Morphorexin receptor antagonists

Abstract

The present invention relates to compounds of formula (I) as orexin antagonists or pharmaceutically acceptable salts, solvates, adducts, polymorphs and isomers thereof, compositions, and methods of using orexin antagonists to treat or prevent diseases or conditions mediated by orexin receptor activity.

Description

[0001] TECHNICAL FIELD The present invention relates to compounds, pharmaceutically acceptable salts and derivatives thereof, which are useful as orexin antagonists; pharmaceutical compositions comprising such compounds, salts or derivatives; and methods of using such compounds to treat or prevent diseases or disorders 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), psychomotor stimulant (such as cocaine, opioids, nicotine and alcohol) addiction, opioid use disorder, drug abuse or addiction, sleep disorders, cognitive dysfunction in psychiatric or neurological diseases, depression, anxiety, panic disorder, post-traumatic stress disorder, conduct disorder and mood disorder depression. BACKGROUND Orexins are a family of homologous peptides that include both orexin A (OR-A) and orexin B (OR-B). Orexins (also known as hypothalamic secretagogues) are neuropeptides secreted by a population of neurons located in the lateral hypothalamic area (LHA), which includes the lateral hypothalamus and the perifornical-periventricular region. Both orexin A (OR-A) and orexin B (OR-B) are synthesized from a precursor protein, prepro-orexin. OR-A is a 33-amino acid long peptide that contains two intra-chain disulfide bonds, and OR-B is a linear 28-amino acid long peptide. The orexin peptides bind to at least two different G protein-coupled receptors, known as the OX1 and OX2 receptors (OX1R or OX2R). The OX1 receptor is selective for OR-A, with an affinity that is about 100 times greater than for OR-B, while the OX2 receptor can bind both OR-A and OR-B with similar affinities.

[0003] Orexins have been found to stimulate food intake, modulate sleep and wakefulness, and can be involved in the neural mechanisms of drug abuse and addiction. The neural pathways and receptors involved in these processes by orexins appear to overlap, in part, and to be independent, in part. For example, the wakefulness-promoting function of orexins is found to be mediated primarily through the OX2 receptor, while the role of orexins in modulating reward and feeding is mediated primarily by the OX1 receptor.

[0004] Orexin receptors are ideal targets for the development of drug candidates to treat 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 promote sleep by blocking the binding of orexin to its receptors, thereby inhibiting orexin signaling. The development of orexin receptor antagonists has primarily focused on OX2 receptor antagonists for modulating wakefulness and vigilance. However, the development of OX1 receptor antagonists has also received attention, which are expected to be useful in the treatment of substance addiction, obesity, and other metabolic disorders.

[0005] Patent application WO2020247447A1 relates to substituted pyrazole and imidazole derivative compounds having orexin receptor antagonistic activity, which are useful in the treatment or prevention of neurological and psychiatric diseases and disorders in which the orexin receptor is involved or implicated. The patent also relates to pharmaceutical compositions comprising these compounds, as well as the use of these compounds and compositions for the prevention or treatment of diseases in which the orexin receptor is involved.

[0006] Patent application WO2017139603A1 relates to halogenated substituted piperidine compounds, pharmaceutical compositions comprising the same, and methods of use thereof, including methods for treating substance addiction, panic disorder, anxiety, post-traumatic stress disorder, pain, depression, seasonal affective disorder, an eating disorder, or hypertension.

[0007] Patent application WO2002090355A1 relates to N-acyl cyclic amine derivatives as orexin receptor antagonists, and their use in the treatment of obesity (including obesity in patients with type 2 (non-insulin dependent) diabetes mellitus) and / or sleep disorders, stroke (particularly ischaemic or haemorrhagic stroke), and / or inhibition of emetic responses (i.e. for the treatment of nausea and vomiting).

[0008] Patent application WO2020247445A1 relates to substituted imidazo[2,1-b]oxazole, imidazo[2,1-b]thiazole, imidazo[2,1-b]oxazole, imidazo[2,1-b]oxadiazole derivatives as orexin receptor antagonists, which are useful in the treatment or prevention of neurological and psychiatric diseases and disorders.

[0009] Patent application WO2013068935A1 relates to derivatives of 2-(1,2,3-triazol-2-yl)benzamides and 3-(1,2,3-triazol-2-yl)picolinamides, 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 for OX1R over OX2R, and exhibited poor metabolic stability.

[0010] However, there is still a need to develop new and potent OX1 receptor selective antagonists for the treatment of diseases or disorders mediated by orexin receptor activity, such as central nervous system (CNS) diseases, nervous system diseases, eating disorders, sleep disorders, and substance addiction. Furthermore, there is a need to develop drugs with improved brain penetration for the treatment of diseases or disorders mediated by orexin receptor activity, such as central nervous system (CNS) diseases, nervous system diseases, or eating disorders, sleep disorders, and substance addiction. SUMMARY The present invention provides novel compounds or pharmaceutically acceptable salts and derivatives thereof, compositions, and uses of the compounds in the treatment or prevention of diseases or disorders mediated by orexin receptor activity. The present invention provides novel OX1 receptor antagonists with good selectivity and binding properties, high potency, good brain penetration, improved pharmacokinetic properties, biological activity, improved solubility, good metabolic stability, and chemical stability. Pharmaceutically acceptable salts and derivatives of the compounds of the present invention include, but are not limited to, hydrochloride, chloride, bromide, iodide, potassium salt, sodium salt, acetate, sulfate, sulfonate, oxalate, maleate, malonate, nitrate, tartrate, gluconate, succinate, mesylate, citrate, phosphate, diphosphate, aluminate, enantiomers, solvates, adducts, polymorphs, hydrates, tautomers, prodrugs, isotopes, or radiolabeled derivatives or isomers.

[0012] According to one aspect of the present invention, there is provided a compound or pharmaceutically acceptable salts and derivatives thereof, wherein the compound has the structure of Formula I: Formula I wherein: X and X' are halogen, preferably X and X' are fluorine; Het represents a heteroaryl 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 the heteroaryl is unsubstituted, mono-substituted or di-substituted, wherein the substituents of the heteroaryl, if present, are independently selected from the group consisting of unsubstituted (Ci-C4)-straight chain alkyl, unsubstituted (Ci-C4)-branched chain alkyl, substituted (Ci-C4)-straight chain alkyl, substituted (Ci-C4)-branched chain alkyl, alkoxy, C3-C8)-cycloalkyl, cyano, and halogen. Preferably, the substituents of the heteroaryl in Het include alkyl, fluoroalkyl, alkoxy, cycloalkyl, cyano, or halogen. More preferably, the substituents of the heteroaryl in Het are F, CI, CHF2, CF3, methyl, methoxy, nitrile, or cyclopropyl.

[0013] R is selected from a five- or six-membered aryl or heteroaryl group, wherein the aryl or heteroaryl group is unsubstituted or substituted with one or more substituents.

[0014] Preferably, R in the compound of formula I includes: a five-membered heteroaryl group that is unsubstituted pyrazole, unsubstituted oxazole, unsubstituted thiazole, unsubstituted imidazole, substituted pyrazole, substituted oxazole, substituted thiazole, substituted imidazole, or derivatives thereof; a six-membered aryl group that is unsubstituted aryl or substituted aryl, or derivatives thereof; or a six-membered heteroaryl group that is unsubstituted pyridine, unsubstituted pyrimidine, unsubstituted pyridazine, unsubstituted pyrazine, substituted pyridine, substituted pyrimidine, substituted pyridazine, substituted pyrazine, or derivatives thereof.

[0015] According to another aspect of the present application, the compound of formula I is the 5R, 6S-stereoisomer: .

[0016] Preferably, the compound of formula I is a deuterated form. In particular, in certain instances, one or more hydrogen atoms in the compound of formula I are substituted or replaced with one or more deuterium (e.g., a hydrogen atom on a (C1-C6)-alkyl group or a (C1-C6)-alkoxy group in the side chain of the morpholine ring, or a hydrogen atom on a carbon atom adjacent to the nitrogen in the morpholine ring, is substituted with deuterium).

[0017] According to another aspect of the present application, the compound of formula I is a deuterated compound having the structure shown below.

[0018] or X, X', R and Het are each independently as defined for formula I.

[0019] According to another aspect of the present application, there is provided a compound or pharmaceutically acceptable salts and derivatives thereof, wherein the compound has the structure of formula I(a): Formula I(a) wherein: Het represents a heteroaryl selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof, wherein the heteroaryl is unsubstituted, mono- or di-substituted, wherein the substituents of the heteroaryl, if present, are independently selected from the group consisting of unsubstituted (Ci-C4)-linear alkyl, unsubstituted (Ci-C4)-branched alkyl, substituted (Ci-C4)-linear alkyl, substituted (Ci-C4)-branched alkyl, alkoxy, (C3-C8)-cycloalkyl, cyano and halogen; preferably the substituents are alkyl, fluoroalkyl, alkoxy, cycloalkyl or halogen; more preferably the substituents are F, CI, CHF2, CF3, methyl, methoxy, nitrile or cyclopropyl; R 1 is selected from the group consisting of hydrogen, unsubstituted (Ci-C6)-linear alkyl; unsubstituted (Ci-C6)-branched alkyl; substituted (Ci-C6)-linear alkyl; substituted (Ci-C6)-branched alkyl; deuterated (Ci-C6)-linear alkyl; deuterated (Ci-C6)-branched alkyl and halogen; preferably the halogen comprises fluorine, chlorine or bromine; preferably R 1 is hydrogen, fluorine, chlorine, -CH3or -CD3; and Het' is selected from the group consisting of a heteroaryl selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof, wherein the heteroaryl is unsubstituted, mono- or di-substituted, wherein the substituents of the heteroaryl, if present, are independently selected from the group consisting of (Ci-C6)-linear or branched alkyl, (Ci-C6)-substituted linear or branched alkyl, and halogen, preferably the halogen comprises fluorine, chlorine or bromine; preferably the substituents are -CH3.

[0020] According to another aspect of the present application, there is provided a compound or a pharmaceutically acceptable salt and derivative thereof, wherein the compound has the structure of formula I(b)-I(d):

[0021] wherein: R 1 , Het and Het' are each independently as defined herein for formula I(a); R 2 is selected from the group consisting of hydrogen, unsubstituted (Ci-C6)-linear alkyl; unsubstituted (Ci-C6)-branched alkyl; substituted (Ci-C6)-linear alkyl; substituted (Ci-C6)-branched alkyl; deuterated (Ci-C6)-linear alkyl; deuterated (Ci-C6)-branched alkyl and halogen; preferably the halogen comprises fluorine, chlorine or bromine; preferably R2 is hydrogen, fluorine, chlorine, -CH3, or -CD3; According to another aspect of the present application, there is provided a compound or pharmaceutically acceptable salts and derivatives thereof, wherein the compound has the structure of formula I(e)-I(g):

[0022] wherein: R 1 , Het and Het' are each independently as defined herein for formula I(a); and R 6 and R 7 are each independently hydrogen or deuterium.

[0023] Preferably, the compound of formula I(a)-(g) is the 5R, 6S-stereoisomer.

[0024] According to another aspect of the present application, there is provided a compound or pharmaceutically acceptable salts and derivatives thereof, wherein the compound has the structure of formula I(h): formula I(h); wherein: Het is as defined for formula I or I(a); and Y represents an aromatic or heteroaromatic group; substituted or unsubstituted aromatic, substituted or unsubstituted heteroaromatic, wherein the Y is independently selected from the group consisting of: aryl, pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, picolinitrile, 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: (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano and halogen; the halogen can be fluorine, chlorine or bromine; preferably, the substituents are cyano, alkoxy or halogen; more preferably, the aromatic or heteroaromatic group is substituted with CN, F, Cl, -O-alkyl, preferably the alkyl comprises 1-4 carbon atoms, for example -O-CH3.

[0025] According to another aspect of the present application, there is provided a compound or pharmaceutically acceptable salts and derivatives thereof, wherein the compound has the structure of formula I(i) or I(j):

[0026] wherein: R 3 and R 4 are each independently selected from the group consisting of hydrogen, (C1-C 10 )-linear alkyl; (C1-C 10 )-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; or deuterated (Ci-C4) -branched alkyl; R 3 and R 4 may form a fused, substituted or unsubstituted ring; preferably, R 3 and R 4 are each independently -CH3or -CD3; and Het and Y are each independently as defined for formula I(h).

[0027] According to another aspect of the application, there is provided a compound, or a pharmaceutically acceptable salt and derivative thereof, wherein the compound has the structure of formula I(k): formula I(k); and wherein Het and Y are each independently as defined herein for formula I(h).

[0028] According to another aspect of the application, there is provided a compound, or a pharmaceutically acceptable salt and derivative thereof, wherein the compound has the structure of formula I(l): formula I(l) wherein Het and Y are each independently as defined herein for formula I(h).

[0029] According to another aspect of the application, there is provided a compound, or a pharmaceutically acceptable salt and derivative thereof, wherein the compound has the structure of formula I(m): formula I(m) wherein Het and Y are each independently as defined herein for formula I(h).

[0030] According to another aspect of the application, there is provided a compound, or a pharmaceutically acceptable salt and derivative thereof, wherein the compound has the structure of formula I(n)-(q):

[0031] wherein: Het and Y are each independently as defined herein for formula I(h); R 3 as defined in formula I(j) or I(i); R 5 is selected from hydrogen, (Ci-C 10 ) -straight chain alkyl; (Ci-C 10) - substituted or unsubstituted alkyl, optionally (Ci-C4) - straight chain alkyl; (Ci-C4) - branched chain alkyl; (Ci-C4) - substituted or unsubstituted alkyl; deuterated (Ci-C4) - straight chain alkyl; deuterated (Ci-C4) - branched chain alkyl; or halogen; preferably, R 10 ) - substituted or unsubstituted alkyl, optionally (Ci-C4) - straight chain alkyl; (Ci-C4) - branched chain alkyl; (Ci-C4) - substituted or unsubstituted alkyl; deuterated (Ci-C4) - straight chain alkyl; deuterated (Ci-C4) - branched chain alkyl; or halogen; preferably, R 5 is hydrogen, -CH3, or -CD3; and R 6 and R 7 each independently is hydrogen or deuterium.

[0032] Preferably, the compounds of formula I(h) - I(q) are the 5R, 6S-stereoisomer.

[0033] According to another aspect of the application, there is provided a pharmaceutical composition comprising a compound of formula I or I(a-q) as described herein; and one or more pharmaceutically acceptable excipients.

[0034] According to another aspect of the application, there is provided a compound of formula I or I(a-q) as described herein, or a pharmaceutical composition comprising a compound of formula I or I(a-q), for use as a medicament. Preferably, the pharmaceutical composition is in solid form, such as a tablet or capsule.

[0035] According to another aspect of the application, there is provided a method of treating or preventing a disease or disorder mediated by orexin receptor activity, comprising administering to an individual in need of such treatment an effective amount of at least one compound of formula I or I(a-q) as described herein, or a pharmaceutically acceptable salt and derivative thereof, preferably administered at a dosage, frequency and duration that provides a beneficial effect, or a pharmaceutical composition as described herein.

[0036] According to another aspect of the application, there is provided the use of a compound of formula I or I(a-q) as described herein, or the pharmaceutical composition, for the manufacture of a medicament for the treatment of a disease or disorder modulated by orexin receptor activity, and the use of such compounds for the treatment or prevention of such diseases and disorders.

[0037] According to a further aspect of the application, there is provided a method of modulating the activity of an orexin receptor OX1, OX2, or both, comprising contacting a cell containing the orexin receptor with an effective amount of at least one compound of formula I or I(a-q) as described herein, or a pharmaceutical composition as described herein.

[0038] According to another aspect of the application, there is provided a process for the preparation of a compound of the application. DETAILED DESCRIPTION Formula I According to one aspect of the application, there is provided a compound of formula I or a pharmaceutically acceptable salt or derivative thereof, wherein X and X' are halogen, for example fluorine, chlorine or bromine. Preferably, X and X' are fluorine. Het represents a heteroaryl group, and R is a five or six membered aryl or heteroaryl group. The heteroaryl group Het can be selected from pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof. The heteroaryl group can be unsubstituted, mono-substituted or di-substituted, wherein the substituents of the heteroaryl 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, cyano and halogen such as fluorine, chlorine or bromine. Preferably, the substituents of the heteroaryl group in Het comprise alkyl, fluoroalkyl such as CF3, alkoxy, cycloalkyl, cyano or halogen. More preferably, the substituents of the heteroaryl group in Het are F, Cl, CHF2, CF3, methyl, methoxy, nitrile or cyclopropyl.

[0040] The five or six membered aryl or heteroaryl group R can be unsubstituted or substituted by one or more substituents.

[0041] Preferably, the compound provided by formula I is the 5R,6S-stereoisomer: The 5R,6S-stereoisomer provided by the compound of formula I or I(a-q) can bind more strongly to orexin receptors and can have a higher selectivity for the OX1 receptor compared to other stereoisomers provided by the compound of formula I or I(a-q).

[0042] The term "heteroaryl" as used herein refers to an aromatic compound containing a heteroatom such as oxygen, nitrogen or sulfur as part of the cyclic conjugated π system.

[0043] The term "alkyl" as used herein refers to a monovalent group derived from an alkane by removing one hydrogen atom from any carbon atom of the alkane - C n H 2n+1 The term "substituted alkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl group are replaced by one or more substituents selected from, but not limited to, halogen such as fluorine, chlorine or bromine, -OH, -CN.

[0044] The term "deuterated alkyl" as used herein refers to an alkyl group in which one or more protons are replaced by deuterium atoms.

[0045] The term "deuterated compound" as used herein refers to a compound in which one or more hydrogen atoms have been replaced by deuterium atoms.

[0046] The term "fluoroalkyl" as used herein refers to an alkyl group substituted with at least one fluorine atom.

[0047] The term "alkoxy" as used herein refers to an alkyl group bonded to an oxygen (i.e., R-O).

[0048] 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.

[0049] "halogen" can be F, CI, Br, or I, but in preferred embodiments, halogen is F, CI, or Br.

[0050] The term "substituted" as used herein refers to the replacement of one functional group in a particular group (e.g., alkyl, aryl, heteroaryl, aromatic) with another functional group (e.g., replacement of an alkyl hydrogen with fluorine to give a fluoroalkyl group).

[0051] The term "solvate" as used herein is used to describe a compound of the present application that includes a stoichiometric or sub-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" refers to the case when the solvent is water.

[0052] By "pharmaceutically acceptable" is meant that the ingredients of the pharmaceutical composition are compatible with each other and not deleterious to the individual to which it is administered.

[0053] The term "therapeutically effective amount" (or simply "effective amount") as used herein means the amount of active agent or active ingredient sufficient to achieve the intended therapeutic or prophylactic effect in the individual to which it is administered.

[0054] Preferably, when the "R" group in the compound of Formula I is a five-membered heteroaryl, it can include an unsubstituted pyrazole, oxazole, thiazole, imidazole, substituted pyrazole oxazole, thiazole, imidazole, or derivatives thereof. Preferably, when the R group in the compound of Formula I is a six-membered aryl, it can include an unsubstituted aryl, or substituted aryl, or derivatives thereof.

[0055] More preferably, when the R group in the compound of Formula I is a six-membered aryl, the six-membered aryl has the structure of Formula II or Formula II(a):

[0056] wherein R 1 may be selected from the group consisting of: hydrogen; unsubstituted (Ci-C6)-straight chain alkyl; unsubstituted (Ci-C6)-branched alkyl; substituted (Ci-C6)-straight chain alkyl; substituted (Ci-C6)-branched alkyl; deuterated (Ci-C6)-straight chain alkyl; deuterated (Ci-C6)-branched alkyl; and halogen; preferably, R 1 is CI, F, -CH3, or -CD3; and Het' can be selected from: heteroaryl selected from pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole, and any derivative thereof, wherein the heteroaryl is unsubstituted, mono-substituted or di-substituted, wherein the substituents of the heteroaryl, if present, can be independently selected from: unsubstituted (Ci-C4)-straight or branched alkyl, substituted (Ci-C4)-straight or branched alkyl, and halogen; preferably, the substituents of the heteroaryl are halogen, e.g. fluorine, chlorine or bromine; preferably, the substituents are -CH3.

[0057] In some examples, the Het' group of formula II or formula II(a) can be selected from: ; ; or .

[0058] Further, when the R group in the compound of formula I is a six-membered heteroaryl group, the six-membered heteroaryl group has the structure of formula III or III(a):

[0059] wherein: R 1 can be selected from: hydrogen; unsubstituted (Ci-C6)-straight alkyl; unsubstituted (Ci-C6)-branched alkyl; substituted (Ci-C6)-straight alkyl; substituted (Ci-C6)-branched alkyl; deuterated (Ci-C6)-straight alkyl; deuterated (Ci-C6)-branched alkyl; and halogen; preferably, the halogen comprises fluorine, chlorine or bromine; preferably, R 1 is H, CI, F, -CH3, or -CD3; R 2 can be selected from: hydrogen; unsubstituted (Ci-C6)-straight alkyl; unsubstituted (Ci-C6)-branched alkyl; substituted (Ci-C6)-straight alkyl; substituted (Ci-C6)-branched alkyl; deuterated (Ci-C6)-straight alkyl; deuterated (Ci-C6)-branched alkyl; and halogen; preferably, the halogen comprises fluorine, chlorine or bromine; preferably, R 2 is H, F, CI, -CH3, or -CD3; and Het' can be as defined herein for formula II or II(a).

[0060] In some examples, the Het' of formula III or III(a) can be selected from: or .

[0061] When the R group in Formula I is a five-membered heteroaryl, the five-membered heteroaryl can have the structure of Formula IV, IV(a), or IV(b):

[0062] wherein: R 3 and R 4 may each independently be selected from the group consisting of: hydrogen, (Ci-C 10 )-linear alkyl; (Ci-C 10 )-branched alkyl; (Ci-C 10 )-substituted or unsubstituted alkyl, optionally (Ci-C4)-linear alkyl; (Ci-C4)-branched alkyl; (Ci-C4)-substituted or unsubstituted alkyl; deuterated (Ci-C4)-linear alkyl; and deuterated (Ci-C4)-branched alkyl; R 3 and R 4 may form a fused substituted or unsubstituted ring; preferably, R 3 and R 4 may each independently be -CH3or -CD3; and Y can represent aryl; substituted or unsubstituted aryl, heteroaryl, substituted or unsubstituted heteroaryl. Preferably, Y can be independently selected from the group consisting of: aryl, pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, picolinitrile, benzonitrile, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole, and any derivatives thereof; and Y can be unsubstituted, mono-substituted or di-substituted, wherein the substituents can be independently selected from the group consisting of: (Ci-C4)-alkyl, unsubstituted or substituted (Ci-C4)-alkyl, (Ci-C4)-alkoxy, cyano, and halogen.

[0063] When Y is mono-substituted or di-substituted and the substituents are halogen, the halogen can preferably be fluorine, chlorine, or bromine. When Y is mono-substituted or di-substituted, and the substituents are cyano, (Ci-C4)-alkoxy, the alkoxy can be -OCH3; preferably, the substituents are CN, F, CI, CH3, or -OCH3.

[0064] In some examples, “Y” of Formula IV, IV(a), or IV(b) can be selected from: ; ; ; ; ; ; ; ; ; ; or , , , or .

[0065] Further, when "R" in Formula I is a five-membered heteroaryl group, the five- membered heteroaryl group can have the structural Formula V: Formula V; wherein Y can be as defined for Formula IV, IV(a), or IV(b).

[0066] In some examples, "Y" of Formula V can be or .

[0067] Further, when "R" in Formula I is a five-membered heteroaryl group, the five- membered heteroaryl group can have the structural Formula VI: Formula VI; wherein Y can be as defined for Formula IV, IV(a), or IV(b).

[0068] In some examples, "Y" of Formula VI can be or .

[0069] Further, when "R" in Formula I is a five-membered heteroaryl group, the five- membered heteroaryl group can have the structural Formula VII: Formula VII; wherein Y can be as defined for Formula IV, IV(a), or IV(b).

[0070] In some examples, "Y" of Formula VII can be: .

[0071] In some examples, "R" of the compounds of Formula I described herein can be selected from: ; ; ; ; ; ; ; ; ; ; ; ; ; ,

[0072] In other examples, "R" in the compounds of Formula I described herein can be selected from:

[0073] In some examples, Het in the compounds of Formula I described herein can be selected from:

[0074] According to one aspect of the application, there is provided a deuterated compound of Formula I or a pharmaceutically acceptable salt or derivative thereof, having the structure of Formula I(D): Formula I(D) wherein: X, X', Het and R are each independently as defined herein for Formula I; and R 6 and R 7 are each independently hydrogen or deuterium.

[0075] ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​In preferred aspects, the deuterated compound of formula ID has the following structure: Formula ID(a) Het is a heteroaryl, preferably, the heteroaryl can be selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof. The heteroaryl can be unsubstituted, mono-substituted or di-substituted, wherein the substituents of the heteroaryl, 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, C3-C8)-cycloalkyl, cyano, alkoxy and halogen such as fluorine, chlorine or bromine. Preferably, the substituents of the heteroaryl include F, CI, CHF2, CF3, methyl, methoxy, nitrile or cyclopropyl.

[0076] R is a five- or six-membered aryl or heteroaryl group. The five- or six-membered aryl or heteroaryl group R can be unsubstituted or substituted by one or more substituents.

[0077] Preferably, when the R group in the compound of formula ID(a) is a six-membered aryl group, it can include an unsubstituted aryl group, or a substituted aryl group, or a derivative thereof.

[0078] Preferably, when the R group in the compound of formula ID(a) is a six-membered aryl group, it can include 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.

[0079] Preferably, when the R group in the compound of formula ID(a) is a five-membered heteroaryl group, it can include an unsubstituted pyrazole, an unsubstituted oxazole, an unsubstituted thiazole, an unsubstituted imidazole, a substituted pyrazole oxazole, a substituted thiazole, a substituted imidazole, or a derivative thereof.

[0080] R of formula ID(a) 6 may be hydrogen or deuterium.

[0081] When the R group in formula ID(a) is a five-membered heteroaryl group, the five- membered heteroaryl group can have the structural formula VIII: Formula VIII; wherein Y is as defined herein for formula IV, IV(a), IV(b).

[0082] In some examples, the Y group of formula VIII can be selected from: .

[0083] When the R group in formula ID(a) is a five-membered heteroaryl group, the five- membered heteroaryl group can have the structural formula IX: Formula IX; wherein: R 3 is independently selected from the group consisting of: hydrogen, (C1-C 10 )-straight chain alkyl; (C1-C 10 )-branched chain alkyl; (C1-C 10 )-substituted or unsubstituted alkyl, optionally (C1-C4)-straight chain alkyl; (C1-C4)-branched chain alkyl; and (C1-C4)-substituted or unsubstituted alkyl; deuterated (C1-C4)-straight chain alkyl; and deuterated (C1-C4)-branched chain alkyl; preferably, R 3 is -CH3or -CD3; Y can be as defined herein for formula IV, IV(a), IV(b).

[0084] In some examples, the Y group of formula IX can be selected from: ; ; or Further, when “R” in formula ID(a) is a five-membered heteroaryl group, the five- membered heteroaryl group can have the structural formula X: Formula X; wherein Y can be as defined herein for formula IV, IV(a), IV(b).

[0085] In some examples, the Y group of formula X can be selected from: or More preferably, when the R group in the compound of formula ID(a) is a six-membered aryl group, the six-membered aryl group has the structure of formula XI or XI(a):

[0086] wherein R 1 and Het’ can each independently be as defined herein for formula II and III; In some examples, the Het’ of formula XI or XI(a) can be selected from: or .

[0087] In preferred aspects, the deuterated compound of formula ID has the following structure: Formula ID(b) wherein: Het and R can each independently be as defined herein for Formula ID(a); and R 7 may be hydrogen or deuterium.

[0088] More preferably, when the R group in a compound of Formula ID(b) is a five-membered aryl group, the five-membered aryl group has the structure of Formula XII: Formula XII; wherein R 3 may be as defined herein for Formula IX; and Y can be as defined herein for Formula IV, IV(a), or IV(b).

[0089] In some examples, the Y group of Formula XII can be selected from: ; .

[0090] More preferably, when the R group in a compound of Formula ID(b) is a six-membered aryl group, the six-membered aryl group has the structure of Formula XIII: Formula XIII; wherein R 1 and Het' can each independently be as defined herein for Formula III or III(a).

[0091] In some examples, the Het' group of Formula XIII can be selected from: .

[0092] In some examples, the "R" of a compound of Formula ID, ID(a), or ID(b) described herein can be selected from: ; ; ; or .

[0093] In some additional examples, the "R" of a compound of Formula ID, ID(a), or ID(b) described herein can be selected from: or .

[0094] In some examples, the Het of a compound of Formula ID, ID(a), or ID(b) described herein can be selected from: ; ; or .

[0095] Preferably, the compounds of formula ID, ID(a) and ID(b) are the 5R, 6S-stereoisomer.

[0096] In yet another example, the compounds of formula I described herein have the structure of formula I(a), I(b), I(c), I(d), I(e), I(f), I(g), I(h), I(i), I(j), (I(k), I(l), l(m), ((n), I(o), I(p) or I(q):

[0097] wherein Het, Het', R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and Y can each independently be as defined herein for formula I, ID, ID(a), ID(b) and II to XIII.

[0098] In further examples, the compounds of the application can be selected from:

[0099] or pharmaceutically acceptable salts and derivatives thereof.

[0100] One aspect of the present application provides a compound of Formula I-aa or pharmaceutically acceptable salts and derivatives thereof, Formula I-aa wherein: R 6 and R 7 are each independently hydrogen or deuterium; R 8 is CF3; W 1 is selected from CH, N, or C-O-CH3; W 2 is selected from CH, N, C-CH3; and R is selected from a five-membered heteroaryl group comprising unsubstituted pyrazole, unsubstituted oxazole, unsubstituted thiazole, unsubstituted imidazole, substituted pyrazole, substituted oxazole, substituted thiazole, substituted imidazole, or derivatives thereof; or a six-membered heteroaryl group comprising unsubstituted pyridine, unsubstituted pyrimidine, unsubstituted pyridazine, unsubstituted pyrazine, substituted pyridine, substituted pyrimidine, substituted pyridazine, substituted pyrazine, or derivatives thereof.

[0101] When the R group in Formula I-aa is a five-membered heteroaryl group, the five- membered heteroaryl group can have the following structure: ; wherein R 3 and R 4 may each independently be CH3or CD3; and Y can be or ; When the R group in Formula I-aa is a six-membered heteroaryl group, the six- membered heteroaryl group can have the following structure: ; wherein Het' can be .

[0102] In one aspect of the present application, the compound of Formula I-aa is selected from: [6],

[36] ,

[54] ,

[55] ,

[61] ,

[82] ,

[89] ,

[93]

[102] ,or

[103] .

[0103] Preferably, the compound of Formula I-aa is the 5R,6S-stereoisomer.

[0104] In some examples, the compounds provided by Formula I and I(a-q) can be deuterated, wherein at least one hydrogen atom is replaced by a deuterium atom. Preferably, the N-methyl or C-methyl group of the compounds provided by Formula I and I(a-g) is deuterated. Preferably, compounds 6, 7, 23, 24, 26, 27, 28, 29, 35, 36, and 37 are deuterated. More preferably, the N-Me or C-methyl group on the pyrazole ring of compounds 6, 7, 23, 24, 26, 27, 28, 29, 35, 36, and 37 is 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 forms of compound 6. In some examples, compound 91 is a 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. Deuterated compounds provided by Formula I and I(a-q) can have higher metabolic stability than the non-deuterated counterparts.

[0105] The compounds of the present application can be in the form of a pharmaceutically acceptable salt. By pharmaceutically acceptable salt is meant a salt of a free acid or base described herein which is nontoxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. The compounds described herein can have groups sufficiently acidic, groups sufficiently basic, both types of functional groups, or more than one of each type, and thus react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

[0106] Examples of pharmaceutically acceptable salts include, but are not limited to, hydrochloride, chloride, bromide, iodide, potassium salt, sodium salt, acetate, trifluoroacetate, sulfate, sulfonate, oxalate, maleate, malonate, nitrate, tartrate, gluconate, succinate, methanesulfonate, citrate, phosphate or diphosphate, and aluminate.

[0107] In some examples, the compounds of the present application can be in the form of a trifluoroacetate salt.

[0108] Any structural formula depicted herein is intended to represent the compound having that structural formula and certain variants or forms thereof. For example, a structural formula given herein is intended to include the racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or tautomeric forms, prodrugs, or mixtures thereof.

[0109] A "pharmaceutically acceptable derivative" of a compound of the application disclosed herein includes, but is not limited to, an enantiomer, solvate, adduct, polymorph, hydrate, tautomer, prodrug, isotopically or radiolabelled derivative, isomer, or mixture thereof.

[0110] Isotopically-labelled The present application further includes all pharmaceutically acceptable isotopically-labelled compounds [e.g., compounds of Formula I or I(a-d)]. An "isotopically-labelled" or "radiolabelled" compound is one in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (i.e., naturally occurring). For example, in certain embodiments, a hydrogen atom in a compound [e.g., a compound of Formula I or I(a-d)] is replaced by one or more deuterium or tritium (e.g., a hydrogen atom on a (C1-C6)-alkyl or (C1-C6)-alkoxy group is replaced by deuterium, such as d3-methoxy or 1,1,2,2-d4-3-methylbutyl).

[0111] Certain isotopically-labelled compounds [e.g., compounds of Formula I or I(a-d)], for example those into which radioactive isotopes are incorporated, are useful in drug and / or substrate tissue distribution studies and / or metabolic studies, preferably using positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiotherapy. 14 C), reaction kinetic studies (for example, using 2 H or 3 H), 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 radiotherapy. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0112] Isotopically-labeled compounds of the present application, e.g., compounds of Formula I, ID, ID(a), ID(b), I-aa, or I(a-q), or prodrugs thereof, 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-labeled reagent in place of the non-labeled reagent previously used. Suitable isotopes for incorporation into the compounds of the application include, but are not limited to, tritium, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H (also written as D, deuterium), 3 H (also written as T, tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, I31 I, 31 P, and 32 P.

[0113] Isotopically-labeled compounds of the present application, and prodrugs thereof, can generally be prepared by carrying out the procedures described in the Schemes and Preparations disclosed herein, by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent.

[0114] The compounds provided herein are non-peptide antagonists of the human orexin receptors. The compounds provided herein are useful for the potential treatment or prevention of central nervous system (CNS) diseases, neurological diseases, or eating disorders. The compounds of the present application are useful for treating diseases or conditions associated with dysfunction of the orexin 1 receptor.

[0115] The novel compounds provided by the present invention are non-peptide antagonists of the human orexin receptors, in particular 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), psychomotor stimulant (such as cocaine, opioids, nicotine and alcohol) addiction, opioid use disorder, substance abuse or addiction, sleep disorders, cognitive dysfunction in psychiatric or neurological diseases, depression, anxiety, panic disorder, post-traumatic stress disorder, conduct disorder and mood disorder depression. The compounds of the present invention can be used to treat diseases or disorders associated with dysfunction of the orexin 1 receptor.

[0116] Preferably, the compounds provided by the present invention are OX1 receptor selective antagonists. OX1 receptor antagonists can be used to treat diseases and disorders such as, but not limited to, substance use disorders, personality disorders, eating disorders or anxiety-related disorders. However, antagonists that target both OX1 and OX2 receptors are known to have a pro-sleep effect; therefore, to prevent side effects such as drowsiness or fatigue, it is highly desirable to identify highly OX1 selective antagonists with a sufficient window on OX2 mediated effects.

[0117] The present invention can use the half maximal inhibitory concentration (IC 50 ) to indicate the potency of the compounds provided by the present invention. The IC 50 values provided in the present disclosure indicate how much drug is needed to inhibit the orexin receptor by half, thus providing a measure of the potency of the compounds provided by the present invention.

[0118] The IC 50 of the compounds provided by the present invention for the OX1 receptor can be at least 700 nM. Preferably, the IC 50 values of the compounds provided by the present invention for the OX1 receptor can be between 2 nM and 700 nM. The IC 50values can be between 2 nM and 650 nM; between 2 nM and 600 nM; between 2 nM and 500 nM; between 2 nM and 400 nM; between 2 nM and 350 nM; between 2 nM and 300 nM; between 2 nM and 250 nM; between 2 nM and 200 nM; between 2 nM and 150 nM; between 2 nM and 100 nM; between 50 nM and 700 nM; between 50 nM and 650 nM; between 50 nM and 600 nM; between 50 nM and 500 nM; between 50 nM and 400 nM; between 50 nM and 350 nM; between 50 nM and 300 nM; between 50 nM and 250 nM; between 50 nM and 200 nM; between 50 nM and 150 nM; between 50 nM and 400 nM; between 100 nM and 350 nM; between 100 nM and 300 nM; between 100 nM and 250 nM; between 100 nM and 200 nM; or between 100 nM and 150 nM.

[0119] More preferably, the compounds provided by the present application have an IC50 value for the OX1 receptor of less than 100 nM. 50 values can be between 2 nM and 100 nM. The compounds provided by the present application have an IC50 value for the OX1 receptor of less than 100 nM. 50 values can be between 2 nM and 90 nM; between 2 nM and 70 nM; between 2 nM and 50 nM; between 2 nM and 30 nM; between 2 nM and 10 nM; between 5 nM and 90 nM; between 5 nM and 80 nM; between 5 nM and 60 nM; between 5 nM and 50 nM; between 5 nM and 30 nM; between 5 nM and 20 nM; between 5 nM and 10 nM; between 10 nM and 80 nM; between 10 nM and 60 nM; between 10 nM and 70 nM; between 10 nM and 50 nM; between 10 nM and 30 nM; or between 10 nM and 20 nM.

[0120] Most preferably, the compounds provided by the present application have an IC50 value for the OX1 receptor of less than 10 nM. 50 values can be between 2 nM and 50 nM. The compounds of Formula I have an IC50 value for the OX1 receptor of less than 50 nM. 50The value can be between 2 nM and 40 nM; between 2 nM and 30 nM; between 2 nM and 25 nM; between 2 nM and 20 nM; between 2 nM and 10 nM; between 2 nM and 5 nM; between 3 nM and 40 nM; between 3 nM and 30 nM; between 3 nM and 25 nM; between 3 nM and 20 nM; between 3 nM and 10 nM; between 3 nM and 5 nM; between 5 nM and 40 nM; between 5 nM and 30 nM; between 5 nM and 25 nM; between 5 nM and 20 nM; between 5 nM and 10 nM; between 7 nM and 40 nM; between 7 nM and 30 nM; between 7 nM and 25 nM; between 7 nM and 20 nM; or between 7 nM and 10 nM.

[0121] Most preferably, the compounds provided by the present application have an IC50 for the OX1 receptor of less than 100 nM. 50 The value can be 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.

[0122] The compounds provided by the present application have an IC50 for the OX2 receptor of at least 3000 nM. 50 The value can be 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. 50 The value can be at least 5000 nM.

[0123] The compounds provided by the present application have a binding potency for the OX1 receptor that is at least 12-fold higher than for the OX2 receptor. Preferably, the compounds provided by the present application have a binding potency for the OX1 receptor that is at least 50-fold higher than for the OX2 receptor. More preferably, the compounds provided by the present application have a binding potency for the OX1 receptor that is at least 100-fold higher than for the OX2 receptor. Most preferably, the compounds provided by the present application have a binding potency for the OX1 receptor that is at least 500-fold higher than for the OX2 receptor.

[0124] It was found that the compounds of the present application have improved residence time compared to known OX1 receptors. Orexin A was incubated with human OX1 receptor membranes at different incubation times in the presence or absence of 6 different concentrations of the compounds. Non-specific binding was assessed at each incubation time by the presence of unlabelled SB 334867 (1-(2-methylbenzo[d]oxazol-6-yl)-3-(1,5- naphthyridin-4-yl)urea, OX1R-ANT commercially available). Kinetic parameters (kon, koff, residence time) were calculated by applying the Motulsky Mahan equation. It was found that the compounds of the present application show higher residence time than reference compounds, which indicates a longer half-life of the ligand-OX1R complex, which has a positive impact on human therapeutic doses. For example, the compounds of the present application (such as compounds 26, 54) show higher ranking compared to known compounds (such as those in WO2017129829, WO2017139603, JNJ-61393215 and ACT-539313). Improved drug residence time is advantageous because longer drug-target residence time is generally more effective in the body. Therefore, lower therapeutic doses are required. It is also generally known that drugs with longer residence time have higher efficacy and fewer side effects because they can occupy a higher proportion of their target for a longer time even after being cleared from the systemic circulation.

[0125] The compounds provided by the present application can have improved pharmacokinetic properties, such as improved bioavailability, brain exposure, improved cellular permeability, and metabolic stability, and thus can require lower therapeutic doses.

[0126] According to another aspect of the present application, there is provided a pharmaceutical composition comprising a compound of the present application as described herein and one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients can be added to facilitate the preparation of the pharmaceutical composition and ultimately to promote the physiological absorption of the drug. Furthermore, the pharmaceutically acceptable excipients used in the present application can provide key benefits such as solubilization, stabilization, delivery enhancement, and formulation preservation.

[0127] The compounds of the present application can be combined with one or more additional active ingredients for use in a pharmaceutical composition or method to treat the diseases and conditions described herein. The additional active ingredients can include other active agents that are known to be effective in treating the diseases and conditions described herein. For example, the additional active ingredients include drugs known to be useful in improving sleep quality and in the prevention and treatment of sleep disorders and sleep disturbances, anti-diabetic drugs, cardiovascular therapies, anti-obesity agents, other orexin receptor antagonists, analgesics, anti-depressants, anti-anxiety agents, cognitive enhancers, anti-Alzheimer's therapies, and other active ingredients.

[0128] Non-limiting examples of excipient types include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersants, disintegrants, emulsifiers, wetting agents, suspending agents, thickening agents, solvents, isotonic agents, buffers, pH adjusting agents, absorption delaying agents, stabilizers, antioxidants, preservatives, antimicrobials, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweeteners, flavorings, colorants, encapsulating materials, and coating materials. The use of such excipients in pharmaceutical formulations is known in the art.

[0129] The pharmaceutical composition or compound of the present application provided herein can be used as a medicament. The medicament can be used for preventing and / or treating a disorder selected from, but 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), psychomotor stimulant (such as cocaine, opioids, nicotine and alcohol) addiction, opioid use disorder, drug abuse or addiction, sleep disorders, cognitive dysfunction in psychiatric or neurological diseases, depression, anxiety, panic disorder, post-traumatic stress disorder, conduct disorder and mood disorder depression.

[0130] The pharmaceutical composition provided herein can be in the form of a tablet, capsule, hard candy, powder, spansule, soft gel, liquid or aqueous suspension. Preferably, the pharmaceutical composition provided herein is in the form of a tablet or capsule.

[0131] The pharmaceutical composition provided herein can be administered orally, parenterally (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intraperitoneal, intracavitary and topical), topically (including transdermal, transmucosal, intranasal (e.g., by nasal spray or drops), ocular (e.g., by eye drop), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; proper formulation is selected having due regard to particle size), and / or other appropriate routes of administration. Preferably, the pharmaceutical composition provided herein is administered orally.

[0132] According to yet another aspect of the present application, there is provided a method of treating or preventing a disease or disorder mediated by orexin receptor activity. The method comprises administering to an individual in need of such treatment an effective amount of at least one compound of the present application (or any pharmaceutically acceptable salt, solvate, adduct, polymorph, isotopically labeled or radiolabeled derivative thereof, and isomers thereof), or a pharmaceutical composition comprising at least one compound of the present application (or any pharmaceutically acceptable salt, solvate, adduct, polymorph, isotopically labeled or radiolabeled derivative thereof, and isomers thereof).

[0133] The methods provided herein can be used to treat or prevent a disease or disorder selected from, but not limited to, the following: eating disorders, obesity, binge eating disorder (BED), schizophrenia (negative symptoms and CIAS), psychomotor stimulant (e.g., cocaine, opioids, nicotine, and alcohol) addiction, opioid use disorder, drug abuse or addiction, sleep disorders, cognitive dysfunction in psychiatric or neurological disorders, depression, anxiety, panic disorder, post-traumatic stress disorder, conduct disorder, and mood disorder depression.

[0134] As used herein, the term "effective amount" means an amount of a compound that, when administered, will relieve to some extent one or more of the symptoms of the disorder being treated.

[0135] Dosage regimens can be adjusted to provide the optimum desired response. It is noted that dosage values can vary with the type and severity of the condition being alleviated, and can include single or multiple doses. It is further to be understood that for any particular individual, 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 compositions, and that the concentration ranges set forth herein are exemplary only.

[0136] The amount of a compound administered according to the application will depend on the subject to be treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the judgment of the prescribing physician.

[0137] As used herein, the term "individual" includes a human or non-human animal. Exemplary human individuals include a human individual (referred to as a patient) suffering from a disease (e.g., one described herein), or a normal individual. As used herein, the term "non-human animal" includes all vertebrates, e.g., non-mammalian vertebrates.

[0138] According to another aspect of the application, there is provided the use of a compound of the application or a pharmaceutical composition comprising a compound of the application. The compound according to the application or the pharmaceutical composition comprising a compound according to the application is used for the manufacture of a medicament for the treatment of a disease or disorder modulated by orexin receptor activity and for the treatment or prevention of such diseases and disorders.

[0139] According to yet another aspect of the application, there is provided a method of modulating the activity of an orexin receptor OX1, OX2 or both. The method comprises contacting a cell comprising the orexin receptor with an effective amount of at least one compound according to the application or a pharmaceutical composition comprising a compound according to the application. The method of contacting a cell comprising an orexin receptor with an effective amount of at least one compound according to the application or a pharmaceutical composition comprising a compound according to the application can be performed in vivo, in vitro or ex vivo.

[0140] Preferably, the application provides a method of selectively modulating the activity of an OX1 receptor.

[0141] According to yet another aspect of the present application, the compounds of the present application can be prepared by the synthetic routes described in the following examples.

[0142] Abbreviations used in the present disclosure are summarized as follows:

[0143] The term "hexaalkyldistannane" as used herein refers to a general reagent used in the preparation of organotin stannanes in Stille cross-coupling. Examples of "hexaalkyldistannane" include, but are not limited to, hexamethyldistannane or hexabutyldistannane.

[0144] The compounds of the present application can be prepared starting from commercially available starting material N-benzyl-L-allothreonine (a). N-benzyl-L-allothreonine (a) can be reduced by reaction with a reducing agent to form intermediate (b). The primary alcohol of intermediate (b) can be selectively protected by reaction with a suitable protecting group to form intermediate (c). Intermediate (c) can undergo a nucleophilic substitution reaction with 2-bromo-2,2-difluoroacetic acid or 2,2-difluoro-2-iodoacetic acid to form intermediate (d). Intermediate (d) can undergo an intramolecular amide coupling in the presence of a coupling reagent to form intermediate (e). Preferably, the coupling reagent used to prepare intermediate (e) is propylphosphonic anhydride (T3P). Intermediate (e) can be reduced to form intermediate (f). The alcohol protecting group is removed from intermediate (f) to form intermediate (g). The benzyl protecting group in intermediate (g) can be removed by Pd / C catalyzed hydrogenation. The deprotected amine can be reacted with a suitable protecting group to form intermediate (h). Intermediate (h) can be reacted with isoindoline-1,3-dione to form intermediate (i). Intermediate (i) can be reacted with hydrazine or hydrazine hydrate to form intermediate (j). Intermediate (j) can undergo a nucleophilic aromatic substitution reaction with a halogenated heteroaromatic compound to form one of intermediates k-z2. Intermediates k-z2 are deprotected to form the corresponding intermediates aa-ar. Intermediates aa-ar can be reacted with a carboxylic acid having the general formula R-COOH to form compounds 1-49, 60-69, 78-88, and 92-102.

[0145] The compounds of the present application can be prepared starting from commercially available starting material (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholin-3-one (intermediate e) or an intermediate (e) disclosed herein. Intermediate (e) can be reduced with a deuterating reagent to form intermediate (fl). Removal of the alcohol protecting group from intermediate (fl) forms intermediate (gl). The benzyl protecting group in intermediate (gl) can be removed by Pd / C catalyzed hydrogenation. The deprotected amine can be reacted with a suitable protecting group to form intermediate (hl). Intermediate (hl) can be reacted with isoindoline-1,3-dione to form intermediate (il). Intermediate (il) can be reacted with hydrazine or hydrazine hydrate to form intermediate (jl). Intermediate (jl) can undergo a nucleophilic aromatic substitution reaction with a halogenated heteroaromatic compound to form one of intermediates kl, li or ml. Intermediate kl, li or ml is deprotected to form the corresponding intermediate ab 1, ac 1 or ad 1. Intermediate ab 1, ac 1 or ad 1 can be reacted with a carboxylic acid having the general formula R-COOH to form compounds 50-59, 70-77.

[0146] The compounds of the present application can be prepared starting from commercially available starting material N-benzyl-L-allothreonine (a). N-benzyl-L-allothreonine (a) can be reacted with sodium (2-bromo-2,2-difluoroacetyl)oxy to form intermediate (e2'). Intermediate (e2') can be reduced with a deuterating reagent to form intermediate (e2"). Intermediate (e2") can be reduced with a reducing agent to form intermediate (g2). The benzyl protecting group in intermediate (g2) can be removed by Pd / C catalyzed hydrogenation. The deprotected amine can be reacted with a suitable protecting group to form intermediate (h2). Intermediate (h2) can 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 halogenated heteroaromatic compound to form one of intermediates k2, l2, m2 or n2. Intermediate k2, l2, m2 or n2 is deprotected to form the corresponding intermediate aa2, ab2, ac2 or ad2. Intermediate aa2, ab2, ac2 or ad2 can be reacted with a carboxylic acid having the general formula R-COOH to form compounds 89-91 and 103.

[0147] The present application provides a method of synthesizing intermediate b as shown in the following synthetic pathway: N-benzyl-L-allothreonine (a) is reduced by reaction with a reducing agent (e.g. borane dimethyl sulfide) to form intermediate b. Other suitable reducing agents can be used in place of borane dimethyl sulfide, such as, but not limited to, lithium aluminum hydride, boron trifluoride etherate and diborane.

[0148] The reducing agent can be used in excess relative to the starting material a. The excess is preferably 2-fold to 10-fold of the reducing agent relative to the starting material a. Preferably, a 5-fold excess of the reducing agent is used relative to the starting material a.

[0149] The reaction can be carried out in a polar aprotic solvent such as THF, DMF, DMSO, or a mixture thereof. Preferably, the reaction is carried out in THF.

[0150] The reaction can be carried out at a temperature ranging from about 50 °C to about 120 °C. Preferably, the reaction is carried out in a range from about 60 °C to about 100 °C. More preferably, the reaction is carried out in a range from about 60 °C to about 80 °C.

[0151] The reaction can be carried out for a period of time ranging from about 3 to about 10 hours. Preferably, the period of time ranges from about 5 to about 8 hours. More preferably, the reaction is carried out for a period of about 6 hours.

[0152] The present application provides a method of synthesizing intermediate c as shown in the following synthetic pathway, wherein PG represents a protecting group: The primary alcohol of intermediate b can be selectively protected using a suitable reagent such as tert-butyldiphenylsilyl to form intermediate c. Other suitable protecting groups can be used including, but not limited to, tert-butyldimethylsilyl, triisopropylsilyl, or trimethylsilyl protecting groups.

[0153] Intermediate b can be reacted with tert-butyldiphenylsilyl chloride to form intermediate c. Alternatively, intermediate b can be reacted with a reagent such as tert-butyldimethylchlorosilane, triisopropylchlorosilane, or trimethylchlorosilane to form intermediate c.

[0154] The reagent can be used in excess relative to intermediate b. A 1.1-fold to 1.5-fold excess of the reagent can be used relative to intermediate b. Preferably, a 1.2-fold excess of the reagent is used relative to intermediate b.

[0155] The reaction can be carried out in the presence of a catalyst such as DMAP, imidazole, or a mixture thereof. Preferably, imidazole is used as the catalyst.

[0156] The catalyst can be used in excess relative to intermediate b. A 1.1-fold to 2-fold excess of the catalyst can be used relative to intermediate b. Preferably, a 1.5-fold excess of the catalyst is used relative to intermediate b.

[0157] The reaction can be carried out in a polar solvent such as acetonitrile, DMF, DMSO, pyridine, THF, or a mixture thereof. Preferably, the reaction is carried out in THF.

[0158] The reaction can be carried out at a temperature of about 20 °C to about 66 °C. Preferably, the reaction is carried out at about 25 °C. The reaction can be carried out for about 5 to about 18 hours. Preferably, the reaction is carried out for about 12 hours.

[0159] The present application provides a method of synthesizing intermediate d as shown in the following synthetic pathway, wherein PG represents a protecting group: Intermediate c can be reacted with 2-bromo-2,2-difluoroacetic acid or 2,2-difluoro-2-iodoacetic acid to form intermediate d. Preferably, intermediate c is reacted with 2-bromo-2,2-difluoroacetic acid to form intermediate d.

[0160] An excess of 2-bromo-2,2-difluoroacetic acid (or 2,2-difluoro-2-iodoacetic acid) can be used relative to intermediate c. A 2-fold to 7-fold excess of 2-bromo-2,2-difluoroacetic acid (or 2,2-difluoro-2-iodoacetic acid) can be used relative to intermediate c. Preferably, a 3-fold excess of 2-bromo-2,2-difluoroacetic acid (or 2,2-difluoro-2-iodoacetic acid) is used relative to intermediate c.

[0161] The reaction is carried out in the presence of a Lewis base. Examples of Lewis bases that can be used to synthesize intermediate d include, but are not limited to, butyllithium, diisopropylamino lithium (LDA), diethylamino lithium (LDEA), sodium amide (NaNH2), sodium hydride (NaH), bis(trimethylsilyl)amido lithium, or mixtures thereof. Preferably, the Lewis base used to synthesize intermediate d is sodium hydride.

[0162] The Lewis base can be used in excess relative to intermediate c. A 2-fold to 6-fold excess of the Lewis base can be used relative to intermediate c. Preferably, a 4.5-fold excess of the Lewis base is used relative to intermediate c.

[0163] The reaction can be carried out in a non-polar solvent (e.g., diethyl ether, benzene, toluene, chloroform, 1,4-dioxane, or mixtures thereof). Preferably, the reaction is carried out in 1,4-dioxane.

[0164] The reaction can be carried out at a temperature of about 15 °C to about 101 °C. Preferably, the reaction can be carried out at a temperature of about 20 °C to about 80 °C. More preferably, the reaction is carried out at about 20 °C. The reaction can be carried out for about 5 to about 18 hours. Preferably, the reaction is carried out for about 12 hours.

[0165] The present application provides a method of synthesizing intermediate e as shown in the following synthetic pathway, wherein PG represents a protecting group: Intermediate d is subjected to 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, DIC, EDC-HCl, BOP, PyBOP, PyAOP, PyBrOP, BOP-Cl, HATU, HBTU, HCTU, TATU, TBTU, T3P, DEPBT, or CDI. Preferably, T3P is used as the coupling reagent.

[0166] The reaction can be carried out in a polar aprotic solvent, such as DMF, DMSO, or a mixture thereof. Preferably, the reaction is carried out in DMF.

[0167] The reaction can be carried out at a temperature of about 15 °C to about 153 °C. Preferably, the reaction can be carried out at a temperature 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.

[0168] The reaction can be carried out for about 1 hour to about 5 hours. Preferably, the reaction is carried out for about 2 hours.

[0169] The present application provides a method of synthesizing intermediate f as shown in the following synthetic pathway, wherein PG represents a protecting group: Intermediate e is reduced by reaction with a reducing agent, such as borane dimethyl sulfide, to form intermediate f. Other suitable reducing agents can be used in place of borane dimethyl sulfide, such as, but not limited to, lithium aluminum hydride, boron trifluoride etherate, and diborane.

[0170] The reducing agent can be used in excess relative to intermediate e. A 2-fold to 10-fold excess of the reducing agent can be used relative to intermediate e. Preferably, a 4-fold excess of the reducing agent is used relative to intermediate e.

[0171] The reaction can be carried out in a polar aprotic solvent, such as THF, DMF, DMSO, or a mixture thereof. Preferably, the reaction is carried out in THF.

[0172] The reaction can be carried out at a temperature of about 20 °C to about 66 °C. Preferably, the reaction can be carried out at a temperature of about 30 °C to about 50 °C. More preferably, the reaction is carried out at about 30 °C. The reaction can be carried out for about 1 hour to about 5 hours. Preferably, the reaction is carried out for about 3 hours.

[0173] The present application provides a method of synthesizing intermediate g as shown in the following synthetic pathway, wherein PG' represents a protecting group: The tert-butyl-diphenylsilyl protecting group can be removed from intermediate f by reaction with a fluorine source to form intermediate g. Suitable reagents for the fluorine source include, but are not limited to, tetra-n-butylammonium fluoride (TBAF) or triethylamine trihydrofluoride. Preferably, TBAF is used to form intermediate g.

[0174] The reagent can be used in excess relative to intermediate f. The reagent can be used in a 1.1-fold to 2-fold excess relative to intermediate f. Preferably, the reagent is used in a 1.5-fold excess relative to intermediate f.

[0175] The reaction can be carried out in a polar aprotic solvent such as THF, DMF, DMSO, or a mixture thereof. Preferably, the reaction is carried out in THF.

[0176] The reaction can be carried out at a temperature 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 can be carried out for about 1 hour to about 5 hours. Preferably, the reaction is carried out for about 2 hours.

[0177] The present application provides a method of synthesizing intermediate h as shown in the synthesis pathway below, wherein PG represents a protecting group: Intermediate g is reacted with hydrogen and palladium on carbon and subsequently deprotected to form intermediate h. Preferably, the reaction is carried out under a hydrogen atmosphere (pressure ranging from about 10 Psi to about 30 Psi). Preferably, the reaction is carried out at about 15 Psi.

[0178] The conversion from intermediate g to intermediate h can be a one-pot process.

[0179] Preferably, about 0.02 to about 0.5 equivalents of palladium on carbon are used. More preferably, about 0.05 equivalents of palladium on carbon are used.

[0180] Any suitable protecting group can be used to form intermediate h. Examples of suitable protecting groups that can be used include Fmoc, BOC, or Ts. Preferably, BOC is used as the protecting group.

[0181] Examples of suitable protecting group reagents to form intermediate h include, but are not limited to, fluorenylmethoxycarbonyl chloride, 9-fluorenylmethyl succinimidyl carbonate, 9-fluorenylmethoxycarbonyl azide, BOC-anhydride, p-toluenesulfonyl chloride. Preferably, BOC-anhydride is used.

[0182] The protecting group reagent can be used in excess relative to intermediate g. The reagent can be used in a 1.1-fold to 2-fold excess relative to intermediate g. Preferably, the reagent is used in a 1.5-fold excess relative to intermediate g.

[0183] The reaction can be carried out in a polar aprotic solvent, such as ethyl acetate, dichloromethane, THF, or a mixture thereof. Preferably, the reaction is carried out in ethyl acetate.

[0184] The reaction can be carried out at a temperature of about 15 °C to about 77 °C. Preferably, the reaction is carried out at about 25 °C. The reaction can be carried out for about 6 to about 18 hours. Preferably, the reaction is carried out for about 12 hours.

[0185] The present application provides a method of synthesizing intermediate I as shown in the following synthetic pathway, wherein PG represents a protecting group: Intermediate h is reacted with isoindoline-1,3-dione to form intermediate i. Isoindoline-1,3-dione can be used in excess relative to intermediate h. Isoindoline-1,3-dione can be used in a 1.1-fold to 2-fold excess relative to intermediate h. Preferably, isoindoline-1,3-dione is used in a 1.5-fold excess relative to intermediate h.

[0186] Preferably, the reaction is carried out in the presence of triphenylphosphine.

[0187] Triphenylphosphine can be used in excess relative to intermediate h. Triphenylphosphine can be used in a 1.1-fold to 2-fold excess relative to intermediate h. Preferably, triphenylphosphine is used in a 1.5-fold excess relative to intermediate h.

[0188] The reaction is carried out in the presence of an oxidizing agent, such as DIAD or DEAD. Preferably, the oxidizing agent DIAD is used. The oxidizing agent can be used in excess relative to intermediate h. The oxidizing agent can be used in a 1.1-fold to 2-fold excess relative to intermediate h. Preferably, the oxidizing agent is used in a 1.5-fold excess relative to intermediate h.

[0189] The reaction can be carried out in a polar aprotic solvent, such as THF, DMF, DMSO, or a mixture thereof. Preferably, the reaction is carried out in THF.

[0190] The reaction can be carried out at a temperature of about -10 °C to about 66 °C. Preferably, the reaction is carried out at about 0 °C to about 20 °C. The reaction can be carried out for about 5 to about 20 hours. Preferably, the reaction is carried out for about 16 hours.

[0191] The present application provides a method of synthesizing intermediate j as shown in the following synthetic pathway, wherein PG' represents a protecting group: 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.

[0192] The hydrazine or hydrazine hydrate can be used in excess relative to intermediate i. The hydrazine or hydrazine hydrate can be used in a 5-fold to 20-fold excess relative to intermediate i. Preferably, the hydrazine or hydrazine hydrate is used in a 10-fold excess relative to intermediate i.

[0193] The reaction can be carried out in a polar protic solvent (e.g., an alcohol, including but not limited to methanol, ethanol, isopropanol, or a mixture thereof). Preferably, the reaction is carried out in methanol.

[0194] The reaction can be carried out at a temperature of about 40 °C to about 65 °C. Preferably, the reaction is carried out at about 60 °C. The reaction can be carried out for about 1 to about 5 hours. Preferably, the reaction is carried out for about 2 hours.

[0195] The present application provides a method of synthesizing intermediate f1 as shown in the synthesis pathway below, wherein PG refers to a protecting group: Intermediate e ((5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2- difluoro-6-methylmorpholin-3-one) is reduced by reaction with a deuterating reagent to form intermediate f1. Suitable deuterating reagents include, but are not limited to, trideuteroborane, LiAlD4, NaBD4. Preferably, the deuterating reagent is trideuteroborane.

[0196] The protecting group (PG) includes, but is not limited to, tert-butyldimethylsilyl, triisopropylsilyl, or trimethylsilyl protecting groups. Preferably, the protecting group is tert- butyldiphenylsilyl.

[0197] The reducing agent can be used in excess relative to intermediate e.

[0198] The reaction can be carried out in a polar aprotic solvent (e.g., THF, DMF, DMSO, or a mixture thereof). Preferably, the reaction is carried out in THF.

[0199] The reaction can be carried out at a temperature of about 0 °C to about 60 °C. Preferably, the reaction can be carried out at a temperature of about 0 °C to about 40 °C. The reaction can be carried out for about 1 hour to about 3 hours, preferably about 1.5 hours. The PG group can be tert-butyldiphenylsilyl.

[0200] The present application provides a method of synthesizing intermediate g1 as shown in the synthesis pathway below, wherein PG refers to a protecting group: The tert-butyldiphenylsilane protecting group can be removed from intermediate fl by reacting it with a fluorine source to form intermediate gl. Suitable reagents that act as a fluorine source include, but are not limited to, tetra-n-butylammonium fluoride (TBAF) or triethylamine trihydrofluoride; preferably TBAF is used. The method of making intermediate gl can be similar to the method described herein for making intermediate g. Reaction conditions, such as reagent amounts, type of solvent used (polar aprotic solvent), and reaction temperature, can be similar to those used when synthesizing intermediate g.

[0201] The reaction can be allowed to proceed for about 1 hour to about 15 hours, preferably about 12 hours.

[0202] The present application provides a method of synthesizing intermediate hi as shown in the synthesis pathway below, wherein PG' refers to a protecting group: The method of making intermediate hi can be similar to the method described herein for making intermediate h.

[0203] Intermediate gl is reacted with hydrogen gas and palladium on carbon, followed by protection to form intermediate hi. Any suitable protecting group can be used to form intermediate hi. Examples of suitable protecting groups that can be used include Fmoc, BOC, or Ts. Preferably, BOC is used as the protecting group.

[0204] Reaction conditions, such as pressure, amount of palladium, protecting group reagent, amount of protecting group reagent, and solvent, can be similar to those used when synthesizing intermediate h.

[0205] The conversion of intermediate gl to intermediate hi can be a one-pot process. The reaction can be carried out at a temperature of about 15 °C to about 77 °C. Preferably, it is carried out at about 20 °C. The reaction can be allowed to proceed for about 6 hours to about 18 hours. Preferably, about 16 hours.

[0206] The present application provides a method of synthesizing intermediate il as shown in the synthesis pathway below, wherein PG' refers to a protecting group: The method of making intermediate il can be similar to the method described herein for making intermediate i.

[0207] Intermediate hi is reacted with isoindoline-1,3-dione to form intermediate il. Process conditions, such as amount of isoindoline-1,3-dione, type of solvent, amount of solvent, type of oxidizing agent, polar aprotic solvent, reaction temperature, and duration of the reaction, can be similar to those used in the method described herein for making intermediate i.

[0208] The present application provides a method of synthesizing intermediate jl as shown in the synthesis pathway below, wherein PG' refers to a protecting group: Intermediate i 1 is reacted with hydrazine or hydrazine hydrate to form intermediate j 1. Preferably, intermediate i is reacted with hydrazine hydrate to form intermediate j 1.

[0209] The method of preparing intermediate j 1 can be similar to the method of preparing intermediate j described herein. Process conditions, such as the amount of hydrazine or hydrazine hydrate, solvent, reaction temperature, and reaction duration, can be similar to the conditions used in the method of preparing intermediate j described herein.

[0210] The present application provides a method of synthesizing intermediate e2' as shown in the following synthetic pathway: N-benzyl-L-allothreonine is reacted with sodium (2-bromo-2,2-difluoroacetyl)oxy 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 sodium (2-bromo-2,2-difluoroacetyl)oxy to form intermediate e2'.

[0211] Examples of the base that can be used include, but are not limited to, potassium tert-butoxide (t-BuOK), lithium tert-butoxide (t-BuOLi), or sodium tert-butoxide (t-BuONa). Preferably, t-BuONa is used.

[0212] The reaction can be carried out in a non-polar solvent (e.g., diethyl ether, benzene, toluene, chloroform, 1,4-dioxane, or a mixture thereof). Preferably, the reaction is carried out in 1,4-dioxane.

[0213] An excess of sodium (2-bromo-2,2-difluoroacetyl)oxy can be used relative to intermediate a. Preferably, a 3-fold excess is used relative to intermediate a.

[0214] The reaction can be carried out at a temperature ranging from about 0 °C to about 35 °C. Preferably, in the range of about 0 °C to about 20 °C. The reaction can be carried out for about 1 hour to about 3 hours. Preferably, the reaction is carried out for about 2 hours.

[0215] Intermediate d2' can be formed in situ, which is preferably quenched with an acid (e.g., hydrochloric acid) to form intermediate e2'. The reaction can be carried out in a polar aprotic solvent (e.g., ethyl acetate, dichloromethane, THF, or a mixture thereof). Preferably, the reaction is carried out in ethyl acetate.

[0216] The reaction can be carried out at a temperature ranging from about 0 °C to about 35 °C. Preferably, in the range of about 0 °C to about 25 °C. The reaction can be carried out for about 1 hour to about 3 hours. Preferably, the reaction is carried out for about 2 hours.

[0217] The present application provides a method of synthesizing intermediate e2'' as shown in the following synthetic pathway: Intermediate e2' is reduced to form intermediate e2". Intermediate e2' is reacted with isobutyl chloroformate and a deuterated reducing agent or deuterated reagent. The deuterated reagent can be deuterium oxide, sodium borodeuteride, or any combination thereof. Preferably, the deuterated reagent can be sodium borodeuteride or sodium borodeuteride with deuterium oxide.

[0218] An excess of the deuterated reagent can be used relative to the starting material e2'.

[0219] The reaction can be carried out in the presence of a base. Suitable bases include, but are not limited to, triethylamine (TEA), DIPEA, and the like. Preferably, TEA is used to form intermediate e2".

[0220] The reaction can be carried out in a polar aprotic solvent, such as THF, DMF, DMSO, or a mixture thereof. Preferably, the reaction is carried out in THF.

[0221] The reaction can be carried out at a temperature ranging from about 0 °C to about 35 °C. Preferably, the reaction can be carried out at a temperature ranging from about 20 °C to about 0 °C to about 25 °C. The reaction can be carried out for about 1 hour to about 3 hours. Preferably, the reaction is carried out for about 2 hours.

[0222] The present application provides a method of synthesizing intermediate g2 as shown in the following synthetic pathway: Intermediate e2" is reduced by reaction with a reducing agent, such as borane dimethyl sulfide, to form intermediate g2. Other suitable reducing agents can be used in place of borane dimethyl sulfide, such as, but not limited to, lithium aluminum hydride, boron trifluoride diethyl etherate, and diborane.

[0223] The reaction can be carried out in a polar aprotic solvent, such as THF, DMF, DMSO, or a mixture thereof. Preferably, the reaction is carried out in THF.

[0224] The reaction can be carried out at a temperature ranging from about 0 °C to about 60 °C. Preferably, the temperature ranges from about 0 °C to about 45 °C. The reaction can be carried out for about 1 hour to about 3 hours. Preferably, the reaction is carried out for about 2.5 hours.

[0225] The present application provides a method of synthesizing intermediate h2 as shown in the following synthetic pathway, wherein PG' refers to a protecting group: Intermediate g2 is reacted with hydrogen gas and palladium on carbon, followed by protection to form intermediate h2. The method of preparing intermediate h2 can be similar to the method of preparing intermediate h described herein. Any suitable protecting group can be used to form intermediate h2. Examples of suitable protecting groups that can be used include Fmoc, BOC, or Ts. Preferably, BOC is used as the protecting group.

[0226] Preferably, the reaction conditions, such as pressure, amount of palladium, suitable protecting group reagent, amount of protecting group reagent, and solvent, are similar to the reaction conditions used in the method of preparing intermediate h. The conversion of intermediate g2 to intermediate h2 can be a one pot process.

[0227] The reaction can be carried out at a temperature of about 15 °C to about 30 °C. Preferably, the reaction is carried out at about 20 °C. The reaction can be carried out for about 6 to about 18 hours, preferably about 12 hours.

[0228] The present application provides a method of synthesizing intermediate i2 as shown in the synthesis pathway below, wherein PG refers to a protecting group: Intermediate h2 is reacted with isoindoline-1,3-dione to form intermediate i2. Preferably, the reaction is carried out in the presence of triphenylphosphine.

[0229] The method of preparing intermediate i2 can be similar to the method of preparing intermediate i described herein.

[0230] Preferably, the reaction conditions, such as amount of triphenylphosphine, oxidizing agent, amount of oxidizing agent, solvent (e.g., polar aprotic solvent), reaction temperature, and reaction duration, are similar to the reaction conditions used in the method of preparing intermediate h described herein.

[0231] The present application provides a method of synthesizing intermediate j2 as shown in the synthesis pathway below, wherein PG refers to a protecting group: Intermediate i2 is reacted with hydrazine or hydrazine hydrate to form intermediate j2. Preferably, intermediate i2 is reacted with hydrazine hydrate to form intermediate j2.

[0232] Preferably, the method of preparing intermediate j2 is similar to the method of preparing intermediate j described herein. Process conditions, such as amount of hydrazine or hydrazine hydrate, solvent, reaction temperature, and reaction duration, can be similar to the conditions used in the method of preparing intermediate j described herein.

[0233] The present application also provides a compound, which is: - (2R,3S)-2-(benzylamino)butane-1,3-diol (intermediate b); - (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); - 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); - ( 5R,6S )-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylic acid tert-butyl ester (Intermediate h); - ( 5R,6S )-5-((1,3-dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (Intermediate i); - (5R,6S )-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (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); - (5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (Intermediate h1); - (5R,6S)-5-((1,3-dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (Intermediate i1); - (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester-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); - (2S, 3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3-methylpiperidine-1 -carboxylic acid tert-butyl ester (intermediate h2); - (5R, 6S)-5-((1,3-dioxoisoindolin-2-yl)methyl-d2)-2,2-difluoro-6-methylmorpholine-4- carboxylic acid tert-butyl ester (intermediate i2); or - (5R, 6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert- butyl ester (intermediate j2).

[0234] Preferably, (5R, 6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (intermediate j) can be prepared starting from compound (a) or any of the intermediate compounds (b-i).

[0235] Preferably, (5R, 6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester is prepared by the following process: - reducing N-benzyl-L-allothreonine (a) by reaction 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-difluoroacetic 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-morpholin-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-morpholine (intermediate f); - reacting intermediate (f) with a fluorine source to form ((2S,3R)-4-benzyl-6,6- difluoro-2-methylmorpholin-3-yl)methanol (intermediate g); - reacting intermediate (g) with hydrogen gas and palladium on 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).

[0236] Preferably, tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate-3,3-d2 (intermediate j1) can be prepared starting from any one of the intermediate compounds (e, f1 - i1).

[0237] Preferably, tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate-3,3-d2 (intermediate j1) can be prepared by the following method: - reducing (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6- methylmorpholin-3-one (intermediate e) with a deuterating reagent to form (5R,6S)-4- benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholin-3,3-d2 (intermediate f1); - reacting intermediate (f1) with a fluorine source to form ((2S,3R)-4-benzyl-6,6- difluoro-2-methylmorpholin-3-yl-5,5-d2)methanol (intermediate g1); - reacting intermediate (g1) with hydrogen gas and palladium on 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 h1); - reacting intermediate (h1) 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).

[0238] Preferably, tert-butyl (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2) can be prepared starting from any one of compounds (a) or intermediate compounds (e2' - i2).

[0239] Preferably, tert-butyl (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2) is prepared by the following method: - reacting N-benzyl-L-allothreonine (a) with sodium (2-bromo-2,2-difluoroacetyl)oxy followed by reaction 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 deuterating 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)methanol-d2 (intermediate g2); - reacting intermediate (g2) with hydrogen and palladium on carbon and di-tert-butyl dicarbonate to form (2S,3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3-methylpiperidine-1- carboxylate tert-butyl ester (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).

[0240] The present application provides a method of synthesizing compounds 1-49, 60-69, 78-88, 92-102 as shown in the following synthetic pathways: The structures of compounds 1-49, 60-69, 78-88, and 92-102 are shown above.

[0241] The present application also provides a process for preparing a compound of Formula I: wherein X, X', R and Het can each independently be as defined above; The process comprises the steps of: (a) reacting (5R,6S)-tert-butyl 5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate with a halogenated heteroaromatic compound in the presence of a base to form a first intermediate compound; (b) reacting the first intermediate compound with an acid to form a second intermediate compound; and (c) reacting the second intermediate compound with a carboxylic acid having the general formula R-COOH to obtain a compound of Formula I.

[0242] The intermediate j undergoes a nucleophilic aromatic substitution reaction with a halogenated heteroaromatic compound to form one of the intermediates k-z2.

[0243] Preferably, the intermediate k-z2 is: ( 5R,6S ) tert-butyl 2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate k); ( 5R,6S ) tert-butyl 2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate 1); ( 5R,6S ) tert-butyl 2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate m); ( 5R,6S ) tert-butyl 5-(((5-chloropyridin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate n); ( 5R,6S ) tert-butyl 5-(((5-chloropyrimidin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate o); (5R,6S)-tert-butyl 2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate p); (5R,6S)-tert-butyl 2,2-difluoro-6-methyl-5-(((6-(trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate q); (5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester (Intermediate r); (5R,6S)-2,2-difluoro-5-(((3-fluoro-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)-6-methylmorpholine-4-carboxylic acid tert-butyl ester (Intermediate s); (5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester (Intermediate t) (5R,6S)-5-(((5-cyclopropylpyrimidin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylic acid tert-butyl ester (Intermediate u); (5R,6S)-2,2-difluoro-5-(((3-methoxy-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)-6-methylmorpholine-4-carboxylic acid tert-butyl ester (Intermediate v); (5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester (Intermediate w); (5R,6S)-5-(((3-cyano-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,2- difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (Intermediate x): (5R,6S)-5-(((5-chloro-3-fluoropyridin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylic acid tert-butyl ester (Intermediate y); (5R,6S)-2,2-difluoro-6-methyl-5-(((4-methyl-5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester (Intermediate z); (5R,6S)-5-(((5-(difluoromethyl)pyrimidin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylic acid tert-butyl ester (Intermediate z1); or 5R,6S (5R,6S)-5-(((5-(difluoromethyl)pyrazin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylic acid tert-butyl ester (Intermediate z2). 5R,6S

[0244] ​​In some embodiments, (5R,6S)-tert-butyl 5-(aminomethyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate is a deuterated compound. Preferably, the deuterated compound is (5R,6S)-tert-butyl 5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate-3,3-d2 or (5R,6S)-tert-butyl 5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine- 4-carboxylate, which is reacted with a halogenated heteroaromatic compound in the presence of a base in step (a) to form the first intermediate compound. The first intermediate compound can be reacted with an acid to form the second intermediate compound; and the second intermediate compound can be reacted with a carboxylic acid having the general formula R-COOH to yield a deuterated compound of Formula I.

[0245] The present application provides a method of synthesizing compounds 50-59, 70-77 as shown in the following synthetic pathways: The structures of compounds 50-59, 70-77 are shown above.

[0246] The present application also provides a method of preparing a compound of Formula ID(a): ID(a); wherein X, X', R and Het can each independently be as defined above; and R 6 may be hydrogen or deuterium, The method comprises the following steps: (a) reacting (5R,6S)-tert-butyl 5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate-3,3-d2 (intermediate j1) with a halogenated heteroaromatic compound in the presence of a base to form a first intermediate compound; (b) reacting the first intermediate compound with an acid to form a second intermediate compound; and (c) reacting the second intermediate compound with a carboxylic acid having the general formula R-COOH to yield a compound of Formula ID(a).

[0247] Intermediate j1 can undergo a nucleophilic aromatic substitution reaction with a halogenated heteroaromatic compound to form one of intermediates k1, 11 and m1.

[0248] Preferably, intermediates k1, 11 and m1 are: ( 5R,6S ) -2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4- carboxylic acid tert-butyl ester-3,3-d2 (k1); ( 5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (ml); or (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (ml).

[0249] The present application provides a method of synthesizing compounds 89-91 and 103 as shown in the following synthetic pathways: The structures of compounds 89-91 and 103 are shown above.

[0250] The present application also provides a method of preparing a compound of formula ID(b): ID(b); wherein X, X', R and Het can each independently be as defined above; and R 7 may be hydrogen or deuterium, The method comprises the following steps: (a) reacting (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (intermediate j2) with a halogenated heteroaromatic compound in the presence of a base to form a first intermediate compound; (b) reacting the first intermediate compound with an acid to form a second intermediate compound; and (c) reacting the second intermediate compound with a carboxylic acid having the general formula R-COOH to give a compound of formula ID(b).

[0251] Preferably, (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (intermediate j2) is prepared by the following method: - reacting N-benzyl-L-allothreonine (a) with sodium (2-bromo-2,2-difluoroacetyl)oxy followed by reaction 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 deuterating 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)methanol-d2 (intermediate g2); - The intermediate (g2) is reacted with hydrogen, palladium on carbon, and di-tert-butyl dicarbonate to form (2S,3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3-methylpiperidine-1-carboxylic acid tert-butyl ester (intermediate h2); - The intermediate (h2) is reacted with isoindoline-1,3-dione to form (5R,6S)-5-((1,3-dioxoisoindoline-2-yl)methyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (intermediate i2); and - React intermediate (i2) with hydrazine or hydrazine hydrate to form (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (intermediate j2).

[0252] Intermediate j2 undergoes a nucleophilic aromatic substitution reaction with a halogenated heteroaromatic compound to form one of intermediates k2, l2, m2, and n2.

[0253] Preferably, the intermediates k2, l2, m2, and n2 are: ( 5R,6S 2,2-Difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl-d2)morpholine-4-carboxylic acid tert-butyl ester (k2); ( 5R,6S )-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl-d2)morpholine-4-carboxylate (l2); ( 5R,6S 2,2-Difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl-d2)morpholine-4-carboxylic acid tert-butyl ester (m2); or ( 5R,6S 5-(((5-chloropyridin-2-yl)amino)methyl-d2)-2,2-difluoro-6-methylmorpholino-4-carboxylic acid tert-butyl ester (n2). The halogen substituted heteroaromatic compound can be selected from the group consisting of halogen substituted pyridine, halogen substituted pyridazine, halogen substituted pyrazine, halogen substituted pyrimidine, halogen substituted triazole, halogen substituted tetrazole, halogen substituted pyrazole, halogen substituted furan, halogen substituted thiophene, halogen substituted pyrrole, halogen substituted imidazole, halogen substituted isoxazole, halogen substituted oxazole, halogen substituted isothiazole, halogen substituted thiazole and any derivatives thereof, wherein the halogen substituted heteroaromatic group can be further substituted; wherein the further substituents of the halogen substituted heteroaromatic group, if present, are independently selected from the group consisting of unsubstituted (Ci-C4)-straight chain alkyl, unsubstituted (Ci-C4)-branched chain alkyl, unsubstituted (Ci-C4)-alkoxy, unsubstituted (C3-C8)-cycloalkyl, substituted (Ci-C4)-straight chain alkyl, substituted (Ci-C4)-branched chain alkyl, substituted (Ci-C4)-alkoxy, substituted (C3-C8)-cycloalkyl, cyano and halogen (e.g. F, CI, Br). Preferably, the further substituents of the heteroaryl group are CI, F, CF3, CH3, methoxy, nitrile or cyclopropyl.

[0254] The halogen substituted heteroaromatic compound can be a fluorine substituted heteroaromatic compound, a chlorine substituted heteroaromatic compound, a bromine substituted heteroaromatic compound or an iodine substituted heteroaromatic compound. Preferably, the halogen substituted heteroaromatic compound can be a chlorine substituted heteroaromatic compound.

[0255] The halogen substituted heteroaromatic compound is preferably selected from the group consisting of 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)pyrazine-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)pyrimidine, 5-chloro-2-fluoropyridine, 2-fluoro-5-(trifluoromethyl)pyridine, 2-chloro-5-(trifluoromethyl)pyrimidine, 2-chloro-5-(trifluoromethyl)pyrazine.

[0256] The nucleophilic aromatic substitution reaction is carried out in the presence of a base. Examples of bases that can be used include, but are not limited to, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydride, TEA or DIPEA. Preferably, the nucleophilic aromatic substitution reaction is carried out in the presence of potassium carbonate.

[0257] An excess of base can be used relative to intermediate j, j1, or j2. A 2-fold to 6-fold excess of base can be used relative to intermediate j. Preferably, a 3-fold excess of base is used relative to intermediate j, j1, or j2.

[0258] The reaction can be carried out in a polar aprotic solvent (e.g., THF, DMF, DMSO, or a mixture thereof). Preferably, the reaction is carried out in DMSO.

[0259] The reaction can be carried out at a temperature of about 50 °C to about 189 °C. Preferably, the reaction is carried out at about 80 °C.

[0260] The reaction can be carried out for about 6 to about 18 hours. Preferably, the reaction is carried out for about 12 hours.

[0261] Deprotection of intermediate k-z2 by treatment with an acid to form the corresponding intermediate aa-ar.

[0262] Preferably, intermediate aa-ar is: 5-chloro- N -((( 5R,6S )-6,6-difluoro-2-methylmorpholin-3-yl)methyl)pyridin-2-amine hydrochloride (intermediate aa); N -((( 2S,3R )-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride (intermediate ab); N-((( 2S,3R )-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride (intermediate ac); N -((( 2S,3R )-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride (intermediate ad); 5-chloro-N-((( 2S,3R )-6,6-difluoro-2-methylmorpholin-3-yl)methyl)pyrimidin-2-amine hydrochloride (intermediate ae); N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-4-(trifluoromethyl)pyrimidin-2-amine hydrochloride (intermediate af); N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-6-(trifluoromethyl)pyrazin-2-amine hydrochloride (intermediate ag); N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-4-(trifluoromethyl)pyridine-2-amine hydrochloride (intermediate ah); N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3-fluoro-5-(trifluoromethyl)pyridine-2-amine hydrochloride (intermediate ai); N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyridine-2-amine (intermediate aj); 5-Cyclopropyl-N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)pyrimidine-2-amine hydrochloride (intermediate ak); N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3-methoxy-5-(trifluoromethyl)pyridine-2-amine (intermediate al); N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyrazine-2-amine hydrochloride (intermediate am); 2-((((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)amino)-5-(trifluoromethyl)nicotinonitrile hydrochloride (intermediate an); 5-Chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3-fluoropyridine-2-amine hydrochloride (intermediate ao); N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-4-methyl-5-(trifluoromethyl)pyrimidin-2-amine (intermediate ap). N-((( 2S,3R )-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-5-(difluoromethyl)pyrimidine-2-amine hydrochloride (intermediate aq); or. N-((( 2S,3R )-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-5-(difluoromethyl)pyrazine-2-amine hydrochloride (intermediate ar).

[0263] Intermediates k1, l1, and m1 are deprotected by acid treatment to form the corresponding intermediates ab1, ac1, and ad1. Preferably, intermediates ab1, ac1, and ad1 are: N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyrazine-2-amine hydrochloride (intermediate ab1); 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).

[0264] intermediates k2, 1 2, m2, and n2 to form the corresponding intermediates aa2, ab2, ac2, and ad2. Preferably, intermediates aa2, ab2, ac2, and ad2 are: 5-chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl-5,5-d2)methyl)- pyrimidin-2-amine hydrochloride (aa2); 2S,3R 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)pyrimidin-2-amine hydrochloride (intermediate ac1); or 2S,3R 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)pyrimidin-2-amine hydrochloride (intermediate ac1); or 2S,3R 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)pyrimidin-2-amine hydrochloride (intermediate ac1); or

[0265] Examples of acids that can be used for deprotection include, but are not limited to, aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid. Preferably, hydrochloric acid is used for deprotection of intermediates k2-z2, k1-m1, and k2-n2.

[0266] The deprotection can be carried out in a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1,4-dioxane, or a mixture thereof. Preferably, the reaction is carried out in 1,4-dioxane.

[0267] The deprotection can be carried out at a temperature of about 12 °C to about 40 °C. Preferably, the reaction is carried out at about 20 °C.

[0268] The deprotection can be carried out for about 30 minutes to about 5 hours. Preferably, the reaction is carried out for about 2 hours.

[0269] Intermediates aa-ar, ab1-ad1, aa2-ad2 are reacted with a carboxylic acid having the general formula R-COOH to form compounds 1-103 disclosed herein; wherein R is selected from a five- or six-membered aryl or heteroaryl group, wherein the aryl or heteroaryl group is unsubstituted or substituted with one or more substituents. Preferably, R in the compound of Formula I includes a five-membered heteroaryl group that 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 aryl group that is an unsubstituted aryl or a substituted aryl, or a derivative thereof; or a six-membered heteroaryl group that 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 embodiments, at least one hydrogen in R is replaced with deuterium.

[0270] The carboxylic acids R-COOH preferably include 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-1H-pyrazole-3-carboxylic acid (CAS 2125741-28-6), 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-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-1H-pyrazole-3-carboxylic acid (CAS 2044704-99-4), 1-methyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylic acid (CAS 2125740-38-5), 4-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (CAS 2024759-24-6), 4-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (CAS 2125740-41-0), 4-(4-fluorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (CAS 127919-87-3), 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid, 4-(5-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid, 5-(5-fluoropyrimidin-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid, 5-(5-methoxypyridin-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid, 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-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)-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyridin-2-yl)-5-methyl-1 -(methyl-d3)-1H-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, H - 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)-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyridin-3-yl)-1,5-dimethyl-1H-pyrazole-carboxylic acid; 4-(4-fluoropyridin-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid, 4-(4-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyrimidin-2-yl)-1 -methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylic acid.

[0271] The carboxylic acids R-COOH described herein can be deuterated, wherein at least one hydrogen is replaced by 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-1H-pyrazole-3-carboxylic acid are deuterated. More preferably, the N-Me or C-Me group of the pyrazole ring of the carboxylic acids R-COOH is deuterated. More preferably, 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 is deuterated.

[0272] 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 -(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-l,2,3-triazol-2-yl)picolinic acid hydrochloride.

[0273] The reaction of the intermediate aa-ar, ab1-ad1, aa2-ad2 with the carboxylic acid R-COOH can be carried out in the presence of a coupling reagent. Suitable coupling reagents include, but are not limited to, DCC, DIC, EDC-HCl, BOP, PyBOP, PyAOP, PyBrOP, BOP-Cl, HATU, HBTU, HCTU, TATU, TBTU, T3P, DEPBT, or CDI. Preferably, HATU is used as the coupling reagent.

[0274] The reaction of the intermediate aa-ar, ab1-ad1, aa2-ad2 with the carboxylic acid R-COOH can be carried out in the presence of a base. Any suitable base can be used for the reaction. Examples of suitable bases include, but are not limited to, DIPEA or TEA. Preferably, DIPEA is used as the base in the reaction.

[0275] The reaction of the intermediate aa-ar, ab1-ad1, aa2-ad2 with the carboxylic acid R-COOH can be carried out in a polar aprotic solvent (e.g., THF, dichloromethane, ethyl acetate, DMF, or DMSO). Preferably, the reaction is carried out in dichloromethane.

[0276] The reaction of the intermediate aa-ar, ab1-ad1, aa2-ad2 with the carboxylic acid R-COOH can be carried out at a temperature of about -10 °C to about 40 °C. Preferably, the reaction is carried out at about 0 °C to about 20 °C.

[0277] The reaction of the intermediate aa-ar, ab1-ad1, aa2-ad2 with the carboxylic acid R-COOH can be carried out for about 1 hour to about 6 hours. Preferably, the reaction is carried out for about 2.5 hours.

[0278] The present application also provides a method of synthesizing a carboxylic acid having the general formula R-COOH as shown in the following synthetic pathway: Preferably, the R-COOH is 4-(4-cyanophenyl)- 1 -methyl- 1 H-pyrazole-3-carboxylic acid.

[0279] The starting material selected from tert-butyl 4-iodo-1-methyl-1H-pyrazole-3-carboxylate, tert-butyl 4-bromo-1-methyl-1H-pyrazole-3-carboxylate or tert-butyl 4-chloro-1-methyl-1H-pyrazole-3-carboxylate can be reacted with (4-cyanophenyl)boronic acid or its derivatives (e.g. boronic ester or organotrifluoroborate) via Suzuki coupling to form the intermediate.

[0280] Alternatively, the starting material selected from tert-butyl 4-iodo-1-methyl-1H-pyrazole-3-carboxylate, tert-butyl 4-bromo-1-methyl-1H-pyrazole-3-carboxylate or tert-butyl 4-chloro-1-methyl-1H-pyrazole-3-carboxylate can be reacted with 4-cyanophenyl derivatives suitable for Hiyama coupling, Stille coupling, Heck coupling, Kumada coupling or Negishi coupling.

[0281] The (4-cyanophenyl)boronic acid or its derivatives can be used in excess relative to the starting material. The (4-cyanophenyl)boronic acid or its derivatives can be used in 1.1-fold to 1.5-fold excess relative to the starting material. Preferably, the (4-cyanophenyl)boronic acid or its derivatives is used in 1.2-fold excess relative to the starting material.

[0282] The reaction can 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.

[0283] The reaction can 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)Cl2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2 or Pd(dppp)Cl2. More preferably, Pd(dtbpf)Cl2 is used as the catalyst.

[0284] Preferably, about 0.02 to about 0.5 equivalents of the catalyst is used relative to the starting material. More preferably, about 0.05 equivalents of the catalyst is used.

[0285] The reaction can be carried out in the presence of a base. Examples of the base that can be used include, but are not limited to, K2CO3, KOH, Cs2CO3, K3PO4, NaOH or NEt3. Preferably, K3PO4 is used. t Bu, Cs2CO3, K3PO4, NaOH or NEt3. Preferably, K3PO4 is used.

[0286] The base can be used in excess relative to the starting material. The base can be used in 2-fold to 6-fold excess relative to the starting material. Preferably, the base is used in 3-fold excess relative to the starting material.

[0287] The reaction can be carried out at a temperature of about 50 °C to about 100 °C. Preferably, the reaction is carried out at about 80 °C. The reaction can be carried out for about 30 minutes to about 5 hours. Preferably, the reaction is carried out for about 2 hours.

[0288] The reaction can be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0289] The formed intermediate can be deprotected by reaction with an acid. Examples of acids that can be used include, but are not limited to, hydrochloric acid, trifluoroacetic acid, or phosphoric acid. Preferably, hydrochloric acid is used.

[0290] The deprotection can be carried out in a non-polar solvent, such as diethyl ether, benzene, toluene, chloroform, 1,4-dioxane, or a mixture thereof. Preferably, the reaction is carried out in 1,4-dioxane.

[0291] The deprotection can be carried out at a temperature of about 20 °C to about 80 °C. Preferably, the reaction is carried out at about 50 °C. The deprotection can be carried out for about 30 minutes to about 5 hours. Preferably, the reaction is carried out for about 2 hours.

[0292] The present application also provides another method of synthesizing a carboxylic acid having the general formula R-COOH, as shown in the following synthetic pathway: Preferably, the R-COOH is 4-(5-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-3- carboxylic acid.

[0293] The starting material selected from 6-iodopyridine-3-carbonitrile, 6-bromopyridine-3- carbonitrile, or 6-chloropyridine-3-carbonitrile can be reacted with (3-(tert- butyloxycarbonyl)-1-methyl-1H-pyrazol-4-yl)boronic acid or a derivative thereof (e.g., boronic ester or organic trifluoroborate salt) via Suzuki coupling to form an intermediate.

[0294] Alternatively, the starting material can be reacted with a (3-(tert-butyloxycarbonyl)-1- methyl-1H-pyrazol-4-yl) derivative suitable for Hiyama coupling, Stille coupling, Heck coupling, Kumada coupling, or Negishi coupling.

[0295] The compound selected from 6-iodopyridine-3-carbonitrile, 6-bromopyridine-3- carbonitrile, or 6-chloropyridine-3-carbonitrile can be used in excess relative to the starting material. A 1.1-fold to 1.5-fold excess relative to the starting material can be used. Preferably, a 1.2-fold excess relative to the starting material is used.

[0296] The reaction can 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.

[0297] The reaction can 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)Cl2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2, or Pd(dppp)Cl2. More preferably, Pd(dtbpf)Cl2 is used as the catalyst.

[0298] Preferably, about 0.02 to about 0.5 equivalents of the catalyst is used relative to the starting material. Preferably, about 0.05 equivalents of the catalyst is used.

[0299] The reaction can be carried out in the presence of a base. Examples of bases that can be used include, but are not limited to, K2CO3, KOH, Cs2CO3, K3PO4, NaOH, or NEt3. Preferably, K3PO4 is used. t Bu, Cs2CO3, K3PO4, NaOH, or NEt3. Preferably, K3PO4 is used.

[0300] The base can be used in excess relative to the starting material. The base can be used in a 1.1-fold to 5-fold excess relative to the starting material. Preferably, the base is used in a 1.5-fold excess relative to the starting material.

[0301] The reaction can be carried out at a temperature of about 50 °C to about 100 °C. Preferably, the reaction is carried out at about 80 °C. The reaction can be carried out for about 30 minutes to about 5 hours. Preferably, the reaction is carried out for about 2 hours.

[0302] The reaction can be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0303] The formed intermediate can be deprotected by reaction with an acid. Examples of acids that can be used include, but are not limited to, hydrochloric acid, trifluoroacetic acid, or phosphoric acid. Preferably, hydrochloric acid is used.

[0304] The deprotection can be carried out in a non-polar solvent (such as diethyl ether, benzene, toluene, chloroform, 1,4-dioxane, or a mixture thereof). Preferably, the reaction is carried out in 1,4-dioxane.

[0305] The deprotection can be carried out at a temperature of about 10 °C to about 50 °C. Preferably, the reaction is carried out at about 20 °C. The deprotection can be carried out for about 6 hours to about 18 hours. Preferably, the reaction is carried out for about 12 hours.

[0306] The present application also provides another method for synthesizing a carboxylic acid having the general formula R-COOH, as shown in the following synthetic pathway: Preferably, R-COOH is 5-(5-fluoropyrimidin-2-yl)-l-methyl-lH-imidazole-4- carboxylic acid.

[0307] The starting material is selected from the group consisting of 5-bromo-l-methyl-lH- imidazole-4-carboxylate, methyl 5-iodo-l-methyl-lH-imidazole-4-carboxylate or methyl 5-chloro-l-methyl-lH-imidazole-4-carboxylate, which can be converted to an organotin stannane intermediate by reaction with a hexaalkyldistannane, such as hexamethyldistannane or hexabutyldistannane.

[0308] The hexaalkyldistannane can be used in excess relative to the starting material. A 1.2-fold to 5-fold excess relative to the starting material can be used. Preferably, a 2-fold excess relative to the starting material is used.

[0309] The reaction can be carried out in a non-polar solvent, such as chloroform, 1,4- dioxane or toluene. Preferably, the reaction is carried out in toluene.

[0310] The reaction can 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)Cl2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2or Pd(dppp)Cl2. More preferably, Pd(PPh3)4is used as the catalyst.

[0311] Preferably, about 0.02 to about 0.8 equivalents of the catalyst relative to the starting material are used. More preferably, about 0.1 equivalents of the catalyst are used.

[0312] The reaction can be carried out at a temperature 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 can be carried out for about 3 minutes to about 10 hours. Preferably, the reaction is carried out for about 6 hours.

[0313] The reaction can be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0314] The organotin stannane intermediate can form a second intermediate by a Stille coupling reaction with a compound selected from the group consisting of 2-bromo-5-fluoro- pyrimidine, 2-iodo-5-fluoro-pyrimidine or 2-chloro-5-fluoro-pyrimidine.

[0315] Alternatively, a compound selected from 2-bromo-5-fluoro-pyrimidine, 2-iodo-5-fluoro-pyrimidine or 2-chloro-5-fluoro-pyrimidine can be reacted with a 1-methyl-1H-imidazole-4-carboxylate derivative suitable for Hiyama coupling, Suzuki coupling, Heck coupling, Kumada coupling or Negishi coupling.

[0316] A compound selected from 2-bromo-5-fluoro-pyrimidine, 2-iodo-5-fluoro-pyrimidine or 2-chloro-5-fluoro-pyrimidine can be used in excess relative to the organotin stannane intermediate. A 1.1-fold to 3-fold excess relative to the organotin stannane intermediate can be used. Preferably, a 1.5-fold excess relative to the organotin stannane intermediate is used.

[0317] The reaction can 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.

[0318] The reaction can 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)Cl2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2or Pd(dppp)Cl2. More preferably, Pd(PPh3)4is used as the catalyst.

[0319] Preferably, about 0.02 to about 0.5 equivalents of the catalyst relative to the organotin stannane intermediate are used. Preferably, about 0.1 equivalents of the catalyst are used.

[0320] The reaction can be carried out at a temperature of about 50 °C to about 140 °C. Preferably, the reaction is carried out at about 120 °C. The reaction can be carried out for about 10 hours to about 22 hours. Preferably, the reaction is carried out for 16 hours.

[0321] The reaction can be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0322] The second intermediate can be deprotected by reaction with an acid or a base. Examples of acids that can be used include, but are not limited to, hydrochloric acid, trifluoroacetic acid or phosphoric acid. Examples of bases that can be used include, but are not limited to, lithium hydroxide, sodium hydroxide or potassium hydroxide. Preferably, hydrochloric acid is used.

[0323] The deprotection can be carried out in neat acid or base.

[0324] The concentration of the acid or base can range from about 3 M to about 10 M. Preferably, a concentration of about 6 M is used.

[0325] The deprotection can be carried out at a temperature of from about 50 °C to about 100 °C. Preferably, the reaction is carried out at about 80 °C. The deprotection can be carried out for a period of from about 6 hours to about 22 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0326] The present application also provides another method of synthesizing a carboxylic acid having the general formula R-COOH, as shown in the following synthetic pathway: Preferably, R-COOH is 5-(5-methoxypyridin-2-yl)-l-methyl-lH-imidazole-4- carboxylic acid.

[0327] The starting material selected from the group consisting of methyl 5-bromo-l-methyl- lH-imidazole-4-carboxylate, methyl 5-chloro-l-methyl-lH-imidazole-4-carboxylate or methyl 5-iodo-l-methyl-lH-imidazole-4-carboxylate can be reacted with tributyl-(5-methoxy-2-pyridyl)stannane or its derivatives (e.g. trimethyl-(5-methoxy-2-pyridyl)stannane) via a Stille coupling reaction to form the intermediate.

[0328] Alternatively, the starting material selected from the group consisting of methyl 5-bromo-l-methyl-lH-imidazole-4-carboxylate, methyl 5-chloro-l-methyl-lH-imidazole-4-carboxylate or methyl 5-iodo-l-methyl-lH-imidazole-4-carboxylate can be reacted with a 5-methoxy-2-pyridyl derivative suitable for Hiyama coupling, Suzuki coupling, Heck coupling, Kumada coupling or Negishi coupling.

[0329] The tributyl-(5-methoxy-2-pyridyl)stannane or its derivatives can be used in excess relative to the starting material. The tributyl-(5-methoxy-2-pyridyl)stannane or its derivatives can be used in an excess of from 1.1 times to 1.5 times relative to the starting material. Preferably, the tributyl-(5-methoxy-2-pyridyl)stannane or its derivatives are used in an excess of 1.2 times relative to the starting material.

[0330] The reaction can be carried out in a non-polar solvent (e.g. chloroform, 1,4- dioxane, xylene or toluene). Preferably, the reaction is carried out in xylene.

[0331] The reaction can 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)Cl2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2 or Pd(dppp)Cl2. More preferably, Pd(PPh3)4 is used as the catalyst.

[0332] Preferably, about 0.02 to about 0.5 equivalents of the catalyst is used relative to the starting material. Preferably, about 0.1 equivalents of the catalyst is used.

[0333] The reaction can be carried out at a temperature of about 50 °C to about 140 °C. Preferably, the reaction is carried out at about 140 °C.

[0334] The reaction can be carried out for about 10 hours to about 20 hours. Preferably, the reaction is carried out for about 16 hours.

[0335] The reaction can be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0336] The intermediate can be deprotected by reaction with an acid or a base. Examples of acids that can be used include, but are not limited to, hydrochloric acid, trifluoroacetic acid, or phosphoric acid. Examples of bases that can be used include, but are not limited to, lithium hydroxide, sodium hydroxide, or potassium hydroxide. Preferably, hydrochloric acid is used.

[0337] The deprotection can be carried out in neat acid or base.

[0338] The concentration of the acid or base can range from about 3 M to about 10 M. Preferably, a concentration of about 6 M is used.

[0339] The deprotection can be carried out at a temperature of about 50 °C to about 100 °C. Preferably, the reaction is carried out at about 80 °C. The deprotection can be carried out for about 6 hours to about 22 hours. Preferably, the reaction is carried out for about 16 hours.

[0340] The present application also provides another method of synthesizing a carboxylic acid having the general formula R-COOH, as shown in the following synthetic pathway, wherein PG refers to a protecting group: Preferably, R-COOH is 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1 H-pyrazole-3- carboxylic acid.

[0341] The starting material is 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 can be used. Examples of suitable protecting groups that can be used include Me, BOC, or benzyl. Preferably, BOC is used as the protecting group.

[0342] 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.

[0343] The reagent can be used in excess relative to the first intermediate. The reagent can be used in a 1.5-fold to 5-fold excess relative to the first intermediate. Preferably, the reagent is used in a 3-fold excess relative to the first intermediate.

[0344] The reaction can be carried out in the presence of a catalyst, such as DMAP, imidazole, or a mixture thereof. Preferably, imidazole is used as the catalyst.

[0345] The reaction can be carried out in a polar aprotic solvent, such as THF, DMF, DMSO, a polar protic solvent, such as water, methanol, ethanol, isopropanol, tert-butanol, 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 tert-butanol.

[0346] The reaction can be carried out at a temperature of about 10 °C to about 50 °C. Preferably, the reaction is carried out at about 20 °C. The reaction can be carried out for about 6 to about 18 hours. Preferably, the reaction is carried out for about 12 hours.

[0347] The first intermediate can be converted to a boronic acid or a derivative thereof (e.g., a boronate ester or an organic trifluoroborate salt), forming a second intermediate. The first intermediate can be reacted with a trialkyl borate ester, such as trimethyl borate, tributyl borate, or triisopropyl borate, to form the second intermediate.

[0348] The trialkyl borate ester can be used in excess relative to the first intermediate. The trialkyl borate ester can be used in a 1.2-fold to 3-fold excess relative to the first intermediate. Preferably, the trialkyl borate ester is used in a 1.5-fold excess relative to the first intermediate.

[0349] The reaction can be carried out in a polar aprotic solvent, such as THF, DMF, DMSO, or a mixture thereof. Preferably, the reaction is carried out in THF.

[0350] The reaction is carried out in the presence of a Lewis base. Examples of Lewis bases that can be used to synthesize the second intermediate include, but are not limited to, butyl lithium, diisopropylamino lithium (LDA), diethylamino lithium (LDEA), sodium amide (NaNH2), sodium hydride (NaH), bis(trimethylsilyl)amino lithium, or a mixture thereof. Preferably, the Lewis base used to synthesize the second intermediate is butyl lithium.

[0351] The Lewis base can be used in excess relative to the first intermediate. The Lewis base can be used in a 1.2-fold to 3-fold excess relative to the first intermediate. Preferably, the Lewis base is used in a 1.5-fold excess relative to the first intermediate.

[0352] The reaction can be carried out at a temperature of about -78 °C to about 60 °C. Preferably, the reaction is carried out at about -78 °C to about 20 °C. The reaction can be carried out for about 1 hour to about 8 hours. Preferably, the reaction is carried out for about 3 hours.

[0353] The second intermediate can react with 2-bromo-5-fluoro-pyrimidine / 2-iodo-5-fluoro- pyrimidine / 2-chloro-5-fluoro-pyrimidine to form a third intermediate via Suzuki coupling reaction.

[0354] Alternatively, 2-bromo-5-fluoro-pyrimidine / 2-iodo-5-fluoro-pyrimidine / 2-chloro-5- fluoro-pyrimidine can react with (3-(tert-butoxycarbonyl)-l,5-dimethyl-lH-pyrazol-4- yl) derivative suitable for Hiyama coupling, Stille coupling, Heck coupling, Kumada coupling or Negishi coupling.

[0355] 2-bromo-5-fluoro-pyrimidine / 2-iodo-5-fluoro-pyrimidine / 2-chloro-5-fluoro-pyrimidine can be used in excess relative to the second intermediate. The base can be used in a 1.1-fold to 3-fold excess relative to the second intermediate. Preferably, the base is used in a 1.5-fold excess relative to the second intermediate.

[0356] The reaction can be carried out in a polar aprotic solvent such as DMF, DMSO, or a mixture thereof; or in a polar protic solvent such as water, methanol, ethanol, isopropanol, tert-butanol, or any combination thereof. Preferably, the reaction is carried out in a combination of DMF and water.

[0357] The reaction can 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)Cl2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2, or Pd(dppp)Cl2. More preferably, Pd(PPh3)4 is used as the catalyst.

[0358] Preferably, about 0.02 to about 0.5 equivalents of the catalyst are used relative to the second intermediate. Preferably, about 0.05 equivalents of the catalyst are used.

[0359] The reaction can be carried out in the presence of a base. Examples of bases that can be used include, but are not limited to, K2CO3, KOH, Cs2CO3, K3PO4, NaOH, or NEt3. Preferably, K2CO3 is used. t Bu, Cs2CO3, K3PO4, NaOH, or NEt3. Preferably, K2CO3 is used.

[0360] The base can be used in excess relative to the second intermediate. The base can be used in a 1.1-fold to 3-fold excess relative to the second intermediate. Preferably, the base is used in a 1.5-fold excess relative to the second intermediate.

[0361] The reaction can be carried out at a temperature of about 50 °C to about 153 °C. Preferably, the reaction is carried out at about 80 °C. The reaction can be carried out for about 8 hours to about 20 hours. Preferably, the reaction is carried out for about 12 hours.

[0362] The reaction can be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere.

[0363] The formed third intermediate can be deprotected by reaction with an acid. Examples of acids that can be used include, but are not limited to, hydrochloric acid, trifluoroacetic acid, or phosphoric acid. Preferably, hydrochloric acid is used.

[0364] The deprotection can be carried out in a non-polar solvent (e.g., diethyl ether, benzene, toluene, chloroform, 1,4-dioxane, or a mixture thereof). Preferably, the reaction is carried out in 1,4-dioxane.

[0365] The deprotection can be carried out at a temperature of about 20 °C to about 80 °C. Preferably, the reaction is carried out at about 20 °C. The deprotection can be carried out for about 8 hours to about 20 hours. Preferably, the reaction is carried out for about 12 hours.

[0366] The present application also provides another method of synthesizing a carboxylic acid having the general formula R-COOH as shown in the following synthetic pathway: Preferably, the R-COOH is 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3- carboxylic acid.

[0367] The starting material selected from 2-bromo-5-methoxypyridine, 2-iodo-5- methoxypyridine, or 2-chloro-5-methoxypyridine can be reacted with (3-(tert- butyloxycarbonyl)-1,5-dimethyl-1H-pyrazol-4-yl)boronic acid or its derivatives (e.g., boronic ester or organic trifluoroborate salt) to form an intermediate via Suzuki coupling reaction.

[0368] Alternatively, the starting material can be reacted with (3-(tert-butyloxycarbonyl)-1,5- dimethyl-1H-pyrazol-4-yl) derivative suitable for Hiyama coupling, Stille coupling, Heck coupling, Kumada coupling, or Negishi coupling.

[0369] The reaction can be carried out in a polar aprotic solvent (e.g., THF, DMF, DMSO), a protic polar solvent (e.g., water, methanol, ethanol, isopropanol), a non-polar solvent (e.g., chloroform, 1,4-dioxane), or any combination thereof. Preferably, the reaction is carried out in a combination of DMF and water.

[0370] The reaction can 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)Cl2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2, or Pd(dppp)Cl2. More preferably, Pd(PPh3)4is used as the catalyst.

[0371] Preferably, about 0.02 to about 0.5 equivalents of the catalyst is used relative to the starting material. Preferably, about 0.05 equivalents of the catalyst is used.

[0372] The reaction can be carried out in the presence of a base. Examples of bases that can be used include, but are not limited to, K2CO3, KOH, Cs2CO3, K3PO4, NaOH, or NEt3. Preferably, K2CO3is used. t Bu, Cs2CO3, K3PO4, NaOH, or NEt3. Preferably, K2CO3is used.

[0373] An excess of the base can be used relative to the starting material. A 1.1-fold to 5-fold excess of the base can be used relative to the starting material. Preferably, a 1.5-fold excess of the base is used relative to the starting material.

[0374] The reaction can be carried out at a temperature of about 50 °C to about 100 °C. Preferably, the reaction is carried out at about 80 °C. The reaction can be carried out for about 6 hours to about 18 hours. Preferably, the reaction is carried out for about 12 hours.

[0375] The reaction can be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0376] The formed intermediate can be deprotected by reaction with an acid. Examples of acids that can be used include, but are not limited to, hydrochloric acid, trifluoroacetic acid, or phosphoric acid. Preferably, hydrochloric acid is used.

[0377] The deprotection can be carried out in a non-polar solvent, such as diethyl ether, benzene, toluene, chloroform, 1,4-dioxane, or a mixture thereof. Preferably, the reaction is carried out in 1,4-dioxane.

[0378] The deprotection can be carried out at a temperature of about 10 °C to about 50 °C. Preferably, the reaction is carried out at about 20 °C. The deprotection can be carried out for about 6 hours to about 18 hours. Preferably, the reaction is carried out for about 12 hours.

[0379] The present application also provides a method of preparing 3-(5-fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxylic acid: Bromine can be added to a solution of 5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2- carboxylic acid in a solvent. Examples of solvents 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 can be carried out at a temperature of about -10 °C to about 10 °C. Preferably, the reaction is carried out at about 0 °C. The reaction can be carried out for about 30 minutes to about 4 hours. Preferably, the reaction can be carried out for about 2 hours.

[0380] The reaction mixture can be quenched by the addition of saturated aqueous sodium thiosulfate solution to yield 3-bromo-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxylic acid.

[0381] 3-Bromo-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxylic acid tert-butyl ester can be reacted with triisopropyl borate in a solvent. Examples of solvents include, but are not limited to, THF, DMF, DMSO, or a mixture thereof. Preferably, the reaction is carried out in THF. The reaction can be carried out at a temperature of about -10 °C to about 40 °C. Preferably, the reaction is carried out in the range of about 0 °C to about 20 °C. n-Butyllithium can then be added. The reaction can be carried out at a temperature of about -100 °C to about -50 °C. Preferably, the reaction is carried out at about -78 °C. The reaction can be carried out for about 30 minutes to about 4 hours. Preferably, the reaction is carried out for about 2 hours.

[0382] The reaction mixture can be quenched by the addition of saturated aqueous ammonium chloride solution to yield (2-(tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3- yl)boronic acid.

[0383] 3-Bromo-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxylic acid tert-butyl ester can be reacted with triisopropyl borate in a solvent. Examples of solvents include, but are not limited to, THF, DMF, DMSO, or a mixture thereof. Preferably, the reaction is carried out in THF. The reaction can be carried out at a temperature of about -10 °C to about 40 °C. Preferably, the reaction is carried out in the range of about 0 °C to about 20 °C. n-Butyllithium can then be added. The reaction can be carried out at a temperature of about -100 °C to about -50 °C. Preferably, the reaction is carried out at about -78 °C. The reaction can be carried out for about 30 minutes to about 4 hours. Preferably, the reaction is carried out for about 2 hours.

[0384] The reaction mixture can then be quenched by the addition of saturated aqueous ammonium chloride solution as described above to yield (2-(tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3- yl)boronic acid.

[0385] (2-(tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl)boronic acid can be added to 2-bromo-5-fluoro-pyrimidine in the presence of a base and one or more solvents. Examples of bases that can be used include, but are not limited to, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydride, TEA or DIPEA, or mixtures thereof. Preferably, the base is potassium carbonate. The reaction can be carried out in a solvent such as THF, DMF, DMSO, water, or mixtures thereof. Preferably, the solvent is DMF and water. The reaction can be carried out at a temperature of about 0 °C to about 40 °C. Preferably, the reaction is carried out at about 20 °C.

[0386] Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) can be added to yield tert-butyl 3-(5-fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxylate. The reaction can be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere. The reaction can be carried out at a temperature of about 50 °C to about 150 °C. Preferably, the reaction is carried out at about 80 °C. The reaction can be carried out for about 10 hours to about 16 hours. Preferably, the reaction is carried out for about 12 hours.

[0387] Tert-butyl 3-(5-fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxylate can be treated with an acid to yield 3-(5-fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxylic acid. Examples of acids that can 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 can be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane, or mixtures thereof. Preferably, the solvent is dioxane. The reaction can be carried out at a temperature of about 10 °C to about 40 °C. Preferably, the reaction is carried out at about 20 °C. The reaction can be carried out for about 1 hour to about 4 hours. Preferably, the reaction is carried out for about 2 hours.

[0388] The present application also provides a process for preparing 5,6-dimethyl-3-(pyrimidin-2-yl)pyridine carboxylic acid: 3-Bromo-5,6-dimethylpyridin-2-amine can be added to tributyl(pyrimidin-2-yl)stannane and cesium fluoride in a solvent. Examples of solvents include, but are not limited to, diethyl ether, benzene, toluene, chloroform, dioxane, or mixtures thereof. Preferably, the solvent is dioxane.

[0389] Cuprous iodide and palladium triphenylphosphine can be added to the mixture. The reaction can be carried out at a temperature of about 70 °C to about 130 °C. Preferably, the reaction is carried out at about 100 °C. The reaction can be carried out for about 13 hours to about 19 hours. Preferably, the reaction is carried out for about 16 hours.

[0390] The residue can be purified to obtain 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-amine. Preferably, the purification is carried out by silica gel column chromatography.

[0391] 5,6-Dimethyl-3-(pyrimidin-2-yl)pyridin-2-amine can be added to an acid or a combination of acids. Examples of acids can be sulfuric acid, acetic acid, phosphoric acid, hydrochloric acid, trifluoroacetic acid, or a mixture thereof. Preferably, the acid is sulfuric acid and acetic acid. An aqueous solution of sodium nitrite can be added to obtain 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-ol. The reaction can be carried out at a temperature of about 0 °C to about 40 °C. Preferably, the reaction is carried out at about 20 °C. The reaction can be carried out for about 30 minutes to about 4 hours. Preferably, the reaction is carried out for about 2 hours.

[0392] 5,6-Dimethyl-3-(pyrimidin-2-yl)pyridin-2-ol can be added to trifluoromethylsulfonyl triflate in the presence of a solvent and a base to obtain residue 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl triflate. Examples of solvents that can be used include, but are not limited to, THF, dichloromethane, ethyl acetate, DMF or DMSO, or a mixture thereof. Preferably, the solvent is dichloromethane. Examples of bases that can be used include, but are not limited to, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydride, TEA or DIPEA, or a mixture thereof. Preferably, the base is DIPEA. The reaction can be carried out at a temperature of about 0 °C to about 60 °C. Preferably, the reaction is carried out at about 30 °C. The reaction can be carried out for about 13 hours to about 19 hours. Preferably, the reaction is carried out for about 16 hours.

[0393] Dichlorobis(diphenylphosphino)ferrocenepalladium(ll) (Pd(dppf)Cl2) can 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, cesium carbonate, sodium carbonate, sodium hydride, TEA, DIPEA, 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 can be carried out at a temperature of about 50 °C to about 100 °C. Preferably, the reaction is carried out at about 70 °C. The reaction can be carried out for about 13 hours to about 19 hours. Preferably, the reaction is carried out for about 16 hours. The reaction can be carried out in the presence of carbon monoxide at a pressure of 50 psi.

[0394] Lithium hydroxide monohydrate can 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 solvent is methanol and THF. The reaction can be carried out at a temperature of about 0 °C to about 40 °C. Preferably, the reaction is carried out at about 20 °C. The reaction can be carried out for about 1 hour to about 5 hours. Preferably, the reaction is carried out for about 3 hours.

[0395] The present application also provides a process for preparing 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid: 5-bromo-2,4-dimethylpyridine can be reacted with a mixture of tributyl(pyrimidin-2-yl)stannane, cesium fluoride, cuprous iodide, and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)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 can be carried out at a temperature of about 70 °C to about 130 °C. Preferably, the reaction is carried out at about 100 °C. The reaction can be carried out for about 13 hours to about 19 hours. Preferably, the reaction is carried out for about 16 hours.

[0396] The crude product can be purified to give 2-(4,6-dimethylpyridin-3-yl)pyrimidine. Preferably, the purification can be carried out by silica gel column chromatography.

[0397] M-chloroperbenzoic acid can be added to a solution of 2-(4,6-dimethylpyridin-3- yl)pyrimidine in the presence of a solvent. Examples of solvents can 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 can be carried out at a temperature of about 0 °C to about 40 °C. Preferably, the reaction is carried out at about 20 °C. The reaction can be carried out for about 30 minutes to about 4 hours. Preferably, the reaction is carried out for about 2 hours.

[0398] The reaction mixture can be quenched by the addition of sodium sulfite to obtain 2,4-dimethyl-5-(pyrimidin-2-yl)pyridine 1-oxide.

[0399] Trimethylsilyl cyanide can be added to 2,4-dimethyl-5-(pyrimidin-2-yl)pyridine 1-oxide in a solvent. Examples of solvents can include, but are not limited to, THF, dichloromethane, ethyl acetate, DMF, DMSO, or a mixture thereof. Preferably, the solvent is dichloromethane. The reaction can be carried out at a temperature of about 0 °C to about 40 °C. Preferably, the reaction is carried out at about 20 °C. The reaction can be carried out for about 30 minutes to about 3 hours. Preferably, the reaction is carried out for about 1 hour. N,N-dimethylcarbamoyl chloride can then be added. The reaction can be carried out at a temperature of about 0 °C to about 40 °C. Preferably, the reaction is carried out at about 20 °C. The reaction can be carried out for about 13 hours to about 19 hours. Preferably, the reaction is carried out for about 16 hours.

[0400] Sodium hydroxide can be added to 4,6-dimethyl-3-(pyrimidin-2-yl)pyridinecarbonitrile in the presence of one or more solvents to obtain 4,6-dimethyl-3-(pyrimidin-2- yl)pyridinecarboxylic acid. Examples of solvents include, but are not limited to, THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, dioxane, or a mixture thereof. Preferably, the solvent is methanol and water. The reaction can be carried out at a temperature of about 30 °C to about 90 °C. Preferably, the reaction is carried out at about 60 °C. The reaction can be carried out for about 36 hours to about 60 hours. Preferably, the reaction is carried out for about 48 hours.

[0401] The present application also provides a process for preparing 4-chloro-6-methyl-3- (pyrimidin-2-yl)pyridinecarboxylic acid: The acid and solvent can 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 a mixture 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 a mixture thereof. Preferably, the solvent is methanol. The reaction can be carried out at a temperature of about 40 °C to about 100 °C. Preferably, the reaction is carried out at about 70 °C. The reaction can be carried out for about 13 hours to about 19 hours. Preferably, the reaction is carried out for about 16 hours.

[0402] Methyl 3-bromo-6-methylpicolinate can be added to tributyl(pyrimidin-2-yl)stannane, cesium fluoride, cuprous iodide, triphenylphosphine palladium in the presence of a solvent. Examples of solvents include, but are not limited to, diethyl ether, benzene, toluene, chloroform, dioxane, or a mixture thereof. Preferably, the solvent is dioxane. The reaction can be carried out at a temperature of about 60 °C to about 140 °C. Preferably, the reaction is carried out at about 100 °C. The reaction can be carried out for about 13 hours to about 19 hours. Preferably, the reaction is carried out for about 16 hours.

[0403] 3-Chlorobenzenecarboperoxoic acid can be added to 6-methyl-3-(pyrimidin-2-yl)picolinic acid methyl ester in a solvent. Examples of solvents 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 can be carried out at a temperature of about -20 °C to about 50 °C. Preferably, the reaction is carried out at a temperature of about 0 °C to about 30 °C. The reaction can be carried out for about 13 hours to about 19 hours. Preferably, the reaction is carried out for about 16 hours.

[0404] The reaction mixture can be quenched by the addition of saturated sodium sulfite solution.

[0405] Phosphorus oxychloride can be added to 2-(methoxycarbonyl)-6-methyl-3-(pyrimidin-2-yl)pyridine 1-oxide to form 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid methyl ester. The reaction can be carried out at a temperature of about 90 °C to about 150 °C. Preferably, the reaction is carried out at about 120 °C. The reaction can be carried out for about 30 minutes to about 4 hours. Preferably, the reaction is carried out for about 2 hours.

[0406] Lithium hydroxide monohydrate can be added to methyl 4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridinecarboxylate 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 solvent is methanol and THF. The reaction can be carried out at a temperature of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction can continue for about 13 hours to about 19 hours. Preferably, the reaction continues for about 16 hours.

[0407] The present invention also provides a method for preparing 4-(5-fluoropyrimidin-2-yl)-1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylic acid.

[0408] In the presence of a solvent, 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (5 g, 24.39 mmol, 1 eq) can be added to di-tert-butyl dicarbonate, tert-butanol, and 4-dimethylaminopyridine. 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 can be carried out at a temperature of about 00°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction can continue for about 9 hours to about 15 hours. Preferably, the reaction continues for about 12 hours.

[0409] 5-Bromo-1-methyl-1H-pyrazole-3-carboxylic acid tert-butyl ester can be reacted with n-BuLi and trideuterated (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 THF. The reaction can be carried out at a temperature of about -10°C to about 40°C. Preferably, the reaction is carried out in the range of about 0°C to about 20°C. Then, n-butyllithium can be added. The reaction can be carried out at a temperature of about -100°C to about -50°C. Preferably, the reaction is carried out at about -78°C. The reaction can continue for about 30 minutes to about 4 hours. Preferably, the reaction continues for about 3 hours.

[0410] The reaction mixture can be quenched by adding a saturated ammonium chloride solution.

[0411] N-Bromosuccinimide can be added to 1 -methyl-5-(methyl-d3)- 1 H-pyrazole-3- carboxylic acid tert-butyl ester in a solvent. Examples of solvents include, but are not limited to, THF, DMF, DMSO, or a mixture thereof. Preferably, the reaction is carried out in DMF. The reaction can be carried out at a temperature of about 0 °C to about 40 °C. Preferably, the reaction is carried out at about 20 °C. The reaction can be carried out for about 9 hours to about 15 hours. Preferably, the reaction is carried out for about 12 hours.

[0412] Isopropylmagnesium chloride lithium chloride can be added to 4-bromo-1 -methyl-5-(methyl-d3)- 1 H-pyrazole-3-carboxylic acid tert-butyl ester in a solvent. Examples of solvents include, but are not limited to, THF, DMF, DMSO, or a mixture thereof. Preferably, the reaction is carried out in THF. The reaction can be carried out at a temperature of about -80 °C to about -20 °C. Preferably, the reaction is carried out at about -50 °C. The reaction can be carried out for about 30 minutes to about 2 hours. Preferably, the reaction is carried out for about 1 hour. Then triisopropyl borate can be added to the reaction mixture. The reaction can be carried out at a temperature of about -80 °C to about -20 °C. Preferably, the reaction is carried out at about -50 °C. The reaction can be carried out for about 1 hour to about 5 hours. Preferably, the reaction is carried out for about 3 hours.

[0413] 2-Bromo-5-fluoro-pyrimidine and potassium carbonate can be added to (3-(tert- butyloxycarbonyl)- 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 a mixture thereof. Preferably, the reaction is carried out in THF and water. Then tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) can be added. The reaction can be carried out at a temperature of about 60 °C to about 120 °C. Preferably, the reaction is carried out at about 90 °C. The reaction can be carried out for about 9 hours to about 15 hours. Preferably, the reaction is carried out for about 12 hours.

[0414] 4-(5-Fluoropyrimidin-2-yl)-l-methyl-5-(methyl-d3)-lH-pyrazole-3-carboxylic acid tert-butyl ester can be treated with an acid to produce 4-(5-fluoropyrimidin-2-yl)-l-methyl-5-(methyl-d3)-lH-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 can be performed in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane, or mixtures thereof. Preferably, the reaction is performed in dioxane. The reaction can be performed at a temperature of about 0 °C to about 40 °C. Preferably, the reaction is performed at about 20 °C. The reaction can be performed for about 5 hours to about 11 hours. Preferably, the reaction is performed for about 8 hours.

[0415] The present application also provides a method of making 4-(5-fluoropyrimidin-2-yl)-5-methyl-l-(methyl-d3)-lH-pyrazole-3-carboxylic acid.

[0416] Sodium hydride can be added to 4-bromo-5-methyl-lH-pyrazole-3-carboxylic acid ethyl ester 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 can be performed at a temperature of about -20 °C to about 20 °C. Preferably, the reaction is performed at about 0 °C. The reaction can be performed for about 15 minutes to about 1 hour. Preferably, the reaction is performed for about 30 minutes.

[0417] Trideuterated (iodo)methane can be added to the mixture. The reaction can be performed at a temperature of about 0 °C to about 40 °C. Preferably, the reaction is performed at about 20 °C. The reaction can be performed for about 2 hours to about 4 hours. Preferably, the reaction is performed for about 3.5 hours.

[0418] The mixture can be quenched with saturated ammonium chloride solution. The product can be purified to yield 4-bromo-5-methyl-l-(methyl-d3)-lH-pyrazole-3-carboxylic acid ethyl ester. Preferably, purification is by silica gel column chromatography.

[0419] Lithium hydroxide monohydrate can be added to 4-bromo-5-methyl-l-(methyl-d3)-lH- pyrazole-3-carboxylic acid ethyl ester in the presence of one or more solvents to provide 4-bromo-5-methyl-l-(methyl-d3)-lH-pyrazole-3-carboxylic acid. Examples of solvents include, but are not limited to, THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, dioxane, or a mixture thereof. Preferably, the solvent is methanol and water. The reaction can be carried out at a temperature of about 0 °C to about 40 °C. Preferably, the reaction is carried out at about 20 °C. The reaction can be carried out for about 1 hour to about 3 hours. Preferably, the reaction is carried out for about 2 hours.

[0420] 2-tert-Butyl-l,3-diisopropylisourea can be added to 4-bromo-5-methyl-l-(methyl-d3)-lH- pyrazole-3-carboxylic acid in the presence of a solvent to provide tert-butyl 4-bromo-5-methyl- l-(methyl-d3)-lH-pyrazole-3-carboxylate. Examples of solvents include, but are not limited to, THF, dichloromethane, ethyl acetate, DMF, DMSO, or a combination thereof. Preferably, the reaction is carried out in dichloromethane. The reaction can be carried out at a temperature of about 20 °C to about 80 °C. Preferably, the reaction is carried out at about 50 °C. The reaction can be carried out for about 13 hours to about 19 hours. Preferably, the reaction is carried out for about 16 hours.

[0421] Triisopropyl borate can be added to tert-butyl 4-bromo-5-methyl-l-(methyl-d3)-lH-pyrazole- 3-carboxylate in the presence of a solvent. Examples of solvents include, but are not limited to, THF, DMF, DMSO, or a mixture thereof. Preferably, the solvent is THF.

[0422] n-Butyllithium can then be added to provide (3-(tert-butoxycarbonyl)-5-methyl-l-(methyl- d3)-lH-pyrazol-4-yl)boronic acid. The reaction can be carried out at a temperature of about -100 °C to about -50 °C. Preferably, the reaction is carried out at about -78 °C. The reaction can be carried out for about 30 minutes to about 4 hours. Preferably, the reaction is carried out for about 2 hours. The reaction can be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0423] The reaction mixture can be quenched by the addition of saturated ammonium chloride solution to provide (3-(tert-butoxycarbonyl)-5-methyl-l-(methyl-d3)-lH-pyrazol-4-yl)boronic acid.

[0424] 2-Bromo-5-fluoro-pyrimidine and potassium carbonate can be added to (3-(tert- butyloxycarbonyl)-5-methyl-l-(methyl-d3)-lH-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 solvent is DMF and water. The reaction can be performed under an inert atmosphere. Preferably, the reaction is performed under an argon atmosphere.

[0425] Palladium (0) tetrakis(triphenylphosphine) (Pd(PPh3)4) can then be added. The reaction can be performed at a temperature of about 40 °C to about 120 °C. Preferably, the reaction is performed at about 80 °C. The reaction can be continued for about 9 hours to about 15 hours. Preferably, the reaction is continued for about 12 hours. The mixture is stirred at 80 °C for 12 hours.

[0426] The product can be purified to yield 4-(5-fluoropyrimidin-2-yl)-5-methyl-l- (methyl-d3)-lH-pyrazole-3-carboxylic acid tert-butyl ester. Preferably, purification is by silica gel column chromatography.

[0427] 4-(5-Fluoropyrimidin-2-yl)-5-methyl-l-(methyl-d3)-lH-pyrazole-3-carboxylic acid tert-butyl ester can be treated with an acid to yield 4-(5-fluoropyrimidin-2-yl)-5- methyl-l-(methyl-d3)-lH-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 can be performed in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane, or mixtures thereof. Preferably, the reaction is performed in dioxane. The reaction can be performed at a temperature of about 0 °C to about 40 °C. Preferably, the reaction is performed at about 20 °C. The reaction can be continued for about 13 hours to about 19 hours. Preferably, the reaction is continued for about 16 hours.

[0428] The present invention also provides a method of making 4-(5-fluoropyrimidin-2-yl)- 5-methyl-l-(methyl-d3)-lH-pyrazole-3-carboxylic acid.

[0429] 2-bromo-5-fluoropyridine, potassium carbonate, and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) can be added to (3-(tert-butoxycarbonyl)-5-methyl-1-(methyl-d3)-1H-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 a mixture thereof. Preferably, the reaction is carried out in DMF and water. The reaction can be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere. The reaction can be carried out at a temperature of about 50 °C to about 150 °C. Preferably, the reaction is carried out at about 80 °C. The reaction can be carried out for about 10 hours to about 16 hours. Preferably, the reaction is carried out for about 12 hours.

[0430] The product can be purified to yield tert-butyl 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate. Preferably, the product is purified by silica gel column chromatography.

[0431] Tert-butyl 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate can be treated with an acid to produce 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid. Examples of acids include, but are not limited to, aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid, or a mixture thereof. Preferably, hydrochloric acid is used. The reaction can be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane, or a mixture thereof. Preferably, the reaction is carried out in dioxane. The reaction can be carried out at a temperature of about 0 °C to about 40 °C. Preferably, the reaction is carried out at about 20 °C. The reaction can be carried out for about 13 hours to about 19 hours. Preferably, the reaction is carried out for about 16 hours.

[0432] The present application also provides a method of making 6-(methyl-d3)-3-(pyrimidin-2-yl)pyridine carboxylic acid.

[0433] A mixture of tributyl(pyrimidin-2-yl)stannane and methyl 6-amino-3-bromopyridine carboxylate, cesium fluoride, cuprous iodide, and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) can be reacted in the presence of a solvent. Examples of solvents include, but are not limited to, THF, dichloromethane, ethyl acetate, DMF, DMSO, or a combination thereof. Preferably, the reaction is carried out in dichloromethane. The reaction can be carried out under a nitrogen atmosphere. The reaction can be carried out at a temperature of about 80 °C to about 140 °C. Preferably, the reaction is carried out at about 110 °C. The reaction can be carried out for about 9 hours to about 15 hours. Preferably, the reaction is carried out for about 12 hours.

[0434] The residue can be quenched with aqueous potassium fluoride to yield methyl 6-amino-3- (pyrimidin-2-yl)pyridinecarboxylate.

[0435] tert-butylnitrite and copper bromide can be added to methyl 6-amino-3-(pyrimidin-2- yl)pyridinecarboxylate 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 can be carried out at a temperature of about 0 °C to about 50 °C. Preferably, the reaction is carried out at about 25 °C. The reaction can be carried out for 9 hours to about 15 hours. Preferably, the reaction is carried out for about 12 hours.

[0436] trideuterated (deuteratedoxy)methane can be added to 5,7-di-tert-butyl-3-phenyl-1,3- benzoxazol-3-ium tetrafluoroborate in methyl tert-butyl ether. The reaction can be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere. The reaction can be carried out at a temperature of about 0 °C to about 50 °C. Preferably, the reaction is carried out at about 25 °C.

[0437] pyridine can be added to the mixture under an argon atmosphere. The reaction can be carried out at a temperature of about 0 °C to about 50 °C. Preferably, the reaction is carried out at about 25 °C. The reaction can be carried out for about 15 minutes to about 1 hour. Preferably, the reaction is carried out for about 30 minutes.

[0438] bis[2-(2-pyridyl)phenyl]iridium(l+) 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine hexafluorophosphate, 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine nickel dibromide, quinuclidine can be added to the mixture. Subsequently, methyl 6-bromo-3-(pyrimidin-2- yl)pyridinecarboxylate in dimethylacetamide can be added to the mixture under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere. The reaction can be carried out at a temperature of about 0 °C to about 50 °C. Preferably, the reaction is carried out at about 25 °C. The reaction can be carried out for about 30 minutes to about 4 hours. Preferably, the reaction is carried out for about 2 hours.

[0439] Subsequently, methyl 6-(methyl-d3)-3-(pyrimidin-2-yl)pyridinecarboxylate can be added to 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 can be carried out at a temperature of about 40 °C to about 120 °C. Preferably, the reaction is carried out at about 80 °C. The reaction can be carried out for about 9 hours to about 15 hours. Preferably, the reaction is carried out for about 12 hours.

[0440] The present application also provides a process for preparing 6-(methyl-d3)-3-(2H- 1,2,3-triazol-2-yl)picolinic acid hydrochloride.

[0441] 2H-triazole, cesium carbonate, N1,N2-dimethylcyclohexane-1,2-diamine, and copper iodide can 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 a mixture thereof. Preferably, the solvent is dioxane and water. The reaction can be carried out at a temperature of about 80 °C to about 120 °C. Preferably, the reaction is carried out at about 100 °C. The reaction can be carried out for about 9 hours to about 15 hours. Preferably, the reaction is carried out for about 12 hours.

[0442] 2-tert-butyl-1,3-diisopropylisourea can 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 a mixture thereof. Preferably, the reaction is carried out in THF. The reaction can be carried out at a temperature of about 0 °C to about 50 °C. Preferably, the reaction is carried out at about 25 °C. The reaction can be carried out for about 9 hours to about 15 hours. Preferably, the reaction is carried out for about 12 hours.

[0443] (1,1'-bis(diphenylphosphino)ferrocene) dichloropalladium(ll) (Pd(dppf)Cl2), tri-potassium phosphate, and tert-butyl 6-chloro-3-(2H-1,2,3-triazol-2-yl)picolinic acid can be added to (methyl-d3)boronic acid in the presence of a solvent to give methyl 5,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid. Examples of solvents include, but are not limited to, water, acetonitrile, DMF, DMSO, pyridine, THF, or a mixture thereof. Preferably, the reaction is carried out in THF and water. The reaction can be carried out at a temperature of about 40 °C to about 120 °C. Preferably, the reaction is carried out at about 80 °C. The reaction can be carried out for about 2 hours to about 6 hours. Preferably, the reaction is carried out for about 4 hours.

[0444] tert-Butyl 6-(methyl-d3)-3-(2H-l,2,3-triazol-2-yl)picolinic acid can be treated with an acid in the presence of a solvent to form 6-(methyl-d3)-3-(2H-l,2,3-triazol-2-yl)picolinic acid hydrochloride. Examples of acids include, but are not limited to, aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid. Preferably, hydrochloric acid is used. Examples of solvents include, but are not limited to, diethyl ether, benzene, toluene, chloroform, dioxane, methanol, or mixtures thereof. Preferably, the reaction is carried out in dioxane and methanol. The reaction can be carried out at a temperature of about 30 °C to about 90 °C. Preferably, the reaction is carried out at about 60 °C. The reaction can be carried out for about 1 hour to about 4 hours. Preferably, the reaction is carried out for about 2 hours.

[0445] The present application also provides a process for preparing 1,5-dimethyl-4-(pyrazin-2-yl)-lH-pyrazole-3-carboxylic acid.

[0446] 2-chloropyrazine, a base, and a solvent can be added to (3-(tert-butoxycarbonyl)-l,5-dimethyl-lH-pyrazol-4-yl)boronic acid. Examples of bases that can be used include, but are not limited to, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydride, TEA or DIPEA, or mixtures thereof. Preferably, the base is potassium carbonate. The reaction can be carried out in a solvent, such as THF, DMF, DMSO, water, or mixtures thereof. Preferably, the solvent is DMF and water.

[0447] Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) can be added to the reaction mixture. The reaction can be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere. The reaction can be carried out at a temperature of about 50 °C to about 150 °C. Preferably, the reaction is carried out at about 80 °C. The reaction can be carried out for about 13 hours to about 19 hours. Preferably, the reaction is carried out for about 16 hours. The reaction mixture can be purified to obtain tert-butyl l,5-dimethyl-4-(pyrazin-2-yl)-lH-pyrazole-3-carboxylate. Preferably, the purification is carried out by silica gel column chromatography.

[0448] tert-Butyl 1,5-dimethyl-4-(pyrazin-2-yl)-1 H-pyrazole-3-carboxylate can be treated with an acid to form 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 a mixture thereof. Preferably, hydrochloric acid is used. The reaction can be performed in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane, or a mixture thereof. Preferably, the reaction is performed in dioxane. The reaction can be performed at a temperature of about 0 °C to about 40 °C. Preferably, the reaction is performed at about 20 °C. The reaction can be performed for about 13 hours to about 19 hours. Preferably, the reaction is performed for about 16 hours.

[0449] The present application also provides a method of making 4-(5-fluoropyridin-3-yl)- 1,5-dimethyl-1 H-pyrazole-3-carboxylic acid.

[0450] 3-Chloro-5-fluoropyridine, a base, and a solvent can be added to (3-(tert- butoxycarbonyl)-1,5-dimethyl-1 H-pyrazol-4-yl)boronic acid. Examples of bases that can be used include, but are not limited to, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydride, TEA or DIPEA, or a mixture thereof. Preferably, the base is potassium carbonate. The reaction can be performed in a solvent such as THF, DMF, DMSO, water, or a mixture thereof. Preferably, the solvent is DMF and water.

[0451] Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) can be added to the reaction mixture. The reaction can be performed under an inert atmosphere. Preferably, the reaction is performed under an argon atmosphere. The reaction can be performed at a temperature of about 50 °C to about 150 °C. Preferably, the reaction is performed at about 80 °C. The reaction can be performed for about 13 hours to about 19 hours. Preferably, the reaction is performed for about 16 hours.

[0452] The reaction mixture can be purified to yield 4-(5-fluoropyridin-3-yl)-1,5- dimethyl-1 H-pyrazole-3-carboxylic acid tert-butyl ester. Preferably, the purification is performed by silica gel column chromatography.

[0453] tert-Butyl 4-(5-fluoropyridin-3-yl)-l,5-dimethyl-lH-pyrazole-3-carboxylate can be treated with an acid to form 4-(5-fluoropyridin-3-yl)-l,5-dimethyl-lH-pyrazole-3- carboxylic acid. Examples of acids include, but are not limited to, aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid, or a mixture thereof. Preferably, hydrochloric acid is used. The reaction can be performed in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane, or a mixture thereof. Preferably, the reaction is performed in dioxane. The reaction can be performed at a temperature of about 0 °C to about 40 °C. Preferably, the reaction is performed at about 20 °C. The reaction can be performed for about 13 hours to about 19 hours. Preferably, the reaction is performed for about 16 hours.

[0454] The present application also provides a process for preparing 4-(4-fluoropyridin-3-yl)- 1,5-dimethyl-lH-pyrazole-3-carboxylic acid.

[0455] (3-(tert-Butoxycarbonyl)-l,5-dimethyl-lH-pyrazol-4-yl)boronic acid, 3-chloro-4- fluoropyridine, [2-(2-aminophenyl)phenyl]-chloro-palladium dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphine, tripotassium phosphate, and butan-l-ol can be added in the presence of a solvent. Examples of solvents include, but are not limited to, water, acetonitrile, DMF, DMSO, pyridine, THF, or a mixture thereof. Preferably, the solvent is water. The reaction can be performed under an inert atmosphere. Preferably, the reaction is performed under an argon atmosphere. The reaction can be performed at a temperature of about 50 °C to about 150 °C. Preferably, the reaction is performed at about 100 °C. The reaction can be performed for about 1 hour to about 5 hours. Preferably, the reaction is performed for about 3 hours.

[0456] The reaction mixture can be purified to yield tert-butyl 4-(4-fluoropyridin-3-yl)-l,5- dimethyl-lH-pyrazole-3-carboxylate. Preferably, the purification is performed by silica gel column chromatography.

[0457] tert-Butyl 4-(4-fluoropyridin-3-yl)-l,5-dimethyl-lH-pyrazole-3-carboxylate can be treated with an acid to form 4-(4-fluoropyridin-3-yl)-l,5-dimethyl-lH-pyrazole-3- carboxylic acid. Examples of acids include, but are not limited to, aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid, or a mixture thereof. Preferably, hydrochloric acid is used. The reaction can be performed in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane, or a mixture thereof. Preferably, the reaction is performed in dioxane. The reaction can be performed at a temperature of about 0 °C to about 40 °C. Preferably, the reaction is performed at about 20 °C. The reaction can be performed for about 9 hours to about 15 hours. Preferably, the reaction is performed for about 12 hours.

[0458] The present application also provides a method of making 4-(4-fluoropyridin-2-yl)-l,5- dimethyl-lH-pyrazole-3-carboxylic acid.

[0459] 2-Chloro-4-fluoropyridine, a base, and a solvent can be added to (3-(tert- butoxycarbonyl)-l,5-dimethyl-lH-pyrazol-4-yl)boronic acid. Examples of bases that can be used include, but are not limited to, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydride, TEA or DIPEA, or a mixture thereof. Preferably, the base is potassium carbonate. The reaction can be performed in a solvent such as THF, DMF, DMSO, water, or a mixture thereof. Preferably, the solvent is DMF and water.

[0460] Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) can be added to the reaction mixture. The reaction can be performed under an inert atmosphere. Preferably, the reaction is performed under an argon atmosphere. The reaction can be performed at a temperature of about 50 °C to about 150 °C. Preferably, the reaction is performed at about 80 °C. The reaction can be performed for about 13 hours to about 19 hours. Preferably, the reaction is performed for about 16 hours.

[0461] The reaction mixture can be purified to yield tert-butyl 4-(4-fluoropyridin-2-yl)-l,5- dimethyl-lH-pyrazole-3-carboxylate. Preferably, the purification is performed by silica gel column chromatography.

[0462] tert-Butyl 4-(4-fluoropyridin-2-yl)-l,5-dimethyl-lH-pyrazole-3-carboxylate can be treated with an acid to form 4-(4-fluoropyridin-2-yl)-l,5-dimethyl-lH-pyrazole-3- carboxylic acid. Examples of acids include, but are not limited to, aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid, or a mixture thereof. Preferably, hydrochloric acid is used. The reaction can be performed in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane, or a mixture thereof. Preferably, the reaction is performed in dioxane. The reaction can be performed at a temperature of about 0 °C to about 40 °C. Preferably, the reaction is performed at about 20 °C. The reaction can be performed for about 13 hours to about 19 hours. Preferably, the reaction is performed for about 16 hours.

[0463] EMBODIMENT The present application is further described with reference to the following examples, which are not intended to limit the scope of the present application.

[0464] I. General Synthetic Methods and Procedures EMBODIMENT 2S,3R Synthesis of (b) 2-(benzylamino)butane-l,3-diol To a solution of N-benzyl-L-Ophthalamidic acid (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 h. LCMS showed all starting material consumed, desired MW detected. The reaction was cooled to 0 °C and then quenched with methanol (100 mL). The solution was then concentrated under reduced pressure to give the crude product (14 g, 64.53 mmol, 94.75% yield) as a colorless oil, which was used without further purification.

[0465] 1 H NMR (400 MHz, DMSO- d 6): δ 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). EMBODIMENT (2R,3S Synthesis of (c) 3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol To a solution of (2R,3S)-2-(benzylamino)butane-l,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 TBDPSC1 (25.34 g, 92.19 mmol, 23.59 mL, 1.2 eq). The mixture was stirred at 25 °C for 12 h. LCMS showed all starting material was consumed; desired MW was detected. To the reaction mixture was added water (1000 mL) at 0 °C to quench, 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 Na2S04, filtered and concentrated to give the crude product. The residue was purified by column chromatography (Si02, 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.

[0466] 1 H NMR (400 MHz, DMSO- d 6): δ ppm 7.57 - 7.68 (m, 4 H) 7.37 - 7.50 (m, 6H) 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). Example 3: 2-((( 2S,3R )-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)oxy)-2,2- difluoroacetic acid (d) 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-difluoroacetic acid (4.11 g, 23.52 mmol, 3 eq). The solution was cooled to 0 °C. To the solution was added NaH (1.41 g, 35.28 mmol, 60% purity, 4.5 eq) at 0 °C. The mixture was stirred at 20 °C for 12 h. LCMS showed all starting material was consumed, target molecular weight was detected. The reaction was poured into 1 N HC1, pH was adjusted to 7 at 0 °C, then extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with brine (40 mL x 2), dried over Na2S04, filtered and concentrated to give the crude product (5 g, 7.58 mmol, 96.69% yield) as yellow oil. The product was used directly in the next step without further purification.

[0467] 1 H NMR (400 MHz, DMSO- d 6): δ ppm 7.55 - 7.73 (m, 5 H) 7.35 - 7.52 (m,10 H) 4.59 (br d, J =3.25 Hz, 1 H) 3.75 (br d, J =10.38 Hz, 2 H) 3.27 - 3.43 (m,2 H) 2.99 - 3.21 (m, 2 H) 1.12 (br d, J =6.38 Hz, 3 H) 0.99 (s, 9 H). Example 4: Synthesis of (2S,3R)-3-(benzylamino)-5-(((tert-butyldiphenylsilyl)oxy)methyl)- 2,2-difluoro-6-methylmorpholin-4-ium-3-olate (e) 2S,3R Example 4: Synthesis of (2S,3R)-3-(benzylamino)-5-(((tert-butyldiphenylsilyl)oxy)methyl)- 2,2-difluoro-6-methylmorpholin-4-ium-3-olate (e) 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 dimethylformamide (164 mL) was added 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 hours. LCMS showed all starting material was consumed, target molecular weight was detected. The reaction mixture was poured into ice water (150 mL) and extracted with ethyl acetate (150 mL x 3). The organic phase was combined, dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, 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 a colorless oil.

[0468] 1 H NMR (400 MHz, DMSO- d 6): δ ppm 7.55 - 7.67 (m, 4 H) 7.40 - 7.55 (m, 6H) 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). Example 5: Synthesis of (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2- difluoro-6-methylmorpholin-3-one (f) 5R,6S Example 5: Synthesis of (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2- difluoro-6-methylmorpholin-3-one (f) At 25 °C, BH3·DMS (10 M, 2.33 mL, 4 eq) was added to a tetrahydrofuran (33 mL) 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). The mixture was then stirred at 30 °C for 3 hours. LCMS showed that all starting materials were consumed and the target molecular weight was detected. The reaction mixture was quenched with methanol (30 mL) at 20 °C, and the mixture was stirred at 40 °C for 1 hour, followed by concentration under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO2, 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), which was a white solid.

[0469] 1 H NMR (400 MHz, DMSO-) d 6): δ 7.72 - 7.59 (m, 4H), 7.56 - 7.40 (m, 6H), 7.36 - 7.18 (m, 5H), 4.53 - 4.42 (m, 1H), 3.99 - 3.83 (m, 2H), 3.74 (d, J = 6.1Hz, 2H), 2.99 - 2.75 (m, 3H), 1.22 (d, J = 6.8 Hz, 3H), 1.00 (s, 9H). Example 6: (( 5R,6S Synthesis of 4-benzyl-6,6-difluoro-2-methylmorpholin-3-yl)methanol (g) 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. The mixture was then stirred at 25 °C for 1 h. LCMS showed all starting material was consumed, target molecular weight was detected. The residue was quenched with water (40 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic phase was 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 (SiO2, 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 a white solid.

[0470] 1 H NMR (400 MHz, DMSO- d 6): δ 7.43 - 7.20 (m, 5H), 4.62 (t, J = 4.9 Hz,1H), 4.49 - 4.38 (m, 1H), 3.88 (s, 2H), 3.81 - 3.72 (m, 1H), 3.70 - 3.61 (m,1H), 3.01 - 2.77 (m, 2H), 2.67 (br s, 1H), 1.22 (d, J = 6.8 Hz, 3H). Example 7: Synthesis of tert-butyl (5R)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4- carboxylate (h) 2S,3R Example 7: Synthesis of tert-butyl (5R)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4- carboxylate (h) 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), Boc20 (1.03 g, 4.72 mmol, 1.08 mL, 1.5 eq) at 25 °C under H2atmosphere, 15 Psi. The mixture was then stirred at 25 °C for 16 h. LCMS showed all starting material was consumed, target molecular weight was detected. The reaction mixture was filtered through a pad of celite, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (Si02, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give (5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylic acid tert-butyl ester (0.73 g, 2.46 mmol, 78.08% yield) as a white solid.

[0471] 1 H NMR (400 MHz, DMSO- d 6): δ ppm 4.77 (t, J =5.57 Hz, 1 H) 4.29 (br s, 1H) 4.13 (br d, J =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, J =6.50 Hz, 3 H). Example 8: Synthesis of tert-butyl 5-((1,3-dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate (i) 5R,6S Synthesis of tert-butyl 5-((1,3-dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate (i) 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 N2 for 3 times. To the reaction mixture was added PPh3 (662.43 mg, 2.53 mmol, 1.5 eq) at 20 °C. To the mixture was added DIAD (510.69 mg, 2.53 mmol, 489.64 μL, 1.5 eq) at 0 °C. The mixture was then stirred at 20 °C for 12 hours under N2 atmosphere. LCMS showed all starting material was consumed, the target molecular weight was detected. The residue was quenched with ice water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic phase was 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 (SiO2, 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.

[0472] 1 H NMR (400 MHz, DMSO- d 6): δ ppm 7.75 - 8.04 (m, 4 H) 4.04 - 4.52 (m, 3H) 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). Example 9: 5R,6S Synthesis of tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate (j) At 25 °C, hydrazine hydrate (818.37 mg, 16.35 mmol, 793.00 μL, 10 eq) was added to a methanol (7 mL) solution of (5R,6S)-5-((1,3-dioxoisoindoline-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (720.00 mg, 1.63 mmol, 1 eq). The mixture was then stirred at 60 °C for 2 h under a nitrogen atmosphere. LC-MS showed that all starting materials were consumed and the target molecular weight was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (420 mg, 86.83% yield) as a white solid. This crude product was used directly in the next step without further purification.

[0473] 1 H NMR (400 MHz, DMSO-) d 6): δ 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). Example 10: ( (5R,6S Synthesis of tert-butyl morpholine-4-carboxylate (k) -2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate (k), general steps To a mixture of (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylic acid tert-butyl ester (210 mg, 788.63 pmol, 1 eq) and K2CO3 (217.99 mg, 1.58 mmol, 2 eq) in dimethylformamide (5 mL) was added 2-chloro-5- (trifluoromethyl)pyrazine (215.92 mg, 1.18 mmol, 1.5 eq) at 25 °C. The mixture was stirred at 80 °C for 12 h. LCMS showed the reaction was completed, the target molecular weight was detected. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, PE:EA = 1:1) to give (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester (105 mg, 29.20% yield) as a colorless oil.

[0474] 1 H NMR (400 MHz, DMSO- d 6): δ ppm 8.37 - 8.47 (m, 1 H) 7.87 - 8.13 (m, 2H) 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). Similarly, the following intermediates were prepared.

[0475] Example 11: ( 5R,6S Synthesis of (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester (1) Using (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(trifluoromethyl)pyrimidine, the general procedure for the preparation of compound (k) was repeated (see Example 10). Yield 65%, white solid.

[0476] LCMS (ESI+): m / z = 413.3 (M+1), RT: 0.573 min (column Agilent Poroshell SB-C18 3.0 30 mm, 4 um. The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 50-2000. The mobile phase A was water containing 0.04% trifluoroacetic acid and the mobile phase B was HPLC grade acetonitrile containing 0.02% trifluoroacetic acid. The gradient was 5-95% B in 1.50 min, 5% B for 0.01 min, 5-95% B (0.01-0.70 min), 95% B (0.70-1.16 min), 95-5% B (1.16-1.17 min) and 5% B for 0.33 min. The flow rate was 1.5 mL / min. Example 12: 5R,6S Synthesis of tert-butyl (5-(((5-chloropyridin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate (n) Using (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(trifluoromethyl)pyridine, the general procedure for the preparation of compound (k) was repeated (see Example 10). Yield 43%, yellow oil.

[0477] 1 H NMR (400 MHz, DMSO- d 6): δ 8.36 - 8.25 (m, 1H), 7.69 - 7.57 (m, 1H),7.50 - 7.24 (m, 1H), 6.60 (br d, J = 8.8 Hz, 1H), 4.42 - 4.16 (m, 3H), 3.81 -3.67 (m, 1H), 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). Example 13: 5R,6S Synthesis of tert-butyl (5-(((5-chloropyridin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate (n), general procedure To a mixture of DIPEA (135.90 mg, 1.05 mmol) in DMSO (1.5 mL) was added (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (0.07 g, 262.88 μmol) and 5-chloro-2-fluoropyridine (69.16 mg, 525.75 μmol) at 20 °C. The reaction was stirred at 140 °C for 16 h. LCMS showed the reaction was completed. The reaction mixture was poured into NH4Cl (2 mL) at 0 °C and extracted with ethyl acetate (10 mL x 3). The combined organic phase was 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 silica gel column chromatography eluting with ethyl acetate in petroleum ether from 0% to 40% gradient to give (5R,6S)-5-(((5-chloropyridin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (50 mg, 25.17% yield) as a brown solid.

[0478] 1 H NMR (400 MHz, DMSO- d 6 ): δ = 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, 5H) 1.10 (s, 7 H). Similarly, the following intermediates were prepared.

[0479] Example 14: 5R,6S Synthesis of tert-butyl 5-(((5-chloropyrimidin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate (o) Using (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester and 5-chloro-2-fluoropyrimidine, the general procedure used to prepare compound (n) was repeated (see Example 13). Yield 49%, white solid.

[0480] 1 H NMR (400 MHz, Chloroform- d): δ 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, 0.57H) 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). Example 15: 5R,6S Synthesis of tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((4- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylate (p) The general procedure for the preparation of compound (n) (see Example 13) was repeated using tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate and 5-chloro-2-fluoropyrimidine. Yield 46%, white solid.

[0481] 1 H NMR (400 MHz, Chloroform-d) δ ppm 8.35 - 8.60 (m, 0.81 H) 6.87 (dd, d =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). J 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) 5R,6S The general procedure for the preparation of compound (n) (see Example 13) was repeated using tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate and 2-chloro-6-(trifluoromethyl)pyrazine. Yield 82%, yellow solid.

[0482] 1 H NMR (400 MHz, Chloroform-d) δ ppm 8.35 - 8.60 (m, 0.81 H) 6.87 (dd, d ​): δ 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). Example 17. 5R,6S Synthesis of tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((4- (trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylate (r) Using (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester and 2-fluoro-4-(trifluoromethyl)pyridine, the general procedure for the preparation of compound (n) (see Example 13) was repeated. Yield 39%, light yellow solid.

[0483] 1 H NMR (400 MHz, DMSO- d 6) δ ppm 8.16 - 8.25 (m, 1 H) 7.00 - 7.27 (m, 1H) 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). Example 18: 5R,6S Synthesis of tert-butyl (5R,6S)-2,2-difluoro-5-(((3-fluoro-5- (trifluoromethyl)pyridin-2-yl)amino)methyl)-6-methylmorpholine-4-carboxylate (s) Using (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester and 2,3-difluoro-5-(trifluoromethyl)pyridine, the general procedure for the preparation of compound (n) (see Example 13) was repeated. Yield 65%, white solid.

[0484] 1 HNMR (400 MHz, DMSO- d6): δ 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). Example 19: (5R,6S)-5-(((3-bromo-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,2- difluoro-6-methylmorpholine-4-carboxylic acid 5R,6S Synthesis of tert-butyl (5R,6S)-5-(((3-bromo-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)- 2,2-difluoro-6-methylmorpholine-4-carboxylate Using tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 3-bromo-2-fluoro-5-(trifluoromethyl)pyridine, the general procedure used for the preparation of compound (n) (see Example 13) was repeated to give tert-butyl (5R,6S)-5-(((3-bromo-5- (trifluoromethyl)pyridin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate.

[0485] Yield 65%, yellow solid.

[0486] 1 HNMR (400 MHz, DMSO- d 6 ): δ 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). 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)Cl2 (73.12 mg, 112.18 μmol, 0.1 eq) under N2. The mixture was stirred at 80 °C for 2 h. LCMS showed the starting material was consumed completely and one major peak with target mass was detected. The reaction mixture was quenched by adding water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with 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 (SiO2, 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.

[0487] 1 HNMR (400 MHz, DMSO- d 6 ): δ 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, 2.90H), 1.33 (br d, J= 6.50 Hz, 3.00 H), 1.21 (s, 2.60 H), 0.99 (s, 6.60 H). Example 20: 5R,6S Synthesis of tert-butyl (5-(((5-cyclopropylpyrimidin-2-yl)amino)methyl)-2,2- difluoro-6-methylmorpholine-4-carboxylate (u) Using (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-cyclopropylpyrimidine, the general procedure for the preparation of compound (n) (see Example 13) was repeated.

[0488] Yield 84%, white solid.

[0489] 1 H NMR (400 MHz, DMSO- d 6 ): δ = 8.01 - 8.17 (m, 2 H), 7.00 (br t, J=6.19Hz, 0.80 H), 6.73 (br t, J=5.88 Hz, 0.20 H), 4.27 - 4.41 (m, 2 H), 4.21 (brdd, J=14.20, 4.44 Hz, 1 H), 3.58 - 3.71 (m, 1 H), 3.52 (br d, J=6.50 Hz, 0.50H), 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). Example 21: 5R,6S Synthesis of tert-butyl (2,2-difluoro-5-(((3-methoxy-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)-6-methylmorpholine-4-carboxylate (v) Using (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester and 2-chloro-3-methoxy-5-(trifluoromethyl)pyridine, the general procedure for the preparation of compound (n) (see Example 13) was repeated. Yield 49%, colorless oil.

[0490] 1 H NMR (400 MHz, DMSO- d 6): δ 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, 2.00H), 4.20 (br dd, J = 14.01, 4.50 Hz, 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). Example 22: Synthesis of tert-butyl (5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5- (trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate (w) 5R,6S 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 μL, 3 eq) at 0 °C, followed by BOP (498.28 mg, 1.13 mmol, 1.5 eq) in portions at 0 °C, the mixture was stirred at 0 °C for 0.5 h. Then tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (j) (0.2 g, 751.08 μmol, 1 eq) was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 16 h. LCMS showed the reaction was completed. The reaction mixture was quenched by adding water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was 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 silica gel column chromatography eluting with ethyl acetate in petroleum ether from 0% to 11% gradient to give tert-butyl (5R,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.

[0491] 1 ​H NMR (400 MHz, DMSO- d 6 ): δ 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). Example 23: Synthesis of tert-butyl (5R,6S)-5-(((3-cyano-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (x) 5R,6S Example 23: Synthesis of tert-butyl (5R,6S)-5-(((3-cyano-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (x) Using tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate and 2-chloro-5-(trifluoromethyl)nicotinonitrile, the general procedure for the preparation of compound (n) (see Example 13) was repeated. Yield 59%, yellow solid.

[0492] 1 H NMR (400 MHz, Methanol-d4) δ ppm 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). d 4 ): δ = 8.51 - 8.61 (m, 1 H), 8.05 - 8.21 (m, 1H), 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). Example 24: Synthesis of tert-butyl (5R,6S)-5-(((3-cyano-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (x) Using tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate and 5-chloro-2,3-difluoropyridine, the general procedure for the preparation of compound (n) (see Example 13) was repeated. Yield 94%, colorless oil.

[0493] 1 H NMR (400 MHz, Chloroform-d) δ ppm 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). d): δ 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, 1H), 1.29 - 1.46 (m, 12 H). Example 25: (5R,6S)-5-(((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)- 2,2-difluoro-6-methylmorpholine-4-carboxylic acid 5R,6S Synthesis of tert-butyl (5R,6S)-5-(((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (z) Using tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4- carboxylate and 2,4-dichloro-5-(trifluoromethyl)pyrimidine, the general procedure for preparing compound (n) (see Example 13) was repeated to give tert-butyl (5R,6S)-5-(((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate.

[0494] Yield 33%, yellow solid.

[0495] 1 HNMR (400 MHz, DMSO- d 6 ): δ 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). A mixture of (5R,6S)-5-(((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (0.54 g, 1.21 mmol, 1 eq), 2,4,6-trimethyl-1,3,5,2,4,6-trioxabicyclohexane (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 μmol, 0.1 eq) was taken in a microwave tube in dioxane (10.8 mL). The mixture was then degassed and purged with N2for 3 times. The sealed tube was heated at 140 °C for 4 h under microwave. LCMS showed complete consumption of starting material and one major peak with target mass was detected. After cooling to 25 °C, the reaction mixture was quenched by addition of water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was 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 (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 100) to give (5R,6S)-2,2-difluoro-6-methyl-5-(((4-methyl-5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester (0.32 g, 62.10% yield) as a yellow oil.

[0496] 1 HNMR (400 MHz, Chloroform- d ): δ 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). Example 26: Synthesis of (5R,6S)-5-(((5-(difluoromethyl)pyrimidin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (z1) 5R,6S Example 26: Synthesis of (5R,6S)-5-(((5-(difluoromethyl)pyrimidin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (z1) Using (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(difluoromethyl)pyrimidine, the general procedure for the preparation of compound (n) was repeated (see Example 13). Yield 88%, yellow solid.

[0497] 1H NMR (400 MHz, DMSO- d 6 ): δ = 8.37 - 8.58 (m, 2 H), 7.79 (br t, J=6.00Hz, 0.70 H), 7.48 - 7.66 (m, 0.25 H), 6.76 - 7.17 (m, 1 H), 4.28 - 4.43 (m, 2H), 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, 9H). Example 27: Synthesis of (5R,6S)-5-(((5-(difluoromethyl)pyrazin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (z2) 5R,6S Example 27: Synthesis of (5R,6S)-5-(((5-(difluoromethyl)pyrazin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (z2) Using (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(difluoromethyl)pyrazine, the general procedure for the preparation of compound (n) (see Example 13) was repeated. Yield 95%, colorless oil.

[0498] 1 H NMR (400 MHz, DMSO- d 6 ): δ = 8.19 - 8.28 (m, 1 H), 7.88 - 8.04 (m, 1H), 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). Example 28: Synthesis of 5-chloro- N -((( 5R,6S )-6,6-difluoro-2-methylmorpholin-3-yl)methyl)pyridin-2-amine hydrochloride (aa), general procedure To a solution of (5R,6S)-5-(((5-chloropyridin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylic acid tert-butyl ester (50 mg, 92.64 pmol) in dioxane (0.5 mL) was added HC1 / dioxane (4 N, 0.5 mL) and the reaction was stirred at 20 °C for 2 h. LCMS showed the reaction was complete. 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.

[0499] 1 H NMR (400 MHz, DMSO- d 6 ): δ = 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 (brdd, 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). Similarly, the following intermediates were prepared.

[0500] Example 29: N -((( 2S,3R )-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride (ab) Using (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester (k), the general procedure used to prepare compound (aa) was repeated (see Example 28). Yield 99%, white solid.

[0501] LCMS (ESI+): m / z = 313.1 (M+1), RT: 0.669 min (column Kinetex EVO C18 2.1 30 mm, 5 um. The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100-1000. The mobile phase A was water with 0.04% TFA and the mobile phase B was HPLC grade acetonitrile with 0.02% TFA. The gradient was 5-95% B in 1.50 min, 5% B for 0.01 min, 5-95% B (0.01-0.70 min), 95% B (0.70-1.16 min), 95-5% B in (1.16-1.5 min). The flow rate was 1.5 mL / min. Example 30: N-((( 2S,3R Synthesis of N-((5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholin-4-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride (ac) Using (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester, the general procedure for the preparation of compound (aa) was repeated (see Example 28). Yield 89%, yellow solid.

[0502] LCMS (ESI+): m / z = 313.2 (M+1), RT: 0.361 min (column Agilent Poroshell SB-C18 3.0 30 mm, 4 um. The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 50-2000. The mobile phase A was water with 0.04% trifluoroacetic acid and the mobile phase B was HPLC grade acetonitrile with 0.02% trifluoroacetic acid. The gradient was 5-95% B in 1.50 min, 5% B for 0.01 min, 5-95% B (0.01-0.70 min), 95% B (0.70-1.16 min), 95-5% B (1.16-1.17 min) and 0.33 min hold at 5% B. The flow rate was 1.5 mL / min. Example 31: N -((( 2S,3R Synthesis of N-((5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholin-4-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride (ac) Using (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester, the general procedure for the preparation of compound (aa) was repeated (see Example 28). Yield 89%, yellow solid.

[0503] LCMS (ESI+): m / z = 312.2 (M+1), RT: 0.602 min (column Agilent Poroshell SB-C18 3.0 30 mm, 4 um. The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 50-2000. The mobile phase A was water containing 0.04% trifluoroacetic acid and the mobile phase B was HPLC grade acetonitrile containing 0.02% trifluoroacetic acid. The gradient was 5-95% B in 1.50 min, 5% B for 0.01 min, 5-95% B (0.01-0.70 min), 95% B (0.70-1.16 min), 95-5% B (1.16-1.17 min) and 0.33 min at 5% B. The flow rate was 1.5 mL / min. Example 32: Synthesis of 5-chloro-N-((( 2S,3R )-6,6-difluoro-2-methylmorpholin-3-yl)methyl)pyrimidin-2-amine hydrochloride (ae) Using (5R,6S)-5-(((5-chloropyrimidin-2-yl)amino)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylic acid tert-butyl ester, the general procedure for the preparation of compound (aa) was repeated (see Example 28). Yield 98%, white solid.

[0504] 1 H NMR (400 MHz, DMSO- d 6): δ 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). Example 33. Synthesis of N-((( 2S,3R )-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-4-(trifluoromethyl)pyrimidin-2-amine hydrochloride (af) Using (5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester, the general procedure for the preparation of compound (aa) was repeated (see Example 28). Yield 79%, light yellow solid.

[0505] 1 H NMR (400 MHz, DMSO- d 6) δ 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). Example 34. N-((( 2S,3R )-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-6-(trifluoromethyl)pyrazin-2-amine hydrochloride (ag) synthesis Using (5R,6S)-2,2-difluoro-6-methyl-5-(((6-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester, repeat the general procedure for the preparation of compound (aa) (see Example 28). Yield 97%, yellow solid.

[0506] 1 H NMR (400 MHz, DMSO- d 6): δ 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). Example 34. N-((( 2S,3R )-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-6-(trifluoromethyl)pyrazin-2-amine hydrochloride (ag) synthesis Using (5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester, repeat the general procedure for the preparation of compound (aa) (see Example 28). Yield 89%, light yellow solid.

[0507] 1 H NMR (400 MHz, DMSO- d 6): δ 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). Example 36. N-((( 2S,3R Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3- fluoro-5-(trifluoromethyl)pyridin-2-amine hydrochloride (ai) Using (5R,6S)-2,2-difluoro-5-(((3-fluoro-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)-6-methylmorpholine-4-carboxylic acid tert-butyl ester, the general procedure for preparing compound (aa) was repeated (see Example 28). Yield 94%, white solid.

[0508] 1 HNMR (400 MHz, DMSO- d 6): δ 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). Example 36. N-((( 2S,3R Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3- fluoro-5-(trifluoromethyl)pyridin-2-amine hydrochloride (ai) (5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester (0.42 g, 987.32 pmol, 1 eq) was dissolved in HC1 / dioxane (4 M, 4.2 mL, 17.02 eq). The mixture was stirred at 25 °C for 1 hour. LCMS showed complete consumption of starting material, one major peak with target mass was detected. The mixture was pH adjusted to 9 with NaHC03(aq), and extracted with ethyl acetate (3 x 15 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous 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.

[0509] 1 H NMR (400 MHz, DMSO-) d 6): δ 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). Example 38. 5-Cyclopropyl-N-((( 2S,3R Synthesis of 6,6-difluoro-2-methylmorpholino-3-yl)methyl)pyrimidine-2-amine hydrochloride (ak) Using (5R,6S)-5-(((5-cyclopropylpyrimidin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester, repeat the general steps used to prepare compound (aa) (see Example 28). Yield 85%, brown oil.

[0510] 1 H NMR (400 MHz, DMSO-) d 6 ): δ = 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, 3H), 0.86 - 0.98 (m, 2 H), 0.64 - 0.76 (m, 2 H). Example 39. N-((( 2S,3R Synthesis of 6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3-methoxy-5-(trifluoromethyl)pyridine-2-amine (al) use( 2S,3R 2,2-Difluoro-5-(((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-6-methylmorpholine-4-carboxylic acid tert-butyl ester, repeated using the general steps for the preparation of compound (aj) (see Example 37). Yield 64%, yellow solid.

[0511] LCMS: m / z = 342.2 (M+1), RT: 0.621 min. Example 40. Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyrazine-2-amine hydrochloride (am) use( 5R,6S 3-Methyl-5-(((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester, repeated using the general steps for the preparation of compound (aa) (see Example 28). Yield 99%, pale yellow solid.

[0512] 1 H NMR (400 MHz, DMSO-) d 6): δ 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). Example 41. 2-(((( 5R,6S Synthesis of 6,6-difluoro-2-methylmorpholin-3-yl)methyl)amino)-5-(trifluoromethyl)nicotinonitrile hydrochloride (an) use( 2S,3R 3-Cyano-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester, repeated using the general steps for the preparation of compound (aa) (see Example 28). Yield 95%, yellow solid.

[0513] LCMS: (ESI+): m / z=337.2 (M+1), RT: 0.404 min. Example 42. 5-Chloro-N-((( 5R,6S Synthesis of 6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3-fluoropyridine-2-amine hydrochloride (ao) use( 2S,3R 5-(((5-chloro-3-fluoropyridin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester, repeated using the general steps for the preparation of compound (aa) (see Example 28). Yield 94%, white solid.

[0514] 1 H NMR (400 MHz, DMSO-) d 6 ): δ 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). Example 43. N-((( 5R,6S Synthesis of 6,6-difluoro-2-methylmorpholin-3-yl)methyl)-4-methyl-5-(trifluoromethyl)pyrimidine-2-amine (ap) use( 2S,3R 4-Methyl-5-(((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester, repeated using the general steps for the preparation of compound (aj) (see Example 37). Yield 82%, yellow oil.

[0515] 1 HNMR (400 MHz, DMSO- d 6 ): δ 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 - 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). Example 44: N-((( 5R,6S Synthesis of 6,6-difluoro-2-methylmorpholin-3-yl)methyl)-5-(difluoromethyl)pyrimidine-2-amine hydrochloride (aq) use( 2S,3R5-(((5-(difluoromethyl)pyrimidin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholino-4-carboxylic acid tert-butyl ester, repeated using the general steps for the preparation of compound (aa) (see Example 28). Yield 92%, yellow solid.

[0516] 1 H NMR (400 MHz, DMSO-) d 6 ): δ = 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). Example 45: N-((( 5R,6S Synthesis of 6,6-difluoro-2-methylmorpholin-3-yl)methyl)-5-(difluoromethyl)pyrazine-2-amine hydrochloride (ar) use( 2S,3R 5-(((5-(difluoromethyl)pyrazin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester, repeated using the general steps for the preparation of compound (aa) (see Example 28). Yield 87%, yellow solid.

[0517] 1 H NMR (400 MHz, DMSO-) d 6 ): δ = 8.19 (d, J =1.00 Hz, 1 H), 8.00 (d, J =1.13Hz, 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). Example 46: ( 5R,6S Synthesis of 4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine-3,3-d2 (f1). (5R,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 trideuteroborane (1 M in THF, 23.00 mL, 5.10 eq) at 20 °C. The mixture was then stirred at 40 °C for 1.5 hours. LCMS showed 30% starting material remained, 60% target mass detected. The reaction mixture was quenched with MeOH (30 mL) at 20 °C. The mixture was stirred at 40 °C for 1 hour, then concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6- methylmorpholin-3,3-d2 (1.1 g, 1.99 mmol, 44.08% yield, 90% purity) as a colorless oil.

[0518] 1 H NMR (400 MHz, DMSO-d6): δ 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, 1H), 3.97 - 3.83(m, 2H), 3.74 (d, J = 5.4 Hz, 2H), 2.83 - 2.76 (m, 1H), 1.22 (d, J = 6.6 Hz, 3H),1.00 (s, 9H). Example 47: (( 5R,6S )-4-benzyl-6,6-difluoro-2-methylmorpholin-3-yl-5,5-d2) methanol (g1). 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. The mixture was then stirred at 20 °C for 12 h. LCMS showed all starting material was consumed, target mass was detected. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic phase was 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 column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholin-3-yl-5,5-d2)methanol (150 mg, 549.58 µmol, 39.07% yield, 95% purity) as a colorless oil.

[0519] 1 H NMR (400 MHz, DMSO-d6): δ 7.42 – 7.19 (m, 5H), 4.60 (t, J = 5.0 Hz,1H), 4.44 (dq, J = 2.8, 6.7 Hz, 1H), 3.88 (s, 2H), 3.81 – 3.60 (m, 2H), 2.73 –2.60 (m, 1H), 1.23 (d, J = 6.7 Hz, 3H). Example 48: Synthesis of tert-butyl (5R)-2,2-difluoro-5-(hydroxymethyl)-6- methylmorpholine-4-carboxylate-3,3-d2 (h2). 2S,3R Synthesis of tert-butyl (5R)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4- carboxylate-3,3-d2 (h1). To a solution of ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpho lin-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 μmol, 10% purity, 0.05 eq), (Boc)20 (631.28 mg, 2.89 mmol, 664.51 μL, 1.5 eq) and TEA (390.26 mg, 3.86 mmol, 536.81 μL, 2 eq) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 20 °C under H2 (15 psi) for 12 h. LCMS showed all starting material was consumed and target 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. This crude product was used directly for the next step. (5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (519 mg, 1.93 mmol, 99.95% yield) was obtained as a colorless oil.

[0520] 1 H NMR (400 MHz, DMSO-d6): δ = 4.76 (t, J = 5.6 Hz, 1H), 4.35 - 4.24 (m,1H), 4.07 - 3.91 (m, 1H), 3.72 - 3.52 (m, 2H), 1.41 (s, 9H), 1.22 (br d, J =6.4 Hz, 3H). Example 49: Synthesis of tert-butyl 5-((1,3-dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate-3,3-d2 (ii). 5R,6S Example 49: Synthesis of tert-butyl 5-((1,3-dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6- methylmorpholine-4-carboxylate-3,3-d2 (ii). To a solution of (519 mg, 1.93 mmol, 1 eq) in tetrahydrofuran (5 mL) was added isoindoline-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. To the reaction mixture was added PPh3 (758.29 mg, 2.89 mmol, 1.5 eq) at 20 °C. To the mixture was added DIAD (584.59 mg, 2.89 mmol, 560.49 μL, 1.5 eq) at 0 °C. The mixture was then stirred at 20 °C for 12 h under N2 atmosphere. LCMS showed all starting material was consumed and the target mass was detected. The residue was quenched with ice water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic phase was 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 (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1). Compound (5R,6S)-tert-butyl 5-((1,3-dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (440 mg, 993.98 μmol, 51.57% yield, 90% purity) was obtained as a yellow solid.

[0521] 1 H NMR (400 MHz, DMSO-d6): δ 8.01 - 7.74 (m, 4H), 4.48 - 4.19 (m, 2H), 3.94 (dd, J = 11.9, 14.3 Hz, 1H), 3.74 (dd, J = 3.1, 14.4 Hz, 1H), 1.38 (d, J = 6.6Hz, 3H), 1.05 - 0.91 (m, 9H). Example 50: Synthesis of (5R,6S)-tert-butyl 5-(azidomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (j2). 5R,6S Example 50: Synthesis of (5R,6S)-tert-butyl 5-(azidomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (j2). 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 μL, 10 eq) at 25 °C. Then the mixture was stirred at 60 °C for 4 h under N2atmosphere. LCMS showed all starting material was consumed, target mass was detected. The reaction mixture was filtered to get the filtrate, which was concentrated under reduced pressure to get the crude product. The crude product was used directly for the next step. (5R,6S)-tert-Butyl 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.

[0522] 1 H NMR (400 MHz, DMSO-d6): δ 4.26 (br s, 1H), 4.02 – 3.84 (m, 1H), 2.82– 2.69 (m, 2H), 1.41 (s, 9H), 1.19 (d, J = 6.8 Hz, 3H). 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) 5R,6S ​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 (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (230.00 mg, 685.81 μmol, 1 eq) at 25 °C. To the reaction mixture was added K2CO3 (189.57 mg, 1.37 mmol, 2 eq) at 25 °C. The mixture was then stirred at 80 °C for 2 h. LCMS showed all starting materials were consumed and the target mass was detected. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic phase was washed with 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 preparative thin layer chromatography (petroleum ether: ethyl acetate = 1 : 1) to give the product. Compound (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (90 mg, yield 25.34%) was obtained as a yellow solid.

[0523] 1 H NMR (400 MHz, DMSO- d 6): δ 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). Example 52: Synthesis of (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (ml) At 25 °C, DIPEA (61.66 mg, 477.08 μmol, 83.10 μL, 2 eq) and 2-fluoro-5-(trifluoromethyl)pyridine (59.07 mg, 357.81 μmol, 1.5 eq) were added to a DMSO (1.6 mL) solution of (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (80.00 mg, 238.54 μmol, 1 eq). The mixture was then stirred at 140 °C for 16 h. LCMS showed that all starting materials were consumed and the target mass was detected. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic phases were washed with 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 preparative thin-layer chromatography (petroleum ether: ethyl acetate = 1:1) to obtain (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (40 mg, yield 32.45%), which is a yellow solid.

[0524] LCMS(ESI+): m / z =414.2 (M+1), RT: 0.564 min. Similarly, the following compounds were prepared.

[0525] Example 53: ( 5R,6S )-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (l1) use( 5R,6S 3,3-d2-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester and 2-chloro-5-(trifluoromethyl)pyrimidine were used in the same general steps as those used to prepare compound (m1) (see Example 52). Yield 85%, colorless oil.

[0526] 1 HNMR (400 MHz, DMSO- d 6): δ 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). 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) 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 HCl / dioxane (4 M, 2 mL, 46.04 eq) was added at 20 °C. Then the mixture was stirred at 20 °C for 1 h. LCMS showed all starting material was consumed, target mass was detected. The reaction mixture was concentrated under reduced pressure to give the crude product 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.

[0527] LCMS (ESI+): m / z = 315.1 (M+1), RT: 0.584 min. Similarly, the following compounds were prepared.

[0528] Example 55: N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl-5,5-d2)methyl)-5- (trifluoromethyl)pyrimidin-2-amine hydrochloride (ac1) Using ( 5R,6S )-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4- carboxylic acid tert-butyl ester-3,3-d2, the general procedure for preparing compound (ab1) was repeated (see Example 54).

[0529] Yield 97%, white solid.

[0530] LCMS (ESI+): m / z = 315.2 (M+1), RT: 0.574 min. Example 56: N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyridine-2-amine hydrochloride (ad1) Using (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester-3,3-d2, repeat the general steps used to prepare compound (ab1) (see Example 54).

[0531] Yield 99%, yellow solid.

[0532] LCMS(ESI+): m / z =314.2 (M+1), RT: 0.380 min. Example 57: ( 5R,6S Synthesis of 4-benzyl-6,6-difluoro-2-methyl-5-oxomorpholine-3-carboxylic acid (e2'). In a 50 L reactor equipped with a stirrer, a feeding funnel, and a thermometer, dioxane (20 L, 20 V) was added, followed by t-BuONa (1.09 kg, 11.35 mol, 5 eq) in four batches at 25 °C. After cooling to 10 °C, benzyl-L-allethreonine (CAS 1932485-18-1) (500.00 g, 2.27 mol, 1 eq) and sodium (2-bromo-2,2-difluoroacetyl)oxy (1.34 kg, 6.81 mol, 3 eq) were added to the reactor in five batches at 10 °C: benzyl-L-allethreonine (100 g, 0.2 eq) and sodium (2-bromo-2,2-difluoroacetyl)oxy (268 g, 0.6 eq) were added alternately, waiting for the temperature to drop to 10 °C after each addition, until all the additions were completed. A yellow suspension was eventually formed. The suspension was stirred at 25°C under N2 for 1 hour. LCMS showed that benzyl-L-allothreonine was consumed, and the target mass was detected.

[0533] The reaction was quenched with aqueous hydrochloric acid (5 L, 10 V, 4 mol / L) at 0 °C and the pH of the solution was adjusted to 2. Then EtOAc (5 L, 10 V) was added to the reaction at 25 °C. The solution was stirred at 25 °C under N2for 12 h. LCMS showed the intermediate was consumed and the target mass was detected. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3 x 5 L). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, 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 a grey solid.

[0534] 1 H NMR (400 MHz, DMSO- d 6): δ ppm 13.64 (br s, 1H), 7.25 - 7.34 (m, 5H), 4.75 – 4.83 (m, 2H), 4.13 – 4.16 (m, 2H), 1.28 (d, J=6.50 Hz, 3 H). Example 58: Synthesis of (2S,3S)-4-benzyl-2,2-difluoro-5-(hydroxymethyl-d2)-6- methylmorpholine-3-one (e2”). 2S,3S Example 58: Synthesis of (2S,3S)-4-benzyl-2,2-difluoro-5-(hydroxymethyl-d2)-6- methylmorpholine-3-one (e2”). 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. To the solution was added isobutyl chloroformate (7.18 g, 52.59 mmol, 6.88 mL, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 30 min. LCMS showed (2S,3S)-4-benzyl-6,6-difluoro-2-methyl-5-oxomorpholine-3-carboxylic acid was consumed, target 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 to the filtrate at 0 °C. The reaction was then stirred at 25 °C for 2 h. LCMS showed all starting materials were consumed, target mass was detected. Then extracted with water (100 mL), ethyl acetate mL (100 mL x 3). The combined organic phase was washed with brine mL (50 mL x 2), dried over Na2SO4, filtered and concentrated to give the crude product. This crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1). Compound (5R,6S)-4-benzyl-2,2-difluoro-5-(hydroxymethyl-d2)-6-methylmorpholin-3-one (6 g, 62.63% yield) was obtained as a colorless oil.

[0535] 1 H NMR (400 MHz, DMSO- d 6): δ 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). Example 59: Synthesis of (5R,6S)-4-benzyl-2,2-difluoro-5-(hydroxymethyl-d2)-6- methylmorpholin-3-one (g2). 5R,6S Synthesis of (5R,6S)-4-benzyl-2,2-difluoro-5-(hydroxymethyl-d2)-6-methylmorpholin-3- one (g2). 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 to a 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 hours. LCMS showed all starting material was consumed and the target mass was detected. The reaction was poured into HC1 (1 N) and adjusted to pH 7, then extracted with ethyl acetate mL (200 mL x 3). The combined organic phase was washed with brine mL (200 mL x 2), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by column chromatography (Si02, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1). ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholin-3-yl)methanol-d2 (4.2 g, 73.78% yield) was obtained as a colorless oil.

[0536] 1 H NMR (400 MHz, DMSO- d 6): δ 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). Example 60: Synthesis of tert-butyl (2S,3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3- methylpiperidine-1-carboxylate (h2). 2S,3R Example 60: Synthesis of tert-butyl (2S,3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3- methylpiperidine-1-carboxylate (h2). To a solution of ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholin-3-yl)methanol- d2 (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)20 (4.95 g, 5.21 mL, 1.4 eq). The mixture was stirred at 20 °C under 15 Psi H2for 12 hours. TLC showed all starting material was consumed. The reaction was filtered and concentrated to give the crude product. The residue was purified by column chromatography (Si02, 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.

[0537] 1 H NMR (400 MHz, DMSO- d 6): δ 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). Example 61: Synthesis of tert-butyl (5-((1,3-dioxoisoindolin-2-yl)methyl-d2)-2,2- difluoro-6-methylmorpholine-4-yl)carbamate (i2). 2S,3R Synthesis of tert-butyl (5-((1,3-dioxoisoindolin-2-yl)methyl-d2)-2,2-difluoro-6- methylmorpholine-4-yl)carbamate (i2). 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, 1.5 eq) and PPh3(5.00 g, 1.5 eq) at 0 °C. Then DIAD (3.85 g, 1.5 eq) was added to the mixture. The mixture was stirred at 20 °C for 16 hours. LCMS showed all starting materials were consumed and the target mass was detected. The reaction was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL x 3), the organic phase was combined, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 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 a white solid.

[0538] 1 H NMR (400 MHz, DMSO- d 6): δ 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). Example 62: Synthesis of tert-butyl (5-((1,3-dioxoisoindolin-2-yl)methyl-d2)-2,2- difluoro-6-methylmorpholine-4-yl)carbamate (i2). 5R,6SSynthesis of tert-butyl (5-amino-2,2-difluoro-6-methylmorpholin-4-yl)methyl-d2 To a solution of tert-butyl (5R,6S)-5-((l,3-dioxoisoindolin-2-yl)methyl-d2)-2,2- difluoro-6-methylmorpholine-4-carboxylate (3.4 g, 1 eq) in methanol (68 mL) was added hydrazine hydrate (4.06 g, 3.93 mL, 10 eq) at 25 °C. The mixture was then stirred at 60 °C for 2 h under N2atmosphere. LCMS showed all starting material was consumed, target mass was detected. The reaction mixture was filtered to get the filtrate, which was concentrated under reduced pressure to get the crude product. This crude product was used directly 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.

[0539] 1 H NMR (400 MHz, DMSO- d 6): δ ppm 4.27 (br s, 1 H), 4.14 (br t, J=15.01Hz, 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). Example 63: ( 5R,6S tert-butyl 2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl-d2)morpholine-4-carboxylate (k2) To a solution of tert-butyl (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6- methylmorpholine-4-carboxylate (100 mg, 372.72 μmol, 1 eq) in DMSO (2 mL) was added DIPEA (96.34 mg, 745.44 μmol, 129.84 μL, 2 eq) and 2-chloro-5- (trifluoromethyl)pyrimidine (81.64 mg, 447.27 μmol, 1.2 eq) at 25 °C. The mixture was then stirred at 80 °C for 2 h. LCMS showed all starting material was consumed and target mass was detected. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was 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 preparative thin layer chromatography (petroleum ether: ethyl acetate = 3: 1) to give tert-butyl (2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl-d2)piperidine-l-carboxylate (115 mg, 67.01% yield) as a yellow oil.

[0540] 1 HNMR (400 MHz, DMSO- d 6): δ 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, J = 6.38 Hz, 3 H), 1.24 (s, 3 H), 1.06 (s, 6 H). Example 64: Synthesis of tert-butyl (2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl-d2)piperidine-l-carboxylate (12) 5R,6S ​To a solution of (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4- carboxylic acid tert-butyl ester (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) at 25 °C. The mixture was stirred at 140 °C for 5 h. LCMS showed starting material was consumed, target mass was detected. The reaction mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (5 mL x 3), the combined organic phase was washed with brine (10 mL), dried over Na2S04, filtered and concentrated under reduced pressure to get a residue which was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash column eluted with 5% ethyl acetate / petroleum ether gradient, flow rate 50 mL / min) to get (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl-d2)morpholine-4-carboxylic acid tert-butyl ester (650 mg, yield 84.17%) as a yellow oil.

[0541] LCMS (ESI+): m / z = 415.2 (M+l), RT: 0.586 min. Similarly, the following compounds were prepared.

[0542] Example 65: (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl-d2)morpholine-4-carboxylic acid tert-butyl ester (m2) 5R,6S )-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl-d2)morpholine- 4-carboxylic acid tert-butyl ester (m2) The title compound (m2) was prepared in analogy to the procedure described for compound (12), using (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4- carboxylic acid tert-butyl ester and 2-fluoro-5-(trifluoromethyl)pyridine. Yield 42%, yellow oil. 5R,6S )-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester and 2-fluoro-5-(trifluoromethyl)pyridine. Yield 42%, yellow oil.

[0543] 1 H NMR (400 MHz, DMSO- d 6): d 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, 4H), 1.31 (br d, J = 6.38 Hz, 3 H), 1.07 (s, 9 H). Example 66: (R)-5-(((5-chloropyridin-2-yl)amino)methyl-d2)-2,2-difluoro-6- methylmorpholine-4-carboxylic acid tert-butyl ester (n2) 5R,6S The title compound (n2) was prepared in analogy to the procedure described for compound (12) using (R)-5-(((5-chloropyridin-2-yl)amino)methyl-d2)-2,2-difluoro-6- methylmorpholine-4-carboxylic acid tert-butyl ester (n2) 5R,6S (R)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert- butyl ester and 5-chloro-2-fluoropyridine. Yield 45%, yellow oil.

[0544] 1 HNMR (400 MHz, DMSO- d 6): δ ppm 7.91 - 8.01 (m, 1 H), 7.32 - 7.48 (m, 1H), 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). Example 67: N-((( 5R,6S (R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl)pyrimidin-2- amine (ac2). ​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 HCl / dioxane (2 mL) was stirred at 25 °C for 1 h. LCMS showed complete consumption of starting material and target mass was detected. The reaction mixture was neutralized to pH 9 with aq. Na2CO3(5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was 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.

[0545] LCMS (ESI+): m / z = 315.2 (M+1), RT: 0.349 min. Similarly, the following compounds were prepared.

[0546] Example 68: N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl-d2)-5- (trifluoromethyl)pyridin-2-amine (ad2) The title compound (ad2) was prepared in analogy to the procedures 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). Yield 70%, white solid.

[0547] 1 H NMR (400 MHz, DMSO- d 6): d ppm 8.30 (s, 1 H), 7.62 (dd, J = 8.88, 2.38 Hz, 1 H), 7.19 (s, 1 H), 6.64 (d, J = 8.88 Hz, 1 H), 4.36 (qd, J = 6.75, 3.38 Hz, 1 H), 2.87 - 3.15 (m, 4 H), 1.22 (d, J = 6.63 Hz, 3 H). Example 68: N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl-d2)-5- (trifluoromethyl)pyridin-2-amine (ad2) 2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride (ab2) The title compound (aa2) was prepared in analogy to the procedure described for compound (ac2) using (5R,6S)-5-(((5-chloropyridin-2-yl)amino)methyl-d2)-2,2-difluoro-6- methylmorpholine-4-carboxylic acid tert-butyl ester (n2). Yield 92%, yellow solid.

[0548] 1 HNMR (400 MHz, DMSO- d 6): δ 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). Example 70: 5-chloro-N-((( 2S,3R )-6,6-difluoro-2-methylmorpholin-3-yl)methyl-d2)pyridin-2-amine hydrochloride (aa2) The title compound (aa2) was prepared in analogy to the procedure described for compound (ac2) using (5R,6S)-5-(((5-chloropyridin-2-yl)amino)methyl-d2)-2,2-difluoro-6- methylmorpholine-4-carboxylic acid tert-butyl ester (n2). Yield 94%, yellow solid.

[0549] 1 HNMR (400 MHz, DMSO- d 6): δ 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). Example 71 : Synthesis of 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid To a solution of tert-butyl 4-iodo-1-methyl-1H-pyrazole-3-carboxylate (1.5 g, 4.87 mmol, 1 eq) in THF (60 mL) and H20 (15 mL) was added (4-cyanophenyl)boronic acid (929.95 mg, 6.33 mmol, 1.3 eq), K3P04(3.10 g, 14.60 mmol, 3 eq) and Pd(dtbpf)Cl2(158.65 mg, 243.42 μmol, 0.05 eq). The mixture was stirred at 80 °C under N2for 2 hr. LC-MS showed the starting material was completely consumed and one major 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 (Si02, petroleum ether / ethyl acetate = 0 / 1 to 30 / 1) to give tert-butyl 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylate (1.4 g, 4.94 mmol, 72.50% yield) as a brown solid.

[0550] LCMS (ESI+): m / z = 284.5 (M+1), RT: 0.718 min. 1 H NMR (400 MHz, DMSO- d 6): δ 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). A solution of tert-butyl 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylate (1 g, 3.53 mmol, 1 eq) in HC1 / dioxane (15 mL) was stirred at 50 °C for 2 hr. LC-MS showed the starting material was completely consumed and one major peak with desired mass was detected. The reaction mixture was filtered and the filter cake was dried to give 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (0.9 g, 3.96 mmol, 86.33% yield) as a brown solid.

[0551] LCMS (ESI+): m / z = 228.1 (M+1), RT: 0.552 min. 1 H NMR (400 MHz, DMSO- d6): δ 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). Example 72: Synthesis of 4-(5-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-3- carboxylic acid To a solution of (3-(tert-butoxycarbonyl)-1-methyl-1H-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 (485.78 mg, 2.65 mmol, 1.2 eq) and K3PO4 (1.41 g, 6.64 mmol, 3 eq) at 25 °C. The mixture was degassed and purged with N2 for 3 times. Then ditert-butyl(cyclopentyl)phosphane palladium dichloride iron (72.08 mg, 110.60 μmol, 0.05 eq) was added to the reaction mixture at 25 °C. The mixture was degassed and purged with N2 for 3 times and stirred at 80 °C for 2 hours. LCMS showed all starting material was consumed, desired MS was detected. The reaction mixture was poured into H2O (50 mL) and extracted with ethyl acetate (3x 100 mL). The combined organics were washed with 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 (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 2) to give tert-butyl 4-(5-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylate (520 mg, 82.68% yield) as a yellow solid.

[0552] 1 H NMR:(400 MHz, Chloroform- d ): δ 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). A solution of tert-butyl 4-(5-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylate (520 mg, 1.83 mmol, 1 eq) in 4 N / HCI in dioxane (10 mL) was stirred at 20 °C for 12 h. LCMS showed all starting material was consumed, desired MS was detected. The reaction mixture was filtered to get the filter cake, which was dried in vacuum to get 4-(5-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (470 mg, 97.09% yield, HCI) as a white solid.

[0553] 1 H NMR: (400 MHz, DMSO- d 6): δ 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). Example 73: Synthesis of 1,5-dimethyl-4-(pyrazin-2-yl)-1H-pyrazole-3-carboxylic acid To a solution of (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-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 μL, 1.5 eq) at 20 °C. The vessel was evacuated and backfilled with argon (this process was repeated three times), and to the mixture was added triphenylphosphine palladium (23.04 mg, 62.48 μmol, 0.05 eq) under argon protection, the vessel was evacuated and backfilled with argon (this process was repeated three times). The mixture was stirred at 80 °C for 16 h. LCMS showed all starting material was consumed; the desired mass was detected. The reaction mixture was concentrated under reduced pressure to get the crude product. The crude product was dissolved with ethyl acetate (10 mL) and filtered; the filtrate was concentrated under reduced pressure to get the residue. The residue was purified by silica gel column chromatography (eluted with ethyl acetate in petroleum ether from 0% to 100%) to get tert-butyl 1,5-dimethyl-4-(pyrazin-2-yl)-1H-pyrazole-3-carboxylate (270 mg, yield 78.76%) as a yellow oil.

[0554] 1 H NMR (400 MHz, Chloroform- d ): δ 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). A solution of tert-butyl 1,5-dimethyl-4-(pyrazin-2-yl)-1H-pyrazole-3-carboxylate (270 mg, 984.26 μmol, 1 eq) in HCl / dioxane (4 N, 6 mL) was stirred at 20 °C for 16 h. LCMS showed all starting material consumed; target mass detected. The reaction mixture was concentrated under reduced pressure to give 1,5-dimethyl-4-(pyrazin-2-yl)-1H-pyrazole-3-carboxylic acid (210 mg, yield 97.78%) as a white solid.

[0555] 1 H NMR (400 MHz, DMSO- d 6): δ 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). Example 74: Synthesis of 4-(5-fluoropyridin-3-yl)-1,5-dimethyl-1H-pyrazole-3- carboxylic acid To a solution of (3-(tert-butoxycarbonyl)-l,5-dimethyl-lH-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-fluoropyridine (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), to the mixture was added triphenylphosphine palladium (23.04 mg, 62.48 μmol, 0.05 eq) under argon protection, the vessel was evacuated and backfilled with argon (this process was repeated three times). The mixture was stirred at 80 °C for 16 h. LCMS showed all starting materials consumed; the target mass was detected. The reaction mixture was concentrated under reduced pressure to give a 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 silica gel column chromatography (eluted with ethyl acetate in petroleum ether from 0% to 100%) to give tert-butyl 4-(5-fluoropyridin-3-yl)-l,5-dimethyl-lH-pyrazole-3-carboxylate (110 mg, yield 30.22%) as a yellow oil.

[0556] 1 H NMR (400 MHz, Chloroform- d ): δ 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, 9H). A solution of tert-butyl 4-(5-fluoropyridin-3-yl)-l,5-dimethyl-lH-pyrazole-3- carboxylate (110 mg, 377.59 μmol, 1 eq) in HCl / dioxane (4 N, 2.5 mL) was stirred at 20 °C for 16 h. LCMS showed all starting materials consumed; the target MS was detected. The reaction mixture was concentrated under reduced pressure to give 4-(5-fluoropyridin-3-yl)-l,5-dimethyl-lH-pyrazole-3-carboxylic acid (87 mg, yield 97.96%) as a white solid.

[0557] 1 H NMR (400 MHz, DMSO- d 6): δ 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). Example 75: Synthesis of 4-(4-fluoropyridin-3-yl)-1,5-dimethyl-1 H-pyrazole-3- carboxylic acid 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-fluoropyridine (164.38 mg, 1.25 mmol, 1 eq), K3PO4(530.53 mg, 2.50 mmol, 128.17 μL, 2 eq), [2-(2-aminophenyl)phenyl]-chloro-palladium-dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphine (98.32 mg, 124.97 μmol, 0.1 eq) in H2O (0.225 mL) and butan-1 -ol (0.9 mL) was vacuumed and purged with argon gas for 3 times, then 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 organic phase was washed with 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 silica gel column chromatography eluting with ethyl acetate in petroleum ether from 0% to 60% to give 4-(4-fluoropyridin-3-yl)-1,5-dimethyl-1 H-pyrazole-3-carboxylic acid tert-butyl ester (0.27 g, yield 74.16%) as colorless oil.

[0558] 1 H NMR (400 MHz, DMSO- d 6 ): δ 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). A solution of tert-butyl 4-(4-fluoropyridin-3-yl)-1,5-dimethyl-1 H-pyrazole-3- carboxylate (0.27 g, 926.82 μmol, 1 eq) in HCl / dioxane (4 N, 3 mL) was stirred at 20 °C for 12 h. 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, yield 96.33%) as a white solid.

[0559] 1 H NMR (400 MHz, DMSO- d 6 ): δ 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). Example 76: Synthesis of 4-(4-fluoropyridin-2-yl)-1,5-dimethyl-1 H-pyrazole-3- carboxylic acid 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-fluoropyridine (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), to the mixture was added triphenylphosphine palladium (23.04 mg, 62.48 μmol, 0.05 eq) under argon protection, the vessel was evacuated and backfilled with argon (this process was repeated three times). The mixture was stirred at 80 °C for 16 h. LCMS showed all starting materials were consumed and the target 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 silica gel column chromatography (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, yield 24.72%) as a yellow oil.

[0560] 1 H NMR (400 MHz, Chloroform- d ): δ 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). A solution of tert-butyl 4-(4-fluoropyridin-2-yl)-1,5-dimethyl-1 H-pyrazole-3- carboxylate (90 mg, 308.94 μmol, 1 eq) in HCl / dioxane (4 N, 2 mL) was stirred at 20 °C for 16 h. LCMS showed all starting material consumed; target mass 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, yield 96.33%) as a white solid.

[0561] 1 H NMR (400 MHz, DMSO- d 6): δ 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). Example 77: Synthesis of 5-(5-fluoropyrimidin-2-yl)-1 -methyl-1 H-imidazole-4- carboxylic acid Methyl 5-bromo-1 -methyl-1 H-imidazole-4-carboxylate (2 g, 9.13 mmol, 1 eq) was dissolved in DMF (20 mL) and stirred at 20 °C. Potassium fluoride (1.22 g, 20.26 mmol, 2.22 eq) was added and the reaction mixture was stirred at 20 °C for 16 h. LCMS showed all starting material consumed; target mass detected. The reaction mixture was concentrated under reduced pressure to give 5-bromo-1 -methyl-1 H-imidazole-4-carboxylic acid (1.5 g, yield 96.67%) as a white solid. 2S,3R) in toluene (20 mL) was degassed and purged with N2for 3 times. Pd(PPh3)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) were added into the reaction mixture at 20 °C. The suspension was degassed and purged with N2for 3 times, then the mixture was stirred at 120 °C under N2for 6 hours. LCMS showed all starting material was consumed, desired Ms was detected. The reaction mixture was concentrated under reduced pressure to get the crude product. The residue was purified by column chromatography (Al2O3, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) to give methyl 1-methyl-5-(trimethylstannyl)-1H-imidazole-4-carboxylate (1.7 g, yield 49.17%) as yellow oil.

[0562] 1 H NMR (400 MHz, DMSO- d 6): δ 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). methyl 1-methyl-5-(trimethylstannyl)-1H-imidazole-4-carboxylate (1 g, 2.64 mmol, 1 eq eq) in toluene (20 mL) was added 2-bromo-5-fluoro-pyrimidine (701.02 mg, 3.96 mmol, 1.5 eq eq) at 20 °C. The suspension was degassed and purged with N2for 3 times. Pd(PPh3)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 N2for 3 times. Then the mixture was stirred at 140 °C under N2for 16 hours. LCMS showed all starting material was consumed, desired Ms was detected. The residue was quenched with water (20 mL) and extracted with dichloromethane (5 x 30 mL). The combined organic was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 1 to 0 / 1). The crude product 5-(5-fluoropyrimidin-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid methyl ester (600 mg, yield 67.33%) was obtained as a brown solid.

[0563] LCMS (ESI+): m / z = 237.3 (M+1), RT: 0.186 min. Methyl 5-(5-fluoropyrimidin-2-yl)-l-methyl-lH-imidazole-4-carboxylate (600 mg, 1.78 mmol, 1 eq) was dissolved in 6N HC1 (12 mL) at 20 °C, then the mixture was stirred at 80 °C for 2 h. LCMS showed all starting material was consumed, desired Ms was detected. The residue was quenched with water (10 mL) and extracted with ethyl acetate (3 x 330 mL). The aqueous phase was concentrated under reduced pressure to give the crude product. The crude product was used directly for the next step. The crude 5-(5-fluoropyrimidin-2-yl)-l-methyl-lH-imidazole-4-carboxylic acid (400 mg, yield 69.58%) was obtained as a yellow solid, which was used without further purification. eq ) was dissolved in 6N HC1 (12 mL) at 20 °C, then the mixture was stirred at 80 °C for 2 h. LCMS showed all starting material was consumed, desired Ms was detected. The residue was quenched with water (10 mL) and extracted with ethyl acetate (3 x 330 mL). The aqueous phase was concentrated under reduced pressure to give the crude product. The crude product was used directly for the next step. The crude 5-(5-fluoropyrimidin-2-yl)-l-methyl-lH-imidazole-4-carboxylic acid (400 mg, yield 69.58%) was obtained as a yellow solid, which was used without further purification.

[0564] LCMS (ESI+): m / z = 223.2 (M+1), RT: 0.255 min Example 78: Synthesis of 5-(5-methoxypyridin-2-yl)-l-methyl-lH-imidazole-4- carboxylic acid Methyl 5-(5-fluoropyrimidin-2-yl)-l-methyl-lH-imidazole-4-carboxylate (600 mg, 1.78 mmol, 1 eq) was dissolved in 6N HC1 (12 mL) at 20 °C, then the mixture was stirred at 80 °C for 2 h. LCMS showed all starting material was consumed, desired Ms was detected. The residue was quenched with water (10 mL) and extracted with ethyl acetate (3 x 330 mL). The aqueous phase was concentrated under reduced pressure to give the crude product. The crude product was used directly for the next step. The crude 5-(5-fluoropyrimidin-2-yl)-l-methyl-lH-imidazole-4-carboxylic acid (400 mg, yield 69.58%) was obtained as a yellow solid, which was used without further purification. eq ) was dissolved in 6N HC1 (12 mL) at 20 °C, then the mixture was stirred at 80 °C for 2 h. LCMS showed all starting material was consumed, desired Ms was detected. The residue was quenched with water (10 mL) and extracted with ethyl acetate (3 x 330 mL). The aqueous phase was concentrated under reduced pressure to give the crude product. The crude product was used directly for the next step. The crude 5-(5-fluoropyrimidin-2-yl)-l-methyl-lH-imidazole-4-carboxylic acid (400 mg, yield 69.58%) was obtained as a yellow solid, which was used without further purification. eq ) was dissolved in 6N HC1 (12 mL) at 20 °C, then the mixture was stirred at 80 °C for 2 h. LCMS showed all starting material was consumed, desired Ms was detected. The residue was quenched with water (10 mL) and extracted with ethyl acetate (3 x 330 mL). The aqueous phase was concentrated under reduced pressure to give the crude product. The crude product was used directly for the next step. The crude 5-(5-fluoropyrimidin-2-yl)-l-methyl-lH-imidazole-4-carboxylic acid (400 mg, yield 69.58%) was obtained as a yellow solid, which was used without further purification.

[0565] 1 H NMR (400 MHz, DMSO- d 6): δ ppm 8.40 (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). 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). methyl-1H-imidazole-4-carboxylate (200 mg, 768.45 μmol, 1 eq ) in 6 N HC1 (4 mL) was stirred at 80 °C for 24 h. LCMS showed all starting material was consumed, desired Ms was detected. The reaction mixture was concentrated under reduced pressure to get the crude 5-(5-methoxypyridin-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid as yellow solid (220 mg, yield 95.54%). The crude product was used directly for the next step.

[0566] 1 H NMR (400 MHz, DMSO- d 6): δ ppm 9.35 (s, 0.95 H) 8.48 (d, 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). 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). 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). Example 79: Synthesis of 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3- carboxylic acid To a solution of 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (10 g, 46.65 mmol, 1 eqDMAP (557.75 mg, 4.57 mmol, 0.1 eq) and tert-butoxycarbonyl tert-butyl carbonate (29.89 g, 136.96 mmol, 3 eq) were added to a solution of THF (50 mL) and t-BuOH (50 mL), and the mixture was stirred at 20 °C for 12 h. LCMS showed that all starting materials were consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was then diluted with water (300 mL) and extracted with dichloromethane (300 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether from 0% to 20%) to give tert-butyl 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylate (3.5 g, yield 27.86%) as a white solid.

[0567] 1 H NMR (400 MHz, DMSO-) d 6): δ ppm 3.84 (s, 3.00 H) 2.25 (s, 3.00 H) 1.51 (s, 9.00 H). At -78°C, tert-butyl 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylate (3.5 g, 12.72 mmol, 1 eq A solution of n-BuLi (1.22 g, 19.08 mmol, 4.39 mL, 1.5 eq) in THF (70 mL) and triisopropyl borate (3.59 g, 19.08 mmol, 4.39 mL, 1.5 eq) was added dropwise, and the mixture was stirred at -78 °C for 1 h. LCMS showed that all starting materials were consumed and the desired mass was detected. The reaction mixture was quenched by adding a saturated ammonium chloride solution (50 mL) at 0 °C, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was ground 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 under high vacuum to obtain (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazol-4-yl)boronic acid (2.52 g, yield 82.52%) as a white solid.

[0568] 1 H NMR: (400 MHz, DMSO- d6): δ 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). To a mixture of (3-(tert-butoxy carbonyl)-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 eq) followed by a solution of K2CO3(2.16 g, 15.62 mmol, 1.5 eq) in H2O (7.5 mL) at 20 °C. The vessel was evacuated and backfilled with argon (this process was repeated three times), triphenylphosphine palladium (601.70 mg, 520.70 μmol, 0.05 eq) was added to the mixture under argon, the vessel was evacuated and backfilled with argon (this process was repeated three times) and the mixture was stirred at 80 °C for 12 h. LCMS showed all starting material was 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 layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield the crude product. The crude product was purified by silica gel column chromatography (eluted with ethyl acetate in petroleum ether from 0% to 20%) to yield 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1 H-pyrazole-3-carboxylic acid tert-butyl ester (2.51 g, yield 82.73%) as a light yellow solid.

[0569] LCMS (ESI+): m / z = 292.0 (M+1), RT: 0.417 min. A solution of 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1 H-pyrazole-3-carboxylic acid tert-butyl ester (2.5 g, 8.58 mmol, 1 eq eq) in HC1 / dioxane (4 M, 50 mL) was stirred at 20 °C for 12 h. LCMS showed all starting material was consumed; desired mass was detected. The reaction mixture was concentrated under reduced pressure to yield 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1 H-pyrazole-3-carboxylic acid (2.3 g, yield 98.65%, HC1) as a white solid.

[0570] 1 H NMR (400 MHz, DMSO- d6): δ 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). Example 80: Synthesis of 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3- carboxylic acid To a solution of (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazol-4-yl)boronic acid (1 g, 3.04 mmol, 1 eq) in DMF (7.2 mL) was added a solution of 2-bromo-5-methoxy- pyridine (571.75 mg, 3.04 mmol, 1 eq) and 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(PPh3)4 (175.70 mg, 152.04 μmol, 0.05 eq) was added to the mixture under N2, the vessel was evacuated and backfilled with N2 (this process was repeated three times). The mixture was then stirred at 80 °C for 12 h. 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 layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether from 0% to 50%) to give tert-butyl 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (0.5 g, 50.95% yield) as a white solid.

[0571] 1 H NMR (400 MHz, DMSO- d 6 ): δ = 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). LCMS (ESI+): m / z = 304.0 (M+1), RT: 0.312 min. 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 h. 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 under high vacuum to afford 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1 H-pyrazole-3-carboxylic acid as a white solid (0.37 g, 76.79% yield).

[0572] 1 H NMR (400 MHz, DMSO- d 6 ): δ = 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). LCMS (ESI+): m / z = 248.2 (M+1), RT: 0.095 min. Example 81 : 3-(5-Fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2- carboxylic acid 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 dropwise Br2(52.52 g, 328.62 mmol, 16.93 mL, 2 eq) at 0 °C. The reaction mixture was then stirred at 0 °C for 2 h. LCMS showed the starting material was consumed and product with desired mass was detected. The reaction mixture was quenched by the addition of saturated aqueous sodium thiosulfate solution (100 mL), the reaction solution was filtered and the filter cake was dried under high reduced pressure to afford 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid as a yellow solid (36.5 g, 95.18% yield).

[0573] 1 H NMR (400 MHz, DMSO- d6): δ = 4.13 - 4.24 (m, 2 H), 2.82 (t, J=7.32Hz, 2 H), 2.55 (dt, J=14.85, 7.52 Hz, 2 H). To a solution of 3-bromo-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxylic acid (10 g, 42.85 mmol, 1 eq) in THF (200 mL) was added 2-tert-butyl-3-isopropyl-l,l-dimethyl- isourea (23.95 g, 128.55 mmol, 3 eq) at 0 °C. The mixture was stirred at 20 °C for 16 h. TLC showed the starting material was completely consumed and a new spot was observed. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (500 mL), extracted with ethyl acetate (2 x 300 mL), the combined organic layers were washed with brine (200 mL), dried over anhydrous Na2S04, filtered, concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether from 0% to 50%) to give tert-butyl 3-bromo-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxylate (10 g, 77.21% yield) as a white solid. 1 H NMR (400 MHz, DMSO- d 6): δ = 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). To a solution of tert-butyl 3-bromo-5,6-dihydro-4H-pyrrolo[l,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 dropwise to the mixture 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 the addition of saturated aqueous ammonium chloride 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 Na2S04, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography eluting with methanol in ethyl acetate from 0% to 50% to give (2-(tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl)boronic acid as a white solid (0.9 g, 35.40% yield).

[0574] 1 H NMR (400 MHz, DMSO- d 6): δ = 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). To a solution of (2-(tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3- yl)boronic acid (0.9 g, 2.93 mmol, 1 eq) in DMF (13.5 mL) was added a solution of 2-bromo-5-fluoro-pyrimidine (518.13 mg, 2.93 mmol, 1 eq) and K2CO3(606.94 mg, 4.39 mmol, 1.5 eq) in H2O (3 mL) at 20 °C, the vessel was evacuated and backfilled with N2(three times), then Pd(PPh3)4(53.97 mg, 146.39 μmol, 0.05 eq) was added to the mixture under N2, the vessel was evacuated and backfilled with N2(three times). The mixture was then stirred at 80 °C for 12 h. 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 layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to get a residue. The residue was purified by silica gel column chromatography (eluted with ethyl acetate in petroleum ether from 0% to 30%) to get tert-butyl 3-(5-fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxylate (0.78 g, 73.54% yield) as a yellow solid.

[0575] 1 H NMR (400 MHz, DMSO- d 6): δ = 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). A solution of tert-butyl 3-(5-fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole- 2-carboxylate (0.78 g, 2.15 mmol, 1 eq) in 4N HCl / dioxane (16 mL) was stirred at 20 °C for 1 h. LCMS showed the starting material was consumed and product with desired mass was detected. The reaction solution was concentrated under reduced pressure to get 3-(5-fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2-carboxylic acid (0.45 g, 82.52% yield, 98% purity) as a white solid.

[0576] 1 H NMR (400 MHz, DMSO- d6): δ = 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). LCMS (ESI+): m / z = 249.1 (M+1), RT: 0.322 min. Example 82: 5,6-Dimethyl-3-(pyrimidin-2-yl)pyridinecarboxylic acid 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 3 times, then Cul (397.83 mg, 2.09 mmol, 0.1 eq) and triphenylphosphine palladium (770.17 mg, 2.09 mmol, 0.1 eq) were added to the mixture at 20 °C, the mixture was degassed and purged with argon 3 times. The mixture was stirred at 100 °C for 16 hours. LCMS showed all starting material was consumed, the desired mass was detected. The mixture was filtered, then the filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by silica gel column chromatography (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.

[0577] 1 H NMR (400 MHz, DMSO- d 6 ): δ ppm 8.86 (d, J=4.88 Hz, 2 H), 8.37 (s, 1H), 7.33 (t, J=4.88 Hz, 1 H), 2.30 (s, 3 H), 2.16 (s, 3 H). 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 hours. LCMS showed all starting material was consumed, desired mass was detected. The reaction mixture was concentrated under reduced pressure to get a residue. The residue was purified by preparative HPLC. 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-ol (1.62 g, 80.60% yield) was obtained as a yellow solid.

[0578] 1 H NMR (400 MHz, DMSO- d 6): δ 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). 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 triflate (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 hours. LCMS showed all starting material was 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 get a residue. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether from 0% to 20%) to get a residue. 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl trifluoromethanesulfonate (1.9 g, 81.94% yield) was obtained as a yellow solid.

[0579] 1 H NMR (400 MHz, DMSO- d6): δ ppm 8.98 (d, J=4.88 Hz, 2 H), 8.48 (s, 1H), 7.58 (t, J=4.88 Hz, 1 H), 2.50 (s, 3 H), 2.40 (s, 3 H). To a solution of 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl trifluoromethanesulfonate in methanol (40 mL) was added Pd(dppf)Cl2(417.13 mg, 570.08 μmol, 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 under CO (50 psi) for 16 hours. LCMS showed all starting material was consumed; the desired mass was detected. The mixture was filtered off, then the filtrate was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether from 0% to 20%) to give methyl 5,6-dimethyl-3-(pyrimidin-2-yl)pyridinecarboxylate (500 mg, 36.05% yield) as a yellow solid.

[0580] 1 H NMR (400 MHz, DMSO- d 6): δ ppm 8.90 (d, J=4.88 Hz, 2 H), 8.29 (s, 1H), 7.49 (t, J=4.94 Hz, 1 H), 3.72 (s, 3 H), 2.50 (s, 3 H), 2.37 (s, 3 H). To a solution of methyl 5,6-dimethyl-3-(pyrimidin-2-yl)pyridinecarboxylate (100 mg, 411.08 μmol, 1 eq) in methanol (0.5 mL) and THF (0.5 mL) and H2O (0.5 mL) was added LiOH.H2O (34.50 mg, 822.16 μmol, 2 eq) at 20 °C. The mixture was stirred at 20 °C for 3 hours. LCMS showed all starting material was consumed, desired mass was detected. The reaction mixture was concentrated under reduced pressure to get a residue. The phase layer was adjusted to pH=3 with 1N HC1 at 0 °C, the mixture was diluted with water (10 mL) and extracted with dichloromethane / methanol (5:1, 10 mL x 3). The combined organic layer was washed with saturated sodium chloride solution (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to get 5,6-dimethyl-3-(pyrimidin-2-yl)pyridinecarboxylic acid (90 mg, 95.51% yield) as a yellow solid.

[0581] 1 H NMR (400 MHz, DMSO- d 6): δ 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, 3H). Example 83: 4,6-dimethyl-3-(pyrimidin-2-yl)pyridinecarboxylic acid 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(PPh3)4 (621.11 mg, 537.49 μmol, 0.1 eq) and Cul (102.37 mg, 537.49 μmol, 0.1 eq) in dioxane (20 mL) was degassed and purged with argon for 3 times, then the mixture was stirred at 100 °C for 16 hours under argon atmosphere. LCMS showed the reaction was complete. The reaction was filtered, and the filtrate was concentrated under reduced pressure to get a residue. The crude product was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether from 0% to 60% to get 2-(4,6-dimethylpyridin-3-yl)pyrimidine (0.5 g, 50.22% yield) as a white solid.

[0582] 1 H NMR (400 MHz, DMSO- d 6 ): δ ppm 8.95 (d, J=4.88 Hz, 2 H), 8.84 (s, 1H), 7.49 (t, J=4.88 Hz, 1 H), 7.23 (s, 1 H), 2.52 (s, 3 H), 2.49 (s, 3 H). 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) portion wise 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 adding Na2SO3(20 mL) at 0 °C, then adjusted to pH=8 with NaHCO3at 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.

[0583] 1 H NMR (400 MHz, DMSO- d 6 ): δ ppm 8.97 (d, J=5.02 Hz, 2 H), 8.61 (s, 1H), 7.55 (t, J=4.89 Hz, 1 H), 7.44 - 7.51 (m, 1 H), 2.50 (s, 3 H), 2.39 (s, 3H). 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), TMSCN (739.55 mg, 7.45 mmol, 932.60 μL, 3 eq) was added, the mixture was stirred at 20 °C for 1 h, then N,N-dimethylcarbamoyl chloride (400.82 mg, 3.73 mmol, 341.99 μL, 1.5 eq) was added to the mixture, the mixture was stirred at 20 °C for 16 h. LCMS showed the reaction was completed. The reaction mixture was diluted with water (20 mL) and adjusted to pH=8 with aqueous NaHC03solution 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 Na2S04, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether from 0% to 30% to give 4,6-dimethyl-3-(pyrimidin-2-yl)pyridinecarbonitrile (0.4 g, 76.57% yield) as a white solid.

[0584] 1 H NMR (400 MHz, DMSO- d 6 ): δ 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). To a solution of 4,6-dimethyl-3-(pyrimidin-2-yl)pyridinecarbonitrile (0.3 g, 1.43 mmol, 1 eq) in methanol (3 mL) and H20 (3 mL), NaOH (171.23 mg, 4.28 mmol, 3 eq) was added, the mixture was stirred at 60 °C for 48 h. 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 HC1 at 0 °C, then the mixture was lyophilized to give 4,6-dimethyl-3-(pyrimidin-2-yl)pyridinecarboxylic acid (0.8 g, 85.60% yield, 35% purity) as a white solid.

[0585] 1 H NMR (400 MHz, DMSO- d 6): δ 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). Example 84: 4-Chloro-6-methyl-3-(pyrimidin-2-yl)pyridinecarboxylic acid At 20 °C, a solution of 3-bromo-6-methylpyridinecarboxylic acid (5 g, 23.14 mmol, 1 eq) in MeOH (50 mL) was added to H₂SO₄ (2.27 g, 23.14 mmol, 1.23 mL, 1 eq) and stirred at 70 °C for 16 h. LCMS showed that all starting materials were consumed and a product of the desired quality 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 layers were washed with a saturated aqueous sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 3-bromo-6-methylpyridinecarboxylate (5 g, 93.90% yield) as a yellow oil.

[0586] 1 H NMR (400 MHz, chloroform-) d ): δ 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). At 20 °C and under N2, cuprous iodide (331.13 mg, 1.74 mmol, 0.1 eq) and triphenylphosphine palladium (2.01 g, 1.74 mmol, 0.1 eq) were added to a solution of methyl 3-bromo-6-methylpyridinecarboxylate (4 g, 17.39 mmol, 1 eq), tributyl(pyrimidin-2-yl)stanane (7.70 g, 20.86 mmol, 1.2 eq), and cesium fluoride (5.28 g, 34.77 mmol, 2 eq) in dioxane (80 mL). The mixture was stirred at 100 °C for 16 hours. LCMS showed that all starting materials were consumed and a product of the desired quality was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether from 0% to 50%) to give methyl 6-methyl-3-(pyrimidin-2-yl)pyridinecarboxylate (4.1 g, 51.43% yield, 50% purity) as a yellow oil.

[0587] 1 H NMR (400 MHz, DMSO- d 6 ): δ = 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, 3H), 2.57 (s, 3 H). To a solution of methyl 6-methyl-3-(pyrimidin-2-yl)pyridine-1-carboxylate (4.1 g, 8.94 mmol, 50% purity 1 eq) in DCM (40 mL) was added 3-chloroperbenzoic acid (3.63 g, 17.89 mmol, 85% purity, 2 eq) portion wise at 0°C and stirred at 30°C for 16 h. LCMS showed all starting material was consumed and product with desired mass was detected. The reaction mixture was quenched by adding saturated sodium sulfite solution (50 mL) at 0°C and extracted with dichloromethane (30 mL x 3). The combined organic layer was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get the crude product. The crude product was purified by silica gel column chromatography (eluted with methanol in ethyl acetate from 0% to 10% in ethyl acetate) to get 2-(methoxycarbonyl)-6-methyl-3-(pyrimidin-2-yl)pyridine 1-oxide (1.77 g, 80.71% yield) as a yellow solid.

[0588] 1 H NMR (400 MHz, DMSO- d 6 ): δ = 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). A solution of 2-(methoxycarbonyl)-6-methyl-3-(pyrimidin-2-yl)pyridine 1-oxide (500 mg, 2.04 mmol, 1 eq) in POCl3(5 mL) was stirred at 120 °C for 2 h. LCMS showed all starting material was consumed and product with desired mass was detected. The reaction mixture was concentrated under reduced pressure to get 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 layer was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get the crude product. The crude product was purified by silica gel column chromatography (eluted with methanol in ethyl acetate from 0% to 20%) to get methyl 4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridinecarboxylate (430 mg, 79.98% yield) as a yellow oil.

[0589] 1 H NMR (400 MHz, DMSO- d 6 ): δ = ppm 8.94 (d, J=4.88 Hz, 2 H), 7.85 (s, 1H), 7.57 (t, J=4.94 Hz, 1 H), 3.58 (s, 3 H), 2.59 (s, 3 H). To a solution of methyl 4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridinecarboxylate (400 mg, 758.50 μmol, 1 eq) in MeOH (4 mL) and THF (4 mL) was added a solution of LiOH.H2O (63.65 mg, 1.52 mmol, 2 eq) in H2O (4 mL) at 20 °C and stirred for 16 h at 20 °C. LCMS showed all starting material was consumed and product with desired mass was detected. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane and methanol (10 mL x 3, 5:1). The combined organic layer was washed with saturated aqueous sodium chloride solution...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt and derivative thereof, Formula I in: X and X' are halogens such as fluorine; Het represents a heteroaryl group selected from pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetraazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole, and any derivative thereof, wherein the heteroaryl group is unsubstituted, monosubstituted, or disubstituted, and wherein the substituents of the heteroaryl group, if present, are independently selected from: unsubstituted (C1-C4)-linear alkyl, unsubstituted (C1-C4)-branched alkyl, unsubstituted (C1-C4)-alkoxy, unsubstituted (C3-C8)-cycloalkyl, substituted (C1-C4)-linear alkyl, substituted (C1-C4)-branched alkyl, substituted (C1-C4)-alkoxy, substituted (C3-C8)-cycloalkyl, cyano, and halogen; and R is selected from five- or six-membered aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one or more substituents.

2. The compound according to claim 1, wherein the compound of formula I is a 5R,6S-stereoisomer: 。 3. The compound according to claim 1, wherein the compound of formula I is a deuterated compound, wherein one or more hydrogen atoms are substituted by one or more deuterium atoms, having the following structure: Formula I(D) Where X, X', Het, and R are each independently defined as in equation I; and R 6 and R 7 Each is either hydrogen or deuterium.

4. The compound according to any one of claims 1 to 3, wherein the substituent of the heteroaryl group in Het is (C1-C4)-fluoroalkyl, (C3-C8)-cycloalkyl, cyano, (C1-C4)-alkoxy, or halogen; preferably, the substituent of the heteroaryl group in Het is Cl, F, CHF2, CF3, CH3, methoxy, nitrile, or cyclopropyl.

5. The compound according to any one of claims 1 to 4, wherein R comprises a five-membered heteroaryl 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 aryl group, which is an unsubstituted aryl group, or a substituted aryl group, or a derivative thereof; or a six-membered heteroaryl 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. The compound according to any one of claims 1 to 5, wherein R is ; ; ; ; ;or ; in: R 3 and R 4 Each is independently selected from: hydrogen, (C1-C 10 )- Straight-chain alkyl; (C1-C 10 )-branched alkyl; (C1-C 10 )-substituted or unsubstituted alkyl, optionally (C1-C4)-linear alkyl; (C1-C4)-branched alkyl; and (C1-C4)-substituted or unsubstituted alkyl; deuterated (C1-C4)-linear alkyl; deuterated (C1-C4)-branched alkyl; R 3 and R 4 It can form fused substituted or unsubstituted rings; preferably, R 3 and R 4 Each is independently -CH3 or -CD3; and Y represents an aryl or heteroaryl group; a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, wherein the Y is independently selected from: aryl, pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetraazole, pyrazole, nicotinamide, benzonitrile, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole, and any derivative thereof, wherein the substituent is independently selected from: unsubstituted or substituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy, cyano, and halogen; preferably, the halogen is fluorine, bromine, or chlorine.

7. The compound according to claim 6, wherein the aryl or heteroaryl 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. The compound according to claim 6 or 7, wherein Y is selected from: ; ; ; ; ; ; ; ; ; ; ; ; ; ; and .

9. The compound according to any one of claims 1 to 8, wherein R is selected from: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;and .

10. The compound according to any one of claims 1 to 5, wherein R is ; ; ;or ; in: R 1 and R 2 Each is independently selected from: hydrogen, unsubstituted (C1-C6)-linear alkyl; unsubstituted (C1-C6)-branched alkyl; substituted (C1-C6)-linear alkyl; substituted (C1-C6)-branched alkyl; deuterated (C1-C6)-linear alkyl, deuterated (C1-C6)-branched alkyl, and halogen; preferably, the halogen includes fluorine, chlorine, or bromine; preferably, R 1 It can be H, Cl, F, CH3 or CD3; and Het' is a heteroaryl group selected from pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazolium, imidazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole, and any derivative thereof, wherein the heteroaryl group is unsubstituted, monosubstituted, or disubstituted, and wherein the substituents of the heteroaryl group, if present, are independently selected from: (C1-C4)-straight-chain or branched alkyl groups, substituted straight-chain or branched (C1-C4)-alkyl groups, and halogens; preferably, the substituents are F, Cl, or CH3.

11. The compound according to any one of claims 1 to 5 and 10, wherein Het' is selected from: ; ;or .

12. The compound according to any one of claims 1 to 5, 10, and 11, wherein R is selected from: ; ; ; ; ; ; ; ; ; ; ; ; ; and .

13. The compound according to any one of claims 1 to 12, wherein Het is selected from: ; ; ; ; ; ; ; ; , , ; ; , ; ; ; ; ;and .

14. A compound having the structure of formula I(a)-I(q): in: R 1 R 2 R 3 R 4 R 5 R 6 R 7 Het, Het', and Y are each independently defined as in any one of claims 1 to 13.

15. The compound according to any one of claims 1 to 9, 13 and 14, wherein the compound is selected from: [1]； [2]； [5]； [6]； [7]； [12]； [13]; [14]; [15]; [16]; [17]; [18]; [19]; [20]; [21]; [22]； [23]； [24]； [25]; [26]; [27]; [28]; [29]; [30]; [31]; [32]; [33]; [34]; [35]; [36]; [37]; [38]; [39]; [40]; [41]; [47]; [48]; [49]; [50]; [51]; [53]; [54]; [55]; [56]; [57]; [60]; [61]; [62]; [63]; [64]; [65]; [66]; [70]; [71]; [72] [73]; [74]; [75]; [77]; [78]; [79]; [80]; [81]; [82]; [83]; [84]; [85]; [86]; [87]; [88]; [90]; [91]; [93]; [99]; [100]; [102]; [103]; Or its pharmaceutically acceptable salts and derivatives.

16. The compound according to any one of claims 1 to 5 and 10 to 14, wherein the compound is selected from: [3]； [4]； [8]； [9]； [10]； [11]； [42]； [43]； [44]； [45]； [46]； [52]； [58]; [59]; [67]; [68]; [69]; [76]; [89]; [92]; [94]; [95]; [96]; [97]; [98]； [101]； Or its pharmaceutically acceptable salts and derivatives.

17. Compounds of formula I-aa or their pharmaceutically acceptable salts and derivatives, Formula I(aa); in: R 6 and R 7 Each is independently either hydrogen or deuterium; R 8 For CF3; W 1 Selected from -CH, N, or -CO-CH3; W 2 Selected from -CH, N, -C-CH3; and R is selected from five-membered heteroaryl groups, including unsubstituted pyrazoles, unsubstituted oxazoles, unsubstituted thiazoles, unsubstituted imidazoles, substituted pyrazoles, substituted oxazoles, substituted thiazoles, substituted imidazoles, or derivatives thereof; or six-membered heteroaryl groups, including unsubstituted pyridines, unsubstituted pyrimidines, unsubstituted pyridazines, unsubstituted pyrazines, substituted pyridines, substituted pyrimidines, substituted pyridazines, substituted pyrazines, or derivatives thereof.

18. The compound according to claim 17, wherein R is selected from... or ;in R 3 and R 4 Each can be independently -CH3 or -CD3; Y is or ;and Het' for .

19. The compound according to claim 17 or 18, wherein the compound of formula I-aa is selected from: [6] [36]； [54]， [55]， [61]， [82]， [89]， [93]， [102], or [103] 20. The compound according to any one of the preceding claims, wherein the pharmaceutically acceptable salt and derivative are selected from: hydrochloride, chloride, bromide, iodide, potassium salt, sodium salt, acetate, trifluoroacetate, sulfate, sulfonate, oxalate, maleate, malonate, nitrate, tartrate, gluconate, succinate, methanesulfonate, citrate, phosphate or diphosphate, aluminate, enantiomer, solvate, adduct, polymorph, hydrate, tautomer, isomer, prodrug, isotope or radiolabeled derivative, and mixtures thereof.

21. The compound according to any one of the preceding claims, wherein the compounds of formula I and I(aq) are deuterated, wherein at least one hydrogen atom is substituted with deuterium.

22. A pharmaceutical composition comprising (a) a compound according to any one of claims 1 to 21; and (b) one or more pharmaceutically acceptable excipients; preferably, the pharmaceutical composition is in the form of tablets or capsules.

23. The compound according to claims 1 to 21 or the pharmaceutical composition according to claim 22, used as a medicament.

24. A method for treating or preventing a disease or condition mediated by orexin receptor activity, comprising administering to an individual in need of such treatment an effective amount of at least one compound according to any one of claims 1 to 21 or a pharmaceutical composition according to claim 22.

25. The method of claim 24, wherein the disease or condition is selected from: eating disorders, obesity, bulimia (BED), schizophrenia (negative symptoms and CIAS), psychomotor stimulant (such as cocaine, opioids, nicotine and alcohol) addiction, opioid use disorder, opioid dependence, substance abuse or addiction, sleep disorders, cognitive impairment in mental or neurological diseases, depression, anxiety disorders, panic disorder, post-traumatic stress disorder, behavioral disorders and mood disorders of depression.

26. Use of the compound according to any one of claims 1 to 21 or the pharmaceutical composition according to claim 22 in the preparation of a medicament for treating a disease or condition regulated by orexin receptor activity, and use of such compounds for treating or preventing such diseases and conditions.

27. A method for modulating the activity of orexin receptors OX1, OX2, or both, comprising exposing cells containing orexin receptors to an effective amount of at least one compound according to any one of claims 1 to 21 or a pharmaceutical composition according to claim 22.

28. The method of claim 27, wherein the step of contacting the cells is performed in vivo, in vitro, or ex vivo. 。 29. A method for preparing the compound of formula I according to claim 1 Wherein X, X', R and Het are as defined in any one of claims 1 to 21 above. The method includes the following steps: (a) Reaction of (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester with a halogenated heteroaromatic compound in the presence of a base to form a first intermediate compound; (b) React the first intermediate compound with an acid to form a second intermediate compound; as well as (c) React the second intermediate compound with a carboxylic acid having the general formula R-COOH to obtain the compound of formula I.

30. The method of claim 29, wherein (5R, 6S) 5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester is a deuterated compound, preferably deuterated. (5R, 6S) 5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester is (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (intermediate j1) or (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (intermediate j2).

31. The method according to claim 29 or 30, wherein the compound of formula I is a deuterated compound having the following structure: in, R and Het are each independently defined as in any one of claims 1 to 21 above; And R 6 and R 7 Each is independently either H or deuterium; The method includes the following steps: (a) Reaction of (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (intermediate j1) or (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (intermediate j2) with a halogenated heteroaromatic compound in the presence of a base to form a first intermediate compound; (b) Reacting the first intermediate compound with an acid to form a second intermediate compound; and (c) React the second intermediate compound with a carboxylic acid having the general formula R-COOH to obtain a compound of formula ID(a) or ID(b), respectively.

32. The method according to any one of claims 29 to 31, wherein the halogenated heteroaromatic compound is selected from: halogenated pyridines, halogenated pyridazines, halogenated pyrazines, halogenated pyrimidines, halogenated triazoles, halogenated tetraazoles, halogenated pyrazoles, halogenated furans, halogenated thiophenes, halogenated pyrroles, halogenated imidazoles, halogenated isoxazoles, halogenated oxazoles, halogenated isothiazoles, halogenated thiazoles, and any derivatives thereof, wherein... The halogenated heteroaryl group may be additionally substituted; wherein the additional substituent of the halogenated heteroaryl group, if present, is independently selected from: unsubstituted (C1-C4)-linear alkyl, unsubstituted (C1-C4)-branched alkyl, unsubstituted (C1-C4)-alkoxy, unsubstituted (C3-C8)-cycloalkyl, substituted (C1-C4)-linear alkyl, substituted (C1-C4)-branched alkyl, substituted (C1-C4)-alkoxy, substituted (C3-C8)-cycloalkyl, cyano, and halogen.

33. The method of claim 32, wherein the additional substituent of the heteroaryl group is Cl, F, CHF2, CF3, CH3, methoxy, nitrile, or cyclopropyl.

34. The method according to any one of claims 29 to 33, wherein the halogenated heteroaromatic compound is selected from: fluorine-substituted heteroaromatic compounds, chlorine-substituted heteroaromatic compounds, bromine-substituted heteroaromatic compounds, and iodine-substituted heteroaromatic compounds.

35. The method according to any one of claims 29 to 34, wherein the halogenated heteroaromatic compound is selected from: 2-chloro-5-(trifluoromethyl)pyrazine, 2-chloro-5-(trifluoromethyl)pyrimidine, 2-chloro-5-(trifluoromethyl)pyrimidine, 5-chloro-2-fluoropyrimidine, 5-chloro-2-fluoropyrimidine, 2-chloro-6-(trifluoromethyl)pyrazine, 2-fluoro-4-(trifluoromethyl)pyrimidine, 2,3-difluoro-5-(trifluoromethyl)pyrimidine, 3-bromo-2-fluoro-5-(trifluoromethyl)pyrimidine, 2- Chloro-5-cyclopropylpyrimidine, 2-chloro-3-methoxy-5-(trifluoromethyl)pyridine, 3-methyl-5-(trifluoromethyl)pyrazine-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 one of claims 29 to 35, wherein the base is potassium carbonate.

37. The method according to any one of claims 29 to 36, wherein step (a) is carried out in the presence of a solvent, preferably a polar aprotic solvent selected from THF, DMF, DMSO and mixtures thereof, more preferably DMSO.

38. The method according to any one of claims 29 to 37, wherein the method further comprises at least one of the following features: - Step (a) is carried out at a temperature of about 50°C to about 189°C, preferably at a temperature of about 80°C; - The duration of step (a) is from about 6 hours to about 18 hours, preferably from about 12 hours.

39. The method according to any one of claims 29 to 38, wherein the acid is selected from: aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid, and mixtures thereof, preferably, the acid is hydrochloric acid.

40. The method according to any one of claims 29 to 39, wherein step (b) is carried out in the presence of a nonpolar solvent selected from: diethyl ether, benzene, toluene, chloroform, 1,4-dioxane, or mixtures thereof, preferably, the nonpolar solvent is 1,4-dioxane.

41. The method according to any one of claims 29 to 40, wherein the method further comprises at least one of the following features: - Step (b) is carried out at a temperature of about 12°C to about 40°C, preferably at about 20°C; - The duration of step (b) is from about 30 minutes to about 5 hours, preferably from about 2 hours.

42. The method according to any one of claims 29 to 41, wherein R in the R-COOH group is selected from: a five- or six-membered aryl or heteroaryl group, wherein the aryl or heteroaryl group is unsubstituted or substituted by one or more substituents; preferably, R comprises a five-membered heteroaryl group, which is an unsubstituted pyrazole, oxazole, thiazole, imidazole, substituted pyrazole, oxazole, thiazole, imidazole, or derivatives thereof; a six-membered aryl group, which is an unsubstituted aryl group, or a substituted aryl group, or derivatives thereof; or a six-membered heteroaryl 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 derivatives thereof; optionally, at least one hydrogen atom in R is substituted with deuterium.

43. The method according to any one of claims 29 to 42, wherein the carboxylic acid R-COOH is selected from: 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-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid, 5-methyl-2-( ... 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-1H-pyrazole-3-carboxylic acid, 1-methyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylic acid, 4-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid 4-(4-fluorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid, 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid, 4-(5-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid, 5-(5-fluoropyrimidin-2-yl)-1-methyl-1H-imidazol-4-carboxylic acid, 5-(5-methoxypyridin-2-yl)-1-methyl-1H-imidazol-4-carboxylic acid, 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid, 2-Methyl-5-(pyridin-2-yl)thiazolyl-4-carboxylic acid, 2-methyl-5-(pyrimidin-2-yl)thiazolyl-4-carboxylic acid, 2-methyl-5-(pyridin-2-yl)oxazol-4-carboxylic acid, 6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridinecarboxylic acid, 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid, 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid, or 6-methyl-3-(pyrimidin-2-yl)pyridinecarboxylic 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)pyridinecarboxylic acid, 4,6-dimethyl-3-(pyrimidin-2-yl)pyridinecarboxylic acid, 4-chloro-6-methyl-3-(pyrimidin-2-yl)pyridinecarboxylic acid, 1-methyl-4-(pyridin-2-yl)-1 H -Pyrazole-3-carboxylic acid, 2-(2H-1,2,3-triazol-2-yl)benzoic acid; 1,5-dimethyl-4-(pyrazin-2-yl)-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyridin-3-yl)-1,5-dimethyl-1H-pyrazole-carboxylic acid, 4-(4-fluoropyridin-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid and 4-(4-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.

44. The method according to any one of claims 30 or 31, wherein the carboxylic acid comprises 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)-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid, 6-(methyl-d3)-3-(pyrimidin-2-yl)pyridinecarboxylic acid, or 6-(methyl-d3)-3-(2H-1,2,3-triazol-2-yl)pyridinecarboxylic acid salt.

45. The method according to any one of claims 29 to 44, wherein the method further comprises at least one of the following features: - wherein step (c) is performed in the presence of a coupling agent, preferably HATU; - wherein step (c) is carried out in the presence of an alkali, preferably DIPEA; - The step (c) is carried out in the presence of a polar aprotic solvent selected from THF, dichloromethane, ethyl acetate, DMF, DMSO and combinations thereof, preferably dichloromethane.

46. ​​The method according to any one of claims 29 to 45, wherein the method further comprises at least one of the following features: - The step (c) is performed at a temperature of about -10°C to about 40°C, preferably at a temperature of about 0°C to about 20°C; - The duration of step (c) is from about 1 hour to about 6 hours, preferably about 2.5 hours.

47. The method according to any one of claims 29, 32 to 46, wherein the first intermediate compound is: ( 5R, 6S 2,2-Difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester; ( 5R, 6S 2,2-Difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester; ( 5R, 6S 2,2-Difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester; ( 5R, 6S 5-(((5-chloropyridin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholin-4-carboxylic acid tert-butyl ester; ( 5R, 6S 5-(((5-chloropyrimidin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholin-4-carboxylic acid tert-butyl ester; (5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester; (5R,6S)-2,2-difluoro-6-methyl-5-(((6-(trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester; (5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester; (5R,6S)-2,2-difluoro-5-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-6-methylmorpholino-4-carboxylic acid tert-butyl ester; ( 5R, 6S 2,2-Difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester; (5R,6S)-5-(((5-cyclopropylpyrimidin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholino-4-carboxylic acid tert-butyl ester; (5R,6S)-2,2-difluoro-5-(((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-6-methylmorpholino-4-carboxylic acid tert-butyl ester; (5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester; (5R,6S)-5-(((3-cyano-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholino-4-carboxylic acid tert-butyl ester; (5R,6S)-5-(((5-chloro-3-fluoropyridin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholino-4-carboxylic acid tert-butyl ester; (5R,6S)-2,2-difluoro-6-methyl-5-(((4-methyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester; (5R,6S)-5-(((5-(difluoromethyl)pyrimidin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholino-4-carboxylic acid tert-butyl ester; or (5R,6S)-5-(((5-(difluoromethyl)pyrazin-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester.

48. The method according to any one of claims 29, 32 to 46, wherein the second intermediate compound is: 5-Chloro- N -((( 2S,3R 6,6-Difluoro-2-methylmorpholin-3-yl)methyl)pyridine-2-amine hydrochloride; N -((( 2S,3R )-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazine-2-amine hydrochloride; N-((( 2S,3R )-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidine-2-amine hydrochloride; N -((( 2S,3R )-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridine-2-amine hydrochloride; 5-Chloro-N-((( 2S,3R 6,6-Difluoro-2-methylmorpholino-3-yl)methyl)pyrimidine-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)pyrazine-2-amine hydrochloride; or N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-4-(trifluoromethyl)pyridine-2-amine hydrochloride; N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3-fluoro-5-(trifluoromethyl)pyridine-2-amine hydrochloride; N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyridine-2-amine; 5-Cyclopropyl-N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)pyrimidine-2-amine hydrochloride; N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3-methoxy-5-(trifluoromethyl)pyridine-2-amine; N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyrazine-2-amine hydrochloride; 2-((((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)amino)-5-(trifluoromethyl)nicotinonitrile hydrochloride; 5-Chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-3-fluoropyridine-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)pyrimidine-2-amine hydrochloride; or N-((( 2S,3R )-6,6-difluoro-2-methylmorpholin-3-yl)methyl)-5-(difluoromethyl)pyrazine-2-amine hydrochloride.

49. The method according to any one of claims 30 to 46, wherein the first intermediate compound is: ( 5R, 6S 2,2-Difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester-3,3-d2; ( 5R, 6S 2,2-Difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester-3,3-d2; (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester-3,3-d2; ( 5R, 6S 5-(((5-chloropyridin-2-yl)amino)methyl-d2)-2,2-difluoro-6-methylmorpholin-4-carboxylic acid tert-butyl ester; ( 5R, 6S 2,2-Difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl-d2)morpholine-4-carboxylic acid tert-butyl ester; ( 5R, 6S 2,2-Difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl-d2)morpholine-4-carboxylate; or ( 5R, 6S 2,2-Difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl-d2)morpholine-4-carboxylic acid tert-butyl ester.

50. The method according to any one of claims 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)pyrazine-2-amine hydrochloride; N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyrimidine-2-amine hydrochloride; N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyridine-2-amine hydrochloride; 5-Chloro-N-((( 2S,3R 6,6-Difluoro-2-methylmorpholin-3-yl)methyl-d2)pyridine-2-amine hydrochloride; N-((( 2S,3R )-6,6-difluoro-2-methylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl)pyrazine-2-amine hydrochloride; N-((( 2S,3R )-6,6-difluoro-2-methylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl)pyrimidin-2-amine; or N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl)pyridine-2-amine.

51. The method according to claim 29, wherein tert-butyl (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate is prepared by the following manner: - By reacting N-benzyl-L-allothreonine (a) with a reducing agent, (2R,3S)-2-(benzylamino)butane-1,3-diol (intermediate b) is formed; - React intermediate (b) with tert-butyl(chloro)diphenylsilane to form (2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)but-2-ol (intermediate c); - React intermediate (c) with 2-bromo-2,2-difluoroacetic 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)but-2-yl)oxy)-2,2-difluoroacetic acid (intermediate d); - The intermediate (d) is subjected to an intramolecular amide coupling reaction in the presence of a coupling agent to form (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholin-3-one (intermediate e); - The intermediate (e) is reacted with a reducing agent to form (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine (intermediate f); - React intermediate (f) with a fluorine source to form ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholin-3-yl)methanol (intermediate g); - The intermediate (g) is reacted with hydrogen and palladium on carbon and ditert-butyl dicarbonate to form (5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylic acid tert-butyl ester (intermediate h); - Reaction of intermediate (h) with isoindoline-1,3-dione to form (5R,6S)-5-((1,3-dioxoisoindoline-2-yl)methyl)-2,2-difluoro-6-methylmorpholino-4-carboxylic acid tert-butyl ester (intermediate i); and - React intermediate (i) with hydrazine or hydrazine hydrate to form (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (intermediate j).

52. The method according to claim 30 or 31, wherein (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (intermediate j1) is prepared by the following manner: - (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholin-3-one (intermediate e) was reduced with a deuterating reagent to form (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholin-3,3-d2 (intermediate f1); - React intermediate (f1) with a fluorine source to form ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholin-3-yl-5,5-d2)methanol (intermediate g1); - The intermediate (g1) is reacted with hydrogen, palladium on carbon, and ditert-butyl dicarbonate to form (5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (intermediate h1). - Reaction of intermediate (h1) with isoindoline-1,3-dione to form (5R,6S)-5-((1,3-dioxoisoindoline-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (intermediate i1); and - React intermediate (i1) with hydrazine or hydrazine hydrate to form (5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (intermediate j1).

53. The method according to claim 30 or 31, wherein (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (intermediate j2) is prepared by the following manner: - Reaction of N-benzyl-L-allethreonine (a) with sodium 2-bromo-2,2-difluoroacetyl)oxy, followed by reaction with a suitable acid, yields (2S,3S)-4-benzyl-6,6-difluoro-2-methyl-5-oxomorpholine-3-carboxylic acid (intermediate e2'). - The intermediate e2' was reduced using a deuterated reagent to form (5R,6S)-4-benzyl-2,2-difluoro-5-(hydroxymethyl-d2)-6-methylmorpholin-3-one (intermediate e2''); - Reduce intermediate (e2'') with a reducing agent to form ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholin-3-yl)methanol-d2 (intermediate g2); - The intermediate (g2) is reacted with hydrogen, palladium on carbon, and ditert-butyl dicarbonate to form (2S,3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3-methylpiperidine-1-carboxylic acid tert-butyl ester (intermediate h2); - React intermediate (h2) with isoindoline-1,3-dione to form (5R,6S)-5-((1,3-dioxoisoindoline-2-yl)methyl-d2)-2,2-difluoro-6-methylmorpholino-4-carboxylic acid tert-butyl ester (intermediate i2); and - React intermediate (i2) with hydrazine or hydrazine hydrate to form (5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (intermediate j2).

54. The compound is: - (2R,3S)-2-(benzylamino)butane-1,3-diol (intermediate b); - ( 2S,3R )-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)but-2-ol (intermediate c); - 2-((( 2S,3R )-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)but-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); - (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); - ( 5R, 6S 2,2-Difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylic acid tert-butyl ester (intermediate h); - ( 5R, 6S )-5-((1,3-dioxoisoindoline-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (intermediate i); - (5R, 6S) 5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (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); - ( 5R, 6S 2,2-Difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (intermediate h1); - ( 5R, 6S )-5-((1,3-dioxoisoindoline-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester-3,3-d2 (intermediate i1); - ( 5R, 6S 5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester-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)methyl-d2-ol (intermediate g2); - ( 2S,3R 5,5-Difluoro-2-(hydroxymethyl-d2)-3-methylpiperidine-1-carboxylic acid tert-butyl ester (intermediate h2); - ( 5R, 6S )-5-((1,3-dioxoisoindoline-2-yl)methyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (intermediate i2); or - ( 5R, 6S 5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylic acid tert-butyl ester (intermediate J2).

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