Morpholine orexin receptor antagonists

Abstract

The present invention relates to compounds of Formula (I): or pharmaceutically acceptable salts, solvates, adducts, polymorphs, and isomers thereof of orexin antagonist, compositions, and methods of using orexin antagonists to treat or prevent a disease or disorder mediated by orexin receptor activity

Description

[0001] DESCRIPTION

[0002] TITLE OF THE INVENTION: MORPHOLINE OREXIN RECEPTOR ANTAGONISTS

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to compounds, or pharmaceutically acceptable salts and derivatives thereof, that are useful as orexin antagonists; pharmaceutical compositions comprising such compounds, salts or derivatives thereof and, methods of using such compounds to treat or prevent a disease or disorder mediated by orexin receptor activity. Diseases or disorders mediated by orexin receptors include, but are not limited, to central nervous system (CNS) disorders, neurological diseases or eating disorders such as obesity, binge eating disorder (BED), schizophrenia (negative symptoms and CIAS), addiction to psychomotor stimulants such as cocaine, opiates, nicotine and alcohol, opioid use disorder, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, behaviour disorder and mood disorder depression.

[0005] BACKGROUND OF THE INVENTION

[0006] Orexins are a family of homologous peptides including species orexin A (OR-A) and orexin B (OX-B). Orexins, also known as hypocretin, are neuropeptides produced by a group of neurons located in the lateral hypothalamic area including the lateral hypothalamus and dorsomedial-perifornical area. Both orexin A (OR-A) and orexin B (OR-B) are synthesized from the precursor prepro-orexin. OR-A is a 33 amino acid-long peptide and has two intrachain disulfide bonds and OR-B is a linear 28 amino acid-long peptide. The orexin peptides bind to at least two distinct G-protein-coupled receptors, termed 0X1 and 0X2 receptors (0X1 R or 0X2R). The 0X1 receptor is selective for OR-A, with about 100-fold higher affinity than OR-B while the 0X2 receptor can bind both OR-A and OR-B with similar affinities.

[0007] Orexins have been found to stimulate food consumption, regulate states of sleep and wakefulness, and may be involved in neural mechanisms of drug abuse and addiction. The neuronal pathways and receptors via which orexins are involved in these processes seem to be partly overlapping and partly distinct. For example, findings have suggested that the

[0008] 1

[0009] SUBSTITUTE SHEET (RULE 26) arousal-promoting function of orexins is mainly promoted by 0X2 receptor whereas the role of orexin in regulating reward and feeding is predominantly mediated by 0X1 receptor.

[0010] Orexin receptors are suitable targets for the development of drug candidates for the treatment of a variety of orexin-related pathologies and symptoms, such as, but not limited to, central nervous system (CNS) disorders, sleep / wake disorders, anxiety, and obesity. Orexin receptor antagonists have been developed as potential treatments for sleep disorders such as insomnia and narcolepsy. These antagonists block the binding of orexins to their receptors, thereby reducing orexin signalling and promoting sleep. The development of orexin receptor antagonists has focused primarily on 0X2 receptor antagonists, for the regulation of arousal and wakefulness. However, there is also interest in the development of 0X1 receptor antagonists for the treatment of substance addiction, obesity and other metabolic disorders.

[0011] Patent application WO2020247447A1 is directed towards substituted pyrazole and imidazole derivatives of compounds that are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved or implicated. It also relates to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

[0012] Patent application WO2017139603A1 relates to halo-substituted piperidine compounds, pharmaceutical compositions containing them, and methods of using them, including methods for treating substance addiction, panic disorder, anxiety, post-traumatic stress disorder, pain, depression, seasonal affective disorder, an eating disorder, or hypertension.

[0013] Patent application W02002090355A1 relates to N-aroyl cyclic amine derivatives as orexin receptor antagonists and their potential use in the treatment of obesity, including obesity observed in Type 2 (non-insulin-dependent) diabetes patients, and / or sleep disorders, stroke, particularly ischemic or haemorrhagic stroke, and / or blocking the emetic response, i.e. useful in the treatment of nausea and vomiting.

[0014] Patent application WO2020247445A1 relates to substituted lmidazolo[2,1-b]oxazole, lmidazolo[2,1-b]thiazole, lmidazolo[2,1-b]oxadiazole, lmidazolo[2,1-b]oxadiathiazole derivatives as antagonists of orexin receptors, which may be used in the treatment or prevention of neurological and psychiatric disorders and disease.

[0015] 2

[0016] SUBSTITUTE SHEET (RULE 26) Patent application WO2013068935A1 relates to derivatives of 2-(1 ,2,3-triazol-2-yl)benzamide and 3-(1 ,2,3-triazol-2-yl)picolinamide and their use as orexin receptor antagonists in pharmaceutical compositions. Some of the compounds in this prior art document were found to have poor selectivity towards 0X1 R in comparison to 0X2R, and also exhibit poor metabolic stability.

[0017] However, there is still a need for developing a novel and potent selective 0X1 receptor antagonists for the treatment of a disease or disorder mediated by orexin receptor activity such as central nervous system (CNS) disorders, neurological diseases or eating disorder, sleep disorder and substance addiction. There is also a need for developing an improved brain penetrant for the treatment of a disease or disorder mediated by orexin receptor activity such as central nervous system (CNS) disorders, neurological diseases or eating disorder, sleep disorder and substance addiction.

[0018] SUMMARY OF THE INVENTION

[0019] The present invention provides novel compounds, or pharmaceutically acceptable salts and derivatives thereof, compositions and use of the compounds in the treatment or prevention of diseases or disorders mediated by orexin receptor activity. The present invention provides novel 0X1 receptor antagonists having good selectivity and binding properties, good potency, good brain penetration, improved pharmacokinetic properties, biological activities, improved solubility, good metabolic stability and chemical stability. The pharmaceutically acceptable salts and derivatives of the compounds of the present invention include, but not limited to hydrochlorides, chlorides, bromides, iodides, potassium salts, sodium salts, acetates, sulfates, sulfonates, oxalates, maleates, malonates, nitrates, tartrates, gluconates, succinates, mesylates, citrates, phosphates, diphosphate, aluminate, enantiomers, solvates, adducts, polymorphs, hydrates, tautomers, prodrugs, isotopically or radio-labelled derivatives, or isomers.

[0020] According to an aspect of the present invention, a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of general Formula I:

[0021] 3

[0022] SUBSTITUTE SHEET (RULE 26)

[0023] Formula I wherein:

[0024] X and X’ is halogen, preferably X and X’ is fluorine;

[0025] Het represents a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof, wherein said heteroaromatic group is unsubstituted, mono-, or di-substituted, wherein the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (Ci-C4)-straight chain alkyl, unsubstituted (Ci-C4)-branched alkyl, substituted (Ci-C4)-straight chain alkyl, substituted (Ci-C4)-branched alkyl, alkoxy, C3-C8)-cycloalky, a cyano group and halogen. Preferably, the substituents of the heteroaromatic group in Het comprises alkyl, fluoroalkyl alkoxy, cycloalkyl, cyano or halogen. More preferably, the substituent of the heteroaromatic group in Het is F, Cl, CHF2, CF3, methyl, methoxy, nitrile or cyclopropyl.

[0026] R is selected from the group consisting of a five or a six membered aromatic group or heteroaromatic group, wherein the aromatic group or heteroaromatic group is either unsubstituted or is substituted with one or more substituents.

[0027] Preferably, R in the compound of Formula I comprises a five membered heteroaromatic group which is an unsubstituted pyrazole, an unsubstituted oxazole, an unsubstituted thiazole, an unsubstituted imidazole, a substituted pyrazole, a substituted oxazole, a substituted thiazole, a substituted imidazole or a derivative thereof; a six membered aromatic group which is an unsubstituted aryl, or substituted aryl, or a derivative thereof; or a six membered heteroaromatic group which is an unsubstituted pyridine, an unsubstituted pyrimidine, an unsubstituted pyridazine, an unsubstituted pyrazine, a substituted pyridine, a substituted pyrimidine, a substituted pyridazine, a substituted pyrazine or a derivative thereof.

[0028] SUBSTITUTE SHEET (RULE 26) According to another aspect of the present invention, the compound of Formula I is a 5R,6S- stereoisomer:

[0029] Preferably, the compound of Formula I is a deuterated form. In particular, in certain examples, in the compound of Formula I one or more hydrogen atoms are replaced or substituted by one or more deuterium (e.g., hydrogen atoms on a (Ci-Ce)-alkyl in the side chain of the morpholine ring or a (Ci-Ce)-alkoxy are replaced with deuterium, or the hydrogen atom attached to the carbon atom next to nitrogen in morpholine ring).

[0030] According to another aspect of the present invention, the compound of Formula I is a deuterated compound having the structure as shown below.

[0031] X, X’, R and Het are each independently as defined with respect to Formula I.

[0032] According to another aspect of the present invention, a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of Formula 1(a):

[0033] SUBSTITUTE SHEET (RULE 26)

[0034] Het represents a heteroaromatic group selected from the group consisting of: pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof, wherein said heteroaromatic group is unsubstituted, mono-, or di-substituted, wherein the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (Ci-C4)-straight chain alkyl, unsubstituted (Ci-C4)-branched alkyl, substituted (Ci-C4)-straight chain alkyl, substituted (Ci-C4)-branched alkyl, alkoxy, (C3-C8)-cycloalkyl, a cyano group and halogen; preferably the substituent is a alkyl, fluoroalkyl, alkoxy, cycloalkyl, or halogen; more preferably the substituent is F, Cl, CHF2, CF3, methyl, methoxy, nitrile or cyclopropyl group;

[0035] R1is selected from the group consisting of: hydrogen, unsubstituted (Ci-Ce)-straight chain alkyl; unsubstituted (Ci-Ce)-branched alkyl; substituted (Ci-Ce)-straight chain alkyl; substituted (Ci-Ce)-branched alkyl; deuterated (Ci-Ce)-straight chain alkyl; deuterated (Ci-Ce)-branched alkyl and halogen; preferably the halogen comprises fluorine, chlorine or bromine; preferably R1is hydrogen, fluorine, chlorine, -CH3 or -CDs; and

[0036] Het’ is selected from the group consisting of: a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof, wherein said heteroaromatic group is unsubstituted, mono-, or di-substituted, wherein the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: (Ci-Ce)-straight-chain or branched alkyl, (Ci-Ce)-substituted straight-chain or branched alkyl, and halogen preferably the halogen comprises fluorine, chlorine or bromine; preferably the substituent is -CH3.

[0037] SUBSTITUTE SHEET (RULE 26) According to another aspect of the present invention, a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of Formula 1(b) - 1(d):

[0038] Formula 1(b) Formula 1(c)

[0039] Formula 1(d) wherein:

[0040] R1, Het and Het’ are each independently as defined herein with respect to Formula l(a);

[0041] R2is selected from the group consisting of: hydrogen, unsubstituted (Ci-Ce)-straight chain alkyl; unsubstituted (Ci-Ce)-branched alkyl; substituted (Ci-Ce)-straight chain alkyl; substituted (Ci-Ce)-branched alkyl; deuterated (Ci-Ce)-straight chain alkyl; deuterated (Ci-Ce)-branched alkyl and halogen; preferably the halogen comprises fluorine, chlorine or bromine; preferably R2is hydrogen, fluorine, chlorine, -CH3 or -CDs;

[0042] According to another aspect of the present invention, a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of Formula 1(e) - 1(g):

[0043] SUBSTITUTE SHEET (RULE 26)

[0044]

[0045] Formula 1(g) wherein:

[0046] R1, Het and Het’ are each independently as defined herein with respect to Formula l(a); and R6and R7are each independently hydrogen or deutrium.

[0047] Preferably, the compound of Formula I (a) -(g) is a 5R,6S-stereoisomer.

[0048] According to another aspect of the present invention, a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of Formula l(h):

[0049] SUBSTITUTE SHEET (RULE 26)

[0050] Formula 1(h); wherein:

[0051] Het is as defined with respect to Formula I or 1(a); and

[0052] Y represents an aromatic group or a heteroaromatic group; a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, wherein the Y is independently selected from the group consisting of: aryl, pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, nicotinonitrile, benzonitrile, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof, preferably Y is mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of: (Ci-C4)-alkyl, unsubstituted or substituted (Ci-C4)-alkyl, (Ci-C4)-alkoxy, a cyano group and halogen; the halogen may be fluorine, chlorine or bromine; preferably the substituent is a cyano group, an alkoxy group or halogen; more preferably, the aromatic or heteroaromatic group is substituted with CN, F, Cl, -O-alkyl, preferably the alkyl group comprises 1-4 carbon atoms, such as -O-CH3.

[0053] According to another aspect of the present invention, a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of Formula l(i) or l(j):

[0054] Formula l(i) Formula l(j)

[0055] 9

[0056] RECTIFIED SHEET (RULE 91) ISA / EP wherein:

[0057] R3and R4are each independently selected from hydrogen, (Ci-Cio)-straight chain alkyl; (Ci- Cio)-branched alkyl; (Ci-Cio)-substituted or unsubstituted alkyl, optionally (Ci-C4)-straight chain alkyl; (Ci-C4)-branched alkyl; (Ci-C4)-substituted or unsubstituted alkyl; deuterated (Ci- C4)-straight chain alkyl; or deuterated (Ci-C4)-branched alkyl; R3and R4may form a fused substituted or unsubstituted ring; preferably R3and R4are each independently -CH3 or -CD3; and

[0058] Het and Y are each independently as defined with respect to Formula 1(h).

[0059] According to another aspect of the present invention, a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of Formula l(k):

[0060] Formula l(k); wherein Het and Y are each independently as defined herein with respect to Formula 1(h).

[0061] According to another aspect of the present invention, a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of Formula l(l):

[0062] RECTIFIED SHEET (RULE 91) ISA / EP

[0063] Formula 1(1) wherein Het and Y are each independently as defined herein with respect to Formula 1(h).

[0064] According to another aspect of the present invention, a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of Formula l(m): wherein Het and Y are each independently as defined herein with respect to Formula 1(h).

[0065] According to another aspect of the present invention, a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of Formula l(n) -(q):

[0066] SUBSTITUTE SHEET (RULE 26)

[0067] Formula l(p) Formula l(q) wherein:

[0068] Het and Y are each independently as defined herein with respect to Formula 1(h);

[0069] R3is as defined in Formula l(j) or l(i);

[0070] R5is selected from hydrogen, (Ci-C )-straight chain alkyl; (Ci-C )-branched alkyl; (C1-C10)- substituted or unsubstituted alkyl, optionally (Ci-C4)-straight chain alkyl; (Ci-C4)-branched alkyl; (Ci-C4)-substituted or unsubstituted alkyl; deuterated (Ci-C4)-straight chain alkyl; deuterated (Ci-C4)-branched alkyl; or halogen; preferably R5is hydrogen, -CH3 or -CD3; and

[0071] R6and R7are each independently hydrogen or deutrium.

[0072] Preferably, the compound of Formula 1(h) - I (q) is a 5R,6S-stereoisomer.

[0073] SUBSTITUTE SHEET (RULE 26) According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of Formula I or l(a-q) described herein; and one or more pharmaceutically acceptable excipients.

[0074] According to another aspect of the present invention, there is provided a compound of Formula I or l(a-q) described herein or a pharmaceutical composition comprising the compound of Formula I or l(a-q) for use as a medicament. Preferably, the pharmaceutical composition is in a solid form such as a tablet or a capsule.

[0075] According to another aspect of the present invention, there is provided a method of treating or preventing a disease or disorder mediated by orexin receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula I or l(a-q) described herein or pharmaceutically acceptable salts, and derivatives thereof, preferably in a dose, at a frequency, and for a duration to provide a beneficial effect a pharmaceutical composition described herein.

[0076] According to another aspect of the present invention, there is provided use of a compound of Formula I or l(a-q) described herein, or a pharmaceutical composition described therein, in the preparation of a medicament for the treatment of diseases or disorders regulated by orexin receptor activity, and the use of such compounds for treatment or prevention of such diseases and disorders.

[0077] According to yet another aspect of the present invention, there is provided a method of modulating the activity of orexin receptors 0X1 , 0X2, or both, comprising contacting a cell comprising the orexin receptor with an effective amount of at least one compound of Formula I or l(a-q) described herein, or a pharmaceutical composition described herein.

[0078] According to another aspect of the present invention, a method for the preparation of the compounds of the present invention is provided.

[0079] 13

[0080] SUBSTITUTE SHEET (RULE 26) DETAILED DESCRIPTION OF THE INVENTION

[0081] Formula I

[0082] According to one aspect of the present invention, a compound of Formula I or pharmaceutically acceptable salts or derivatives thereof is provided, wherein X and X’ is a halogen such as fluorine, chlorine or bromine. Preferably, X and X’ is fluorine. Het represents a heteroaromatic group and R is a five or six membered aromatic group or heteroaromatic group. The heteroaromatic group, Het, may be selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof. The heteroaromatic group may be unsubstituted, mono-, or di-substituted, wherein the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (Ci-C4)-straight chain alkyl, unsubstituted (Ci-C4)-branched alkyl, substituted (Ci-C4)-straight chain alkyl, substituted (Ci-C4)-branched alkyl, alkoxy, cycloalkyl, a cyano group and halogen such as fluorine, chlorine or bromine. Preferably, the substituents of the heteroaromatic group in Het comprises alkyl, fluoroalkyl such as CF3, alkoxy, cycloalkyl, cyano, or halogen. More preferably, the substituent of the heteroaromatic group in Het is F, Cl, CHF2, CF3, methyl, methoxy, nitrile or cyclopropyl.

[0083] The five or six membered aromatic group or heteroaromatic group R may either be unsubstituted or substituted with one or more substituents.

[0084] Preferably, the compound provided by Formula I is a 5R,6S-stereoisomer:

[0085] SUBSTITUTE SHEET (RULE 26) The 5R,6S stereoisomer provided by the compound of Formula I or l(a-q) may bind stronger to the orexin receptors and may be more selective at binding to the 0X1 receptor in comparison to other stereoisomers provided by compounds of Formula I or l(a-q).

[0086] The term “heteroaromatic group” as used herein refers to an aromatic compound which contains heteroatoms such as oxygen, nitrogen or sulfur as part of the cyclic conjugated TT system.

[0087] The term “alkyl” as used herein refers to univalent groups derived from alkanes by removal of a hydrogen atom from any carbon atom -CnH2n+i. The term substituted alkyl refers to an alkyl wherein one or more hydrogen atoms of the alkyl group are replaced with one or more substituents selected from but not limited to halogen (such as fluorine, chlorine, or bromine), -OH, -CN.

[0088] The term “deuterated alkyl” used herein refers to an alkyl group with one or more protons replaced with deuterium atoms.

[0089] The term “deuterated compound” used herein refers to a compound in which one or morel of the hydrogen atoms have been replaced by deuterium atoms.

[0090] The term “fluoroalkyl” as used herein refers to an alkyl substituted by at least one fluorine atom.

[0091] The term “alkoxy” as used herein refers to an alkyl bonded to oxygen (i.e. R-0).

[0092] The term "aryl" as used herein refers to a monocyclic or bicyclic carbocyclic aromatic or aryl ring system. Phenyl is an example of a monocyclic aromatic or aryl ring system.

[0093] “Halogen” can be F, Cl, Br or I, however, in preferred examples the halogen is F, Cl or Br.

[0094] The term “substituted” as used herein refers to, for a particular group (e.g, alkyl, aryl, heteroaryl, aromatic), the replacement of one functional group by another (e.g., the substitution of an alkyl hydrogen by fluorine to provide fluoroalkyl).

[0095] 15

[0096] SUBSTITUTE SHEET (RULE 26) The term “solvate” is used herein to describe a compound in this invention that contains stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule such as ethanol. The term “hydrate” refers to when the said solvent is water.

[0097] By “pharmaceutically acceptable” is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the subject to which it is administered.

[0098] The term “therapeutically effective amount” (or more simply an “effective amount”) as used herein means the amount of active agent or active ingredient that is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which / whom it is administered.

[0099] Preferably, where the R group in the compound of Formula I is a five-membered heteroaromatic group, it may comprise an unsubstituted pyrazole, oxazole, thiazole, imidazole, a substituted pyrazole oxazole, thiazole, imidazole or a derivative thereof. Preferably, where the R group in the compound of Formula I is a six-membered aromatic group, it may comprise an unsubstituted aryl, or substituted aryl, or a derivative thereof.

[0100] More preferably, where the R group in the compound of Formula I is a six-membered aromatic group, the six-membered aromatic group has the structure of Formula II or 11(a):

[0101] Formula II Formula 11(a) wherein R1may be selected from the group consisting of: hydrogen; unsubstituted (Ci-Ce)- straight chain alkyl; unsubstituted (Ci-Ce)-branched alkyl; substituted (Ci-Ce)-straight chain alkyl; substituted (Ci-Ce)-branched alkyl; deuterated (Ci-Ce)-straight chain alkyl; deuterated (Ci-Ce)-branched alkyl and halogen; preferably R1is a Cl, F, -CH3 or -CDs; and

[0102] Het’ may be selected from the group consisting of: a heteroaromatic group selected from the group consisting of: pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof, wherein said heteroaromatic group is unsubstituted, mono-, or di-

[0103] SUBSTITUTE SHEET (RULE 26) substituted, wherein the substituents of the heteroaromatic group, if present, may be independently selected from the group consisting of: unsubstituted (Ci-C4)-straight chain or branched alkyl, substituted (Ci-C4)-straight-chain or branched alkyl, and halogen; preferably the substituent(s) of the heteroaromatic group is a halogen such fluorine, chlorine or bromine; preferably the substituent is -CH3.

[0104] In some examples, the Het’ group of Formula II or 11(a) may be selected from:

[0105] Further, where the R group in the compound of Formula I is a six-membered heteroaromatic group, the six-membered heteroaromatic group has the structure of Formula III or 111 (a) :

[0106] Formula III Formula II 1(a)

[0107] Wherein:

[0108] R1may be selected from the group consisting of: hydrogen; unsubstituted (Ci-Ce)-straight chain alkyl; unsubstituted (Ci-Ce)-branched alkyl; substituted (Ci-Ce)-straight chain alkyl; substituted (Ci-Ce)-branched alkyl ; deuterated (Ci-Ce)-straight chain alkyl; deuterated (Ci- Ce)-branched alkyl; and halogen; preferably the halogen comprises fluorine, chlorine or bromine; preferably R1is a H, Cl, F, -CHs or -CDs ;

[0109] R2may be selected from the group consisting of hydrogen; unsubstituted (Ci-Ce)-straight chain alkyl; unsubstituted (Ci-Ce)-branched alkyl; substituted (Ci-Ce)-straight chain alkyl; substituted (Ci-Ce)-branched alkyl; deuterated (Ci-Ce)-straight chain alkyl; deuterated (Ci- Ce)-branched alkyl; and halogen; preferably the halogen comprises fluorine, chlorine or bromine; preferably R2is a H, F, Cl, -CH3 or -CDs; and

[0110] Het’ may be as defined herein with respect to Formula II or I l(a) .

[0111] 17

[0112] SUBSTITUTE SHEET (RULE 26) In some examples, the Het’ of Formula III or lll(a) may be selected from:

[0113] Where the R group in Formula I is a five-membered heteroaromatic group, the five-membered heteroaromatic group may have the structure Formula IV, IV(a) or IV(b): wherein:

[0114] R3and R4may be each independently selected from the group consisting of: hydrogen, (Ci- Cio)-straight chain alkyl; (Ci-C )-branched alkyl; (Ci-Cw)-substituted or unsubstituted alkyl, optionally (Ci-C4)-straight chain alkyl; (Ci-C4)-branched alkyl; (Ci-C4)-substituted or unsubstituted alkyl; deuterated (Ci-C4)-straight chain alkyl; and deuterated (Ci-C4)-branched alkyl; R3and R4may form a fused substituted or unsubstituted ring; preferably R3and R4may be each independently -CH3 or -CD3; and

[0115] Y may represent an aromatic group; a substituted or unsubstituted aromatic group, a heteroaromatic group, a substituted or unsubstituted heteroaromatic group. Preferably, Y may be independently selected from the group consisting of: aryl, pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, nicotinonitrile, benzonitrile, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof; and Y may be unsubstituted, mono-, or di-substituted, wherein the substituents may be independently selected from the group consisting of: (Ci-C4)-alkyl, unsubstituted or substituted (Ci-C4)-alkyl, (Ci-C4)-alkoxy, a cyano group and halogen.

[0116] Where Y is mono-, or di-substituted and the substituent(s) is a halogen, the halogen may preferably be fluorine, chlorine or bromine. Where Y is mono-, or di-substituted and the

[0117] 18

[0118] SUBSTITUTE SHEET (RULE 26) substituent(s) is cyano group, (Ci-C4)-alkoxy, the alkoxy group may be -OCH3; preferably the substituent(s) is CN, F, Cl, CH3 or -OCHs.

[0119] In some examples, “Y” of Formula IV, IV(a) or IV(b) may be selected from:

[0120] Further, where the “R” in Formula I is a five-membered heteroaromatic group, the fivemembered heteroaromatic group may have the structure Formula V: Formula V; wherein Y may be as defined with respect to Formula IV, IV(a) or IV(b).

[0121] In some examples, the “Y” of Formula V may be

[0122] SUBSTITUTE SHEET (RULE 26) Further, where the “R” in Formula I is a five-membered heteroaromatic group, the fivemembered heteroaromatic group may have the structure Formula VI:

[0123] Formula VI; wherein Y may be as defined with respect to Formula IV, IV(a) or IV(b).

[0124] In some examples, “Y” of Formula VI may be

[0125] Further, where the “R” in Formula I is a five-membered heteroaromatic group, the fivemembered heteroaromatic group may have the structure Formula VII:

[0126] Formula VII; wherein Y may be as defined with respect to Formula IV, IV(a) or IV(b).

[0127] In some examples, “Y” of Formula VII may be:

[0128] In some examples, the “R” of the compound of Formula I described herein may be selected from:

[0129] 20

[0130] SUBSTITUTE SHEET (RULE 26)

[0131]

[0132] SUBSTITUTE SHEET (RULE 26)

[0133]

[0134] In further examples, the “R” in the compound of Formula I described herein may be selected from:

[0135] In some examples, the Het in the compound of Formula I described herein may be selected from:

[0136] 22

[0137] SUBSTITUTE SHEET (RULE 26)

[0138]

[0139] According to one aspect of the present invention, there is provided a deuterated compound of Formula I or pharmaceutically acceptable salts or derivatives thereof, having a structure as shown in Formula 1(D):

[0140] Formula 1(D) wherein:

[0141] X, X’, Het and R are each independently as defined herein with respect to Formula I; and R6and R7are each independently hydrogen or deuterium.

[0142] 23

[0143] SUBSTITUTE SHEET (RULE 26) In a preferred aspect, the deuterated compound of Formula ID has the following structure:

[0144] Formula ID(a)

[0145] Het is a heteroaromatic group, preferably the heteroaromatic group, may be selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof. The heteroaromatic group may be unsubstituted, mono-, or di-substituted, wherein the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (Ci-C4)-straight chain alkyl, unsubstituted (C1-C4)- branched alkyl, substituted (Ci-C4)-straight chain alkyl, substituted (Ci-C4)-branched alkyl, C3- C8)-cycloalkyl, a cyano group, alkoxy and halogen such as fluorine, chlorine or bromine. Preferably, the substituents of the heteroaromatic group comprises F, Cl, CHF2, CF3, methyl, methoxy, nitrile or cyclopropyl group.

[0146] R is a five or six membered aromatic group or heteroaromatic group. The five or six membered aromatic group or heteroaromatic group R may either be unsubstituted or substituted with one or more substituents.

[0147] Preferably, where the R group in the compound of Formula ID(a) is a six-membered aromatic group, it may comprise an unsubstituted aryl, or substituted aryl, or a derivative thereof.

[0148] Preferably, where the R group in the compound of Formula ID(a) is a six-membered aromatic group, it may comprise which is an unsubstituted pyridine, an unsubstituted pyrimidine, an unsubstituted pyridazine, an unsubstituted pyrazine, a substituted pyridine, a substituted pyrimidine, a substituted pyridazine, a substituted pyrazine or a derivative thereof.

[0149] Preferably, where the R group in the compound of Formula ID(a) is a five-membered heteroaromatic group, it may comprise an unsubstituted pyrazole, unsubstituted oxazole,

[0150] 24

[0151] SUBSTITUTE SHEET (RULE 26) unsubstituted thiazole, unsubstituted imidazole, a substituted pyrazole oxazole, substituted thiazole, substituted imidazole or a derivative thereof.

[0152] R6of Formula ID(a) may be hydrogen or deuterium.

[0153] Where the R group in Formula ID(a) is a five-membered heteroaromatic group, the fivemembered heteroaromatic group may have the structure Formula VIII: Formula VIII; wherein Y may be as defined herein with respect to Formula IV, IV(a), IV(b).

[0154] In some examples, Y group of Formula VIII may be selected from:

[0155] Where the R group in Formula ID(a) is a five-membered heteroaromatic group, the fivemembered heteroaromatic group may have the structure Formula IX:

[0156] Formula IX; wherein:

[0157] R3is independently selected from the group consisting of: hydrogen, (Ci-C )-straight chain alkyl; (Ci-C )-branched alkyl; (Ci-Cw)-substituted or unsubstituted alkyl, optionally (C1-C4)- straight chain alkyl; (Ci-C4)-branched alkyl; and (Ci-C4)-substituted or unsubstituted alkyl; deuterated (Ci-C4)-straight chain alkyl; and deuterated (Ci-C4)-branched alkyl; preferably R3is -CH3or -CD3;

[0158] Y may be as defined herein with respect to Formula IV, IV(a), IV(b).

[0159] SUBSTITUTE SHEET (RULE 26) In some examples, Y group of Formula IX may be selected from:

[0160] Further, where the “R” in Formula ID(a) is a five-membered heteroaromatic group, the fivemembered heteroaromatic group may have the structure Formula X:

[0161] Formula X; wherein Y may be as defined herein with respect to Formula IV, IV(a), IV(b).

[0162] In some examples, Y group of Formula X may be selected from:

[0163] More preferably, where the R group in the compound of Formula ID(a) is a six-membered aromatic group, the six-membered aromatic group has the structure of Formula XI or XI (a):

[0164] Formula XI or Formula Xl(a) wherein R1and Het’ may be each independently as defined herein with respect to Formula II and III;

[0165] In some examples, the Het’ of Formula XI or Xl(a) may be selected from:

[0166] SUBSTITUTE SHEET (RULE 26) In a preferred aspect, the deuterated compound of Formula ID has the following structure:

[0167] Formula ID(b) wherein:

[0168] Het and R may be each independently as defined herein with respect to Formula ID(a); and R7may be hydrogen or deuterium.

[0169] More preferably, where the R group in the compound of Formula I D(b) is a five-membered aromatic group, the five-membered aromatic group has the structure of Formula XII:

[0170] Formula XII; wherein R3may be as defined herein with respect to Formula IX; and

[0171] Y may be as defined herein with respect to Formula IV, IV(a) or IV(b).

[0172] In some examples Y group of Formula XII may be selected from:

[0173] More preferably, where the R group in the compound of Formula I D(b) is a six-membered aromatic group, the six-membered aromatic group has the structure of Formula XIII:

[0174] 27

[0175] SUBSTITUTE SHEET (RULE 26) Formula XIII; wherein R1and Het’ may be each independently as defined herein with respect to Formula III or lll(a).

[0176] In some examples Het’ group of Formula XIII may be selected from:

[0177] In some examples, the “R” of the compound of Formula ID, ID(a) or ID(b) described herein may be selected from:

[0178] In some further examples, the “R” of the compound of Formula ID, ID(a) or I D(b) described herein may be selected from:

[0179] In some examples, the Het of the compound of Formula ID, ID(a) or ID(b) described herein may be selected from:

[0180] SUBSTITUTE SHEET (RULE 26)

[0181] Preferably, the compound of Formula ID, ID(a) and I D(b) is a 5R,6S-stereoisomer.

[0182] In yet another example, the compound of Formula I described herein has the structure of

[0183] Formula 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), l(i), IQ), (l(k), 1(1), l(m),((n), l(o),l(p) or l(q):

[0184] Formula 1(e) Formula 1(f)

[0185] SUBSTITUTE SHEET (RULE 26)

[0186]

[0187] Formula l(i)

[0188] Formula l(k) Formula 1(1)

[0189] RECTIFIED SHEET (RULE 91) ISA / EP

[0190]

[0191] Formula l(o) Formula l(p)

[0192] Formula l(q); wherein Het, Het’, R1, R2, R3, R4, R5, R6, R7and Y may be each independently as defined herein with respect to Formula I, ID, ID(a), ID(b) and II to XIII.

[0193] In further examples, a compound of the present invention may be selected from:

[0194] SUBSTITUTE SHEET (RULE 26)

[0195] RECTIFIED SHEET (RULE 91) ISA / EP

[0196] SUBSTITUTE SHEET (RULE 26)

[0197]

[0198] SUBSTITUTE SHEET (RULE 26)

[0199]

[0200] SUBSTITUTE SHEET (RULE 26)

[0201]

[0202] SUBSTITUTE SHEET (RULE 26)

[0203] SUBSTITUTE SHEET (RULE 26)

[0204]

[0205] SUBSTITUTE SHEET (RULE 26)

[0206] SUBSTITUTE SHEET (RULE 26)

[0207]

[0208] SUBSTITUTE SHEET (RULE 26)

[0209] SUBSTITUTE SHEET (RULE 26)

[0210] SUBSTITUTE SHEET (RULE 26)

[0211] SUBSTITUTE SHEET (RULE 26)

[0212]

[0213] SUBSTITUTE SHEET (RULE 26)

[0214]

[0215] SUBSTITUTE SHEET (RULE 26)

[0216]

[0217] SUBSTITUTE SHEET (RULE 26)

[0218] SUBSTITUTE SHEET (RULE 26)

[0219] SUBSTITUTE SHEET (RULE 26)

[0220] SUBSTITUTE SHEET (RULE 26)

[0221] SUBSTITUTE SHEET (RULE 26)

[0222] SUBSTITUTE SHEET (RULE 26)

[0223]

[0224] SUBSTITUTE SHEET (RULE 26)

[0225] SUBSTITUTE SHEET (RULE 26) or pharmaceutically acceptable salts and derivatives thereof.

[0226] In one aspect of the present invention there is provided a compound of Formula l-aa, or pharmaceutically acceptable salts and derivatives thereof,

[0227] Formula l-aa wherein:

[0228] R6and R7are each independently H or deuterium;

[0229] R8is CF3;

[0230] W1is selected from CH, N, or C-O-CH3;

[0231] W2is selected from CH, N, C-CH3; and

[0232] R is selected from a five membered heteroaromatic group which comprises an unsubstituted pyrazole, an unsubstituted oxazole, an unsubstituted thiazole, an unsubstituted imidazole, a substituted pyrazole, a substituted oxazole, a substituted thiazole, a substituted imidazole or a derivative thereof; or a six membered heteroaromatic group which comprises an unsubstituted pyridine, an unsubstituted pyrimidine, an unsubstituted pyridazine, an unsubstituted pyrazine, a substituted pyridine, a substituted pyrimidine, a substituted pyridazine, a substituted pyrazine or a derivative thereof.

[0233] Where the R group in Formula l-aa is a five-membered heteroaromatic group, the fivemembered heteroaromatic group may have the structure:

[0234] SUBSTITUTE SHEET (RULE 26)

[0235] Where the R group in Formula l-aa is a six-membered heteroaromatic group, the sixmembered heteroaromatic group may have the structure:

[0236] In one aspect of the present invention a compound of Formula l-aa is selected from:

[0237] SUBSTITUTE SHEET (RULE 26)

[0238]

[0239] Preferably, the compound of Formula l-aa is a 5R,6S-stereoisomer.

[0240] In some examples, the compounds provided by Formula I and l(a-q) may be deuterated where at least one of the hydrogen is replaced with deuterium. Preferably, the N-Me or C-Me group of the compounds provided by Formula I and l(a-g) are deuterated. Preferably, compounds 6, 7, 23, 24, 26, 27, 28, 29 35, 36, and 37 are deuterated. Even more preferably, the N-Me or C- Me group of the pyrazole ring of compounds 6, 7, 23, 24, 26, 27, 28, 29 35, 36, and 37 are deuterated. In some examples compounds 50, 51 , 52, 53, 54, 55, 56, 57,60, 62, 70, 71 , 72, 73, 89, 90, 91 , 102 and 103 are deuterated forms of compounds 1 , 2, 3, 6, 23, 26, 36, 37, 38, and 46 respectively. More specifically, compounds 54, 60, 70, 102 and 103 are deuterated

[0241] 56

[0242] SUBSTITUTE SHEET (RULE 26) forms of compound 6. In some examples, compound 91 is the deuterated form of compound 23. In some examples, compounds 55 and 72 are deuterated forms of compound 26. In some examples, compounds 53 and 71 are deuterated forms of compound 36. In some examples, compounds 56, 62, 73 and 90 are deuterated forms of compound 37. The deuterated compounds provided by Formula I and l(a-q) may be metabolically more stable than the nondeuterated equivalent.

[0243] The compounds of the present invention may be in the form of pharmaceutically acceptable salts. A "pharmaceutically acceptable salt" is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

[0244] Examples of “pharmaceutically acceptable salts” include, but not limited to, hydrochlorides, chlorides, bromides, iodides, potassium salts, sodium salts, acetates, trifluoroacetates, sulfates, sulfonates, oxalates, maleates, malonates, nitrates, tartrates, gluconates, succinates, mesylates, citrates, phosphates or diphosphates and aluminates.

[0245] In some examples, the compound of the present invention may be in the form of trifluoroacetate.

[0246] Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or tautomeric forms, prodrugs or a mixture thereof.

[0247] The “pharmaceutically acceptable derivatives” of the compounds of the present invention disclosed herein includes, but is not limited to, enantiomers, solvates, adducts, polymorphs, hydrates, tautomers, prodrugs, isotopically or radio-labelled derivatives, isomers or a mixture thereof.

[0248] Isotopic Labelling in Described Compounds

[0249] 57

[0250] SUBSTITUTE SHEET (RULE 26) The present application further includes all pharmaceutically acceptable isotopically labelled compound [e.g., of Formula I or l(a-d)] An "isotopically" or "radio-labelled" compound is a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e. , naturally occurring). For example, in certain examples, in compounds [e.g., of Formula I or l(a-d)], hydrogen atoms are replaced or substituted by one or more deuterium or tritium (e.g., hydrogen atoms on a (Ci-Ce)-alkyl or a (Ci-Ce)-alkoxy are replaced with deuterium, such as d3-methoxy or 1 ,1 ,2,2-d4-3-methylbutyl).

[0251] Certain isotopically labelled compounds [e.g., compounds of Formula I or I (a-d)], for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies and in metabolic studies (preferably with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.

[0252] Isotopically labelled compounds [e.g., of Formula I, ID, ID(a), ID(b), l-aa or l(a-q)] or their corresponding prodrugs can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically labelled reagent in place of the non-labelled reagent previously employed. Suitable isotopes that may be incorporated in compounds of the present application include but are not limited to isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H (also written as D for deuterium),3H (also written as T for tritium),11C,13C,14C,13N,15N,15O,170,18O,18F,35S,36CI,82Br,75Br,76Br,77Br,123l,124l,125l,1311,31P, and32P.

[0253] Isotopically labelled compounds of this application and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

[0254] 58

[0255] SUBSTITUTE SHEET (RULE 26) Compounds provided by the present invention are non-peptide antagonists of human orexin receptors. The compounds provided by the present invention may be useful for the potential treatment or prevention of central nervous system (CNS) disorders, neurological diseases or eating disorders. The compounds of the present invention may be useful to treat diseases or disorders relating to dysfunctions of the orexin 1 receptor.

[0256] The novel compounds provided by the present invention are non-peptide antagonists of human orexin receptors, especially the orexin- 1 receptor. These compounds are particularly useful for the potential treatment or prevention of central nervous system (CNS) disorders, neurological diseases or eating disorders such as obesity, binge eating disorder (BED), schizophrenia (negative symptoms and CIAS), addiction to psychomotor stimulants such as cocaine, opiates, nicotine and alcohol, opioid use disorder, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, behaviour disorder and mood disorder depression. The compounds of the present invention may be useful to treat diseases or disorders relating to dysfunctions of the orexin 1 receptor.

[0257] Preferably, the compounds provided by the present invention are 0X1 receptor selective antagonists. 0X1 receptor antagonists are useful for treating diseases and disorders such as, but not limited to, substance abuse disorders, personality disorders, eating disorders, or anxiety-related disorders. However, antagonists targeting both 0X1 and 0X2 receptors are known to have sleep-inducing effects; therefore, identifying a highly 0X1 selective antagonist with a sufficient window to 0X2-mediated effects is very desirable, to prevent side-effects such as drowsiness or tiredness.

[0258] Half-maximal inhibitory concentration (IC50) may be used in the present invention to demonstrate the efficiency of compounds provided by the present invention). The IC50 values provided in this disclosure indicates how much drug is needed to inhibit orexin receptors by half, thus providing a measure of compounds provided by the present invention.

[0259] Compounds provided by the present invention may have an IC50 of at least 700 nM for 0X1 receptors. Preferably, compounds provided by the present invention may have an IC50 value between 2 nM to 700 nM for 0X1 receptors. Compounds provided by Formula I may have an IC50 value between 2 nM to 650 nM; between 2 nM to 600 nM; between 2 nM to 500 nM; between 2 nM to 400 nM; between 2 nM to 350 nM; between 2 nM to 300 nM between 2 nM

[0260] 59

[0261] SUBSTITUTE SHEET (RULE 26) to 250 nM; between 2 nM to 200 nM; between 2 nM to 150 nM; between 2 nM to 100 nM; between 50 nM to 700 nM; between 50 nM to 650 nM; between 50 nM to 600 nM; between 50 nM to 500 nM; between 50 nM to 400 nM; between 50 nM to 350 nM; between 50 nM to 300 nM; between 50 nM to 250 nM; between 50 nM to 200 nM; between 50 nM to 150 nM; between 50 nM to 400 nM; between 100 nM to 350 nM; between 100 nM to 300 nM; between 100 nM to 250 nM; between 100 nM to 200 nM; or between 100 nM to 150 nM for 0X1 receptors.

[0262] More preferably, compounds provided by the present invention may have an IC50 value between 2 nM to 100 nM for 0X1 receptors. Compounds provided by the present invention may have an IC50 value between 2 nM to 90 nM; between 2 nM to 70 nM; between 2 nM to 50 nM; between 2 nM to 30 nM; between 2 nM to 10 nM; between 5 nM to 90 nM; between 5 nM to 80 nM; between 5 nM to 60 nM; between 5 nM to 50 nM; between 5 nM to 30 nM; between 5 nM to 20 nM; between 5 nM to 10 nM; between 10 nM to 80 nM; between 10 nM to 60 nM; between 10 nM to 70 nM; between 10 nM to 50 nM; between 10 nM to 30 nM; or between 10 nM to 20 nM for 0X1 receptors.

[0263] Most preferably, compounds provided by the present invention may have an IC50 value between 2 nM to 50 nM for 0X1 receptors. Compounds provided by Formula I may have an IC50 value between 2 nM to 40 nM; between 2 nM to 30 nM; between 2 nM to 25 nM; between 2 nM to 20 nM; between 2 nM to 10 nM; between 2 nM to 5 nM; 3 nM to 40 nM; between 3 nM to 30 nM; between 3 nM to 25 nM; between 3 nM to 20 nM; between 3 nM to 10 nM; between 3 nM to 5 nM; 5 nM to 40 nM; between 5 nM to 30 nM; between 5 nM to 25 nM; between 5 nM to 20 nM; between 5 nM to 10 nM; 7 nM to 40 nM; between 7 nM to 30 nM; between 7 nM to 25 nM; between 7 nM to 20 nM; or between 7 nM to 10 nM for 0X1 receptors.

[0264] Most preferably, compounds provided by the present invention may have an IC50 of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17,18, 19, 20, 21 , 23, 24, 25, 26, 27, 28, 32, 33, 36, 40, 44, 48, 49, 55, 56, 57, 60, 69, 73, 75, 81 , 94, 137, 160, 166,172, 245, 296, 302, 351 or 638 nM for 0X1 receptors.

[0265] Compounds provided by the present invention may have an IC50 of at least 3000 nM for 0X2 receptors. Preferably, compounds provided by the present invention have an IC50 of at least 5000 nM for 0X2 receptors.

[0266] 60

[0267] SUBSTITUTE SHEET (RULE 26) Compounds provided by the present invention are at least 12 times more effective at binding to 0X1 receptors compared to 0X2 receptors. Preferably, compounds provided by the present invention are at least 50 times more effective at binding to 0X1 receptors compared to 0X2 receptors. Even more preferably, compounds provided by the present invention are at least 100 times more effective at binding to 0X1 receptors compared to 0X2 receptors. Most preferably, compounds provided by the present invention are at least 500 times more effective at binding to 0X1 receptors compared to 0X2 receptors.

[0268] It was found that the compounds of the present invention have improved residence time compared to known 0X1 receptors. Orexin A was incubated with human 0X1 receptor membranes for different incubation times in the presence or absence of 6 different concentrations of compounds. The non-specific binding was assessed in presence of unlabeled SB 334867 (1-(2-methylbenzo[d]oxazol-6-yl)-3-(1 ,5-naphthyridin-4-yl)urea, which is commercially available 0X1 R-ANT) for each incubation time. Kinetic parameters (kon, koff, residence time) were calculated by applying the Motulsky Mahan equation. Compounds of the present invention were found to show a higher residence time compared to reference compounds, suggesting a higher ligand-OX1 R complex half-life which positively impacts the therapeutic dose in humans. For instance, compounds of present invention (such as compounds 26, 54) showed higher ranking compared to known compounds such as those in WO2017129829, WO2017139603, JNJ-61393215 and ACT-539313. Improved drug residence time is advantageous, as longer drug-target residence time are generally more efficacious in vivo. As a result, lower therapeutic doses are needed. It is also generally known that drugs with longer residence times have increased efficacy and fewer side effects because they occupy a higher fraction of their target over a longer period of time, even after clearance from systemic circulation.

[0269] Compounds provided by the present invention may have improved pharmacokinetic properties such as improved bioavailability, brain exposure, improved permeability into cells, and metabolic stability, and thus, lower therapeutic doses may be needed.

[0270] According to another aspect of the present invention, a pharmaceutical composition is provided, the pharmaceutical composition comprising a compound of the present invention described herein and one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients may be added to streamline the manufacture of the pharmaceutical composition and ultimately facilitate physiological absorption of the drug. Further,

[0271] 61

[0272] SUBSTITUTE SHEET (RULE 26) pharmaceutically acceptable excipients used in the present invention may provide key benefits such as solubilisation, stabilisation, delivery enhancement, and formulation preservation.

[0273] The compounds of the present application may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein. The additional active ingredients may include other active agents that are effective in treating the diseases and disorders described herein. For example, additional active ingredients include those that are known to be useful for enhancing sleep quality and preventing and treating sleep disorders and sleep disturbances, anti-diabetic agents, cardiovascular therapies, anti-obesity agents, other orexin receptor antagonists, pain medications, anti-depressants, anti-anxiety agents, cognition-enhancing agents, antiAlzheimer’s Disease therapies, and other active ingredients.

[0274] Non-limiting examples of types of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersing agents, disintegration agents, emulsifying agents, wetting agents, suspending agents, thickeners, solvents, isotonic agents, buffers, pH adjusters, absorption-delaying agents, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweetening agents, flavoring agents, coloring agents, encapsulating materials and coating materials. The use of such excipients in pharmaceutical formulations is known in the art.

[0275] The pharmaceutical composition or the compound of the present invention provided by the present invention may be used as a medicament. The medicament may be used for preventing and / or treating a condition selected from, but are not limited to, central nervous system (CNS) disorders, neurological diseases or eating disorders such as obesity, binge eating disorder (BED), schizophrenia (negative symptoms and CIAS), addiction to psychomotor stimulants such as cocaine, opiates, nicotine and alcohol, opioid use disorder, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, behaviour disorder and mood disorder depression.

[0276] The pharmaceutical composition provided by the present invention may be in the form of tablets, capsules, hard candies, powders, spansules, softgels, liquid or aqueous suspensions. Preferably, the pharmaceutical composition provided by the present invention is in the form of tablets or capsules.

[0277] 62

[0278] SUBSTITUTE SHEET (RULE 26) The pharmaceutical composition provided by the present invention may be administered through oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intra-arterial, intraperitoneal, intracavitary and topical), topical (including transdermal, transmucosal, intranasal (e.g., by nasal spray or drop), ocular (e.g., by eye drop), pulmonary (e.g., by oral or nasal inhalation), and / or other suitable routes. Preferably, the pharmaceutical composition provided by the present invention is administered orally.

[0279] According to yet another aspect of the present invention, a method of treating or preventing a disease or disorder mediated by orexin receptor activity is provided. The method comprising administering to a subject in need of such treatment an effective amount of at least one compound of the present invention (or any pharmaceutically acceptable salts, solvates, adducts, polymorphs, isotopically or radio-labelled derivatives, and isomers thereof) or a pharmaceutical composition comprising of at least one compound of the present invention (or any pharmaceutically acceptable salts, solvates, adducts, polymorphs, isotopically or radio- labelled derivatives, and isomers thereof).

[0280] The method provided by the present invention may be used for the treatment or for the prevention of diseases or disorders selected from but not limited to eating disorders, obesity, binge eating disorder (BED), schizophrenia (negative symptoms and CIAS), addiction to psychomotor stimulants such as cocaine, opiates, nicotine and alcohol, opioid use disorder, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, behaviour disorder and mood disorder depression.

[0281] As used herein, the term “effective amount” refers to the amount of a compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.

[0282] Dosage regimens may be adjusted to provide the optimum desired response. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition.

[0283] 63

[0284] SUBSTITUTE SHEET (RULE 26) The amount of the compound of the present invention administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician.

[0285] As used herein, the term “subject” includes a human or non-human animal. An exemplary human subject includes a human subject having a disease (such as one described herein) (referred to as a patient), or a normal subject. The term “non-human animal” as used herein includes all vertebrates, such as non-mammals.

[0286] According to another aspect of the present invention, the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention is provided. The compound in accordance with the present invention or the pharmaceutical composition comprising the compound in accordance with the present invention is used in the preparation of a medicament for the treatment of diseases or disorders regulated by orexin receptor activity and is used for treatment or prevention of such diseases and disorders.

[0287] According to yet another aspect of the present invention, a method of modulating the activity of orexin receptors 0X1 , 0X2, or both. The method comprising contacting a cell comprising the orexin receptor with an effective amount of at least one compound in accordance with present invention or a pharmaceutical composition comprising a compound in accordance with present invention. The method of contacting the cell comprising the orexin receptor with an effective amount of at least one compound in accordance with present invention or a pharmaceutical composition comprising a compound in accordance with present invention can either be carried out in vivo, in vitro or ex vivo.

[0288] Preferably, the present invention provides a method of selectively modulating the activity of 0X1 receptors.

[0289] According to yet another aspect of the present invention, compounds of the present invention may be prepared by the synthetic pathway described in the examples below.

[0290] The abbreviations used in the present disclosure are summarised:

[0291] BOC tert-butyloxycarbonyl

[0292] DMF dimethylformamide

[0293] DMS dimethyl sulfide

[0294] 64

[0295] SUBSTITUTE SHEET (RULE 26) DMSO dimethylsulfoxide

[0296] DMAP 4-dimethylaminopyridine

[0297] DIAD diisopropyl azodicarboxylate

[0298] DEAD diethyl azodicarboxylate

[0299] DIPEA N, N-Diisopropylethylamine

[0300] Fmoc Fluorenylmethyloxycarbonyl

[0301] PG protecting group

[0302] TBAF tetra-n-butylammonium fluoride

[0303] THF tetrahydrofuran

[0304] TEA triethanolamine

[0305] Ts Tosyl eq Equivalents

[0306] N Normality

[0307] V Volume

[0308] The term “hexaalkylditin” as used herein refers to general reagents used to prepare organostannes for Stille cross-coupling. Examples of “hexaalkylditin” include but are not limited to hexamethylditin or hexabutylditin.

[0309] Compounds of the present invention may be prepared by starting with commercially available starting material N-benzyl-L-allothreonine (a). N-benzyl-L-allothreonine a may be reduced by reacting with a reducing agent to form intermediate (b). The primary alcohol of intermediate (b) may be selectively protected by reacting with a suitable protecting group to form intermediate (c). Intermediate (c) undergoes a nucleophilic substitution reaction with 2-bromo- 2,2-difluoro-acetic acid or 2,2-difluoro-2-iodoacetic acid to form intermediate (d). Intermediate (d) undergoes intramolecular amide coupling in the presence of a coupling reagent to form intermediate (e). Preferably, the coupling reagent used to make intermediate (e) is propylphosphonic anhydride (T3P). Intermediate (e) may be reduced to form intermediate (f). The alcohol protecting, protecting group is removed from intermediate (f) to form intermediate (g). The benzyl protecting group from intermediate (g) may be removed through Pd / C- catalyzed hydrogenation. The deprotected amine may react with a suitable protecting group to form intermediate (h). Intermediate (h) may be reacted with isoindoline-1 , 3-dione to form intermediate (i). Intermediate (i) is reacted with hydrazine or hydrazine hydrate to form intermediate (j). Intermediate (j) undergoes a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of intermediate k-z2. Intermediates

[0310] 65

[0311] SUBSTITUTE SHEET (RULE 26) k-z2 is deprotected to form corresponding intermediates aa-ar. Intermediates aa-ar may be reacted with a carboxylic acid having general formula R-COOH to form compounds 1-49, 60- 69, 78-88 and 92-102.

[0312] Compounds of the present invention may be prepared by starting with commercially available starting material (5R,6S)-4-Benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6- methylmorpholin-3-one (intermediate e), or intermediate (e) as disclosed herein. Intermediate (e) may be reduced with a deuterated reagent to form intermediate (f1). The alcohol protecting, protecting group is removed from intermediate (f1) to form intermediate (g1). The benzyl protecting group from intermediate (g1) may be removed through Pd / C-catalyzed hydrogenation. The deprotected amine may react with a suitable protecting group to form intermediate (hi). Intermediate (hi) may be reacted with isoindoline-1 , 3-dione to form intermediate (i1). Intermediate (i1) is reacted with hydrazine or hydrazine hydrate to form intermediate (j1). Intermediate (j1) undergoes a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of intermediate k1 , 11 or ml . Intermediates k1 , 11 or ml is deprotected to form corresponding intermediates ab1 , ac1 or ad1. Intermediates ab1 , ac1 or ad1 may be reacted with a carboxylic acid having general formula R-COOH to form compounds 50-59, 70-77.

[0313] Compounds of the present invention may be prepared by starting with commercially available starting material N-benzyl-L-allothreonine (a). N-benzyl-L-allothreonine (a) may be reacted with (2-bromo-2,2-difluoro-acetyl)oxysodium to form intermediate (e2’). Intermediate (e2’) may be reduced with a deuterated reagent to form intermediate (e2”). Intermediate (e2”) may be reduced with a reducing agent to form intermediate (g2). The benzyl protecting group from intermediate (g2) may be removed through Pd / C-catalyzed hydrogenation. The deprotected amine may react with a suitable protecting group to form intermediate (h2). Intermediate (h2) may be reacted with isoindoline-1 ,3-dione to form intermediate (i2). Intermediate (i2) is reacted with hydrazine or hydrazine hydrate to form intermediate (j2). Intermediate (j2) undergoes a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of intermediate k2, I2, m2 or n2. Intermediates k2, I2, m2 or n2 is deprotected to form corresponding intermediates aa2, ab2, ac2 or ad2. Intermediates aa2, ab2, ac2 or ad2 may be reacted with a carboxylic acid having general formula R-COOH to form compounds 89-91 and 103.

[0314] 66

[0315] SUBSTITUTE SHEET (RULE 26) The present invention provides a method for synthesizing intermediate b as shown in the synthetic pathway below:

[0316] N-benzyl-L-allothreonine a is reduced by reacting with a reducing agent such as borane dimethyl sulfide to form intermediate b. Other suitable reducing agents may be used instead of borane dimethyl sulfide such as but not limited to lithium aluminum hydride, boron trifluoride diethyl etherate and diborane.

[0317] The reducing agent may be used in excess with respect to starting material a. The excess is preferably 2-times to 10-times of the reducing agent with respect to starting material a. Preferably, a 5-times excess of the reducing agent is used with respect to starting material a.

[0318] The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF.

[0319] The reaction may be carried out at a temperature in the range of about 50°C to about 120°C. Preferably, the reaction is carried out in the range of about 60°C to about 100°C. More preferably, the reaction is carried out in the range of about 60°C to about 80°C. The reaction may be carried out for a duration of about 3 to about 10 hours. Preferably, for a duration of about 5 to about 8 hours. More preferably, the reaction is carried out for a duration of about 6 hours.

[0320] The present invention provides a method for synthesizing intermediate c as shown in the synthetic pathway below, where PG refers to protecting group:

[0321] The primary alcohol of intermediate b may be selectively protected using a suitable reagent such as tert-butyldiphenylsilyl to form intermediate c. Other suitable protecting groups may be used including but not limited to tert-butyldimethylsilyl, triisopropylsilyl or trimethylsilyl protecting group.

[0322] SUBSTITUTE SHEET (RULE 26) Intermediate b may be reacted with tert-butyl(chloro)diphenylsilane to form intermediate c. Alternatively, intermediate b may be reacted with reagents such as tert-butyldimethylsilyl chloride, triisopropylsilyl chloride or trimethylsilyl chloride to form intermediate c.

[0323] The reagent may be used in excess with respect to intermediate b. A 1.1 -times to 1.5-times excess of the reagent may be used with respect to intermediate b. Preferably, a 1.2-times excess of the reagent is used with respect to intermediate b.

[0324] The reaction may be carried out in the presence of a catalyst such as DMAP, imidazole or mixtures thereon. Preferably imidazole is used as the catalyst.

[0325] The catalyst may be used in excess with respect to intermediate b. A 1.1 -times to 2-times excess of the catalyst may be used with respect to intermediate b. Preferably, a 1.5-times excess of the catalyst is used with respect to intermediate b.

[0326] The reaction may be carried out in polar solvents such as acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in THF.

[0327] The reaction may be carried out at a temperature in the range of about 20°C to about 66°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a duration of about 5 to about 18 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0328] The present invention provides a method for synthesizing intermediate d as shown in the synthetic pathway below, where PG refers to protecting group:

[0329] Intermediate c may be reacted with 2-bromo-2,2-difluoro-acetic acid or 2,2-difluoro-2- iodoacetic acid to form intermediate d. Preferably, intermediate c is reacted with 2-bromo-2,2- difluoro-acetic acid to form intermediate d.

[0330] 2-bromo-2,2-difluoro-acetic (or 2,2-difluoro-2-iodoacetic acid) acid may be used in excess with respect to intermediate c. A 2-times to 7-times excess of 2-bromo-2,2-difluoro-acetic acid (2,2- difluoro-2-iodoacetic acid) may be used with respect to intermediate c. Preferably, a 3-times

[0331] 68

[0332] SUBSTITUTE SHEET (RULE 26) excess of 2-bromo-2,2-difluoro-acetic (2,2-difluoro-2-iodoacetic acid) acid is used with respect to intermediate c.

[0333] The reaction is carried out in the presence of a Lewis base. Examples of Lewis bases that may be used for the synthesis of intermediate d include but are not limited to butyl lithium, lithium diisopropylamide (LDA), lithium diethylamide (LDEA), sodium amide (NaNH2), sodium hydride (NaH), lithium bis(trimethylsilyl)amide, or mixtures thereof. Preferably, the Lewis base used in the synthesis of intermediate d is sodium hydride.

[0334] The Lewis base may be used in excess with respect to intermediate c. A 2-times to 6-times excess of the Lewis base may be used with respect to intermediate c. Preferably, a 4.5-times excess of the Lewis base is used with respect to intermediate c.

[0335] The reaction may be carried out in a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1 ,4-dioxane or mixtures thereof. Preferably the reaction is carried out in 1 ,4- dioxane.

[0336] The reaction may be carried out at a temperature in the range of about 15°C to about 101°C. Preferably, the reaction may be carried out at a temperature in the range of about 20°C to about 80°C. More preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a duration of about 5 to about 18 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0337] The present invention provides a method for synthesizing intermediate e as shown in the synthetic pathway below, where PG refers to protecting group:

[0338] Intermediate d undergoes an intramolecular amide coupling reaction, optionally in the presence of a coupling reagent to form intermediate e. Suitable coupling reagents include, but are not limited to, DCC, DIG, EDC-HCI, BOP, PyBOP, PyAOP, PyBrOP, BOP-CI, HATU, HBTU, HCTU, TATU, TBTU, T3P, DEPBT or GDI. Preferably, T3P is used as the coupling reagent.

[0339] The reaction may be carried out in a polar aprotic solvent such as DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in DMF.

[0340] SUBSTITUTE SHEET (RULE 26) The reaction may be carried out at a temperature in the range of about 15°C to about 153°C. Preferably, the reaction may be carried out at a temperature in the range of about 20°C to about 130°C or about 50°C to about 100°C. More preferably, the reaction is carried out at about 20°C.

[0341] The reaction may be carried out for a duration of about 1 hour to about 5 hours. Preferably, the reaction is carried out for a duration of about 2 hours.

[0342] The present invention provides a method for synthesizing intermediate f as shown in the synthetic pathway below, where PG refers to protecting group:

[0343] Intermediate e is reduced by reacting with a reducing agent such as borane dimethyl sulfide to form intermediate f. Other suitable reducing agents may be used instead of borane dimethyl sulfide such as but not limited to lithium aluminum hydride, boron trifluoride diethyl etherate and diborane.

[0344] The reducing agent may be used in excess with respect to intermediate e. A 2-times to 10- times excess of the reducing agent may be used with respect to intermediate e. Preferably, a 4-times excess of the reducing agent is used with respect to intermediate e.

[0345] The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF.

[0346] The reaction may be carried out at a temperature in the range of about 20°C to about 66°C. Preferably, the reaction may be carried out at a temperature in the range of about 30°C to about 50°C. More preferably, the reaction is carried out at about 30°C. The reaction may be carried out for a duration of about 1 hour to about 5 hours. Preferably, the reaction is carried out for a duration of about 3 hours.

[0347] The present invention provides a method for synthesizing intermediate g as shown in the synthetic pathway below, where PG refers to protecting group:

[0348] 70

[0349] SUBSTITUTE SHEET (RULE 26)

[0350] The tert-butyl-diphenylsilane protecting group may be removed from intermediate f by reacting with a source of fluorine to form intermediate g. Suitable reagents as a source of fluorine include but are not limited to tetra-n-butylammonium fluoride (TBAF) or triethylamine trihydrofluoride. Preferably, TBAF is used to form intermediate g.

[0351] The reagent may be used in excess with respect to intermediate f. A 1.1 -times to 2-times excess of the reagent may be used with respect to intermediate f. Preferably, a 1.5-times excess of the reagent is used with respect to intermediate f.

[0352] The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF.

[0353] The reaction may be carried out at a temperature in the range of about 15°C to about 66°C. Preferably, the reaction is carried out at about 20°C to about 50°C. More preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a duration of about 1 hour to about 5 hours. Preferably, the reaction is carried out for a duration of about 2 hours.

[0354] The present invention provides a method for synthesizing intermediate h as shown in the synthetic pathway below, where PG refers to protecting group:

[0355] Intermediate g is reacted with hydrogen and palladium over carbon and is subsequently protected to form intermediate h. Preferably, the reaction is carried out under a hydrogen atmosphere at a pressure in the range of about 10 Psi to about 30 Psi. Preferably, the reaction is carried out at about 15 Psi.

[0356] The conversion of intermediate g to intermediate h may be a one-pot process.

[0357] Preferably, about 0.02 to about 0.5 equivalents of palladium over carbon is used. More preferably, about 0.05 equivalents of palladium over carbon is used.

[0358] 71

[0359] SUBSTITUTE SHEET (RULE 26) Any suitable protecting group may be used form intermediate h. Examples of suitable protecting groups that may be used include Fmoc, BOC or Ts. Preferably, BOC is used as the protecting group. Examples of suitable protecting group reagents to form intermediate h include but are not limited to fluorenylmethyloxycarbonyl chloride, 9- fluorenylmethylsuccinimidyl carbonate, 9-fluorenylmethyloxycarbonyl azide, BOC-anhydride, tosylchloride. Preferably, BOC-anhydride is used.

[0360] The protecting group reagent may be used in excess with respect to intermediate g. A 1.1- times to 2-times excess of the reagent may be used with respect to intermediate g. Preferably, a 1 ,5-times excess of the reagent with respect to intermediate g.

[0361] The reaction may be carried out in a polar aprotic solvent such as ethyl acetate, dichloromethane, THF, or mixtures thereof. Preferably, the reaction is carried out in ethyl acetate.

[0362] The reaction may be carried out at a temperature in the range of about 15°C to about 77°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a duration of about 6 to about 18 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0363] The present invention provides a method for synthesizing intermediate I as shown in the synthetic pathway below, where PG refers to protecting group:

[0364] Intermediate h is reacted with isoindoline-1 , 3-dione to form intermediate i. Isoindoline-1 , 3- dione may be used in excess with respect to intermediate h. A 1.1 -times to 2-times excess of isoindoline-1 , 3-dione may be used with respect to intermediate h. Preferably, a 1.5-times excess of isoindoline-1 , 3-dione is used with respect to intermediate h.

[0365] Preferably, the reaction is carried out in the presence of triphenylphosphine.

[0366] SUBSTITUTE SHEET (RULE 26) Triphenylphosphine may be used in excess with respect to intermediate h. A 1.1-times to 2- times excess of triphenylphosphine may be used with respect to intermediate h. Preferably, a 1.5-times excess of triphenylphosphine is used with respect to intermediate h.

[0367] The reaction is carried out in the presence of an oxidizer such as DIAD or DEAD. Preferably, the oxidizer DIAD is used. The oxidiser may be used in excess with respect to intermediate h. A 1.1-times to 2-times excess of the oxidiser may be used with respect to intermediate h. Preferably, a 1.5-times excess of the oxidiser is used with respect to intermediate h.

[0368] The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF.

[0369] The reaction may be carried out at a temperature in the range of about -10°C to about 66°C. Preferably, the reaction is carried out at about 0°C to about 20°C. The reaction may be carried out for a duration of about 5 to about 20 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0370] The present invention provides a method for synthesizing intermediate j as shown in the synthetic pathway below, where PG refers to protecting group:

[0371] Intermediate i is reacted with hydrazine or hydrazine hydrate to form intermediate j. Preferably, intermediate i is reacted with hydrazine hydrate to form intermediate j.

[0372] Hydrazine or hydrazine hydrate may be used in excess with respect to intermediate i. A 5- times to 20-times excess of hydrazine or hydrazine hydrate may be used with respect to intermediate i. Preferably, a 10-times excess of hydrazine or hydrazine hydrate is used with respect to intermediate i.

[0373] The reaction may be carried out in a polar protic solvent such as alcohols including but not limited to methanol, ethanol, isopropanol or mixtures thereof. Preferably the reaction is carried out in methanol.

[0374] SUBSTITUTE SHEET (RULE 26) The reaction may be carried out at a temperature in the range of about 40°C to about 65°C. Preferably, the reaction is carried out at about 60°C. The reaction may be carried out for a duration of about 1 to about 5 hours. Preferably, the reaction is carried out for a duration of about 2 hours.

[0375] The present invention provides a method for synthesizing intermediate f1 as shown in the synthetic pathway below, where PG refers to protecting group:

[0376] Intermediate e ((5 ?,6S)-4-Benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6- methylmorpholin-3-one) is reduced by reacting with a deuterated reagent to form intermediate f1. Suitable deuterated reagents include but not limited to trideuterioborane UAID4, NaBD4.. Preferably, deuterated reagent is trideuterioborane.

[0377] The protecting group (PG) includes but not limited to tert-butyldimethylsilyl, triisopropylsilyl or trimethylsilyl protecting group. Preferably, the protecting group is tert-butyl-diphenylsilane.

[0378] The reducing agent may be used in excess with respect to intermediate e.

[0379] The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF.

[0380] The reaction may be carried out at a temperature in the range of about 0°C to about 60°C. Preferably, the reaction may be carried out at a temperature in the range of about 0°C to about 40°C. The reaction may be carried out for a duration of about 1 hour to about 3hours, preferably, for about 1.5 hours. The PG group may be tert-butyl-diphenylsilane.

[0381] The present invention provides a method for synthesizing intermediate g1 as shown in the synthetic pathway below, where PG refers to protecting group:

[0382] 74

[0383] SUBSTITUTE SHEET (RULE 26)

[0384] The tert-butyl-diphenylsilane protecting group may be removed from intermediate f1 by reacting with a source of fluorine to form intermediate g1. Suitable reagents as a source of fluorine include but are not limited to tetra-n-butylammonium fluoride (TBAF) or triethylamine trihydrofluoride, preferably, TBAF is used. The process of preparing intermediate g1 may be analogous to the process of preparing intermediate g decribed herein. The reactions conditions such as the amount of reagent, type of solvent (polar aprotic solvent) used and the reaction temperature may be similar to the ones used in synthesis of intermediate g.

[0385] The reaction may be carried out for a duration of about 1 hour to about 15 hours, preferably about 12 hours.

[0386] The present invention provides a method for synthesizing intermediate hi as shown in the synthetic pathway below, where PG’ refers to protecting group: hi

[0387] The method of preparing intermediate hi may be analogous to the method of preparing the intermediate h as described herein.

[0388] Intermediate g1 is reacted with hydrogen and palladium over carbon and is subsequently protected to form intermediate hi. Any suitable protecting group may be used to form intermediate hi. Examples of suitable protecting groups that may be used include Fmoc, BOC or Ts. Preferably, BOC is used as the protecting group.

[0389] The reaction conditions such as pressure, amount of palladium, protecting group reagents, amount of protecting group reagents and solvent, may be similar to the ones used in the synthesis of intermediate h.

[0390] SUBSTITUTE SHEET (RULE 26) The conversion of intermediate g1 to intermediate hi may be a one-pot process. The reaction may be carried out at a temperature in the range of about 15°C to about 77°C. Preferably, at about 20°C. The reaction may be carried out for a duration of about 6 to about 18 hours. Preferably about 16 hours.

[0391] The present invention provides a method for synthesizing intermediate i1 as shown in the synthetic pathway below, where PG’ refers to protecting group:

[0392] The method of preparing intermediate i1 may be analogous to the method of preparing the intermediate i as described herein.

[0393] Intermediate hi is reacted with isoindoline-1 , 3-dione to form intermediate i1. The process conditions such as amount of isoindoline-1, 3-dione, type of solvent, amount of solvent, type of oxidizer, polar aprotic solvent, reaction temperature, and reaction duration may be similar to the ones used in the method of preparing intermediate i described herein.

[0394] The present invention provides a method for synthesizing intermediate j1 as shown in the synthetic pathway below, where PG’ refers to protecting group:

[0395] Intermediate i1 is reacted with hydrazine or hydrazine hydrate to form intermediate j1. Preferably, intermediate i is reacted with hydrazine hydrate to form intermediate j1.

[0396] The method of preparing intermediate j1 may be analogous to the method of preparing the intermediate j as described herein. The process conditions such as amount of hydrazine or hydrazine, solvent, reaction temperature, and reaction duration may be similar to the ones used in the method of preparing intermediate j described herein.

[0397] SUBSTITUTE SHEET (RULE 26) The present invention provides a method for synthesizing intermediate e2’ as shown in the synthetic pathway below:

[0398] N-benzyl-L-allothreonine is reacted with 2-bromo-2,2-difluoro-acetyl)oxysodium or 2,2- difluoro-2-iodoacetic acid in the presence of a base to form intermediate e2’. Preferably, N- benzyl-L-allothreonine is reacted with 2-bromo-2,2-difluoro-acetyl)oxysodium to form intermediate e2’.

[0399] Examples of bases that may be used include but are not limited to potassium t-butoxide (t- BuOK) and lithium t-butoxide (t-BuOLi) or Sodium t-butoxide (t-BuONa). Preferably, t-BuONa is used.

[0400] The reaction may be carried out in a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1 ,4-dioxane or mixtures thereof. Preferably the reaction is carried out in 1 ,4- dioxane.

[0401] 2-2-bromo-2,2-difluoro-acetyl)oxysodium may be used in excess with respect to intermediate a. Preferably, a 3-times excess is used with respect to intermediate a.

[0402] The reaction may be carried out at a temperature in the range of about 0°C to about 35°C. Preferably, in the range of about 0°C to about 20°C. The reaction may be carried out for a duration of about 1 hour to about 3 hours. Preferably, the reaction is carried out for a duration of about 2 hours.

[0403] An intermediate d2’ may be formed in situ, which is preferably quenched with an acid such as hydrochloric acid to form intermediate e2’. The reaction may be carried out in a polar aprotic solvent such as ethyl acetate, dichloromethane, THF, or mixtures thereof. Preferably, the reaction is carried out in ethyl acetate.

[0404] 77

[0405] SUBSTITUTE SHEET (RULE 26) The reaction may be carried out at a temperature in the range of about 0°C to about 35°C. Preferably, in the range of about 0°C to about 25°C. The reaction may be carried out for a duration of about 1 hour to about 3 hours. Preferably, the reaction is carried out for a duration of about 2 hours.

[0406] The present invention provides a method for synthesizing intermediate e2” as shown in the synthetic pathway below: e2'

[0407] Intermediate e2’ is reduced to form intermediate e2”. Intermediate e2’ is reacted with isobutyl carbonochloridate and a a deuterated reducing agent or deuterated reagent. The deuterated reagent may be deuterium oxide, sodium borodeuteride or any combination thereof. Preferably, the deuterated agent may be sodium borodeuteride or sodium borodeuteride and deteurium oxide.

[0408] The deuterated reagent may be used in excess with respect to starting material e2’.

[0409] The reaction may be carried our in the presence of a base. Suitable bases include but are not limited to triethylamine (TEA), DIPEA or alike. Preferably, TEA is used to form intermediate e2”.

[0410] The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF.

[0411] The reaction may be carried out at a temperature in the range of about 0°C to about 35°C. Preferably, the reaction may be carried out at a temperature in the range of about 20°C to about 0°C to about 25°C. The reaction may be carried out for a duration of about 1 hour to about 3 hours. Preferably, the reaction is carried out for a duration of about 2 hours.

[0412] The present invention provides a method for synthesizing intermediate g2 as shown in the synthetic pathway below:

[0413] 78

[0414] SUBSTITUTE SHEET (RULE 26)

[0415] Intermediate e2” is reduced by reacting with a reducing agent such as borane dimethyl sulfide to form intermediate g2. Other suitable reducing agents may be used instead of borane dimethyl sulfide such as but not limited to lithium aluminum hydride, boron trifluoride diethyl etherate and diborane.

[0416] The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF.

[0417] The reaction may be carried out at a temperature in the range of about 0°C to about 60°C. Preferably, in the range of about 0°C to about 45°C. The reaction may be carried out for a duration of about 1 hour to about 3 hours. Preferably, the reaction is carried out for a duration of about 2.5 hours.

[0418] The present invention provides a method for synthesizing intermediate h2 as shown in the synthetic pathway below, where PG’ refers to protecting group:

[0419] Intermediate g2 is reacted with hydrogen and palladium over carbon and is subsequently protected to form intermediate h2. The process of preparing the intermediate h2 may be analogous to the process of preparing intermediate h decribed herein. Any suitable protecting group may be used form intermediate h2. Examples of suitable protecting groups that may be used include Fmoc, BOC or Ts. Preferably, BOC is used as the protecting group.

[0420] Preferably, the reaction conditions such as pressure, amount of palladium, suitable protecting group reagents, amount of protecting group reagents, and solvents are similar to the reaction conditions used in the process of preparing the intermediate h. The conversion of intermediate g2 to intermediate h2 may be a one-pot process.

[0421] SUBSTITUTE SHEET (RULE 26) The reaction may be carried out at a temperature in the range of about 15°C to about 30°C. Preferably, the reaction is carried out at about 20°C.The reaction may be carried out for a duration of about 6 to about 18 hours, preferably about 12 hours.

[0422] The present invention provides a method for synthesizing intermediate i2 as shown in the synthetic pathway below, where PG refers to protecting group: h2 i2

[0423] Intermediate h2 is reacted with isoindoline-1 , 3-dione to form intermediate i2. Preferably, the reaction is carried out in the presence of triphenylphosphine.

[0424] The process of preparing the intermediate i2 may be analogous to the process of preparing intermediate i decribed herein.

[0425] Preferably, the reaction conditions such as amount of triphenylphosphine, oxidizers, amount of oxidize, solvent such as polar aprotic, reaction temperature and reaction duration are similar to the reaction conditions used in the process of preparing the intermediate h described herein.

[0426] The present invention provides a method for synthesizing intermediate j2 as shown in the synthetic pathway below, where PG refers to protecting group: i2 j2

[0427] Intermediate i2 is reacted with hydrazine or hydrazine hydrate to form intermediate j2.

[0428] Preferably, intermediate i2 is reacted with hydrazine hydrate to form intermediate j2.

[0429] Preferably, the method of preparing intermediate j2 is analogous to the method of preparing the intermediate j as described herein. The process conditions, such as amount of hydrazine

[0430] SUBSTITUTE SHEET (RULE 26) or hydrazine, solvent, reaction temperature and reaction duration may be similar to the ones used in the method of preparing intermediate j described herein.

[0431] The present invention also provides a compound which is:

[0432] 2R,3S)-2-(Benzylamino)butane-1,3-diol (intermediate b);

[0433] (2S, 3R)-3-(Benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (intermediate c);

[0434] 2-(((2S,3R)-3-(Benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)oxy)-2,2- difluoroacetic acid (intermediate d);

[0435] (5R,6S)-4-Benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6- methylmorpholin-3-one (intermediate e);

[0436] 5R,6S)-4-Benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6- methylmorpholine (intermediate f);

[0437] ((2S, 3R)-4-Benzyl-6,6-difluoro-2-methylmorpholin-3-yl)methanol (intermediate g); tert-Butyl(5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylate (intermediate h); tert-Butyl(5R,6S)-5-((1,3-dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate (intermediate i); tert-Butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j);

[0438] 5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6- methylmorpholine-3,3-d2 (intermediate f1);

[0439] ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholin-3-yl-5,5-d2)methanol

[0440] (intermediate g1); tert-butyl (5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylate- 3,3-d2 (intermediate hi); tert-butyl (5R,6S)-5-((1 ,3-dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate-3,3-d2 (intermediate i1); tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate- 3,3-d2 (intermediate j1);

[0441] (2S,3S)-4-benzyl-6,6-difluoro-2-methyl-5-oxomorpholine-3-carboxylic acid

[0442] (intermediate e2’);

[0443] 5R,6S)-4-benzyl-2,2-difluoro-5-(hydroxymethyl-d2)-6-methylmorpholin-3-one

[0444] (intermediate e2”);

[0445] ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholin-3-yl)methan-d2-ol (intermediate g2);

[0446] 81

[0447] SUBSTITUTE SHEET (RULE 26) tert-butyl (2S,3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3-methylpiperidine-1 -carboxylate (intermediate h2); tert-butyl (5R,6S)-5-((1 ,3-dioxoisoindolin-2-yl)methyl-d2)-2,2-difluoro-6- methylmorpholine-4-carboxylate (intermediate i2); or tert-butyl (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2).

[0448] Preferably, tert-Butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j) can be prepared starting from compound (a) or from any one of the intermediate compounds (b-i).

[0449] Preferably, tert-Butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate is prepared by:

[0450] - reducing N-benzyl-L-allothreonine (a) by reacting with a reducing agent to form 2R,3S)-2-(Benzylamino)butane-1,3-diol (intermediate b);

[0451] - reacting intermediate (b) with tert-butyl(chloro)diphenylsilane to form (2S,3R)-3- (Benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (intermediate c);

[0452] - reacting intermediate (c) with 2-bromo-2,2-difluoro-acetic acid or 2,2-difluoro-2- iodoacetic acid in the presence of a lewis base to form 2-(((2S,3R)-3-(Benzylamino)-

[0453] 4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)oxy)-2,2-difluoroacetic acid (intermediate d);

[0454] - subjecting intermediate (d) to an intramolecular amide coupling reaction in the presence of a coupling reagent to form (5R,6S)-4-Benzyl-5-(((tert- butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholin-3-one (intermediate e);

[0455] - reacting intermediate (e) with a reducing agent to form (5R,6S)-4-Benzyl-5-(((tert- butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine (intermediate f);

[0456] - reacting intermediate (f) with a source of fluorine to form ((2S,3R)-4-Benzyl-6,6- difluoro-2-methylmorpholin-3-yl)methanol (intermediate g);

[0457] - reacting intermediate (g) with hydrogen and palladium over carbon and di-tert-butyl dicarbonate to form tert-Butyl (5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6- methylmorpholine-4-carboxylate (intermediate h);

[0458] - reacting intermediate (h) with isoindoline-1 , 3-dione to form tert-Butyl (5R,6S)-5-((1 ,3- dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate i); and

[0459] - reacting intermediate (i) with hydrazine or hydrazine hydrate to form tert-Butyl (5R,6S)-

[0460] 5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j).

[0461] 82

[0462] SUBSTITUTE SHEET (RULE 26) Preferably, tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate-3,3-d2 (intermediate j lean be prepared starting from any one of the intermediate compounds (e, f1 -i1).

[0463] Preferably, tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate-3,3-d2 (intermediate j1) may be prepared by: reducing (5R,6S)-4-Benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6- methylmorpholin-3-one (intermediate e) with a deuterated reagent to form (5R,6S)-4-benzyl- 5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methyl morpholine-3,3-d2 (intermediate fl); reacting intermediate (f1) with a source of fluorine to ((2S,3R)-4-benzyl-6,6-difluoro- 2-methylmorpholin-3-yl-5,5-d2)methanol (intermediate g1); reacting intermediate (g1) with hydrogen and palladium over carbon and di-tert-butyl dicarbonate to form tert-butyl (5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4- carboxylate-3,3-d2 (intermediate hi); reacting intermediate (hi) with isoindoline-1 ,3-dione to form tert-butyl (5R,6S)-5-((1 ,3- dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (intermediate i1); and reacting intermediate (i1) with hydrazine or hydrazine hydrate to form tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (intermediate j1).

[0464] Preferably, tert-butyl (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4- carboxylate (intermediate j2) is can be prepared starting from compound (a) or from any one of the intermediate compounds (e2’ - i2).

[0465] Preferably, tert-butyl (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4- carboxylate (intermediate j2) is prepared by: reacting N-benzyl-L-allothreonine (a) with 2-bromo-2,2-difluoro-acetyl) oxysodium, followed by reacting with a suitable acid to form (2S,3S)-4-benzyl-6,6-difluoro-2-methyl-5- oxomorpholine-3-carboxylic acid (intermediate e2’); reducing intermediate e2’ with a deuterated reagent to form 5R,6S)-4-benzyl-2,2- difluoro-5-(hydroxymethyl-d2)-6-methylmorpholin-3-one (intermediate e2”);

[0466] 83

[0467] SUBSTITUTE SHEET (RULE 26) reducing intermediate (e2”) with a reducing agent to form ((2S,3R)-4-benzyl-6,6- difluoro-2-methylmorpholin-3-yl)methan-d2-ol (intermediate g2); reacting intermediate (g2) with hydrogen and palladium over carbon and di-tert-butyl dicarbonate to form tert-butyl (2S,3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3-methylpiperidine- 1 -carboxylate (intermediate h2); reacting intermediate (h2) with isoindoline-1 ,3-dione to form tert-butyl (5R,6S)-5-((1 ,3- dioxoisoindolin-2-yl)methyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate i2); and reacting intermediate (i2) with hydrazine or hydrazine hydrate to form tert-butyl (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2).

[0468] The present invention provides a method for synthesizing compounds 1-49, 60-69,78-88, 92- 102 as shown in the synthetic pathway below:

[0469] 1-49, 60-69,78-88, 92-102

[0470] The structure of compounds 1-49, 60-69, 78-88 and 92-102 is as shown herein above.

[0471] The present invention also provides a method for preparing a compound of Formula I:

[0472] 84

[0473] SUBSTITUTE SHEET (RULE 26) wherein X, X’, R and Het may be each independently as herein defined above; said method comprising the steps of:

[0474] (a) reacting tert-Butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate with a halo-substituted heteroaromatic compound in the presence of a base to form a first intermediate compound;

[0475] (b) reacting the first intemediate compound with an acid to form a second intermediate compound; and

[0476] (c) reacting the second intemediate compound with a carboxylic acid having a general formula R-COOH to obtain a compound of Formula I.

[0477] Intermediate j undergoes a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of intermediates k-z2.

[0478] Preferably, intermediates k-z2 are, tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl) morpholine-4-carboxylate (intermediate k); tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl) morpholine-4-carboxylate (intermediate I); tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl) morpholine-4-carboxylate (intermediate m); tert-Butyl (5R,6S)-5-(((5-chloropyridin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate (intermediate n); tert-Butyl (5R,6S)-5-(((5-chloropyrimidin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine- 4-carboxylate (intermediate o); tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylate (intermediate p); tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((6-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate (intermediate q);

[0479] 85

[0480] SUBSTITUTE SHEET (RULE 26) tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylate (intermediate r); tert-Butyl (5R,6S)-2,2-difluoro-5-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-6- methylmorpholine-4-carboxylate (intermediate s); tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylate (intermediate t) tert-Butyl (5R,6S)-5-(((5-cyclopropylpyrimidin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate (intermediate u); tert-Butyl (5R,6S)-2,2-difluoro-5-(((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-6- methylmorpholine-4-carboxylate (intermediate v); tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate (intermediate w); tert-Butyl (5R,6S)-5-(((3-cyano-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate (intermediate x): tert-Butyl (5R,6S)-5-(((5-chloro-3-fluoropyridin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate (intermediate y); tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((4-methyl-5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylate (intermediate z); tert-butyl (5R,6S)-5-(((5-(difluoromethyl)pyrimidin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate (intermediate z1); or tert-butyl (5R,6S)-5-(((5-(difluoromethyl)pyrazin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate (intermediate z2).

[0481] In some examples, tert-Butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate is a deuterated compound. Preferably, the deuterated compound is tert-butyl (5R, 6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 or tert-butyl (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate, which is reacted with a halo-substituted heteroaromatic compound in the presence of a base in step (a) to form the first intermediate compound. The first intemediate compound may be reacted with an acid to form the second intermediate compound; and the second intemediate compound may be reacted with a carboxylic acid having a general formula R-COOH to obtain a deuterated compound of Formula I.

[0482] The present invention provides a method for synthesizing compounds 50-59, 70-77 as shown in the synthetic pathway below:

[0483] 86

[0484] SUBSTITUTE SHEET (RULE 26)

[0485] 50-59, 70-77

[0486] The structure of compounds 50-59, 70-77 is as shown herein above.

[0487] The present invention also provides a method for preparing a compound of Formula ID(a): wherein X, X’, R and Het may be each independently as herein defined above; and R6may be hydrogen or deuterium, said method comprising the steps of:

[0488] (a) reacting tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate-3,3-d2 (intermediate j1) with a halo-substituted heteroaromatic compound in the presence of a base to form a first intermediate compound;

[0489] (b) reacting the first intemediate compound with an acid to form a second intermediate

[0490] 87

[0491] SUBSTITUTE SHEET (RULE 26) compound; and

[0492] (c) reacting the second intemediate compound with a carboxylic acid having a general formula R-COOH to obtain a compound of Formula ID(a).

[0493] Intermediate j1 may undergo a nucleophilic aromatic substitution reaction with a halo- substituted heteroaromatic compound to form one of intermediates k1, 11 and ml .

[0494] Preferably, intermediates k1, 11 and ml are: tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl) morpholine-4-carboxylate-3,3-d2 (k1); tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl) morpholine-4-carboxylate-3,3-d2 (11); or tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl) morpholine-4-carboxylate-3,3-d2 (ml).

[0495] The present invention provides a method for synthesizing compounds 89-91 and 103 as shown in the synthetic pathway below:

[0496] 89-91 and 103

[0497] The structure of compounds 89-91 and 103 is as shown herein above.

[0498] SUBSTITUTE SHEET (RULE 26) The present invention also provides a method for preparing a compound of Formula I D(b): wherein X, X’, R and Het may be each independently as herein defined above; and R7may be hydrogen or deuterium, said method comprising the steps of:

[0499] (a) reacting tert-butyl (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4- carboxylate (intermediate j2) with a halo-substituted heteroaromatic compound in the presence of a base to form a first intermediate compound;

[0500] (b) reacting the first intemediate compound with an acid to form a second intermediate compound; and

[0501] (c) reacting the second intemediate compound with a carboxylic acid having a general formula R-COOH to obtain a compound of Formula I D(b).

[0502] Preferably, tert-butyl (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4- carboxylate (intermediate j2) is prepared by: reacting N-benzyl-L-allothreonine (a) with 2-bromo-2,2-difluoro-acetyl) oxysodium, followed by reacting with a suitable acid to form (2S,3S)-4-benzyl-6,6-difluoro-2-methyl-5- oxomorpholine-3-carboxylic acid (intermediate e2’); reducing intermediate e2’ with a deuterated reagent to form 5R,6S)-4-benzyl-2,2- difluoro-5-(hydroxymethyl-d2)-6-methylmorpholin-3-one (intermediate e2”); reducing intermediate (e2”) with a reducing agent to form ((2S,3R)-4-benzyl-6,6- difluoro-2-methylmorpholin-3-yl)methan-d2-ol (intermediate g2); reacting intermediate (g2) with hydrogen and palladium over carbon and di-tert-butyl dicarbonate to form tert-butyl (2S,3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3-methylpiperidine- 1 -carboxylate (intermediate h2); reacting intermediate (h2) with isoindoline-1 ,3-dione to form tert-butyl (5R,6S)-5-((1 ,3- dioxoisoindolin-2-yl)methyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate

[0503] SUBSTITUTE SHEET (RULE 26) i2); and reacting intermediate (i2) with hydrazine or hydrazine hydrate to form tert-butyl (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2).

[0504] Intermediate j2 undergoes a nucleophilic aromatic substitution reaction with a halo- substituted heteroaromatic compound to form one of intermediates k2, 12, m2 and n2.

[0505] Preferably, intermediates k2, 12, m2 and n2 are: tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2-yl)amino) methyl- d2)morpholine-4-carboxylate (k2);

[0506] (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl- d2)morpholine-4-carboxylate (12); tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2-yl)amino) methyl- d2)morpholine-4-carboxylate (m2); or tert-Butyl (5R,6S)-5-(((5-chloropyridin-2-yl)amino)methyl-d2)-2,2-difluoro-6- methylmorpholine-4-carboxylate (n2).

[0507] The halo-substituted heteroaromatic compound may be selected from the group consisting of halo-substituted pyridine, halo-substituted pyridazine, halo-substituted pyrazine, halo- substituted pyrimidine, halo-substituted triazole, halo-substituted tetrazole, halo-substituted pyrazole, halo-substituted furan, halo-substituted thiophene, halo-substituted pyrrole, halo- substituted imidazole, halo-substituted isoxazole, halo-substituted oxazole, halo-substituted isothiazole, halo-substituted thiazole and any derivatives thereof, wherein said halo- substituted heteroaromatic group may be further substituted; wherein the further substituents of the halo-substituted heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (Ci-C4)-straight chain alkyl, unsubstituted (Ci-C4)-branched alkyl, unsubstituted (Ci-C4)-alkoxy group, unsubstituted (C3-C8)-cycloalkyl, substituted (Ci- C4)-straight chain alkyl, substituted (Ci-C4)-branched alkyl, substituted (Ci-C4)-alkoxy group, substituted (C3-C8)-cycloalkyl, a cyano group and halogen (such as F,CI, Br). Preferably, the further substituents of the heteroaromatic group is Cl, F, CF3, CH3, methoxy, nitrile or cyclopropyl.

[0508] The halo-substituted heteroaromatic compound may be a fluoro-substituted heteroaromatic compound, chloro-substituted heteroaromatic compound, bromo-substituted heteroaromatic

[0509] 90

[0510] SUBSTITUTE SHEET (RULE 26) compound or iodo-substituted heteroaromatic compound. Preferably, the halo-substituted heteroaromatic compound may be a chloro-substituted heteroaromatic compound.

[0511] The halo-substituted heteroaromatic compound is preferably selected from 2-chloro-5- (trifluoromethyl) pyrazine, 2-chloro-5-(trifluoromethyl)pyrimidine, 2-chloro-5- (trifluoromethyl)pyridine, 5-chloro-2-fluoro-pyridine, 5-chloro-2-fluoropyrimidine, 2-chloro-6- (trifluoromethyl)pyrazine, 2-fluoro-4-(trifluoromethyl)pyridine, 2,3-difluoro-5- (trifluoromethyl)pyridine, 3-bromo-2-fluoro-5-(trifluoromethyl)pyridine, 2-chloro-5- cyclopropylpyrimidine, 2-chloro-3-methoxy-5-(trifluoromethyl)pyridine, 3-methyl-5-

[0512] (trifluoromethyl)pyrazin-2-ol, 2-chloro-5-(trifluoromethyl)nicotinonitrile, 5-chloro-2,3- difluoropyridine, 2,4-dichloro-5-(trifluoromethyl)pyrimidine, 2-chloro-5-

[0513] (difluoromethyl)pyrazine or 2-chloro-5-(difluoromethyl)pyrimidine, 5-chloro-2-fluoropyridine, 2- fluoro-5-(trifluoromethyl)pyridine, 2-chloro-5-(trifluoromethyl)pyrimidine, 2-chloro-5- (trifluoromethyl)pyrazine.

[0514] The nucleophilic aromatic substitution reaction is carried out in the presence of a base. Examples of bases that may be used include but are not limited to potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA or DI PEA. Preferably, the nucleophilic aromatic substitution reaction is carried out in the presence of potassium carbonate.

[0515] The base may be used in excess with respect to intermediate j, j1 or j2. A 2-times to 6-times excess of the base may be used with respect to intermediate j. Preferably, a 3-times excess of the base is used with respect to intermediate j, j1 orj2.

[0516] The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in DMSO.

[0517] The reaction may be carried out at a temperature in the range of about 50°C to about 189°C. Preferably, the reaction is carried out at about 80°C.

[0518] The reaction may be carried out for a duration of about 6 to about 18 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0519] 91

[0520] SUBSTITUTE SHEET (RULE 26) Intermediates k-z2 are deprotected by treatment with an acid to form corresponding intermediates aa-ar.

[0521] Preferably, intermediates aa-ar are:

[0522] 5-Chloro- / V-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)pyridin-2-amine hydrochloride (intermediate aa);

[0523] / V-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride (intermediate ab);

[0524] N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride (intermediate ac);

[0525] / V-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride (intermediate ad);

[0526] 5-Chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)pyrimidin-2-amine hydrochloride (intermediate ae);

[0527] N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-4-(trifluoromethyl)pyrimidin-2-amine hydrochloride (intermediate af);

[0528] N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-6-(trifluoromethyl)pyrazin-2-amine hydrochloride (intermediate ag);

[0529] N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-4-(trifluoromethyl)pyridin-2-amine hydrochloride (intermediate ah);

[0530] N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-3-fluoro-5-(trifluoromethyl)pyridin-2- amine hydrochloride (intermediate ai);

[0531] N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyridin- 2-amine (intermediate aj);

[0532] 5-Cyclopropyl-N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)pyrimidin-2-amine hydrochloride (intermediate ak);

[0533] N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-3-methoxy-5- (trifluoromethyl)pyridin-2-amine (intermediate al);

[0534] N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyrazin- 2-amine hydrochloride (intermediate am);

[0535] 2-((((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)amino)-5- (trifluoromethyl)nicotinonitrile hydrochloride (intermediate an);

[0536] 5-Chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3-fluoropyridin-2-amine hydrochloride (intermediate ao);

[0537] 92

[0538] SUBSTITUTE SHEET (RULE 26) N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-4-methyl-5- (trifluoromethyl)pyrimidin-2-amine (intermediate ap).

[0539] N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-5-(difluoromethyl)pyrimidin-2-amine hydrochloride (intermediate aq); or . N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-5-(difluoromethyl)pyrazin-2-amine hydrochloride (intermeadiate ar)

[0540] Intermediates k1, 11 and ml are deprotected by treatment with an acid to form corresponding intermediates ab1 , ac1 , ad1. Preferably, intermediates ab1, ac1, ad1 are: N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyrazin-2- amine hydrochloride (intermediate ab1);

[0541] N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyrimidin- 2-amine hydrochloride (intermediate ac1); or N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyridin-2- amine hydrochloride (intermediate ad1).

[0542] Intermediates k2, I2, m2 and n2 are deprotected by treatment with an acid to form corresponding intermediates aa2, ab2, ac2, and ad2. Preferably, intermediates aa2, ab2, ac2, and ad2 are:

[0543] 5-Chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl-d2)pyridin-2-amine hydrochloride (aa2);

[0544] N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl)pyrazin-2- amine hydrochloride (intermediate ab2);

[0545] N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl)pyrimidin-2- amine (intermediate ac2); or N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl)pyridin-2- amine (intermediate ad2).

[0546] Examples of acids that may be used for the deprotection include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid. Preferably, hydrochloric acid is used for the deprotection of intermediates k - z2, k1 - ml and k2 -- n2.

[0547] 93

[0548] SUBSTITUTE SHEET (RULE 26) The deprotection may be carried out in a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1 ,4-dioxane or mixtures thereof. Preferably the reaction is carried out in 1 ,4-dioxane.

[0549] The deprotection may be carried out at a temperature in the range of about 12°C to about 40°C. Preferably, the reaction is carried out at about 20 °C.

[0550] The deprotection may be carried out for a duration of about 30 mins to about 5 hours. Preferably, the reaction is carried out for a duration of about 2 hours.

[0551] Intermediates aa-ar, ab1-ad1 , aa2-ad2 are reacted with carboxylic acid having the general formula R-COOH to form compounds 1-103 disclosed herein; wherein R is selected from the group consisting of a five or a six membered aromatic or heteroaromatic group, wherein the aromatic group or heteroaromatic group is either unsubstituted or is substituted with one or more substituents. Preferably, R in the compound of Formula I comprises a five membered heteroaromatic group which is an unsubstituted pyrazole, an unsubstituted oxazole, an unsubstituted thiazole, an unsubstituted imidazole, a substituted pyrazole, a substituted oxazole, a substituted thiazole, a substituted imidazole or a derivative thereof; a six membered aromatic group which is unsubstituted aryl, or substituted aryl, or a derivative thereof; or a six membered heteroaromatic group which is an unsubstituted pyridine, an unsubstituted pyrimidine, an unsubstituted pyridazine, an unsubstituted pyrazine, a substituted pyridine, a substituted pyrimidine, a substituted pyridazine, a substituted pyrazine or a derivative thereof. In some examples, at least one of the hydrogen in R is replaced with deuterium.

[0552] The carboxylic acid R-COOH preferably comprises 4-(4-chlorophenyl)-1-methyl-pyrazole-3- carboxylic acid (CAS 1534651-22-3), 5-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (CAS 956317-36-5), 3-fluoro-2-(pyrimidin-2-yl)benzoic acid (CAS 1293285-04-7), 4-(5- chloropyridin-2-yl)-1-methyl-1 H-pyrazole-3-carboxylic acid (CAS 2125741-28-6), 4-(5- fluoropyrimidin-2-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid (CAS 2125741-56-0), 5- methyl-2-(pyrimidin-2-yl)benzoic acid (CAS 1088994-22-2), 5-methyl-2-(2-methyl-2H-tetrazol- 5-yl)benzoic acid (CAS 1861694-01-0), 5-chloro-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid (CAS 1858774-05-6), 4-(5-fluoropyrimidin-2-yl)- 1 -methyl- 1 H-pyrazole-3-carboxylic acid (CAS 2044704-99-4), 1-methyl-4-(pyrimidin-2-yl)-1 H-pyrazole-3-carboxylic acid (CAS 2125740-38- 5), 4-(5-methoxypyridin-2-yl)- 1 -methyl- 1 H-pyrazole-3-carboxylic acid (CAS 2024759-24-6), 4- (5-fluoropyridin-2-yl)- 1 -methyl- 1 H-pyrazole-3-carboxylic acid (CAS 2125740-41-0), 4-(4-

[0553] 94

[0554] SUBSTITUTE SHEET (RULE 26) fluorophenyl)- 1 -methyl- 1H-pyrazole-3-carboxylic acid (CAS 127919-87-3), 4-(4- cyanophenyl)-1-methyl-1 H-pyrazole-3-carboxylic acid, 4-(5-cyanopyridin-2-yl)- 1 -methyl- 1 H- pyrazole-3-carboxylic acid, 5-(5-fluoropyrimidin-2-yl)-1-methyl-1 H-imidazole-4-carboxylic acid, 5-(5-methoxypyridin-2-yl)-1-methyl-1 H-imidazole-4-carboxylic acid, 4-(5-fluoropyridin-2- yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid, 2-methyl-5-(pyridin-2-yl)thiazole-4-carboxylic acid (CAS 1267878-49-8), 2-methyl-5-(pyrimidin-2-yl)thiazole-4-carboxylic acid (CAS 1817687-92-5), 2-methyl-5-(pyridin-2-yl)oxazole-4-carboxylic acid (CAS 2090936-92-6), 6- methyl-3-(2H-1 ,2,3-triazol-2-yl)picolinic acid (CAS 1228188-37-1), 5-fluoro-2-(2H-1,2,3- triazol-2-yl)benzoic acid (CAS 1186050-64-5), 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H- pyrazole-3-carboxylic acid, or 6-methyl-3-(pyrimidin-2-yl)picolinic acid (CAS 1228188-18-8), 5-fluoro-3-(pyrimidin-2-yl)picolinic acid (CAS 1935682-37-3), 3-(5-fluoropyrimidin-2-yl)-5,6- dihydro-4H-pyrrolo[1 ,2-b]pyrazole-2-carboxylic acid, 5,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid, 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid, 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid, 4-(5-Fluoropyrimidin-2-yl)-1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylic acid, 4-(5- Fluoropyrimidin-2-yl)-5-methyl-1-(methyl-d3)-1 H-pyrazole-3-carboxylic acid, 4-(5- Fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1 H-pyrazole-3-carboxylic acid, 6-(Methyl-d3)-3- (pyrimidin-2-yl)picolinic acid, 6-(Methyl-d3)-3-(2H-1,2,3-triazol-2-yl)picolinic acid hydrochloride, 1-methyl-4-(pyridin-2-yl)-1 / 7-pyrazole-3-carboxylic acid (CAS 1540679-95-5), 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS 1001401-62-2); 1,5-dimethyl-4-(pyrazin-2-yl)-1 H- pyrazole-3-carboxylic acid, 4-(5-fluoropyridin-3-yl)-1,5-dimethyl-1 H-pyrazole-carboxylic acid; 4-(4-fluoropyridin-3-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid, 4-(4-fluoropyridin-2-yl)- 1,5-dimethyl-1 H-pyrazole-3-carboxylic acid, 4-(5-fluoropyrimidin-2-yl)-1-methyl-5-(methyl- d3)-1 H-pyrazole-3-carboxylic acid.

[0555] The carboxylic acid R-COOH described herein may be deuterated where at least one of the hydrogen is replaced with deuterium, preferably, the carboxylic acids 4-(5-fluoropyrimidin-2- yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid and 4-(5-fluoropyridin-2-yl)-1 ,5-dimethyl-1 H- pyrazole-3-carboxylic acid are deuterated. More peferably, the N-Me or C-Me group of the pyrazole ring of carboxylic acid R-COOH acid are deuterated. More peferably, the N-Me or C- Me group of the pyrazole ring of the carboxylic acids 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl- 1H-pyrazole-3-carboxylic acid and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3- carboxylic acid are deuterated.

[0556] The deuterated carboxylic acid R-COOH preferably comprises 4-(5-Fluoropyrimidin-2-yl)-1- methyl-5-(methyl-d3)-1 H-pyrazole-3-carboxylic acid, 4-(5-Fluoropyrimidin-2-yl)-5-methyl-1-

[0557] 95

[0558] SUBSTITUTE SHEET (RULE 26) (methyl-d3)-1 H-pyrazole-3-carboxylic acid, 4-(5-Fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)- 1 H-pyrazole-3-carboxylic acid, 6-(Methyl-d3)-3-(pyrimidin-2-yl)picolinic acid, or 6-(Methyl-d3)- 3-(2H-1 ,2,3-triazol-2-yl)picolinic acid hydrochloride.

[0559] The reaction of intermediates aa-ar, ab1-ad1 , aa2-ad2 with carboxylic acid R-COOH may be carried out in the presence of a coupling reagent. Suitable coupling reagents include but are not limited to DCC, DIG, EDC-HCI, BOP, PyBOP, PyAOP, PyBrOP, BOP-CI, HATU, HBTU, HCTLI, TATU, TBTLI, T3P, DEPBT or GDI. Preferably, HATU is used as the coupling reagent.

[0560] The reaction of intermediates aa-ar, ab1-ad1, aa2-ad2 with carboxylic acid R-COOH may be carried out in the presence of a base. Any suitable base may be used for this reaction. Examples of suitable bases include but are not limited DIPEA or TEA. Preferably, DIPEA is used as the base in the reaction.

[0561] The reaction of intermediates aa-ar, ab1- ad1, aa2 - ad2 with carboxylic acid R-COOH may be carried out in a polar aprotic solvent such as THF, dichloromethane, ethyl acetate, DMF or DMSO. Preferably the reaction is carried out in dichloromethane.

[0562] The reaction of intermediates aa-ar, ab1-ad1, aa2-ad2 with carboxylic acid R-COOH may be carried out at a temperature in the range of about -10°C to about 40°C. Preferably, the reaction is carried out from about 0°C to about 20°C.

[0563] The reaction of intermediates aa-ar, ab1-ad1, aa2-ad2 with carboxylic acid R-COOH may be carried out for a duration of about 1 hours to about 6 hours. Preferably, the reaction is carried out for a duration of about 2.5 hours.

[0564] The present invention also provides a method for synthesizing carboxylic acid with general formula R-COOH as shown in the synthetic pathway below:

[0565] SUBSTITUTE SHEET (RULE 26) Preferably, the R-COOH is 4-(4-cyanophenyl)- 1 -methyl- 1 H-pyrazole-3-carboxylic acid.

[0566] The starting material selected from tert-butyl 4-iodo- 1 -methyl- 1 H-pyrazole-3-carboxylate, tertbutyl 4-bromo- 1 -methyl- 1 H-pyrazole-3-carboxylate, or tert-butyl 4-chloro-1-methyl-1 H- pyrazole-3-carboxylate may be reacted with (4-cyanophenyl)boronic acid or derivatives thereof (for example boronic esters or organotrifluoroborate salts), via Suzuki coupling to form an intermediate.

[0567] Alternatively, the starting material selected from tert-butyl 4-iodo-1-methyl-1 H-pyrazole-3- carboxylate, tert-butyl 4-bromo-1-methyl-1 H-pyrazole-3-carboxylate, or tert-butyl 4-chloro-1- methyl-1 H-pyrazole-3-carboxylate may be reacted with 4-cyanophenyl derivatives that are suitable for Hiyama coupling, Stille coupling, Heck coupling, Kumada coupling or Negishi coupling.

[0568] (4-cyanophenyl)boronic acid or derivatives thereof may be used in excess with respect to the starting material. A 1.1 -times to 1.5-times excess of (4-cyanophenyl)boronic acid or derivatives thereof may be used with respect to the starting material. Preferably, a 1 ,2-times excess of (4- cyanophenyl)boronic acid or derivatives thereof is used with respect to the starting material.

[0569] The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO, a polar protic solvent such as water, methanol, ethanol, isopropanol, a non-polar solvent such as chloroform, 1 ,4-dioxane or any combination thereof. Preferably the reaction is carried out in a combination of THF and water.

[0570] The reaction may be carried out in the presence of a catalyst. Preferably, the catalyst is a palladium compound. Examples of such palladium compounds include but are not limited to Pd(dtbpf)CI2, Pd(PPh3)4, PdCI2(PPh3)2, Pd(dppf)CI2, or Pd(dppp)CI2. More preferably, Pd(dtbpf)CI2is used as the catalyst.

[0571] Preferably, about 0.02 to about 0.5 equivalents of the catalyst is used with respect to the starting material. More preferably, about 0.05 equivalents of the catalyst is used.

[0572] The reaction may be carried out in the presence of a base. Examples of bases that may be used include but are not limited to K2CO3, KO‘Bu, Cs2CO3, KsPC , NaOH, or NEt3. Preferably, KsPC is used.

[0573] 97

[0574] SUBSTITUTE SHEET (RULE 26) The base may be used in excess with respect to the starting material. A 2-times to 6-times excess of the base may be used with respect to the starting material. Preferably, a 3-times excess of the base is used with respect to the starting material.

[0575] The reaction may be carried out at a temperature in the range of about 50 °C to about 100 °C. Preferably, the reaction is carried out at about 80 °C. The reaction may be carried out for a duration of about 30 mins to about 5 hours. Preferably, the reaction is carried out for a duration of about 2 hours.

[0576] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0577] The intermediate formed may be deprotected by reacting with an acid. Examples of acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid. Preferably, hydrochloric acid is used.

[0578] The deprotection may be carried out in a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1 ,4-dioxane or mixtures thereof. Preferably the reaction is carried out in 1 ,4-dioxane.

[0579] The deprotection may be carried out at a temperature in the range of about 20°C to about 80°C. Preferably, the reaction is carried out at about 50°C. The deprotection may be carried out for a duration of about 30 mins to about 5 hours. Preferably, the reaction is carried out for a duration of about 2 hours.

[0580] The present invention also provides an alternative method for synthesizing carboxylic acid with general formula R-COOH as shown in the synthetic pathway below:

[0581] Preferably, the R-COOH is 4-(5-Cyanopyridin-2-yl)-1-methyl-1 H-pyrazole-3-carboxylic acid.

[0582] 98

[0583] SUBSTITUTE SHEET (RULE 26) The starting material selected from 6-iodopyridine-3-carbonitrile, 6-bromopyridine-3- carbonitrile or 6-chloropyridine-3-carbonitrile may be reacted with (3-(tert-butoxycarbonyl)-1- methyl-1 H-pyrazol-4-yl)boronic acid or derivatives thereof (for example boronic esters or organotrifluoroborate salts), via Suzuki coupling to form an intermediate.

[0584] Alternatively, the starting material may be reacted with (3-(tert-butoxycarbonyl)-1-methyl-1 H- pyrazol-4-yl) derivatives that are suitable for Hiyama coupling, Stille coupling, Heck coupling, Kumada coupling or Negishi coupling.

[0585] The compounds selected from 6-iodopyridine-3-carbonitrile, 6-bromopyridine-3-carbonitrile or 6-chloropyridine-3-carbonitrile may be used in excess with respect to the starting material. A 1.1 -times to 1.5-times excess of may be used with respect to the starting material. Preferably, a 1 ,2-times excess of is used with respect to the starting material.

[0586] The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO, a polar protic solvent such as water, methanol, ethanol, isopropanol, a non-polar solvent such as chloroform, 1 ,4-dioxane or any combination thereof. Preferably the reaction is carried out in a combination of 1 ,4-dioxane and water.

[0587] The reaction may be carried out in the presence of a catalyst. Preferably, the catalyst is a palladium compound. Examples of such palladium compounds include but are not limited to Pd(dtbpf)CI2, Pd(PPh3)4, PdCI2(PPh3)2, Pd(dppf)CI2, or Pd(dppp)CI2. More preferably, Pd(dtbpf)CI2is used as the catalyst.

[0588] Preferably, about 0.02 to about 0.5 equivalents of the catalyst is used with respect to the starting material. Preferably, about 0.05 equivalents of the catalyst is used.

[0589] The reaction may be carried out in the presence of a base. Examples of bases that may be used include but are not limited to K2CO3, KO‘Bu, Cs2CO3, KsPC , NaOH, or NEt3. Preferably, KsPC is used.

[0590] The base may be used in excess with respect to the starting material. A 1.1-times to 5-times excess of the base may be used with respect to the starting material. Preferably, a 1.5-times excess of the base is used with respect to the starting material.

[0591] 99

[0592] SUBSTITUTE SHEET (RULE 26) The reaction may be carried out at a temperature in the range of about 50°C to about 100°C. Preferably, the reaction is carried out at about 80°C. The reaction may be carried out for a duration of about 30 mins to about 5 hours. Preferably, the reaction is carried out for a duration of about 2 hours.

[0593] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0594] The intermediate formed may be deprotected by reacting with an acid. Examples of acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid. Preferably, hydrochloric acid is used.

[0595] The deprotection may be carried out in a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1 ,4 dioxane or mixtures thereof. Preferably the reaction is carried out in 1 ,4 dioxane.

[0596] The deprotection may be carried out at a temperature in the range of about 10°C to about 50°C. Preferably, the reaction is carried out at about 20°C. The deprotection may be carried out for a duration of about 6 hours to about 18 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0597] The present invention also provides another alternative method for synthesizing carboxylic acid with general formula R-COOH as shown in the synthetic pathway below:

[0598] Preferably, R-COOH is 5-(5-Fluoropyrimidin-2-yl)-1-methyl-1 H-imidazole-4-carboxylic acid.

[0599] The starting material selected from methyl 5-bromo-1-methyl-1 H-imidazole-4-carboxylate, methyl 5-iodo- 1 -methyl- 1 H-imidazole-4-carboxylate, or methyl 5-chloro-1-methyl-1 H- imidazole-4-carboxylate may be converted to an organostannane intermediate by reacting with hexaalkylditin such as hexamethylditin or hexabutylditin.

[0600] 100

[0601] SUBSTITUTE SHEET (RULE 26) The hexaalkylditin may be used in excess with respect to the starting material. A 1.2-times to 5-times excess of may be used with respect to the starting material. Preferably, a 2-times excess of is used with respect to the starting material.

[0602] The reaction may be carried out in a non-polar solvent such as chloroform, 1 ,4-dioxane, or toluene. Preferably the reaction is carried out in toluene.

[0603] The reaction may be carried out in the presence of a catalyst. Preferably, the catalyst is a palladium compound. Examples of such palladium compounds include but are not limited to Pd(dtbpf)CI2, Pd(PPh3)4, PdCI2(PPh3)2, Pd(dppf)CI2, or Pd(dppp)CI2. More preferably, Pd(PPh3)4 is used as the catalyst.

[0604] Preferably about 0.02 to about 0.8 equivalents of the catalyst is used with respect to the starting material. More preferably, about 0.1 equivalents of the catalyst is used.

[0605] The reaction may be carried out at a temperature in the range of about 50°C to about 120°C. Preferably, the reaction is carried out in the range of about 100°C to about 120°C. The reaction may be carried out for a duration of about 3 mins to about 10 hours. Preferably, the reaction is carried out for a duration of about 6 hours.

[0606] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0607] The organostannane intermediate may be reacted with compounds selected from 2-bromo-5- fluoro-pyrimidine, 2-iodo-5-fluoro-pyrimidine or 2-chloro-5-fluoro-pyrimidine, via Stille coupling to form a second intermediate.

[0608] Alternatively, compounds selected from 2-bromo-5-fluoro-pyrimidine, 2-iodo-5-fluoro- pyrimidine or 2-chloro-5-fluoro-pyrimidine may be reacted with 1-methyl-1 H-imidazole-4- carboxylate derivatives that are suitable for Hiyama coupling, Suzuki coupling, Heck coupling, Kumada coupling or Negishi coupling.

[0609] Compounds selected from 2-bromo-5-fluoro-pyrimidine, 2-iodo-5-fluoro-pyrimidine or 2- chloro-5-fluoro-pyrimidine may be used in excess with respect to the organostannane

[0610] 101

[0611] SUBSTITUTE SHEET (RULE 26) intermediate. A 1.1 -times to 3-times excess of may be used with respect to the organostannane intermediate. Preferably, a 1 ,5-times excess of is used with respect to the the organostannane intermediate.

[0612] The reaction may be carried out in a non-polar solvent such as chloroform, 1 ,4-dioxane, xylene or toluene. Preferably the reaction is carried out in xylene.

[0613] The reaction may be carried out in the presence of a catalyst. Preferably, the catalyst is a palladium compound. Examples of such palladium compounds include but are not limited to Pd(dtbpf)CI2, Pd(PPh3)4, PdCI2(PPh3)2, Pd(dppf)CI2, or Pd(dppp)CI2. More preferably, Pd(PPh3)4 is used as the catalyst.

[0614] Preferably about 0.02 to about 0.5 equivalents of the catalyst is used with respect to the organostannane intermediate. Preferably, about 0.1 equivalents of the catalyst is used.

[0615] The reaction may be carried out at a temperature in the range of about 50°C to about 140°C. Preferably, the reaction is carried out at about 120°C. The reaction may be carried out for a duration of about 10 hours to about 22 hours. Preferably, the reaction is carried out for a duration of 16 hours.

[0616] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0617] The second intermediate may be deprotected by reacting with an acid or a base. Examples of acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid. Examples of bases that may be used include but are not limited to lithium hydroxide, sodium hydroxide or potassium hydroxide. Preferably, hydrochloric acid is used.

[0618] The deprotection may be carried out in neat acid or base.

[0619] The concentration of the acid or base may range from about 3 M to about 10 M. Preferably, a concentration of about 6 M is used.

[0620] The deprotection may be carried out at a temperature in the range of about 50°C to about 100°C. Preferably, the reaction is carried out at about 80°C. The deprotection may be carried

[0621] 102

[0622] SUBSTITUTE SHEET (RULE 26) out for a duration of about 6 hours to about 22 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0623] The present invention also provides yet another alternative method for synthesizing carboxylic acid with general formula R-COOH as shown in the synthetic pathway below:

[0624] Preferably, R-COOH is 5-(5-Methoxypyridin-2-yl)-1-methyl-1 H-imidazole-4-carboxylic acid.

[0625] The starting material selected from methyl 5-bromo-1-methyl-1 H-imidazole-4-carboxylate, methyl 5-chloro-1-methyl-1 H-imidazole-4-carboxylate, or methyl 5-iodo-1-methyl-1 H- imidazole-4-carboxylate may be reacted with tributyl-(5-methoxy-2-pyridyl)stannane or derivatives thereof (for example trimethyl-(5-methoxy-2-pyridyl)stannane), via Stille coupling to form an intermediate.

[0626] Alternatively, starting material selected from methyl 5-bromo-1-methyl-1 H-imidazole-4- carboxylate, methyl 5-chloro-1-methyl-1 H-imidazole-4-carboxylate or methyl 5 iodo-1-methyl- 1 H-imidazole-4-carboxylate may be reacted with 5-methoxy-2-pyridyl derivatives that are suitable for Hiyama coupling, Suzuki coupling, Heck coupling, Kumada coupling or Negishi coupling.

[0627] Tributyl-(5-methoxy-2-pyridyl)stannane or derivatives thereof may be used in excess with respect to the starting material. A 1.1 -times to 1.5-times excess of tributyl-(5-methoxy-2- pyridyl)stannane or derivatives thereof may be used with respect to the starting material. Preferably, a 1.2-times excess of tributyl-(5-methoxy-2-pyridyl)stannane or derivatives thereof is used with respect to the starting material.

[0628] The reaction may be carried out in a non-polar solvent such as chloroform, 1 ,4-dioxane, xylene or toluene. Preferably the reaction is carried out in xylene.

[0629] The reaction may be carried out in the presence of a catalyst. Preferably, the catalyst is a palladium compound. Examples of such palladium compounds include but are not limited to

[0630] 103

[0631] SUBSTITUTE SHEET (RULE 26) Pd(dtbpf)CI2, Pd(PPh3)4, PdCI2(PPh3)2, Pd(dppf)CI2, or Pd(dppp)CI2. More preferably, Pd(PPh3)4 is used as the catalyst.

[0632] Preferably about 0.02 to about 0.5 equivalents of the catalyst is used with respect to the starting material. Preferably, about 0.1 equivalents of the catalyst is used.

[0633] The reaction may be carried out at a temperature in the range of about 50°C to about 140°C. Preferably, the reaction is carried out at about 140°C. The reaction may be carried out for a duration of about 10 hours to about 20 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0634] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0635] The intermediate may be deprotected by reacting with an acid or a base. Examples of acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid. Examples of bases that may be used include but are not limited to lithium hydroxide, sodium hydroxide or potassium hydroxide. Preferably, hydrochloric acid is used.

[0636] The deprotection may be carried out in neat acid or base.

[0637] The concentration of the acid or base may range from about 3 M to about 10 M. Preferably, a concentration of about 6 M is used.

[0638] The deprotection may be carried out at a temperature in the range of about 50°C to about 100°C. Preferably, the reaction is carried out at about 80°C. The deprotection may be carried out for a duration of about 6 hours to about 22 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0639] The present invention also provides yet another alternative method for synthesizing carboxylic acid with general formula R-COOH as shown in the synthetic pathway below, where PG refers to protecting group:

[0640] 104

[0641] SUBSTITUTE SHEET (RULE 26)

[0642] Preferably, R-COOH is 4-(5-Fluoropyridin-2-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid.

[0643] The starting material selected from 4-bromo-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid, 4- iodo-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid or 4-chloro-1 ,5-dimethyl-1 H-pyrazole-3- carboxylic acid is protected to form a first intermediate. Any suitable protecting group may be used. Examples of suitable protecting groups that may be used include Me, BOC or benzyl. Preferably, BOC is used as the protecting group.

[0644] Examples of suitable reagents to form the first intermediate include but are not limited to, BOC- anhydride, MeOH, benzyl alcohol or 2-benzyloxy-1 -methylpyridinium triflate. Preferably, BOC- anhydride is used.

[0645] The reagent may be used in excess with respect to the first intermediate. A 1.5-times to 5- times excess of the reagent may be used with respect to the first intermediate. Preferably, a 3-times excess of the reagent with respect to the first intermediate.

[0646] The reaction may be carried out in the presence of a catalyst such as DMAP, imidazole or mixtures thereof. Preferably imidazole is used as the catalyst.

[0647] The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO, a polar protic solvent such as water, methanol, ethanol, isopropanol, tert-butyl alcohol, a non-polar solvent such as chloroform, 1 ,4-dioxane or any combinations thereof. Preferably the reaction is carried out in a combination of THF and tert-butyl alcohol.

[0648] The reaction may be carried out at a temperature in the range of about 10°C to about 50°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a duration of about 6 to about 18 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0649] 105

[0650] SUBSTITUTE SHEET (RULE 26) The first intermediate may be converted into a boronic acid or derivatives thereof (for example boronic esters or organotrifluoroborate salts) to form a second intermediate. The first intermediate may be reacted with a tri(alkyl)borate such as trimethylborate, tri butyl borate or triisopropylborate to form the second intermediate.

[0651] The tri (alkyl) borate may be used in excess with respect to the first intermediate. A 1.2-times to 3-times excess of tri(alkyl)borate may be used with respect to the first intermediate. Preferably, a 1 ,5-times excess of tri(alkyl)borate is used with respect to the first intermediate.

[0652] The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF.

[0653] The reaction is carried out in the presence of a Lewis base. Examples of Lewis bases that may be used for the synthesis of the second intermediate include but are not limited to butyl lithium, lithium diisopropylamide (LDA), lithium diethylamide (LDEA), sodium amide (NaNH2), sodium hydride (NaH), lithium bis(trimethylsilyl)amide, or mixtures thereof. Preferably, the Lewis base used in the synthesis of the second intermediate is butyl lithium.

[0654] The Lewis base may be used in excess with respect to the first intermediate. A 1.2-times to 3- times excess of the Lewis base may be used with respect to the first intermediate. Preferably, a 1 ,5-times excess of the Lewis base is used with respect to the first intermediate.

[0655] The reaction may be carried out at a temperature b in the range of about -78°C to about 60°C. Preferably, the reaction is carried out at about -78°C to about 20°C. The reaction may be carried out for a duration of about 1 hour to about 8 hours. Preferably, the reaction is carried out for a duration of about 3 hours.

[0656] The second intermediate may be reacted with may be reacted with 2-bromo-5-fluoro- pyrimidine / 2-iodo-5-fluoro-pyrimidine / 2-chloro-5-fluoro-pyrimidine, via Suzuki coupling to form a third intermediate.

[0657] Alternatively, 2-bromo-5-fluoro-pyrimidine / 2-iodo-5-fluoro-pyrimidine / 2-chloro-5-fluoro- pyrimidine may be reacted with (3-(tert-butoxycarbonyl)-1 ,5-dimethyl-1 H-pyrazol-4-yl) derivatives that are suitable for Hiyama coupling, Stille coupling, Heck coupling, Kumada coupling or Negishi coupling.

[0658] 106

[0659] SUBSTITUTE SHEET (RULE 26) 2-bromo-5-fluoro-pyrimidine / 2-iodo-5-fluoro-pyrimidine / 2-chloro-5-fluoro-pyrimidine may be used in excess with respect to the second intermediate. A 1.1 -times to 3-times excess of may be used with respect to the second intermediate. Preferably, a 1 ,5-times excess of is used with respect to the second intermediate.

[0660] The reaction may be carried out in a polar aprotic solvent such as DMF, DMSO or mixtures thereof; in a polar protic solvent such as water, methanol, ethanol, isopropanol, tert-butyl alcohol, or any combination thereof. Preferably the reaction is carried out in a combination of DMF and water.

[0661] The reaction may be carried out in the presence of a catalyst. Preferably, the catalyst is a palladium compound. Examples of such palladium compounds include but are not limited to Pd(dtbpf)CI2, Pd(PPh3)4, PdCI2(PPh3)2, Pd(dppf)CI2, or Pd(dppp)CI2. More preferably, Pd(PPh3)4 is used as the catalyst.

[0662] Preferably, about 0.02 to about 0.5 equivalents of the catalyst is used with respect to the second intermediate. Preferably, about 0.05 equivalents of the catalyst is used.

[0663] The reaction may be carried out in the presence of a base. Examples of bases that may be used include but are not limited to K2CO3, KO‘Bu, Cs2CO3, KsPC , NaOH, or NEt3. Preferably, K2CO3is used.

[0664] The base may be used in excess with respect to the second intermediate. A 1.1 -times to 3- times excess of the base may be used with respect to the second intermediate. Preferably, a 1.5-times excess of the base is used with respect to the second intermediate.

[0665] The reaction may be carried out at a temperature in the range of about 50°C to about 153°C. Preferably, the reaction is carried out at about 80°C. The reaction may be carried out for a duration of about 8 hours to about 20 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0666] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere.

[0667] 107

[0668] SUBSTITUTE SHEET (RULE 26) The third intermediate formed may be deprotected by reacting with an acid. Examples of acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid. Preferably, hydrochloric acid is used.

[0669] The deprotection may be carried out in a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1 ,4-dioxane or mixtures thereof. Preferably the reaction is carried out in 1 ,4-dioxane.

[0670] The deprotection may be carried out at a temperature in the range of about 20°C to about 80°C. Preferably, the reaction is carried out at about 20°C. The deprotection may be carried out for a duration of about 8 hours to about 20 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0671] The present invention also provides another method for synthesizing carboxylic acid with general formula R-COOH as shown in the synthetic pathway below:

[0672] Preferably, R-COOH is 4-(5-Methoxypyridin-2-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid.

[0673] The starting material selected from 2-bromo-5-methoxy-pyridine, 2-iodo-5-methoxy-pyridine or 2-chloro-5-methoxy-pyridine may be reacted with 3-(tert-butoxycarbonyl)-1 ,5-dimethyl-1 H- pyrazol-4-yl)boronic acid or derivatives thereof (for example boronic esters or organotrifluoroborate salts), via Suzuki coupling to form an intermediate.

[0674] Alternatively, the starting material may be reacted with 3-(tert-butoxycarbonyl)-1 ,5-dimethyl- 1 H-pyrazol-4-yl derivatives that are suitable for Hiyama coupling, Stille coupling, Heck coupling, Kumada coupling or Negishi coupling.

[0675] The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO, a polar protic solvent such as water, methanol, ethanol, isopropanol, a non-polar solvent such as

[0676] 108

[0677] SUBSTITUTE SHEET (RULE 26) chloroform, 1 ,4-dioxane or any combination thereof. Preferably the reaction is carried out in a combination of DMF and water.

[0678] The reaction may be carried out in the presence of a catalyst. Preferably, the catalyst is a palladium compound. Examples of such palladium compounds include but are not limited to Pd(dtbpf)CI2, Pd(PPh3)4, PdCI2(PPh3)2, Pd(dppf)CI2, or Pd(dppp)CI2. More preferably, Pd(PPh3)4 is used as the catalyst.

[0679] Preferably, about 0.02 to about 0.5 equivalents of the catalyst is used with respect to the starting material. Preferably, about 0.05 equivalents of the catalyst is used.

[0680] The reaction may be carried out in the presence of a base. Examples of bases that may be used include but are not limited to K2CO3, KO‘Bu, Cs2CO3, KsPC , NaOH, or NEt3. Preferably, K2CO3is used.

[0681] The base may be used in excess with respect to the starting material. A 1.1 -times to 5-times excess of the base may be used with respect to the starting material. Preferably, a 1.5-times excess of the base is used with respect to the starting material.

[0682] The reaction may be carried out at a temperature in the range of about 50°C to about 100°C. Preferably, the reaction is carried out at about 80°C. The reaction may be carried out for a duration of about 6 hours to about 18 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0683] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0684] The intermediate formed may be deprotected by reacting with an acid. Examples of acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid. Preferably, hydrochloric acid is used.

[0685] The deprotection may be carried out in a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1 ,4-dioxane or mixtures thereof. Preferably the reaction is carried out in 1 ,4-dioxane.

[0686] 109

[0687] SUBSTITUTE SHEET (RULE 26) The deprotection may be carried out at a temperature in the range of about 10°C to about 50°C. Preferably, the reaction is carried out at about 20°C. The deprotection may be carried out for a duration of about 6 hours to about 18 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0688] The present invention also provides a method for preparing 3-(5-Fluoropyrimidin-2-yl)-5,6- dihydro-4H-pyrrolo[1 ,2-b]pyrazole-2-carboxylic acid.

[0689] Bromine may be added to a solution of 5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole-2-carboxylic acid in a solvent. Examples of a solvent include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or a mixture thereof. Preferably the reaction is carried out in dichloromethane. The reaction may be carried out at a temperature in the range of about - 10°C to about 10°C. Preferably, the reaction is carried out at about 0 °C. The reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, the reaction may be carried out for a duration of about 2 hours.

[0690] The reaction mixture may be quenched by addition of saturated sodium thiosulfate aqueous solution to give 3-bromo-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole-2-carboxylic acid.

[0691] 3-bromo-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole-2-carboxylic acid may be reacted with 2-tert- butyl-3-isopropyl-1 ,1-dimethyl-isourea in a solvent. Examples of a solvent include but are not limited to THF, DMF, DMSO or mixtures thereof. Preferably the solvent is carried out in THE The reaction may be carried out at a temperature in the range of about -10°C to about 40°C. Preferably, the reaction is carried out in the range of at about 0 °C to about 20 °C. The reaction

[0692] 110

[0693] SUBSTITUTE SHEET (RULE 26) may be carried out for a duration of about 10 hours to about 20 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0694] The reaction mixture may be was quenched by addition of saturated ammonium chloride aqueous solution to give tert-butyl 3-bromo-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole-2- carboxylate.

[0695] Tert-butyl 3-bromo-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole-2-carboxylate may be reacted with triisopropyl borate in a solvent. Examples of a solvent include but are not limited to THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about -10°C to about 40°C. Preferably, the reaction is carried out in the range of at about 0 °C to about 20 °C. n-BuLi may then be added. The reaction may be carried out at a temperature in the range of about -100°C to about -50°C. Preferably, the reaction is carried out at about -78°C The reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours.

[0696] The reaction mixture may then be quenched by addition saturated ammonium chloride aqueous solution as described above to give (2-(tert-butoxycarbonyl)-5,6-dihydro-4H- pyrrolo[1 ,2-b]pyrazol-3-yl)boronic acid.

[0697] (2-(tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazol-3-yl)boronic acid may be added to 2-bromo-5-fluoro-pyrimidine in the presence of a base and one or more solvents. Examples of a base that may be used include but are not limited to potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA or DI PEA, or mixtures thereof. Preferably, the base is potassium carbonate. The reaction may be carried out in a solvent such as THF, DMF, DMSO, water or mixtures thereof. Preferably the solvent is DMF and water. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C.

[0698] Tetrakis(triphenylphosphine)palladium(0) (Pd(PPhs)4) may be added to give tert-butyl 3-(5- fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole-2-carboxylate. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere. The reaction may be carried out at a temperature in the range of about 50°C to about 150°C. Preferably, the reaction is carried out at about 80°C The reaction may

[0699] 111

[0700] SUBSTITUTE SHEET (RULE 26) be carried out for a duration of about 10 hours to about 16 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0701] Tert-butyl 3-(5-fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole-2-carboxylate may be treated with an acid to produce 3-(5-Fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1 ,2- b]pyrazole-2-carboxylic acid. Examples of acids that may be used include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid or mixtures thereof. Preferably, hydrochloric acid is used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof. Preferably the solvent is dioxane. The reaction may be carried out at a temperature in the range of about 10°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 1 hours to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours.

[0702] The present invention also provides a method for preparing 5,6-Dimethyl-3-(pyrimidin-2- yl)picolinic acid.

[0703] 3-bromo-5,6-dimethylpyridin-2-amine may be added to tributyl(pyrimidin-2-yl)stannane in a solvent and caesium fluoride. Examples of solvents include but are not limited to as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof. Preferably, the solvent is dioxane. lodocopper and palladiumtriphenylphosphane may be added to the mixture. The reaction may be carried out at a temperature in the range of about 70°C to about 130°C. Preferably, the reaction is carried out at about 100 °C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0704] 112

[0705] SUBSTITUTE SHEET (RULE 26) The residue may be purified to give 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-amine. Preferably it is purified by column chromatography on silica gel.

[0706] 5.6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-amine may be added to an acid or a combination of the acids. Example of acids may be sulfuric acid, acetic acid, phosphoric acid, hydrochloric acid, trifluoroacetic acid, or a mixture thereof. Preferably, the acid is sulfuric acid and acetic acid. A solution of sodium nitrite in water may be added to give 5,6-Dimethyl-3-(pyrimidin-2- yl)pyridin-2-ol. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours.

[0707] 5.6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-ol may be added to trifluoromethylsulfonyl trifluoromethanesulfonate in the presence of a solvent and a base to give residue 5,6- Dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl trifluoromethanesulfonate. Examples of a solvent that may be used include but are not limited to THF, dichloromethane, ethyl acetate, DMF or DMSO or mixtures thereof. Preferably the solvent is dichloromethane. Examples of bases that may be used include but are not limited to potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA or DI PEA or mixtures thereof. Preferably the base is DI PEA. The reaction may be carried out at a temperature in the range of about 0°C to about 60°C. Preferably, the reaction is carried out at about 30°C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0708] Bis(diphenylphosphino)ferrocene)palladium(ll) dichloride (Pd(dppf)Ch) may be added to 5,6- dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl trifluoromethanesulfonate in the presence of a solvent and a base to give methyl 5,6-dimethyl-3-(pyrimidin-2-yl)picolinate. Examples of bases include but are not limited to potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA, DI PEA or mixtures thereof. Preferably, the base is TEA. Examples of solvents include but are not limited to THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, dioxane or mixtures thereof. Preferably the solvent is methanol. The reaction may be carried out at a temperature in the range of about 50°C to about 100°C. Preferably, the reaction is carried out at about 70°C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16

[0709] 113

[0710] SUBSTITUTE SHEET (RULE 26) hours. The reaction may be carried out in the presence of carbon monoxide at a pressure of 50 psi.

[0711] Lithium hydroxide monohydrate may be added to methyl 5,6-dimethyl-3-(pyrimidin-2- yl)picolinate in the presence of one or more solvents. Examples of solvents include but are not limited to THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, dioxane or mixtures thereof. Preferably, the solvents are methanol and THE The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a duration of about 1 hours to about 5 hours. Preferably, the reaction is carried out for a duration of about 3 hours.

[0712] The present invention also provides a method for preparing 4,6-Dimethyl-3-(pyrimidin-2- yl)picolinic acid.

[0713] 5-bromo-2,4-dimethylpyridine may be reacted with a mixture of tributyl(pyrimidin-2- yl)stannane, caesium fluoride, iodocopper and Tetrakis(triphenylphosphine)palladium(0) (Pd(PPhs)4) in the presence of a solvent. Examples of solvents include but are not limited to diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof. Preferably the reaction is carried out in dioxane. The reaction may be carried out at a temperature in the range of about 70°C to about 130°C. Preferably, the reaction is carried out at about 100°C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0714] The crude product may be purified to give 2-(4,6-dimethylpyridin-3-yl)pyrimidine. Preferably, purified is done by column chromatography on silica gel.

[0715] 114

[0716] SUBSTITUTE SHEET (RULE 26) Meta-chloroperoxybenzoic acid is added to a solution of 2-(4,6-dimethylpyridin-3-yl)pyrimidine in the presence of a solvent. Examples of solvent include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in dichloromethane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a duration of about 30 minutes hours to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours.

[0717] The reaction mixture may be quenched by addition of sodium sulfite to give 2,4-dimethyl-5- (pyrimidin-2-yl)pyridine 1 -oxide.

[0718] Trimethylsilyl cyanide may be added to 2,4-dimethyl-5-(pyrimidin-2-yl)pyridine 1-oxide in a solvent. Examples of solvent may include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or mixtures thereof. Preferably the solvent is dichloromethane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a duration of about 30 minutes to about 3 hours. Preferably, the reaction is carried out for a duration of about 1 hours. N,N-dimethylcarbamoyl chloride may then be added. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a duration of 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0719] Sodium hydroxide may be added to 4,6-dimethyl-3-(pyrimidin-2-yl)picolinonitrile in the presence of one or more solvents to give 4,6-Dimethyl-3-(pyrimidin-2-yl)picolinic acid. Examples of solvents include but are not limited to THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, dioxane or mixtures thereof. Preferably, the solvents are methanol and water. The reaction may be carried out at a temperature in the range of about 30°C to about 90°C. Preferably, the reaction is carried out at about 60°C. The reaction may be carried out for a duration of 36 hours to about 60 hours. Preferably, the reaction is carried out for a duration of about 48 hours.

[0720] The present invention also provides a method for preparing 4-Chloro-6-methyl-3-(pyrimidin-2- yl)picolinic acid.

[0721] 115

[0722] SUBSTITUTE SHEET (RULE 26)

[0723]

[0724] An acid and a solvent may be added to 3-bromo-6-methylpicolinic acid. Examples of acids include but are not limited to sulfuric acid, acetic acid, phosphoric acid, hydrochloric acid, trifluoroacetic acid, or mixtures thereof. Preferably, the acid is sulfuric acid and acetic acid. Examples of solvents include but are not limited to THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, 1 ,4-dioxane or mixtures thereof. Preferably, the solvent is methanol. The reaction may be carried out at a temperature in the range of about 40°C to about 100°C. Preferably, the reaction is carried out at about 70°C. The reaction may be carried out for a duration of 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0725] Methyl 3-bromo-6-methylpicolinate may be added to tributyl(pyrimidin-2-yl)stannane, cesium fluoride, iodocopper, palladiumtriphenylphosphane in the presence of a solvent. Examples of solvents include but are not limited to as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof. Preferably, the solvent is dioxane. The reaction may be carried out at a temperature in the range of about 60°C to about 140°C. Preferably, the reaction is carried out at about 100°C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0726] 3-chlorobenzenecarboperoxoic acid may be added to methyl 6-methyl-3-(pyrimidin-2- yl)picolinate in a solvent. Examples of solvent include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in dichloromethane. The reaction may be carried out at a temperature in the range of about -20°C to about 50°C. Preferably, the reaction is carried out at a range of about 0°C to about 30°C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0727] 116

[0728] SUBSTITUTE SHEET (RULE 26) The reaction mixture may be quenched by addition of a saturated sodium sulfite solution.

[0729] Phosphoryl chloride may be added to 2-(methoxycarbonyl)-6-methyl-3-(pyrimidin-2-yl)pyridine 1 -oxide to form methyl 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinate. The reaction may be carried out at a temperature in the range of about 90°C to about 150°C. Preferably, the reaction is carried out at about 120°C. The reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours.

[0730] Lithium hydroxide monohydrate may be added to methyl 4-chloro-6-methyl-3-(pyrimidin-2- yl)picolinate in the presence of one or more solvents. Examples of solvents include but are not limited to THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, 1 ,4- dioxane or mixtures thereof. Preferably, the solvents are methanol and THF. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0731] The present invention also provides a method for preparing 4-(5-fluoropyrimidin-2-yl)-1- methyl-5-(methyl-d3)-1 H-pyrazole-3-carboxylic acid.

[0732] 5-bromo-1-methyl-1 H-pyrazole-3-carboxylic acid (5 g, 24.39 mmol, 1 eq) may be added to Di- tert-butyl dicarbonate, tert-butyl alcohol and 4-Dimethylaminopyridine in the presence of a solvent. Examples of solvents include but are not limited to water, acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about 00°C to about 40°C. Preferably, the

[0733] 117

[0734] SUBSTITUTE SHEET (RULE 26) reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0735] Tert-butyl 5-bromo-1-methyl-1 H-pyrazole-3-carboxylate may be reacted with n-BuLi trideuterio(iodo)methane in a suitable solvent. Examples of solvents include but are not limited to THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THE The reaction may be carried out at a temperature in the range of about -10°C to about 40°C. Preferably, the reaction is carried out in the range of at about 0 °C to about 20 °C. n-BuLi may then be added. The reaction may be carried out at a temperature in the range of about -100°C to about -50°C. Preferably, the reaction is carried out at about -78°C The reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a duration of about 3 hours.

[0736] The reaction mixture may be quenched by addition of saturated ammonium chloride solution.

[0737] N-Bromosuccinimide may added to a solution of tert-butyl 1-methyl-5-(methyl-d3)-1 H- pyrazole-3-carboxylate in a solvent. Examples of solvents include but are not limited to THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in DMF. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0738] Isopropylmagnesium chloride lithium chloride may be added to tert-butyl 4-bromo-1-methyl-5- (methyl-d3)-1 H-pyrazole-3-carboxylate in a solvent. Examples of solvents include but are not limited to THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about -80°C to about -20°C. Preferably, the reaction is carried out at about -50 °C. The reaction may be carried out for a duration of about 30 minutes to about 2 hours. Preferably, the reaction is carried out for a duration of about 1 hour. Triisopropyl borate may then be added to the reaction mixture. The reaction may be carried out at a temperature in the range of about -80°C to about -20°C. Preferably, the reaction is carried out at about -50 °C. The reaction may be carried out for a duration of about 1 hours to about 5 hours. Preferably, the reaction is carried out for a duration of about 3 hours.

[0739] 118

[0740] SUBSTITUTE SHEET (RULE 26) 2-bromo-5-fluoro-pyrimidine and potassium carbonate may be added to (3-(tert- butoxycarbonyl)-1-methyl-5-(methyl-d3)-1 H-pyrazol-4-yl)boronic acid in a solvent. Examples of solvents include but are not limited to water, THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF and water. Tetrakis(triphenylphosphine)palladium(0) (Pd(PPhs)4) may then be added. The reaction may be carried out at a temperature in the range of about 60°C to about 120°C. Preferably, the reaction is carried out at about 90 °C. The reaction may be carried out for a duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0741] Tert-butyl 4-(5-fluoropyrimidin-2-yl)-1-methyl-5-(methyl-d3)-1 H-pyrazole-3-carboxylate may be treated with an acid to produce 4-(5-fluoropyrimidin-2-yl)-1-methyl-5-(methyl-d3)-1 H- pyrazole-3-carboxylic acid. Examples of acids include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid or mixtures thereof. Preferably, hydrochloric acid is used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof. Preferably the reaction is carried out in dioxane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 5 hours to about 11 hours. Preferably, the reaction is carried out for a duration of about 8 hours.

[0742] The present invention also provides a method for preparing 4-(5-Fluoropyrimidin-2-yl)-5- methyl-1 -(methyl-d3)-1 H-pyrazole-3-carboxylic acid.

[0743] 119

[0744] SUBSTITUTE SHEET (RULE 26)

[0745] Sodium hydride may be added to ethyl 4-bromo-5-methyl-1 H-pyrazole-3-carboxylate in a solvent. Examples of solvents include but are not limited to water, acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably, the solvent is THF. The reaction may be carried out at a temperature in the range of about -20°C to about 20°C. Preferably, the reaction is carried out at about 0 °C. The reaction may be carried out for a duration of about 15 minutes to about 1 hour. Preferably, the reaction is carried out for a duration of about 30 minutes.

[0746] Trideuterio(iodo)methane may be added into the mixture. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 2 hours to about 4 hours. Preferably, the reaction is carried out for a duration of about 3.5 hours.

[0747] The mixture may be quenched with saturated ammonium chloride solution. The product may be purified to give ethyl 4-bromo-5-methyl-1-(methyl-d3)-1 H-pyrazole-3-carboxylate. Preferably, it is purified by column chromatography on silica gel.

[0748] Lithium hydroxide monohydrate may be added to ethyl 4-bromo-5-methyl-1-(methyl-d3)-1 H- pyrazole-3-carboxylate in the presence of one or more solvents to give 4-bromo-5-methyl-1- (methyl-d3)-1 H-pyrazole-3-carboxylic acid. Examples of solvents include but are not limited to THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, dioxane or mixtures thereof. Preferably, the solvents are methanol and water. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out

[0749] 120

[0750] SUBSTITUTE SHEET (RULE 26) at about 20 °C. The reaction may be carried out for a duration of about 1 hours to about 3 hours. Preferably, the reaction is carried out for a duration of about 2 hours.

[0751] 2-tert-butyl-1 ,3-diisopropyl-isourea may be added to 4-bromo-5-methyl-1-(methyl-d3)-1 H- pyrazole-3-carboxylic acid in the presence of a solvent to give tert-butyl 4-bromo-5-methyl-1- (methyl-d3)-1 H-pyrazole-3-carboxylate. Examples of solvent include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or combinations thereof. Preferably the reaction is carried out in dichloromethane. The reaction may be carried out at a temperature in the range of about 20°C to about 80°C. Preferably, the reaction is carried out at about 50°C. The reaction may be carried out for a duration of 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0752] Triisopropyl borate may be added to tert-butyl 4-bromo-5-methyl-1-(methyl-d3)-1 H-pyrazole-

[0753] 3-carboxylate in the presence of a solvent. Examples of solvents include but are not limited to THF, DMF, DMSO or mixtures thereof. Preferably the solvent is THF. n-BuLi may then be added to give (3-(tert-Butoxycarbonyl)-5-methyl-1-(methyl-d3)-1 H- pyrazol-4-yl)boronic acid. The reaction may be carried out at a temperature in the range of about - 100°C to about -50°C. Preferably, the reaction is carried out at about -78°C The reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0754] The reaction mixture may be quenched by addition of saturated ammonium chloride solution to obtain (3-(tert-Butoxycarbonyl)-5-methyl-1-(methyl-d3)-1 H-pyrazol-4-yl)boronic acid.

[0755] 2-bromo-5-fluoro-pyrimidine and potassium carbonate may be added to 3-(tert- butoxycarbonyl)-5-methyl-1-(methyl-d3)-1 H-pyrazol-4-yl)boronic acid in the presence of one or more solvents. Examples of solvents include but are not limited to water, THF, DMF, DMSO or mixtures thereof. Preferably the solvents are DMF and water. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere.

[0756] Tetrakis(triphenylphosphine)palladium(0) (Pd(PPhs)4) may then be added. The reaction may be carried out at a temperature in the range of about 40°C to about 120°C. Preferably, the reaction is carried out at about 80 °C. The reaction may be carried out for a duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours. The mixture was stirred at 80°C for 12 hours.

[0757] 121

[0758] SUBSTITUTE SHEET (RULE 26) The product may be purified to give tert-butyl 4-(5-fluoropyrimidin-2-yl)-5-methyl-1-(methyl- d3)-1 H-pyrazole-3-carboxylate. Preferably it is purified by column chromatography on silica gel.

[0759] Tert-butyl 4-(5-fluoropyrimidin-2-yl)-5-methyl-1-(methyl-d3)-1 H-pyrazole-3-carboxylate may be treated with an acid to produce 4-(5-fluoropyrimidin-2-yl)-5-methyl-1-(methyl-d3)-1 H- pyrazole-3-carboxylic acid. Examples of acids include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid or mixtures thereof. Preferably, hydrochloric acid is used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof. Preferably the reaction is carried out in dioxane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0760] The present invention also provides a method for preparing 4-(5-Fluoropyridin-2-yl)-5-methyl-

[0761] 1-(methyl-d3)-1 H-pyrazole-3-carboxylic acid.

[0762] 2-bromo-5-fluoro-pyridine, potassium carbonate, and tetrakis(triphenylphosphine)palladium(0) (Pd(PPhs)4) may be added to (3-(tert- butoxycarbonyl)-5-methyl-1-(methyl-d3)-1 H-pyrazol-4-yl)boronic acid in the presence of one or more solvents. Examples of solvents include but are not limited to water, acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in DMF and water. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere. The reaction may be carried out at a temperature in the range of about 50°C to about 150°C. Preferably, the reaction is carried out at about 80°C The reaction may be carried out for a duration of about 10 hours to about 16 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0763] 122

[0764] SUBSTITUTE SHEET (RULE 26) The product may be purified to give tert-butyl 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)- 1 H-pyrazole-3-carboxylate. Preferably the product is purified by column chromatography on silica gel.

[0765] Tert-butyl 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1 H-pyrazole-3-carboxylate may be treated with an acid to produce 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1 H-pyrazole-3- carboxylic acid. Examples of acids include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid or mixtures thereof. Preferably, hydrochloric acid is used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof. Preferably the reaction is carried out in dioxane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0766] The present invention also provides a method for preparing 6-(Methyl-d3)-3-(pyrimidin-2- yl)picolinic acid.

[0767] Tributyl(pyrimidin-2-yl)stannane may be reacted with a mixture of methyl 6-amino-3- bromopicolinate, caesium fluoride, iodocopper and Tetrakis(triphenylphosphine)palladium(0) (Pd(PPhs)4) in the presence of a solvent. Examples of solvent include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or combinations thereof. Preferably the reaction is carried out in dichloromethane. The reaction may be carried out in nitrogen. The reaction may be carried out at a temperature in the range of about 80°C to about 140°C. Preferably, the reaction is carried out at about 110°C. The reaction may be carried out for a duration of 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0768] 123

[0769] SUBSTITUTE SHEET (RULE 26) The residue may be quenched with a potassium fluoride aqueous solution to give methyl 6- amino-3-(pyrimidin-2-yl)picolinate.

[0770] Tert-butyl nitrite and copper bromide may be added to methyl 6-amino-3-(pyrimidin-2- yl)picolinate in the presence of a solvent. Examples of solvents include but are not limited to acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in acetonitrile. The reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a duration of 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0771] Trideuterio(deuteriooxy)methane was added to 5,7-ditert-butyl-3-phenyl-1 ,3-benzoxazol-3- ium tetrafluoroborate in methyl tert-butyl ether. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere. The reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction is carried out at about 25°C.

[0772] Pyridine may be added into the mixture under an argon atmosphere. The reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a duration of about 15 minutes to about 1 hour. Preferably, the reaction is carried out for a duration of about 30 minutes. bis[2-(2-pyridyl)phenyl]iridium(1 +)4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine hexafluorophosphate, 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine dibromonickel, quinuclidine may be added to the mixture. Methyl 6-bromo-3-(pyrimidin-2-yl)picolinate may then be added in dimethylacetamide to the mixture under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere. The reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours.

[0773] Methyl 6-(methyl-d3)-3-(pyrimidin-2-yl)picolinate may then be added to an acid and water. Examples of acids include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid. Preferably, hydrochloric acid is used. The reaction may be carried out at a temperature in the range of about 40°C to about 120°C. Preferably, the reaction is carried out

[0774] 124

[0775] SUBSTITUTE SHEET (RULE 26) at about 80°C. The reaction may be carried out for a duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0776] The present invention also provides a method for preparing 6-(Methyl-d3)-3-(2H-1 ,2,3-triazol- 2-yl)picolinic acid hydrochloride.

[0777] 2H-triazole, caesium carbonate, Ni,N2-dimethylcyclohexane-1 ,2-diamine, iodocopper may be added to a solution of 3-bromo-6-chloropicolinic acid in a solvent. Examples of solvents include but are not limited to diethyl ether, benzene, toluene, chloroform, dioxane, methanol or mixtures thereof. Preferably the solvents are dioxane and water. The reaction may be carried out at a temperature in the range of about 80°C to about 120°C. Preferably, the reaction is carried out at about 100°C. The reaction may be carried out for a duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0778] 2-tert-butyl-1 ,3-diisopropyl-isourea may be added to 6-chloro-3-(2H-1 ,2,3-triazol-2-yl)picolinic acid in the presence of a solvent. Examples of solvents include but are not limited to acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0779] Bis(diphenylphosphino)ferrocene)palladium(ll) dichloride (Pd(dppf)Cl2), tripotassium phosphate and tert-butyl 6-chloro-3-(2H-1 ,2,3-triazol-2-yl)picolinate may be added to (methyl-

[0780] 125

[0781] SUBSTITUTE SHEET (RULE 26) d3)boronic acid in the presence of a solvent to give methyl 5,6-dimethyl-3-(pyrimidin-2- yl)picolinate. Examples of solvents include but are not limited to water, acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in THF and water. The reaction may be carried out at a temperature in the range of about 40°C to about 120°C. Preferably, the reaction is carried out at about 80°C. The reaction may be carried out for a duration of about 2 hours to about 6 hours. Preferably, the reaction is carried out for a duration of about 4 hours.

[0782] Tert-butyl 6-(methyl-d3)-3-(2H-1 ,2,3-triazol-2-yl)picolinate be treated with an acid to produce 6-(Methyl-d3)-3-(2H-1 ,2, 3-triazol-2-yl) picolinic acid hydrochloride in the presence of a solvent. Examples of acids include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid. Preferably, hydrochloric acid is used. Example of solvents include but are not limited to as diethyl ether, benzene, toluene, chloroform, dioxane, methanol or mixtures thereof. Preferably the reaction is carried out in dioxane and methanol. The reaction may be carried out at a temperature in the range of about 30°C to about 90°C. Preferably, the reaction is carried out at about 60 °C. The reaction may be carried out for a duration of about 1 hours to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours.

[0783] The present invention also provides a method for preparing 1 ,5-Dimethyl-4-(pyrazin-2-yl)-1 H- pyrazole-3-carboxylic acid.

[0784] 2-chloropyrazine, a base and a solvent may be added to (3-(tert-butoxycarbonyl)-1 ,5-dimethyl- 1 H-pyrazol-4-yl)boronic acid. Examples of a base that may be used include but are not limited to potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA or DI PEA, or mixtures thereof. Preferably, the base is potassium carbonate. The reaction may be carried out in a solvent such as THF, DMF, DMSO, water or mixtures thereof. Preferably the solvent is DMF and water.

[0785] Tetrakis(triphenylphosphine)palladium(0) (Pd(PPhs)4) may be added to the reaction mixture.

[0786] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried

[0787] 126

[0788] SUBSTITUTE SHEET (RULE 26) out under an argon atmosphere. The reaction may be carried out at a temperature in the range of about 50°C to about 150°C. Preferably, the reaction is carried out at about 80°C The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours. The reaction mixture may be purified to give tert-butyl 1 ,5-dimethyl-4-(pyrazin-2-yl)-1 H-pyrazole-3-carboxylate. Preferably, the purification is by column chromatograph on silica gel.

[0789] Tert-butyl 1 ,5-dimethyl-4-(pyrazin-2-yl)-1 H-pyrazole-3-carboxylate may be treated with an acid to produce 1 ,5-dimethyl-4-(pyrazin-2-yl)-1 H-pyrazole-3-carboxylic acid. Examples of acids include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid or mixtures thereof. Preferably, hydrochloric acid is used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof. Preferably the reaction is carried out in dioxane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0790] The present invention also provides a method for preparing 4-(5-Fluoropyridin-3-yl)-1 ,5-

[0791] 3-chloro-5-fluoro-pyridine, a base and a solvent may be added to (3-(tert-butoxycarbonyl)-1 ,5- dimethyl-1 H-pyrazol-4-yl)boronic acid. Examples of a base that may be used include but are not limited to potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA or DI PEA, or mixtures thereof. Preferably, the base is potassium carbonate. The reaction may be carried out in a solvent such as THF, DMF, DMSO, water or mixtures thereof. Preferably the solvent is DMF and water.

[0792] Tetrakis(triphenylphosphine)pal!adium(0) (Pd(PPhs)4) may be added to the reaction mixture.

[0793] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried

[0794] 127

[0795] SUBSTITUTE SHEET (RULE 26) out under an argon atmosphere. The reaction may be carried out at a temperature in the range of about 50°C to about 150°C. Preferably, the reaction is carried out at about 80°C The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0796] The reaction mixture may be purified to give tert-butyl 4-(5-fluoropyridin-3-yl)-1 ,5-dimethyl-1 H- pyrazole-3-carboxylate. Preferably, the purification is by column chromatograph on silica gel.

[0797] Tert-butyl 4-(5-fluoropyridin-3-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylate may be treated with an acid to produce 4-(5-fluoropyridin-3-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid. Examples of acids include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid or mixtures thereof. Preferably, hydrochloric acid is used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof. Preferably the reaction is carried out in dioxane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0798] The present invention also provides a method for preparing 4-(4-Fluoropyridin-3-yl)-1 ,5- dimethyl-1 H-pyrazole-3-carboxylic acid.

[0799] (3-(tert-butoxycarbonyl)-1 ,5-dimethyl-1 H-pyrazol-4-yl)boronic acid, 3-chloro-4-fluoro-pyridine, [2-(2-aminophenyl)phenyl]-chloro-palladium dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane, tripotassium phosphate and butan-1-ol may be added in the presence of a solvent. Examples of solvents include but are not limited to water, acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the solvent is water. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere. The reaction may be carried out at a temperature in the range of about 50°C to about 150°C. Preferably, the reaction is carried out at about 100°C The

[0800] 128

[0801] SUBSTITUTE SHEET (RULE 26) reaction may be carried out for a duration of about 1 hours to about 5 hours. Preferably, the reaction is carried out for a duration of about 3 hours.

[0802] The reaction mixture may be purified to give tert-butyl 4-(4-fluoropyridin-3-yl)-1 ,5-dimethyl-1 H- pyrazole-3-carboxylate. Preferably, the purification is by column chromatograph on silica gel.

[0803] Tert-butyl 4-(4-fluoropyridin-3-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylate may be treated with an acid to produce 4-(4-fluoropyridin-3-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid. Examples of acids include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid or mixtures thereof. Preferably, hydrochloric acid is used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof. Preferably the reaction is carried out in dioxane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours.

[0804] The present invention also provides a method for preparing 4-(4-Fluoropyridin-2-yl)-1 ,5- dimethyl-1 H-pyrazole-3-carboxylic acid.

[0805] 2-chloro-4-fluoro-pyridine, a base and a solvent may be added to (3-(tert-butoxycarbonyl)-1 ,5- dimethyl-1 H-pyrazol-4-yl)boronic acid. Examples of a base that may be used include but are not limited to potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA or DI PEA, or mixtures thereof. Preferably, the base is potassium carbonate. The reaction may be carried out in a solvent such as THF, DMF, DMSO, water or mixtures thereof. Preferably the solvent is DMF and water.

[0806] Tetrakis(triphenylphosphine)palladium(0) (Pd(PPhs)4) may be added to the reaction mixture. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere. The reaction may be carried out at a temperature in the range

[0807] 129

[0808] SUBSTITUTE SHEET (RULE 26) of about 50°C to about 150°C. Preferably, the reaction is carried out at about 80°C The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0809] The reaction mixture may be purified to give tert-butyl 4-(4-fluoropyridin-2-yl)-1 ,5-dimethyl-1 H- pyrazole-3-carboxylate. Preferably, the purification is by column chromatograph on silica gel.

[0810] Tert-butyl 4-(4-fluoropyridin-2-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylate may be treated with an acid to produce 4-(4-fluoropyridin-2-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid. Examples of acids include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid or mixtures thereof. Preferably, hydrochloric acid is used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof. Preferably the reaction is carried out in dioxane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.

[0811] EXAMPLES

[0812] The present invention is further described with reference to the following examples, which are not provided to limit the scope of the present invention.

[0813] I. General Synthetic Methods and Procedures

[0814] 130

[0815] SUBSTITUTE SHEET (RULE 26) aa-ar DCM (20 V) 1-49, 60-69, 78-88, 92-102

[0816] Example 1 : Synthesis of (2R,3S)-2-(Benzylamino)butane-1,3-diol (b)

[0817] To a solution of N-benzyl-L-allothreonine (15 g, 68.10 mmol, 1 eq) in tetrahydrofuran (300 mL) was added BH3.DMS (10 M, 34.05 mL, 5 eq) at 0°C under N2. The mixture was stirred at 80°C for 6 hrs. LCMS showed all the starting materials were consumed, desired MW was detected. This reaction was cooled 0°C, then was quenched with methyl alcohol (100 mL). Then the solution was concentrated under reduced pressure to give crude product (14 g, 64.53 mmol, 94.75% yield) as a colorless oil, which was used without further purification.

[0818] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 7.32 (br d, J=1 .25 Hz, 5 H) 4.38 (br d, J=2.25 Hz, 1 H) 3.89 (br s, 2 H) 2.99 - 3.61 (m, 3 H) 1.73 - 2.47 (m, 2 H) 0.75 - 1.52 (m, 3 H).

[0819] 131

[0820] SUBSTITUTE SHEET (RULE 26) Example 2: Synthesis of (2S,3R)-3-(Benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan- 2-ol (c)

[0821] To a solution of (2R,3S)-2-(benzylamino)butane-1 ,3-diol (15 g, 76.82 mmol, 1 eq) in dimethyl sulfoxide (300 mL) was added imidazole (7.85 g, 115.23 mmol, 1.5 eq) and TBDPSCI (25.34 g, 92.19 mmol, 23.59 mL, 1.2 eq). The mixture was stirred at 25°C for 12 hrs. LCMS showed all the starting materials were consumed; desired MW was detected. This reaction mixture was quenched by addition of water (1000 mL) at 0°C, then the mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (2 x 1000 mL), dried over Na2SO4, filtered, and concentrated to give crude product. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate, 1 / 0 to 4 / 1) to give (2S, 3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (6 g, 19.38 mmol, 25.23% yield) as colorless oil.

[0822] 1H NMR (400 MHz, DMSO-cfe): 5 ppm 7.57 - 7.68 (m, 4 H) 7.37 - 7.50 (m, 6 H) 7.15 - 7.31 (m, 5 H) 4.43 (d, J=4.88 Hz, 1 H) 3.60 - 3.85 (m, 5 H) 2.54 (m, 1 H) 1.05 (d, J=6.38 Hz, 3 H) 0.98 (s, 9 H).

[0823] Example 3: Synthesis of 2-(((2S,3R)-3-(Benzylamino)-4-((tert- butyldiphenylsilyl)oxy)butan-2-yl)oxy)-2,2-difluoroacetic acid (d)

[0824] To a solution of (2S, 3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (3.4 g, 7.84 mmol, 1 eq) in dioxane (68 mL) was added 2-bromo-2,2-difluoro-acetic acid (4.11 g, 23.52 mmol, 3 eq). The solution was cooled to 0°C. The NaH (1.41 g, 35.28 mmol, 60% purity, 4.5 eq) was added into the solution at 0°C. The mixture was stirred at 20°C for 12 hrs. LCMS showed all the starting materials were consumed, desired MW was detected. This reaction was poured into 1 N HCI, adjusted to pH 7 at 0°C, then extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (40 mL x 2), dried over Na2SO4, filtered, and concentrated to give crude product (5 g, 7.58 mmol, 96.69% yield) as yellow oil. The product was used for the next step directly, without further purification.

[0825] 1H NMR (400 MHz, DMSO-cfe): 5 ppm 7.55 - 7.73 (m, 5 H) 7.35 - 7.52 (m, 10 H) 4.59 (br d, 3=3.25 Hz, 1 H) 3.75 (br d, 3=10.38 Hz, 2 H) 3.27 - 3.43 (m, 2 H) 2.99 - 3.21 (m, 2 H) 1.12 (br d, 3=6.38 Hz, 3 H) 0.99 (s, 9 H).

[0826] Example 4: Synthesis of (5R,6S)-4-Benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2- difluoro-6-methylmorpholin-3-one (e)

[0827] To a solution of 2-(((2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)oxy)- 2,2-difluoroacetic acid (4.1 g, 7.77 mmol, 1 eq) in dimethyl formamide (164 mL) was added

[0828] 132

[0829] SUBSTITUTE SHEET (RULE 26) T3P (4.94 g, 7.77 mmol, 4.63 mL, 50% purity, 1 eq) at 0°C. The mixture was stirred at 20°C for 2 hrs. LCMS showed all the starting materials were consumed; desired MW was detected. The reaction mixture was poured into ice water (150 mL), and extracted with ethyl acetate (150 mLx 3). Combined the organic layer, dried with Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=1 / 0 to 5 / 1) to give (5R,6S)-4-benzyl-5-(((tert- butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholin-3-one (3.1 g, 5.47 mmol, 70.45% yield) as colorless oil.

[0830] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 7.55 - 7.67 (m, 4 H) 7.40 - 7.55 (m, 6 H) 7.25 - 7.36 (m, 3 H) 7.21 (br d, J=6.75 Hz, 2 H) 4.97 (d, J=15.13 Hz, 1 H) 4.62 - 4.73 (m, 1 H) 4.09 (d, J=15.13 Hz, 1 H) 3.88 (m, 1 H) 3.75 (m, 1 H) 3.53 (br s, 1 H) 1.29 (br d, J=6.50 Hz, 3 H) 0.91 - 1.03 (m, 9 H).

[0831] Example 5: Synthesis of (5R,6S)-4-Benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2- difluoro-6-methylmorpholine (f)

[0832] To a solution of (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6- methylmorpholin-3-one (3.3 g, 5.83 mmol, 1 eq) in tetra hydrofuran (33 mL) was added BH3.DMS (10 M, 2.33 mL, 4 eq) at 25°C. Then the mixture was stirred at 30°C for 3 hrs. LCMS showed all the starting materials were consumed; desired MW was detected. The reaction mixture was quenched by addition of methanol (30 mL) at 20°C, the mixture was stirred at 40°C for 1 h, then concentrated under reduced pressure to give crude product. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=1 / 0 to 10 / 1) to give (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6- methylmorpholine (1.9 g, 3.45 mmol, 59.20% yield) as a white solid.

[0833] 1H NMR (400 MHz, DMSO-cfe): 5 7.72 - 7.59 (m, 4H), 7.56 - 7.40 (m, 6H), 7.36 - 7.18 (m, 5H), 4.53 - 4.42 (m, 1 H), 3.99 - 3.83 (m, 2H), 3.74 (d, J = 6.1 Hz, 2H), 2.99 - 2.75 (m, 3H), 1.22 (d, J = 6.8 Hz, 3H), 1.00 (s, 9H).

[0834] Example 6: Synthesis of ((2S,3R)-4-Benzyl-6,6-difluoro-2-methylmorpholin-3- yl)methanol (g)

[0835] To a solution of (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6- methylmorpholine (1.8 g, 3.27 mmol, 1 eq) in tetrahydrofuran (36 mL) was added TBAF (1 M, 4.90 mL, 1.5 eq) at 25°C. Then the mixture was stirred at 25°C for 1 hr. LCMS showed all the starting material was consumed; desired MW was detected. The residue was quenched with water (40 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic was

[0836] 133

[0837] SUBSTITUTE SHEET (RULE 26) washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=1 / 0 to 10 / 1) to give ((2S, 3R)-4-benzyl- 6,6-difluoro-2-methylmorpholin-3-yl)methanol (0.9 g, 3.15 mmol, 96.33% yield) as white solid.1H NMR (400 MHz, DMSO-cfe): 6 7.43 - 7.20 (m, 5H), 4.62 (t, J= 4.9 Hz, 1 H), 4.49 - 4.38 (m, 1H), 3.88 (s, 2H), 3.81 - 3.72 (m, 1 H), 3.70 - 3.61 (m, 1 H), 3.01 - 2.77 (m, 2H), 2.67 (br s, 1 H), 1.22 (d, J= 6.8 Hz, 3H).

[0838] Example 7: Synthesis of tert-Butyl (5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6- methylmorpholine-4-carboxylate (h)

[0839] To a solution of ((2S, 3R)-4-benzyl-6,6-difluoro-2-methylmorpholin-3-yl)methanol (0.9 g, 3.15 mmol, 1 eq) in ethyl acetate (30 mL) was added Pd / C (410 mg, 10% purity, 0.05 eq), BOC2O (1.03 g, 4.72 mmol, 1.08 mL, 1.5 eq) at 25°C 15 Psi under H2 atmosphere. Then the mixture was stirred at 25°C for 16 hrs. LCMS showed all the starting materials were consumed, desired MW was detected. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=1 / 0 to 5 / 1) to give the tert-butyl (5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylate (0.73 g, 2.46 mmol, 78.08% yield) as a white solid.

[0840] 1H NMR (400 MHz, DMSO-cfe): 5 ppm 4.77 (t, 3=5.57 Hz, 1 H) 4.29 (br s, 1 H) 4.13 (br d, 3=8.38 Hz, 1 H) 3.90 - 4.07 (m, 1 H) 3.53 - 3.72 (m, 2 H) 3.13 - 3.33 (m, 1 H) 1.41 (s, 9 H) 1.22 (br d, 3=6.50 Hz, 3 H).

[0841] Example 8: Synthesis of tert-Butyl (5R,6S)-5-((1,3-dioxoisoindolin-2-yl)methyl)-2,2- difluoro-6-methylmorpholine-4-carboxylate (i)

[0842] To a solution of tert-butyl (5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4- carboxylate (500 mg, 1.68 mmol, 1 eq) in tetrahydrofuran (5 mL) was added isoindoline-1 , 3- dione (371.59 mg, 2.53 mmol, 1.5 eq) at 25°C. The reaction mixture was degassed and purged with N23 times. PPhs (662.43 mg, 2.53 mmol, 1.5 eq) was added into reaction mixture at 20°C. DIAD (510.69 mg, 2.53 mmol, 489.64 pL, 1.5 eq) was added into the mixture at 0°C. Then the mixture was stirred at 20°C for 12 hrs under N2 atmosphere. LCMS showed all the starting materials were consumed; desired MW was detected. The residue was quenched with ice water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic was washed brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by column

[0843] 134

[0844] SUBSTITUTE SHEET (RULE 26) chromatography (SiC>2, petroleum ether / ethyl acetate=1 / 0 to 10 / 1). tert-butyl (5R,6S)-5-((1 ,3- dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (720 mg, 1.63 mmol, 97.09% yield, 90% purity) was obtained as a white solid.

[0845] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 7.75 - 8.04 (m, 4 H) 4.04 - 4.52 (m, 3 H) 3.94 (m, 1 H) 3.75 (br d, J=14.38 Hz, 1 H) 3.37 - 3.62 (m, 1 H) 1.38 (d, J=6.50 Hz, 3 H) 0.87 - 1.10 (m, 9 H).

[0846] Example 9: Synthesis of tert-Butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate (j)

[0847] To a solution of tert-butyl (5R,6S)-5-((1 ,3-dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate (720.00 mg, 1.63 mmol, 1 eq) in methyl alcohol (7 mL) was added hydrazine hydrate (818.37 mg, 16.35 mmol, 793.00 pL, 10 eq) at 25°C. Then the mixture was stirred at 60°C for 2 hrs under N2 atmosphere. LCMS showed all the starting materials were consumed; desired MW was detected. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro- 6-methylmorpholine-4-carboxylate (420 mg, 86.83% yield) as a white solid. The crude product was used for the next step without further purification.

[0848] 1H NMR (400 MHz, DMSO-cfe): 5 ppm 4.27 (br s, 1 H) 4.06 - 4.22 (m, 1 H) 3.83 - 4.04 (m, 1 H) 3.10 - 3.33 (m, 3 H) 2.69 - 2.86 (m, 2 H) 1.42 (s, 9 H) 1.19 (d, J=6.63 Hz, 3 H).

[0849] Example 10: Synthesis of tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5- (trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate (k), general procedure

[0850] To a mixture of tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate (210 mg, 788.63 pmol, 1 eq) and K2CO3 (217.99 mg, 1.58 mmol, 2 eq) in dimethylformamide (5 mL) 2-chloro-5-(trifluoromethyl) pyrazine (215.92 mg, 1.18 mmol, 1.5 eq) was added at 25°C. The mixture was stirred at 80°C for 12 hrs. LCMS showed the reaction was completed; desired MW was detected. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 * 10 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiC>2, PE: EA = 1 :1), tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate (105 mg, 29.20% yield) was obtained as a colorless oil.

[0851] 1H NMR (400 MHz, DMSO-cfe): 5 ppm 8.37 - 8.47 (m, 1 H) 7.87 - 8.13 (m, 2 H) 3.99 - 4.40 (m, 3 H) 3.67 - 3.82 (m, 1 H) 3.36 - 3.65 (m, 2 H) 1.31 (br d, J=6.38 Hz, 3 H) 1.02 - 1.26 (m, 9 H).

[0852] 135

[0853] SUBSTITUTE SHEET (RULE 26) Similarly, the following intermediates were prepared.

[0854] Example 11 : Synthesis of tert-Butyl (5 / ?,6S)-2,2-difluoro-6-methyl-5-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylate (I)

[0855] General procedure (see Example 10) used for making compound (k) was repeated, using tert- butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2-chloro- 5-(trifluoromethyl)pyrimidine. Yield 65%, white solid.

[0856] LCMS (ESI+): m / z = 413.3 (M+1), RT: 0.573 min (Column Agilent Poroshell SB-C18 3.0*30mm, 4um. Detection method was diode array (DAD). MS mode was positive electrospray ionization. MS range was 50-2000. Mobile phase A was 0.04% Trifluoroacetic acid in water, and mobile phase B was 0.02% Trifluoroacetic acid in HPLC grade acetonitrile. The gradient was 5-95% B in1.50 min .5% B in 0.01 min, 5-95% B (0.01-0.70 min), 95% B (0.70-1.16min), 95-5% B (1.16-1.17min) with a hold at 5% B for 0.33 min. The flow rate was 1.5 mL / min).

[0857] Example 12: Synthesis of tert-Butyl (5 / ?,6S)-2,2-difluoro-6-methyl-5-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylate (m)

[0858] General procedure (see Example 10) used for making compound (k) was repeated, using tert- butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2-chloro- 5-(trifluoromethyl)pyridine. Yield 43%, yellow oil.

[0859] 1H NMR (400 MHz, DMSO-cfe): 6 8.36 - 8.25 (m, 1 H), 7.69 - 7.57 (m, 1 H), 7.50 - 7.24 (m, 1 H), 6.60 (br d, J = 8.8 Hz, 1 H), 4.42 - 4.16 (m, 3H), 3.81 - 3.67 (m, 1 H), 3.65 - 3.51 (m, 0.5H), 3.45 - 3.34 (m, 1.56H), 1.31 (br d, J = 6.4 Hz, 3H), 1.25 (s, 2H), 1.07 (s, 7H).

[0860] Example 13: Synthesis of tert-Butyl (5 / ?,6S)-5-(((5-chloropyridin-2-yl)amino)methyl)-2,2- difluoro-6-methylmorpholine-4-carboxylate (n), general procedure

[0861] To a mixture of DIPEA (135.90 mg, 1.05 mmol) in DMSO (1.5 mL) was added tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (0.07 g, 262.88 pmol) and 5-chloro-2-fluoro-pyridine (69.16 mg, 525.75 pmol) at 20°C, the reaction was stirred at 140°C for 16 hours. LCMS showed the reaction was completed. The reaction mixture was poured into NH4CI (2 mL) at 0°C and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water (5 mL x 3) and brine (3 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether

[0862] 136

[0863] SUBSTITUTE SHEET (RULE 26) from 0% to 40% to afford tert-butyl (5R,6S)-5-(((5-chloropyridin-2-yl)amino)methyl)-2,2- difluoro-6-methylmorpholine-4-carboxylate (50 mg, 25.17% yield) as a brown solid.

[0864] 1H NMR (400 MHz, DMSO-d6): 5 = 7.98 (d, J=2.50 Hz, 1 H) 7.44 (dd, J=8.88, 2.50 Hz, 1 H) 6.89 (br t, J=6.19 Hz, 1 H) 6.50 (d, J=9.01 Hz, 1 H) 4.17 - 4.40 (m, 3 H) 3.36 - 3.70 (m, 2 H) 3.26 - 3.31 (m, 1 H) 1.28 - 1.33 (m, 5 H) 1.10 (s, 7 H).

[0865] Similarly, the following intermediates were prepared.

[0866] Example 14: Synthesis of tert-Butyl (5R,6S)-5-(((5-chloropyrimidin-2-yl)amino)methyl)- 2,2-difluoro-6-methylmorpholine-4-carboxylate (o)

[0867] General procedure (see Example 13) used for making compound (n) was repeated, using tertbutyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 5-chloro- 2-fluoropyrimidine. Yield 49%, white solid.

[0868] 1H NMR (400 MHz, CHLOROFORM-d): 5 ppm 8.22 (br d, J=5.13 Hz, 1.72H) 5.06 - 5.29 (m, 1 H) 4.32 - 4.51 (m, 2 H) 4.09 - 4.29 (m, 1 H) 3.85 - 3.99 (m, 0.57 H) 3.70 (br t, J=6.82 Hz, 0.85 H) 3.56 (dt, J=14.13, 4.19 Hz, 0.57 H) 3.10 - 3.40 (m, 1 H) 1.27 - 1.46 (m, 12 H).

[0869] Example 15: Synthesis of tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((4- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylate (p)

[0870] General procedure (see Example 13) used for making compound (n) was repeated, using tertbutyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 5-chloro- 2-fluoropyrimidine. Yield 46%, white solid.

[0871] 1H NMR (400 MHz, CHLOROFORM-d): 5 ppm 8.35 - 8.60 (m, 0.81 H) 6.87 (dd, J=15.51 , 4.88 Hz, 0.83 H) 5.33 - 5.57 (m, 0.85 H) 4.21 - 4.51 (m, 2.22 H) 3.90 - 4.20 (m, 1.14 H) 3.15 - 3.85 (m, 2.29 H) 1.18 - 1.45 (m, 12 H).

[0872] Example 16. Synthesis of tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((6- (trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate (q)

[0873] General procedure (see Example 13) used for making compound (n) was repeated, using tertbutyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2-chloro- 6-(trifluoromethyl)pyrazine. Yield 82%, yellow solid.

[0874] 1H NMR (400 MHz, CHLOROFORM-d): 5 7.92 - 8.26 (m, 1.66 H) 4.92 - 5.18 (m, 0.87 H) 4.29 - 4.54 (m, 2 H) 3.82 - 4.23 (m, 1.59 H) 3.10 - 3.63 (m, 1.77 H) 1.14 - 1.46 (m, 12 H).

[0875] 137

[0876] SUBSTITUTE SHEET (RULE 26) Example 17. Synthesis of tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((4- (trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylate (r)

[0877] General procedure (see Example 13) used for making compound (n) was repeated, using tertbutyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2-fluoro-4- (trifluoromethyl)pyridine. Yield 39%, light yellow solid.

[0878] 1H NMR (400 MHz, DMSO-cfe) 6 ppm 8.16 - 8.25 (m, 1 H) 7.00 - 7.27 (m, 1 H) 6.65 - 6.78 (m, 2 H) 4.01 - 4.40 (m, 3 H) 3.34 - 3.82 (m, 3 H) 1 .31 (d, J=6.63 Hz, 3 H) 1.00 - 1.26 (m, 9 H).

[0879] Example 18: Synthesis of tert-Butyl (5R,6S)-2,2-difluoro-5-(((3-fluoro-5- (trifluoromethyl)pyridin-2-yl)amino)methyl)-6-methylmorpholine-4-carboxylate (s)

[0880] General procedure (see Example 13) used for making compound (n) was repeated, using tertbutyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2,3- difluoro-5-(trifluoromethyl)pyridine. Yield 65%, white solid.

[0881] 1HNMR (400 MHz, DMSO-cfe): 6 ppm 8.17 - 8.29 (m, 1.00 H), 7.68 - 7.87 (m, 1.00 H), 7.32 - 7.66 (m, 1.00 H), 4.29 - 4.45 (m, 2.00 H), 3.99 - 4.29 (m, 1.05 H), 3.62 - 3.85 (m, 1.55 H), 3.38 - 3.55 (m, 1.55 H), 1.29 - 1.36 (m, 3.00 H), 1.23 (s, 2.45 H), 1.05 (s, 6.50 H).

[0882] Example 19: Synthesis of tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5- (trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylate (t)

[0883] General procedure (see Example 13) used for making compound (n) was repeated, using tertbutyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 3-bromo- 2-fluoro-5-(trifluoromethyl)pyridine to give tert-butyl (5R,6S)-5-(((3-bromo-5- (trifluoromethyl)pyridin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate. Yield 65%, yellow solid.

[0884] 1HNMR (400 MHz, DMSO-d6): 5 ppm 8.47 - 8.67 (m, 1.70 H), 7.91 - 8.06 (m, 0.25 H), 7.70 (br d, J=4.38 Hz, 0.65 H), 4.08 - 4.68 (m, 1.90 H), 3.75 - 3.94 (m, 0.50 H), 3.56 - 3.74 (m, 2.50 H), 3.37 - 3.55 (m, 1.90 H), 2.91 - 3.25 (m, 1.50 H), 2.14 - 2.36 (m, 0.40 H), 1.41 - 1.60 (m, 1.20 H), 1.26 - 1.39 (m, 8.00 H), 1.14 - 1.25 (m, 5.20 H), 1.12 (br d, J=5.88 Hz, 3.00 H).

[0885] To a solution of tert-butyl (5R,6S)-5-(((3-bromo-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)- 2,2-difluoro-6-methylmorpholine-4-carboxylate (550 mg, 1.12 mmol, 1 eq) in THF (22 mL) and H2O (5.5 mL) was added K3PO4(714.39 mg, 3.37 mmol, 3 eq), MeB(OH)2(100.73 mg, 1.68 mmol, 1.5 eq) and Pd(dtbpf)CI2(73.12 mg, 112.18 pmol, 0.1 eq). The mixture was stirred at

[0886] 138

[0887] SUBSTITUTE SHEET (RULE 26) 80°C for 2 hrs under N2. LCMS showed starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by adding water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=100 / 1 to 1 / 100). tert-Butyl (5R,6S)-2,2- difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4- carboxylate (0.42 g, 83.61% yield) was obtained as a yellow solid.

[0888] 1HNMR (400 MHz, DMSO-d6): 5 ppm 8.13 - 8.28 (m, 0.90 H), 7.42 - 7.57 (m, 0.90 H), 6.78 (br t, J=5.69 Hz, 0.70 H), 6.55 (br t, J=5.63 Hz, 0.25 H), 4.31 - 4.45 (m, 1.90 H), 4.23 (br dd, J=14.20, 4.57 Hz, 0.75 H), 3.98 - 4.07 (m, 0.30 H), 3.77 - 3.90 (m, 1.00 H), 3.61 - 3.76 (m, 0.40 H), 3.46 - 3.59 (m, 0.80 H), 3.40 (ddd, J=13.70, 11.32, 6.13 Hz, 0.70 H), 1.97 - 2.10 (m, 2.90 H), 1.33 (br d, J=6.50 Hz, 3.00 H), 1.21 (s, 2.60 H), 0.99 (s, 6.60 H).

[0889] Example 20: Synthesis of tert-Butyl (5R,6S)-5-(((5-cyclopropylpyrimidin-2- yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (u)

[0890] General procedure (see Example 13) used for making compound (n) was repeated, using tertbutyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2-chloro- 5-cyclopropylpyrimidine.

[0891] Yield 84%, white solid.

[0892] 1H NMR (400 MHz, DMSO-d6): 5 = 8.01 - 8.17 (m, 2 H), 7.00 (br t, J=6.19 Hz, 0.80 H), 6.73 (br t, J=5.88 Hz, 0.20 H), 4.27 - 4.41 (m, 2 H), 4.21 (br dd, J=14.20, 4.44 Hz, 1 H), 3.58 - 3.71 (m, 1 H), 3.52 (br d, J=6.50 Hz, 0.50 H), 3.36 - 3.49 (m, 1 H), 3.22 - 3.30 (m, 0.50 H), 1.67 - 1.81 (m, 1 H), 1.24 - 1.32 (m, 5 H), 1.08 (s, 7 H), 0.79 - 0.89 (m, 2 H), 0.52 - 0.63 (m, 2 H).

[0893] Example 21 : Synthesis of tert-Butyl (5R,6S)-2,2-difluoro-5-(((3-methoxy-5- (trifluoromethyl)pyridin-2-yl)amino)methyl)-6-methylmorpholine-4-carboxylate (v)

[0894] General procedure (see Example 13) used for making compound (n) was repeated, using tertbutyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2-chloro- 3-methoxy-5-(trifluoromethyl)pyridine. Yield 49%, colourless oil.

[0895] 1HNMR (400 MHz, DMSO-d6): 5 ppm 7.87 - 8.02 (m, 0.90 H), 7.08 - 7.22 (m, 0.95 H), 6.64 - 7.05 (m, 0.95 H), 4.37 (ddd, J=13.04, 10.29, 2.81 Hz, 2.00 H), 4.20 (br dd, J=14.01 , 4.50 Hz,

[0896] 139

[0897] SUBSTITUTE SHEET (RULE 26) 0.80 H), 3.79 - 3.88 (m, 2.80 H), 3.66 - 3.79 (m, 1.20 H), 3.37 - 3.65 (m, 1.95 H), 1.27 - 1.36 (m, 3.00 H), 1.23 (s, 1.95 H), 1.00 (s, 6.50 H).

[0898] Example 22: Synthesis of tert-Butyl (5 / ?,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5- (trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate (w)

[0899] DMF (10 V) 0-20°C, 16 hrs

[0900] To a solution of 3-methyl-5-(trifluoromethyl)pyrazin-2-ol (200.66 mg, 1.13 mmol, 1.5 eq) in DMF (5 mL) was added DBU (343.02 mg, 2.25 mmol, 339.63 pL, 3 eq), then BOP (498.28 mg, 1.13 mmol, 1.5 eq) was added in portions at 0°C, the mixture was stirred at 0°C for 0.5 hours. Then tert-butyl (5F?,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate (j) (0.2 g, 751.08 pmol, 1 eq) was added to the mixture at 0°C. The mixture was stirred at 20°C for 16 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition of water (5 mL), extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether from 0% to 11% to afford tert-butyl (5F?,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyrazin- 2-yl)amino)methyl)morpholine-4-carboxylate (0.2 g, 62.45% yield) as a yellow oil.

[0901] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.23 - 8.42 (m, 1 H), 7.16 - 7.51 (m, 1 H), 4.06 - 4.47 (m, 3 H), 3.38 - 3.88 (m, 3 H), 2.23 - 2.37 (m, 3 H), 1.32 (br d, J=6.25 Hz, 3 H), 1.19 (s, 3 H), 0.99 (s, 6 H).

[0902] Example 23: Synthesis of tert-Butyl (5 / ?,6S)-5-(((3-cyano-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (x)

[0903] 140

[0904] SUBSTITUTE SHEET (RULE 26) General procedure (see Example 13) used for making compound (n) was repeated, using tertbutyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2-chloro- 5-(trifluoromethyl)nicotinonitrile. Yield 59%, yellow solid.

[0905] 1H NMR (400 MHz, METHANOL-^): 6 = 8.51 - 8.61 (m, 1 H), 8.05 - 8.21 (m, 1 H), 4.26 - 4.53 (m, 3 H), 3.43 - 4.19 (m, 4 H), 1.31 - 1.47 (m, 9 H), 1.20 (s, 6 H), 0.84 - 0.94 (m, 1 H).

[0906] Example 24: Synthesis of tert-Butyl (y)

[0907] General procedure (see Example 13) used for making compound (n) was repeated, using tertbutyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 5-chloro- 2,3-difluoropyridine. Yield 94%, colourless oil.

[0908] 1H NMR (400 MHz, CHLOROFORM-d): 5 ppm 7.81 - 7.92 (m, 1 H), 7.11 - 7.24 (m, 1 H), 4.62 - 4.92 (m, 1 H), 4.26 - 4.49 (m, 2.40 H), 4.11 - 4.20 (m, 1 H), 3.66 - 3.87 (m, 1 H), 3.55 (dt, J=13.85, 3.77 Hz, 0.60 H), 3.10 - 3.42 (m, 1 H), 1.29 - 1.46 (m, 12 H).

[0909] Example 25: Synthesis of tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((4-methyl-5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylate (z)

[0910] General procedure (see Example 13) used for making compound (n) was repeated, using tertbutyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2,4- dichloro-5-(trifluoromethyl)pyrimidine to give tert-butyl (5R,6S)-5-(((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate. Yield 33%, yellow solid.

[0911] 1HNMR (400 MHz, DMSO-d6): 5 ppm 8.38 - 8.80 (m, 2.00 H), 3.98 - 4.44 (m, 3.10 H), 3.35 - 3.76 (m, 2.90 H), 1.19 - 1.33 (m, 6.00 H), 1.12 (d, J=3.00 Hz, 6.45 H). tert-Butyl (5R,6S)-5-(((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate (0.54 g, 1.21 mmol, 1 eq), 2,4,6-trimethyl-1 , 3, 5, 2,4,6- trioxatriborinane (606.88 mg, 2.42 mmol, purity = 50%, 2 eq), CS2CO3 (1.18 g, 3.63 mmol, 3 eq) and Pd(dppf)Cl2 (88.43 mg, 120.86 pmol, 0.1 eq) were taken up into a microwave tube in dioxane (10.8 mL). Then the mixture was degassed and purged with N2 for 3 time. The sealed tube was heated at 140°C for 4 hrs under Microwave. LCMS showed starting material was consumed completely and one main peak with desired mass was detected. After cooling to 25°C, the reaction mixture was quenched by adding water (20 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed brine (30 mL), dried over

[0912] 141

[0913] SUBSTITUTE SHEET (RULE 26) anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate= 100 / 1 to 1 / 100) to give tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((4-methyl-5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylate (0.32 g, 62.10% yield) as a yellow oil.

[0914] 1HNMR (400 MHz, CHLOROFORM-d): 5 ppm 8.12 - 8.42 (m, 0.90 H), 5.19 - 5.60 (m, 0.95 H), 3.81 - 4.44 (m, 4.00 H), 3.14 - 3.79 (m, 2.35 H), 2.08 - 2.62 (m, 2.75 H), 1.17 - 1.34 (m, 12.00 H).

[0915] Example 26: Synthesis of tert-butyl (5R,6S)-5-(((5-(difluoromethyl)pyrimidin-2- yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (z1)

[0916] General procedure (see Example 13) used for making compound (n) was repeated, using tertbutyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2-chloro- 5-(difluoromethyl)pyrimidine. Yield 88%, yellow solid.

[0917] 1H NMR (400 MHz, DMSO-d6): 5 = 8.37 - 8.58 (m, 2 H), 7.79 (br t, J=6.00 Hz, 0.70 H), 7.48 - 7.66 (m, 0.25 H), 6.76 - 7.17 (m, 1 H), 4.28 - 4.43 (m, 2 H), 4.23 (br dd, J=14.10, 4.82 Hz, 0.70 H), 3.99 - 4.11 (m, 0.30 H), 3.68 (td, J=9.74, 4.76 Hz, 1 H), 3.53 - 3.63 (m, 0.60 H), 3.47 (br d, J=13.73 Hz, 0.40 H), 3.34 - 3.43 (m, 1 H), 1.30 (br d, J=6.43 Hz, 3 H), 1.03 - 1.27 (m, 9 H).

[0918] Example 27: Synthesis of tert-butyl (5R,6S)-5-(((5-(difluoromethyl)pyrazin-2- yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (z2)

[0919] General procedure (see Example 13) used for making compound (n) was repeated, using tertbutyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2-chloro- 5-(difluoromethyl)pyrazine. Yield 95%, colourless oil.

[0920] 1H NMR (400 MHz, DMSO-d6): 5 = 8.19 - 8.28 (m, 1 H), 7.88 - 8.04 (m, 1 H), 7.76 (br s, 0.70 H), 7.61 (br s, 0.30 H), 6.62 - 7.06 (m, 1 H), 4.06 - 4.44 (m, 3 H), 3.35 - 3.79 (m, 3 H), 1.32 (br d, J=6.50 Hz, 3 H), 1 .00 - 1.28 (m, 9 H).

[0921] Example 28: Synthesis of 5-Chloro- / V-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3- yl)methyl)pyridin-2-amine hydrochloride (aa), general procedure

[0922] 142

[0923] SUBSTITUTE SHEET (RULE 26) To a solution of tert-butyl (5R,6S)-5-(((5-chloropyridin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate (50 mg, 92.64 pmol) in dioxane (0.5 mL) was added HCI / dioxane (4 N, 0.5 mL), the reaction was stirred at 20°C for 2 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give 5-chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)pyridin-2-amine hydrochloride (40 mg, 96.2% yield) as a brown solid.

[0924] 1H NMR (400 MHz, DMSO-d6): 5 = 8.05 (d, J=2.50 Hz, 1 H) 7.59 (dd, J=9.01 , 2.50 Hz, 1 H) 6.71 (d, J=9.01 Hz, 1 H) 5.23 - 5.59 (m, 2 H) 4.63 (br dd, J=6.69, 2.31 Hz, 1 H) 3.68 - 3.85 (m, 4 H) 3.58 - 3.67 (m, 1 H) 1.37 (d, J=6.75 Hz, 3 H).

[0925] Similarly, the following intermediates were prepared.

[0926] Example 29: Synthesis of A / -(((2S,3 / ?)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyrazin-2-amine hydrochloride (ab)

[0927] General procedure (see Example 28) used for making compound (aa) was repeated, using tert- butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl) morpholine -4-carboxylate (k). Yield 99%, white solid.

[0928] LCMS (ESI+): m / z =313.1 (M+1), RT: 0.669 min (Column Kinetex EVO C18 2.1*30mm, 5um. Detection method was diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 1.50 min .5% B in 0.01 min, 5- 95% B (0.01-0.70 min), 95% B (0.70-1.16min), 95-5%B in (1.16-1.5min). The flow rate was 1.5 mL / min).

[0929] Example 30: Synthesis of N-(((2S,3 / ?)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyrimidin-2-amine hydrochloride (ac)

[0930] General procedure (see Example 28) used for making compound (aa) was repeated, using tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylate. Yield 89%, yellow solid.

[0931] LCMS (ESI+): m / z =313.2 (M+1), RT: 0.361 min (Column Agilent Poroshell SB-C183.0*30mm, 4um. Detection method was diode array (DAD). MS mode was positive electrospray ionization. MS range was 50-2000. Mobile phase A was 0.04% Trifluoroacetic acid in water, and mobile phase B was 0.02% Trifluoroacetic acid in HPLC grade acetonitrile. The gradient was 5-95%

[0932] 143

[0933] SUBSTITUTE SHEET (RULE 26) B in1 .50 min .5% B in 0.01 min, 5-95% B (0.01-0.70 min), 95% B (0.70-1.16min), 95-5% B (1.16-1.17min) with a hold at 5% B for 0.33 min. The flow rate was 1.5 mL / min).

[0934] Example 31 : Synthesis of / V-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine hydrochloride (ad)

[0935] General procedure (see Example 28) used for making compound (aa) was repeated, using tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl) morpholine-4-carboxylate. Yield 89%, yellow solid.

[0936] LCMS (ESI+): m / z =312.2 (M+1), RT: 0.602 min (Column Agilent Poroshell SB-C183.0*30mm, 4um. Detection method was diode array (DAD). MS mode was positive electrospray ionization. MS range was 50-2000. Mobile phase A was 0.04% Trifluoroacetic acid in water, and mobile phase B was 0.02% Trifluoroacetic acid in HPLC grade acetonitrile. The gradient was 5-95% B in1 .50 min .5% B in 0.01 min, 5-95% B (0.01-0.70 min), 95% B (0.70-1.16min), 95-5% B (1.16-1.17min) with a hold at 5% B for 0.33 min. The flow rate was 1.5 mL / min).

[0937] Example 32: Synthesis of 5-Chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3- yl)methyl)pyrimidin-2-amine hydrochloride (ae)

[0938] General procedure (see Example 28) used for making compound (aa) was repeated, using tert-butyl (5R,6S)-5-(((5-chloropyrimidin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine- 4-carboxylate. Yield 98%, white solid.

[0939] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 8.43 (s, 1.74 H) 7.48 - 7.56 (m, 1 H) 4.58 - 4.66 (m, 1.17 H) 3.58 - 3.87 (m, 5.38 H) 1.36 (d, J=6.63 Hz, 3 H).

[0940] Example 33. Synthesis of N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-4- (trifluoromethyl)pyrimidin-2-amine hydrochloride (af)

[0941] General procedure (see Example 28) used for making compound (aa) was repeated, using tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyrimidin-2-yl)amino)methyl) morpholine-4-carboxylate. Yield 79%, light yellow solid.

[0942] 1H NMR (400 MHz, DMSO-cfe) 6 ppm 8.69 (br d, J=4.00 Hz, 0.89 H) 7.81 - 8.02 (m, 0.9 H) 7.12 (d, J=4.88 Hz, 0.88 H) 4.62 - 4.71 (m, 0.91 H) 3.63 - 3.92 (m, 4.85 H) 1 .37 (d, J=6.75 Hz, 3 H).

[0943] 144

[0944] SUBSTITUTE SHEET (RULE 26) Example 34. Synthesis of N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-6- (trifluoromethyl)pyrazin-2-amine hydrochloride (ag)

[0945] General procedure (see Example 28) used for making compound (aa) was repeated, using tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((6-(trifluoromethyl)pyrazin-2-yl)amino)methyl) morpholine-4-carboxylate. Yield 97%, yellow solid.

[0946] 1H NMR (400 MHz, DMSO-cfe): 6 7.84 - 8.40 (m, 1.64 H) 4.79 - 5.56 (m, 2.72 H) 4.55 - 4.72 (m, 0.67 H) 3.64 - 3.94 (m, 3 H) 1.06 - 1.46 (m, 3 H).

[0947] Example 35. Synthesis of N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-4- (trifluoromethyl)pyridin-2-amine hydrochloride (ah)

[0948] General procedure (see Example 28) used for making compound (aa) was repeated, using tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyridin-2-yl)amino)methyl) morpholine-4-carboxylate. Yield 89%, light yellow solid.

[0949] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 8.25 (d, J=5.38 Hz, 1 H) 7.63 - 7.83 (m, 0.69 H) 6.95 (s, 1 H) 6.89 (d, J=5.50 Hz, 1 H) 4.61 - 4.69 (m, 1.16 H) 3.67 - 3.85 (m, 5.34 H) 1.39 (d, J=6.75 Hz, 3 H).

[0950] Example 36. Synthesis of N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-3- fluoro-5-(trifluoromethyl)pyridin-2-amine hydrochloride (ai)

[0951] General procedure (see Example 28) used for making compound (aa) was repeated, using tert-butyl (5R,6S)-2,2-difluoro-5-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-6- methyl morpholine-4-carboxylate. Yield 94%, white solid.

[0952] 1HNMR (400 MHz, DMSO-cfe): 5 ppm 8.24 (s, 1 H), 7.85 (dd, J=11.32, 1.69 Hz, 1 H), 7.62 (br s, 1 H), 4.60 - 4.75 (m, 1 H), 3.71 - 3.93 (m, 5 H), 1.38 (d, J=6.75 Hz, 3 H).

[0953] Example 37. Synthesis of N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-3- methyl-5-(trifluoromethyl)pyridin-2-amine (aj), general procedure tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylate (0.42 g, 987.32 pmol, 1 eq) was dissolved in HCI / dioxane (4 M, 4.2 mL, 17.02 eq). The mixture was stirred at 25 °C for 1 hr. LCMS showed starting material was consumed completely and one main peak with desired mass was detected. The mixture was adjusted to pH 9 with NaHCOs (aq), and extracted with ethyl acetate (3x15 mL). The combined organic layers were washed brine (30 mL), dried over anhydrous

[0954] 145

[0955] SUBSTITUTE SHEET (RULE 26) sodium sulfate, filtered and concentrated under reduced pressure to give N-(((2S,3R)-6,6- difluoro-2-methylmorpholin-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyridin-2-amine (0.27 g, 79.03% yield) as a yellow solid.

[0956] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 8.20 (s, 0.90 H), 7.52 (d, J=1.38 Hz, 1.00 H), 6.47 (br t, J=5.32 Hz, 1.00 H), 4.36 (qd, J=6.73, 3.31 Hz, 1.00 H), 3.41 - 3.57 (m, 2.20 H), 3.14 (br s, 2.10 H), 2.92 (br s, 2.00 H), 2.11 (s, 2.95 H), 1.24 (d, J=6.63 Hz, 3.00 H).

[0957] Example 38. Synthesis of 5-Cyclopropyl-N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3- yl)methyl)pyrimidin-2-amine hydrochloride (ak)

[0958] General procedure (see Example 28) used for making compound (aa) was repeated, using tert-butyl (5R,6S)-5-(((5-cyclopropylpyrimidin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate. Yield 85%, brown oil.

[0959] 1H NMR (400 MHz, DMSO-d6): 5 = 8.37 (s, 2 H), 7.85 (br s, 1 H), 4.61 - 4.75 (m, 1 H), 3.85 (br s, 5 H), 1.78 - 1.94 (m, 1 H), 1.38 (d, J=6.63 Hz, 3 H), 0.86 - 0.98 (m, 2 H), 0.64 - 0.76 (m, 2 H).

[0960] Example 39. Synthesis of N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-3- methoxy-5-(trifluoromethyl)pyridin-2-amine (al)

[0961] General procedure (see Example 37) used for making compound (aj) was repeated, using tert-butyl (5R,6S)-2,2-difluoro-5-(((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-6- methylmorpholine-4-carboxylate. Yield 64%, yellow solid.

[0962] LCMS: m / z = 342.2 (M+1), RT: 0.621 min.

[0963] Example 40. Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3- methyl-5-(trifluoromethyl)pyrazin-2-amine hydrochloride (am)

[0964] General procedure (see Example 28) used for making compound (aa) was repeated, using tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate. Yield 99%, light yellow solid.

[0965] 1H NMR (400 MHz, DMSO-cfe): 5 ppm 8.32 (s, 1 H), 7.54 (br t, J=5.25 Hz, 1 H), 4.75 - 5.14 (m, 2 H), 4.67 (br dd, J=6.69, 2.19 Hz, 1 H), 3.65 - 3.93 (m, 5 H), 2.43 (s, 3 H), 1 .39 (d, J=6.75 Hz, 3 H).

[0966] Example 41. Synthesis of 2-((((2S,3R)-6,6-Difluoro-2-methylmorpholin-3- yl)methyl)amino)-5-(trifluoromethyl)nicotinonitrile hydrochloride (an)

[0967] 146

[0968] SUBSTITUTE SHEET (RULE 26) General procedure (see Example 28) used for making compound (aa) was repeated, using tert-butyl (5R,6S)-5-(((3-cyano-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate. Yield 95%, yellow solid.

[0969] LCMS: (ESI+): m / z=337.2 (M+1), RT: 0.404 min.

[0970] Example 42. Synthesis of 5-Chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3- yl)methyl)-3-fluoropyridin-2-amine hydrochloride (ao)

[0971] General procedure (see Example 28) used for making compound (aa) was repeated, using tert-butyl (5R,6S)-5-(((5-chloro-3-fluoropyridin-2-yl)amino)methyl)-2,2-difluoro-6-methyl morpholine-4-carboxylate. Yield 94%, white solid.

[0972] 1H NMR (400 MHz, DMSO-d6): 5 ppm 7.93 (d, J=2.00 Hz, 1 H), 7.73 (dd, J=10.88, 2.00 Hz, 1 H), 7.08 (br d, J=1 .25 Hz, 1 H), 4.60 - 4.71 (m, 2 H), 3.73 - 3.89 (m, 4 H), 3.60 - 3.72 (m, 1 H), 1.37 (d, J=6.75 Hz, 3 H).

[0973] Example 43. Synthesis of N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-4- methyl-5-(trifluoromethyl)pyrimidin-2-amine (ap)

[0974] General procedure (see Example 37) used for making compound (aj) was repeated, using tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino) methyl)morpholine-4-carboxylate. Yield 82%, yellow oil.

[0975] 1HNMR (400 MHz, DMSO-d6): 5 ppm 8.22 - 8.57 (m, 0.85 H), 7.66 - 7.91 (m, 0.90 H), 4.28 - 4.42 (m, 1.00 H), 3.43 - 3.58 (m, 1.30 H), 3.35 - 3.43 (m, 1.05 H), 2.99 - 3.18 (m, 1.95 H), 2.85

[0976] - 2.99 (m, 1.90 H), 2.32 - 2.46 (m, 2.50 H), 1.21 (br t, J=6.32 Hz, 3.00 H).

[0977] Example 44: Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-5- (difluoromethyl)pyrimidin-2-amine hydrochloride (aq)

[0978] General procedure (see Example 28) used for making compound (aa) was repeated, using tert-butyl (5R,6S)-5-(((5-(difluoromethyl)pyrimidin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate. Yield 92%, yellow solid.

[0979] 1H NMR (400 MHz, DMSO-d6): 5 = 8.56 (s, 2 H), 7.80 - 7.98 (m, 1 H), 6.81 - 7.17 (m, 1 H), 4.61 - 4.80 (m, 1 H), 3.65 - 3.89 (m, 5 H), 1.37 (br d, J=6.68 Hz, 3 H).

[0980] Example 45 : Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-5- (difluoromethyl)pyrazin-2-amine hydrochloride (ar)

[0981] 147

[0982] SUBSTITUTE SHEET (RULE 26) General procedure (see Example 28) used for making compound (aa) was repeated, using tert-butyl (5F?,6S)-5-(((5-(difluoromethyl)pyrazin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate. Yield 87%, yellow solid.

[0983] 1H NMR (400 MHz, DMSO-d6): 5 = 8.19 (d, J=1.00 Hz, 1 H), 8.00 (d, =1.13 Hz, 1 H), 7.93 (br s, 1 H), 6.83 (t, J=54.84 Hz, 1 H), 4.52 - 4.70 (m, 1 H), 3.57 - 3.84 (m, 5 H), 1.32 (d, J=6.75 Hz, 3 H).

[0984] Example 46: Synthesis of (5 / ?,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2- difluoro-6-methylmorpholine-3,3-d2 (f1).

[0985] (5F?,6S)-4-Benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholin-3- one (2.3 g, 4.51 mmol, 1 eq) was dissolved in trideuterioborane (1 M in THF, 23.00 mL, 5.10 eq) at 20°C. Then the mixture was stirred at 40°C for 1.5 hrs. LCMS showed 30% of starting materials were remained, 60% of desired mass was detected. The reaction mixture was quenched by addition of MeOH (30 mL) at 20 °C. The mixture was stirred at 40°C for 1 hr,

[0986] 148

[0987] SUBSTITUTE SHEET (RULE 26) then concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=1 / 0 to 10 / 1) to give the (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine- 3,3-d2 (1.1 g, 1.99 mmol, 44.08% yield, 90% purity) as a colourless oil.

[0988] 1H NMR (400 MHz, DMSO-d6): 5 7.64 (ddd, J = 1.8, 3.0, 7.6 Hz, 4H), 7.54 - 7.41 (m, 6H), 7.35 - 7.20 (m, 5H), 4.48 (dq, J = 3.0, 6.7 Hz, 1 H), 3.97 - 3.83 (m, 2H), 3.74 (d, J = 5.4 Hz, 2H), 2.83 - 2.76 (m, 1 H), 1 .22 (d, J = 6.6 Hz, 3H), 1.00 (s, 9H).

[0989] Example 47: Synthesis of ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholin-3-yl-5,5- d2)methanol (g1).

[0990] To a solution of (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6- methylmorpholine-3,3-d2 (0.7 g, 1.41 mmol, 1 eq) in tetrahydrofuran (14 mL) was added TBAF (1 M, 2.81 mL, 2 eq) at 20°C. Then the mixture was stirred at 20°C for 12 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was quenched with water (30 mL), and extracted with ethyl acetate (3 x 30 mL). The combined organics were washed brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=1 / 0 to 5 / 1) to give the ((2S, 3R)-4-benzyl-6,6-difluoro-2-methylmorpholin-3-yl-5,5-d2)methanol (150 mg, 549.58 pmol, 39.07% yield, 95% purity) as a colourless oil.

[0991] 1H NMR (400 MHz, DMSO-d6): 5 7.42 - 7.19 (m, 5H), 4.60 (t, J = 5.0 Hz, 1 H), 4.44 (dq, J = 2.8, 6.7 Hz, 1 H), 3.88 (s, 2H), 3.81 - 3.60 (m, 2H), 2.73 - 2.60 (m, 1 H), 1.23 (d, J = 6.7 Hz, 3H).

[0992] Example 48: Synthesis of tert-butyl (5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6- methylmorpholine-4-carboxylate-3,3-d2 (hi).

[0993] To a solution of ((2S, 3R)-4-benzyl-6,6-difluoro-2-methylmorpholin-3-yl-5,5-d2)methanol (0.5 g, 1.93 mmol, 1 eq) in ethyl acetate (20 mL) was added Pd / C (410.43 mg, 385.67 pmol, 10% purity, 0.05 eq), (Boc)2O (631.28 mg, 2.89 mmol, 664.51 pL, 1.5 eq) and TEA (390.26 mg, 3.86 mmol, 536.81 pL, 2 eq) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 20°C for 12 hrs. LCMS showed all the starting materials were consumed; desired mass was detected. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was directly used for the next

[0994] 149

[0995] SUBSTITUTE SHEET (RULE 26) step. tert-Butyl (5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylate-

[0996] 3.3-d2 (519 mg, 1.93 mmol, 99.95% yield) was obtained as a colourless oil.

[0997] 1H NMR (400 MHz, DMSO-d6): 5 = 4.76 (t, J = 5.6 Hz, 1 H), 4.35 - 4.24 (m, 1 H), 4.07 - 3.91 (m, 1 H), 3.72 - 3.52 (m, 2H), 1.41 (s, 9H), 1.22 (br d, J = 6.4 Hz, 3H).

[0998] Example 49: Synthesis of tert-butyl (5R,6S)-5-((1,3-dioxoisoindolin-2-yl)methyl)-2,2- difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (i1).

[0999] To a solution of (519 mg, 1.93 mmol, 1 eq) in tetrahydrofuran (5 mL) was added isoindoline-

[1000] 1.3-dione (425.36 mg, 2.89 mmol, 1.5 eq) at 25°C. The reaction mixture was degassed and purged with N2 for 3 times. PPhs (758.29 mg, 2.89 mmol, 1.5 eq) was added into reaction mixture at 20°C. DIAD (584.59 mg, 2.89 mmol, 560.49 pL, 1 .5 eq) was added into the mixture at 0°C. Then the mixture was stirred at 20°C for 12 hrs under N2 atmosphere. LCMS showed all the starting materials were consumed; desired mass was detected. The residue was quenched with ice water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organics were washed brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=1 / 0 to 10 / 1). Compound tertbutyl (5R,6S)-5-((1 ,3-dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate-3,3-d2 (440 mg, 993.98 pmol, 51.57% yield, 90% purity) was obtained as a yellow solid.

[1001] 1H NMR (400 MHz, DMSO-d6): 5 8.01 - 7.74 (m, 4H), 4.48 - 4.19 (m, 2H), 3.94 (dd, J = 11.9, 14.3 Hz, 1 H), 3.74 (dd, J = 3.1 , 14.4 Hz, 1 H), 1.38 (d, J = Q.Q Hz, 3H), 1.05 - 0.91 (m, 9H).

[1002] Example 50: Synthesis of tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate-3,3-d2 (j1).

[1003] To a solution of (5R,6S)-5-((1 ,3-dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6-methylmorpholine- 4-carboxylate-3,3-d2 (640 mg, 1.45 mmol, 1 eq) in MeOH (24 mL) was added hydrazine hydrate (723.77 mg, 14.46 mmol, 701.33 pL, 10 eq) at 25°C. Then the mixture was stirred at 60°C for 4 hrs under N2 atmosphere. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was filtered to afford filtrate and concentrated under reduced pressure to give the crude product. The crude product was directly used for the next step. Tert-Butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate-3,3-d2 (450 mg, 1.34 mmol, 92.81% yield, 80% purity) was obtained as a white solid.

[1004] 150

[1005] SUBSTITUTE SHEET (RULE 26)1H NMR (400 MHz, DMSO-d6): 6 4.26 (br s, 1 H), 4.02 - 3.84 (m, 1 H), 2.82 - 2.69 (m, 2H), 1.41 (s, 9H), 1.19 (d, J = 6.8 Hz, 3H).

[1006] Example 51 : Synthesis of tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5- (trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate-3,3-d2 (k1) ,

[1007] To a solution of 2-chloro-5-(trifluoromethyl)pyrazine (187.77 mg, 1.03 mmol, 1.5 eq) in DMF (4.6 mL) was added tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate-3,3-d2 (230.00 mg, 685.81 pmol, 1 eq) at 25°C. K2CO3 (189.57 mg, 1.37 mmol, 2 eq) was added into reaction mixture at 25°C. Then the mixture was stirred at 80°C for 2 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was quenched with water (10 mL), and extracted with ethyl acetate (2x20 mL). The combined organic layer was washed brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by pre-TLC (petroleum ether: ethyl acetate=1 :1) to give the product. Compound tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate-3,3-d2 (90 mg, yield 25.34%) was obtained as a yellow solid.

[1008] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 8.86 - 8.22 (m, 1.85 H), 8.06 - 7.89 (m, 1.15 H), 4.85 - 4.22 (m, 2.10 H), 3.83 - 3.66 (m, 0.80 H), 3.65 - 3.41 (m, 1.05 H), 1.39 (s, 2.70 H), 1.31 (br d, J = 6.5 Hz, 1.50 H), 1.17 (br d, J = 6.3 Hz, 1.55 H), 1.06 (s, 6.00 H).

[1009] Example 52: Synthesis of tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylate-3,3-d2 (ml) ,

[1010] 151

[1011] SUBSTITUTE SHEET (RULE 26) To a solution of tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate-3,3-d2 (80.00 mg, 238.54 pmol, 1 eq) in DMSO (1.6 mL) was added DIPEA (61.66 mg, 477.08 pmol, 83.10 pL, 2 eq) and 2-fluoro-5-(trifluoromethyl)pyridine (59.07 mg, 357.81 pmol, 1.5 eq) at 25°C. Then the mixture was stirred at 140°C for 16 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2x20 mL). The combined organic layer was washed brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by pre-TLC (petroleum ether: ethyl acetate = 1 :1) to give tert-butyl (5R,6S)-2,2- difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylate- 3,3-d2 (40 mg, yield 32.45%) as a yellow solid.

[1012] LCMS (ESI+): m / z =414.2 (M+1), RT: 0.564 min.

[1013] Similarly, the following compound was prepared.

[1014] Example 53: tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylate-3,3-d2 (11)

[1015] General procedure (see Example 52) used for making compound (ml) was repeated, using tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 and 2-chloro-5-(trifluoromethyl)pyrimidine. Yield 85%, colourless oil.

[1016] 1HNMR (400 MHz, DMSO-cfe): 6 ppm 8.46 - 8.78 (m, 2 H), 8.13 (s, 1 H), 4.23 - 4.44 (m, 2 H), 3.55 - 3.74 (m, 1 H), 3.39 (ddd, J=14.13, 11.44, 6.44 Hz, 1 H), 1.29 (br d, J=6.50 Hz, 3 H), 1.06 - 1.26 (m, 9 H).

[1017] Example 54: Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl-5,5- d2)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride (ab1)

[1018] 152

[1019] SUBSTITUTE SHEET (RULE 26)

[1020] To a solution of tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate-3,3-d2 (90 mg, 173.76 pmol, 1 eq) in HCI / dioxane (4 M, 2 mL, 46.04 eq) at 20°C. Then the mixture was stirred at 20°C for 1 hr. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was concentrated under reduced pressure to give crude N-(((2S,3R)-6,6-difluoro-2- methylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride (60 mg, yield 98.46%) as a yellow solid.

[1021] LCMS (ESI+): m / z =315.1 (M+1), RT: 0.584 min.

[1022] Similarly, the following compounds were prepared.

[1023] Example 55: N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl-5,5-d2)methyl)-5-

[1024] (trifluoromethyl)pyrimidin-2-amine hydrochloride (ac1)

[1025] General procedure (see Example 54) used for making compound (ab1) was repeated, using tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylate-3,3-d2.

[1026] Yield 97%, white solid.

[1027] LCMS (ESI+): m / z =315.2 (M+1), RT: 0.574min.

[1028] Example 56: N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl-5,5-d2)methyl)-5-

[1029] (trifluoromethyl)pyridin-2-amine hydrochloride (ad1)

[1030] 153

[1031] SUBSTITUTE SHEET (RULE 26)

[1032] General procedure (see Example 54) used for making compound (ab1) was repeated, using tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylate-3,3-d2.

[1033] Yield 99%, yellow solid.

[1034] LCMS (ESI+): m / z =314.2 (M+1), RT: 0.380 min.

[1035] DCM (20 V) aa2-ad2 89-91 and 103

[1036] Example 57: Synthesis of (2S,3S)-4-benzyl-6,6-difluoro-2-methyl-5-oxomorpholine-3- carboxylic acid (e2’).

[1037] To a 50 L reactor equipped with stirrer, an addition funnel and a thermometer, charge dioxane (20 L, 20 V), followed by the f-BuONa (1.09 kg, 11.35 mol, 5 eq.) was added to the suspension at 25 °C in four portions. After cooling to 10 °C, benzyl-L-allothreonine (CAS 1932485-18-1) (500.00 g, 2.27 mol, 1 eq.) and (2-bromo-2,2-difluoro-acetyl)oxysodium (1.34 kg, 6.81 mol, 3

[1038] 154

[1039] SUBSTITUTE SHEET (RULE 26) eq.) were added to the reactor at 10 °C in five portions: keeping alternating between benzyl- L-allothreonine (100 g, 0.2 eq.) and (2-bromo-2,2-difluoro-acetyl)oxysodium (268 g, 0.6 eq.), waiting for the temperature to drop to 10 °C after each addition, until they are all added up. Finally, a yellow suspension was generated. The suspension was stirred at 25 °C for 1 hr under N2. LCMS showed benzyl-L-allothreonine was consumed and desired mass was detected.

[1040] The reaction was quenched with hydrochloric acid aqueous solution (5 L, 10 V, 4 mol / L) at 0 °C, and the pH value of solution was adjusted to 2. Then EtOAc (5 L, 10 V) was added into the reaction at 25 °C. The solution was stirred at 25 °C for 12 hrs under N2. LCMS showed the intermediate was consumed and desired mass was detected. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (3 x 5 [_). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=1 / 0 to 3 / 1) to give (2S,3S)-4-benzyl-6,6- difluoro-2-methyl-5-oxomorpholine-3-carboxylic acid (250 g, 37% yield) as gray solid.

[1041] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 13.64 (br s, 1 H), 7.25 - 7.34 (m, 5 H), 4.75 - 4.83 (m, 2H), 4.13 - 4.16 (m, 2H), 1.28 (d, J=6.50 Hz, 3 H).

[1042] Example 58: Synthesis of (5 / ?,6S)-4-benzyl-2,2-difluoro-5-(hydroxymethyl-d2)-6- methylmorpholin-3-one (e2”).

[1043] To a solution of (2S, 3S)-4-benzyl-6,6-difluoro-2-methyl-5-oxomorpholine-3-carboxylic acid (10 g, 35.06 mmol, 1 eq) in THF (200 mL) was added TEA (5.32 g, 52.59 mmol, 7.32 mL, 1.5 eq). The solution was cooled to 0°C. The isobutyl carbonochloridate (7.18 g, 52.59 mmol, 6.88 mL, 1.5 eq) was added into the solution at 0°C. The mixture was stirred at 25°C for 30 mins. LCMS showed the (2S, 3S)-4-benzyl-6,6-difluoro-2-methyl-5-oxomorpholine-3-carboxylic acid was consumed, the desired mass was detected. The reaction mixture was filtered. Sodium borodeuteride (1.46 g, 38.56 mmol, 1.1 eq) was dissolved in D2O (6 mL) and the solution was added into the filtrate at 0°C. Then the reaction was stirred at 25°C for 2 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. Then extracted with ethyl acetate mL (100 mL x 3) water (100 mL). The combined organic layers were washed with brine mL (50 mL x 2), dried over Na2SO4, filtered and concentrate to give crude product. This crude product was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=1 / 0 to 3 / 1). Compound (5 ?,6S)-4-benzyl-2,2-difluoro-5-(hydroxymethyl-d2)-6- methylmorpholin-3-one (6 g, 62.63% yield) as colorless oil.

[1044] 155

[1045] SUBSTITUTE SHEET (RULE 26)1H NMR (400 MHz, DMSO-cfe): 6 ppm 7.21 - 7.48 (m, 5 H), 4.98 - 5.16 (m, 2 H), 4.61 (m, 1 H), 4.27 (d, J=15.26 Hz, 1 H), 3.38 (d, J=1.88 Hz, 1 H), 1.32 (d, J=6.50 Hz, 3 H).

[1046] Example 59: Synthesis of ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholin-3- yl)methan-d2-ol (g2).

[1047] A solution of (5R,6S)-4-benzyl-2,2-difluoro-5-(hydroxymethyl-d2)-6-methylmorpholin-3-one (6 g, 21.96 mmol, 1 eq) in THF (12 mL) was added into the stirred solution of BH3.THF (1 M, 60.38 mL, 2.75 eq) at 0°C. The reaction was warmed to 45°C and stirred for 2.5 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. This reaction was poured into HCI (1 N,), adjusted to pH 7, then extracted with ethyl acetate mL (200 mL x 3). The combined organic layers were washed with brine mL (200 mLx 2), dried over Na2SO4, filtered and concentrate to give crude product. The crude product was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=1 / 0 to 3 / 1). ((2S,3R)-4-Benzyl-6,6- difluoro-2-methylmorpholin-3-yl)methan-d2-ol (4.2 g, 73.78% yield) was obtained as a colorless oil.

[1048] 1H NMR (400 MHz, DMSO-cfe): 5 ppm 7.19 - 7.49 (m, 5 H), 4.58 (s, 1 H), 4.45 (m, 1 H), 3.89 (s, 2 H), 2.78 - 3.02 (m, 2 H), 2.67 (br s, 1 H), 1 .24 (d, J=6.75 Hz, 3 H).

[1049] Example 60: Synthesis of tert-butyl (2S,3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3- methylpiperidine-1 -carboxylate (h2).

[1050] To a solution of ((2S, 3R)-4-benzyl-6,6-difluoro-2-methylmorpholin-3-yl)methan-d2-ol (4.2 g, 16.20 mmol, 1 eq) in EtOAc (84 mL) was added Pd / C (861.91 mg, 10% purity, 0.05 eq) and (Boc)2O (4.95 g, 5.21 mL, 1.4 eq). The mixture was stirred at 20°C for 12 hrs under 15 Psi H2. TLC showed all the starting materials were consumed. This reaction was filtered and concentrated to give crude product. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 4 / 1) to give tert-butyl (2S,3R)-5,5-difluoro-2- (hydroxymethyl-d2)-3-methylpiperidine-1 -carboxylate (3.6 g, 82.53% yield) as a white solid.1H NMR (400 MHz, DMSO-cfe): 5 ppm 4.73 (s, 1 H), 4.29 (br s, 1 H), 4.14 (br d, J=8.88 Hz, 1 H), 3.87 - 4.06 (m, 1 H), 3.40 (br d, J=13.88 Hz, 1 H), 3.13 - 3.29 (m, 1 H), 1.42 (s, 9 H), 1.23 (br d, J=6.75 Hz, 3 H).

[1051] Example 61 : Synthesis of tert-butyl (5R,6S)-5-((1,3-dioxoisoindolin-2-yl)methyl-d2)-2,2- difluoro-6-methylmorpholine-4-carboxylate (i2).

[1052] To a solution of tert-butyl (2S,3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3-methylpiperidine-1- carboxylate (3.6 g, 1 eq) in THF (36 mL) was added isoindoline-1 , 3-dione (2.80 g, 19.05 mmol,

[1053] 156

[1054] SUBSTITUTE SHEET (RULE 26) 1.5 eq) and PPhs (5.00 g, 1.5 eq) at 0°C. Then DIAD (3.85 g, 1.5 eq) was added into the mixture. The mixture was stirred at 20°C for 16 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. This reaction was poured into ice water (50 mL), and extracted with ethyl acetate (50 mL x 3), combined the organic layer, dried with Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=1 / 0 to 4 / 1) to give tert-butyl (5R,6S)-5-((1 ,3-dioxoisoindolin-2-yl)methyl-d2)-2,2-difluoro-6-methylmorpholine-4- carboxylate (3.4 g, 63.84% yield) as white solid.

[1055] 1H NMR (400 MHz, DMSO-cfe): 5 ppm 7.74 - 8.02 (m, 4 H), 4.42 (m, 1 H), 4.06 - 4.38 (m, 2 H), 3.37 - 3.67 (m, 1 H), 1.39 (d, J=6.63 Hz, 3 H), 0.90 - 1.08 (m, 9 H).

[1056] Example 62: Synthesis of tert-butyl (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6- methylmorpholine-4-carboxylate (j2).

[1057] To a solution of tert-butyl (5R,6S)-5-((1 ,3-dioxoisoindolin-2-yl)methyl-d2)-2,2-difluoro-6- methylmorpholine-4-carboxylate (3.4 g, 1 eq) in methyl alcohol (68 mL) was added hydrazine hydrate (4.06 g, 3.93 mL, 10 eq) at 25°C. Then the mixture was stirred at 60°C for 2 hrs under N2 atmosphere. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was filtered to afford filtrate and concentrated under reduced pressure to give the crude product. The crude product was directly used for the next step. Compound tert-butyl (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4- carboxylate (1.5 g, 68.9% yield) was obtained as a colorless oil.

[1058] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 4.27 (br s, 1 H), 4.14 (br t, J= 15.01 Hz, 1 H), 3.82 - 4.03 (m, 1 H), 3.11 - 3.32 (m, 1 H), 1.43 (s, 9 H), 1.20 (d, J=6.63 Hz, 3 H).

[1059] Example 63: tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl-d2)morpholine-4-carboxylate (k2)

[1060] 80°C, 2 hrs

[1061] 157

[1062] SUBSTITUTE SHEET (RULE 26) To a solution of tert-butyl (5F?,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4- carboxylate (100 mg, 372.72 pmol, 1 eq) in DMSO (2 mL) was added DIPEA (96.34 mg, 745.44 pmol, 129.84 pL, 2 eq) and 2-chloro-5-(trifluoromethyl)pyrazine (81.64 mg, 447.27 pmol, 1.2 eq) at 25°C. Then the mixture was stirred at 80°C for 2 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organics were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by pre-TLC (petroleum ether: ethyl acetate = 3:1) to give tert-butyl (2S,3F?)-5,5- difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl-d2)piperidine-1- carboxylate (115 mg, 67.01% yield) as a yellow oil.

[1063] 1HNMR (400 MHz, DMSO-d6): 6 ppm 8.36 - 8.51 (m, 1 H), 8.05 (br s, 2 H), 4.06 - 4.42 (m, 3 H), 3.36 - 3.67 (m, 1 H), 1.31 (br d, 3=6.38 Hz, 3 H), 1.24 (s, 3 H), 1.06 (s, 6 H).

[1064] Example 64: Synthesis of tert-butyl (5 / ?,6S)-2,2-difluoro-6-methyl-5-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl-d2)morpholine-4-carboxylate (12)

[1065] 140°C, 5 hrs

[1066] To a solution of tert-butyl (5F?,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4- carboxylate (250 mg, 931.80 pmol, 1 eq) and 2-chloro-5-(trifluoromethyl)pyrimidine (204.10 mg, 1.12 mmol, 1.2 eq) in DMSO (2.5 mL) was added DIPEA (240.85 mg, 1.86 mmol, 324.60 pL, 2 eq). The mixture was stirred at 140°C for 5hrs. LCMS showed the starting material was consumed and desired mass was detected. The reaction mixture was diluted with H2O (5 mL) and extracted with Ethyl acetate (5 mL x 3), the combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 5% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to give tert-butyl (5R, 6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl-d2)morpholine-4-carboxylate (650 mg, yield 84.17 %) as a yellow oil.

[1067] LCMS (ESI+): m / z =415.2 (M+1), RT :0.586 min.

[1068] 158

[1069] SUBSTITUTE SHEET (RULE 26) Similarly, the following compounds were prepared.

[1070] Example 65: tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl-d2)morpholine-4-carboxylate (m2)

[1071] The titled compound (m2) was prepared in analogy to the procedure described for compound (12) using tert-butyl (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4- carboxylate and 2-fluoro-5-(trifluoromethyl)pyridine. Yield 42%, yellow oil.

[1072] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 8.26 - 8.34 (m, 1 H), 7.64 (br d, J=8.63 Hz, 1 H), 7.42 (s, 1 H), 6.60 (br d, J=8.88 Hz, 1 H), 4.19 - 4.42 (m, 4 H), 1.31 (br d, J=6.38 Hz, 3 H), 1.07 (s, 9 H).

[1073] Example 66: tert-Butyl (5R,6S)-5-(((5-chloropyridin-2-yl)amino)methyl-d2)-2,2-difluoro- 6-methylmorpholine-4-carboxylate (n2)

[1074] The titled compound (n2) was prepared in analogy to the procedure described for compound (I2) using tert-butyl (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4- carboxylate and 5-chloro-2-fluoropyridine.

[1075] Yield 45%, yellow oil.

[1076] 1HNMR (400 MHz, DMSO-cfe): 6 ppm 7.91 - 8.01 (m, 1 H), 7.32 - 7.48 (m, 1 H), 6.64 - 6.90 (m, 1 H), 6.40 - 6.54 (m, 1 H), 4.05 - 4.40 (m, 3 H), 3.36 - 3.62 (m, 1 H), 1.30 (br s, 2 H), 1 .29 (s, 3 H), 1.10 (s, 7 H).

[1077] Example 67: Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl-d2)-5- (trifluoromethyl)pyrimidin-2-amine (ac2).

[1078] 159

[1079] SUBSTITUTE SHEET (RULE 26)

[1080] A solution of tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl-d2)morpholine-4-carboxylate (200 mg, 482.66 pmol, 1 eq) in HCI / dioxane (2 mL) was stirred at 25°C for 1 hr. LCMS showed the starting material consumed completely and desired mass was detected. The reaction mixture was neutralized with aq. Na2COs (5 mL) to pH 9 and extracted with Ethyl acetate (5mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl-d2)-5- (trifluoromethyl)pyrimidin-2-amine (500 mg, yield 76.36 %) as a yellow solid.

[1081] LCMS (ESI+): m / z =315.2 (M+1), RT: 0.349 min.

[1082] Similarly, the following compounds were prepared.

[1083] Example 68: N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl-d2)-5-

[1084] (trifluoromethyl)pyridin-2-amine (ad2)

[1085] The titled compound (ad2) was prepared in analogy to the procedure described for compound (ac2) using tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl-d2)morpholine-4-carboxylate (m2).

[1086] Yield 70%, white solid.

[1087] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 8.30 (s, 1 H), 7.62 (dd, 3=8.88, 2.38 Hz, 1 H), 7.19 (s, 1 H), 6.64 (d, 3=8.88 Hz, 1 H), 4.36 (qd, 3=6.75, 3.38 Hz, 1 H), 2.87 - 3.15 (m, 4 H), 1.22 (d, 3=6.63 Hz, 3 H).

[1088] Example 69: N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl-d2)-5-

[1089] (trifluoromethyl)pyrazin-2-amine hydrochloride (ab2)

[1090] 160

[1091] SUBSTITUTE SHEET (RULE 26)

[1092] The titled compound (ab2) was prepared in analogy to the procedure described for compound (ac2) using tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl-d2)morpholine-4-carboxylate (k2).

[1093] Yield 92%, yellow solid.

[1094] 1HNMR (400 MHz, DMSO-cfe): 6 ppm 8.44 (s, 1 H), 8.03 - 8.18 (m, 2 H), 4.62 (qd, J=6.61, 2.81 Hz, 1 H), 3.76 - 3.81 (m, 1 H), 3.73 (br s, 1 H), 3.66 - 3.71 (m, 1 H), 1 .37 (d, J=6.75 Hz, 3 H).

[1095] Example 70: 5-Chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl- d2)pyridin-2-amine hydrochloride (aa2)

[1096] The titled compound (aa2) was prepared in analogy to the procedure described for compound (ac2) using tert-Butyl (5R,6S)-5-(((5-chloropyridin-2-yl)amino)methyl-d2)-2,2-difluoro-6- methylmorpholine-4-carboxylate (n2).

[1097] Yield 94%, yellow solid.

[1098] 1HNMR (400 MHz, DMSO-cfe): 6 ppm 8.05 (d, J=2.50 Hz, 1 H), 7.58 (br d, J=9.01 Hz, 1 H), 6.69 (br d, J=9.01 Hz, 1 H), 4.58 - 4.69 (m, 1 H), 3.67 - 3.85 (m, 3 H), 1.37 (d, J=6.75 Hz, 3 H).

[1099] Example 71 : Synthesis of 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid

[1100] 161

[1101] SUBSTITUTE SHEET (RULE 26) To a solution of tert-butyl 4-iodo-1-methyl-1 H-pyrazole-3-carboxylate (1.5 g, 4.87 mmol, 1 eq) in THF (60 mL) and H2O (15 mL) was added (4-cyanophenyl)boronic acid (929.95 mg, 6.33 mmol, 1.3 eq), K3PO4 (3.10 g, 14.60 mmol, 3 eq) and Pd(dtbpf)Cl2 (158.65 mg, 243.42 pmol, 0.05 eq). The mixture was stirred at 80 °C for 2hr under N2. LC-MS showed the starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and the filter was concentrated to give the crude product. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=0 / 1 to 30 / 1) to give tert-butyl 4-(4-cyanophenyl)- 1 -methyl- 1 H-pyrazole-3-carboxylate (1.4 g, 4.94 mmol, 72.50% yield) as a brown solid.

[1102] LCMS (ESI+): m / z =284.5 (M+1), RT: 0.718 min.

[1103] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 8.09 (s, 1 H) 7.82 - 7.88 (m, 2 H) 7.57 - 7.63 (m, 2 H) 3.93 (s, 3 H) 1.41 (s, 9 H).

[1104] A solution of tert-butyl 4-(4-cyanophenyl)-1-methyl-1 H-pyrazole-3-carboxylate (1 g, 3.53 mmol, 1 eq) in HCI / dioxane (15 mL) was stirred at 50 °C for 2hr. LC-MS showed the starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and the filter cake was dried to give 4-(4-cyanophenyl)-1-methyl- 1 H-pyrazole-3-carboxylic acid (0.9 g, 3.96 mmol, 86.33% yield) as a brown solid.

[1105] LCMS (ESI+): m / z =228.1 (M+1), RT: 0.552 min.

[1106] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 12.76 (br s, 1 H) 8.13 (s, 1 H) 7.79 - 7.85 (m, 2 H) 7.64 - 7.71 (m, 2 H) 3.93 (s, 3 H).

[1107] Example 72: Synthesis of 4-(5-Cyanopyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid ,

[1108] To a solution of (3-(tert-butoxycarbonyl)-1-methyl-1 H-pyrazol-4-yl)boronic acid (500 mg, 2.21 mmol, 1 eq) in H2O (0.1 mL) and dioxane (0.5 mL) was added 6-bromopyridine-3-carbonitrile

[1109] 162

[1110] SUBSTITUTE SHEET (RULE 26) (485.78 mg, 2.65 mmol, 1.2 eq) and K3PO4 (1.41 g, 6.64 mmol, 3 eq) at 25°C. The mixture degassed and purged with N2 for 3 times. Then ditert-butyl(cyclopentyl)phosphane dichloropalladium iron (72.08 mg, 110.60 pmol, 0.05 eq) was added into the reaction mixture at 25°C. The mixture was degassed and purged with N2 for 3 times and stirred at 80°C for 2 hrs. LCMS showed all the starting materials were consumed, desired MS was detected. The reaction mixture was pour into H2O (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organics were washed brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=1 / 0 to 1 / 2) to give tert-butyl 4-(5-cyanopyridin-2-yl)- 1 -methyl- 1 H-pyrazole-3-carboxylate (520 mg, 82.68% yield) as a yellow solid.

[1111] 1H NMR: (400 MHz, CHLOROFORM-d): 5 ppm 8.82 (d, J=1.75 Hz, 1 H), 8.14 (d, J=8.38 Hz, 1 H), 7.89 - 8.06 (m, 2 H), 4.02 (s, 3 H), 1 .61 (s, 9 H).

[1112] A solution of tert-butyl 4-(5-cyanopyridin-2-yl)-1-methyl-1 H-pyrazole-3-carboxylate (520 mg, 1.83 mmol, 1 eq) in 4N / HCI dioxane (10 mL) was stirred at 20°C for 12 hrs. LCMS showed all the starting materials were consumed, desired MS was detected. The reaction mixture was filtered to afford filter cake and filter cake dried in vacuum to give 4-(5-cyanopyridin-2-yl)-1- methyl-1 H-pyrazole-3-carboxylic acid (470 mg, 97.09% yield, HCI) as a white solid.

[1113] 1H NMR: (400 MHz, DMSO-cfe): 6 ppm 9.04 (dd, J=2.13, 0.75 Hz, 1 H), 8.57 (s, 1 H), 8.39 (dd, J=8.44, 2.19 Hz, 1 H), 8.13 (dd, J=8.51 , 0.75 Hz, 1 H), 3.97 (s, 3 H).

[1114] Example 73: Synthesis of 1,5-Dimethyl-4-(pyrazin-2-yl)-1 H-pyrazole-3-carboxylic acid 80°C, 12 hrs

[1115] To a solution of (3-(tert-butoxycarbonyl)-1 ,5-dimethyl-1 H-pyrazol-4-yl)boronic acid (300 mg, 1.25 mmol, 1 eq) in DMF (4.5 mL) and H2O (0.9 mL) was added K2CO3 (259.08 mg, 1.87 mmol, 1.5 eq) and 2-chloropyrazine (214.69 mg, 1.87 mmol, 167.34 pL, 1.5 eq) at 20°C. The vessel was evacuated and backfilled with argon (this process was repeated three times), the palladium triphenylphosphane (23.04 mg, 62.48 pmol, 0.05 eq) was added into the mixture

[1116] 163

[1117] SUBSTITUTE SHEET (RULE 26) under argon, the vessel was evacuated and backfilled with argon (this process was repeated three times). The mixture was stirred at 80°C for 16 hours. LCMS showed all the starting materials were consumed; desired mass was detected. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was dissolved with ethyl acetate (10 mL) and filtered; the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 100%) to give tert-butyl 1 ,5-dimethyl- 4-(pyrazin-2-yl)-1 H-pyrazole-3-carboxylate (270 mg, 78.76% yield) as a yellow oil.

[1118] 1H NMR (400 MHz, CHLOROFORM-d): 6 ppm 8.71 (d, J=1.38 Hz, 1 H), 8.61 (dd, J=2.38, 1.63 Hz, 1 H), 8.47 (d, J=2.63 Hz, 1 H), 3.92 (s, 3 H), 2.33 (s, 3 H), 1.44 (s, 9 H).

[1119] A solution of tert-butyl 1 ,5-dimethyl-4-(pyrazin-2-yl)-1 H-pyrazole-3-carboxylate (270 mg, 984.26 pmol, 1 eq) in HCI / dioxane (4 N, 6 mL) was stirred at 20°C for 16 hours. LCMS showed all the starting materials were consumed; desired mass was detected. The reaction mixture was concentrated under reduced pressure to give 1 ,5-dimethyl-4-(pyrazin-2-yl)-1 H-pyrazole- 3-carboxylic acid (210 mg, 97.78% yield) as a white solid.

[1120] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 8.72 (d, J=1.00 Hz, 1 H), 8.66 (d, J=2.25 Hz, 1 H), 8.51 (d, J=2.50 Hz, 1 H), 3.87 (s, 3 H), 2.30 (s, 3 H).

[1121] Example 74: Synthesis of 4-(5-Fluoropyridin-3-yl)-1 ,5-dimethyl-1 H-pyrazole-3- carboxylic acid

[1122] To a solution of (3-(tert-butoxycarbonyl)-1 ,5-dimethyl-1 H-pyrazol-4-yl)boronic acid (300 mg, 1.25 mmol, 1 eq) in DMF (4.5 mL) and H2O (0.9 mL) was added K2CO3 (259.08 mg, 1.87 mmol, 1.5 eq) and 3-chloro-5-fluoro-pyridine (246.56 mg, 1.87 mmol, 1.5 eq) at 20°C. The vessel was evacuated and backfilled with argon (this process was repeated three times), the palladium triphenylphosphane (23.04 mg, 62.48 pmol, 0.05 eq) was added into the mixture under argon, the vessel was evacuated and backfilled with argon (this process was repeated three times). The mixture was stirred at 80°C for 16 hours. LCMS showed all the starting materials were consumed; desired mass was detected. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was

[1123] 164

[1124] SUBSTITUTE SHEET (RULE 26) dissolved with ethyl acetate (10 mL) and filtered; the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 100%) to give tert-butyl 4-(5- fluoropyridin-3-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylate (110 mg, 30.22% yield) as a yellow oil.

[1125] 1H NMR (400 MHz, CHLOROFORM-d): 5 ppm 8.44 (d, J=2.75 Hz, 1 H), 8.31 (t, J=1.44 Hz, 1 H), 7.32 - 7.44 (m, 1 H), 3.93 (s, 3 H), 2.22 (s, 3 H) 1.41 (s, 9 H).

[1126] A solution of tert-butyl 4-(5-fluoropyridin-3-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylate (110 mg, 377.59 pmol, 1 eq) in HCI / dioxane (4 N, 2.5 mL) was stirred at 20°C for 16 hours. LCMS showed all the starting material was consumed; desired MS was detected. The reaction mixture was concentrated under reduced pressure to give 4-(5-fluoropyridin-3-yl)-1 ,5- dimethyl-1 H-pyrazole-3-carboxylic acid (87 mg, 97.96% yield) as a white solid.

[1127] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 8.55 (d, J=2.75 Hz, 1 H), 8.38 (t, J=1.63 Hz, 1 H), 7.66 - 7.85 (m, 1 H), 3.87 (s, 3 H), 2.22 (s, 3 H).

[1128] Example 75: Synthesis of 4-(4-Fluoropyridin-3-yl)-1,5-dimethyl-1H-pyrazole-3- carboxylic acid

[1129] A mixture of (3-(tert-butoxycarbonyl)-1 ,5-dimethyl-1 H-pyrazol-4-yl)boronic acid (0.3 g, 1.25 mmol, 1 eq), 3-chloro-4-fluoro-pyridine (164.38 mg, 1.25 mmol, 1 eq), K3PO4 (530.53 mg, 2.50 mmol, 128.17 pL, 2 eq), [2-(2-aminophenyl)phenyl]-chloro-palladium dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane (98.32 mg, 124.97 pmol, 0.1 eq) in H2O (0.225 mL) and butan-1-ol (0.9 mL) was degassed and purged with argon for 3 times, and then the mixture was stirred at 100°C for 3 hours under argon atmosphere. LCMS showed the reaction was completed. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organics were washed brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether from 0% to 60% to give tert-butyl 4-(4-fluoropyridin-3-yl)-1 ,5- dimethyl-1 H-pyrazole-3-carboxylate (0.27 g, 74.16% yield) as a colorless oil.

[1130] 165

[1131] SUBSTITUTE SHEET (RULE 26)1H NMR (400 MHz, DMSO-d6): 6 ppm 8.58 (dd, J=8.00, 5.63 Hz, 1 H), 8.47 (d, J=10.13 Hz, 1 H), 7.40 (dd, J=9.94, 5.57 Hz, 1 H), 3.87 (s, 3 H), 2.16 (s, 3 H), 1.28 (s, 9 H).

[1132] A solution of tert-butyl 4-(4-fluoropyridin-3-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylate (0.27 g, 926.82 pmol, 1 eq) in HCI / dioxane (4 N, 3 mL) was stirred at 20 °C for 12 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give 4-(4-fluoropyridin-3-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid (0.21 g, 96.33% yield) as a white solid.

[1133] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.75 - 9.02 (m, 2 H), 7.93 (dd, J=8.69, 6.32 Hz, 1 H), 3.90 (s, 3 H), 2.22 (s, 3 H).

[1134] Example 76: Synthesis of 4-(4-Fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3- carboxylic acid 80°C, 16 hrs

[1135] To a solution of (3-(tert-butoxycarbonyl)-1 ,5-dimethyl-1 H-pyrazol-4-yl)boronic acid (300 mg, 1.25 mmol, 1 eq) in DMF (4.5 mL) and H2O (0.9 mL) was added K2CO3 (259.08 mg, 1.87 mmol, 1.5 eq) and 2-chloro-4-fluoro-pyridine (246.56 mg, 1.87 mmol, 1.5 eq) at 20°C. The vessel was evacuated and backfilled with argon (this process was repeated three times), the palladium triphenylphosphane (23.04 mg, 62.48 pmol, 0.05 eq) was added into the mixture under argon, the vessel was evacuated and backfilled with argon (this process was repeated three times). The mixture was stirred at 80°C for 16 hours. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was dissolved with ethyl acetate (10 mL) and filtered; the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 100%) to give tert-butyl 4-(4- fluoropyridin-2-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylate (90 mg, 24.72% yield) as a yellow oil.

[1136] 1H NMR (400 MHz, CHLOROFORM-d): 5 ppm 8.61 (dd, J=8.75, 5.75 Hz, 1 H), 7.19 (dd, J=10.01 , 2.25 Hz, 1 H), 6.98 (ddd, J=8.29, 5.72, 2.38 Hz, 1 H), 3.81 - 3.97 (m, 3 H), 2.32 (s, 3 H), 1.45 (s, 9 H).

[1137] 166

[1138] SUBSTITUTE SHEET (RULE 26) A solution of tert-butyl 4-(4-fluoropyridin-2-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylate (90 mg, 308.94|jmol, 1 eq) in HCI / dioxane (4 N, 2 mL) was stirred at 20°C for 16 hours. LCMS showed all the starting material was consumed; desired mass was detected. The reaction mixture was concentrated under reduced pressure to give 4-(4-fluoropyridin-2-yl)-1 ,5-dimethyl-1 H- pyrazole-3-carboxylic acid (70 mg, 96.33% yield) as a white solid.

[1139] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 8.86 (t, J=6.88 Hz, 1 H), 7.71 - 7.97 (m, 1 H), 7.61 - 7.69 (m, 1 H), 3.89 (s, 3 H), 2.34 (s, 3 H).

[1140] Example 77: Synthesis of 5-(5-Fluoropyrimidin-2-yl)-1-methyl-1H-imidazole-4- carboxylic acid

[1141] A suspension of methyl 5-bromo-1-methyl-1 H-imidazole-4-carboxylate (2 g, 9.13 mmol, 1 eq) in toluene (20 mL) at 20°C was degassed and purged with N2 for 3 times. Pd (PPhs)4 (1.06 g, 913.09 pmol, 0.1 eq) and trimethyl(trimethylstannyl)stannane (5.98 g, 18.26 mmol, 3.79 mL, 2 eq) was added into the reaction mixture at 20°C. The suspension was degassed and purged with N2 for 3 times, then the mixture was stirred at 120°C for 6 hrs under N2. LCMS showed all the starting materials were consumed, desired Ms was detected. The reaction mixture was concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (AI2O3, petroleum ether / ethyl acetate=1 / 0 to 0 / 1) to give methyl 1- methyl-5-(trimethylstannyl)-1 H-imidazole-4-carboxylate (1.7 g, yield 49.17%) as a yellow oil.

[1142] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 7.78 - 7.82 (m, 0.90 H) 3.71 (d, J=7.63 Hz, 6.10 H) 0.24 - 0.41 (m, 9.00 H).

[1143] To a solution of methyl 1-methyl-5-(trimethylstannyl)-1 H-imidazole-4-carboxylate (1 g, 2.64 mmol, 1 eq) in xylene (20 mL) was added 2-bromo-5-fluoro-pyrimidine (701.02 mg, 3.96 mmol, 1.5 eq) at 20°C. The suspension was degassed and purged with N2 for 3 times. Pd (PPhs)4 (305.15 mg, 264.07 pmol, 0.1 eq) was added into the reaction mixture at 20°C. The suspension was degassed and purged with N2 for 3 times. Then the mixture was stirred at

[1144] 167

[1145] SUBSTITUTE SHEET (RULE 26) 140°C for 16 hrs under N2. LCMS showed all the starting materials were consumed, desired Ms was detected. The residue was quenched with water (20 mL), and extracted with dichloromethane (5x30 mL). The combined organics were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=1 / 1 to 0 / 1). The crude methyl 5-(5-fluoropyrimidin-2-yl)-1-methyl-1 H- imidazole-4-carboxylate (600 mg, yield 67.33%) was obtained as a brown solid.

[1146] LCMS (ESI+): m / z =237.3 (M+1), RT: 0.186 min.

[1147] Methyl 5-(5-fluoropyrimidin-2-yl)-1-methyl-1 H-imidazole-4-carboxylate (600 mg, 1.78 mmol, 1 eq) was dissolved in 6N HCI (12 mL) at 20°C, then the mixture was stirred at 80°C for 2 hrs. LCMS showed all the starting materials were consumed, desired Ms was detected. The residue was quenched with water (10 mL), and extracted with ethyl acetate (3x30 mL). The aqueous phase were concentrated under reduced pressure to give the crude product. The crude product was directly used for the next step. The crude 5-(5-fluoropyrimidin-2-yl)-1- methyl-1 H-imidazole-4-carboxylic acid (400 mg, yield 69.58%) was obtained as a yellow solid, was used without further purification.

[1148] LCMS (ESI+): m / z =223.2 (M+1), RT: 0.255 min

[1149] Example 78: Synthesis of 5-(5-Methoxypyridin-2-yl)-1-methyl-1H-imidazole-4- carboxylic acid

[1150] To a solution of methyl 5-bromo-1-methyl-1 H-imidazole-4-carboxylate (500 mg, 2.28 mmol, 1 eq) in xylene (10 mL) was added Pd (PPhs)4 (263.78 mg, 228.27 pmol, 0.1 eq) at 20°C. The suspension was degassed and purged with N2 for 3 times. Tributyl-(5-methoxy-2- pyridyl)stannane (1.09 g, 2.74 mmol, 1.2 eq) was added into the reaction mixture at 20°C. The suspension was degassed and purged with N2 for 3 times. Then the mixture was stirred at 140°C for 16 hrs under N2. LCMS showed all the starting materials were consumed, desired Ms was detected. The residue was quenched with water (20 mL), and extracted with ethyl

[1151] 168

[1152] SUBSTITUTE SHEET (RULE 26) acetate (4x20 mL). The combined organics were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=1 / 4 to 0 / 1). Compound methyl methyl 5-(5-methoxypyridin-2-yl)- 1 -methyl- 1 H- imidazole-4-carboxylate (400 mg, yield 67.33%) was obtained as a light yellow solid.

[1153] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 8.40 (d, J=2.63 Hz, 0.95 H) 7.81 (s, 1.00 H) 7.63 (d, J=8.25 Hz, 1.05 H) 7.49 (dd, J=8.76, 3.10 Hz, 1.00 H) 3.90 (s, 3.00 H) 3.63 (s, 3 H) 3.56 (s, 3.00 H).

[1154] A solution of methyl 5-(5-methoxypyridin-2-yl)-1-methyl-1 H-imidazole-4-carboxylate (200 mg, 768.45 pmol, 1 eq in 6N HCI (4 mL) was stirred at 80°C for 24 hrs. LCMS showed all the starting materials were consumed, desired Ms was detected. The reaction mixture was concentrated under reduced pressure to give the crude 5-(5-methoxypyridin-2-yl)-1-methyl- 1 H-imidazole-4-carboxylic acid (220 mg, yield 95.54%) as a yellow solid. The crude product was directly used for the next step.

[1155] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 9.35 (s, 0.95 H) 8.48 (d, J=2.75 Hz, 0.95 H) 7.82 (d, J=8.75 Hz, 1.00 H) 7.62 (dd, J=8.76, 3.00 Hz, 1.15 H) 3.93 (s, 3.05 H) 3.74 (s, 3.00 H).

[1156] Example 79: Synthesis of 4-(5-Fluoropyridin-2-yl)-1,5-dimethyl-1 H-pyrazole-3- carboxylic acid

[1157] To a solution of 4-bromo-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid (10 g, 46.65 mmol, 1 eq in THF (50 mL) and t-BuOH (50 mL) was added DMAP (557.75 mg, 4.57 mmol, 0.1 eq) and tert-butoxycarbonyl tert-butyl carbonate (29.89 g, 136.96 mmol, 3 eq at 20°C, then the mixture was stirred at 20°C for 12 hours. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. Then the residue was diluted with water (300 mL) and extracted with dichloromethane (300 mL x 3). The combined organic layer was washed brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatograph

[1158] 169

[1159] SUBSTITUTE SHEET (RULE 26) on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 20%) to give tert-butyl 4- bromo-1 ,5-dimethyl-1 H-pyrazole-3-carboxylate (3.5 g, yield 27.86%) as a white solid.

[1160] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 3.84 (s, 3.00 H) 2.25 (s, 3.00 H) 1.51 (s, 9.00 H).

[1161] To a solution of tert-butyl 4-bromo-1 ,5-dimethyl-1 H-pyrazole-3-carboxylate (3.5 g, 12.72 mmol, 1 eq) and triisopropyl borate (3.59 g, 19.08 mmol, 4.39 mL, 1.5 eq) in THF (70 mL) was added n-BuLi (1.22 g, 19.08 mmol, 1.5 eq) dropwise at -78°C, then the mixture was stirred at -78°C for 1 hour. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was quenched by addition saturated ammonium chloride solution (50 mL) at 0°C, and then diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was triturated with petroleum ether: ethyl acetate (50 mL, 10:1) at 20°C for 30 minutes, the mixture was filtered and the filter cake was dried in high vacuum to give (3- (tert-butoxycarbonyl)-1 ,5-dimethyl-1 H-pyrazol-4-yl)boronic acid (2.52 g, yield 82.52%) as a white solid.

[1162] 1H NMR: (400 MHz, DMSO-cfe): 5 ppm 8.49 (s, 2.00 H) 3.79 (s, 3.00 H) 2.41 (s, 3.00 H) 1.53 (s, 9.00 H).

[1163] To a mixture of (3-(tert-butoxycarbonyl)-1 ,5-dimethyl-1 H-pyrazol-4-yl)boronic acid (2.5 g, 10.41 mmol, 1 eq) in DMF (37.5 mL) was added 2-bromo-5-fluoro-pyridine (2.75 g, 15.62 mmol, 1.5 eq) and then a solution of K2CO3 (2.16 g, 15.62 mmol, 1.5 eq) in H2O (7.5 mL) was added at 20°C. The vessel was evacuated and backfilled with argon (this process was repeated three times), the palladiumtriphenylphosphane (601.70 mg, 520.70 pmol, 0.05 eq) was added into the mixture under argon, the vessel was evacuated and backfilled with argon (this process was repeated three times), then the mixture was stirred at 80°C for 12 hours. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 20%) to give tert-butyl 4-(5-fluoropyridin-2-yl)-1 ,5-dimethyl-1 H- pyrazole-3-carboxylate (2.51 g, yield 82.73%) as a light-yellow solid.

[1164] LCMS (ESI+): m / z =292.0 (M+1), RT: 0.417 min.

[1165] 170

[1166] SUBSTITUTE SHEET (RULE 26) A solution of tert-butyl 4-(5-fluoropyridin-2-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylate (2.5 g, 8.58 mmol, 1 eq) in HCI / dioxane (4 M, 50 mL) was stirred at 20°C for 12 hours. LCMS showed all the starting materials were consumed; desired mass was detected. The reaction mixture was concentrated under reduced pressure to give 4-(5-fluoropyridin-2-yl)-1 ,5-dimethyl-1 H- pyrazole-3-carboxylic acid (2.3 g, yield 98.65%, HCI) as a white solid.

[1167] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 8.62 (d, J=2.88 Hz, 1.00 H) 7.79 (td, J=8.76, 3.00 Hz, 1.00 H) 7.58 (dd, J=8.82, 4.57 Hz, 1.00 H) 3.85 (s, 3.00 H) 2.27 (s, 3.00 H).

[1168] Example 80: Synthesis of 4-(5-Methoxypyridin-2-yl)-1,5-dimethyl-1 H-pyrazole-3- carboxylic acid 80 C, 12 hrs

[1169] To a solution of (3-(tert-butoxycarbonyl)-1 ,5-dimethyl-1 H-pyrazol-4-yl)boronic acid (1 g, 3.04 mmol, 1 eq) in DMF (7.2 mL) was added 2-bromo-5-methoxy-pyridine (571.75 mg, 3.04 mmol, 1 eq) and a solution of K2CO3 (630.42 mg, 4.56 mmol, 1.5 eq) in H2O (1.44 mL) at 20°C, the vessel was evacuated and backfilled with N2 (this process was repeated three times), then Pd(PPhs)4 (175.70 mg, 152.04 pmol, 0.05 eq) was added into the mixture under N2, the vessel was evacuated and backfilled with N2 (this process was repeated three times). Then the mixture was stirred at 80°C for 12 hours. LCMS showed the starting material was consumed and product with desired mass was detected. The reaction solution was poured into ice water (20 mL), extracted with ethyl acetate (3 x 30 mL), the combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give a residue. The residue was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 50%) to give tert-butyl 4-(5- methoxypyridin-2-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylate (0.5 g, 50.95% yield) as a white solid.

[1170] 1H NMR (400 MHz, DMSO-d6): 5 = 8.30 (d, J=2.88 Hz, 1 H) 7.41 (dd, J=8.63, 3.00 Hz, 1 H) 7.28 - 7.35 (m, 1 H) 3.84 (s, 3 H) 3.82 (s, 3 H) 2.73 (s, 3 H) 1.33 (s, 9 H).

[1171] 171

[1172] SUBSTITUTE SHEET (RULE 26) LCMS (ESI+): m / z =304.0 (M+1), RT: 0.312 min.

[1173] A solution of tert-butyl 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1 H-pyrazole-3-carboxylate (0.5 g, 1.55 mmol, 1 eq) in dioxane / HCI (4N) (10 mL) was stirred at 20°C for 12 hours. LCMS showed the starting material was consumed and product with desired mass was detected. The reaction mixture was filtered, and the filter cake was dried in high vacuum to give 4-(5- methoxypyridin-2-yl)-1,5-dimethyl-1 H-pyrazole-3-carboxylic acid (0.37 g, 76.79% yield) as a white solid.

[1174] 1H NMR (400 MHz, DMSO-d6): 5 = 8.62 (d, J=2.88 Hz, 1 H) 8.09 (dd, J=8.94, 2.81 Hz, 1 H) 7.87 (d, J=8.88 Hz, 1 H) 4.01 (s, 3 H) 3.90 (s, 3 H) 2.30 (s, 3 H).

[1175] LCMS (ESI+): m / z =248.2 (M+1), RT: 0.095 min.

[1176] Example 81 : 3-(5-Fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2- carboxylic acid

[1177] To a solution of 5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole-2-carboxylic acid (25 g, 164.31 mmol, 1 eq) in DCM (370 mL) was added Br2 (52.52 g, 328.62 mmol, 16.93 mL, 2 eq) dropwise at 0°C. Then the reaction mixture was stirred at 0°C for 2 hours. LCMS showed the starting material was consumed and product with desired mass was detected. The reaction mixture was quenched by addition saturated sodium thiosulfate aqueous solution (100 mL), the reaction solution was filtered, and the filter cake was dried over under high reduced pressure to give 3-bromo-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole-2-carboxylic acid (36.5 g, 95.18% yield) as a yellow solid.

[1178] 172

[1179] SUBSTITUTE SHEET (RULE 26)1H NMR (400 MHz, DMSO-cfe): 6 = 4.13 - 4.24 (m, 2 H), 2.82 (t, J=7.32 Hz, 2 H), 2.55 (dt, J=14.85, 7.52 Hz, 2 H).

[1180] To a solution of 3-bromo-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole-2-carboxylic acid (10 g, 42.85 mmol, 1 eq) in THF (200 mL) was added 2-tert-butyl-3-isopropyl-1 ,1-dimethyl-isourea (23.95 g, 128.55 mmol, 3 eq) at 0°C. The mixture was stirred at 20°C for 16 hours. TLC showed the starting material was consumed completely and new spot was observed. The reaction mixture was quenched by addition of saturated ammonium chloride aqueous solution (500 mL), extracted with ethyl acetate (2 x 300 mL), the combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give a residue. The residue was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 50%) to give tert-butyl 3-bromo-5,6-dihydro-4H- pyrrolo[1 ,2-b]pyrazole-2-carboxylate (10 g, 77.21% yield) as a white solid.

[1181] 1H NMR (400 MHz, DMSO-cfe): 5 = 4.18 (t, J=7.32 Hz, 2 H), 2.76 - 2.88 (m, 2 H), 2.52 - 2.59 (m, 2 H), 1.51 (s, 9 H).

[1182] To a solution of tert-butyl 3-bromo-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole-2-carboxylate (2.5 g, 8.27 mmol, 1 eq) in THF (40 mL) was added triisopropyl borate (2.33 g, 12.41 mmol, 2.85 mL, 1.5 eq) at 20°C. Then n-BuLi (2.5 M, 4.96 mL, 1.5 eq) was added into the mixture dropwise at -78°C and the mixture was stirred at -78°C for 2 hours. LCMS showed product with desired mass was detected. The reaction mixture was quenched by addition saturated ammonium chloride aqueous solution (100 mL) and then extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatograph on silica gel (eluted with methanol in ethyl acetate from 0% to 50%) to give (2- (tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazol-3-yl)boronic acid (0.9 g, 35.40% yield) as a white solid.

[1183] 1H NMR (400 MHz, DMSO-cfe): 5 = 4.08 - 4.15 (m, 2 H), 3.57 (s, 2 H), 2.82 - 2.96 (m, 2 H), 2.50 - 2.56 (m, 2 H), 1 .54 (s, 9 H).

[1184] To a solution of (2-(tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazol-3-yl)boronic acid (0.9 g, 2.93 mmol, 1 eq) in DMF (13.5 mL) was added 2-bromo-5-fluoro-pyrimidine (518.13 mg, 2.93 mmol, 1 eq) and a solution of K2COs (606.94 mg, 4.39 mmol, 1.5 eq) in H2O (3 mL) at 20°C, the vessel was evacuated and backfilled with N2 (this process was repeated three times), then Pd(PPhs)4 (53.97 mg, 146.39 pmol, 0.05 eq) was added into the mixture under N2, the vessel was evacuated and backfilled with N2 (this process was repeated three

[1185] 173

[1186] SUBSTITUTE SHEET (RULE 26) times). Then the mixture was stirred at 80°C for 12 hours. LCMS showed the starting material was consumed and product with desired mass was detected. The reaction solution was poured into ice water (50 mL), extracted with ethyl acetate (3 x 30 mL), the combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give a residue. The residue was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 30%) to give tert-butyl 3- (5-fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole-2-carboxylate (0.78 g, 73.54% yield) as a yellow solid.

[1187] 1H NMR (400 MHz, DMSO-cfe): 6 = 8.86 (s, 2 H), 4.14 (t, J=7.36 Hz, 2 H), 3.04 (t, J=7.36 Hz, 2 H,) 2.59 (quin, J=7.33 Hz, 2 H), 1.45 (s, 9 H).

[1188] A solution of tert-butyl 3-(5-fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole-2- carboxylate (0.78 g, 2.15 mmol, 1 eq) in 4N HCI / dioxane (16 mL) was stirred at 20°C for 1 hour. LCMS showed the starting material was consumed and product with desired mass was detected. The reaction solution was concentrated under reduced pressure to give 3-(5- fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole-2-carboxylic acid (0.45 g, 82.52% yield, 98% purity) as a white solid.

[1189] 1H NMR (400 MHz, DMSO-cfe): 5 = 14.44 - 15.49 (m, 1 H), 9.03 (s, 2 H), 4.22 (t, J=7.38 Hz, 2 H), 3.15 (br t, J=7.38 Hz, 2 H), 2.62 (br t, J=7.38 Hz, 2 H).

[1190] LCMS (ESI+): m / z =249.1 (M+1), RT: 0.322 min.

[1191] Example 82: 5,6-Dimethyl-3-(pyrimidin-2-yl)picolinic acid

[1192] 174

[1193] SUBSTITUTE SHEET (RULE 26) H2O (5 V) 20°C, 3 hrs

[1194] To a solution of 3-bromo-5,6-dimethylpyridin-2-amine (4.2 g, 20.89 mmol, 1 eq) in dioxane (85 mL) was added tributyl(pyrimidin-2-yl)stannane (9.25 g, 25.07 mmol, 1.2 eq) and CsF (6.35 g, 41.78 mmol, 2 eq), the mixture was degassed and purged with argon for 3 times, and then Cui (397.83 mg, 2.09 mmol, 0.1 eq) and palladiumtriphenylphosphane (770.17 mg, 2.09 mmol, 0.1 eq) was added to the mixture at 20°C, the mixture was degassed and purged with argon for 3 times. The mixture was stirred at 100°C for 16 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. The mixture was filtered, and then the filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 40%) to give 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-amine (3.6 g, 86.07% yield) as a yellow solid.

[1195] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.86 (d, J=4.88 Hz, 2 H), 8.37 (s, 1 H), 7.33 (t, J=4.88 Hz, 1 H), 2.30 (s, 3 H), 2.16 (s, 3 H).

[1196] To a solution of 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-amine (2 g, 9.99 mmol, 1 eq) in AcOH (20 mL) was added H2SO4 (3.2 mL) dropwise at 0°C. Then a solution of NaNO2 (1.38 g, 19.98 mmol, 2 eq) in H2O (10 mL) was added dropwise at 0°C. The mixture was stirred at 20°C for 2 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. 5,6-Dimethyl-3-(pyrimidin-2-yl)pyridin-2-ol (1.62 g, 80.60% yield) was obtained as a yellow solid.

[1197] 175

[1198] SUBSTITUTE SHEET (RULE 26)1H NMR (400 MHz, DMSO-cfe): 6 ppm 11.30 - 13.96 (m, 1 H), 8.89 (br d, J=3.01 Hz, 2 H), 7.83 - 8.46 (m, 1 H), 7.44 (br s, 1 H), 2.28 (br s, 3 H), 2.13 (br s, 3 H).

[1199] To a solution of 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-ol (1.4 g, 6.96 mmol, 1 eq) in DCM (28 mL) was added DIPEA (3.60 g, 27.83 mmol, 4.85 mL, 4 eq) at 20°C, then trifluoromethylsulfonyl trifluoromethanesulfonate (2.94 g, 10.44 mmol, 1.72 mL, 1.5 eq) was added dropwise at 0°C. The mixture was stirred at 30°C for 16 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (20 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 20%) to give residue. 5,6-Dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl trifluoromethanesulfonate (1.9 g, 81.94% yield) was obtained as a yellow solid.

[1200] 1H NMR (400 MHz, DMSO-cfe): 5 ppm 8.98 (d, J=4.88 Hz, 2 H), 8.48 (s, 1 H), 7.58 (t, J=4.88 Hz, 1 H), 2.50 (s, 3 H), 2.40 (s, 3 H).

[1201] To a solution of 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl trifluoromethanesulfonate in methanol (40 mL) was added Pd(dppf)Ch (417.13 mg, 570.08 pmol, 0.1 eq) and TEA (1.73 g, 17.10 mmol, 2.38 mL, 3 eq) at 20°C. The mixture was stirred at 70°C for 16 hrs under CO (50 psi). LCMS showed all the starting materials were consumed; desired mass was detected. The mixture reaction was filtered and then the filtrate was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 20%) to give methyl 5,6-dimethyl-3- (pyrimidin-2-yl)picolinate (500 mg, 36.05% yield) as a yellow solid.

[1202] 1H NMR (400 MHz, DMSO-cfe): 5 ppm 8.90 (d, J=4.88 Hz, 2 H), 8.29 (s, 1 H), 7.49 (t, J=4.94 Hz, 1 H), 3.72 (s, 3 H), 2.50 (s, 3 H), 2.37 (s, 3 H).

[1203] To a solution of methyl 5,6-dimethyl-3-(pyrimidin-2-yl)picolinate (100 mg, 411.08 pmol, 1 eq) in methanol (0.5 mL) and THF (0.5 mL) and H2O (0.5 mL) was added UOH.H2O (34.50 mg, 822.16 pmol, 2 eq) at 20°C. The mixture was stirred at 20°C for 3 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The phase layer was adjusted to pH=3 with 1 N HCI at 0°C, the mixture was diluted with water (10 mL) and extracted with

[1204] 176

[1205] SUBSTITUTE SHEET (RULE 26) dichloromethane / methanol (5:1 , 10 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid (90 mg, 95.51% yield) as a yellow solid.

[1206] 1H NMR (400 MHz, DMSO-cfe): 6 ppm 12.90 (br s, 1 H), 8.89 (d, J=4.88 Hz, 2 H), 8.18 (s, 1 H), 7.48 (t, J=4.88 Hz, 1 H), 2.51 (br s, 3 H), 2.37 (s, 3 H).

[1207] Example 83: 4,6-Dimethyl-3-(pyrimidin-2-yl)picolinic acid 60°C, 48 hrs

[1208] A mixture of 5-bromo-2,4-dimethylpyridine (1.00 g, 5.37 mmol, 1 eq), tributyl(pyrimidin-2- yl)stannane (2.38 g, 6.45 mmol, 1.2 eq), CsF (1.63 g, 10.75 mmol, 2 eq), Pd(PPhs)4 (621.11 mg, 537.49 pmol, 0.1 eq) and Cui (102.37 mg, 537.49 pmol, 0.1 eq) in dioxane (20 mL) was degassed and purged with argon for 3 times, and then the mixture was stirred at 100°C for 16 hours under argon atmosphere. LCMS showed the reaction was completed. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether from 0% to 60% to afford 2-(4,6-dimethylpyridin-3-yl)pyrimidine (0.5 g, 50.22% yield) as a white solid.

[1209] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.95 (d, J=4.88 Hz, 2 H), 8.84 (s, 1 H), 7.49 (t, J=4.88 Hz, 1 H), 7.23 (s, 1 H), 2.52 (s, 3 H), 2.49 (s, 3 H).

[1210] 177

[1211] SUBSTITUTE SHEET (RULE 26) To a solution of 2-(4,6-dimethylpyridin-3-yl)pyrimidine (0.5 g, 2.70 mmol, 1 eq) in DCM (10 mL) was added m-CPBA (822.05 mg, 4.05 mmol, 85% purity, 1.5 eq) in portions at 0°C. The mixture was stirred at 20°C for 2 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition Na2SOs (20 mL) at 0°C, and then adjusted to pH=8 with NaHCCh at 0°C, then diluted with DCM (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2,4-dimethyl-5-(pyrimidin-2-yl)pyridine 1-oxide (0.5 g, 92.05% yield) as a white solid.

[1212] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.97 (d, J=5.02 Hz, 2 H), 8.61 (s, 1 H), 7.55 (t, J=4.89 Hz, 1 H), 7.44 - 7.51 (m, 1 H), 2.50 (s, 3 H), 2.39 (s, 3 H).

[1213] To a solution of 2,4-dimethyl-5-(pyrimidin-2-yl)pyridine 1-oxide (0.5 g, 2.48 mmol, 1 eq) in DCM (10 mL) was added TMSCN (739.55 mg, 7.45 mmol, 932.60 pL, 3 eq), the mixture was stirred at 20°C for 1 hour, then N,N-dimethylcarbamoyl chloride (400.82 mg, 3.73 mmol, 341.99 pL, 1.5 eq) was added to the mixture, the mixture was stirred at 20°C for 16 hours. LCMS showed the reaction was completed. The reaction mixture was diluted with water (20 mL) and adjusted to pH=8 with aq. NaHCOs at 0°C, extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether from 0% to 30% to afford 4,6-dimethyl-3-(pyrimidin-2-yl)picolinonitrile (0.4 g, 76.57% yield) as a white solid.

[1214] 1H NMR (400 MHz, DMSO-d6): 5 ppm 9.06 (d, J=4.88 Hz, 2 H), 7.61 - 7.73 (m, 2 H), 2.56 (s, 3 H), 2.28 (s, 3 H).

[1215] To a solution of 4,6-dimethyl-3-(pyrimidin-2-yl)picolinonitrile (0.3 g, 1.43 mmol, 1 eq) in methanol (3 mL) and H2O (3 mL) was added NaOH (171.23 mg, 4.28 mmol, 3 eq), the mixture was stirred at 60°C for 48 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved with water (10 mL) and adjusted to pH=5 with 1 N HCI at 0°C, then the mixture was lyophilized to give 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid (0.8 g, 85.60% yield, 35% purity) as a white solid.

[1216] 1H NMR (400 MHz, DMSO-d6): 5 ppm 8.89 (d, J=5.00 Hz, 2 H), 7.49 (t, J=4.88 Hz, 1 H), 7.45 (s, 1 H), 2.54 (s, 3 H), 2.20 (s, 3 H).

[1217] 178

[1218] SUBSTITUTE SHEET (RULE 26) Example 84: 4-Chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid

[1219] To a solution of 3-bromo-6-methylpicolinic acid (5 g, 23.14 mmol, 1 eq) in MeOH (50 mL) was added H2SO4 (2.27 g, 23.14 mmol, 1.23 mL, 1 eq) at 20°C and stirred at 70°C for 16 hours. LCMS showed all the starting material was consumed and product with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layer was washed with saturated sodium chloride aqueous solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 3-bromo-6-methylpicolinate (5 g, 93.90% yield) as a yellow oil.

[1220] 1H NMR (400 MHz, CHLOROFORM-d): 5 ppm 7.84 (d, J=8.25 Hz, 1 H), 7.14 (d, J=8.25 Hz, 1 H), 3.99 (s, 3 H), 2.56 (s, 3 H).

[1221] To a solution of methyl 3-bromo-6-methylpicolinate (4 g, 17.39 mmol, 1 eq), tributyl(pyrimidin- 2-yl)stannane (7.70 g, 20.86 mmol, 1.2 eq) and cesium fluoride (5.28 g, 34.77 mmol, 2 eq) in dioxane (80 mL) was added iodocopper (331.13 mg, 1.74 mmol, 0.1 eq) and palladiumtriphenylphosphane (2.01 g, 1.74 mmol, 0.1 eq) at 20°C under N2. The mixture was stirred at 100°C for 16 hours. LCMS showed all the starting materials were consumed and product with desired mass was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude product which was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 50%) to

[1222] 179

[1223] SUBSTITUTE SHEET (RULE 26) give methyl 6-methyl-3-(pyrimidin-2-yl)picolinate (4.1 g, 51.43% yield, 50% purity) as a yellow oil.

[1224] 1H NMR (400 MHz, DMSO-d6): 5 = ppm 8.91 (d, J=4.75 Hz, 2 H), 8.49 (d, J=8.13 Hz, 1 H), 7.53 - 7.55 (m, 1 H), 7.50 (br t, J=4.82 Hz, 1 H), 3.75 (s, 3 H), 2.57 (s, 3 H).

[1225] To a solution of methyl 6-methyl-3-(pyrimidin-2-yl)picolinate (4.1 g, 8.94 mmol, 50% purity 1 eq) in DCM (40 mL) was added 3-chlorobenzenecarboperoxoic acid (3.63 g, 17.89 mmol, 85% purity, 2 eq) in portions at 0°C and stirred at 30°C for 16 hours. LCMS showed all the starting materials were consumed and product with desired mass was detected. The reaction mixture was quenched by addition saturated with sodium sulfite solution (50 mL) at 0°C and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatograph on silica gel (eluted with methanol in ethyl acetate ether from 0% to 10%) to give 2-(methoxycarbonyl)-6-methyl-3-(pyrimidin-2-yl)pyridine 1 -oxide (1.77 g, 80.71 % yield) as a yellow solid.

[1226] 1H NMR (400 MHz, DMSO-d6): 5 = ppm 8.94 (d, J=4.88 Hz, 2 H), 8.23 (d, J=8.26 Hz, 1 H), 7.75 (d, J=8.38 Hz, 1 H), 7.56 (t, J=4.88 Hz, 1 H), 3.88 (s, 3 H), 2.44 (s, 3 H).

[1227] A solution of 2-(methoxycarbonyl)-6-methyl-3-(pyrimidin-2-yl)pyridine 1-oxide (500 mg, 2.04 mmol, 1 eq) in POCL (5 mL) was stirred at 120°C for 2 hours. LCMS showed all the starting materials were consumed and product with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (10 mL) and adjusted to pH=8 at 0°C, then the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated ...

Claims

CLAIMS:

1. A compound of Formula I, or pharmaceutically acceptable salts and derivatives thereof,Formula I wherein:X and X’ is halogen such as fluorine;Het represents a heteroaromatic group selected from the group consisting of: pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof, wherein said heteroaromatic group is unsubstituted, mono-, or di-substituted, wherein the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (Ci-C4)-straight chain alkyl, unsubstituted (Ci-C4)-branched alkyl, unsubstituted, (Ci-C4)-alkoxy group, unsubstituted (C3-C8)-cycloalkyl, substituted (C1-C4)- straight chain alkyl, substituted (Ci-C4)-branched alkyl, substituted (Ci-C4)-alkoxy group, substituted (C3-C8)-cycloalkyl, cyano group and halogen; andR is selected from the group consisting of a five or a six membered aromatic group or heteroaromatic group, wherein the aromatic group or heteroaromatic group is either unsubstituted or is substituted with one or more substituents.

2. A compound according to claim 1 wherein the compound of Formula I is a 5R,6S- stereoisomer:SUBSTITUTE SHEET (RULE 26)3. A compound according to claim 1 wherein the compound of Formula I is a deuterated compound, in which one or more hydrogen atom is replaced with one or more deuterium, having the following structure:Formula l(D) wherein X, X’, Het and R are each independently as defined herein with respect to Formula I; andR6and R7are each independently hydrogen or deuterium.

4. A compound according to any one of the claims 1 to 3 wherein the substituent of the heteroaromatic group in Het is (Ci-C4)-fluoroalkyl, (C3-C8)-cycloalkyl, a cyano group, (C1-C4)- alkoxy or halogen; preferably the substituent of the heteroaromatic group in Het is Cl, F, CHF2, CF3, CH3, methoxy, nitrile or cyclopropyl.

5. A compound according to any one of the claims 1 to 4 wherein R comprises a five membered heteroaromatic group which is an unsubstituted pyrazole, an unsubstituted oxazole, an unsubstituted thiazole, an unsubstituted imidazole, a substituted pyrazole, a substituted oxazole, a substituted thiazole, a substituted imidazole or a derivative thereof; a six membered aromatic group which is unsubstituted aryl, or substituted aryl, or a derivative thereof; or a six membered heteroaromatic group which is an unsubstituted pyridine, an unsubstituted pyrimidine, an unsubstituted pyridazine, an unsubstituted pyrazine, a substituted pyridine, a substituted pyrimidine, a substituted pyridazine, a substituted pyrazine or a derivative thereof.

6. A compound according to any one of the claims 1 to 5 wherein R isSUBSTITUTE SHEET (RULE 26)wherein:R3and R4are each independently selected from the group consisting of: hydrogen, (C1-C10)- straight chain alkyl; (Ci-C )-branched alkyl; (Ci-Cw)-substituted or unsubstituted alkyl, optionally (Ci-C4)-straight chain alkyl; (Ci-C4)-branched alkyl; and (Ci-C4)-substituted or unsubstituted alkyl, deuterated (Ci-C4)-straight chain alkyl; deuterated (Ci-C4)-branched alkyl; R3and R4may form fused substituted or unsubstituted ring; preferably, R3and R4are each independently -CH3 or -CD3; andY represents an aromatic group or a heteroaromatic group; a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, wherein the Y is independently selected from the group consisting of: aryl, pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, nicotinonitrile, benzonitrile, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof, wherein the substituents are independently selected from the group consisting of: unsubstituted or substituted (Ci-C4)-alkyl group, unsubstituted or substituted (Ci-C4)-alkoxy group, a cyano group and halogen; preferably, the halogen is fluorine, bromine or chlorine.

7. A compound according to claim 6 wherein the aromatic group or heteroaromatic group of Y is substituted with CN, F, Cl, CH3 or -O-alkyl, wherein the alkyl group comprises 1-4 carbon atoms, preferably O-alkyl is -OCH3.

8. A compound according to claim 6 or 7 wherein Y is selected from the group consisting of:SUBSTITUTE SHEET (RULE 26)A compound according to any one of the claims 1 to 8 wherein R is selected from the group consisting of:284SUBSTITUTE SHEET (RULE 26)10. A compound according to any one of the claims 1 to 5 wherein R iswherein:R1and R2are each independently selected from the group consisting of: hydrogen, unsubstituted (Ci-Ce)-straight chain alkyl group; unsubstituted (Ci-Ce)-branched alkyl group; substituted (Ci-Ce)-straight chain alkyl group; substituted (Ci-Ce)-branched alkyl group;285SUBSTITUTE SHEET (RULE 26)deuterated (Ci-Ce)-straight chain alkyl, deuterated (Ci-Ce)-branched alkyl and halogen; preferably the halogen comprises fluorine, chlorine or bromine; preferably R1is a H, Cl, F, CHsor CD3; andHet’ is a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof, wherein said heteroaromatic group is unsubstituted, mono-, or di-substituted, wherein the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: (Ci-C4)-straight chain or branched alkyl, substituted straight chain or branched (C1-C4)- alkyl, and halogen; preferably the substituent is F, Cl or CH3.

11. A compound according to any one of the claims 1 to 5 and 10, wherein the Het’ is selected from:

12. A compound according to any one of the claims 1 to 5, and 10 and 11 wherein R is selected from the group consisting of:286SUBSTITUTE SHEET (RULE 26)13. A compound according to any preceding claim 1 to 12 wherein Het is selected from the group consisting of:287SUBSTITUTE SHEET (RULE 26)14. A compound having the structure of Formula l(a) - l(q):Formula 1(c) Formula 1(d)SUBSTITUTE SHEET (RULE 26)Formula l(k) Formula 1(1)289SUBSTITUTE SHEET (RULE 26)Formula l(m) Formula l(n)Formula l(q); wherein:R1, R2, R3, R4, R5, R6, R7, Het, Het’ and Y are each independently as defined in any preceding claims 1 to 13.

15. A compound according to any one of the claims 1 to 9, 13 and 14 wherein the compound is selected from the group consisting of:290SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)or Ipharmaceutically acceptable salts and derivatives thereof.

16. A compound according to any one of the claims 1 to 5 and 10 to 14 wherein the compound is selected from the group consisting of:SUBSTITUTE SHEET (RULE 26)SUBSTITUTE SHEET (RULE 26)or pharmaceutically acceptable salts and derivatives thereof.

17. A compound of Formula l-aa, or pharmaceutically acceptable salts and derivatives thereof,Formula l(aa); wherein:R6and R7are each independently H or deuterium;R8is CF3;W1is selected from -CH, N, or -C-O-CH3;W2is selected from -CH, N, -C-CH3; andR is selected from a five membered heteroaromatic group which comprises an unsubstituted pyrazole, an unsubstituted oxazole, an unsubstituted thiazole, an unsubstituted imidazole, a substituted pyrazole, a substituted oxazole, a substituted thiazole, a substituted imidazole or a derivative thereof; or a six membered heteroaromatic group which comprises an unsubstituted pyridine, an unsubstituted pyrimidine, an unsubstituted pyridazine, an unsubstituted pyrazine, a substituted pyridine, a substituted pyrimidine, a substituted pyridazine, a substituted pyrazine or a derivative thereof.

18. A compound according to claim 17 wherein R is selected fromwhereinR3and R4are each independently -CH3 or -CD3;SUBSTITUTE SHEET (RULE 26)19. A compound according to claim 17 or 18 wherein the compound of Formula l-aa is selected from:

20. A compound according to any preceding claim, wherein the pharmaceutically acceptable salt and derivative is selected from the group consisting of: hydrochlorides, chlorides, bromides, iodides, potassium salts, sodium salts, acetates, trifluoroacetates, sulfates, sulfonates, oxalates, maleates, malonates, nitrates, tartrates, gluconates,298SUBSTITUTE SHEET (RULE 26)succinates, mesylates, citrates, phosphates or diphosphates, aluminates, enantiomers, solvates, adducts, polymorphs, hydrates, tautomers, isomers, prodrugs, isotopically or radio- labelled derivatives, and mixtures thereof.

21. A compound according to any preceding claim, wherein the compound of Formula I and l(a-q) is deuterated, where at least one of the hydrogen is replaced with deuterium.

22. A pharmaceutical composition comprising (a) a compound according to any of claims 1 to 21 ; and (b) one or more pharmaceutically acceptable excipients, preferably the pharmaceutical composition is in the form of a tablet or a capsule.

23. A compound according to claims 1 to 21 or a pharmaceutical composition according to claim 22 for use as a medicament.

24. A method of treating or preventing a disease or disorder mediated by orexin receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound of any one of claims 1 to 21 or a pharmaceutical composition according to claim 22.

25. The method according to claim 24, wherein the disease or disorder is selected from the group consisting of: an eating disorder, obesity, binge eating disorder (BED), schizophrenia (negative symptoms and CIAS), addiction to psychomotor stimulants such as cocaine, opiates, nicotine and alcohol, opioid use disorder, opioid dependence, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, behavior disorder and mood disorder depression.

26. Use of a compound according to any of claims 1 to 21 or a pharmaceutical composition according to claim 22, in the preparation of a medicament for the treatment of diseases or disorders regulated by orexin receptor activity, and the use of such compounds for treatment or prevention of such diseases and disorders.

27. A method of modulating the activity of an orexin receptor 0X1 , 0X2, or both, comprising contacting a cell comprising the orexin receptor with an effective amount of at least one compound according to any one of claims 1 to 21 , or a pharmaceutical composition according to 22.299SUBSTITUTE SHEET (RULE 26)28. A method according to claim 27 wherein the step of contacting the cell is in vivo, in vitro or ex vivo.

29. A method for preparing a compound of Formula I according to claim 1wherein X, X’, R and Het are as defined in any preceding claim 1 to 21, said method comprising the steps of:(a) reacting tert-Butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate with a halo-substituted heteroaromatic compound in the pesence a base to form a first intermediate compound;(b) reacting the first intemediate compound with an acid to form a second intermediate compound; and(c) reacting the second intemediate compound with a carboxylic acid having a general formula R-COOH to obtain a compound of Formula I.

30. The method according to according to claim 29, wherein tert-Butyl (5R,6S)-5- (aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate is a deuterated compound, preferably the deuterated tert-Butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate is tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate-3,3-d2 (intermediate j1) or tert-butyl (5R,6S)-5- (aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2)31. The method according to according to claim 29 or 30 wherein the compound of Formula I is a deuterated compound having the following structures:Formula ID (b)300SUBSTITUTE SHEET (RULE 26)wherein, R and Het are each independently as defined in any preceding claim 1 to 21 ; and R6and R7are each independently H or Deuterium; said method comprising the steps of:(a) reacting tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate-3,3-d2 (intermediate j1) or tert-butyl (5R,6S)-5-(aminomethyl-d2)-2,2- difluoro-6-methylmorpholine-4-carboxylate (intermediate j2) with a halo-substituted heteroaromatic compound in the presence a base to form a first intermediate compound;(b) reacting the first intemediate compound with an acid to form a second intermediate compound; and(c) reacting the second intemediate compound with a carboxylic acid having a general formula R-COOH to obtain a compound of Formula ID(a) or ID(b) respectively.

32. The method according to any one of claim 29 - 31 wherein the halo-substituted heteroaromatic compound is selected from the group consisting of: halo-substituted pyridine, halo-substituted pyridazine, halo-substituted pyrazine, halo-substituted pyrimidine, halo- substituted triazole, halo-substituted tetrazole, halo-substituted pyrazole, halo-substituted furan, halo-substituted thiophene, halo-substituted pyrrole, halo-substituted imidazole, halo- substituted isoxazole, halo-substituted oxazole, halo-substituted isothiazole, halo-substituted thiazole and any derivatives thereof, wherein said halo-substituted heteroaromatic group may be further substituted; wherein the further substituents of the halo-substituted heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (Ci-C4)-straight chain alkyl, unsubstituted (Ci-C4)-branched alkyl, unsubstituted (Ci-C4)-alkoxy group, unsubstituted (C3-C8)-cycloalkyl, substituted (C1-C4)- straight chain alkyl, substituted (Ci-C4)-branched alkyl, substituted (Ci-C4)-alkoxy group, substituted (C3-C8)-cycloalkyl, a cyano group and halogen.

33. The method according to claim 32 wherein the further substituents of the heteroaromatic group is Cl, F, CHF2, CF3, CH3, methoxy, nitrile or cyclopropyl.

34. The method according to any preceding claim 29 to 33 wherein the halo-substituted heteroaromatic compound is selected from the group consisting of: a fluoro-substituted heteroaromatic compound, chloro-substituted heteroaromatic compound, bromo-substituted heteroaromatic compound and iodo-substituted heteroaromatic compound.301SUBSTITUTE SHEET (RULE 26)35. The method according to any preceding claim 29 to 34 wherein the halo-substituted heteroaromatic compound is selected from 2-chloro-5-(trifluoromethyl) pyrazine, 2-chloro-5- (trifluoromethyl)pyrimidine, 2-chloro-5-(trifluoromethyl)pyridine, 5-chloro-2-fluoro-pyridine, 5- chloro-2-fluoropyrimidine, 2-chloro-6-(trifluoromethyl)pyrazine, 2-fluoro-4-(trifluoromethyl)pyridine, 2,3-difluoro-5-(trifluoromethyl)pyridine, 3-bromo-2-fluoro-5- (trifluoromethyl)pyridine, 2-chloro-5-cyclopropylpyrimidine, 2-chloro-3-methoxy-5- (trifluoromethyl)pyridine, 3-methyl-5-(trifluoromethyl)pyrazin-2-ol, 2-chloro-5-(trifluoromethyl)nicotinonitrile, 5-chloro-2,3-difluoropyridine, 2,4-dichloro-5-(trifluoromethyl)pyrimidine, 2-chloro-5-(difluoromethyl)pyrazine or 2-chloro-5-(difluoromethyl), 5-chloro-2-fluoropyridine, 2-fluoro-5-(trifluoromethyl)pyridine, 2-chloro-5-(trifluoromethyl)pyrimidine, 2-chloro-5-(trifluoromethyl)pyrazine.

36. The method according to any preceding claim 29 to 35 wherein the base is potassium carbonate.

37. The method according to any preceding claim 29 to 36 wherein the step (a) is carried out in the presence of a solvent, preferably the solvent is a polar aprotic solvent selected from the group consisting of: THF, DMF, DMSO and mixtures thereof, more preferably the solvent is DMSO.

38. The method according to any preceding claim 29 to 37 wherein the method further comprises at least one of the following features: wherein the step (a) is carried out at a temperature in the range of about 50°C to about 189°C, preferably at a temperature about 80°C; wherein the step (a) is carried out for a duration of about 6 to about 18 hours, preferably for a duration of about 12 hours.

39. The method according to any preceding claim 29 to 38 wherein the acid is selected from the group consisting of: aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid and mixture thereof, preferably the acid is hydrochloric acid.

40. The method according to any preceding claim 29 to 39 wherein the step (b) is carried out in the presence of a non-polar solvent selected from the group consisting of: diethyl ether, benzene, toluene, chloroform, 1,4-dioxane or mixtures thereof, preferably the nonpolar solvent is 1 ,4-dioxane.302SUBSTITUTE SHEET (RULE 26)41. The method according to any preceding claim 29 to 40 wherein the method further comprises at least one of the following features: wherein the step (b) is carried out at a temperature in the range of about 12°C to about 40°C, preferably at about 20°C. wherein the step (b) is carried out for a duration of about 30 mins to about 5 hours, preferably for a duration of about 2 hours.

42. The method according to any preceding claim 29 to 41 wherein R in R-COOH group is selected from the group consisting of: a five or a six membered aromatic or heteroaromatic group, wherein the aromatic group or heteroaromatic group is either unsubstituted or is substituted with one or more substituents, preferably, R comprises a five membered heteroaromatic group which is an unsubstituted pyrazole, oxazole, thiazole, imidazole, a substituted pyrazole oxazole, thiazole, imidazole or a derivative thereof; a six membered aromatic group which is unsubstituted aryl, or substituted aryl, or a derivative thereof; or a six membered heteroaromatic group which is an unsubstituted pyridine, an unsubstituted pyrimidine, an unsubstituted pyridazine, an unsubstituted pyrazine, a substituted pyridine, a substituted pyrimidine, a substituted pyridazine, a substituted pyrazine or a derivative thereof; optionally at least one of the hydrogen in R is replaced with deuterium.

43. The method according to any preceding claim 29 to 42 wherein the carboxylic acid R-COOH is selected from the group consisting of: 4-(4-chlorophenyl)-1-methyl-pyrazole-3- carboxylic acid, 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid, 3-fluoro-2-(pyrimidin-2- yl)benzoic acid, 4-(5-chloropyridin-2-yl)-1-methyl-1 H-pyrazole-3-carboxylic acid, 4-(5- fluoropyrimidin-2-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid, 5-methyl-2-(pyrimidin-2- yl)benzoic acid, 5-methyl-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid, 5-chloro-2-(2-methyl-2H- tetrazol-5-yl)benzoic acid, 4-(5-fluoropyrimidin-2-yl)-1-methyl-1 H-pyrazole-3-carboxylic acid,1-methyl-4-(pyrimidin-2-yl)-1 H-pyrazole-3-carboxylic acid, 4-(5-methoxypyridin-2-yl)-1- methyl-1 H-pyrazole-3-carboxylic acid, 4-(5-fluoropyridin-2-yl)-1-methyl-1 H-pyrazole-3- carboxylic acid, 4-(4-fluorophenyl)-1-methyl-1 H-pyrazole-3-carboxylic acid, 4-(4- cyanophenyl)-1-methyl-1 H-pyrazole-3-carboxylic acid, 4-(5-cyanopyridin-2-yl)-1-methyl-1 H- pyrazole-3-carboxylic acid, 5-(5-fluoropyrimidin-2-yl)-1-methyl-1 H-imidazole-4-carboxylic acid, 5-(5-methoxypyridin-2-yl)-1-methyl-1 H-imidazole-4-carboxylic acid, 4-(5-fluoropyridin-2- yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid, 2-methyl-5-(pyridin-2-yl)thiazole-4-carboxylic acid, 2-methyl-5-(pyrimidin-2-yl)thiazole-4-carboxylic acid, 2-methyl-5-(pyridin-2-yl)oxazole- 4-carboxylic acid, 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid, 5-fluoro-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid, 4-(5-methoxypyridin-2-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid, or303SUBSTITUTE SHEET (RULE 26)6-methyl-3-(pyrimidin-2-yl)picolinic acid; 3-(5-fluoropyrimidin-2-yl)-5,6-dihydro-4H- pyrrolo[1 ,2-b]pyrazole-2-carboxylic acid, 5,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid, 4,6- dimethyl-3-(pyrimidin-2-yl)picolinic acid, 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acidl- methyl-4-(pyridin-2-yl)-1 / 7-pyrazole-3-carboxylic acid , 2-(2H-1 ,2,3-triazol-2-yl)benzoic acid; 1 ,5-dimethyl-4-(pyrazin-2-yl)-1 H-pyrazole-3-carboxylic acid 4-(5-fluoropyridin-3-yl)-1 ,5- dimethyl-1 H-pyrazole-carboxylic acid, 4-(4-fluoropyridin-3-yl)-1 ,5-dimethyl-1 H-pyrazole-3- carboxylic acid, and 4-(4-fluoropyridin-2-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid.

44. The method according to any preceding claim 30 or 31 wherein the carboxylic acids comprises 4-(5-Fluoropyrimidin-2-yl)-1-methyl-5-(methyl-d3)-1 H-pyrazole-3-carboxylic acid, 4-(5-Fluoropyrimidin-2-yl)-5-methyl-1-(methyl-d3)-1 H-pyrazole-3-carboxylic acid, 4-(5- Fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1 H-pyrazole-3-carboxylic acid, 6-(Methyl-d3)-3- (pyrimidin-2-yl)picolinic acid, or 6-(Methyl-d3)-3-(2H-1 ,2,3-triazol-2-yl)picolinic acid hydrochloride.

45. The method according to any preceding claim 29 to 44 wherein the method further comprises at least one of the following features: wherein the step (c) is carried out in the presence of a coupling reagent, preferably the coupling reagent is HATU; wherein the step (c) is carried out in the presence of a base, preferably the base is DIPEA; wherein the step (c) is carried out in the presence of a polar aprotic solvent selected from the group consisting of THF, dichloromethane, ethyl acetate, DMF, DMSO and combinations thereof, preferably polar aprotic solvent is dichloromethane.

46. The method according to any preceding claim 29 to 45 wherein the method further comprises at least one of the following features: wherein the step (c) is carried out at a temperature in the range of about -10°C to about 40°C, preferably in the range of about 0°C to about 20°C; wherein the step (c) is carried out for a duration of about 1 hours to about 6 hours, preferably for a duration of about 2.5 hours.

47. The method according to any preceding claim 29, 32 to 46 wherein the first intermediate compound is: tert-Butyl (5F?,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl) morpholine-4-carboxylate;304SUBSTITUTE SHEET (RULE 26)tert-Butyl (5 / ?,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl) morpholine-4-carboxylate; tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl) morpholine-4-carboxylate; tert-Butyl (5R,6S)-5-(((5-chloropyridin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate; tert-Butyl (5R,6S)-5-(((5-chloropyrimidin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine- 4-carboxylate; tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylate; tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((6-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate; tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylate; tert-Butyl (5R,6S)-2,2-difluoro-5-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-6- methylmorpholine-4-carboxylate; tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl--(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylate; tert-Butyl (5R,6S)-5-(((5-cyclopropylpyrimidin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate; tert-Butyl (5R,6S)-2,2-difluoro-5-(((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-6- methylmorpholine-4-carboxylate; tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate; tert-Butyl (5R,6S)-5-(((3-cyano-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate; tert-Butyl (5R,6S)-5-(((5-chloro-3-fluoropyridin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate; tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((4-methyl-5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylate; tert-butyl (5R,6S)-5-(((5-(difluoromethyl)pyrimidin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate; or tert-butyl (5R,6S)-5-(((5-(difluoromethyl)pyrazin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate48. The method according to any preceding claim 29, 32 to 46 wherein the second intermediate compound is:305SUBSTITUTE SHEET (RULE 26)5-Chloro- / V-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)pyridin-2-amine hydrochloride; / V-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride;N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride; / V-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride;5-Chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)pyrimidin-2-amine hydrochloride;N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-4-(trifluoromethyl)pyrimidin-2-amine hydrochloride;N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-6-(trifluoromethyl)pyrazin-2-amine hydrochloride; orN-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-4-(trifluoromethyl)pyridin-2-amine hydrochloride;N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-3-fluoro-5-(trifluoromethyl)pyridin-2- amine hydrochloride ;N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyridin-2-amine;5-Cyclopropyl-N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)pyrimidin-2-amine hydrochloride;N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-3-methoxy-5-(trifluoromethyl) pyridin-2-amine;N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyrazin-2-amine hydrochloride;2-((((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)amino)-5-(trifluoromethyl)nicotino nitrile hydrochloride;5-Chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3-fluoropyridin-2-amine hydrochloride;N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl)-4-methyl-5-(trifluoromethyl) pyrimidin-2-amine;N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-5-(difluoromethyl)pyrimidin-2-amine hydrochloride; orN-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-5-(difluoromethyl)pyrazin-2-amine hydrochloride.306SUBSTITUTE SHEET (RULE 26)49. The method according to any preceding claim 30 to 46 wherein the first intermediate compound is: tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl) morpholine-4-carboxylate-3,3-d2; tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl) morpholine-4-carboxylate-3,3-d2; tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl) morpholine-4-carboxylate-3,3-d2; tert-Butyl (5R,6S)-5-(((5-chloropyridin-2-yl)amino)methyl-d2)-2,2-difluoro-6- methylmorpholine-4-carboxylate; tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2-yl)amino) methyl- d2)morpholine-4-carboxylate;(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl- d2)morpholine-4-carboxylate; or tert-Butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2-yl)amino) methyl- d2)morpholine-4-carboxylate.

50. The method according to any preceding claim 30 to 46 wherein the second intermediate compound is:N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl) pyrazineamine hydrochloride;N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl) pyrimidin- 2-amine hydrochloride;N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl )pyridin-2- amine hydrochloride;5-Chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl-d2)pyridin-2-amine hydrochloride;N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl )pyrazin-2- amine hydrochloride;N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl) pyrimidineamine; or N-(((2S,3R)-6,6-Difluoro-2-methylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl)pyridin-2- amine.307SUBSTITUTE SHEET (RULE 26)51. The method according to claim 29, wherein tert-Butyl (5R,6S)-5-(aminomethyl)-2,2- difluoro-6-methylmorpholine-4-carboxylate is prepared by: reducing N-benzyl-L-allothreonine (a) by reacting with a reducing agent to form 2R,3S)-2-(Benzylamino)butane-1,3-diol (intermediate b); reacting intermediate (b) with tert-butyl(chloro)diphenylsilane to form (2S,3R)-3- (Benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (intermediate c); reacting intermediate (c) with 2-bromo-2,2-difluoro-acetic acid or 2,2-difluoro-2- iodoacetic acid in the presence of a lewis base to form 2-(((2S,3R)-3-(Benzylamino)-4-((tert- butyldiphenylsilyl)oxy)butan-2-yl)oxy)-2,2-difluoroacetic acid (intermediate d); subjecting intermediate (d) to an intramolecular amide coupling reaction in the presence of a coupling reagent to form (5R,6S)-4-Benzyl-5-(((tert- butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholin-3-one (intermediate e); reacting intermediate (e) with a reducing agent to form (5R,6S)-4-Benzyl-5-(((tert- butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine (intermediate f); reacting intermediate (f) with a source of fluorine to form ((2S,3R)-4-Benzyl-6,6- difluoro-2-methylmorpholin-3-yl)methanol (intermediate g); reacting intermediate (g) with hydrogen and palladium over carbon and di-tert-butyl dicarbonate to form tert-Butyl (5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4- carboxylate (intermediate h); reacting intermediate (h) with isoindoline-1 , 3-dione to form tert-Butyl (5R,6S)-5-((1 ,3- dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate i); and reacting intermediate (i) with hydrazine or hydrazine hydrate to form tert-Butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j).

52. The method according to claim 30 or 31, wherein tert-butyl (5R,6S)-5-(aminomethyl)-2,2- difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (intermediate j1) is prepared by: reducing (5R,6S)-4-Benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6- methylmorpholin-3-one (intermediate e) with a deuterated reagent to form (5R,6S)-4-benzyl- 5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methyl morpholine-3,3-d2 (intermediate fl); reacting intermediate (f1) with a source of fluorine to ((2S,3R)-4-benzyl-6,6-difluoro- 2-methylmorpholin-3-yl-5,5-d2)methanol (intermediate g1);308SUBSTITUTE SHEET (RULE 26)13 AUG 2024 (13.08.2024) reacting intermediate (g1) with hydrogen and palladium over carbon and di-tert-butyl dicarbonate to form tert-butyl (5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4- carboxylate-3,3-d2 (intermediate hi); reacting intermediate (hi) with isoindoline-1 , 3-dione to form tert-butyl (5R,6S)-5- ((1 ,3-dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (intermediate i1); and reacting intermediate (i1) with hydrazine or hydrazine hydrate to form tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (intermediate j1).

53. The method according to claim 30 or 31 , wherein tert-butyl (5R,6S)-5-(aminomethyl-d2)- 2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2) is prepared by: reacting N-benzyl-L-allothreonine (a) with 2-bromo-2,2-difluoro-acetyl) oxysodium, followed by reacting with a suitable acid to form (2S,3S)-4-benzyl-6,6-difluoro-2-methyl-5- oxomorpholine-3-carboxylic acid (intermediate e2’); reducing intermediate e2’ with a deuterated reagent to form 5R,6S)-4-benzyl-2,2- difluoro-5-(hydroxymethyl-d2)-6-methylmorpholin-3-one (intermediate e2”); reducing intermediate (e2”) with a reducing agent to form ((2S,3R)-4-benzyl-6,6- difluoro-2-methylmorpholin-3-yl)methan-d2-ol (intermediate g2); reacting intermediate (g2) with hydrogen and palladium over carbon and di-tert-butyl dicarbonate to form tert-butyl (2S,3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3-methylpiperidine- 1 -carboxylate (intermediate h2); reacting intermediate (h2) with isoindoline-1 , 3-dione to form tert-butyl (5R,6S)-5- ((1 ,3-dioxoisoindolin-2-yl)methyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate i2); and reacting intermediate (i2) with hydrazine or hydrazine hydrate to form tert-butyl (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2).

54. A compound which is:2R,3S)-2-(Benzylamino)butane-1,3-diol (intermediate b);(2S, 3R)-3-(Benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (intermediate c);2-(((2S,3R)-3-(Benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)oxy)-2,2- difluoroacetic acid (intermediate d);(5R,6S)-4-Benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6- methylmorpholin-3-one (intermediate e);309SUBSTITUTE SHEET (RULE 26)5R, 6S)-4-Benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6- methylmorpholine (intermediate f);((2S, 3R)-4-Benzyl-6,6-difluoro-2-methylmorpholin-3-yl)methanol (intermediate g); tert-Butyl(5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylate (intermediate h); tert-Butyl(5R,6S)-5-((1,3-dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate (intermediate i); tert-Butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j); 5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6- methylmorpholine-3,3-d2 (intermediate f1);((2S, 3R)-4-benzyl-6,6-difluoro-2-methylmorpholin-3-yl-5,5-d2)methanol(intermediate g1); tert-butyl (5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylate- 3,3-d2 (intermediate hi); tert-butyl (5R,6S)-5-((1,3-dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6-methyl morpholine-4-carboxylate-3,3-d2 (intermediate i1); tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate- 3,3-d2 (intermediate j1);(2S, 3S)-4-benzyl-6,6-difluoro-2-methyl-5-oxomorpholine-3-carboxylic acid (intermediate e2’); 5R,6S)-4-benzyl-2,2-difluoro-5-(hydroxymethyl-d2)-6-methylmorpholin-3-one (intermediate e2”);((2S, 3R)-4-benzyl-6,6-difluoro-2-methylmorpholin-3-yl)methan-d2-ol (intermediate g2); tert-butyl (2S, 3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3-methylpiperidine-1 -carboxylate (intermediate h2); tert-butyl (5R,6S)-5-((1 ,3-dioxoisoindolin-2-yl)methyl-d2)-2,2-difluoro-6- methylmorpholine-4-carboxylate (intermediate i2); or tert-butyl (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2).310SUBSTITUTE SHEET (RULE 26)

Images