dissolved in 100% ethanol (2% ethanol solution) and diluted with medium to the required concentration. Compound A was added to the culture medium 1 hour before CBE and 2 hours before α-syn administration.

[0419] Treatment with CBE: On day 6 of culture, conduritol B epoxide (CBE, 20 μM) was added for 1 h before α-syn injury (to be confirmed and modified).

[0420] Treatment with α-syn: On day 3, human α-syn was incubated at 37°C for 3 days to allow fibril formation (Lin et al.). On day 6, α-syn (250 nM) was directly applied to the cells in the presence of CBE. Injury occurred at 8 days. On day 1, the experiment was continued for another 48 hours in the presence of the test compound.

[0421] Treatment of neurons with CBE and α-syn significantly improved neuronal survival and neurite networks. Compound A administration produced significant neuroprotective effects in the range of 50 nM to 500 nM. At a concentration of 500 nM, Compound A completely prevented the loss of dopaminergic neurons and preserved the intact neurite network (assessed by TH staining).

[0422] Example 41 - GBA1 (SEQ ID NO: 1) Inhibition and Animal Models of Synucleinopathies to Evaluate the Potential of Compounds of Formula 1 to Treat Diseases Associated with Synucleinopathies, Including Gaucher Disease Aged mice (18 months old) were used as a model of age-related neurodegenerative disorders and Parkinson's disease. α-synuclein (α-syn) oligomers / protofibrils (Western blot analysis) were performed. Lesions of the substantia nigra (pars compacta) These animals were administered 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 resulted in mitochondrial and endoplasmic reticulum (ER) stress, impaired autophagy-lysosomal pathway, and impaired mitochondrial function. It mediates toxicity through several intracellular mechanisms, including cytotoxicity (Callizot et al., Plos One. https: / / doi.org / 10.1371 / journal.pone.0215277).

[0423] Evaluation of motor impairment due to synucleinopathy using the Bar test (Figure 3) - 3 weeks after surgery, mice The motor coordination of mice was assessed with the bar test. The principle of this test is based on the ability of mice to cross a horizontal bar connected to a platform (18 mm diameter, 60 cm long). This test requires good forelimb and hindlimb coordination and good balance. Mice are placed on one end of the bar and must reach the platform on the other side of the bar. Motor coordination was investigated after two training sessions (days 1 and 2) prior to the test. The sessions were conducted on the bar. The participants were recorded on a video camera, and the time it took to cross the bar, the number of steps taken, and the number of failed steps taken were measured.

[0424] As shown in Figure 3, mice treated with CBE and α-syn (no compound vs. control) showed a significant increase in BA. The latency to reach the platform was significantly increased in the 1-test. Treatment with Compound B normalized behavior to control levels.

[0425] Tissue collection and immunostaining - At the end of the experiment (28 days after surgery), mice were deeply anesthetized and perfused with cold PBS (3 The brains were then perfused with cold paraformaldehyde (PFA) 4% in PBS (3 min). The brains were dissected and further fixed in PFA 4% overnight at 4°C. They were then placed in 30% sucrose in Tris-phosphate saline (TBS) at 4°C. Using a freezing microtome, 40-μm-thick coronal sections containing the SNpc were cut (4 sections per mouse, 100 mm apart). For immunostaining, free-floating sections were fixed in 0.25% In TBS supplemented with bovine serum albumin, 0.3% Triton X-100, and 1% goat serum, for 1 hour at room temperature This incubation blocks nonspecific binding sites and permeabilizes the tissue. A selected number of sections per animal are treated with the antibody of choice for 4 h. Incubated at 4°C for 24 hours or at room temperature for 2 hours: TH: chicken polyclonal antibody Anti-tyrosine hydroxylase (1 / 1000); α-syn: rabbit polyclonal antibody anti-α-synuclein (1 / 200); IBA1: goat polyclonal antibody anti-IBA1 (1 / 200). These antibodies were purified using Alexa Fluor 488 anti-rabbit IgG and Alexa Fluor 568 anti-chicken IgG in 0.25% donkey serum albumin. The cells were revealed with 1 / 500 dilution in TBS containing 0.3% Triton X-100 and 1% goat serum. Images were acquired with a confocal laser scanning microscope.

[0426] The following results were evaluated: α-syn aggregation in the SNpc (Figure 4) - Treatment of α-syn with CBE (no compound vs. control) significantly increased α-syn aggregation (control vs. no compound). Treatment with the sEH inhibitor Compound B significantly decreased α-syn aggregation.

[0427] Number of TH-positive cells in the SNpc (Fig. 5) - α-syn / CBE-induced synuclein aggregation was significantly increased in the SNpc. This loss was associated with a significant loss of TH(+) neurons in the thyroid gland, and was accompanied by strong neuroinflammation (Ib1+ , Figure 6).

[0428] Administration of Compound A or Compound B inhibited neurodegeneration and suppressed neuronal cell death (Figure 5). Furthermore, a significant decrease in Iba1+ microglial cells was observed, demonstrating this effect on neuroinflammation. The positive effect of the molecule was shown in Figure 6.

[0429] Administration of Compound A or Compound B demonstrated potent protection of dopaminergic neurons (survival and α-syn aggregation) and completely prevented neuroinflammation. Furthermore, complete prevention of motor deficits was observed.

[0430] Example 426 - PINK1 (SEQ ID NO: 2)-null / α-syn zebrafish synuclease Using a Parkinson's disease model, we identified PINK1 (SEQ ID NO: 2) (PTEN-induced PINK1) associated with familial Parkinson's disease. To evaluate the potential of compounds of formula 1 for treating diseases associated with mutations in a putative phosphodiesterase kinase (PKI) Mitochondrial quality control is important in neurological diseases, and mutations in PINK result in impaired autophagy and mitophagy, contributing to aging-related diseases such as PD. PINK1 (SEQ ID NO: 2) mutations cause autosomal recessive PD, and certain clinical features are more common in patients with PINK1 (SEQ ID NO: 2) mutations.

[0431] The genetic method by Solnica-Kreze et al., Development. 1996 Dec; 123:37-46. PMID:9007227, was employed to generate PINK-null zebrafish. Adult male zebrafish were treated with 5 mM ENU chemical mutagen to induce random mutations, and then screened for cognitive and motor deficits. Genotyping was performed using fin clips to identify PINK1+ / - mutants. ( Gene ID: 30214). F1 mutants carrying the PINK1+ / - mutation were inbreeded, and the resulting F2 embryos (hereafter referred to as PINK1- / -) were used for research purposes. α-synuclein was administered to PINK-null zebrafish larvae by intracranial microinjection. 7 days after α-synuclein challenge Synucleinopathy-induced behavioral changes were later monitored by assessing swimming speed (bradykinesia - Figure 7) and cognitive decline (predator avoidance test - Figure 8). Total swimming speed was derived from video recordings and data analysis, including the time and distance traveled by the zebrafish.

[0432] PINK1- / - mutant fish showed a significant decrease in swimming speed (P<0.0001) compared to wild-type (WT), confirming the presence of bradykinesia (Figure 7 - wild-type vs. no compound). The group treated with sEH inhibitor (Compound A of Formula I) showed a significant increase in swimming speed, indicating that bradykinesia was ameliorated. was suggested. In memory tests, 100% of wild-type zebrafish showed spatial memory for predator avoidance compared with the PINK1- / - α-syn model group. Memory was restored to the level of the fish (Figure 8).

[0433] Example 43 - The zebrafish model of MPTP-induced parkinsonism was used to evaluate the potential of compounds of Formula I to treat deficits in motor activity and rescue neuronal damage.

[0434] This study was performed according to the protocol published by Bretaud et al. 2004 Nov-Dec; 26(6), 857-64. For MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced parkinsonism, adult zebrafish were injected with 3 ul of 60 ug / g MPTP intramuscularly along the lateralis muscle. Fish were sedated with ice-cold water to limit movement during the injection. The rod was held at a 40° angle to the injection site, and each dose of MPTP was administered intramuscularly. The test compounds were mixed with food pellets and administered orally. The fish were conditioned to consume three pellets per day. Test compound A was evaluated in both preventive and therapeutic modes (5 days after MPTP administration). MPTP-induced behavioral changes and neuronal damage were assessed by: i) assessing the distance traveled to track locomotor activity; ii) The injury was monitored by iii) peripheral nerve damage assessed by convulsive responses, and iv) assessment of brain neuronal damage assessed by brain pathology.

[0435] Locomotor activity: The observation tank was divided into four zones, each 6.25 cm long, with three equal intervals. Four vertical lines were drawn on the surface of the fish. The number of lines crossed by adult zebrafish within 5 minutes was counted. The animals were allowed to acclimate in the measurement tank for 30 minutes before administration or induction. Time intervals were set.

[0436] The convulsion response was measured as described by Lisse TS et al. (1). The fish were placed on a plastic foil and the distal tail fin was stimulated with an insect pin until a convulsion was observed. The number of stimulations required to induce a convulsion was recorded. Convulsion responses were recorded once each evening for 8 days, approximately 4-6 hours after the morning administration.

[0437] Brain pathology: Zebrafish from each group were euthanized by rapid chilling immediately before sample collection. All fish were used as they were and fixed in 10% NBF solution for 24 hours as primary fixative, followed by Davidson's fixative for 12 hours. Furthermore, the tissue was collected from the Zebrafish International Resource Center (ZIRC). The decalcification was performed according to the protocol described in the manual. Dehydrate the tissue using trichloroacetic acid (TCA), followed by increasing concentrations of ethanol, and then chloroform. The tissue was cleared using cereals containing paraffin wax and xylene, and then infiltrated with ceresin-containing paraffin wax and embedded in a histological mold.

[0438] Compared with the control group, animals administered MPTP showed a significant decrease (p<0.0001) in motor activity, which gradually worsened over the treatment period (Figure 9). The group treated with the sEH inhibitor (Compound A of Formula I) showed rescue of MPTP-induced abnormal motor activity, behaving similarly to the control group. Administration of Compound A 5 days after the daily MPTP challenge rescued the animals' motor dysfunction, as shown in Figure 9.

[0439] Nerve damage (convulsive response) - fine dermal fibers projecting along the bony striae in the distal fin region and The selective loss of axons resulted in a significant temporal change in tactile responses, as demonstrated by the fact that MPTP-treated animals required significantly more pin stimulation of the distal fin to elicit a convulsive response. Compound A administration (administered as a preventative or therapeutic model) significantly reduced the convulsive response induced by MPTP administration. The results showed that the administration of acetaminophen effectively rescued peripheral nerve damage caused by acetaminophen (Fig. 10).

[0440] Dopamine neurons. The MPTP-treated group showed a significant decrease in the number of TH+ cells. Compound A treatment The group showed a dose-dependent rescue activity by preventing the decrease of TH+ cells (Figure 11 Compound A administered in the treatment mode (day 5-treatment) also showed protection from neuronal degeneration. .

[0441] A therapeutically effective amount of a compound of formula I may be administered in a single dose or in multiple doses at regular time intervals. The dose can be administered repeatedly several times. As mentioned above, many factors can be considered by the attending physician in selecting the dosage, including, but not limited to, the potency and duration of action of the compound used, the nature and severity of the disease being treated, and the gender, age, weight, general health and individual responsiveness of the subject being treated, as well as other relevant circumstances. The therapeutic dose for humans can be estimated based on data from animal studies, taking into account factors such as body surface area, pharmacokinetic profile, and related parameters. To estimate the human equivalent dose, allometric scaling and related methodologies can be used, as described in the literature [e.g., J Basic Clin Pharm. March 2016-May 2016; 7(2): 27-31].

[0442] Therapeutically effective compositions of the present disclosure for the treatment of a neurodegenerative disease in a subject may comprise a compound of Formula I administered at a dose of about 0.5 mg / day to about 3000 mg / day.

[0443] GBA mutations have been reported to be associated with Parkinson's disease and Gaucher disease. 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 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

[0444] Mutations in the human kinase PINK1 are associated with Parkinson's disease (PD). See, for example, "PINK1 structure and mechanism of Parkinson's disease-associated mutations," https: / / doi.org / 10.7554 / eLife.29985; "PINK1 Parkinson's disease mutations result in reduced complex I activity and impaired synaptic function." EMBO Mol Med. 2009 May;1(2):99-111. doi: 10.1002 / emmm.200900006.pmid: 20049710; pmcid: pmc3378121.

[0445] Sequence Listing XML Incorporation Statement The sequence listing XML provided herein is incorporated by reference into this application. The previous one was NeuroPn 1.xml, created on September 29, 2023, and is 6 kilobytes in size. <110> NeuroPN Therapeutics, Inc. <120> Piperidine urea derivatives for the treatment of neurodegenerative diseases <130> 0039486.0000020 <140> Unknown <141> *** <150> U.S. Application No. <151> 09 / 29 / 2023 <160> 1 <170> WIPO Sequence <210> 1 <211> 536 <212> PRT <213> Homo sapiens <221> CDS <222> 1-586 <400> 1 MEFSSPSREECPKPLSRVSIMAGSLTGLLLLQAVSWASGARPCIPKSFGYSSVVCVCNATYCDSFDPPTFPALGTFSRYESTRSGRRMELSMGPIQANHTGTGLLLTLQPEQKFQKVKGFGGAMTDAAALNILALSPPAQNLLLKSYFSEEGIGYNIIRVPMASCDFSIRTYTYADTPDDFQLHNFSLPEEDTKLKIPLIHRALQLAQRPVSLLASPWTSPTWLKTNGAVNGKGSLKGQPGDIYHQTWARYFVKFLDAYAEHKLQFWAVTAENEPSAGLLSGYPFQCLGFTPEHQRDFIARDLGPTLANSTHHNVRLLMLDDQRLLLPHWAKVVLTDPEAAKYVHGIAVHWYLDFLAPAKATLGETHRLFPNTMLFASEACVGSKFWEQSVRLGSWDRGMQYSHSIITNLLYHVVGWTDWNLALNPEGGPNWVRNFVDSPIIVDITKDTFYKQPMFYHLGHFSKFIPEGSQRVGLVASQKNDLDAVALMHPDGSAVVVVLNRSSKDVPLTIKDPAVGFLETISPGYSIHTYLWRRQ <210> 2 <211> 581 <212> PRT <213> Homo sapiens <221> CDS <222> 1-581 <400> 2 MAVRQALGRGLQLGRALLLRFTGKPGRAYGLGRPGPAAGCVRGERPGWAAGPGAEPRRVGLGLPNRLRFFRQSVAGLAARLQRQFVVRAWGCAGPCGRAVFLAFGLGLGLIEEKQAESRRAVSACQEIQAIFTQKSKPGPDPLDTRRLQGFRLEEYLIGQSIGKGCSAAVYEATMPTLPQNLEVTKSTGLLPGRGPGTSAPGEGQERAPGAPAFPLAIKMMWNISAGSSSEAILNTMSQELVPASRVALAGEYGAVTYRKSKRGPKQLAPHPNIIRVLRAFTSSVPLLPGALVDYPDVLPSRLHPEGLGHGRTLFLVMKNYPCTLRQYLCVNTPSPRLAAMMLLQLLEGVDHLVQQGIAHRDLKSDNILVELDPDGCPWLVIADFGCCLADESIGLQLPFSSWYVDRGGNGCLMAPEVSTARPGPRAVIDYSKADAWAVGAIAYEIFGLVNPFYGQGKAHLESRSYQEAQLPALPESVPPDVRQLVRALLQREASKRPSARVAANVLHLSLWGEHILALKNLKLDKMVGWLLQQSAATLLANRLTEKCCVETKMKMLFLANLECETLCQAALLLCSWRAAL <210> 3 <211> 579 <212> PRT <213> Homo sapiens <221> CDS <222> 1-579 <400> 3 MVQYELWAALPGASGVALACCFVAAAVALRWSGRRTARGAVVRARQRQRAGLENMDRAAQRFRLQNPDLDSEALLALPLP QLVQKLHSRELAPEAVLFTYVGKAWEVNKGTNCVTSYLADCETQLSQAPRQGLLYGVPVSLKECFTYKGQDSTLGLSLNEGVPAECDSVVVHVLKLQGAVPFVHTNVPQSMFSYDCSNPLFGQTVNPWKSSKSPGGSSGGEGALIGSGGSPLGLGTDIGGSIRFPSSFCGICGLKPTGNRLSKSGLKGCVYGQEAVRLSVGPMARDVESLALCLRALLCEDMFRLDPTVPPLPFREEVYTSSQPLRVGYYETDNYTMPSPAMRRAVLETKQSLEAAGHTLVPFLPSNIPHALETLSTGGLFSDGGHTFLQNFKGDFVDPCLGDLVSILKLPQWLKGLLAFLVKPLLPRLSAFLSNMKSRSAGKLWELQHEIEVYRKTVIAQWRALDLDVVLTPMLAPALDLNAPGRATGAVSYTMLYNCLDFPAGVVPVTTVTAEDEAQMEHYRGYFGDIWDKMLQKGMKKSVGLPVAVQCVALPWQEELCLRFMREVERLMTPEKQSS

Claims

1. 1. A method for treating a neurodegenerative disease or a disease associated with a synucleinopathy, excluding Parkinson's disease, comprising: Therapeutic use of at least one compound of formula I, its stereoisomers or pharmaceutically acceptable salts administering an effective amount to a subject. 【Chemistry 1】 R １ is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １ When is aryl, heteroaryl, or heterocycloalkyl, R １ is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO ２ NHR ２ , or COR ３ is replaced by; R ２ is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R ３ is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , S.O. 2 R 5 , or COR 3 selected from the group consisting of: R ５ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R ６ is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X is O, (CH 2 ) p, NH, where p is 0 to 2; Y １ -Y ２ is CH-CH ２ , CH—O or C═CH, but Y １ -Y ２ is CH—O, X is selected from O or NH, or R １ is not hydrogen; and Y 3 is selected from H or Me.

2. 1. A method for treating a neurodegenerative disease or a disease associated with a synucleinopathy, excluding Parkinson's disease, comprising: Therapeutic use of at least one compound of formula I, its stereoisomers or pharmaceutically acceptable salts administering an effective amount to a subject. 【Chemistry 2】 R １ is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １ When is aryl, heteroaryl, or heterocycloalkyl, R １ is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO ２ NHR ２ , or COR ３ is replaced by; R ２ is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R ３ is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , S.O. 2 R 5 , or COR 3 selected from the group consisting of: R ５ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R ６ is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X is O, (CH 2 ) p, NH, where p is 0 to 2, but when p=0, Y 1 -Y 2 is CH-CH 2 Or R instead of CH-O 1 is not aryl; Y １ -Y ２ is CH-CH ２ , CH—O or °C═CH, １ -Y ２ is CH—O, X is selected from O or NH, and R １ is not hydrogen or alkyl; and Y 3 is selected from H or Me.

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

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

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

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

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

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

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

10. 2. The method of claim 1, wherein the compound of formula 1 is one or more of the following compounds, stereoisomers or pharmaceutically acceptable salts thereof: 【Chemistry 12】

11. Compounds are measured at a concentration (IC 50 ) inhibits soluble epoxide hydrolase at less than 10 μM, Item 1. The method according to item 1.

12. Compounds are measured at a concentration (IC 50 ) inhibits soluble epoxide hydrolase at less than 100 nM, Item 1. The method according to item 1.

13. Compounds are measured at a concentration (IC 50 ) inhibits soluble epoxide hydrolase at less than 100 nM and Inhibition of amidohydrolase (IC 50 , which is at least 10 times more selective than (FAAH (SEQ ID NO: 3)). The method of claim 1 , wherein the method is selective.

14. Compounds are measured at a concentration (IC 50 ) inhibits soluble epoxide hydrolase at concentrations below 100 nM (IC 50 2. The method of claim 1, wherein said compound inhibits fatty acid amide hydrolase (FAAH (SEQ ID NO: 3)) at a level greater than 1000 nM.

15. 2. The method of claim 1, wherein the disease is selected from Gaucher disease, dementia with Lewy bodies, and Alzheimer's disease.

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

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

18. The compound inhibits neuronal loss, neuroinflammation, α-synchrony aggregation, and / or Lewy small intestine.

10. The method of claim 1, wherein the method is administered to treat one or more of the following:

19. 10. The method of claim 1, wherein the compound is administered to treat locomotor activity disorders and other movement and non-movement related conditions.

20. 10. The method of claim 1, wherein the compound is administered to treat cognitive impairment or dementia.

21. 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 1. A method of treating Parkinson's disease, comprising: Therapeutic use of at least one compound of formula I, its stereoisomers or pharmaceutically acceptable salts Administering an effective amount to a subject: 【Chemistry 13】 R １ is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １ When is aryl, heteroaryl, or heterocycloalkyl, R １ is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO ２ NHR ２ , or COR ３ is replaced by; R ２ is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R ３ is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , S.O. 2 R 5 , or COR 3 selected from the group consisting of: R ５ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R ６ is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X is O, (CH 2 ) p, NH, where p is 0 to 2; Y １ -Y ２ is CH-CH ２ , CH—O or C═CH, but Y １ -Y ２ is CH—O, X is selected from O or NH, or R １ is not hydrogen; and Y 3 is selected from H or Me.

22. 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 1. A method of treating Parkinson's disease, comprising: Therapeutic use of at least one compound of formula I, its stereoisomers or pharmaceutically acceptable salts Administering an effective amount to a subject: 【Chemistry 14】 R １ is selected from the group consisting of alkyl, hydrogen, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １ When is aryl, heteroaryl, or heterocycloalkyl, R １ is unsubstituted or is selected from alkyl, hydroxy, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, amine, SO ２ NHR ２ , or COR ３ is replaced by; R ２ is selected from the group consisting of hydrogen, alkyl, haloalkyl, or cycloalkyl; R ３ is selected from the group consisting of alkyl, cycloalkyl, hydroxy, amine, alkylamine, or alkoxy; R 4 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, amine, alkoxy , S.O. 2 R 5 , or COR 3 selected from the group consisting of: R ５ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, or amine; R ６ is selected from the group consisting of alkyl, cycloalkyl, aryl, or heteroaryl; X is O, (CH 2 ) p, NH, where p is 0 to 2; Y １ -Y ２ is CH-CH ２ , CH—O or C═CH, but Y １ -Y ２ is CH—O, X is selected from O or NH, or R １ is not hydrogen; and Y 3 is selected from H or Me.

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

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

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

26. Gaucher disease, Parkinson's disease with dementia (PDD), familial Parkinson's disease associated with mutations in PINK-1 (SEQ ID NO: 2), or associated with mutations in the glucocerebrosidase (GBA) gene 20. A soluble epoxide hydrolase inhibitor for use in the treatment of familial Parkinson's disease.

Images