Novel VDAC1 inhibitors

Abstract

The present invention relates to a compound of general formula I, wherein R1-R4, n and m are as defined in claim (1). Such compound of formula I are inhibitors of oligomerization of VDAC1 and is suitable for use in a method for treating diabetes or pre-diabetes in a subject in need thereof.

Description

[0001]10294PC00 NOVEL VDAC1 INHIBITORSField of the Invention The present invention relates to compounds of formula I, which are inhibitorsof oligomerization of Voltage-Dependent Anion Channel 1 (VDAC1) (usedinterchangeable with VDAC1 modulation or VDAC1 oligomerization inhibitors orVDAC1 inhibitors or inhibitors of VDAC1) for treating i.a. prediabetes and diabetes,prevent diabetes disease progression (deterioration) and prevent progression of prediabetes to diabetes. Background Art Diabetes is a severe metabolic disease that shortens life expectancy through cardiovascular and chronic kidney diseases, as well as causing dementia, stroke, peripheral nerve disease and blindness. Approximately 12% of global health costs are spent on managing diabetes. There are two hallmarks of diabetes with underlyingpathology being either the lack of the pancreatic islets to produce sufficient insulinresponse to elevated blood glucose or the cells of the body not responding properly tothe insulin produced (insulin resistance). There are two main types of diabetes: Type1 Diabetes Mellitus (T1D) and Type 2 Diabetes Mellitus (T2D). T1D is one of the most common multifactorial endocrine and metabolic diseases in childhood resulting in persistent hyperglycemia, due to autoimmune destruction of the insulin-producing beta cells in the pancreatic islets. T1D requires life-long insulin therapy. Several studies have reported that residual beta-cells (β-cells) remain in the pancreatic isletsof T1D patients (Keenan HA, et al. Diabetes. 2010;59(11):2846-53). In fact, up to 40-50% of beta-cells may escape destruction (Elgamal RM et al 2023 Diabetes72(11):1719-1728), but insulin secretion is insufficient to maintain normal bloodglucose regulation (Oram RM et al 2015 Diabetes Care 38(2):323-8). In vitro cultureof islets from T1D subjects at physiological glucose concentration has shown time-dependent improvement of glucose-stimulated insulin secretion (Lupi R, et al. 2004.Diabetes / metabolism research and reviews, 520(3):246-251; Krogvold L et al.2015.Diabetes 64:2506-2512; Brissova M. et al. 2018 Cell Rep. 22:2667-2676). Theseresults suggest that the residual beta-cells are dysfunctional in vivo but can resume regulated insulin secretion after extraction from the harmful in vivo environment. 10294PC00 Type 2 Diabetes is a worldwide health pandemic and currently more than 400million people suffer from the disease. In addition, more than 320 million people are pre-dispositioned (pre-diabetes) to develop T2D adding an even greater burden on the health system and society (Zimmet P and Alberti KG.2016. Nature Rev Endo 10:616- 622). By 2045 almost 800 million people are predicted to have diabetes with the vast majority being T2D (IDF Atlas 2022; https: / / diabetesatlas.org / 2022-reports / ). Type 2 Diabetes shows a chronic, progressive natural course, during whichblood glucose concentrations rise gradually over time (Kahn SE.2001. J ClinEndocrinol Metabol 86: 4047– 4058). None of the on the market therapeutics orcombinations thereof can prevent this deterioration in disease control (Nathan D et al.2022, NEJM; 387: 1063-1074). Although the pathophysiology of T2D is complex,declines in insulin secretion and peripheral insulin resistance are the principal clinicalproblems (DeFronzo RA et al. 2013. Diabetes Care 2013; 36(Suppl 2): S127– S138).Current therapeutics like metformin, sulfonylureas, thiazolidinedione, α- glucosidase inhibitors, meglitinides, DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1receptor agonists (Dalle S. et al 2023; Front Endocrinol (Lausanne) 14, 1076343) aredisease controlling for a period but not disease modifying. This often leads to clinical insufficient regimens and elevated blood glucose treatment failures which over time results in chronic complications and premature mortality (Brown JB et al.2004. Diabetes Care 27:1535–1540; Matthews D et al.2020. Diabetes Ther 11:2465–2476; ElSayed NA et al.2023. Diabetes Care 46(Suppl.1):S140–S157). Consequently, there is a huge unmet medical need for new therapeutics with the benefits of sustained and continuous disease control (disease modifying). Normoglycemia is maintained as long as insulin resistance is compensated by increased insulin secretion. Insulin resistance (IR) is described as a defective physiological response to insulin stimulation of targeted cells, primarily those in the liver, muscles, and various types of adipose tissue as well as endothelial cells. Insulin resistance increases blood glucose levels, leading to a compensatory increase in β-cell insulin secretion that, in turn, results in a hyperinsulinemia state within the whole body. The underlying cause of insulin resistance is not clear, but a family history of T2D, being overweight, and being inactive raise the risk. However, obesity is not the single cause of insulin resistance. Other factors include oxidative stress, glucotoxicity, inflammation, mitochondrial dysfunction, polycystic ovary syndrome (PCOS) and lipodystrophy. Effective treatment of insulin resistance represents a huge unmet 10294PC00 medical need despite some effects being reported using metformin, GLP-1 receptor agonists, and peroxisome proliferator activated receptor (PPAR) agonists (Dalle, S et al idem). Noncommunicable chronic diseases like T2D are complex and multifactorial. Mitochondria are an integrative platform that supports indispensable cell functions, including metabolism and cellular signaling. Several noncommunicable chronic diseases have in common the early development of marked mitochondrial dysfunction (Diaz-Vegas A et al.2020. Endocrine Reviews, 41(3)). In healthy cells, the outer mitochondrial membrane protein VDAC, a multi- functional protein, is positioned at the crossroad of metabolic and survival pathways, acting as master gatekeeper regulating the flux of metabolites and ions between mitochondria and the cytosol. Of the three VDAC isoforms, VDAC1 and VDAC2 mediate ADP / ATP exchange and calcium flux in mitochondria, while VDAC3 function is less clear (Shoshan-Barmatz V et al.2010. Molecular aspects of medicine31:227-285; Shoshan-Barmatz V et al. 2020. Biomolecules, 11:1485; Zinghirino F etal.2021. Front Physiol.12:708695). VDAC1 also plays a key role in apoptosis, participating in the release of apoptotic factors from mitochondria and interacting with anti-apoptotic regulators (Shoshan-Barmatz V et al., 2020, ibid; Shoshan-Barmatz et al.,2010, ibid). Under physiological conditions, VDAC1 largely exists in the form of a highly controlled monomer, while mitochondrial calcium overload and oxidative or nitrosative stresscauses it to oligomerize and loose its physiological function leading to diversepathology in several cardiometabolic diseases (Shoshan‐Barmatz V et al. 2020 ibid).VDAC1 oligomerization can be prevented by small molecule VDAC1 modulators (oligomerization inhibitors) such as VBIT-4 (Ben-Hail D et al.2016 J Biol Chem.291(48):24986-25003). VBIT-4 prevents the development of hyperglycemia in db / dbmice, a model of T2D, and shows a unique mode of action with effects outlasting dosing in this disease model (Zhang E et al.2019. Cell Metabolism, 29:64-77).Simultaneously, VBIT-4 markedly improved insulin sensitivity in the db / db micewithout causing weight loss (Zhang et al 2019 ibid). Mitochondrial proteome analysis reveals altered expression of VDACs and multiple other proteins involved in nutrient metabolism, ATP synthesis, cellular defense, glycoprotein folding and mitochondrial DNA stability in rat clonal pancreatic β-cells exposed to high glucose (Ahmed M et al.2010. Islets, 2:283-292). Under 10294PC00 glucotoxic conditions, the expression of VDAC1 is upregulated while that of VDAC2 is downregulated. In islets of human T2D organ donors, VDAC1 mRNA and proteinare upregulated, while VDAC2 levels are downregulated (Zhang et al. 2019 ibid).VDAC1 is mistargeted to the plasma membrane in the beta cells of T2D organ donors and such translocation is reproduced when islets from non-diabetic organ donors were cultured under glucotoxic conditions. The plasma membrane expression of VDAC1 resulted in loss of ATP, a coupling factor essential for glucose-stimulated insulin secretion (GSIS). Remarkably, prevention of the loss of ATP by acute exposure to VBIT-4, restored GSIS. It is recognized that the opening of the inner mitochondrial membrane permeability transition pore (mPTP), whose opening occurs when VDAC1 is oligomerized, inhibits the flow in the electron transport chain, resulting in increased reactive oxygen species (ROS) formation (Yang Y et al.2022 Mitochondrion.64:103‐ 11). The generation of ROS is increased by high glucose, especially the superoxideanion, formed both in mitochondria and cytosol (Sangwung P et al. 2020.Endocrinology 161(4):1–10). The insulin resistance of skeletal muscle occurring in T2D has been linked to mPTP opening, independent of classical insulin signaling (Taddeo EP, et al.2014 Mol Metab.3:124‐34). Both in insulin resistance of target tissues (Bai J. et al 2017 PNAS 114(46):12196-12201) and in beta cell dysfunction in a T2D model (Hu H. et al 2022 FASEB J.36:e22266), the increased mitochondrial ROS generation leads to mitochondrial DNA (mtDNA) oxidation and fragmentation. The oxidized mtDNA binds to VDAC1, causing its oligomerization and opening of the mPTP. The consequent leakage of double-stranded mtDNA fragments into the cytosol thepromoting inflammasome assembly triggered by binding of NLRP3 to VDAC1oligomers on the mitochondrial surface (Baik S.H. et al 2023 Science Immunol. 8(84), eade7652). The mtDNA leakage activates the cGMP‐AMP synthase (cGAS), inturn inducing stimulator of interferon genes (STING) activation (Kim M. et al 2019 Science 366, 1531-1536; Xiang H. et al 2022 Immunity 55, 1370-1385 e1378). The inflammatory cascade is blunted by the VDAC1 inhibitor VBIT-4 (Kim et al idem; Xiang et al idem). To date VDAC1 oligomerization has been linked to the pathology of autoimmune diseases such as systemic lupus erythematosus (Kim et al idem) and inflammatory bowel disease (Verma A. et al 2022 Mol Ther 30, 726-744). In contrast to VDAC1 alterations in tissue sections of human specimens and mouse models of 10294PC00 T2D (Zhang et al idem) and Alzheimer’s disease (Verma A et al 2022 TranslNeurodegener. 202211(1):58.), such direct evidence is lacking in T1D. However,pro-inflammatory cytokines participating in the innate immunity of beta cell demise in T1D cause beta cell endoplasmic reticulum (ER) stress (Clark LM et al 2017 Sci Rep 7, 5611.), and such stress causes mtDNA leakage in clonal human beta cells (WikS et al 2022. Front. Endocrinol. 13:991632.).In summary, there is ample evidence linking both defective insulin secretion as well as insulin resistance in liver, adipose tissue, endothelial cells and muscle to mitochondrial dysfunction and altered VDAC1 function. By keeping VDAC1 in itsmitochondrial membrane location and in its highly controlled and physiologicalmonomeric form, normal ATP production and cell function is preserved. Therefore, VDAC1 modulation (inhibition of VDAC1 oligomerization) represents an attractiveapproach for the prevention and sustained control of metabolic diseases such as T2D.Summary of the invention In a first aspect the present invention relates to a compound of general formula(I), wherein m is 0-2, wherein when m is 0 the R1group is linked directly to the carbon atom of the morpholino ring, n is 0-2, wherein when n is 0 the R4group is linked directly to the carbon atom having the R3 group linked thereto, R1is selected from the group consisting of 10294PC00 a) phenyl optionally substituted with one or more groups selected from SO2CH3, CN, NH2, NO2, halogen, OH, C1-3alkyl optionally substituted with a halogen, OC1-6 alkyl optionally substituted with a halogen; b) furyl optionally substituted with one or more groups selected from halogen, OC1-3alkyl, OC1-3alkylene-OC1-3alkyl, C1-3alkyl, CN; c) pyridyl optionally substituted with one or more groups selected from halogen, OC1-3 alkyl, OC1-3 alkylene-OC1-3 alkyl, C1-3 alkyl, CN; d) pyrazolyl substituted with one or more groups selected from halogen, C1-3alkyl optionally substituted with a halogen; e) thiazolyl optionally substituted with one or more groups selected from C1-3 alkyl; f) pyrazinyl substituted with one or more groups selected from C1-3alkyl, OC1-6 alkyl; g) oxadiazolyl substituted with one or more groups selected from isopropyl, cyclopropyl, C1-3alkyl and (CH2)0-1-phenyl substituted with one or more groups selected from halogen and C1-3 alkyl; h) triazolyl substituted with one or more groups selected from C1-3 alkyl, cyclopropyl and phenyl; i) quinoxalinyl substituted with one or more groups selected from C1-3alkyl; j) tetrazolyl substituted with one or more groups selected from C1-3 alkyl and phenyl optionally substituted with a C1-3 alkyl; k) indazolyl substituted with one or more groups selected from C1-3alkyl; l) oxazolyl substituted with one or more groups selected from C1-3 alkyl and phenyl optionally substituted with a O C1-6 alkyl; m) 4-oxo-quinazolinyl substituted with one or more groups selected from C1-3alkyl; 10294PC00 n) isoxazolyl substituted with one or more groups selected from halogen, C1-3alkyl, cyclopropyl and phenyl optionally substituted with a group selected from halogen and OC1-6 alkyl; o) imidazolyl substituted with one or more groups selected from C1-3 alkyl; p) quinolyl substituted with one or more groups selected from C1-3alkyl; q) thiadiazolyl substituted with one or more groups selected from C1-3 alkyl; r) pyridazinyl substituted with one or more groups selected from OC1-3 alkyl; s) benzoxazolyl substituted with one or more groups selected from C1-3alkyl; t) imidazole[1,2-a]pyrimidinyl substituted with one or more groups selectedfrom C1-3 alkyl; u) 6-oxo-pyridinyl; v) C1-6alkyl; w) C1-3 alkyl substituted with one group selected from CH3SO2NH and CH3OCH2CH2O; x) CONR5R6where R5and R6are independently selected from hydrogen and C1-3 alkyl; y) pyrimidinyl substituted with one or more groups selected from NR7R8where R7and R8are independently selected from hydrogen and C1-3alkyl; and z) isopropyl or isobutyl, R2is selected from the group consisting of hydrogen and methyl, R3is selected from the group consisting of OH, CONH2 and C1-3 alkyl-OH; R4is selected from the group consisting of a) phenyl optionally substituted with one or more groups selected from SO2CH3, CN, NH2, NO2, halogen, OH, C1-3alkyl optionally substituted with a halogen, OC1-6alkyl optionally substituted with a halogen; b) furyl optionally substituted with one or more groups selected from halogen,OC1-3 alkyl, OC1-3 alkylene-OC1-3 alkyl, C1-3 alkyl, CN; 10294PC00 c) pyridyl optionally substituted with one or more groups selected from halogen, OC1-3alkyl, OC1-3alkylene-OC1-3alkyl, C1-3alkyl, CN; d) pyrazolyl substituted with one or more groups selected from halogen, C1-3 alkyl optionally substituted with a halogen; e) thiazolyl optionally substituted with one or more groups selected from C1-3alkyl; f) pyrazinyl substituted with one or more groups selected from C1-3 alkyl, OC1-6alkyl; g) oxadiazolyl substituted with one or more groups selected from C1-3alkyl,isopropyl, cyclopropyl, and (CH2)0-1-phenyl substituted with one or more groupsselected from halogen and C1-3alkyl; h) triazolyl substituted with one or more groups selected from C1-3alkyl, cyclopropyl and phenyl; i) quinoxalinyl substituted with one or more groups selected from C1-3alkyl; j) tetrazolyl substituted with one or more groups selected from C1-3alkyl and phenyl optionally substituted with a C1-3 alkyl; k) indazolyl substituted with one or more groups selected from C1-3 alkyl; l) oxazolyl substituted with one or more groups selected from C1-3alkyl and phenyl optionally substituted with a OC1-6alkyl; m) 4-oxo-quinazolinyl substituted with one or more groups selected from C1-3 alkyl; n) isoxazolyl substituted with one or more groups selected from halogen, C1-3alkyl, cyclopropyl and phenyl optionally substituted with a group selected from halogen and OC1-6 alkyl; o) imidazolyl substituted with one or more groups selected from C1-3alkyl; p) quinolyl substituted with one or more groups selected from C1-3 alkyl; 10294PC00 q) thiadiazolyl substituted with one or more groups selected from C1-3alkyl; r) pyridazinyl substituted with one or more groups selected from OC1-3alkyl; s) benzoxazolyl substituted with one or more groups selected from C1-3 alkyl; t) imidazole[1,2-a]pyrimidinyl substituted with one or more groups selected from C1-3alkyl; u) 6-oxo-pyridinyl; v) C1-6 alkyl; w) C1-3alkyl substituted with one group selected from CH3SO2NH and CH3OCH2CH2O; x) CONR5aR6awhere R5aand R6aare independently selected from hydrogen and C1-3alkyl, y) pyrimidinyl substituted with one or more groups selected from NR7aR8awhere R7aand R8aare independently selected from hydrogen and C1-3 alkyl; and z) isopropyl or isobutyl; or a pharmaceutically acceptable salt thereof. In a second aspect the present invention relates to a compound of generalformula (I), wherein m is 0-2, wherein when m is 0 the R1group is linked directly to the carbon atom of the morpholino ring, n is 0-2, wherein when n is 0 the R4group is linked directly to the carbon atom having the R3group linked thereto, R1is selected from the group consisting of 10294PC00 a) phenyl optionally substituted with one or more groups selected from halogen, OH, C1-3alkyl optionally substituted with a halogen, OC1-6alkyl optionally substituted with a halogen; b) furyl optionally substituted with one or more groups selected from halogen, OC1-3alkyl, OC1-3alkylene-OC1-3alkyl, C1-3alkyl, CN; c) pyridyl optionally substituted with one or more groups selected from halogen, OC1-3 alkyl, OC1-3 alkylene-OC1-3 alkyl, C1-3 alkyl, CN; d) pyrazolyl substituted with one or more groups selected from halogen, C1-3alkyl optionally substituted with a halogen; e) thiazolyl optionally substituted with one or more groups selected from C1-3 alkyl; f) pyrazinyl substituted with one or more groups selected from C1-3alkyl, OC1-6 alkyl; g) oxadiazolyl substituted with one or more groups selected from C1-3 alkyl and (CH2)0-1-phenyl substituted with one or more groups selected from halogen and C1-3 alkyl; h) triazolyl substituted with one or more groups selected from C1-3 alkyl, cyclopropyl and phenyl; i) quinoxalinyl substituted with one or more groups selected from C1-3alkyl; j) tetrazolyl substituted with one or more groups selected from C1-3 alkyl and phenyl optionally substituted with a C1-3 alkyl; k) indazolyl substituted with one or more groups selected from C1-3alkyl; l) oxazolyl substituted with one or more groups selected from C1-3 alkyl and phenyl optionally substituted with a OC1-6 alkyl; m) 4-oxo-quinazolinyl substituted with one or more groups selected from C1-3alkyl; 10294PC00 n) isoxazolyl substituted with one or more groups selected from halogen, C1-3alkyl, cyclopropyl and phenyl optionally substituted with a group selected from halogen and OC1-6 alkyl; o) imidazolyl substituted with one or more groups selected from C1-3 alkyl; p) quinolyl substituted with one or more groups selected from C1-3alkyl; q) thiadiazolyl substituted with one or more groups selected from C1-3 alkyl;r) pyridazinyl substituted with one or more groups selected from OC1-3 alkyl; s) benzoxazolyl substituted with one or more groups selected from C1-3alkyl; t) imidazole[1,2-a]pyrimidinyl substituted with one or more groups selected from C1-3 alkyl; u) 6-oxo-pyridinyl; v) C1-6 alkyl, andx) CONR5R6where R5and R6are independently selected from hydrogen and C1-3 alkyl, R2is selected from the group consisting of hydrogen and methyl, R3is selected from the group consisting of OH, CONH2 and C1-3 alkyl-OH; R4is selected from the group consisting of a) phenyl optionally substituted with one or more groups selected from halogen, OH, C1-3 alkyl optionally substituted with a halogen, OC1-6 alkyl optionally substituted with a halogen; b) furyl optionally substituted with one or more groups selected from halogen, OC1-3alkyl, OC1-3alkylene-OC1-3alkyl, C1-3alkyl, CN; c) pyridyl optionally substituted with one or more groups selected from halogen, OC1-3alkyl, OC1-3alkylene-OC1-3alkyl, C1-3alkyl, CN; d) pyrazolyl substituted with one or more groups selected from halogen, C1-3alkyl optionally substituted with a halogen; e) thiazolyl optionally substituted with one or more groups selected from C1-3 alkyl; 10294PC00 f) pyrazinyl substituted with one or more groups selected from C1-3alkyl, OC1-6alkyl; g) oxadiazolyl substituted with one or more groups selected from C1-3 alkyland (CH2)0-1-phenyl substituted with one or more groups selected from halogen and C1-3alkyl; h) triazolyl substituted with one or more groups selected from C1-3 alkyl, cyclopropyl and phenyl; i) quinoxalinyl substituted with one or more groups selected from C1-3alkyl; j) tetrazolyl substituted with one or more groups selected from C1-3 alkyl and phenyl optionally substituted with a C1-3 alkyl; k) indazolyl substituted with one or more groups selected from C1-3alkyl; l) oxazolyl substituted with one or more groups selected from C1-3alkyl and phenyl optionally substituted with a O C1-6 alkyl; m) 4-oxo-quinazolinyl substituted with one or more groups selected from C1-3alkyl; n) isoxazolyl substituted with one or more groups selected from halogen, C1-3 alkyl, cyclopropyl and phenyl optionally substituted with a group selected from halogen and OC1-6alkyl; o) imidazolyl substituted with one or more groups selected from C1-3 alkyl; p) quinolyl substituted with one or more groups selected from C1-3 alkyl; q) thiadiazolyl substituted with one or more groups selected from C1-3 alkyl; r) pyridazinyl substituted with one or more groups selected from OC1-3alkyl; s) benzoxazolyl substituted with one or more groups selected from C1-3 alkyl; 10294PC00 t) imidazole[1,2-a]pyrimidinyl substituted with one or more groups selected from C1-3alkyl; u) 6-oxo-pyridinyl; v) C1-6alkyl; and x) CONR5R6where R5and R6are independently selected from hydrogen and C1-3 alkyl; or a pharmaceutically acceptable salt thereof. In one embodiment n is 1 and m is 0. In another embodiment n is 1 and m is 1. Further embodiments of n are 0, 1 or 2. Further embodiments of m are 0, 1 or 2. Additional embodiments are selected from any combinations of n and m. In a further embodiment R1is selected from phenyl substituted with at leastone selected from halogen and OC1-6 alkyl. In a still further embodiment R1 isselected from phenyl substituted with one or two halogen. In a further embodiment R1is selected from phenyl substituted with one OC1-6 alkyl. In a further embodiment R1is selected from phenyl substituted with two halogens, such as two F. In a still furtherembodiment R1is selected from phenyl substituted with one halogen, such as one Cl.In a further embodiment R1 is selected from phenyl substituted with one OC1-6 alkyl,such as OCH3. In a further embodiment R1 is selected from phenyl substituted with atleast one selected from SO2CH3, CN, NH2 and NO2. In a still further embodiment R1is selected from phenyl substituted with one substituent selected from SO2CH3, CN,NH2 and NO2. Typically, when one substituent is present it is in the para position. Inanother embodiment when one substituent is present it is in the meta position. Typically, if two substituents are present they are in meta and para position. In a further embodiment R1 is pyrimidinyl substituted with at least one, suchas one, selected from NR7R8 where R7 and R8 are independently selected fromhydrogen and C1-3 alkyl. Typically, R7and R8are H and / or CH3. Preferably R1ispyrimidyl substituted with one N(CH3)2.In a still further embodiment R1 is oxadiazolyl substituted with at least oneselected from isopropyl and cyclopropyl. Preferably, R1 is oxadiazolyl substitutedwith one cyclopropyl. In another embodiment R1 is oxadiazolyl substituted with oneisopropyl. In a further embodiment R1 is a C1-3 alkyl substituted with one CH3SO2NH. 10294PC00 In a further embodiment R1 is a C1-3 alkyl substituted with oneCH3OCH2CH2O. In a further embodiment R1 is isopropyl or isobutyl. Typically, when m is 0,R1 is isobutyl. Typically, when m is 1, R1 is isopropyl.In a still further embodiment R1 is unsubstituted furyl.In a further embodiment R1 is unsubstituted pyridyl. In a still furtherembodiment R2is hydrogen. In a further embodiment R3is selected from the group consisting of OH,CONH2 and CH2-OH. Typically, R3 is selected from CH2-OH. In anotherembodiment R3 is selected from OH.In a still further embodiment R4is phenyl optionally substituted with at leastone selected from halogen (such as one Cl, one Br, or two F), C1-3 alkyl optionallysubstituted with a halogen (such as one CH3, or one CF3) OH, OC1-3 alkyl optionallysubstituted with a halogen (such as one OCH3, two OCH3, one OCF3). In a furtherembodiment R4 is phenyl. In a further embodiment R4 is phenyl substituted with atleast one selected from Cl, Br, F, CH3, CF3, OH, OCH3, OCH3, OCF3. Typically,when one substituent is present it is in the para position. In another embodiment when one substituent is present it is in the meta position. Typically, if two substituents are present they are in meta and para position. In another embodiment R4is selected from the group consisting of furyl, pyridyl, pyrazolyl optionally substituted with a group selected from halogen and C1-3alkyl. In a further embodiment R4 is C1-6 alkyl. In a further embodiment R4 isbranched C3-5 alkyl. It is to be understood that each and every of the embodiments specified under R1, R2, R3and R4can be combined independently with the first or second aspect of the present invention. In a still further embodiment, a compound of the present invention is selectedfrom any one of: 2-(3,4-difluorophenyl)-N-[3-hydroxy-2-[(3-hydroxy-4-methoxy- phenyl)methyl]propyl]morpholine-4-carboxamide, N-[2-[(4-chlorophenyl)methyl]-3-hydroxy-propyl]-2-(3,4-difluorophenyl)morpholine- 4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-[(4- methoxyphenyl)methyl]morpholine-4-carboxamide, 10294PC00 2-(3,4-difluorophenyl)-N-[2-[(3,4-difluorophenyl)methyl]-3-hydroxy- propyl]morpholine-4-carboxamide, 2-(3,4-difluorophenyl)-N-[2-(3-furylmethyl)-3-hydroxy-propyl]morpholine-4- carboxamide, 2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-(3-pyridyl)propyl]morpholine-4- carboxamide, N-[2-[(3-bromo-4-methoxy-phenyl)methyl]-3-hydroxy-propyl]-2-(3,4- difluorophenyl)morpholine-4-carboxamide, 2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-(1-methylpyrazol-4- yl)propyl]morpholine-4-carboxamide, 2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-(2-pyridyl)propyl]morpholine-4- carboxamide, 2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-[3- (trifluoromethoxy)phenyl]propyl]morpholine-4-carboxamide, 2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-[4- (trifluoromethoxy)phenyl]propyl]morpholine-4-carboxamide, N-(2-benzyl-3-hydroxy-propyl)-2-(3,4-difluorophenyl)morpholine-4-carboxamide, (2S,2R)-N-(3-hydroxy-2-{[4-(trifluoromethyl)phenyl]methyl}propyl)-2-[(4- methoxyphenyl)methyl]morpholine-4-carboxamide, (2S,2S)-N-(3-hydroxy-2-{[4-(trifluoromethyl)phenyl]methyl}propyl)-2-[(4- methoxyphenyl)methyl]morpholine-4-carboxamide,2-(3,4-difluorophenyl)-N-[2- (hydroxymethyl)-3-(m-tolyl)propyl]morpholine-4-carboxamide, 2-(3,4-difluorophenyl)-N-[2-[(2,4-difluorophenyl)methyl]-3-hydroxy- propyl]morpholine-4-carboxamide, 2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-(4-pyridyl)propyl]morpholine-4- carboxamide, 2-(3,4-difluorophenyl)-N-[2-[(3,4-dimethoxyphenyl)methyl]-3-hydroxy- propyl]morpholine-4-carboxamide, 2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-(4- methoxyphenyl)propyl]morpholine-4-carboxamide, N-[2-[(3-chlorophenyl)methyl]-3-hydroxy-propyl]-2-(3,4-difluorophenyl)morpholine- 4-carboxamide, (R,R)-2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, 10294PC00 (S,R)-2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, (R,S)-2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, (S,S)-2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, 2-(3,4-difluorophenyl)-N-[2-hydroxy-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, N-[3-amino-3-oxo-2-[[4-(trifluoromethyl)phenyl]methyl]propyl]-2-(3,4- difluorophenyl)morpholine-4-carboxamide, (2R)-N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-[(4- methoxyphenyl)methyl]morpholine-4-carboxamide and (2S)-N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-[(4-methoxyphenyl)methyl]morpholine-4-carboxamide; ora pharmaceutically acceptable salt or solvate thereof. In a still further embodiment, a compound of the present invention is selected from any one of: racemic-(2S)-N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-[(4- methoxyphenyl)methyl]morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(3- nitrophenyl)morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(3- methoxyphenyl)morpholine-4-carboxamide, 2-(3-cyanophenyl)-N-[2-(hydroxymethyl)-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, N-[2-[(4-chlorophenyl)methyl]-3-hydroxy-propyl]-2-[(4- methoxyphenyl)methyl]morpholine-4-carboxamide, 2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N-[2-(hydroxymethyl)-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, 2-[(3,5-dimethylpyrazol-1-yl)methyl]-N-[2-(hydroxymethyl)-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(4- methoxyphenyl)morpholine-4-carboxamide, 10294PC00 (2S)-N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-isobutyl- morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-[(4-methylpyrazol-1- yl)methyl]morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(4- methylsulfonylphenyl)morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(6-methyl-3- pyridyl)morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(5-isopropyl-1,2,4- oxadiazol-3-yl)morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(2-methoxy-4- pyridyl)morpholine-4-carboxamide, 2-[2-(dimethylamino)pyrimidin-4-yl]-N-[2-(hydroxymethyl)-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, 2-(4-aminophenyl)-N-[2-(hydroxymethyl)-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(5-methyl-2- furyl)morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(3- pyridyl)morpholine-4-carboxamide, 2-(3-furyl)-N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]morpholine-4- carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2- (methanesulfonamidomethyl)morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(2- methoxyethoxymethyl)morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(2- pyridyl)morpholine-4-carboxamide, and N-[2-(hydroxymethyl)-3-[4-(trifluoromethoxy)phenyl]propyl]-2-[(4-methoxyphenyl)methyl]morpholine-4-carboxamide; ora pharmaceutically acceptable salt or solvate thereof. Each of the above listed compounds or a pharmaceutically acceptable salt or solvate thereof are individual embodiments and may be subject to one or more independent claims. 10294PC00 The compounds presented herein are intended to include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. In a second aspect the present invention relates to a compound of any one ofthe above aspects or embodiments for use as a medicament.In a third aspect the present invention relates to a pharmaceutical compositioncomprising a compound of any one of the above aspect or embodiments and at least one pharmaceutically acceptable adjuvant, diluent, excipient and / or carrier. In a fourth aspect the present invention relates to a compound of any one ofthe above aspect or embodiments for use as a medicament and for use in a method for treating diabetes or pre-diabetes, in a subject in need thereof, i.e., for use in treatmentof diabetes or pre-diabetes. Typically, diabetes is type 2. A related aspect of theinvention defines use of a compound of any one of the above aspects or embodimentsin the manufacture of a medicament for treating diabetes or pre-diabetes.In a fifth aspect the present invention relates to a compound of any one of theabove aspect or embodiments for use as a medicament and for use in a method for preventing the progress of diabetes and / or preventing progress of prediabetes to diabetes and / or reversal of diabetes and / or for reversal of diabetes due to reversal of beta cell dysfunction in a subject in need thereof. In a sixth aspect the present invention relates to a method for treating diabetesor pre-diabetes in a subject in need thereof. The method comprises administering tothe subject a therapeutically effective amount of a compound of formula I. In a seventh aspect the present invention relates to a method for preventing the progress of diabetes and / or preventing progress of prediabetes to diabetes and / or reversal of diabetes and / or for reversal of diabetes due to reversal of beta cell dysfunction in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of a compound of formula I. To be sufficiently capable of treating diabetes or pre-diabetes in a humansubject the compound of formula I should have a high affinity to VDAC1 and inhibitVDAC1 function.Further objects and advantages of the present invention will appear from the following description, and claims. Description of the invention 10294PC00 The present invention relates to a compound of formula I interacting with theVoltage-Dependent Anion Channel Type 1 (VDAC1) protein and its use in thetreatment of diabetes or pre-diabetes.Compounds modulating VDAC1 can reduce oligomerization, therebypreventing loss of bioenergetics (ATP), opening of mPTP and the leakage of mtDNA into the cytosol. The prevention of VDAC1 oligomerization also preserves the physiological VDAC1 interaction with the glucose-phosphorylating enzyme glucokinase (in beta cells and hepatocytes) and hexokinase (in fat cells, muscle and other insulin target cells). In a first aspect the present invention relates to a compound of general formulaI. In a second aspect the present invention relates to a compound of any one ofthe above aspects or embodiments for use as a medicament and for use in a methodfor treating diabetes or pre-diabetes, in a subject in need thereof. Typically, for use ina method for treatment of Type 2 Diabetes. In another embodiment it is for use in amethod for treatment of Type 1 Diabetes. In a preferred embodiment the compound offormula I interacts with VDAC1 preventing the formation of its pathological oligomerform thus restoring physiological mitochondrial function (oxygen consumption rate orrespiration) and bioenergetics (ATP formation).In a third aspect the present invention relates to a method for treating diabetesor pre-diabetes in a subject in need thereof, the method comprising administering tothe subject a therapeutically effective amount of a compound of formula I. In an embodiment treating diabetes or pre-diabetes comprises at least one of treating insulin resistance, such as insulin resistance in diabetes type 2; inducing glucose-stimulated insulin secretion; improving glucose tolerance; restoring insulin secretion frompancreatic β-cells of a subject affected with diabetes; and prevention of β-celldysfunction. In a fourth aspect the present invention relates to a method for preventing the progress of diabetes and / or preventing progress of prediabetes to diabetes and / or reversal of diabetes and / or for reversal of diabetes due to reversal of beta cell dysfunction in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I. The term “halogen” as used herein means Cl, F, I or Br. 10294PC00 The term “quaternary ammonium” as used herein means a nitrogen having four valence bonds, such as NH4+or N(CH3)4+. The term “C1-x alkyl” as used herein means a linear alkyl group containing 1-x carbon atoms, e.g. C1-3 or C1-6, such as methyl, ethyl, propyl, butyl, pentyl or hexyl. The term “C5-7 cycloalkyl” as used herein means a cyclic alkyl group containing 5-7 carbon atoms, such as cyclopentyl, cyclohexyl, or cycloheptyl. The term “C2-4 alkenyl” as used herein means means a linear alkenyl having from 2-4 carbonatoms and comprising one double bond, such as ethenyl. The term “Oxo” as used herein means an oxygen atom with double bonds, also indicated as =O. The term “COO-C1-6 alkyl, SO3-C1-6 alkyl, NHCO-C1-3 alkyl, OC1-3 alkyl, SO2-C1-3 alkyl” as used herein means a group selected from COO, SO3, NHCO, O, or SO2to which is attached a C1-xalkyl as defined above. The term “C1-3 alkyl-CN” as used herein means a C1-x alkyl as defined abovehaving a CN attached to one of the carbon atoms. The term “aryl” as used herein means a mono or bicyclic aromatic ring system containing 6-12 carbon atoms, such as phenyl or naphthyl. The term “a monoheterocyclic ring” as used herein means one ring comprising carbon atoms and at least one hetero atom, such as N, O or S. The term “a biheterocyclic group” as used herein means two monoheterocyclic rings fused together and sharing two ring atoms, and each comprising carbon atoms and at least one hetero atom, such as N, O or S. The term “a non-aromatic heterocyclic system” as used herein in connectionwith a monoheterocyclic ring, a biheterocyclic group, a spiroheterocyclic group or afirst and a second monoheterocyclic ring connected by a linker, such as a bond, means a saturated or partly unsaturated system, provide that none of the heterocyclic rings are aromatic. The term “VDAC” as used herein refers to Voltage-Dependent Anion Channel protein of a highly conserved family of mitochondrial porins. Three VDAC isoforms, VDAC Type 1 (VDAC1), VDAC Type 2 (VDAC2) and VDAC Type 3 (VDAC3), encoded by three genes, are known to date. As used herein the term “VDAC1” as mean mammalian VDAC1 and in particular human VDAC1 comprising 283 aminoacids (NP_003365) (Shoshan-Barmatz V et al., 2010. Molecular aspects of medicine31:227-285). 10294PC00 When the compound of formula I and pharmaceutical compositions hereindisclosed are used for the above treatment, a therapeutically effective amount of at least one compound is administered to a mammal in need of said treatment. The term “treatment” and “treating” as used herein means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications,and / or to cure or eliminate the disease, disorder or condition as well as to prevent thecondition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. The treatment may either be performed in an acute or in a chronic way. The patient to be treated is preferably a mammal; in particular, a human being,but it may also include animals, such as dogs, cats, cows, sheep, pigs, rats, mice,rabbits, Guinean pigs.The term "a therapeutically effective amount" of the compound for use of thepresent invention as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. Anamount adequate to accomplish this is defined as a "therapeutically effective amount".Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician or veterinary. In a still further aspect, the present invention relates to a pharmaceuticalcomposition comprising the compound of formula I and optionally a pharmaceuticallyacceptable additive, such as a carrier or an excipient. As used herein “pharmaceutically acceptable additive” is intended without limitation to include carriers, excipients, diluents, adjuvant, colorings, aroma, preservatives etc. that the skilled person would consider using when formulating acompound of the present invention to make a pharmaceutical composition. 10294PC00 The adjuvants, diluents, excipients and / or carriers that may be used in the composition of the invention must be pharmaceutically acceptable in the sense ofbeing compatible with the compound of formula I and the other ingredients of thepharmaceutical composition, and not deleterious to the recipient thereof. It is preferred that the compositions shall not contain any material that may cause anadverse reaction, such as an allergic reaction. The adjuvants, diluents, excipients andcarriers that may be used in the pharmaceutical composition of the invention are well known to a person skilled within the art. As mentioned above, the compositions and particularly pharmaceuticalcompositions as herein disclosed may, in addition to the compounds of formula Iherein disclosed, further comprise at least one pharmaceutically acceptable adjuvant, diluent, excipient and / or carrier. In some embodiments, the pharmaceuticalcompositions comprise from 0.01 to 99.99 % by weight of said at least onepharmaceutically acceptable adjuvant, diluent, excipient and / or carrier and from 0.01to 99.99 % by weight of a compound of formula I as herein disclosed. The combinedamount of the active ingredient and of the pharmaceutically acceptable adjuvant, diluent, excipient and / or carrier may not constitute more than 100% by weight of the composition, particularly the pharmaceutical composition. In some embodiments, only one compound of formula I as herein disclosed is used for the purposes discussed above. In some embodiments, two or more of the compounds of formula I as herein disclosed are used in combination for the purposes discussed above. In further embodiments the compound of formula I as herein disclosed areused in combination with metformin, GLP-1(7-37), GLP-1(7-36), analogs of GLP-1,derivatives of GLP1, insulin, and / or insulin analogs for the purposes discussed above.The composition, particularly pharmaceutical composition comprising a compound set forth herein may be adapted for oral, intravenous, topical, intraperitoneal, nasal, buccal, sublingual, or subcutaneous administration, or for administration via the respiratory tract in the form of, for example, an aerosol or an air-suspended fine powder. Therefore, the pharmaceutical composition may be in the form of, for example, tablets, capsules, powders, nanoparticles, crystals, amorphous substances, solutions, transdermal patches or suppositories. 10294PC00 Further embodiments of the process are described in the experimental section herein, and each individual process as well as each starting material constitutes embodiments that may form part of embodiments. The above embodiments should be seen as referring to any one of the aspects (such as ‘method for treatment’, ‘pharmaceutical composition’, ‘compound of formula I for use as a medicament’, or ‘compound of formula I for use in a method’) described herein as well as any one of the embodiments described herein unless it is specified that an embodiment relates to a certain aspect or aspects of the present invention. All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein. All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way. Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context. The terms “a” and “an” and “the” and similar referents as used in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The term “a” and “an” can be exchanged by “at least one” or “one or more” throughout the specification. The term “and / or” as used herein is intended to mean both alternatives as well as each of the alternatives individually. For instance, expression “xxx and / or yyy” means “the xxx and yyy; the xxx; or the yyy”, all three alternatives are subject to individual embodiments. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within therange, unless otherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. Unless otherwise stated, all exact values provided herein are representative of corresponding approximate values (e.g., all exact exemplary values provided with respect to a particular factor or measurement can be considered to also pro-vide a corresponding approximate measurement, modified by "about," where appropriate). 10294PC00 All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise indicated. No language in the specification should be construed as indicating any element is essential to the practice of the invention unless as much is explicitly stated. The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability and / or enforceability of such patent documents. The description herein of any aspect or embodiment of the invention using terms such as “comprising”, “having”, “including” or “containing” with reference to an element or elements is intended to provide support for a similar aspect or embodiment of the invention that “consists of”, “consists essentially of”, or “substantially comprises” that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context). This invention includes all modifications and equivalents of the subject matter recited in the aspects or claims presented herein to the maximum extent permitted by applicable law. The present invention is further illustrated by the following examples that, however, are not to be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples may, bothseparately and in any combination thereof, be material for realizing the invention indiverse forms thereof.Biological Assays Oxygen Consumption Rate (OCR)Cell Culture - Oxygen Consumption Rate (OCR)HEK 293T cells were cultured in culture medium containing DMEM (Thermo FisherScientific, Waltham, MA, USA), 10 % fetal bovine serum (Sigma–Aldrich), 2mM 10294PC00 Sodium glutamine (Hyclone) and 1 % Penicillin Streptomycin (Hyclone) in a humidified incubator containing 5% CO2at 37°C. They were passaged at 90-95 % confluency.Assay Procedure Mitochondrial respiration - Oxygen Consumption Rate (OCR)Oxygen consumption rate (OCR) was measured in HEK 293T cells. Fifty thousand cells were seeded in black poly-L-Lysine coated plate in culture medium. Next day the cells were pretreated either with test compounds or DMSO in culture medium for 1 h at 37 C. Next the cells were treated with 30 uM freshly prepared sodium selenite (CAS 10102-18-8; Sigma) along with the test compound or DMSO for 3 h at 37°C. The cells were then washed 3 times with starvation buffer (1.16 mM MgSO4, 4.7 mM KCl, 1.2 mM KH2PO4, 114 mM NaCl, 2.5 mM CaCl2, 20 mM HEPES, and 0.2% bovine serum albumin, pH 7.3) and starved for 1 h at 37°C in starvation buffer containing 30 uM sodium selenite along with either test compound or DMSO. Finally, the cells are washed three times with O2P buffer (250 mM sucrose, 15 mM KCl,1 mM EGTA, 5 mM MgCl2, 30 mM K2HPO4 , pH 7.4) and OCR was measured O2Passay buffer (O2P buffer containing 5mM Succinate, 1mM ADP, 2nM Seahorse XFPlasma Membrane Permeabilizer (Agilent), 0.1 % bovine serum albumin and 1 / 10th volume of MitoXpress Xtra (Agilent)). The wells were then overlayered by mineral oil (Agilent). The measurements were recorded for 20 min by CLARIOstar Plus plate reader (BMG Lab Tech) in time-resolved fluorescence (TR-F) mode at 380 nmexcitation and 650 nm emission wavelengths with 30 and 70 microseconds integrationtime at 30°C. Antimycin A at 10 uM and AKOS022075291 (CAS 878983-38-1) at 30uM, a known VDAC1 oligomerization inhibitor were used as negative and positivecontrols, respectively. Data was calculated as % OCR by first normalizing against thebackground (wells without cells) and then setting control wells with sodium seleniteand DMSO to 100 %. EC50 values were calculated using GraphPad Prism softwaresuite. Recovery Effect Assay (CTG Assay) of Compounds in Selenite challenged HEK293T CellsCell culture cell titre glow (CTG) viability Assay 10294PC00HEK293T Cells were cultured in DMEM + 10% FBS. Cells were split twice a weekor upon reaching ~ 80% confluency, washed once in PBS, then added 2ml of TrypLEand incubated for 2min.10mL of media was added to neutralise the TrypLE and thecontents transferred to a Falcon tube. Cells were centrifuged at 300g for 5min (RT) topellet the cells. The cell pellet was resuspended and counted in 10mL fresh media.Assay Procedure Recovery Effect Assay (CTG Assay) Spot Test ^A 384-well plate was seeded with HEK293T cells and incubated overnight at37°C at 9x103 cells / well (in 25µL media)^ The following day, the media was replaced with equal volumes of freshmedia. Two Intermediate plates were prepared; oIntermediate Plate 11 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24A B C D EOSOSO O O O O O O O O OFS S S S S S S S S SiaMiaMiaMiaMiaMiaMiaMiaMiaM M M M GeDeD deD diaiaiad deD deD deD deD deD deD deD deD d DH M%0%2 M0%2 M0%2 M0%2 M0M%0M%0M%0M%0M%0M%0 eM%0IL L L L L2L2L2L2L2L2L2L2 J µfµfµfµfµfµfµfµfµf f f fK02oL0o µ2 L0o µ2 L0o µ2 L0o µ2 L0o µ2 L0o µ2 L0o µ2 L0o µ µ2 L0o µ µ2 L02o µ L02oLL01010101010101010µ10µ10µ101 M N O ^ P oIntermediate Plate 2^ (Entire plate has 50µL of DMEM Media)^ The compounds were dosed using Viaflow, programmed to do the following;o With a single quadrant of tips (Top left)^ Take 5µL of 10mM DMSO stock^ Added to 20µL Media (Intermediate 1)^ Mix (x5)^ 5µL of the mixedsolution aspirated^ Dispensed into 10µL of 20% DMSO in Media^ Mix x5^ The above steps were repeated with a second quadrant of tips(bottom right) oWith a full set of fresh tips^ 5µL of intermediate plate 1 was aspirated 10294PC00 ^Dispensed into 50µL of Media^ Mixedo With a new set of fresh tips^ 5µL of Intermediate plate 2 was added to the assay platecontaining cells and 20µL of media. ^After the dosing, the plates were incubated at 37°C for 1 houro 30mM Selenite stock solution in MilliQ water was prepared fresh onthe day of dosing and diluted to 0.18mM. 5µL of 0.18mM solution wasadded to assay plate (containing 25µL). For negative selenite wells, MilliQ water was added in place of selenite (5µL added to assay plate containing 25µL). The plate was incubated at 37°C for 4 hours. At theend of the incubation CellTitreGlo (CTG) was prepared and 25µLadded to each well. Luminescence was measured 5 mins later.Data Analysis The raw luminescence values for each compound duplicate were averaged and normalised by GraphPad Prism software with 100% defined as the average of the negative selenite control wells, and 0% defined as the average of the positive selenitecontrol wells. From this the % values from 30µM and 10µM were reported in the spottest mode. Reagents: Reagent e.g. Supplier / Codee.g. Fetal Bovine Serum, qualified, Invitrogen / heat inactivated 10500064 D-MEM (HG) W / NA PYR (CE) DMEM High Glucose with L- Glutamine and Invitrogen / Pyruvate 41966029 HEK293T In-House / N / A 10294PC00 CELL CULTURE MICROPLATE, 384 WELL, PS, F- BOTTOM Greiner / 781098Fisher Scientific / Sodium-Selenite 10695882 Abarceo Compounds Abarceo / N / ACellTiter-Glo® 2.0 Assay Promega / G9242Assay Procedure Recovery Effect Assay (CTG Assay, alternative procedure) ^Three plates were seeded with HEK293T Cells and incubated O / N at 37°Co 2x 96well at 3.24x104 cells / well (90µL Media)o 1x 384well at 9x103 cells / well (in 25µL media)^ The next morning, the media was replaced with equal volumes of fresh media^ The compounds were dosed using the D300 dispensero 60µM Top Concentration – ½ fold dilution serieso All 10mM stocks, No intermediate dilutions requiredo Compounds screened in duplicate in 384well plateo Final DMSO concentration 0.6% v / v^ After the dosing, the plates were incubated at 37°C for 1 hour^ 30mM Selenite was prepared fresh on the day of dosing; diluted to 30mMwith MilliQ water ^30mM selenite was diluted further in MilliQ water to;o 0.3mM for the 96well plate – 10µL of this added to cells (90µL)o 0.18mM for the 384well plate – 5µL of this added to cells (25µL)^ For negative selenite wells, MilliQ water was added in place of seleniteo 96well plate – 10µL added to cellso 384well plate – 5µL added to cells^ Plate was incubated 37°C for 4 hours 10294PC00 ^At the end of the incubation CellTitreGlo (CTG) was prepared and added tothe plates; o95µL added to the 96well plateo 25µL added to the 384well plate.^ Luminescence was measured 5 mins later using the EnSpire plate reader.Data Analysis ^The raw luminescence values were plotted against Log (M) used of eachcompound. ^“log(inhibitor) vs. response -- Variable slope (four parameters) - Least squaresfit” was used for every compound / combination No constraints were applied. Key Assaay reagents: Reagent e.g. Supplier / Codee.g. Fetal Bovine Serum, qualified, heat Invitrogen / inactivated 10500064 D-MEM (HG) W / NA PYR (CE) DMEM High Glucose with L- Glutamine and Invitrogen / Pyruvate 41966029 HEK293T In-House / N / ACellTiter-Glo® Luminescent Cell Viability Assay Promega / G7571CELL CULTURE MICROPLATE, 384 Greiner / 781098 10294PC00 WELL, PS, F- BOTTOM Fisher Scientific / Sodium-Selenite 10695882 Test Compounds Abarceo / N / ANanoBRET PPI Assay for VDAC1:VDAC1 dimerization in VDAC1-KO HEK293T Cells Assay Procedure Cell Culture (Day 0) ^Culture VDAC1-KO HEK293T cells (in DMEM +10% FBS) prior to assay.^ Cells were kept between 80-90% confluent, such they are in the growth phase.^ To lift the cells they were washed once in PBS, then added 7ml of TrypLE andincubated for 3-5min.^ An equal volume of media was added to neutralise the TrypLE and thecontents transferred to a Falcon tube. ^Cells were centrifuged at 200g for 5min (RT) to pellet the cells.^ Cell pellets were resuspended and counted in 1mL fresh media.Plate Prep (Day 0) ^384-well plates were coated with 15µL Poly-D-Lysine (diluted 1:1 in PBS)followed by incubation at room temperature for 1 hour. Poly-D-Lysine solution was removed followed by rinsing three times withPBS (30µL) The coated vessles were allowed to dry in a laminar hood.Assay ProcedureDay 1: Transient transfection of VDAC1-KO cells with the donor:acceptor pair ofplasmids ^Cell medium was removed from cell flask via aspiration, washed with PBS,added 7mL TrypLE for 1 min at 37°C allowing cells to dissociate from theflask. 10294PC00 ^TrypLE was neutralized using growth medium and cells pelleted viacentrifugation at 200 x g for 3 min. ^Medium was aspirated and cells resuspended into a single cell suspensionusing 5mL of Opti-MEM™ + 10% FBS.^ Cells were adjusted to a cell density of 5 x 105 / mL in Opti-MEM™ + 10%FBS in a sterile, conical tube. Transfection preparation ^DNA:FuGENE® mixtures were prepared to transfect every 5X105 (1mL) cellsand scaled according to the number of cells for transfection (Table 1).Table 1 Transfection amounts for VDAC-KO HEK293T cellsDonor / Acceptor ratio D:A=1:10Donor expression plasmid VDAC1-NanoLuc 1.25 ngAcceptor expression plasmid HaloTag-VDAC1 12.5 ngpGEM-3Z carrier DNA 1186.25 ngtotal 1250 ngBring up the volume to 100µl with Opti-MEM, then add Fugene HD Fugene HD 3.75 µl^ This was followed by an incubation at room temperature for 20 minutes toallow DNA:FuGENE® complex to form. ^NanoBRET™ 618 HT ligand was diluted 1:1000 into the cell / transfectionmix. 1) DNA: FuGENE® mixture was mixed with cells and dispensed into 384-wellplates at 22.5 µL / well. 2) Plates were incubated overnight at 37°C.Day 2: Preparation of test compound dilution and addition ^The following morning, the media was replaced with 40µL of DMEM +FBS 10294PC00 ^10mM of compound stock solutions in DMSO was prepared prior to assay.a. Cells were dosed using a D300 digital dispenser with 1% DMSOnormalization applied across plate. ^Plates were mixed / shaken for 15 sec at 600rpm on a plate shaker andincubated for 1 hour at 37°C in 5% CO2 incubator for compound pre-treatment. Preparation of sodium selenite dilution and addition. ^Fresh 30mM (1000x) sodium selenite stock solutions were prepared inpure water and diluted 1:100 in water to make 300µM solutions (10xconcentration)4 µL of the 300µM solution was added to each well with4µL of water added to negative selenium wells. ^Plates were mixed / shaken for 15sec at 600rpm on a plate shaker.^ Plates were incubated at 37°C in 5% CO2 for 4 hours, followed byNanoBRETTMAssay protocol as described below.NanoBRET™ Assay^ Immediately prior to BRET measurements, dilutions of 1:100 NanoBRET™NanoGlo® substrate and 1:300 Extracellular NanoLuc® inhibitor in DMEM™ were made in 5X NanoBRETTM Nano-Glo® substrate solution.^ 10 µL of 5X NanoBRETTM Nano-Glo® substrate solution was added to eachwell. ^Plates were incubated at room temperature for 2-3 minutes, then donoremission (e.g. 450nm) and acceptor emission (e.g. 610nm or 630nm) weremeasured using a NanoBRET™-compatible luminometer.CellTitreGlo Assay^ CellTitreGlo 2.0 was warmed to room temperature.^ 25 µL of reagent was added to each well.^ Plates were incubated for 5min with gentle shaking, allowing theCellTitreGlo reagent to lyse the cells and release ATP. ^Plate luminesence was read with the Enspire luminometer. 10294PC00 Data Analysis BRET Ratio Determinations and Data Processing ^To generate raw BRET ratio values, the acceptor emission value (e.g. 610nm)was divided by the donor emission value (e.g.450nm) for each sample. ^Raw BRET units were converted to milliBRET units (mBU) by multiplyingeach raw BRET value by 1000. ^Data was normalized to percent inhibition.100 100 Reagents Supplier / Codee.g. VDAC1-HaloTag Promega / PIP331801A VDAC1-NanoLuc Promega / PIP331801B Transfection Carrier DNA (pGEM-3Z) Promega / E488BSodium-Selenite Fisher Scientific / 10695882 VDAC1-KO Abarceo / N / A HEK293T FuGENE®HD Promega / E2311DMSO SIGMA / D2650618 HaloTag® Ligand Promega / G980AFetal Bovine Serum, qualified, heat Invitrogen / inactivated 10500064 D-MEM (HG) Invitrogen / W / NA PYR (CE) 41966029 10294PC00 DMEM High Glucose with L- Glutamine and Pyruvate TRYPLE Life Technologies EXPRESS / 12604013 Life Technologies DPBS / 14190-094OptiMEM™ w / oLife Technologies phenol red / 11058-021 NanoBRET™ Nano-Glo®Substrate Promega / N157CExtracellular NanoBRET™Inhibitor Promega / N235BNanoBRET(TM) Nano-Glo(R) Detection System*200 assay* Promega / N1661Intracellular TE Nano-GloSubstrate / Inhibitor Promega / N2160CellTiter-Glo® 2.0Assay Promega / G9242Test Compounds Abarceo / N / AExample # OCROCR CTG CTG CTG CTG nBRET nBRET Assay Assay Assay Assay Spot Spot Dimerization Dimerization EC50 EMax EC50 Emax Recovery Recovery Recovery Recovery Mean Mean Mean Mean Mean Mean EC50 [μM] Emax [%] [μM] [%] [μM] [%] (10μM) (30μM) [%] [%] 10294PC00Example 1 2.88 133.5 1.95 101.67 3.59 106.94Example 2 2.72 116.14Example 3 1.17 112.5Example 4 3.99 117.51Example 5 41.1 110Example 6 31.7 27.29Example 7 10 29.77 2.98 3.76Example 8 14.8 107.73 7.22 100.94Example 9 41.4 24.82Example10.11 59.1410 Example15.2 113.4311 Example 30.87 12 Example39.5 11013 Example11.77 44.7314 Example 22.1 15 Example>10 -3 24.14 79.9616 Example 17 Example 18 Example3.5 99 3.63 100.98 110.13 100.93 7.14 89.4119 Example31.67 97.7420 Example17.1 84.46 30.7 84.95 93.25 92.4621 Example4.49 85 3.9 104.75 12.6 97.1222 Example5.4 101.5 4.43 111.21 8.51 105.1923 10294PC00 Example2.79 114.1824 Example4.16 111.73 7.69 114.2125 Example2.7 100 11 101 9.3 11626 Example19 10227 Example4 10528 Example8.0 11929 Example16 9930 Example15 10131 Example1.9 110 13 10232 Example3.6 9933 Example50 100 29 9934 Example17 11535 Example3.2 105 26 7136 Example16 7737 Example4.7 11538 Example2.3 10039 Example32 91 14 8540 Example31 13141 Example28 10542 10294PC00 Example33 10043 Example1.4 10044 Example8 11945 Example26 10346 Example19 11547 Example30 76 20 12248 Example28 10349Preparation of compounds / ExperimentalsReaction progress was generally monitored by TLC and UV exposure or UPLC-MSto decide optimal reaction time. Thus, reaction time for each repetitive step may varyfor different chemical reagents. Example 1-42-(3,4-Difluorophenyl)-N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide (racemate 362) Step 1: Synthesis of ethyl (E)-2-cyano-3-(4-(trifluoromethyl)phenyl)acrylate 10294PC00 To a stirred solution at room temperature (RT) of 4-(trifluoromethyl) benzaldehyde (5.0g, 28.73 mmol) in EtOH (20 mL) was added piperidine (25 drops) and ethyl 2-cyanoacetate (3.89 g, 34.48 mmol, 1.2 eq.) The reaction mixture was stirred at RT for16 h. The reaction mixture was then diluted with water and extracted with ethyl acetate.The combined organic layer was washed with brine solution and dried over anhydrousNa2SO4 and evaporated to dryness to afford ethyl (E)-2-cyano-3-(4-(trifluoromethyl)phenyl acrylate (6.0 g, crude) as white solid. Step 2: 3-hydroxy-2-(4-(trifluoromethyl)benzyl) propanenitrile To a stirred solution of ethyl (E)-2-cyano-3-(4-(trifluoromethyl)phenyl)acrylate (3.0 g,11.14 mmol) in EtOH (20 mL) was added NaBH4 (0.82 g, 22.29 mmoL, 2.0 eq.) at 0˚C. The reaction mixture was stirred at RT for 30 min. The reaction mixture wasreduced in volume and then diluted with water and extracted with ethyl acetate. Thecombined organic layer was washed with brine solution and dried over anhydrous Na2SO4, concentrated under vacuum and purified on silica gel to afford 3-hydroxy-2- (4-(trifluoromethyl) benzyl) propane nitrile (2.50 g, 10.912 mmol, yield: 97.2%) as a colourless liquid. Step 3: 3-((tert-butyldimethylsilyl) oxy)-2-(4-(trifluoromethyl)benzyl) propanenitrile 10294PC00 To a stirred solution of 3-hydroxy-2-(4-(trifluoromethyl)benzyl)propanenitrile (0.80g, 3.49 mmol) in DCM (20 mL) was added DMAP (0.44 g, 3.49 mmol, 1.0 eq.), Et3N(2.7 mL, 10.48 mmol, 3.0 eq.) and TBDMS (1.47 g, 5.24 mmoL, 1.5 eq.). Thereaction mixture was then stirred at RT for 16 h. The reaction mixture was dilutedwith water and extracted with DCM. The combined organic layer was washed with brine solution, dried over anhydrous Na2SO4, and concentrate under vacuum. The crude product was purified using silica gel using 5% EtOAc / hexane as eluent to afford 3-((tert-butyldimethylsilyl) oxy)-2-(4-(trifluoromethyl) benzyl) propanenitrile, (1.5 g, 4.371 mmol, yield: 66.02%) as light brown semi solid. Step 4: 3-((tert-butyldimethylsilyl)oxy)-2-(4-(trifluoromethyl)benzyl)propan-1- amine To a stirred solution of 3-((tert-butyldimethylsilyl) oxy)-2-(4-(trifluoromethyl)benzyl) propanenitrile (0.7 g, 2.04 mmol) in 7M ammonia in methanol(8 mL) was added washed Raney Ni (0.520 g, 6.122 mmol, 3.0 eq.) in MeOH (8 mL)at RT. The reaction mixture was stirred at RT under H2 (50 Psi) pressure for 48 h. The reaction mixture was filtered through celite bed, dried over anhydrous sodium sulfate and evaporated under vacuum, lyophilized for 48h, to afford 3-((tert- butyldimethylsilyl) oxy)-2-(4-(trifluoromethyl) benzyl) propan-1-amine (0.5 g, crude) as a colour less liquid. LCMS: m / z 348.0 [M+1]+.Step 5: 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(4-(trifluoromethyl) benzyl) propyl) carbamate 10294PC00 To a stirred solution of 3-((tert-butyldimethylsilyl)oxy)-2-(4- (trifluoromethyl)benzyl)propan-1-amine (0.40 g, 1.152 mmol) in DCM (5mL) at 0oCwas added 2,2,2-trichloroethyl carbonochloridate (0.36 g, 0.728 mmol, 1.5 eq.) andDIPEA (0.6 mL, 11.520 mmol, 10.0 eq.) The reaction mixture was stirred at RT for 16h. The reaction mixture was then diluted with water and extracted with DCM. Thecombined organic layer was washed with brine solution, dried over anhydrous Na2SO4, and concentrate under vacuum. The crude product was purified on silica gel using 5-8% EtOAc / hexane as eluent to afford 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-(4-(trifluoromethyl) benzyl) propyl) carbamate (0.30 g ,0.58 mmol, yield: 50.1%) as colorless liquid. Step 6: N-(3-((tert-butyldimethylsilyl) oxy)-2-(4-(trifluoromethyl)benzyl)propyl)- 2-(3,4-difluorophenyl)morpholine-4-carboxamide (2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(4-(trifluoromethyl) benzyl)propyl) carbamate (0.10 g, 0.19 mmol), was dissolved in DMSO (5 mL) and cooled to0 ˚C after which the solution was added 2-(3,4-difluorophenyl) morpholine (0.25 g,0.45 mmol, 2.5 eq.) and DIPEA (0.45 mL, 1.15 mmol, 6.0 eq.). The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layer was washed with brine solution, dried over anhydrous Na2SO4, and concentrate under vacuum to afford N-(3-((tert- butyldimethylsilyl) oxy)-2-(4-(trifluoromethyl) benzyl) propyl)-2-(3,4- difluorophenyl) morpholine-4-carboxamide (0.15 g, 0.26 mmol, yield: 50.2%) as colourless liquid. LCMS: m / z 573.0 [M+1]+.Step 7: 2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide 10294PC00 A solution of N-(3-((tert-butyldimethylsilyl)oxy)-2-(4- (trifluoromethyl)benzyl)propyl)-2-(3,4-difluorophenyl)morpholine-4-carboxamide(0.10 g, 0.17 mmol), in THF (10 mL) was cooled to 0oC, added TBAF (0.5 mL), andthen stirred at RT for 2 h. The reaction mixture was evaporated, washed withdiethylether, and dried under vacuum. The crude product was purified by prep HPLCto afford 2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide (0.03 g, 0.061 mmol,yield: 37%) as a white solid. LCMS: m / z 459.85 [M+1]+. Purification of racemate: The target racemate material (racemate 362) was further purified by super fluidchromatography (SFC) to provide the four enantiomers example 1-4.Chiral Chromatography Results:Compound Retention time*Example 1 14.83min Example 2 24.72min Example 3 10.32minExample 4 16.96min*Chiral column chromatography QC using ChiralCel OJ-H (250x4.6 mm, 5 mkm);Mobile phase: Hexane:IPA:MeOH = 90:5:5, Diode array detection (DAD), Flow rate0.6mL / min. In a similar manner was synthesized the following compounds: Example 5 N-(2-(3,4-difluorobenzyl)-3-hydroxypropyl)-2-(3,4-difluorophenyl) morpholine-4-carboxamide: 10294PC00 from 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-(3,4-difluoro benzyl) propyl) carbamate and commercially available 2-(3,4-difluorophenyl) morpholine intwo steps as described above for racemate 362 under examples 1-4. LC-MS: m / z427.20 [M+1]+63% yield as off-white semi-solid.Example 62-(3,4-difluorophenyl)-N-(3-(furan-3-yl)-2-(hydroxymethyl) propyl)morpholine-4-carboxamide: from 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(furan-3-ylmethyl) propyl) carbamate and commercially available 2-(3,4-difluorophenyl) morpholine in two steps as described above for racemate 362 under examples 1-4except in Step 6where the urea formation was performed in MW at 140 oC LC-MS: m / z 381.1 [M+1] +43% yield as white solid. Example 72-(3,4-difluorophenyl)-N-(3-hydroxy-2-(pyridin-3- ylmethyl)propyl)morpholine-4-carboxamide from 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-(pyridin-3- ylmethyl)propyl)carbamate carbamate and commercially available 2-(3,4- difluorophenyl) morpholine in two steps as described above for racemate 362 underexamples 1-4 except in Step 6 where the urea formation was performed in MW at 140oC LC-MS: m / z 392.20 [M+1]+ 24% yield as colorless thick liquid.Example 82-(3,4-difluorophenyl)-N-(3-hydroxy-2-((1-methyl-1H-pyrazol-4-yl)methyl)propyl)morpholine-4-carboxamide: 10294PC00 From 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-((1-methyl-1H-pyrazol- 4-yl)methyl)propyl)carbamate carbamate and commercially available 2-(3,4- difluorophenyl) morpholine in two steps as described above for racemate 362 underexamples 1-4 except in Step 6 where the urea formation was performed in MW at 140oC LC-MS: m / z 395.1 [M+1]+ 35% yield as light yellow viscous liquid.Example 92-(3,4-difluorophenyl)-N-(3-hydroxy-2-(pyridin-2-ylmethyl)propyl)- morpholine-4-carboxamide from 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-(pyridin-2- ylmethyl)propyl)carbamate and commercially available 2-(3,4-difluorophenyl) morpholine in two steps as described above for racemate 362 under examples 1-4 except in Step 6 where the urea formation was performed in MW at 140oC LC-MS:m / z 392.15 [M+1]+ 19% yield as light yellow viscous liquid.Example 102-(3,4-difluorophenyl)-N-(3-hydroxy-2-(3-(trifluoromethoxy) benzyl) propyl) morpholine-4-carboxamide From 2,2,2-trichloroethyl (3-((tert-butyl dimethylsilyl)oxy)-2-(3-(trifluoromethoxy)benzyl) propyl)carbamate and commercially available 2-(3,4-difluorophenyl)morpholine in two steps as described above for racemate 362 under examples 1-4except in Step 6 where the urea formation was performed in MW at 140oC LC-MS:m / z 392.15 [M+1]+ 19% yield as light yellow viscous liquid.Example 112-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-[4- (trifluoromethoxy)phenyl]propyl]morpholine-4-carboxamide 10294PC00 from 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(4- trifluoromethoxybenzyl) propyl) carbamate and commercially available 2-(3,4-difluorophenyl) morpholine in two steps as described above for racemate 362 underexamples 1-4 except in Step 6 where the urea formation was performed in MW at 140oC LC-MS: m / z 375.2 [M+1]+ 19% yield as light yellow viscous liquid.Example 122-(3,4-difluorophenyl)-N-(3-hydroxy-2-(3-methylbenzyl) propyl) morpholine-4-carboxamide from 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(3-methylbenzyl) propyl)carbamate and commercially available 2-(3,4-difluorophenyl) morpholine intwo steps as described above for racemate 362 under examples 1-4 except in Step 6where the urea formation was performed in MW at 140 oC LC-MS: m / z 405.20[M+1]+48% yield as colourless thick liquid. Example 13 N-(2-(2,4-difluorobenzyl)-3-hydroxypropyl)-2-(3,4-difluorophenyl) morpholine-4-carboxamide from 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(2,4-difluorobenzyl)propyl) carbamate and commercially available 2-(3,4-difluorophenyl) morpholine intwo steps as described above for racemate 362 under examples 1-4 except in Step 6where the urea formation was performed in MW at 140 oC LC-MS: m / z 427.70[M+1]+27% yield as colourless thick liquid. 10294PC00 Example 14 N-(2-(3-chlorobenzyl)-3-hydroxypropyl)-2-(3,4-difluorophenyl) morpholine-4-carboxamide From 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(3-chlorobenzyl) propyl) carbamate and commercially available 2-(3,4-difluorophenyl) morpholine in two steps as described above for racemate 362 under examples 1-4except in Step 6where the urea formation was performed in MW at 140 oC LC-MS: m / z 424.87[M+1]+50% yield as a white solid.Example 152-(3,4-difluorophenyl)-N-(3-hydroxy-2-(3-hydroxy-4-methoxybenzyl)propyl)morpholine-4-carboxamide From 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-(3-((tert- butyldimethylsilyl)oxy)-4-methoxybenzyl)propyl)carbamate and commercially available 2-(3,4-difluorophenyl) morpholine in two steps as described above forracemate 362 under examples 1-4 except in Step 6 where the urea formation wasperformed in MW at 140 oC LC-MS: m / z 424.87 [M+1]+ 50% yield as a white solid.Example 16 N-(2-benzyl-3-hydroxypropyl)-2-(3,4-difluorophenyl) morpholine-4- carboxamide From 2,2,2-trichloroethyl (2-benzyl-3((tert-butyldimethylsilyl)oxy) propyl) carbamate and commercially available 2-(3,4-difluorophenyl) morpholine in two steps asdescribed above for racemate 362 under examples 1-4 except in Step 6 where the urea 10294PC00formation was performed in MW at 140 oC LC-MS: m / z 424.87 [M+1]+ 50% yield asa white solid. Example 17 N-(3-((tert-butyldimethylsilyl)oxy)-2-(pyridin-4-ylmethyl)propyl)-2- (3,4-difluorophenyl)morpholine-4-carboxamide From 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(pyridin-4-ylmethyl) propyl) carbamate and commercially available 2-(3,4-difluorophenyl) morpholine intwo steps as described above for racemate 362 under examples 1-4 except in Step 6where the urea formation was performed in MW at 140 oC LC-MS: m / z 392.2 [M+1]+39% yield as a yellow viscous liquid.Example 182-(3,4-difluorophenyl)-N-(2-(3,4-dimethoxybenzyl)-3-hydroxypropyl) morpholine-4-carboxamide From 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(3,4- dimethoxybenzyl)propyl) carbamate and commercially available 2-(3,4- difluorophenyl) morpholine in two steps as described above for racemate 362 underexamples 1-4 except in Step 6 where the urea formation was performed in MW at 140oC LC-MS: m / z 451.2 [M+1]+ 37% yield as a white solid.Example 19 N-{2-[(4-chlorophenyl)methyl]-3-hydroxypropyl}-2-(3,4- difluorophenyl)morpholine-4-carboxamide 10294PC00 To a stirred solution of 2-(3,4-difluorophenyl)morpholine (100.0 mg, 502.31 µmol) and ethylbis(propan-2-yl)amine (258.99 mg, 2.01 mmol, 350.0 µl, 4.0 equiv) in dryCH3CN (1 ml), was added ditrichloromethyl carbonate (66.28 mg, 225.6 µmol) at -30°C. The resulting suspension was allowed to warm up to 0°C over ca.10 min.3- Amino-2-[(4-chlorophenyl)methyl]propan-1-ol (99.8 mg, 501.33 µmol) was then added in one portion. The resulting mixture was allowed to warm to RT. Followed by stirring at 50°C for 4 h. Dry DMSO (1 ml) was added to the mixture and it was subjected to HPLC (0-2-9 min 33-40-55% CH3CN / H2O 30 ml / min (loading pump 4 ml CH3CN), target mass 425 column: Chromatorex C18 SMB100-5T 100*19 mm, 5 microM), yielding N-2-[(4-chlorophenyl)methyl]-3-hydroxypropyl-2-(3,4- difluorophenyl)morpholine-4-carboxamide (62.7 mg, 147.57 µmol, 29.4% yield) LC-MS: m / z 425.0 [M+1]+.Example 20 N-{2-[(3-bromo-4-methoxyphenyl)methyl]-3-hydroxypropyl}-2-(3,4- difluorophenyl)morpholine-4-carboxamide 2-(3,4-Difluorophenyl)morpholine (200.0 mg, 1.0 mmol) was dissolved in THF (4 ml) and the solution was cooled to -200C, then treated with 1M dichloroethane solution of ditrichloromethyl carbonate (118.14 mg, 402.13 µmol, 400.0 µl, 0.4 equiv), added in one portion, followed by ethylbis(propan-2-yl)amine (649.19 mg, 5.03 mmol, 870.0 µl, 5.0 equiv). The mixture was warmed to RT and stirred for 1h.3- Amino-2-[(3-bromo-4-methoxyphenyl)methyl]propan-1-ol hydrochloride (310.66 mg, 1.01 mmol) (solution in 1 ml of THF) was added then, and the mixture was stirred atrt overnight. The solution was concentrated in vacuo and subjected to HPLC (0-2-10min 43-50-70% H2O / MEOH flow 30 ml / min (loading pump 4 ml MEOH), column : Chromatorex C18 SMB100-5T 100*19mm, 5 microM), yielding N-2-[(3-bromo-4- methoxyphenyl)methyl]-3-hydroxypropyl-2-(3,4-difluorophenyl)morpholine-4- carboxamide (107.8 mg, 95.0% purity, 205.09 µmol, 20.4% yield). LC-MS: m / z 499.0 / 501.0 [M+1]+. 10294PC00 methoxyphenyl)methyl]propyl}morpholine-4-carboxamide A solution of N-2-[(3-bromo-4-methoxyphenyl)methyl]-3-hydroxypropyl-2-(3,4- difluorophenyl)morpholine-4-carboxamide (90.0 mg, 180.24 µmol) and triethylamine (21.88 mg, 216.34 µmol, 30.0 µl, 1.2 equiv) in methanol (5 ml) was treated with Pd (30 mg, 10% wt. on carbon). The resulting mixture was hydrogenated at 20 atm. of H2and ambient temperature until spectral data of an aliquot revealed completion of the reaction. The catalyst was removed by filtration and the filtrate was concentrated. The crude product was purified by HPLC (0-2-8 min 17-25-45% H20 / ACN flow 30 ml / min (loading pump 4 ml ACN), column: Chromatorex C18 SMB100-5T 100*19mm, 5 microM) to give 2-(3,4-difluorophenyl)-N-3-hydroxy-2-[(4- methoxyphenyl)methyl]propylmorpholine-4-carboxamide (47.2 mg, 95.0% purity,106.65 µmol, 59.2% yield). LC-MS: m / z 421.2 [M+1]+.Example 22 (2R)-N-(3-hydroxy-2-{[4-(trifluoromethyl)phenyl]methyl}propyl)-2- [(4-methoxyphenyl)methyl]morpholine-4-carboxamide General Scheme: 10294PC00 Step A: tert-Butyl (2S)-2-(bromomethyl)morpholine-4-carboxylate To a stirred solution of tert-butyl (2S)-2-(hydroxymethyl)morpholine-4-carboxylate(10.7 g, 49.28 mmol) and triphenylphosphane (15.5 g, 59.14 mmol) in dry DCM (150ml), 1-bromopyrrolidine-2,5-dione (10.03 g, 56.67 mmol) was added (portion wise), keeping the internal temperature within -30 to -20°C. The reaction mixture was stirred at -20°C for 30 min and then allowed to warm up to RT. Stirring was continued for 16h at RT. Diiodane (1.25 g, 4.93 mmol) was added and the resulting mixture was poured into a water (200 ml). The mixture was treated with sodium sulfite until the organic layer changed color from brown to orange after which the aqueous mixture was extracted with DCM (3x50 ml). The organic layers were combined, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was subjected to Flash Chromatography (9403, ISCO® Companion combiflash; 330 g SiO2,hexane / MTBE with MTBEc from 0 to 95%, flow rate = 100mL / min, Rf = 3,5-5 CV.),yielding tert-butyl (2S)-2-(bromomethyl)morpholine-4-carboxylate (10.3 g, 36.76 mmol, 74.6% yield) as white solid. 10294PC00 Step B: tert-Butyl (2R)-2-[(4-methoxyphenyl)methyl]morpholine-4-carboxylate To a stirred suspension of lithium iodide (3.09 g, 23.07 mmol) and zinc dust (7.2 g, 112.58 mmol) in a mixture of dry CH3CN and DMPU (100 ml, 1:1 v / v), 1,2- dibromoethane (1.89 g, 10.15 mmol) was added (at once), followed by chlorotrimethylsilane (1.1 g, 10.15 mmol) (at once) under Ar atmosphere. The resulting suspension was stirred at RT. until the internal temperature dropped below 35°C (about 15 min at this scale). Then 4-([(4-oxopent-2-en-2-yl)oxy]nickeliooxy)pent-3-en-2-one (787.52 mg, 3.08 mmol) and 3,4,7,8-tetramethyl-1,10-phenanthroline (726.33 mg, 3.08 mmol) were added (at once), followed by 1-bromo-4-methoxybenzene (5.72 g, 30.76 mmol) and tert-butyl 2-(bromomethyl)morpholine-4-carboxylate (10.3 g, 36.91 mmol)under Ar atmosphere and the resulting mixture was stirred at 70°C for 16h, after whichthe reaction mixture was concentrated and subjected to Flash Chromatography (4633,ISCO® Interchim; 120 g SiO2, hexane / EtOAc with EtOAc from 0~95%, flow rate =85 mL / min, Rf = 4-6 CV.), yielding almost pure tert-butyl (2R)-2-[(4-methoxyphenyl)methyl]morpholine-4-carboxylate (6.2 g, 90.0% purity, 18.15 mmol, 59% yield) as yellow oil, which was used directly in the next step. Step C: (2R)-2-[(4-Methoxyphenyl)methyl]morpholine tert-Butyl (2R)-2-[(4-methoxyphenyl)methyl]morpholine-4-carboxylate (1.0 g, 3.25 mmol) was dissolved in TFA (5 ml) and the resulting mixture was stirred at 40°C for1h. The volatiles were removed in vacuo and the resulting residue was diluted withwater (8 ml) and DCM (10 ml). pH was adjusted to 12 with NaOH (2M aq. solution).The organic layer was separated, and the aqueous layer extracted with DCM (2x5 ml).The organic layers were combined, dried over anhydrous sodium sulfate and evaporated in vacuo, yielding almost pure (2R)-2-[(4- methoxyphenyl)methyl]morpholine (600.0 mg, 90.0% purity, 2.61 mmol, 80.1% yield) as yellow oil, which was used directly in the next step (Step F; below). Step D: 3-Hydroxy-2-{[4-(trifluoromethyl)phenyl]methyl}propanenitrile To a stirred solution of methyl (2E)-2-cyano-3-[4-(trifluoromethyl)phenyl]prop-2- enoate (6.0 g, 23.52 mmol) in dry MeOH (80 ml), sodium borhydride (1.79 g, 47.05 mmol) was added (portion wise, over 40 min at this scale), keeping the internal temperature within 0 to 10°C. Then reaction mixture was stirred at 0 to 5°C for 1h, warmed up to RT. (over 30 min) and stirred at RT for another 16h. Acetic acid (5 ml) 10294PC00 was added (at once) and the resulting mixture was stirred at RT. for 15 min. Thevolatiles were removed in vacuo and the resulting residue was redissolved in 20% aq.K2CO3 solution (100 ml) and ethyl acetate (80 ml). The resulting mixture was stirred vigorously at RT for 30 min. The organic layer was separated and the aqueous one was extracted with ethyl acetate (2 x 50 ml). The organic layers were combined, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was subjected to Flash Chromatography (7418, ISCO® : Interchim; 120 g SiO2,CHCl3 / CH3CN with CH3CN from 0~95%, flow rate = 85 mL / min, Rf = 4-5 CV.),yielding 3-hydroxy-2-[4-(trifluoromethyl)phenyl]methylpropanenitrile (2.0 g, 95.0% purity, 8.29 mmol, 35.2% yield) as yellowish solid. Step E: 3-Amino-2-{[4-(trifluoromethyl)phenyl]methyl}propan-1-ol To a stirred solution of 3-hydroxy-2-[4-(trifluoromethyl)phenyl]methylpropanenitrile (2.0 g, 8.73 mmol) in 7N NH3 MeOH solution (60 ml), freshly prepared RaNi (3 g) was added and the resulting mixture was stirred at RT. under H2 atmosphere (10 atm.) for 18h, after which the reaction mixture filtered through a short plug of silica (approx.5 cm high, 24 g of SiO2) and eluted with MeOH (3 x 50 ml). Volatiles were removed in vacuo, yielding almost pure 3-amino-2-[4- (trifluoromethyl)phenyl]methylpropan-1-ol (1.8 g, 92.0% purity, 7.1 mmol, 81.3% yield) as yellow oil, which was used directly into next steps. Step F: (2R)-N-(3-Hydroxy-2-{[4-(trifluoromethyl)phenyl]methyl}propyl)-2-[(4- methoxyphenyl)methyl]morpholine-4-carboxamide To a stirred solution of (2R)-2-[(4-methoxyphenyl)methyl]morpholine (600.0 mg, 2.9 mmol) and ethylbis(propan-2-yl)amine (1.12 g, 8.69 mmol, 1.51 ml, 3.0 equiv) in dry CH3CN (12 ml), ditrichloromethyl carbonate (382.89 mg, 1.3 mmol) was added at - 30°C and the resulting suspension was allowed to warm up to 0°C (30 min at this scale). Then 3-amino-2-[4-(trifluoromethyl)phenyl]methylpropan-1-ol (675.08 mg, 2.9 mmol) in dry CH3CN (1 ml) was added (at once) at 0°C and the resulting mixture was allowed to warm to RT (about 30 min), and stirred at 50°C for 14 h after which the volatiles were removed in vacuo. The resulting residue was dissolved in water (10 ml) and ethyl acetate (10 ml). The organic layer was isolated and the aqueous aqueous extracted with ethyl acetate (3x5 ml). The combined organic layers were dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was dissolved in DMSO (6 ml) and subjected to HPLC (0-2-10 min 18-25-45% 10294PC00 CH3CN / H2O flow 30 ml / min ((loading pump 4 ml CH3CN) target mass 467 column : XBridge BEH C18100*19mm,5 microM), yielding (2R)-N-(3-hydroxy-2-[4- (trifluoromethyl)phenyl]methylpropyl)-2-[(4-methoxyphenyl)methyl]morpholine-4-carboxamide (350.3 mg, 750.92 µmol, 25.9% yield). LC-MS: m / z 421.2 [M+1]+.Example 23 (2S)-N-(3-hydroxy-2-{[4-(trifluoromethyl)phenyl]methyl}propyl)-2-[(4-methoxyphenyl)methyl]morpholine-4-carboxamide In a similar manner to the synthesis of (2S)-N-(3-hydroxy-2-{[4- (trifluoromethyl)phenyl]methyl}propyl)-2-[(4-methoxyphenyl)methyl]morpholine-4- carboxamide was synthesized (2S)-N-(3-hydroxy-2-{[4- (trifluoromethyl)phenyl]methyl}propyl)-2-[(4-methoxyphenyl)methyl]morpholine-4-carboxamide using (2R)-2-(hydroxymethyl)morpholine-4-carboxylate instead of (2S)-2-(hydroxymethyl)morpholine-4-carboxylate. (225.5 mg, 483.39 µmol, 18.2% yield)LC-MS: m / z 467.2 [M+1]+.The two isomers were separated using column chromatography using the following conditions: Column: CHIRALPAK AD-H (250x20 mm, 5 µm)—ADH0EJ-AT001--VI Mobile phase: Hexane:MeOH:IPA, 80:10:10, Flow rate: 12 ml / min, Mass of substance: 33 mg (Amount purified), Injections: 3 injections, 11 mg / injection, Volume phase (Vphase): 2 L, Time on device: 2 hours Example 28: (2S)-N-(3-hydroxy-2-{[4-(trifluoromethyl)phenyl]methyl}propyl)-2-[(4-methoxyphenyl)methyl]morpholine-4-carboxamide ( Fraction 2)Amount obtained: 13.08 mg (39%), Chiral purity: 100%, LCMS purity: 100%,NMR purity: 95%, LC-MS: m / z 467.2 [M+1]+ 10294PC00 Example 29: (2S)-N-(3-hydroxy-2-{[4-(trifluoromethyl)phenyl]methyl}propyl)-2-[(4-methoxyphenyl)methyl]morpholine-4-carboxamide (Fraction 1)Amount obtained: 12.38 mg (38%), Chiral purity: 100%, LCMS purity: 100%,NMR purity: 95%, LC-MS: m / z 467.2 [M+1]+Example 24 2-(3,4-difluorophenyl)-N-{2-hydroxy-3-[4- (trifluoromethyl)phenyl]propyl}morpholine-4-carboxamide General scheme: 10294PC00 Step A: 1-azido-3-[4-(trifluoromethyl)phenyl]propan-2-ol A mixture of 2-[4-(trifluoromethyl)phenyl]methyloxirane (300.0 mg, 1.48 mmol) , sodium azide (192.98 mg, 2.97 mmol) and ammonium chloride (157.37 mg, 2.97 mmol) in methanol was stirred and heated (50-600C) for 72h. The mixture was thenconcentrated in vacuo and extracted with dichloromethane (2x10 ml). The combinedorganic layers were concentrated again to yield crude 1-azido-3-[4- (trifluoromethyl)phenyl]propan-2-ol (310 mg, 1.26 mmol, 85% yield) as yellow oil which was used for the next step without further purification. Step B: The synthesis of 1-amino-3-[4-(trifluoromethyl)phenyl]propan-2-ol To a stirred solution of LiAlH4 (81.45 mg, 2.14 mmol) in THF (10 ml), solution of 1- azido-3-[4-(trifluoromethyl)phenyl]propan-2-ol (350.0 mg, 1.43 mmol) in THF (2 ml) was added dropwise at rt and the mixture was stirred at RT for 2h. Then water (0.3 ml) was cautiously added to quench the reaction at RT followed by 30% aqueous KOH (1 ml), to separate inorganics. The mixture was stirred at RT for 2h. The mixture was diluted with dichloromethane (10 ml) and decanted from the inorganicslurry, concentrated in vacuo to yield almost pure 1-amino-3-[4-(trifluoromethyl)phenyl]propan-2-ol (240 mg, 1.09 mmol, 77% yield, 89% pure) which on standing crystallizes. Step C: 2-(3,4-difluorophenyl)-N-{2-hydroxy-3-[4- (trifluoromethyl)phenyl]propyl}morpholine-4-carboxamide A stirred solution of 2-(3,4-difluorophenyl)morpholine (81.08 mg, 407.3 µmol) and triethylamine (123.42 mg, 1.22 mmol, 170.0 µl, 3.0 equiv) in THF (1.5 ml) was cooled to -200C, then treated with 1M solution of tris-phosgene in THF (0.18 ml, 0.18 mmol), added in one portion. Some precipitation was observed. The colorless solution formed was allowed to warm to RT and stirred for 1h.1-Amino-3-[4- (trifluoromethyl)phenyl]propan-2-ol (71.39 mg, 325.84 µmol) in 1 ml of THF was added then, forming a heterogeneous mixture which was stirred at 400C overnight. The reaction mixture was concentrated to form a viscous oil and subjected to HPLC (BB241610, column : Chromatorex C18 SMB100-5T 100*19mm, 5 microM; eluent: 43-70% methanol / H2O, flow rate: 30 ml / min), to afford 2-(3,4-difluorophenyl)-N-2- 10294PC00 hydroxy-3-[4-(trifluoromethyl)phenyl]propylmorpholine-4-carboxamide (81 mg,0.182 mmol, 56% yield). LC-MS: m / z 445.2 [M+1]+.Example 253-{[2-(3,4-difluorophenyl)morpholine-4-carbonyl]amino}-2-{[4-(trifluoromethyl)phenyl]methyl}propanamide Step A: (2Z)-2-cyano-3-[4-(trifluoromethyl)phenyl]prop-2-enamide 10294PC00 To a stirred solution of 2-cyanoacetamide (482.82 mg, 5.75 mmol) and 4- (trifluoromethyl)benzaldehyde (1.0 g, 5.75 mmol, 780.0 µl, 1.0 equiv) in dry MeOH (20 ml), morpholine (100.05 mg, 1.15 mmol, 100.0 µl, 0.2 equiv) was added (at once)at RT, and the resulting mixture was stirred at 65°C for 16h. After cooling to RT, theresulting mixture was used directly into the next step.Step B: 2-Cyano-3-[4-(trifluoromethyl)phenyl]propanamide To a stirred solution of crude (2Z)-2-cyano-3-[4-(trifluoromethyl)phenyl]prop-2- enamide (60% by LCMS), sodium borontetrahydride (218.58 mg, 5.75 mmol) was added (portion wise), keeping the internal temperature between 0 to 5°C. The resulting mixture was stirred at 5°C for 15 min, allowed to warm up to RT, and stirred at RT for 16h, after which acetic acid (2 ml) was added and the resulting mixture wasstirred at RT. for another 15 min. Then volatiles were removed in vacuo and theresulting residue was dissolved in ethyl acetate (30 ml) and 20% aq. K2CO3 solution(50 ml). The organic layer was isolated, and the aqueous phase extracted with ethylacetate (2x20 ml). The combined organic layers were dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was subjected to Flash Chromatography (BB162981-1, ISCO® Interchim; 40 g SiO2, CHCl3 / CH3CN withCH3CN from 0 to 95%, flow rate = 40 mL / min, Rf = 7-8CV.), yielding almoxt pure(90% by 1H-NMR) 2-cyano-3-[4-(trifluoromethyl)phenyl]propanamide (700.0 mg,2.89 mmol, 50.3% two-step yield) as yellow oil, which was used directly into nextstep. Step C: The synthesis of 3-amino-2-{[4- (trifluoromethyl)phenyl]methyl}propenamide To a stirred solution of 2-cyano-3-[4-(trifluoromethyl)phenyl]propanamide (700.0 mg, 2.89 mmol) in 7N NH3solution in MeOH (50 ml), freshly prepared RaNi (0.5 g) was added and the resulting suspension was stirred at RT, under H2 atmosphere (10 atm.) for 16h., after which the reaction mixture was filtered through a short plug of silica (approx.4 cm high, 15g of SiO2), eluted with MeOH (3x30 ml) and the filtrate was evaporated to dryness, yielding 3-amino-2-[4- (trifluoromethyl)phenyl]methylpropanamide (460.0 mg, 1.87 mmol, 64.6% yield) as orange oil, which slowly crystalized. 10294PC00 Step D: The synthesis of 3-{[2-(3,4-difluorophenyl)morpholine-4- carbonyl]amino}-2-{[4-(trifluoromethyl)phenyl]methyl}propanamide To a stirred solution of 2-(3,4-difluorophenyl)morpholine (63.0 mg, 316.45 µmol) and ethylbis(propan-2-yl)amine (122.46 mg, 948.2 µmol, 170.0 µl, 3.0 equiv) in dry CH3CN (2 ml), ditrichloromethyl carbonate (41.79 mg, 142.23 µmol) was added at - 30°C (reaction mixture changed color from beige to yellowish) and the resulting suspension was allowed to warm up to 0°C (15 min at this scale). Then ditrichloromethyl carbonate (41.79 mg, 142.23 µmol) was added at once and the resulting mixture was warmed to RT, and stirred at 50°C for 14 h. The reaction mixture was evaporated to dryness, dry DMSO (2 ml) was added and it was then subjected to HPLC (SYSTEM 0-2-6 mn 55-65-65% H2O / R1 , flow 30 ml / min ((loading pump 4 ml R1) column : Chromatorex C18 SMB100-5T 100*19mm, 5 microM target mass 471), yielding 3-[2-(3,4-difluorophenyl)morpholine-4- carbonyl]amino-2-[4-(trifluoromethyl)phenyl]methylpropanamide (14.8 mg, 31.39µmol, 9.9% yield). LC-MS: m / z 472.2 [M+1]+.Example 26 N-[2-(hydroxymethyl)-3-(p-tolyl)propyl]-2-[(4- methoxyphenyl)methyl]morpholine-4-carboxamide The preparation of Example 26 was performed as described in Example 21 using 2-[(4-methoxyphenyl)methyl]morpholine (0.25mmol) and 3-amino-2-[(4- chlorophenyl)methyl]propan-1-ol hydrochloride (CAS: 1375474-55-7; 0.25mmol) yielding 27.1mg (25% yield). LC-MS (tR): 1.174 min; ESI-MS (m / z): 433.2 [M]+,431.2 [M]-. Example 48 N-[2-(hydroxymethyl)-3-[4-(trifluoromethoxy)phenyl]propyl]-2-[(4- methoxyphenyl)methyl]morpholine-4-carboxamide 10294PC00 The preparation of Example 48 was performed as described in Example 21 using 2- [(4-methoxyphenyl)methyl]morpholine (0.25mmol) and 3-amino-2-{[4-(trifluoromethoxy)phenyl]methyl}propan-1-ol (CAS: 1019119-11-9; 0.25mmol)yielding 22.1mg (18% yield). LC-MS (tR): 1.178 min; ESI-MS (m / z): 483.2 [M]+,481 [M]-. Example 27, 30-47, 49:All compounds (Example 27, 30-47, 49) were synthesized from 3-amino-2-{[4-(trifluoromethyl)phenyl]methyl}propan-1-ol (prepared in Example 22, Step D+Efrom commercially available Ethyl 2-cyano-3-[4-(trifluoromethyl)phenyl]acrylate(CAS 149550-21-0), and Amine A (table below) at 0.25 mmol scale, by the Generalprocedure described for Example 22, Step F. Synthesis results are listed in below table ExamplCompound Name Chemical structuree N-[2-(hydroxymethyl)- 3-[4- 27 (trifluoromethyl)phenyl] propyl]-2-(5-methyl-2- furyl)morpholine-4- carboxamide N-[2-(hydroxymethyl)- 3-[4- (trifluoromethyl)phenyl] 30 propyl]-2-[(4- methylpyrazol-1- yl)methyl]morpholine- 4-carboxamide 2-[(3,5- dimethylpyrazol-1- yl)methyl]-N-[2- 31 (hydroxymethyl)-3-[4- (trifluoromethyl)phenyl] propyl]morpholine-4- carboxamide 10294PC00 N-[2-(hydroxymethyl)- 3-[4- 32 (trifluoromethyl)phenyl] propyl]-2-(3- methoxyphenyl)morpho line-4-carboxamide N-[2-(hydroxymethyl)- 3-[4- (trifluoromethyl)phenyl] 33 propyl]-2-(4- methylsulfonylphenyl)m orpholine-4- carboxamide N-[2-(hydroxymethyl)- 3-[4- (trifluoromethyl)phenyl] 34 propyl]-2- (methanesulfonamidom ethyl)morpholine-4- carboxamide N-[2-(hydroxymethyl)- 3-[4- (trifluoromethyl)phenyl] 35 propyl]-2-(5-isopropyl- 1,2,4-oxadiazol-3- yl)morpholine-4- carboxamide 2-[2- (dimethylamino)pyrimid in-4-yl]-N-[2- 36 (hydroxymethyl)-3-[4- (trifluoromethyl)phenyl] propyl]morpholine-4- carboxamide N-[2-(hydroxymethyl)- 3-[4- 37 (trifluoromethyl)phenyl] propyl]-2-(6-methyl-3- pyridyl)morpholine-4- carboxamide 2-(3-cyclopropyl-1,2,4- oxadiazol-5-yl)-N-[2- 38 (hydroxymethyl)-3-[4- (trifluoromethyl)phenyl] propyl]morpholine-4- carboxamide 2-(3-cyanophenyl)-N- [2-(hydroxymethyl)-3- 39 [4- (trifluoromethyl)phenyl] propyl]morpholine-4- carboxamide 10294PC00 (2S)-N-[2- (hydroxymethyl)-3-[4- 40 (trifluoromethyl)phenyl] propyl]-2-isobutyl- morpholine-4- carboxamide N-[2-(hydroxymethyl)- 3-[4- (trifluoromethyl)phenyl] 41 propyl]-2-(2- methoxyethoxymethyl) morpholine-4- carboxamide 2-(3-furyl)-N-[2- (hydroxymethyl)-3-[4- 42 (trifluoromethyl)phenyl] propyl]morpholine-4- carboxamide N-[2-(hydroxymethyl)- 3-[4- 43 (trifluoromethyl)phenyl] propyl]-2-(2- pyridyl)morpholine-4- carboxamide N-[2-(hydroxymethyl)- 3-[4- 44 (trifluoromethyl)phenyl] propyl]-2-(3- nitrophenyl)morpholine- 4-carboxamide N-[2-(hydroxymethyl)- 3-[4- 45 (trifluoromethyl)phenyl] propyl]-2-(4- methoxyphenyl)morpho line-4-carboxamide N-[2-(hydroxymethyl)- 3-[4- 46 (trifluoromethyl)phenyl] propyl]-2-(3- pyridyl)morpholine-4- carboxamide N-[2-(hydroxymethyl)- 3-[4- 47 (trifluoromethyl)phenyl] propyl]-2-(2-methoxy- 4-pyridyl)morpholine-4- carboxamide 2-(4-aminophenyl)-N- [2-(hydroxymethyl)-3- 49 [4- (trifluoromethyl)phenyl] propyl]morpholine-4- carboxamide 10294PC00 Isolated Example mass Amine A Name LC-MS: m / z [M+1]+ (mg) YieldLC-MS (tR): 1.191 min; ESI- 27 2-(5-methylfuran-2-MS (m / z): 427.2 [M]+,425.2 yl)morpholine[M]-. 71.8 67.3%LC-MS (tR): 1.272 min; ESI- 30 2-[(4-methyl-1H-pyrazol-MS (m / z): 441.2 [M]+,439.2 1-yl)methyl]morpholine[M]-. 61.4 55.8%2-[(3,5-dimethyl-1H- LC-MS (tR): 1.282 min; ESI- 31 pyrazol-1- MS (m / z): 455.2 [M]+,453.2 yl)methyl]morpholine[M]-. 53.1 46.7%2-(3- LC-MS (tR): 1.391 min; ESI- 32 methoxyphenyl)morpholin MS (m / z): 453.2 [M]+,451.2 e[M]-. 54.2 47.9%2-(4- LC-MS (tR): 1.259 min; ESI- 33 methanesulfonylphenyl)m MS (m / z): 501.2 [M]+,499 [M]- orpholine hydrochloride. 29.3 23.4%N-[(morpholin-2- 34 yl)methyl]methanesulfona LC-MS (tR): 1.129 min; ESI- mideMS (m / z): 454 [M]+,452 [M]-. 52.7 46.5%2-[5-(propan-2-yl)-1,2,4- LC-MS (tR): 1.360 min; ESI- 35 oxadiazol-3-yl]morpholine MS (m / z): 457.2 [M]+,455.2 hydrochloride[M]-. 46.2 40.5%N,N-dimethyl-4- LC-MS (tR): 1.290 min; ESI- 36 (morpholin-2-yl)pyrimidin- MS (m / z): 468.2 [M]+,466 [M]- 2-amine. 46.2 39.5%2-(6-methylpyridin-3- LC-MS (tR): 1.022 min; ESI- 37 yl)morpholine MS (m / z): 438.2 [M]+,436 [M]- dihydrochloride. 41.8 38.2%2-(3-cyclopropyl-1,2,4- LC-MS (tR): 1.320 min; ESI- 38 oxadiazol-5-yl)morpholine MS (m / z): 455.2 [M]+,453.2 hydrochloride[M]-. 44.8 39.4% 10294PC00 3-(morpholin-2- LC-MS (tR): 1.110 min; ESI- 39 yl)benzonitrile MS (m / z): 448.2 [M]+,446 [M]- hydrochloride. 27.5 24.6%(2S)-2-(2- LC-MS (tR): 1.282 min; ESI- 40 methylpropyl)morpholine MS (m / z): 403.2 [M]+,401 [M]- hydrochloride. 50.1 49.8%2-[(2- LC-MS (tR): 0.986 min; ESI- 41 methoxyethoxy)methyl]m MS (m / z): 435.2 [M]+,433 [M]- orpholine. 43.2 39.8%2-(furan-3-yl)morpholine, LC-MS (tR): 1.054 min; ESI- 42 oxalic acidMS (m / z): 413 [M]+,411 [M]-. 30 29.1%LC-MS (tR): 1.034 min; ESI- 43 MS (m / z): 424.2 [M]+,422 [M]- 2-(pyridin-2-yl)morpholine. 32.1 30.3%2-(3- 44 nitrophenyl)morpholine LC-MS (tR): 1.258 min; ESI- hydrochlorideMS (m / z): 468 [M]+,466 [M]-. 33.5 28.7%2-(4- 45 methoxyphenyl)morpholin LC-MS (tR): 1.237 min; ESI- eMS (m / z): 453 [M]+,451 [M]-. 50.4 44.6%LC-MS (tR): 0.816 min; ESI- 46 2-(pyridin-3-yl)morpholineMS (m / z): 424.2 [M]+,422 [M]- dihydrochloride. 23 21.7%2-(2-methoxypyridin-4- LC-MS (tR): 1.173 min; ESI- 47 yl)morpholineMS (m / z): 454 [M]+,452 [M]-. 8 7.1%LC-MS (tR): 0.868 min; ESI- 49 MS (m / z): 438.2 [M]+,436 [M]- 4-(morpholin-2-yl)aniline. 15.6 14.3%Preparation of intermediates 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-(3,4-difluoro benzyl) propyl) carbamate: 10294PC00 The intermediate 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-(3,4-difluorobenzyl) propyl) carbamate used to prepare Example 5 followed the same route as thatdescribed for the synthesis of 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2- (4-(trifluoromethyl) benzyl) propyl) carbamate (vide supra). LC-MS: Product does not ionize under the conditions used. 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(furan-3-ylmethyl) propyl) carbamate The intermediate 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(furan-3-ylmethyl) propyl) carbamate used to prepare Example 6 followed the same route asthat described for the synthesis of 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-(4-(trifluoromethyl) benzyl) propyl) carbamate (vide supra). LC-MS: m / z444.1 [M+1]+. 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-(pyridin-3- ylmethyl)propyl)carbamate The intermediate 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-(pyridin-3-ylmethyl)propyl)carbamate used to prepare Example 7 followed the same route as thatdescribed for the synthesis of 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(4-(trifluoromethyl) benzyl) propyl) carbamate (vide supra). LC-MS: m / z 457.05 [M+1]+50% yield as colourless liquid. 10294PC00 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-((1-methyl-1H-pyrazol-4- yl)methyl)propyl)carbamate The intermediate 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-((1-methyl-1H-pyrazol-4-yl)methyl)propyl)carbamate used to prepare Example 8 followed thegeneral route as that described for the synthesis of 2,2,2-trichloroethyl (3-((tert- butyldimethylsilyl) oxy)-2-(4-(trifluoromethyl) benzyl) propyl) carbamate (videsupra). LC-MS: The product peak did not ionize under the conditions used. 89%yield as light yellow liquid. 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-(pyridin-2- ylmethyl)propyl)carbamate The intermediate 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-(pyridin-2-ylmethyl)propyl)carbamate used to prepare Example 9 followed the general route asthat described for the synthesis of 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(4-(trifluoromethyl) benzyl) propyl) carbamate (vide supra). LC-MS: m / z 506.3 [M+1]+. 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(3-(trifluoromethoxy)- benzyl) propyl)carbamate The intermediate 2,2,2-trichloroethyl (3-((tert-butyl dimethylsilyl)oxy)-2-(3-(trifluoromethoxy) benzyl) propyl)carbamate used to prepare Example 10 followedthe general route as that described for the synthesis of 2,2,2-trichloroethyl (3-((tert- butyldimethylsilyl) oxy)-2-(4-(trifluoromethyl) benzyl) propyl) carbamate (vide 10294PC00supra). The product peak did not ionize under the conditions used. 73% yield as ayellow liquid. 2,2,2-trichloroethyl (3-((tert-butyl dimethylsilyl)oxy)-2-(4-(trifluoromethoxy) benzyl) propyl)carbamate The intermediate 2,2,2-trichloroethyl (3-((tert-butyl dimethylsilyl)oxy)-2-(4-(trifluoromethoxy) benzyl) propyl)carbamate used to prepare Example 11 followedthe general route as that described for the synthesis of 2,2,2-trichloroethyl (3-((tert- butyldimethylsilyl) oxy)-2-(4-(trifluoromethyl) benzyl) propyl) carbamate (videsupra). LC-MS: m / z 483.1 [ M+1]+ 57% yield as colourless liquid.2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(3-methylbenzyl) propyl)carbamate The intermediate 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(3-methylbenzyl) propyl)carbamate used to prepare example 12 followed the generalroute as that described for the synthesis of 2,2,2-trichloroethyl (3-((tert- butyldimethylsilyl) oxy)-2-(4-(trifluoromethyl) benzyl) propyl) carbamate (videsupra). LC-MS: m / z 469.75 [ M+1]+ 59% yield as colourless liquid.2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(2,4-difluorobenzyl) propyl) carbamate 10294PC00 The intermediate 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(2,4-difluorobenzyl) propyl) carbamate used to prepare example 13 followed the generalroute as that described for the synthesis of 2,2,2-trichloroethyl (3-((tert- butyldimethylsilyl) oxy)-2-(4-(trifluoromethyl) benzyl) propyl) carbamate (videsupra). LC-MS: m / z 491.85 [M+1]+ 41% yield as colourless liquid.2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(3-chlorobenzyl) propyl) carbamate The intermediate 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(3-chlorobenzyl) propyl) carbamate used to prepare example 14 followed the generalroute as that described for the synthesis of 2,2,2-trichloroethyl (3-((tert- butyldimethylsilyl) oxy)-2-(4-(trifluoromethyl) benzyl) propyl) carbamate (videsupra). The product did not ionize under the conditions used. LC-MS: m / z 469.75 [M+1]+32% yield as colourless liquid. 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-(3-((tert- butyldimethylsilyl)oxy)-4-methoxybenzyl)propyl)carbamate Step 1: Synthesis of ethyl (E)-2-cyano-3-(3-hydroxy-4-methoxyphenyl)acrylate: To a stirred solution of 3-hydroxy-4-methoxybenzaldehyde (3.0 g, 19.72 mmol, 1.0 eq.) in EtOH was added ethyl 2-cyanoacetate (2.68 g, 23.66 mmol,1.2 eq) followed by piperidine (0.195 ml, 1.972 mmol, 0.1eq.). Stirring was continued at RT for 16h.The reaction mixture was concentrated to remove and then diluted with water and extracted with ethyl acetate. The organic layer was washed with water, saturated brine solution,and dried over sodium sulphate, evaporated to dryness to afford ethyl (E)-2-cyano-3- 10294PC00 (3-hydroxy-4-methoxyphenyl)acrylate (3.5 g, 14.160 mmol, yield: 71.8%) as a colorless liquid. LCMS m / z 246.20 [M-1] -.Step 2: Synthesis of 3-hydroxy-2-(3-hydroxy-4-methoxybenzyl)propanenitrile: To a stirred solution of ethyl (E)-2-cyano-3-(3-hydroxy-4-methoxyphenyl)acrylate (2.0 g, 8.09 mmol, 1.0 eq.) in ethanol (20 mL) was added NaBH4 (0.612 g, 16.18 mmol, 2.eq) at 0 °C in portion wise. The reaction mixture was allowed to warm to RT over 1h, evaporated to remove ethanol and diluted with ethyl acetate. Water was added. Theorganic layer was washed with saturated brine solution, dried over sodium sulphate, and concentrated under vacuum to afford 3-hydroxy-2-(3-hydroxy-4- methoxybenzyl)propanenitrile (2.0 g, crude) as a colorless liquid. LC-MS: The titlecompound did not ionize under the conditions used. Step 3: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-2-(3-((tert-butyldimethyl silyl)oxy)-4-methoxybenzyl) propanenitrile: To a stirred solution of 3-hydroxy-2-(3-hydroxy-4-methoxybenzyl)propanenitrile (2.0g, 9.65 mmol, 1.0 eq.) in dichloromethane (10 ml) was added Et3N (4.03 ml, 29.0 mmol, 3.0 eq.) and DMAP (1.178 g, 9.65 mmol, 1.0 eq). The mixture was cooled to 0 oC andthen added TBDMS (2.90 g, 19.30 mmol, 1.5 eq). The reaction mixture was stirred for 16h. The RM was diluted with water and extracted with DCM. The organic layer waswashed with water, saturated brine solution, dried over sodium sulphate and concentrated under vacuum. The crude product was purified on silica gel using 20% 10294PC00 ethyl acetate and hexane as eluent to afford 3-((tert-butyldimethylsilyl)oxy)-2-(3-((tert- butyldimethylsilyl)oxy)-4-methoxybenzyl)propanenitrile (1.50 g, 3.440 mmol,35.70%) as a colorless liquid. LCMS m / z 436.20 [ M+1] +.Step 4: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-2-(3-((tert-butyldimethylsilyl)oxy)-4-methoxybenzyl)propanenitrile: To a stirred solution of 3-((tert-butyldimethylsilyl)oxy)-2-(3-((tert- butyldimethylsilyl)oxy)-4-methoxybenzyl)propanenitrile (1.5 g, 3.44 mmol, 1.0 eq.) in EtOH (10 mL) was added NH3 solution (2.0 M in methanol; 10 mL), Raney Ni (1.489 g, 17.21 mmol, 5.0 eq.). The reaction mixture was allowed to warm to RT and then stirred for 16 h in H2atmosphere (hydrogen balloon) . The reaction mixture was filtered through a celite bed and washed with 10 % MeOH in DCM. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford ((tert- butyldimethylsilyl)oxy)-2-(2,4-difluorobenzyl) propan-1-amine (1.2 g, crude) as a colorless liquid. LCMS m / z 440.20 [ M+1]+. Step 5: Synthesis of 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-(3- ((tert-butyldimethylsilyl)oxy)-4-methoxybenzyl)propyl)carbamate: 10294PC00 To a stirred solution of 3-((tert-butyldimethylsilyl)oxy)-2-(3-((tert- butyldimethylsilyl)oxy)-4-methoxybenzyl)propan-1-amine (0.5 g, 1.137 mmol), 1.0eq.) in DCM (10 mL) at 0 °C was added DIPEA (0.596 ml, 3.41 mmol, 3.0 eq.)followed by 2,2,2-trichloroethyl carbonochloridate (0.361 mL, 1.705 mmol, 1.5 eq.).The reaction was stirred at RT for 16h. The reaction mixture was quenched with waterand extracted with DCM. The organic layer was washed with saturated brine solution, dried over sodium sulphate and evaporated to dryness. The crude material was purified by silica gel using 20% ethyl acetate and hexane to afford 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(3-((tert-butyldimethylsilyl)oxy)-4- methoxybenzyl)propyl) carbamate (0.52 g, 0.845 mmol, yield: 74.3%) as a colorless liquid. LC-MS: The product did not ionize under the conditions used. 2,2,2-trichloroethyl (2-benzyl-3((tert-butyldimethylsilyl)oxy) propyl) carbamate The intermediate 2,2,2-trichloroethyl (2-benzyl-3((tert-butyldimethylsilyl)oxy)propyl) carbamate used to prepare example 16 followed the general route as thatdescribed for the synthesis of 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2- (4-(trifluoromethyl) benzyl) propyl) carbamate (vide supra). LC-MS: The title compound did not ionize under the conditions used 63% yield as yellow liquid. 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-(pyridin-4- ylmethyl)propyl)carbamate The intermediate 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-(pyridin-4-ylmethyl)propyl)carbamate used to prepare example 17 followed the general route asthat described for the synthesis of 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl) oxy)-2-(4-(trifluoromethyl) benzyl) propyl) carbamate (vide supra). LC-MS m / z 455.1 [M+1]+.50% yield as yellow liquid. 10294PC00 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-(3,4 dimethoxy- benzyl)propyl)carbamate The intermediate 2,2,2-trichloroethyl (3-((tert-butyldimethylsilyl)oxy)-2-(3,4dimethoxy-benzyl)propyl)carbamate used to prepare example 18 followed the generalroute as that described for the synthesis of 2,2,2-trichloroethyl (3-((tert- butyldimethylsilyl) oxy)-2-(4-(trifluoromethyl) benzyl) propyl) carbamate (vide supra). LC-MS: The title product did not ionize under the conditions used.55% yield as yellow liquid. 2-[(4-methoxyphenyl)methyl]morpholine Step A: tert-butyl 2-[(4-methoxyphenyl)methyl]morpholine-4-carboxylateTo a stirred suspension of zinc (416.38 mg, 6.51 mmol), lithium iodide (178.74 mg,1.33 mmol), 4-([(4-oxopent-2-en-2-yl)oxy]nickeliooxy)pent-3-en-2-one (45.56 mg, 177.95 µmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (42.02 mg, 177.95 µmol), 1,3- dimethyl-1,3-diazinan-2-one (455.8 mg, 3.56 mmol, 430.0 µl, 2.0 equiv) and 1- bromo-4-methoxybenzene (330.94 mg, 1.78 mmol, 220.0 µl, 1.0 equiv) in dry DMA (9 ml), tert-butyl 2-(bromomethyl)morpholine-4-carboxylate (496.57 mg, 1.78 mmol,8.9 ml, 1.0 equiv) was added (at once) at r.t., and under Ar atmosphere. The resultingmixture was stirred at 60°C for 16h. After cooling to r.t., evaporated and subjected to flash Chromatography. Step B: 2-[(4-methoxyphenyl)methyl]morpholine 10294PC00 tert-Butyl 2-[(4-methoxyphenyl)methyl]morpholine-4-carboxylate (200.0 mg, 650.65 µmol) was dissolved in TFA (2 ml) and the resulting mixture was stirred at 40°C for1h. The volatiles were removed in vacuo and the resulting residue was diluted withwater (2 ml) and DCM (5 ml). pH was adjusted to 12 with NaOH (2M aq. solution). Organic layer was separated and aqueous layer was extracted by DCM (2x5 ml). The organic layers were combined, dried over anhydrous sodium sulfate and evaporated in vacuo, yielding almost pure (92% by LCMS) 2-[(4- methoxyphenyl)methyl]morpholine (140 mg, 675 µmol, 95% approx. yield) asyellow oil, which was used directly in the next step.List of abbreviations: RT: Room temperature DCM: Dichloromethane EtOH: abs. Ethanol HPLC: High Performance Liquid Chromatography TBAF: tetra-N-butylammonium fluoride DMAP: Dimethyl-4-aminopyridine TBDMS: tert-Butyldimethylsilyl chloride DIPEA: Diisopropylethylamine THF: Tetrahydrofurane TLC: Thin layer chromatography UPLC-MS: Ultra-High Performance Liquid Chromatography Mass Spectroscopy Detection EtOAc: Ethylacetate DMSO: Dimethylsulfoxide IPA: Isopropylalcohol MeOH: Methanol TFA: Trifluoroacetic acid LiAlH4: Lithium aluminium tetrahydride h: hour MW: Microwave reactor

Claims

10294PC00 Claims 1. A compound of general formula (I)wherein m is 0-2, wherein when m is 0 the R1group is linked directly to the carbon atom of the morpholino ring, n is 0-2, wherein when n is 0 the R4group is linked directly to the carbon atom having the R3group linked thereto, R1is selected from the group consisting of a) phenyl optionally substituted with one or more groups selected from SO2CH3, CN, NH2, NO2, halogen, OH, C1-3alkyl optionally substituted with a halogen, OC1-6 alkyl optionally substituted with a halogen; b) furyl optionally substituted with one or more groups selected from halogen, OC1-3alkyl, OC1-3alkylene-OC1-3alkyl, C1-3alkyl, CN; c) pyridyl optionally substituted with one or more groups selected from halogen, OC1-3 alkyl, OC1-3 alkylene-OC1-3 alkyl, C1-3 alkyl, CN; d) pyrazolyl substituted with one or more groups selected from halogen, C1-3 alkyl optionally substituted with a halogen; e) thiazolyl optionally substituted with one or more groups selected from C1-3 alkyl; f) pyrazinyl substituted with one or more groups selected from C1-3alkyl, OC1-6 alkyl; g) oxadiazolyl substituted with one or more groups selected from isopropyl, cyclopropyl, C1-3alkyl and (CH2)0-1-phenyl substituted with one or more groups selected from halogen and C1-3 alkyl;10294PC00 h) triazolyl substituted with one or more groups selected from C1-3alkyl, cyclopropyl and phenyl; i) quinoxalinyl substituted with one or more groups selected from C1-3 alkyl; j) tetrazolyl substituted with one or more groups selected from C1-3alkyl and phenyl optionally substituted with a C1-3alkyl; k) indazolyl substituted with one or more groups selected from C1-3 alkyl; l) oxazolyl substituted with one or more groups selected from C1-3 alkyl and phenyl optionally substituted with a O C1-6alkyl; m) 4-oxo-quinazolinyl substituted with one or more groups selected from C1-3alkyl; n) isoxazolyl substituted with one or more groups selected from halogen, C1-3alkyl, cyclopropyl and phenyl optionally substituted with a group selected from halogen and OC1-6 alkyl; o) imidazolyl substituted with one or more groups selected from C1-3alkyl; p) quinolyl substituted with one or more groups selected from C1-3alkyl; q) thiadiazolyl substituted with one or more groups selected from C1-3 alkyl; r) pyridazinyl substituted with one or more groups selected from OC1-3 alkyl; s) benzoxazolyl substituted with one or more groups selected from C1-3 alkyl;t) imidazole[1,2-a]pyrimidinyl substituted with one or more groups selected from C1-3 alkyl; u) 6-oxo-pyridinyl; v) C1-6alkyl; w) C1-3 alkyl substituted with one group selected from CH3SO2NH and CH3OCH2CH2O;10294PC00 x) CONR5R6where R5and R6are independently selected from hydrogen and C1-3alkyl; y) pyrimidinyl substituted with one or more groups selected from NR7R8where R7and R8are independently selected from hydrogen and C1-3 alkyl; and z) isopropyl or isobutyl, R2is selected from the group consisting of hydrogen and methyl, R3is selected from the group consisting of OH, CONH2 and C1-3 alkyl-OH; R4is selected from the group consisting of a) phenyl optionally substituted with one or more groups selected from SO2CH3, CN, NH2, NO2, halogen, OH, C1-3 alkyl optionally substituted with a halogen, OC1-6alkyl optionally substituted with a halogen; b) furyl optionally substituted with one or more groups selected from halogen, OC1-3 alkyl, OC1-3 alkylene-OC1-3 alkyl, C1-3 alkyl, CN; c) pyridyl optionally substituted with one or more groups selected from halogen, OC1-3alkyl, OC1-3alkylene-OC1-3alkyl, C1-3alkyl, CN; d) pyrazolyl substituted with one or more groups selected from halogen, C1-3 alkyl optionally substituted with a halogen; e) thiazolyl optionally substituted with one or more groups selected from C1-3alkyl; f) pyrazinyl substituted with one or more groups selected from C1-3 alkyl, OC1-6alkyl; g) oxadiazolyl substituted with one or more groups selected from C1-3alkyl,isopropyl, cyclopropyl, and (CH2)0-1-phenyl substituted with one or more groupsselected from halogen and C1-3alkyl; h) triazolyl substituted with one or more groups selected from C1-3alkyl, cyclopropyl and phenyl; i) quinoxalinyl substituted with one or more groups selected from C1-3 alkyl; j) tetrazolyl substituted with one or more groups selected from C1-3alkyl and phenyl optionally substituted with a C1-3 alkyl;10294PC00 k) indazolyl substituted with one or more groups selected from C1-3alkyl; l) oxazolyl substituted with one or more groups selected from C1-3alkyl and phenyl optionally substituted with a OC1-6 alkyl; m) 4-oxo-quinazolinyl substituted with one or more groups selected from C1-3alkyl; n) isoxazolyl substituted with one or more groups selected from halogen, C1-3 alkyl, cyclopropyl and phenyl optionally substituted with a group selected from halogen and OC1-6alkyl; o) imidazolyl substituted with one or more groups selected from C1-3 alkyl; p) quinolyl substituted with one or more groups selected from C1-3 alkyl; q) thiadiazolyl substituted with one or more groups selected from C1-3alkyl; r) pyridazinyl substituted with one or more groups selected from OC1-3alkyl; s) benzoxazolyl substituted with one or more groups selected from C1-3 alkyl; t) imidazole[1,2-a]pyrimidinyl substituted with one or more groups selected from C1-3alkyl; u) 6-oxo-pyridinyl; v) C1-6 alkyl; w) C1-3alkyl substituted with one group selected from CH3SO2NH and CH3OCH2CH2O; x) CONR5aR6awhere R5aand R6aare independently selected from hydrogen and C1-3 alkyl, y) pyrimidinyl substituted with one or more groups selected from NR7aR8awhere R7aand R8aare independently selected from hydrogen and C1-3 alkyl; and z) isopropyl or isobutyl; or a pharmaceutically acceptable salt thereof.10294PC00 2. The compound of claim 1 wherein n is 1 and m is 0.

3. The compound of claim 1 wherein n is 1 and m is 1.

4. The compound of any one of claims 1-3 wherein R1is selected from the group consisting of a) phenyl substituted with at least one selected from halogen, and OC1-6 alkyl; b) phenyl substituted with at least one selected from SO2CH3, CN, NH2 andNO2; c) pyrimidyl substituted with at least one selected from NR7R8 where R7 and R8are independently selected from hydrogen and C1-3 alkyl; d) oxadiazolyl substitutedwith at least one selected from cyclopropyl; and e) R1 is isopropyl or isobutyl.

5. The compound of any one of claims 1-4 wherein R2is hydrogen.

6. The compound of any one of claims 1-5 wherein R3is selected from the group consisting of OH, CONH2and CH2-OH, preferably CH2-OH.

7. The compound of any one of claims 1-6 wherein R4is phenyl optionally substituted with at least one selected from halogen, C1-3alkyl optionally substituted with a halogen, OH, and OC1-3 alkyl optionally substituted with a halogen.

8. The compound of any one of claims 1-6 wherein R4is selected from the group consisting of furyl, pyridyl, pyrazolyl optionally substituted with a group selected from halogen and C1-3 alkyl.

9. The compound of any one of claims 1-6 wherein R4 is C1-6 alkyl.

10. The compound of claim 1 selected from any one of 2-(3,4-difluorophenyl)-N-[3-hydroxy-2-[(3-hydroxy-4-methoxy- phenyl)methyl]propyl]morpholine-4-carboxamide, N-[2-[(4-chlorophenyl)methyl]-3-hydroxy-propyl]-2-(3,4-difluorophenyl)morpholine- 4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-[(4- methoxyphenyl)methyl]morpholine-4-carboxamide,10294PC00 2-(3,4-difluorophenyl)-N-[2-[(3,4-difluorophenyl)methyl]-3-hydroxy- propyl]morpholine-4-carboxamide, 2-(3,4-difluorophenyl)-N-[2-(3-furylmethyl)-3-hydroxy-propyl]morpholine-4- carboxamide, 2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-(3-pyridyl)propyl]morpholine-4- carboxamide, N-[2-[(3-bromo-4-methoxy-phenyl)methyl]-3-hydroxy-propyl]-2-(3,4- difluorophenyl)morpholine-4-carboxamide, 2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-(1-methylpyrazol-4- yl)propyl]morpholine-4-carboxamide, 2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-(2-pyridyl)propyl]morpholine-4- carboxamide, 2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-[3- (trifluoromethoxy)phenyl]propyl]morpholine-4-carboxamide, 2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-[4- (trifluoromethoxy)phenyl]propyl]morpholine-4-carboxamide, N-(2-benzyl-3-hydroxy-propyl)-2-(3,4-difluorophenyl)morpholine-4-carboxamide, (2S,2R)-N-(3-hydroxy-2-{[4-(trifluoromethyl)phenyl]methyl}propyl)-2-[(4- methoxyphenyl)methyl]morpholine-4-carboxamide, (2S,2S)-N-(3-hydroxy-2-{[4-(trifluoromethyl)phenyl]methyl}propyl)-2-[(4- methoxyphenyl)methyl]morpholine-4-carboxamide,2-(3,4-difluorophenyl)-N-[2- (hydroxymethyl)-3-(m-tolyl)propyl]morpholine-4-carboxamide, 2-(3,4-difluorophenyl)-N-[2-[(2,4-difluorophenyl)methyl]-3-hydroxy- propyl]morpholine-4-carboxamide, 2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-(4-pyridyl)propyl]morpholine-4- carboxamide, 2-(3,4-difluorophenyl)-N-[2-[(3,4-dimethoxyphenyl)methyl]-3-hydroxy- propyl]morpholine-4-carboxamide, 2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-(4- methoxyphenyl)propyl]morpholine-4-carboxamide, N-[2-[(3-chlorophenyl)methyl]-3-hydroxy-propyl]-2-(3,4-difluorophenyl)morpholine- 4-carboxamide, (R,R)-2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide,10294PC00 (S,R)-2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, (R,S)-2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, (S,S)-2-(3,4-difluorophenyl)-N-[2-(hydroxymethyl)-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, 2-(3,4-difluorophenyl)-N-[2-hydroxy-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, N-[3-amino-3-oxo-2-[[4-(trifluoromethyl)phenyl]methyl]propyl]-2-(3,4- difluorophenyl)morpholine-4-carboxamide, (2R)-N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-[(4- methoxyphenyl)methyl]morpholine-4-carboxamide, (2S)-N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-[(4- methoxyphenyl)methyl]morpholine-4-carboxamide, racemic-(2S)-N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-[(4- methoxyphenyl)methyl]morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(3- nitrophenyl)morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(3- methoxyphenyl)morpholine-4-carboxamide, 2-(3-cyanophenyl)-N-[2-(hydroxymethyl)-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, N-[2-[(4-chlorophenyl)methyl]-3-hydroxy-propyl]-2-[(4- methoxyphenyl)methyl]morpholine-4-carboxamide, 2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N-[2-(hydroxymethyl)-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, 2-[(3,5-dimethylpyrazol-1-yl)methyl]-N-[2-(hydroxymethyl)-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(4- methoxyphenyl)morpholine-4-carboxamide, (2S)-N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-isobutyl- morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-[(4-methylpyrazol-1- yl)methyl]morpholine-4-carboxamide,10294PC00 N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(4- methylsulfonylphenyl)morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(6-methyl-3- pyridyl)morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(5-isopropyl-1,2,4- oxadiazol-3-yl)morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(2-methoxy-4- pyridyl)morpholine-4-carboxamide, 2-[2-(dimethylamino)pyrimidin-4-yl]-N-[2-(hydroxymethyl)-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, 2-(4-aminophenyl)-N-[2-(hydroxymethyl)-3-[4- (trifluoromethyl)phenyl]propyl]morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(5-methyl-2- furyl)morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(3- pyridyl)morpholine-4-carboxamide, 2-(3-furyl)-N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]morpholine-4- carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2- (methanesulfonamidomethyl)morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(2- methoxyethoxymethyl)morpholine-4-carboxamide, N-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]propyl]-2-(2- pyridyl)morpholine-4-carboxamide, and N-[2-(hydroxymethyl)-3-[4-(trifluoromethoxy)phenyl]propyl]-2-[(4-methoxyphenyl)methyl]morpholine-4-carboxamide; ora pharmaceutically acceptable salt or solvate thereof.

11. A compound of any one of claims 1-10 for use as a medicament.

12. A pharmaceutical composition comprising a compound of any one of claims 1-10 and at least one pharmaceutically acceptable adjuvant, diluent, excipient and / or carrier.10294PC0013. A compound of any one of claims 1-11 for use in a method for treating diabetes orpre-diabetes, such as type 1 or type 2 diabetes, in a subject in need thereof.

14. A compound of any one of claims 1-11 for use in treatment of diabetes or pre-diabetes, such as type 1 or type 2 diabetes, in a subject in need thereof.

15. A compound of any one of claims 1-11 for use in preventing the progress of diabetes and / or preventing progress of prediabetes to diabetes and / or reversal of diabetes and / or for reversal of diabetes due to reversal of beta cell dysfunction in a subject in need thereof.

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