Morpholine orexin receptor antagonist

Abstract

The present invention relates to compounds of formula (I) of orexin antagonists, or pharmaceutically acceptable salts, solvates, adducts, polymorphs, and isomers thereof, compositions, and methods for treating or preventing diseases or disorders mediated by orexin receptor activity using orexin antagonists. JPEG2026524753000299.jpg37149

Description

Detailed description of the invention

[0001] [Field of Invention] The present invention relates to compounds useful as orexin antagonists, or pharmaceutically acceptable salts and derivatives thereof; pharmaceutical compositions comprising such compounds, salts thereof, or derivatives thereof; and methods for treating or preventing diseases or disorders mediated by orexin receptor activity using such compounds. Diseases or disorders mediated by orexin receptors include, but are not limited to, central nervous system (CNS) disorders, neurological disorders, or eating disorders, such as obesity, bulimia nervosa (BED), schizophrenia (negative symptoms and CIAS), addiction to psychomotor stimulants, such as cocaine, opioids, nicotine, and alcohol, opioid use disorder, drug abuse or addiction, sleep disorders, cognitive impairment in psychiatric or neurological disorders, depression, anxiety, panic disorder, post-traumatic stress disorder, behavioral disorders, and mood disorders (depressive states).

[0002] [Background of the Invention] Orexin is a family of homologous peptides, including orexin A (OR-A) and orexin B (OX-B). Also known as hypocretin, orexin is a neuropeptide produced by a group of neurons located in the lateral hypothalamic area, including the lateral hypothalamus, and the dorsomedial-perifornixial area of ​​the hypothalamus. Both orexin A (OR-A) and orexin B (OR-B) are synthesized from the precursor preproorexin. OR-A is a 33-amino acid peptide with two intrachain disulfide bonds, while OR-B is a linear 28-amino acid peptide. Orexin peptides bind to at least two distinct G protein-coupled receptors called OX1 receptors and OX2 receptors (OX1R or OX2R). The OX1 receptor is selective for OR-A with approximately 100 times higher affinity than OR-B, while the OX2 receptor can bind to both OR-A and OR-B with similar affinity.

[0003] Orexins have been found to stimulate food consumption and regulate sleep and wakefulness, and may be involved in the neural mechanisms of drug abuse and addiction. The neural pathways and receptors through which orexins are involved in these processes appear to be partially overlapping and partially distinct. For example, findings suggest that orexin's arousal-promoting function is primarily facilitated by OX2 receptors, while its role in reward and feeding regulation is primarily mediated by OX1 receptors.

[0004] Orexin receptors are a suitable target for developing drug candidates to treat a variety of orexin-related conditions and symptoms, including, but not limited to, central nervous system (CNS) disorders, sleep / wake disorders, anxiety, and obesity. Orexin receptor antagonists have been developed as potential treatments for sleep disorders such as insomnia and narcolepsy. These antagonists block the binding of orexin to its receptor, thereby reducing orexin signaling and promoting sleep. The development of orexin receptor antagonists has primarily focused on OX2 receptor antagonists to control wakefulness and the state of arousal. However, there is also interest in developing OX1 receptor antagonists to treat substance addiction, obesity, and other metabolic disorders.

[0005] The patent application, International Publication No. 2020247447, is directed to substituted pyrazole and imidazole derivatives of compounds that are orexin receptor antagonists and are useful for the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved or associated. The application also relates to pharmaceutical compositions comprising these compounds and to the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

[0006] International Publication No. 2017139603, a patent application, relates to halo-substituted piperidine compounds, pharmaceutical compositions containing them, and methods of using them, including methods for treating substance addiction, panic disorder, anxiety, post-traumatic stress disorder, pain, depression, seasonal affective disorder, eating disorders, or hypertension.

[0007] The patent application, International Publication No. 2002090355, relates to N-aloylcyclic amine derivatives as orexin receptor antagonists and their potential uses in the treatment of obesity, including obesity observed in patients with type 2 (non-insulin-dependent) diabetes, and / or sleep disorders, stroke, particularly ischemic or hemorrhagic stroke, and / or blocking of the vomiting response (i.e., useful in the treatment of nausea and vomiting).

[0008] International Publication No. 2020247445, a patent application, relates to substituted imidazolo[2,1-b]oxazoles, imidazolo[2,1-b]thiazoles, imidazolo[2,1-b]oxadiazoles, and imidazolo[2,1-b]oxadiachiazole derivatives as antagonists of orexin receptors that can be used for the treatment or prevention of neurological and psychiatric disorders and diseases.

[0009] International Publication No. 2013068935, a patent application, relates to derivatives of 2-(1,2,3-triazole-2-yl)benzamide and 3-(1,2,3-triazole-2-yl)picolinamide, and their use as orexin receptor antagonists in pharmaceutical compositions. Some of the compounds in this prior art document have been found to have lower selectivity for OX1R compared to OX2R, and also exhibit lower metabolic stability.

[0010] However, there remains a need to develop novel, potent, and selective OX1 receptor antagonists to treat diseases or disorders mediated by orexin receptor activity, such as central nervous system (CNS) disorders, neurological disorders, or eating disorders, sleep disorders, and substance addictions. There is also a need to develop improved cerebral penetrating agents to treat diseases or disorders mediated by orexin receptor activity, such as central nervous system (CNS) disorders, neurological disorders, or eating disorders, sleep disorders, and substance addictions.

[0011] [Overview of the prefecture] The present invention provides novel compounds, or pharmaceutically acceptable salts and derivatives thereof, compositions, and the use of these compounds in the treatment or prevention of diseases or disorders mediated by orexin receptor activity. The present invention provides novel OX1 receptor antagonists having excellent selectivity and binding properties, excellent potency, excellent brain penetration, improved pharmacokinetic properties, bioactivity, improved solubility, excellent metabolic stability, and chemical stability. Examples of pharmaceutically acceptable salts and derivatives of the compounds of the present invention include, but are not limited to, hydrochlorides, chlorides, bromides, iodides, potassium salts, sodium salts, acetates, sulfates, sulfonates, oxalates, maleates, malons, nitrates, tartrates, glucons, succinates, mesylates, citrates, phosphates, diphosphates, aluminates, enantiomers, solvates, adducts, polymorphs, hydrates, tautomers, prodrugs, isotope-labeled or radiolabeled derivatives, or isomers.

[0012] According to one aspect of the present invention, the structure of general formula I: [ka] ) (In the formula, X and X' are halogens, preferably fluorine; Het represents a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole, and any derivative thereof. The heteroaromatic group is unsubstituted, monosubstituted, or disubstituted. The substituents of the heteroaromatic group, if present, are independently selected from the group consisting of unsubstituted (C1-C4) linear alkyl, unsubstituted (C1-C4) branched alkyl, (C1-C4) linear alkyl, substituted (C1-C4) branched alkyl, alkoxy, (C3-C8) cycloalkyl, cyano group, and halogen. Compounds having the above, or pharmaceutically acceptable salts and derivatives thereof, are provided. Preferably, the substituents on the heteroaromatic group of Het include alkyl, fluoroalkyl, alkoxy, cycloalkyl, cyano, or halogen. More preferably, the substituents on the heteroaromatic group of Het are F, Cl, CHF2, CF3, methyl, methoxy, nitrile, or cyclopropyl.

[0013] R is selected from the group consisting of a 5-membered or 6-membered aromatic group or a heteroaromatic group, and the aromatic group or heteroaromatic group is either unsubstituted or substituted with one or more substituents.

[0014] Preferably, R in the compound of formula I is a five-membered heteroaromatic group which is an unsubstituted pyrazole, unsubstituted oxazole, unsubstituted thiazole, unsubstituted imidazole, substituted pyrazole, substituted oxazole, substituted thiazole, substituted imidazole, or a derivative thereof; an unsubstituted aryl, substituted aryl, or a six-membered heteroaromatic group which is a derivative thereof; or an unsubstituted pyridine, unsubstituted pyrimidine, unsubstituted pyridazine, unsubstituted pyrazine, substituted pyridine, substituted pyrimidine, substituted pyridazine, substituted pyrazine, or a six-membered heteroaromatic group which is a derivative thereof.

[0015] According to another aspect of the present invention, the compound of formula I is a 5R,6S stereoisomer: [ka]

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

[0017] According to another aspect of the present invention, the compound of formula I has the following structure [ka] (X, X', R, and Het are each defined independently with respect to Equation I.) It is a deuterated compound having [a specific characteristic].

[0018] According to another aspect of the present invention, the structure of formula I(a): [ka] (In the formula, Het represents a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole, and any derivative thereof, wherein the heteroaromatic group is unsubstituted, monosubstituted, or disubstituted, and the substituent of the heteroaromatic group, if present, is independently selected from the group consisting of unsubstituted (C1-C4)-linear alkyl, unsubstituted (C1-C4)-branched alkyl, substituted (C1-C4)-linear alkyl, substituted (C1-C4)-branched alkyl, alkoxy, (C3-C8)-cycloalkyl, cyano group, and halogen; preferably, the substituent is alkyl, fluoroalkyl, alkoxy, cycloalkyl, or halogen; more preferably, the substituent is F, Cl, CHF2, CF3, methyl, methoxy, nitrile, or cyclopropyl group; R 1 is selected from the group consisting of 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 These are hydrogen, fluorine, chlorine, -CH3, or -CD3; Het' is selected from the group consisting of a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof, wherein the heteroaromatic group is unsubstituted, monosubstituted, or disubstituted, and the substituent of the heteroaromatic group, if present, is independently selected from the group consisting of (C1-C6)-linear or branched alkyl, (C1-C6)-substituted linear or branched alkyl, and halogen, preferably the halogen includes fluorine, chlorine, or bromine; preferably the substituent is -CH3. Compounds having the property, or pharmaceutically acceptable salts and derivatives thereof, are provided.

[0019] According to another aspect of the present invention, the structure of formulas I(b) to I(d) is: [ka] (In the formula, R 1 Het and Het' are each independently defined herein with respect to formula I(a); R 2 is selected from the group consisting of 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 2 (These are hydrogen, fluorine, chlorine, -CH3, or -CD3.) Compounds having the property, or pharmaceutically acceptable salts and derivatives thereof, are provided.

[0020] According to another aspect of the present invention, the structure of formulas I(e) to I(g): [ka] (In the formula, R 1 Het and Het' are each independently defined herein with respect to formula I(a); R 6 and R 7 (Each is independently hydrogen or deuterium.) Compounds having the property, or pharmaceutically acceptable salts and derivatives thereof, are provided.

[0021] Preferably, the compounds of formula I(a) to (g) are 5R,6S stereoisomers.

[0022] According to another aspect of the present invention, the structure of formula I(h) is: [ka] (wherein Het is as defined with respect to formula I or I(a); Y is an aromatic group or a heteroaromatic group; represents a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, Y is independently selected from the group consisting of aryl, pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, nicotinonitrile, benzonitrile, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof, preferably, Y is mono-substituted or di-substituted, and the substituents are independently selected from the group consisting of (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano group and halogen; halogen can be fluorine, chlorine or bromine; preferably, the substituents are cyano group, alkoxy group or halogen; more preferably, the aromatic or heteroaromatic group is substituted with CN, F, Cl, -O-alkyl (preferably, the alkyl group contains 1 to 4 carbon atoms), for example -O-CH3) There is provided a compound having, or a pharmaceutically acceptable salt and derivative thereof.

[0023] According to another aspect of the present invention, the structure of formula I(i) or I(j): [[ID=十四]] [[ID=十五]] [[ID=十六]]

Chemical formula

[0024] According to another aspect of the present invention, the structure of formula I(k): [ka] (In the formula, Het and Y are defined independently as specified herein with respect to formula I(h)) Compounds having the property, or pharmaceutically acceptable salts and derivatives thereof, are provided.

[0025] According to another aspect of the present invention, the structure of formula I(l): [ka] (In the formula, Het and Y are defined independently as specified herein with respect to formula I(h)) Compounds having the property, or pharmaceutically acceptable salts and derivatives thereof, are provided.

[0026] According to another aspect of the present invention, the structure of formula I(m) is: [ka] (In the formula, Het and Y are defined independently as specified herein with respect to formula I(h)) Compounds having the property, or pharmaceutically acceptable salts and derivatives thereof, are provided.

[0027] According to another aspect of the present invention, the structure of formulas I(n) to I(q) is: [ka] (In the formula, Het and Y are defined independently as specified herein with respect to formula I(h); R 3 This is as defined by formula I(j) or I(i); R 5 is hydrogen, (C1~C 10 )-Linear alkyl; (C1~C 10 )-branched alkyl; (C1~C 10 )-substituted or unsubstituted alkyl, optionally selected from (C1~C4)-linear alkyl; (C1~C4)-branched alkyl; (C1~C4)-substituted or unsubstituted alkyl; deuterated (C1~C4)-linear alkyl; deuterated (C1~C4)-branched alkyl; or halogen; preferably, R 5 is hydrogen, -CH3, or -CD3; R 6 and R 7 (Each is independently hydrogen or deuterium.) Compounds having the property, or pharmaceutically acceptable salts and derivatives thereof, are provided.

[0028] Preferably, the compounds of formulas I(h) to I(q) are 5R,6S stereoisomers.

[0029] According to another aspect of the present invention, a pharmaceutical composition is provided comprising a compound of formula I or I(a-q) described herein and one or more pharmaceutically acceptable excipients.

[0030] According to another aspect of the present invention, a compound of formula I or I(a-q) described herein, or a pharmaceutical composition comprising a compound of formula I or I(a-q) is provided for use as a pharmaceutical. Preferably, the pharmaceutical composition is in solid form, such as a tablet or a capsule.

[0031] Another aspect of the present invention provides a method for treating or preventing a disease or disorder mediated by orexin receptor activity, comprising the step of administering an effective amount of at least one compound of formula I or I(a-q) described herein, or a pharmaceutically acceptable salt and derivative thereof, to a subject in need of such treatment, in a dose, frequency, and duration that produces the beneficial effect of the pharmaceutical composition described herein.

[0032] Another aspect of the present invention provides the use of compounds of formula I or I(a-q) described herein, or pharmaceutical compositions described herein, in the preparation of a pharmacopoeia for treating diseases or disorders controlled by orexin receptor activity, and the use of such compounds for treating or preventing such diseases and disorders.

[0033] A further aspect of the present invention provides a method for modulating the activity of orexin receptors OX1, OX2, or both, comprising the step of contacting cells containing orexin receptors with an effective amount of at least one compound of formula I or I(a-q) described herein, or a pharmaceutical composition described herein.

[0034] According to another aspect of the present invention, a method for preparing the compound of the present invention is provided.

[0035] [Detailed description of the invention] [ka] According to one aspect of the present invention, a compound of formula I or a pharmaceutically acceptable salt or derivative thereof is provided, wherein X and X' are halogens, such as fluorine, chlorine, or bromine. Preferably, X and X' are fluorine. Het represents a heteroaromatic group, and R is a five-membered or six-membered aromatic group or a heteroaromatic group. The heteroaromatic group, Het may be selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole, and any derivative thereof. The heteroaromatic group may be unsubstituted, monosubstituted, or disubstituted, and the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of unsubstituted (C1-C4) linear alkyl, unsubstituted (C1-C4) branched alkyl, substituted (C1-C4) linear alkyl, substituted (C1-C4) branched alkyl, alkoxy, cycloalkyl, cyano, and halogens, such as fluorine, chlorine, or bromine. Preferably, the substituents of the heteroaromatic group of Het include alkyl, fluoroalkyl, such as CF3, alkoxy, cycloalkyl, cyano, or halogen. More preferably, the substituents of the heteroaromatic group of Het are F, Cl, CHF2, CF3, methyl, methoxy, nitrile, or cyclopropyl.

[0036] The five-membered or six-membered aromatic group or heteroaromatic group R may be unsubstituted or substituted with one or more substituents.

[0037] Preferably, the compound provided by formula I is a 5R,6S stereoisomer: [ka]

[0038] The 5R,6S stereoisomers provided by compounds of formula I or I(a-q) may bind more strongly to the orexin receptor and be more selective for binding to the OX1 receptor compared to other stereoisomers provided by compounds of formula I or I(a-q).

[0039] As used herein, the term "heteroaromatic group" refers to an aromatic compound that contains a heteroatom, such as oxygen, nitrogen, or sulfur, as part of a cyclic conjugated π system.

[0040] When used herein, the term "alkyl" refers to a monovalent group derived from an alkane by removing a hydrogen atom from any carbon atom -C n H 2n+ Refers to 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, halogens (e.g., fluorine, chlorine, or bromine), -OH, or -CN.

[0041] As used herein, the term “deuterated alkyl” refers to an alkyl group in which one or more protons are replaced by deuterium atoms.

[0042] As used herein, the term “deuterated compound” refers to a compound in which one or more hydrogen atoms are replaced by deuterium atoms.

[0043] As used herein, the term "fluoroalkyl" refers to an alkyl group substituted with at least one fluorine atom.

[0044] As used herein, the term "alkoxy" refers to an alkyl group bonded to oxygen (i.e., RO).

[0045] As used herein, the term "aryl" refers to a monocyclic or bicyclic carbocyclic aromatic or aryl ring system. Phenyl is an example of a monocyclic aromatic or aryl ring system.

[0046] The "halogen" can be F, Cl, Br, or I, but in preferred examples, the halogen is F, Cl, or Br.

[0047] As used herein, the term "substituted" refers to the substitution of one functional group with another for a particular group (e.g., alkyl, aryl, heteroaryl, aromatic) (e.g., the substitution of an alkyl hydrogen with fluorine to obtain a fluoroalkyl group).

[0048] The term "solvate" is used herein to describe compounds in the present invention that contain one or more pharmaceutically acceptable solvent molecules, such as ethanol, in stoichiometric or quasi-stoichiometric amounts. The term "hydrate" refers to the case where the solvent is water.

[0049] "Pharmacologically acceptable" means that the components of a pharmaceutical composition are compatible with each other and are not harmful to the person to whom it is administered.

[0050] The term “therapeutic effective dose” (or more simply “effective dose”), as used herein, means the amount of an activator or active ingredient sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which it is administered.

[0051] Preferably, when the R group of the compound of formula I is a five-membered heteroaromatic group, this may include unsubstituted pyrazoles, oxazoles, thiazoles, imidazoles, substituted pyrazoles, oxazoles, thiazoles, imidazoles, or derivatives thereof. Preferably, when the R group of the compound of formula I is a six-membered aromatic group, this may include unsubstituted aryls or substituted aryls, or derivatives thereof.

[0052] More preferably, if the R group of the compound of formula I is a 6-membered aromatic group, the 6-membered aromatic group has the structure of formula II or II(a): [ka] (In the formula, R 1This can be selected from the group consisting of 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, R 1 is Cl, F, -CH3, or -CD3; Het' may be selected from the group consisting of a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof, the heteroaromatic group may be unsubstituted, monosubstituted, or disubstituted, and the substituent of the heteroaromatic group, if present, may be independently selected from the group consisting of unsubstituted (C1-C4) linear or branched alkyl, substituted (C1-C4) linear or branched alkyl, and halogen; preferably, The (one or more) substituents of the heteroaromatic group are halogens, such as fluorine, chlorine, or bromine; preferably, the substituent is -CH3. It holds.

[0053] In some cases, the Het' group in formula II or II(a) is [ka] It can be selected from the following.

[0054] Furthermore, if the R group of the compound of formula I is a 6-membered heteroaromatic group, the 6-membered heteroaromatic group has the structure of formula III or III(a): [ka] (In the formula, R 1The halogen may be selected from the group consisting of 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 is H, Cl, F, -CH3, or -CD3; R 2 The halogen may be selected from the group consisting of 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 2 These are H, F, Cl, -CH3, or -CD3; Het' may be as defined herein with respect to formula II or II(a). It holds.

[0055] In some cases, Het' in equation III or III(a) is [ka] It can be selected from the following.

[0056] If the R group in formula I is a 5-membered heteroaromatic group, then the 5-membered heteroaromatic group is represented by structural formulas IV, IV(a), or IV(b): [ka] (In the formula, R 3 and R 4 is hydrogen, (C1~C 10 )-Linear alkyl; (C1~C 10 )-branched alkyl; (C1~C 10)-substituted or unsubstituted alkyl, optionally independently selected from the group consisting of (C1~C4)-linear alkyl; (C1~C4)-branched alkyl; (C1~C4)-substituted or unsubstituted alkyl; deuterated (C1~C4)-linear alkyl; and deuterated (C1~C4)-branched alkyl; R 3 and R 4 The ring may form a condensation substitution or an unsubstituted ring; preferably, R 3 and R 4 These can be -CH3 or -CD3, respectively, independently; Y may represent an aromatic group; a substituted or unsubstituted aromatic group, a heteroaromatic group, or a substituted or unsubstituted heteroaromatic group. It may have the following: Preferably, Y can be independently selected from the group consisting of aryl, pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, nicotinonitrile, benzonitrile, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof; Y can be unsubstituted, monosubstituted or disubstituted, and the substituent can be independently selected from the group consisting of (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano group and halogen.

[0057] If Y is monosubstituted or disubstituted and (one or more) substituents are halogens, the halogens may preferably be fluorine, chlorine, or bromine. If Y is monosubstituted or disubstituted and (one or more) substituents are cyano groups or (C1-C4)-alkoxy groups, the alkoxy group may be -OCH3; preferably, (one or more) substituents are CN, F, Cl, CH3, or -OCH3.

[0058] In some examples, "Y" in equations IV, IV(a), or IV(b) is [ka] It can be selected from the following.

[0059] Furthermore, if "R" in formula I is a 5-membered heteroaromatic group, then the 5-membered heteroaromatic group is structured as follows: [ka] (In the formula, Y may be as defined with respect to formula IV, IV(a), or IV(b)) It may have.

[0060] In some examples, "Y" in equation V is, [ka] It is possible.

[0061] Furthermore, if "R" in formula I is a five-membered heteroaromatic group, then the five-membered heteroaromatic group is structured as follows: [ka] (In the formula, Y may be as defined with respect to formula IV, IV(a), or IV(b)) It may have.

[0062] In some examples, "Y" in expression VI is, [ka] It is possible.

[0063] Furthermore, if "R" in formula I is a five-membered heteroaromatic group, then the five-membered heteroaromatic group is structured as follows: [ka] (In the formula, Y may be as defined with respect to formula IV, IV(a), or IV(b)) It may have.

[0064] In some examples, "Y" in equation VII is, [ka] It is possible.

[0065] In some examples, the "R" in the compounds of formula I described herein is [ka] It can be selected from the following.

[0066] In further examples, the "R" in the compounds of formula I described herein is [ka] It can be selected from the following.

[0067] In some examples, Het of the compound of formula I described herein is [ka] It can be selected from the following.

[0068] According to one aspect of the present invention, the structure represented by formula I(D): [ka] (In the formula, X, X', Het, and R are each independently as defined herein with respect to Formula I; R 6 and R 7 (Each is independently hydrogen or deuterium.) A deuterated compound of formula I having or a pharmaceutically acceptable salt or derivative thereof is provided.

[0069] In a preferred embodiment, the deuterated compound of formula ID has the following structure: [ka] It holds.

[0070] Het is a heteroaromatic group, preferably 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 heteroaromatic group may be unsubstituted, monosubstituted, or disubstituted, and substituents of the heteroaromatic group, if present, are independently selected from the group consisting of unsubstituted (C1-C4) linear alkyl, unsubstituted (C1-C4) branched alkyl, substituted (C1-C4) linear alkyl, substituted (C1-C4) branched alkyl, (C3-C8) cycloalkyl, cyano group, alkoxy, and halogen, such as fluorine, chlorine, or bromine. Preferably, substituents of the heteroaromatic group include F, Cl, CHF2, CF3, methyl, methoxy, nitrile, or cyclopropyl groups.

[0071] R is a five-membered or six-membered aromatic group or a heteroaromatic group. The five-membered or six-membered aromatic group or heteroaromatic group R may be unsubstituted or substituted with one or more substituents.

[0072] Preferably, when the R group of the compound of formula ID(a) is a 6-membered aromatic group, it may include an unsubstituted aryl group, a substituted aryl group, or derivatives thereof.

[0073] Preferably, when the R group of the compound of formula ID(a) is a 6-membered aromatic group, it may include unsubstituted pyridine, unsubstituted pyrimidine, unsubstituted pyridazine, unsubstituted pyrazine, substituted pyridine, substituted pyrimidine, substituted pyridazine, substituted pyrazine, or derivatives thereof.

[0074] Preferably, when the R group of the compound of formula ID(a) is a 5-membered heteroaromatic group, this may include unsubstituted pyrazoles, unsubstituted oxazoles, unsubstituted thiazoles, unsubstituted imidazoles, substituted pyrazoles, oxazoles, substituted thiazoles, substituted imidazoles, or derivatives thereof.

[0075] R of formula ID(a) 6 can be hydrogen or deuterium.

[0076] When the R group of formula ID(a) is a 5-member heteroaromatic group, the 5-member heteroaromatic group has the structural formula VIII:

Chemical formula

[0077] In some examples, the Y group of formula VIII is ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ may be selected from.

[0080] Furthermore, when "R" in formula ID(a) is a 5-member heteroaromatic group, the 5-member heteroaromatic group has the structural formula X:

Chemical formula

[0081] In some examples, the Y group of formula X may be

Chemical formula

[0082] More preferably, when the R group of the compound of formula ID(a) is a 6-member aromatic group, the 6-member aromatic group has the structure of formula XI or XI(a):

Chemical formula

[0083] In some examples, Het’ of formula XI or XI(a) may be

Chemical formula

[0084] In a preferred embodiment, the deuterated compound of formula ID has the following structure:

Chemical formula

[0085] More preferably, if the R group of the compound of formula ID(b) is a 5-membered aromatic group, the 5-membered aromatic group has the structure of formula XII: [ka] (In the formula, R 3 This may be as defined herein with respect to formula IX; Y may be as defined herein with respect to formula IV, IV(a), or IV(b). It holds.

[0086] In some cases, the Y group of formula XII is [ka] It can be selected from the following.

[0087] More preferably, if the R group of the compound of formula ID(b) is a 6-membered aromatic group, the 6-membered aromatic group has the structure of formula XIII: [ka] (In the formula, R 1 (And Het' may be independent of each other as defined herein with respect to Formula III or III(a)) It holds.

[0088] In some cases, the Het' group in formula XIII is [ka] It can be selected from the following.

[0089] In some cases, the "R" in compounds of formula ID, ID(a), or ID(b) described herein is, [ka] It can be selected from the following.

[0090] In some further examples, the "R" in compounds of formula ID, ID(a), or ID(b) described herein is: [ka] It can be selected from the following.

[0091] In some cases, the Het of a compound of formula ID, ID(a), or ID(b) as described herein is [ka] It can be selected from the following.

[0092] Preferably, the compounds of formulas ID, ID(a), and ID(b) are 5R,6S stereoisomers.

[0093] In yet another example, the compounds of formula I described herein have the structures 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), I(m), I(n), I(o), I(p), or I(q): [ka] JPEG2026524753000050.jpg225149 JPEG2026524753000051.jpg54149 (In the formula, Het, Het', R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7(And Y may be independent of each other as defined herein with respect to formulas I, ID, ID(a), ID(b), and II-XIII.) It holds.

[0094] In further examples, the compounds of the present invention are [Table 1] JPEG2026524753000053.jpg203149 JPEG2026524753000054.jpg203149 JPEG2026524753000055.jpg210149 JPEG2026524753000056.jpg216149 JPEG2026524753000057.jpg198149 JPEG2026524753000058.jpg215149 JPEG2026524753000059.jpg165149 JPEG2026524753000060.jpg169149 JPEG2026524753000061.jpg217149 JPEG2026524753000062.jpg207149 JPEG2026524753000063.jpg204149 JPEG2026524753000064.jpg211149 JPEG2026524753000065.jpg213149 JPEG2026524753000066.jpg210149 JPEG2026524753000067.jpg212149 JPEG2026524753000068.jpg216149 JPEG2026524753000069.jpg212149 JPEG2026524753000070.jpg211149 JPEG2026524753000071.jpg217149 JPEG2026524753000072.jpg166149 JPEG2026524753000073.jpg215149 JPEG2026524753000074.jpg169149 JPEG2026524753000075.jpg211149 JPEG2026524753000076.jpg209149 JPEG2026524753000077.jpg167149 JPEG2026524753000078.jpg216149 Alternatively, a selection may be made from their pharmaceutically acceptable salts and derivatives.

[0095] In one aspect of the present invention, the compound of formula I-aa, or pharmaceutically acceptable salts and derivatives thereof, [ka] (In the formula, R 6 and R 7 Each is independently either H or deuterium; R 8 is CF3; W 1 It is selected from CH, N, or CO-CH3; W 2 The following are selected from CH, N, and C-CH3; R is selected from a 5-membered heteroaromatic group comprising an unsubstituted pyrazole, unsubstituted oxazole, unsubstituted thiazole, unsubstituted imidazole, substituted pyrazole, substituted oxazole, substituted thiazole, substituted imidazole, or derivatives thereof; or a 6-membered heteroaromatic group comprising an unsubstituted pyridine, unsubstituted pyrimidine, unsubstituted pyridazine, unsubstituted pyrazine, substituted pyridine, substituted pyrimidine, substituted pyridazine, substituted pyrazine, or derivatives thereof. It will be provided.

[0096] If the R group in formula I-aa is a 5-membered heteroaromatic group, then the 5-membered heteroaromatic group has the following structure: [ka] (In the formula, R 3 and R 4 Each can be independently CH3 or CD3; Y is [ka] (Possible) It may have.

[0097] If the R group in formula I-aa is a 6-membered heteroaromatic group, then the 6-membered heteroaromatic group has the following structure: [ka] (In the formula, Het' is [ka] (Possible) It may have.

[0098] In one aspect of the present invention, the compound of formula I-aa is [ka] Selected from.

[0099] Preferably, the compound of formula I-aa is a 5R,6S stereoisomer.

[0100] In some examples, the compounds provided by formulas I and I(a-q) may be deuterated, with at least one hydrogen atom replaced by deuterium. Preferably, the N-Me or C-Me group of the compounds provided by formulas I and I(a-g) is deuterated. Preferably, compounds 6, 7, 23, 24, 26, 27, 28, 29, 35, 36, and 37 are deuterated. Even more preferably, the N-Me or C-Me group of the pyrazole ring of compounds 6, 7, 23, 24, 26, 27, 28, 29, 35, 36, and 37 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. The deuterated compounds provided by formulas I and I(a~q) may be more metabolically stable than their non-deuterated equivalents.

[0101] The compounds of the present invention may be in the form of pharmaceutically acceptable salts. “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound described herein that is non-toxic, bioacidic, or otherwise biofit for administration to a subject. The compounds described herein may have a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or two or more of each type, and thus may react with several inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts.

[0102] Examples of "pharmaceutically acceptable salts" include, but are not limited to, hydrochlorides, chlorides, bromides, iodides, potassium salts, sodium salts, acetates, trifluoroacetates, sulfates, sulfonates, oxalates, maleates, malons, nitrates, tartrates, glucons, succinates, mesylates, citrates, phosphates or diphosphates, and aluminates.

[0103] In some cases, the compounds of the present invention may be in the form of trifluoroacetates.

[0104] Any formula shown herein is intended to represent a compound of its structural formula and a particular variation or form. For example, formulas given herein are intended to include racemic forms, or one or more enantiomers, diastereomers, geometric isomers, tautomers, prodrugs, or mixtures thereof.

[0105] "pharmaceutically acceptable derivatives" of the compounds of the present invention disclosed herein include, but are not limited to, enantiomers, solvates, adducts, polymorphs, hydrates, tautomers, prodrugs, isotopically labeled or radioactively labeled derivatives, isomers, or mixtures thereof.

[0106] Isotope labeling in the compounds described This application further includes all pharmaceutically acceptable isotope-labeled compounds [e.g., of formula I or I(a-d)]. An “isotope-labeled” or “radio-labeled” compound is a compound in which one or more atoms are replaced or substituted with atoms having an atomic mass or mass number different from that typically found in nature (i.e., naturally occurring). For example, in certain cases, in a compound [e.g., of formula I or I(a-d)], a hydrogen atom is replaced or substituted with one or more deuterium or tritium (e.g., a hydrogen atom in (C1-C6)-alkyl or (C1-C6)-alkoxy compounds is replaced with deuterium, e.g., d3-methoxy or 1,1,2,2-d4-3-methylbutyl).

[0107] Certain specific isotope-labeled compounds [e.g., compounds of formula I or I(a - d)], for example, those incorporating a radioisotope, are useful in drug and / or substrate tissue distribution studies and metabolic studies (preferably, 14 using 2 H or 3 H), kinetic studies (e.g., 2 using deuterium (i.e.,

[0108] [e.g., of formula I, ID, ID(a), ID(b), I-aa or I(a - q)] isotope-labeled compounds or their corresponding prodrugs can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described in the accompanying examples using appropriate isotope-labeled reagents in place of the previously used unlabeled reagents. Suitable isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H (also written as D of deuterium), 3 H (also written as T of tritium), 11 C, 13 C, 14 C, [[ID=二十六]] 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, 131 I,31 P, and 32 P is one example, but it is not limited to these.

[0109] The isotope-labeled compounds and their prodrugs of this application can generally be prepared by using readily available isotope-labeled reagents instead of non-isotopically labeled reagents, by following the procedures disclosed in the scheme or the examples and preparations described below.

[0110] The compounds provided by the present invention are non-peptide antagonists of the human orexin receptor. The compounds provided by the present invention may be useful in the potential treatment or prevention of central nervous system (CNS) disorders, neurological diseases, or feeding disorders. The compounds of the present invention may be useful in treating diseases or disorders associated with orexin 1 receptor dysfunction.

[0111] The novel compounds provided by the present invention are non-peptide antagonists of the human orexin receptor, particularly the orexin-1 receptor. These compounds are particularly useful for the potential treatment or prevention of central nervous system (CNS) disorders, neurological disorders or eating disorders, such as obesity, bulimia nervosa (BED), schizophrenia (negative symptoms and CIAS), psychomotor stimulant addiction, such as cocaine, opioids, nicotine and alcohol, opioid use disorder, drug abuse or addiction, sleep disorders, cognitive impairment in psychiatric or neurological disorders, depression, anxiety, panic disorder, post-traumatic stress disorder, behavioral disorders, and mood disorders and depressive states. The compounds of the present invention may be useful in treating diseases or disorders associated with orexin-1 receptor dysfunction.

[0112] Preferably, the compounds provided by the present invention are OX1 receptor selective antagonists. OX1 receptor antagonists are useful for treating 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 sleep-inducing effect; therefore, it is highly desirable to identify highly OX1-selective antagonists with a sufficient window against OX2-mediated effects to prevent side effects such as drowsiness or fatigue.

[0113] To demonstrate the efficacy of the compounds provided by the present invention, the half maximal inhibitory concentration (IC 50 ) can be used in the present invention. The IC 50 values provided in this disclosure indicate how much drug is required to inhibit the orexin receptor by half, and thus provide a measure of the compounds provided by the present invention.

[0114] The compounds provided by the present invention can have an IC 50 of at least 700 nM for the OX1 receptor. Preferably, the compounds provided by the present invention can have an IC 50 value between 2 nM and 700 nM for the OX1 receptor. The compounds provided by formula I are 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 10 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 for the IC 50It may have a value.

[0115] More preferably, the compounds provided by the present invention have an IC50 between 2 nM and 100 nM for the OX1 receptor. 50 The compounds provided by the present invention may have values ​​between 2nM and 90nM; between 2nM and 70nM; between 2nM and 50nM; between 2nM and 30nM; between 2nM and 10nM; between 5nM and 90nM; between 5nM and 80nM; between 5nM and 60nM; between 5nM and 50nM; between 5nM and 30nM; between 5nM and 20nM; between 5nM and 10nM; between 10nM and 80nM; between 10nM and 60nM; between 10nM and 70nM; between 10nM and 50nM; between 10nM and 30nM; or between 10nM and 20nM IC 50 It may have a value.

[0116] Most preferably, the compounds provided by the present invention have an IC50 between 2 nM and 50 nM for the OX1 receptor. 50 The compound provided by formula I may have values ​​between 2nM and 40nM; between 2nM and 30nM; between 2nM and 25nM; between 2nM and 20nM; between 2nM and 10nM; between 2nM and 5nM; between 3nM and 40nM; between 3nM and 30nM; between 3nM and 25nM; between 3nM and 20nM; between 3nM and 10nM; between 3nM and 5nM; between 5nM and 40nM; between 5nM and 30nM; between 5nM and 25nM; between 5nM and 20nM; between 5nM and 10nM; between 7nM and 40nM; between 7nM and 30nM; between 7nM and 25nM; between 7nM and 20nM; or between 7nM and 10nM IC 50 It may have a value.

[0117] Most preferably, the compounds provided by the present invention have an IC50 of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 23, 24, 25, 26, 27, 28, 32, 33, 36, 40, 44, 48, 49, 55, 56, 57, 60, 69, 73, 75, 81, 94, 137, 160, 166, 172, 245, 296, 302, 351, or 638 nM with respect to the OX1 receptor. 50 It may have.

[0118] The compounds provided by the present invention have an IC50 of at least 3000 nM for the OX2 receptor. 50 It may have. Preferably, the compound provided by the present invention has at least 5000 nM IC for the OX2 receptor. 50 It holds.

[0119] The compounds provided by the present invention are at least 12 times more effective in binding to the OX1 receptor compared to the OX2 receptor. Preferably, the compounds provided by the present invention are at least 50 times more effective in binding to the OX1 receptor compared to the OX2 receptor. Even more preferably, the compounds provided by the present invention are at least 100 times more effective in binding to the OX1 receptor compared to the OX2 receptor. Most preferably, the compounds provided by the present invention are at least 500 times more effective in binding to the OX1 receptor compared to the OX2 receptor.

[0120] The compounds of the present invention were found to have improved residence times compared to known OX1 receptors. Orexin A was incubated with human OX1 receptor membranes for different incubation times in the presence or absence of six different concentrations of the compounds. Nonspecific binding was evaluated for each incubation time in the presence of unlabeled SB334867 (1-(2-methylbenzo[d]oxazole-6-yl)-3-(1,5-naphthirizine-4-yl)urea, a commercially available OX1R-ANT). The kinetic parameters (kon, koff, residence time) were calculated by applying the Motulsky-Mahan equations. The compounds of the present invention were found to exhibit longer residence times compared to the reference compounds, suggesting a longer ligand-OX1R complex half-life that positively impacts therapeutic doses in humans. For example, the compounds of the present invention (e.g., compounds 26 and 54) ranked higher than known compounds, e.g., those in International Publication No. 2017129829, International Publication No. 2017139603, JNJ-61393215, and ACT-539313. Improved drug residence time is advantageous because longer drug-target residence times are generally more effective in vivo. As a result, lower therapeutic doses are required. It is also generally known that drugs with longer residence times have increased efficacy and fewer side effects because they occupy a higher proportion of the target for a longer period, even after clearance from the systemic circulation.

[0121] The compounds provided by the present invention may have improved pharmacokinetic properties, such as improved bioavailability, brain exposure, improved cellular permeability, and metabolic stability, thus requiring lower therapeutic doses.

[0122] According to another aspect of the present invention, a pharmaceutical composition is provided comprising the compounds of the present invention described herein and one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may be added to streamline the manufacture of the pharmaceutical composition and ultimately enhance the physiological absorption of the drug. Furthermore, the pharmaceutically acceptable excipients used in the present invention may provide important benefits such as solubilization, stabilization, delivery enhancement, and formulation preservation.

[0123] The compounds of this application may be used in combination with one or more additional active ingredients in pharmaceutical compositions or methods for the treatment of the diseases and disorders described herein. Additional active ingredients may include other activators effective in treating the diseases and disorders described herein. For example, additional active ingredients may include those known to improve sleep quality and to prevent and treat sleep disorders and sleep disturbances, antidiabetic drugs, cardiovascular drugs, anti-obesity drugs, other orexin receptor antagonists, analgesics, antidepressants, anxiolytics, cognitive enhancers, anti-Alzheimer's disease agents, and other active ingredients.

[0124] Non-limiting examples of excipients include liquid and solid fillers, diluents, binders, lubricants, fluidizers, surfactants, dispersants, disintegrants, emulsifiers, wetting agents, suspending agents, thickeners, solvents, isotonic agents, buffers, pH adjusters, absorption retarders, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweeteners, flavoring agents, colorants, encapsulating materials, and coating materials. The use of such excipients in pharmaceutical formulations is well known in the art.

[0125] The pharmaceutical compositions or compounds provided by the present invention may be used as pharmaceuticals. The pharmaceuticals may be used to prevent and / or treat conditions selected from, but are not limited to, central nervous system (CNS) disorders, neurological disorders or eating disorders, such as obesity, bulimia nervosa (BED), schizophrenia (negative symptoms and CIAS), psychomotor stimulant addiction, such as cocaine, opioids, nicotine and alcohol, opioid use disorder, drug abuse or addiction, sleep disorders, cognitive impairment in psychiatric or neurological disorders, depression, anxiety, panic disorder, post-traumatic stress disorder, behavioral disorders and mood disorders, depressive states.

[0126] The pharmaceutical compositions provided by the present invention may be in the form of tablets, capsules, hard candies, powders, spansules, softgels, liquids, or aqueous suspensions. Preferably, the pharmaceutical compositions provided by the present invention are in the form of tablets or capsules.

[0127] The pharmaceutical compositions provided by the present invention may be administered orally, parenterally (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intraperitoneal, intracavitary, and topical), topically (including transdermal and transmucosal), intranasally (e.g., by nasal spray or nasal solution), orally (e.g., by eye drops), orally (e.g., by oral or nasal inhalation), and / or by other suitable routes. Preferably, the pharmaceutical compositions provided by the present invention are administered orally.

[0128] A further aspect of the present invention provides a method for treating or preventing a disease or disorder mediated by orexin receptor activity. The method comprises the step of administering to a subject requiring such treatment a pharmaceutical composition comprising an effective amount of at least one compound of the present invention (or any pharmaceutically acceptable salt, solvate, adduct, polymorph, isotope-labeled or radiolabeled derivative, and isomer thereof) or at least one compound of the present invention (or any pharmaceutically acceptable salt, solvate, adduct, polymorph, isotope-labeled or radiolabeled derivative, and isomer thereof).

[0129] The methods provided by the present invention may be used to treat or prevent diseases or disorders selected from among eating disorders, obesity, bulimia nervosa (BED), schizophrenia (negative symptoms and CIAS), addiction to psychomotor stimulants such as cocaine, opioids, nicotine and alcohol, opioid use disorder, drug abuse or addiction, sleep disorders, cognitive impairment in psychiatric or neurological disorders, depression, anxiety, panic disorder, post-traumatic stress disorder, behavioral disorders, and mood disorders and depressive states.

[0130] As used herein, the term “effective dose” refers to the amount of compound administered that alleviates, to some extent, one or more symptoms of the disorder being treated.

[0131] The administration regimen may be adjusted to produce the optimal desired response. It should be noted that the dosage may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. It should be further understood that for any particular subject, the specific administration regimen should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition.

[0132] The amount of the compound of the present invention administered depends on the subject being treated, the severity of the disorder or condition, the dosage rate, the properties of the compound, and the discretion of the prescribing physician.

[0133] As used herein, the term “subject” includes human or non-human animals. An exemplary human subject includes a human subject with a disease (e.g., those described herein) (referred to as a patient), or a healthy subject. As used herein, the term “non-human animal” includes all vertebrates, e.g., non-mammals.

[0134] According to another aspect of the present invention, the use of the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention is provided. The compound of the present invention or a pharmaceutical composition comprising the compound of the present invention is used in the preparation of a medicament for treating a disease or disorder controlled by orexin receptor activity, and is used for the treatment or prevention of such diseases and disorders.

[0135] A method for modulating the activity of orexin receptors OX1, OX2, or both, according to yet another aspect of the present invention. The method comprises the step of contacting cells containing orexin receptors with an effective amount of at least one compound according to the present invention or a pharmaceutical composition containing a compound according to the present invention. The method of contacting cells containing orexin receptors with an effective amount of at least one compound according to the present invention or a pharmaceutical composition containing a compound according to the present invention can be carried out in vivo, in vitro, or ex vivo.

[0136] Preferably, the present invention provides a method for selectively regulating the activity of the OX1 receptor.

[0137] According to yet another aspect of the present invention, the compounds of the present invention can be prepared by the synthetic routes described in the following examples.

[0138] The following is a summary of the abbreviations used in this disclosure: BOC tert-butyloxycarbonyl DMF Dimethylformamide DMS (Dimethyl Sulfide) DMSO (Dimethyl Sulfoxide) DMAP 4-dimethylaminopyridine DIAD Diisopropyl Azodicarboxylate DEAD Diethylazodicarboxylate DIPEA N,N-diisopropylethylamine Fmoc Fluorenylmethyloxycarbonyl PG protecting group TBAF Tetra-n-butylammonium fluoride THF (Tetrahydrofuran) TEA Triethanolamine Ts Tosil eq equivalent N normality V Volume

[0139] As used herein, the term "hexaalkyl tin" refers to a common reagent used to prepare organic stannanes for Stillcross coupling. Examples of "hexaalkyl tin" include, but are not limited to, hexamethyl tin or hexabutyl tin.

[0140] The compounds of the present invention can be prepared starting from N-benzyl-L-alotreonine (a), a commercially available starting material. N-benzyl-L-alotreonine a can be reduced by reacting with a reducing agent to form intermediate (b). The primary alcohol of intermediate (b) can be selectively protected by reacting with a suitable protecting group to form intermediate (c). Intermediate (c) undergoes a nucleophilic substitution reaction with 2-bromo-2,2-difluoro-acetic acid or 2,2-difluoro-2-iodoacetic acid to form intermediate (d). Intermediate (d) undergoes intramolecular amide coupling in the presence of a coupling reagent to form intermediate (e). Preferably, the coupling reagent used to prepare intermediate (e) is propylphosphonic anhydride (T3P). Intermediate (e) can be reduced to form intermediate (f). The protecting group protecting the alcohol is removed from intermediate (f) to form intermediate (g). The benzyl protecting group of 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) undergoes a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of the intermediates k-z2. Intermediate k-z2 is deprotected to form the corresponding intermediate aa-ar. Intermediate 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.

[0141] The compounds of the present invention can be prepared starting from the commercially available starting material (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine-3-one (intermediate e), or from intermediate (e) disclosed herein. Intermediate (e) can be reduced with a deuterating agent to form intermediate (f1). The protecting group protecting the alcohol can be removed from intermediate (f1) to form intermediate (g1). The benzyl protecting group of intermediate (g1) can be removed by Pd / C catalytic hydrogenation. The deprotected amine can react with a suitable protecting group to form intermediate (h1). Intermediate (h1) can be reacted with isoindoline-1,3-dione to form intermediate (i1). Intermediate (i1) can be reacted with hydrazine or hydrazine hydrate to form intermediate (j1). Intermediate (j1) undergoes a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of the intermediates k1, l1, or m1. Intermediate k1, l1, or m1 is deprotected to form the corresponding intermediates ab1, ac1, or ad1. Intermediate ab1, ac1, or ad1 can be reacted with a carboxylic acid having the general formula R-COOH to form compounds 50-59 and 70-77.

[0142] The compounds of the present invention can be prepared starting from N-benzyl-L-alotreonine (a), a commercially available starting material. N-benzyl-L-alotreonine (a) can be reacted with (2-bromo-2,2-difluoroacetyl)oxysodium to form intermediate (e2'). Intermediate (e2') can be reduced with a deuterating agent to form intermediate (e2''). Intermediate (e2'') can be reduced with a reducing agent to form intermediate (g2). The benzyl protecting group of intermediate (g2) can be removed by Pd / C catalytic hydrogenation. The deprotected amine can react 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) can be reacted with hydrazine or hydrazine hydrate to form intermediate (j2). Intermediate (j2) undergoes a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of the 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.

[0143] The present invention provides a method for synthesizing intermediate b, as shown in the following synthetic route: [ka]

[0144] N-benzyl-L-alotreonine a is reduced by reacting with a reducing agent such as borane dimethyl sulfide to form intermediate b. Other suitable reducing agents, but not limited to borane dimethyl sulfide, may be used, including lithium aluminum hydride, diethyl etherate of boron trifluoride, and diborane.

[0145] The reducing agent may be used in excess of the starting material a. The excess is preferably 2 to 10 times the amount of reducing agent relative to the starting material a. Preferably, a 5-fold excess of reducing agent relative to the starting material a is used.

[0146] The reaction may 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.

[0147] The reaction may be carried out at a temperature in the range of about 50°C to about 120°C. Preferably, the reaction may be carried out at a temperature in the range of about 60°C to about 100°C. More preferably, the reaction may be carried out at a temperature in the range of about 60°C to about 80°C. The reaction may be carried out for a period of about 3 to about 10 hours. Preferably, for a period of about 5 to about 8 hours. More preferably, the reaction may be carried out for a period of about 6 hours.

[0148] The present invention provides a method for synthesizing intermediate c, as shown in the following synthetic route (PG refers to a protecting group): [ka]

[0149] 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 may be used, including but not limited to tert-butyldimethylsilyl, triisopropylsilyl, or trimethylsilyl protecting groups.

[0150] Intermediate b can be reacted with tert-butyl(chloro)diphenylsilane to form intermediate c. Alternatively, intermediate b can be reacted with a reagent such as tert-butyldimethylsilyl chloride, triisopropylsilyl chloride, or trimethylsilyl chloride to form intermediate c.

[0151] The reagent may be used in excess of intermediate b. A 1.1 to 1.5-fold excess of the reagent relative to intermediate b may be used. Preferably, a 1.2-fold excess of the reagent relative to intermediate b is used.

[0152] The reaction may be carried out in the presence of a catalyst such as DMAP, imidazole, or a mixture thereof. Preferably, imidazole is used as the catalyst.

[0153] The catalyst may be used in excess of intermediate b. A 1.1 to 2 times excess of catalyst may be used relative to intermediate b. Preferably, a 1.5 times excess of catalyst is used relative to intermediate b.

[0154] The reaction may 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.

[0155] The reaction may be carried out at a temperature in the range of about 20°C to about 66°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a period of about 5 to about 18 hours. Preferably, the reaction is carried out for a period of about 12 hours.

[0156] The present invention provides a method for synthesizing intermediate d, as shown in the following synthetic route (PG refers to a protecting group): [ka]

[0157] Intermediate c can be reacted with 2-bromo-2,2-difluoro-acetic acid or 2,2-difluoro-2-iodoacetic acid to form intermediate d. Preferably, intermediate c is reacted with 2-bromo-2,2-difluoro-acetic acid to form intermediate d.

[0158] 2-bromo-2,2-difluoroacetic acid (or 2,2-difluoro-2-iodoacetic acid) may be used in excess of intermediate c. 2 to 7 times the excess of 2-bromo-2,2-difluoroacetic acid (2,2-difluoro-2-iodoacetic acid) may be used relative to intermediate c. Preferably, 3 times the excess of 2-bromo-2,2-difluoroacetic acid (2,2-difluoro-2-iodoacetic acid) relative to intermediate c is used.

[0159] The reaction is carried out in the presence of a Lewis base. Examples of Lewis bases that may be used in the synthesis of intermediate d include, but are not limited to, butyllithium, lithium diisopropylamide (LDA), lithium diethylamide (LDEA), sodium amide (NaNH2), sodium hydride (NaH), lithium bis(trimethylsilyl)amide, or mixtures thereof. Preferably, the Lewis base used in the synthesis of intermediate d is sodium hydride.

[0160] Lewis bases may be used in excess of intermediate c. A 2- to 6-fold excess of Lewis bases may be used relative to intermediate c. Preferably, a 4.5-fold excess of Lewis bases is used relative to intermediate c.

[0161] The reaction may be carried out in a nonpolar 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.

[0162] The reaction may be carried out at a temperature in the range of about 15°C to about 101°C. Preferably, the reaction may be carried out at a temperature in the range of about 20°C to about 80°C. More preferably, the reaction may be carried out at about 20°C. The reaction may be carried out for a period of about 5 to about 18 hours. Preferably, the reaction may be carried out for a period of about 12 hours.

[0163] The present invention provides a method for synthesizing intermediate e, as shown in the following synthetic route (PG refers to a protecting group): [ka]

[0164] Intermediate d undergoes an intramolecular amide coupling reaction in the presence of an optional 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.

[0165] The reaction may be carried out in a polar aprotic solvent such as DMF, DMSO, or a mixture thereof. Preferably, the reaction is carried out in DMF.

[0166] The reaction may be carried out at a temperature in the range of about 15°C to about 153°C. Preferably, the reaction may be carried out at a temperature in the range of about 20°C to about 130°C or about 50°C to about 100°C. More preferably, the reaction is carried out at about 20°C.

[0167] The reaction may take place over a period of approximately 1 to 5 hours. Preferably, the reaction takes place over a period of approximately 2 hours.

[0168] The present invention provides a method for synthesizing intermediate f, as shown in the following synthetic route (PG refers to a protecting group): [ka]

[0169] Intermediate e is reduced by reacting with a reducing agent such as borane dimethyl sulfide to form intermediate f. Other suitable reducing agents, but not limited to borane dimethyl sulfide, may be used, such as lithium aluminum hydride, diethyl etherate of boron trifluoride, and diborane.

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

[0171] The reaction may 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 may be carried out at a temperature in the range of about 20°C to about 66°C. Preferably, the reaction may be carried out at a temperature in the range of about 30°C to about 50°C. More preferably, the reaction may be carried out at about 30°C. The reaction may be carried out for a period of about 1 hour to about 5 hours. Preferably, the reaction may be carried out for a period of about 3 hours.

[0173] The present invention provides a method for synthesizing intermediate g, as shown in the following synthetic route (PG refers to a protecting group): [ka]

[0174] By reacting with a fluorine source, the tert-butyl-diphenylsilane protecting group can be removed from intermediate f to form intermediate g. Suitable reagents as a fluorine source include, but are not limited to, tetra-n-butylammonium fluoride (TBAF) or triethylamine trihydrofluoride. Preferably, TBAF is used to form intermediate g.

[0175] The reagent may be used in excess of intermediate f. A 1.1 to 2 times excess of the reagent relative to intermediate f may be used. Preferably, a 1.5 times excess of the reagent relative to intermediate f is used.

[0176] The reaction may 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.

[0177] The reaction may take place at a temperature in the range of about 15°C to about 66°C. Preferably, the reaction takes place at about 20°C to about 50°C. More preferably, the reaction takes place at about 20°C. The reaction may take place over a period of about 1 hour to about 5 hours. Preferably, the reaction takes place over a period of about 2 hours.

[0178] The present invention provides a method for synthesizing intermediate h as shown in the following synthetic route (PG refers to a protecting group): [ka]

[0179] Intermediate g is reacted with hydrogen and palladium carbon, and then protected to form intermediate h. Preferably, the reaction is carried out under a hydrogen atmosphere at a pressure in the range of about 10 Psi to about 30 Psi. Preferably, the reaction is carried out at about 15 Psi.

[0180] The conversion of intermediate g to intermediate h may be a one-pot process.

[0181] Preferably, about 0.02 to about 0.5 equivalents of palladium-carbon are used. More preferably, about 0.05 equivalents of palladium-carbon are used.

[0182] Intermediate h can be formed using any suitable protecting group. Examples of suitable protecting groups that may be used include Fmoc, BOC, or Ts. Preferably, BOC is used as the protecting group. Examples of suitable protecting group reagents for forming intermediate h include, but are not limited to, fluorenyl methyloxycarbonyl chloride, 9-fluorenyl methyl succinimidyl carbonate, 9-fluorenyl methyloxycarbonyl azide, BOC anhydride, and tosyl chloride. Preferably, BOC anhydride is used.

[0183] The protecting group reagent may be used in excess of intermediate g. A 1.1 to 2 times excess of the reagent relative to intermediate g may be used. Preferably, a 1.5 times excess of the reagent relative to intermediate g is used.

[0184] The reaction may 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.

[0185] The reaction may take place at a temperature in the range of approximately 15°C to approximately 77°C. Preferably, the reaction takes place at approximately 25°C. The reaction may take place over a period of approximately 6 to approximately 18 hours. Preferably, the reaction takes place over a period of approximately 12 hours.

[0186] The present invention provides a method for synthesizing intermediate I, as shown in the following synthetic route (PG refers to a protecting group): [ka]

[0187] Intermediate h is reacted with isoindoline-1,3-dione to form intermediate i. Isoindoline-1,3-dione may be used in excess of intermediate h. Isoindoline-1,3-dione may be used in an excess of 1.1 to 2 times the amount of intermediate h. Preferably, isoindoline-1,3-dione is used in an excess of 1.5 times the amount of intermediate h.

[0188] Preferably, the reaction is carried out in the presence of triphenylphosphine.

[0189] Triphenylphosphine may be used in excess of intermediate h. A 1.1 to 2 times excess of triphenylphosphine relative to intermediate h may be used. Preferably, a 1.5 times excess of triphenylphosphine relative to intermediate h is used.

[0190] 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 may be used in excess of intermediate h. A 1.1 to 2 times excess of the oxidizing agent relative to intermediate h may be used. Preferably, a 1.5 times excess of the oxidizing agent relative to intermediate h is used.

[0191] The reaction may 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.

[0192] The reaction may take place at temperatures ranging from approximately -10°C to approximately 66°C. Preferably, the reaction takes place at approximately 0°C to approximately 20°C. The reaction may take place over a period of approximately 5 to approximately 20 hours. Preferably, the reaction takes place over a period of approximately 16 hours.

[0193] The present invention provides a method for synthesizing intermediate j as shown in the following synthetic route (PG refers to a protecting group): [ka]

[0194] 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.

[0195] Hydrazine or hydrazine hydrate may be used in excess of intermediate i. A 5- to 20-fold excess of hydrazine or hydrazine hydrate may be used relative to intermediate i. Preferably, a 10-fold excess of hydrazine or hydrazine hydrate is used relative to intermediate i.

[0196] The reaction may be carried out in a polar protic solvent such as an alcohol, including but not limited to methanol, ethanol, isopropanol, or a mixture thereof. Preferably, the reaction is carried out in methanol.

[0197] The reaction may be carried out at a temperature in the range of approximately 40°C to approximately 65°C. Preferably, the reaction is carried out at approximately 60°C. The reaction may be carried out for a period of approximately 1 to approximately 5 hours. Preferably, the reaction is carried out for a period of approximately 2 hours.

[0198] The present invention provides a method for synthesizing intermediate f1 as shown in the following synthetic route (PG refers to a protecting group): [ka]

[0199] Intermediate e((5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine-3-one) is reduced by reaction with a deuterating agent to form intermediate f1. Suitable deuterating agents include, but are not limited to, triduterioborane, LiAlD4, and NaBD4. Preferably, the deuterating agent is triduterioborane.

[0200] Examples of protecting groups (PGs) include, but are not limited to, tert-butyldimethylsilyl, triisopropylsilyl, or trimethylsilyl protecting groups. Preferably, the protecting group is tert-butyl-diphenylsilane.

[0201] The reducing agent may be used in excess relative to intermediate e.

[0202] The reaction may 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.

[0203] The reaction may be carried out at a temperature in the range of about 0°C to about 60°C. Preferably, the reaction may be carried out at a temperature in the range of about 0°C to about 40°C. The reaction may be carried out for a period of about 1 hour to about 3 hours, preferably about 1.5 hours. The PG group may be tert-butyl-diphenylsilane.

[0204] The present invention provides a method for synthesizing intermediate g1 as shown in the following synthetic route (PG refers to a protecting group): [ka]

[0205] The tert-butyl-diphenylsilane protecting group can be removed from intermediate f1 by reacting it with a fluorine source to form intermediate g1. Suitable reagents as a fluorine source include, but are not limited to, tetra-n-butylammonium fluoride (TBAF) or triethylamine trihydrofluoride, and preferably TBAF is used. The process for preparing intermediate g1 may be similar to the process for preparing intermediate g described herein. The reaction conditions, such as the amount of reagent, the type of solvent used (polar aprotic solvent), and the reaction temperature, may be similar to those used for the synthesis of intermediate g.

[0206] The reaction may take place over a period of approximately 1 to 15 hours, preferably about 12 hours.

[0207] The present invention provides a method for synthesizing intermediate h1 as shown in the following synthetic route (PG' refers to a protecting group): [ka]

[0208] The method for preparing intermediate h1 may be similar to the method for preparing intermediate h described herein.

[0209] Intermediate g1 is reacted with hydrogen and palladium carbon, and then protected to form intermediate h1. Intermediate h1 can be formed using any suitable protecting group. Examples of suitable protecting groups that may be used include Fmoc, BOC, or Ts. Preferably, BOC is used as the protecting group.

[0210] The reaction conditions, such as pressure, amount of palladium, protecting group reagent, amount of protecting group reagent, and solvent, may be similar to those used in the synthesis of intermediate h.

[0211] The conversion of intermediate g1 to intermediate h1 can be a one-pot process. The reaction may take place at a temperature in the range of about 15°C to about 77°C, preferably at about 20°C. The reaction may take place over a period of about 6 to about 18 hours, preferably about 16 hours.

[0212] The present invention provides a method for synthesizing intermediate i1 as shown in the following synthetic route (PG' refers to a protecting group): [ka]

[0213] A method for preparing intermediate i1 may be similar to the method for preparing intermediate i described herein.

[0214] Intermediate h1 is reacted with isoindoline-1,3-dione to form intermediate i1. Process conditions such as the amount of isoindoline-1,3-dione, the type of solvent, the amount of solvent, the type of oxidizing agent, the polar aprotic solvent, the reaction temperature, and the reaction duration may be similar to those used in the method for preparing intermediate i described herein.

[0215] The present invention provides a method for synthesizing intermediate j1 as shown in the following synthetic route (PG' refers to a protecting group): [ka]

[0216] Intermediate i1 is reacted with hydrazine or hydrazine hydrate to form intermediate j1. Preferably, intermediate i is reacted with hydrazine hydrate to form intermediate j1.

[0217] The method for preparing intermediate j1 may be similar to the method for preparing intermediate j described herein. Process conditions such as hydrazine or the amount of hydrazine, solvent, reaction temperature, and reaction duration may be similar to those used in the method for preparing intermediate j described herein.

[0218] The present invention provides a method for synthesizing the intermediate e2' as shown in the following synthetic route: [ka]

[0219] N-benzyl-L-alotreonine is reacted with 2-bromo-2,2-difluoro-acetyl)oxysodium or 2,2-difluoro-2-iodoacetic acid in the presence of a base to form intermediate e2'. Preferably, N-benzyl-L-alotreonine is reacted with 2-bromo-2,2-difluoro-acetyl)oxysodium to form intermediate e2'.

[0220] Examples of bases that may be used include, but are not limited to, potassium t-butoxide (t-BuOK) and lithium t-butoxide (t-BuOLi) or sodium t-butoxide (t-BuONa). Preferably, t-BuONa is used.

[0221] The reaction may be carried out in a nonpolar 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.

[0222] 2-2-bromo-2,2-difluoroacetyl)oxysodium may be used in excess of intermediate a. Preferably, a 3-fold excess is used.

[0223] The reaction may take place at a temperature in the range of approximately 0°C to approximately 35°C, preferably in the range of approximately 0°C to approximately 20°C. The reaction may take place over a period of approximately 1 hour to approximately 3 hours, preferably over a period of approximately 2 hours.

[0224] Intermediate d2' may be formed in situ, and this is quenched with an acid, preferably hydrochloric acid, to form intermediate e2'. The reaction may 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.

[0225] The reaction may take place at a temperature in the range of approximately 0°C to approximately 35°C, preferably in the range of approximately 0°C to approximately 25°C. The reaction may take place over a period of approximately 1 hour to approximately 3 hours, preferably over a period of approximately 2 hours.

[0226] The present invention provides a method for synthesizing the intermediate e2'' as shown in the following synthetic route: [ka]

[0227] Intermediate e2' is reduced to form intermediate e2''. Intermediate e2' is reacted with isobutyl carbonochloride and a deuterating reducing agent or deuterating reagent. The deuterating reagent may be heavy water, sodium borodeuteride, or any combination thereof. Preferably, the deuterating agent may be sodium borodeuteride or sodium borodeuteride and heavy water.

[0228] Deuterated reagents may be used in excess relative to the starting material e2'.

[0229] The reaction can be carried out in the presence of a base. Suitable bases include, but are not limited to, triethylamine (TEA) and DIPEA. Preferably, TEA is used to form the intermediate e2''.

[0230] The reaction may 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.

[0231] The reaction may take place at a temperature in the range of approximately 0°C to approximately 35°C. Preferably, the reaction may take place at a temperature in the range of approximately 20°C to approximately 0°C to approximately 25°C. The reaction may take place over a period of approximately 1 hour to approximately 3 hours. Preferably, the reaction may take place over a period of approximately 2 hours.

[0232] The present invention provides a method for synthesizing intermediate g2, as shown in the following synthetic route: [ka]

[0233] Intermediate e2'' is reduced by reacting with a reducing agent such as borane dimethyl sulfide to form intermediate g2. Other suitable reducing agents, but not limited to borane dimethyl sulfide, may be used, such as lithium aluminum hydride, diethyl etherate of boron trifluoride, and diborane.

[0234] The reaction may 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.

[0235] The reaction may take place at a temperature in the range of approximately 0°C to approximately 60°C, preferably in the range of approximately 0°C to approximately 45°C. The reaction may take place over a period of approximately 1 hour to approximately 3 hours, preferably over a period of approximately 2.5 hours.

[0236] The present invention provides a method for synthesizing the intermediate h2 as shown in the following synthetic route (PG' indicates a protecting group): [ka]

[0237] Intermediate g2 is reacted with hydrogen and palladium carbon, and then protected to form intermediate h2. The process for preparing intermediate h2 may be similar to the process for preparing intermediate h described herein. Intermediate h2 can be formed using any suitable protecting group. Examples of suitable protecting groups that may be used include Fmoc, BOC, or Ts. Preferably, BOC is used as the protecting group.

[0238] Preferably, the reaction conditions, such as pressure, amount of palladium, appropriate protecting agent, amount of protecting agent, and solvent, are similar to those used in the process of preparing intermediate h. The conversion of intermediate g2 to intermediate h2 can be a one-pot process.

[0239] The reaction may be carried out at a temperature in the range of about 15°C to about 30°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of about 6 to about 18 hours, preferably about 12 hours.

[0240] The present invention provides a method for synthesizing intermediate i2 as shown in the following synthetic route (PG refers to a protecting group): [ka]

[0241] Intermediate h2 is reacted with isoindoline-1,3-dione to form intermediate i2. Preferably, the reaction is carried out in the presence of triphenylphosphine.

[0242] The process for preparing intermediate i2 may be similar to the process for preparing intermediate i described herein.

[0243] Preferably, the reaction conditions, such as the amount of triphenylphosphine, the oxidizing agent, the amount of oxidizing agent, the solvent (such as polar aprotic), the reaction temperature, and the reaction duration, are similar to the reaction conditions used in the process for preparing intermediate h as described herein.

[0244] The present invention provides a method for synthesizing intermediate j2 as shown in the following synthetic route (PG refers to a protecting group): [ka]

[0245] 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.

[0246] Preferably, the method for preparing intermediate j2 is similar to the method for preparing intermediate j described herein. Process conditions such as hydrazine or the amount of hydrazine, solvent, reaction temperature, and reaction duration may be similar to those used in the method for preparing intermediate j described herein.

[0247] The present invention also, (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-methylmorpholine-3-yl)methanol (intermediate g); tert-butyl(5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylate (intermediate h); tert-butyl(5R,6S)-5-((1,3-dioxoisoindoline-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate i); tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j); 5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine-3,3-d2(intermediate f1); ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholine-3-yl-5,5-d2)methanol (intermediate g1); tert-butyl(5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylate-3,3-d2 (intermediate h1); tert-butyl(5R,6S)-5-((1,3-dioxoisoindoline-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2(intermediate i1); tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (intermediate j1); (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-methylmorpholine-3-yl)methane-d2-ol (intermediate g2); tert-butyl(2S,3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3-methylpiperidine-1-carboxylate (intermediate h2); tert-butyl(5R,6S)-5-((1,3-dioxoisoindoline-2-yl)methyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate i2); or tert-butyl(5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2) The present invention provides a compound that is [a compound].

[0248] Preferably, tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j) can be prepared starting from compound (a) or any one of the intermediate compounds (b-i).

[0249] Preferably, tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate is N-benzyl-L-alotreonine (a) is reduced by reacting with a reducing agent to form (2R,3S)-2-(benzylamino)butane-1,3-diol (intermediate b); Intermediate (b) is reacted with tert-butyl(chloro)diphenylsilane to form (2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (intermediate c); In the presence of a Lewis base, intermediate (c) is reacted with 2-bromo-2,2-difluoroacetic acid or 2,2-difluoro-2-iodoacetic acid to form 2-(((2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)oxy)-2,2-difluoroacetic acid (intermediate d); In the presence of a coupling reagent, intermediate (d) is subjected to an intramolecular amide coupling reaction to form (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine-3-one (intermediate e); Reacting intermediate (e) with a reducing agent to form (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine (intermediate f); The intermediate (f) is reacted with a fluorine source to form ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholine-3-yl)methanol (intermediate g); Intermediate (g) is reacted with hydrogen, palladium 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-dioxoisoindoline-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate i); and The intermediate (i) is reacted with hydrazine or hydrazine hydrate to form tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j). It is prepared by [method].

[0250] 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).

[0251] Preferably, tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (intermediate j1) is (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine-3-one (intermediate e) is reduced with a deuterating agent to form (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine-3,3-d2 (intermediate f1); The intermediate (f1) is reacted with a fluorine source to form ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholine-3-yl-5,5-d2)methanol (intermediate g1); The intermediate (g1) is reacted with hydrogen, palladium 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-dioxoisoindoline-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (intermediate i1); and The intermediate (i1) is reacted 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). It can be prepared by [method].

[0252] Preferably, tert-butyl(5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2) can be prepared starting from either compound (a) or intermediate compounds (e2'~i2).

[0253] Preferably, tert-butyl(5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2) is Reacting N-benzyl-L-alotreonine (a) with 2-bromo-2,2-difluoroacetyl)oxysodium, followed by a suitable acid, to form (2S,3S)-4-benzyl-6,6-difluoro-2-methyl-5-oxomorpholine-3-carboxylic acid (intermediate e2'); The intermediate e2' is reduced with a deuterating agent to form (5R,6S)-4-benzyl-2,2-difluoro-5-(hydroxymethyl-d2)-6-methylmorpholine-3-one (intermediate e2''); The intermediate (e2'') is reduced with a reducing agent to form ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholine-3-yl)methane-d2-ol (intermediate g2); The intermediate (g2) is reacted with hydrogen, palladium carbon, and di-tert-butyl dicarbonate to form tert-butyl(2S,3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3-methylpiperidine-1-carboxylate (intermediate h2); Reacting intermediate (h2) with isoindoline-1,3-dione to form tert-butyl(5R,6S)-5-((1,3-dioxoisoindoline-2-yl)methyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate i2); and The intermediate (i2) is reacted with hydrazine or hydrazine hydrate to form tert-butyl(5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2). It is prepared by [method].

[0254] The present invention provides a method for synthesizing compounds 1-49, 60-69, 78-88, and 92-102, as shown in the following synthetic route: [ka]

[0255] The structures of compounds 1-49, 60-69, 78-88, and 92-102 are as shown above in this specification.

[0256] The present invention also concerns compounds of formula I: [ka] (In the formula, X, X', R, and Het may each be independently as defined herein above.) A method for preparing, (a) The step of reacting tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate with a halo-substituted heteroaromatic compound in the presence of a base to form a first intermediate compound; (b) The step of reacting the first intermediate compound with an acid to form a second intermediate compound; (c) The step of reacting the second intermediate compound with a carboxylic acid having the general formula R-COOH to obtain the compound of formula I. This provides a method that includes this.

[0257] Intermediate j undergoes a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of the intermediates k-z2.

[0258] Preferably, the intermediate k-z2 is tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate k); tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate l); tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate m); tert-butyl(5R,6S)-5-(((5-chloropyridine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate n); tert-butyl(5R,6S)-5-(((5-chloropyrimidine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate o); tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate p); tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((6-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate q); tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate r); tert-butyl(5R,6S)-2,2-difluoro-5-(((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-6-methylmorpholine-4-carboxylate (intermediate s); tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate t) tert-butyl(5R,6S)-5-(((5-cyclopropylpyrimidine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate u); tert-butyl(5R,6S)-2,2-difluoro-5-(((3-methoxy-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-6-methylmorpholine-4-carboxylate (intermediate v); tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate w); tert-butyl(5R,6S)-5-(((3-cyano-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate x): tert-butyl(5R,6S)-5-(((5-chloro-3-fluoropyridine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate y); tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((4-methyl-5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate z); tert-butyl(5R,6S)-5-(((5-(difluoromethyl)pyrimidine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate z1); or tert-butyl(5R,6S)-5-(((5-(difluoromethyl)pyrazine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate z2) That is the case.

[0259] In some cases, tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate is a deuterated compound. Preferably, the deuterated compound is tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 or tert-butyl(5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate, which is reacted in step (a) with a halo-substituted heteroaromatic compound in the presence of a base to form a first intermediate compound. The first intermediate compound can be reacted with an acid to form a second intermediate compound; the second intermediate compound can be reacted with a carboxylic acid having the general formula R-COOH to obtain the deuterated compound of formula I.

[0260] The present invention provides a method for synthesizing compounds 50-59 and 70-77, as shown in the following synthetic route: [ka]

[0261] The structures of compounds 50-59 and 70-77 are as shown above in this specification.

[0262] The present invention also relates to compounds of formula ID(a): [ka] (wherein X, X', R and Het may each be independently as defined herein above; R 6 (This can be hydrogen or deuterium.) A method for preparing, (a) The step of reacting tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (intermediate j1) with a halo-substituted heteroaromatic compound in the presence of a base to form a first intermediate compound; (b) The step of reacting the first intermediate compound with an acid to form a second intermediate compound; (c) The step of reacting the second intermediate compound with a carboxylic acid having the general formula R-COOH to obtain the compound of formula ID(a). This provides a method that includes this.

[0263] Intermediate j1 can undergo a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of the intermediates k1, l1, and m1.

[0264] Preferably, the intermediates k1, l1 and m1 are tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate-3,3-d2(k1); tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate-3,3-d2(l1); or tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate-3,3-d2(m1) That is the case.

[0265] The present invention provides a method for synthesizing compounds 89-91 and 103, as shown in the following synthetic route: [ka]

[0266] The structures of compounds 89-91 and 103 are as shown above in this specification.

[0267] The present invention also relates to the compound of formula ID(b): [ka] (wherein X, X', R and Het may each be independently as defined herein above; R 7 (This can be hydrogen or deuterium.) A method for preparing, (a) The step of reacting tert-butyl(5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2) with a halo-substituted heteroaromatic compound in the presence of a base to form a first intermediate compound; (b) The step of reacting the first intermediate compound with an acid to form a second intermediate compound; (c) The second intermediate compound is reacted with a carboxylic acid having the general formula R-COOH to obtain the compound of formula ID(b). This provides a method that includes this.

[0268] Preferably, tert-butyl(5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2) is Reacting N-benzyl-L-alotreonine (a) with 2-bromo-2,2-difluoroacetyl)oxysodium, followed by a suitable acid, to form (2S,3S)-4-benzyl-6,6-difluoro-2-methyl-5-oxomorpholine-3-carboxylic acid (intermediate e2'); The intermediate e2' is reduced with a deuterating agent to form (5R,6S)-4-benzyl-2,2-difluoro-5-(hydroxymethyl-d2)-6-methylmorpholine-3-one (intermediate e2''); The intermediate (e2'') is reduced with a reducing agent to form ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholine-3-yl)methane-d2-ol (intermediate g2); The intermediate (g2) is reacted with hydrogen, palladium carbon, and di-tert-butyl dicarbonate to form tert-butyl(2S,3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3-methylpiperidine-1-carboxylate (intermediate h2); Reacting intermediate (h2) with isoindoline-1,3-dione to form tert-butyl(5R,6S)-5-((1,3-dioxoisoindoline-2-yl)methyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate i2); and The intermediate (i2) is reacted with hydrazine or hydrazine hydrate to form tert-butyl(5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2). It is prepared by [method].

[0269] Intermediate j2 undergoes a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of the intermediates k2, l2, m2, and n2.

[0270] Preferably, intermediates k2, l2, m2 and n2 are tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl-d2)morpholine-4-carboxylate(k2); (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl-d2)morpholine-4-carboxylate(l2); tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl-d2)morpholine-4-carboxylate(m2); or tert-butyl(5R,6S)-5-(((5-chloropyridine-2-yl)amino)methyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate(n2) That is the case.

[0271] The halo-substituted heteroaromatic compounds may be selected from the group consisting of halo-substituted pyridine, halo-substituted pyridazine, halo-substituted pyrazine, halo-substituted pyrimidine, halo-substituted triazole, halo-substituted tetrazole, halo-substituted pyrazole, halo-substituted furan, halo-substituted thiophene, halo-substituted pyrrole, halo-substituted imidazole, halo-substituted isoxazole, halo-substituted oxazole, halo-substituted isothiazole, halo-substituted thiazole, and any derivative thereof, wherein the halo-substituted heteroaromatic group may be further substituted. It is also possible; if present, further substituents on the halo-substituted heteroaromatic group are independently selected from the group consisting of unsubstituted (C1-C4) linear alkyl, unsubstituted (C1-C4) branched alkyl, unsubstituted (C1-C4) alkoxy group, unsubstituted (C3-C8) cycloalkyl, substituted (C1-C4) linear alkyl, substituted (C1-C4) branched alkyl, substituted (C1-C4) alkoxy group, substituted (C3-C8) cycloalkyl, cyano group, and halogen (e.g., F, Cl, Br). Preferably, further substituents on the heteroaromatic group are Cl, F, CF3, CH3, methoxy, nitrile, or cyclopropyl.

[0272] Halo-substituted heteroaromatic compounds may be fluoro-substituted heteroaromatic compounds, chloro-substituted heteroaromatic compounds, bromo-substituted heteroaromatic compounds, or iodine-substituted heteroaromatic compounds. Preferably, the halo-substituted heteroaromatic compound may be a chloro-substituted heteroaromatic compound.

[0273] The halo-substituted heteroaromatic compounds are preferably 2-chloro-5-(trifluoromethyl)pyrazine, 2-chloro-5-(trifluoromethyl)pyrimidine, 2-chloro-5-(trifluoromethyl)pyridine, 5-chloro-2-fluoropyridine, 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- Selected from 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)pyridine, or 2-chloro-5-(trifluoromethyl)pyrazine.

[0274] Nucleophilic aromatic substitution reactions are 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.

[0275] The base may be used in excess of intermediate j, j1, or j2. A 2- to 6-fold excess of the base may be used relative to intermediate j. Preferably, a 3-fold excess of the base is used relative to intermediate j, j1, or j2.

[0276] The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO, or a mixture thereof. Preferably, the reaction is carried out in DMSO.

[0277] The reaction can be carried out at temperatures ranging from approximately 50°C to approximately 189°C. Preferably, the reaction takes about 8 It is performed at 0°C.

[0278] The reaction may take place over a period of approximately 6 to 18 hours. Preferably, the reaction takes place over a period of approximately 12 hours.

[0279] Intermediate k-z2 is deprotected by acid treatment to form the corresponding intermediate aa-ar.

[0280] Preferably, the intermediate aa-ar is 5-Chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)pyridine-2-amine hydrochloride (intermediate aa); N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyrazine-2-amine hydrochloride (intermediate ab); N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyrimidine-2-amine hydrochloride (intermediate ac); N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyridine-2-amine hydrochloride (intermediate ad); 5-Chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)pyrimidine-2-amine hydrochloride (intermediate ae); N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-4-(trifluoromethyl)pyrimidine-2-amine hydrochloride (intermediate af); N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-6-(trifluoromethyl)pyrazine-2-amine hydrochloride (intermediate ag); N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-4-(trifluoromethyl)pyridine-2-amine hydrochloride (intermediate ah); N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-3-fluoro-5-(trifluoromethyl)pyridine-2-amine hydrochloride (intermediate ai); N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyridine-2-amine (intermediate aj); 5-Cyclopropyl-N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)pyrimidine-2-amine hydrochloride (intermediate ak); N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-3-methoxy-5-(trifluoromethyl)pyridine-2-amine (intermediate al); N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyrazine-2-amine hydrochloride (intermediate am); 2-((((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)amino)-5-(trifluoromethyl)nicotinonitrile hydrochloride (intermediate an); 5-Chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-3-fluoropyridine-2-amine hydrochloride (intermediate ao); N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-4-methyl-5-(trifluoromethyl)pyrimidine-2-amine (intermediate ap) N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-5-(difluoromethyl)pyrimidine-2-amine hydrochloride (intermediate aq); or N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-5-(difluoromethyl)pyrazine-2-amine hydrochloride (intermediate ar) That is the case.

[0281] 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)pyrimidine-2-amine hydrochloride (intermediate ac1); or N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyridine-2-amine hydrochloride (intermediate ad1) That is the case.

[0282] Intermediates k2, l2, m2, and n2 are deprotected by acid treatment 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-methylmorpholine-3-yl)methyl-d2)pyridine-2-amine hydrochloride (aa2); N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl)pyrazine-2-amine hydrochloride (intermediate ab2); N-(((2S,3R)-6,6-difluoro-2-methylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl)pyrimidine-2-amine (intermediate ac2); or N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl-d2)-5-(trifluoromethyl)pyridine-2-amine (intermediate ad2) That is the case.

[0283] Examples of acids that can be used for deprotection include, but are not limited to, aqueous phosphoric acid, hydrochloric acid, and trifluoroacetic acid. Preferably, hydrochloric acid is used for deprotection of intermediates k-z2, k1-m1, and k2-n2.

[0284] Deprotection can be carried out in a nonpolar 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.

[0285] Deprotection can be carried out at temperatures ranging from approximately 12°C to approximately 40°C. Preferably, the reaction is carried out at approximately 20°C.

[0286] Deprotection can be carried out over a period of approximately 30 minutes to approximately 5 hours. Preferably, the reaction is carried out over a period of approximately 2 hours.

[0287] Intermediates aa-ar, ab1-ad1, and aa2-ad2 are reacted with a carboxylic acid having the general formula R-COOH (wherein R is selected from the group consisting of 5-membered or 6-membered aromatic or heteroaromatic groups, and the aromatic or heteroaromatic group is unsubstituted or substituted with one or more substituents) to form compounds 1 to 103 disclosed herein. Preferably, R in the compound of formula I includes a 5-membered heteroaromatic group which is an unsubstituted pyrazole, unsubstituted oxazole, unsubstituted thiazole, unsubstituted imidazole, substituted pyrazole, substituted oxazole, substituted thiazole, substituted imidazole or derivative thereof; a 6-membered aromatic group which is an unsubstituted aryl or substituted aryl or derivative thereof; or a 6-membered heteroaromatic group which is an unsubstituted pyridine, unsubstituted pyrimidine, unsubstituted pyridazine, unsubstituted pyrazine, substituted pyridine, substituted pyrimidine, substituted pyridazine, substituted pyrazine or derivative thereof. In some examples, at least one hydrogen of R is replaced by deuterium.

[0288] The carboxylic acid R-COOH is preferably 4-(4-chlorophenyl)-1-methylpyrazole-3-carboxylic acid (CAS 1534651-22-3), 5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoic acid (CAS 956317-36-5), 3-fluoro-2-(pyrimidine-2-yl)benzoic acid (CAS 1293285-04-7), 4-(5-chloropyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (CAS 2125741-28-6), 4-(5-chloropyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (CAS 2125741-28-6), 4-(5-chlorophenyl) Luoropyrimidine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (CAS 2125741-56-0), 5-methyl-2-(pyrimidine-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-fluoropyrimidine-2-yl)-1-methyl Tyl-1H-pyrazole-3-carboxylic acid (CAS 2044704-99-4), 1-methyl-4-(pyrimidine-2-yl)-1H-pyrazole-3-carboxylic acid (CAS 2125740-38-5), 4-(5-methoxypyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (CAS 2024759-24-6), 4-(5-fluoropyridine-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-cyanopyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid, 5-(5-fluoropyrimidine-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid, 5-(5-methoxypyridine-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid, 4-(5-fluoropyridine-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-(pyrimidine-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-triazole-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-methoxypyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid, or 6-methyl-3-(pyrimidine-2-yl)picolinic acid (CAS 1228188-18-8), 5-fluoro-3-(pyrimidine-2-yl)picolinic acid (CAS 1935682-37-3), 3-(5-fluoropyrimidine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid, 5,6-dimethyl -3-(pyrimidine-2-yl)picolinic acid, 4,6-dimethyl-3-(pyrimidine-2-yl)picolinic acid, 4-chloro-6-methyl-3-(pyrimidine-2-yl)picolinic acid, 4-(5-fluoropyrimidine-2-yl)-1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyrimidine-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyridine-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid Rubonic acid, 6-(methyl-d3)-3-(pyrimidine-2-yl)picolinic acid, 6-(methyl-d3)-3-(2H-1,2,3-triazole-2-yl)picolinate, 1-methyl-4-(pyridine-2-yl)-1H-pyrazole-3-carboxylic acid (CAS 1540679-95-5), 2-(2H-1,2,3-triazole-2-yl)benzoic acid (CAS 1001401-62-2); 1,5-dimethyl-4-(pyrazine-2-yl)-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyridine-3-yl)-1,This includes 5-dimethyl-1H-pyrazole-carboxylic acid; 4-(4-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid, 4-(4-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid, and 4-(5-fluoropyrimidine-2-yl)-1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylic acid.

[0289] The carboxylic acid R-COOH described herein may be deuterated, in which at least one hydrogen atom is replaced by deuterium, preferably the carboxylic acid 4-(5-fluoropyrimidine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid and 4-(5-fluoropyridine-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 acid R-COOH acid is deuterated. More preferably, the N-Me or C-Me group of the pyrazole ring of the carboxylic acid 4-(5-fluoropyrimidine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid and 4-(5-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid is deuterated.

[0290] The deuterated carboxylic acid R-COOH preferably includes 4-(5-fluoropyrimidine-2-yl)-1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyrimidine-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyridine-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid, 6-(methyl-d3)-3-(pyrimidine-2-yl)picolinic acid, or 6-(methyl-d3)-3-(2H-1,2,3-triazole-2-yl)picolinate salt.

[0291] The reaction between intermediates aa-ar, ab1-ad1, and aa2-ad2 and 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.

[0292] The reaction between intermediates aa-ar, ab1-ad1, and aa2-ad2 and the carboxylic acid R-COOH can be carried out in the presence of a base. Any suitable base can be used in this reaction. Examples of suitable bases include, but are not limited to, DIPEA or TEA. Preferably, DIPEA is used as the base in the reaction.

[0293] The reaction between intermediates aa-ar, ab1-ad1, and aa2-ad2 and the carboxylic acid R-COOH can be carried out in a polar aprotic solvent such as THF, dichloromethane, ethyl acetate, DMF, or DMSO. Preferably, the reaction is carried out in dichloromethane.

[0294] The reaction between intermediates aa-ar, ab1-ad1, and aa2-ad2 and carboxylic acid R-COOH can be carried out at temperatures ranging from about -10°C to about 40°C. Preferably, the reaction is carried out at about 0°C to about 20°C.

[0295] The reaction between intermediates aa-ar, ab1-ad1, and aa2-ad2 and carboxylic acid R-COOH can take place over a period of approximately 1 to 6 hours. Preferably, the reaction takes place over a period of approximately 2.5 hours.

[0296] The present invention also provides a method for synthesizing carboxylic acids having the general formula R-COOH, as shown in the following synthetic route: [ka] Preferably, R-COOH is 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid.

[0297] An intermediate can be formed by reacting a 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 with (4-cyanophenyl)boronic acid or its derivatives (e.g., boronic acid esters or organic trifluoroborates) via Suzuki coupling.

[0298] Alternatively, a 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 a 4-cyanophenyl derivative suitable for Hiyama coupling, Still coupling, Heck coupling, Kumada coupling, or Negishi coupling.

[0299] (4-cyanophenyl)boronic acid or its derivatives may be used in excess of the starting material. A 1.1 to 1.5 times excess of (4-cyanophenyl)boronic acid or its derivatives relative to the starting material may be used. Preferably, a 1.2 times excess of (4-cyanophenyl)boronic acid or its derivatives relative to the starting material is used.

[0300] The reaction may be carried out in polar aprotic solvents such as THF, DMF, and DMSO; polar protic solvents such as water, methanol, ethanol, and isopropanol; nonpolar solvents such as chloroform and 1,4-dioxane; or any combination thereof. Preferably, the reaction is carried out in a combination of THF and water.

[0301] The reaction may be carried out in the presence of a catalyst. Preferably, the catalyst is a palladium compound. Examples of such palladium compounds include, but are not limited to, Pd(dtbpf)Cl2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2, or Pd(dppp)Cl2. More preferably, Pd(dtbpf)Cl2 is used as the catalyst.

[0302] Preferably, about 0.02 to about 0.5 equivalents of catalyst are used relative to the starting material. More preferably, about 0.05 equivalents of catalyst are used.

[0303] The reaction can be carried out in the presence of a base. Examples of bases that can be used include K2CO3 and KO. t Examples include, but are not limited to, Bu, Cs2CO3, K3PO4, NaOH, or NEt3. Preferably, K3PO4 is used.

[0304] The base may be used in excess of the starting material. A 2:6 to 6:1 excess of base may be used. Preferably, a 3:1 excess of base is used.

[0305] The reaction may be carried out at a temperature in the range of approximately 50°C to approximately 100°C. Preferably, the reaction is carried out at approximately 80°C. The reaction may be carried out for a period of approximately 30 minutes to approximately 5 hours. Preferably, the reaction is carried out for a period of approximately 2 hours.

[0306] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0307] The formed intermediate can be deprotected by reacting it with an acid. Examples of acids that can be used include, but are not limited to, hydrochloric acid, trifluoroacetic acid, or phosphoric acid. Hydrochloric acid is preferably used.

[0308] Deprotection can be carried out in a nonpolar 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.

[0309] Deprotection can be carried out at a temperature in the range of about 20°C to about 80°C. Preferably, the reaction is carried out at about 50°C. Deprotection can be carried out for a period of about 30 minutes to about 5 hours. Preferably, the reaction is carried out for a period of about 2 hours.

[0310] The present invention also provides an alternative method for synthesizing carboxylic acids having the general formula R-COOH, as shown in the following synthetic route: [ka]

[0311] Preferably, R-COOH is 4-(5-cyanopyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid.

[0312] An intermediate can be formed by reacting a starting material selected from 6-iodopyridine-3-carbonil, 6-bromopyridine-3-carbonil, or 6-chloropyridine-3-carbonil with (3-(tert-butoxycarbonyl)-1-methyl-1H-pyrazole-4-yl)boronic acid or its derivative (e.g., boronic acid ester or organic trifluoroborate) via Suzuki coupling.

[0313] Alternatively, the starting material can be reacted with a (3-(tert-butoxycarbonyl)-1-methyl-1H-pyrazole-4-yl) derivative suitable for Hiyama coupling, Still coupling, Heck coupling, Kumada coupling, or Negishi coupling.

[0314] A compound selected from 6-iodopyridine-3-carbonitride, 6-bromopyridine-3-carbonitride, or 6-chloropyridine-3-carbonitride may be used in excess of the starting material. A 1.1 to 1.5-fold excess of the compound may be used. Preferably, a 1.2-fold excess of the compound is used.

[0315] The reaction may be carried out in polar aprotic solvents such as THF, DMF, and DMSO; polar protic solvents such as water, methanol, ethanol, and isopropanol; nonpolar solvents such as chloroform and 1,4-dioxane; or any combination thereof. Preferably, the reaction is carried out in a combination of 1,4-dioxane and water.

[0316] The reaction may be carried out in the presence of a catalyst. Preferably, the catalyst is a palladium compound. Examples of such palladium compounds include, but are not limited to, Pd(dtbpf)Cl2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2, or Pd(dppp)Cl2. More preferably, Pd(dtbpf)Cl2 is used as the catalyst.

[0317] Preferably, about 0.02 to about 0.5 equivalents of catalyst are used relative to the starting material. Preferably, about 0.05 equivalents of catalyst are used.

[0318] The reaction can be carried out in the presence of a base. Examples of bases that can be used include K2CO3 and KO. t Examples include, but are not limited to, Bu, Cs2CO3, K3PO4, NaOH, or NEt3. Preferably, K3PO4 is used.

[0319] The base may be used in excess of the starting material. A 1.1 to 5 times excess of the base may be used relative to the starting material. Preferably, a 1.5 times excess of the base is used relative to the starting material.

[0320] The reaction may be carried out at a temperature in the range of approximately 50°C to approximately 100°C. Preferably, the reaction is carried out at approximately 80°C. The reaction may be carried out for a period of approximately 30 minutes to approximately 5 hours. Preferably, the reaction is carried out for a period of approximately 2 hours.

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

[0322] The formed intermediate can be deprotected by reacting it with an acid. Examples of acids that can be used include, but are not limited to, hydrochloric acid, trifluoroacetic acid, or phosphoric acid. Hydrochloric acid is preferably used.

[0323] Deprotection can be carried out in a nonpolar 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.

[0324] Deprotection can be carried out at a temperature in the range of about 10°C to about 50°C. Preferably, the reaction is carried out at about 20°C. Deprotection can be carried out for a period of about 6 hours to about 18 hours. Preferably, the reaction is carried out for a period of about 12 hours.

[0325] The present invention also provides another alternative method for synthesizing carboxylic acids having the general formula R-COOH, as shown in the following synthetic route: [ka]

[0326] Preferably, R-COOH is 5-(5-fluoropyrimidine-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid.

[0327] A starting material selected from methyl 5-bromo-1-methyl-1H-imidazole-4-carboxylate, methyl 5-iodo-1-methyl-1H-imidazole-4-carboxylate, or methyl 5-chloro-1-methyl-1H-imidazole-4-carboxylate can be converted to an organic stannane intermediate by reacting it with hexaalkyltin such as hexamethyltin or hexabutyltin.

[0328] Hexaalkylnistin may be used in excess of the starting material. A 1.2 to 5 times excess of hexaalkylnistin relative to the starting material may be used. Preferably, a 2 times excess of hexaalkylnistin relative to the starting material is used.

[0329] The reaction may be carried out in a nonpolar solvent such as chloroform, 1,4-dioxane, or toluene. Preferably, the reaction is carried out in toluene.

[0330] The reaction may be carried out in the presence of a catalyst. Preferably, the catalyst is a palladium compound. Examples of such palladium compounds include, but are not limited to, Pd(dtbpf)Cl2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2, or Pd(dppp)Cl2. More preferably, Pd(PPh3)4 is used as the catalyst.

[0331] Preferably, about 0.02 to about 0.8 equivalents of catalyst are used relative to the starting material. More preferably, about 0.1 equivalents of catalyst are used.

[0332] The reaction may take place at a temperature in the range of approximately 50°C to approximately 120°C. Preferably, the reaction takes place in the range of approximately 100°C to approximately 120°C. The reaction may take place over a period of approximately 3 minutes to approximately 10 hours. Preferably, the reaction takes place over a period of approximately 6 hours.

[0333] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0334] The organic stannane intermediate can be reacted via Still coupling with a compound selected from 2-bromo-5-fluoropyrimidine, 2-iodo-5-fluoropyrimidine, or 2-chloro-5-fluoropyrimidine to form a second intermediate.

[0335] Alternatively, a compound selected from 2-bromo-5-fluoropyrimidine, 2-iodo-5-fluoropyrimidine, or 2-chloro-5-fluoropyrimidine 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.

[0336] Compounds selected from 2-bromo-5-fluoropyrimidine, 2-iodo-5-fluoropyrimidine, or 2-chloro-5-fluoropyrimidine may be used in excess of the organic stannane intermediate. A 1.1 to 3-fold excess of the compound may be used. Preferably, a 1.5-fold excess of the compound is used.

[0337] The reaction may be carried out in a nonpolar solvent such as chloroform, 1,4-dioxane, xylene, or toluene. Preferably, the reaction is carried out in xylene.

[0338] The reaction may be carried out in the presence of a catalyst. Preferably, the catalyst is a palladium compound. Examples of such palladium compounds include, but are not limited to, Pd(dtbpf)Cl2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2, or Pd(dppp)Cl2. More preferably, Pd(PPh3)4 is used as the catalyst.

[0339] Preferably, about 0.02 to about 0.5 equivalents of catalyst are used relative to the organic stannane intermediate. Preferably, about 0.1 equivalents of catalyst are used.

[0340] The reaction may be carried out at a temperature in the range of approximately 50°C to approximately 140°C. Preferably, the reaction is carried out at approximately 120°C. The reaction may be carried out for a period of approximately 10 hours to approximately 22 hours. Preferably, the reaction is carried out for a period of 16 hours.

[0341] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0342] The second intermediate can be deprotected by reacting it 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. Hydrochloric acid is preferably used.

[0343] Deprotection can be carried out in a neat acid or base.

[0344] The concentration of the acid or base may be in the range of about 3 M to about 10 M. Preferably, a concentration of about 6 M is used.

[0345] Deprotection can be carried out at a temperature in the range of about 50°C to about 100°C. Preferably, the reaction is carried out at about 80°C. Deprotection can be carried out for a period of about 6 hours to about 22 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0346] The present invention also provides yet another alternative method for synthesizing carboxylic acids having the general formula R-COOH, as shown in the following synthetic route: [ka]

[0347] Preferably, R-COOH is 5-(5-methoxypyridine-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid.

[0348] An intermediate can be formed by reacting a starting material selected from methyl 5-bromo-1-methyl-1H-imidazole-4-carboxylate, methyl 5-chloro-1-methyl-1H-imidazole-4-carboxylate, or methyl 5-iodo-1-methyl-1H-imidazole-4-carboxylate with tributyl-(5-methoxy-2-pyridyl)stannane or its derivative (e.g., trimethyl-(5-methoxy-2-pyridyl)stannane) via Still coupling.

[0349] Alternatively, a starting material selected from methyl 5-bromo-1-methyl-1H-imidazole-4-carboxylate, methyl 5-chloro-1-methyl-1H-imidazole-4-carboxylate, or methyl 5-iodo-1-methyl-1H-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.

[0350] Tributyl-(5-methoxy-2-pyridyl) stannane or its derivatives may be used in excess of the starting material. A 1.1 to 1.5-fold excess of tributyl-(5-methoxy-2-pyridyl) stannane or its derivatives may be used relative to the starting material. Preferably, a 1.2-fold excess of tributyl-(5-methoxy-2-pyridyl) stannane or its derivatives relative to the starting material is used.

[0351] The reaction may be carried out in a nonpolar solvent such as chloroform, 1,4-dioxane, xylene, or toluene. Preferably, the reaction is carried out in xylene.

[0352] The reaction may be carried out in the presence of a catalyst. Preferably, the catalyst is a palladium compound. Examples of such palladium compounds include, but are not limited to, Pd(dtbpf)Cl2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2, or Pd(dppp)Cl2. More preferably, Pd(PPh3)4 is used as the catalyst.

[0353] Preferably, about 0.02 to about 0.5 equivalents of catalyst are used relative to the starting material. Preferably, about 0.1 equivalents of catalyst are used.

[0354] The reaction may be carried out at a temperature in the range of approximately 50°C to approximately 140°C. Preferably, the reaction is carried out at approximately 140°C. The reaction may be carried out for a period of approximately 10 hours to approximately 20 hours. Preferably, the reaction is carried out for a period of approximately 16 hours.

[0355] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0356] The intermediate can be deprotected by reacting it 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. Hydrochloric acid is preferably used.

[0357] Deprotection can be carried out in a neat acid or base.

[0358] The concentration of the acid or base may be in the range of about 3 M to about 10 M. Preferably, a concentration of about 6 M is used.

[0359] Deprotection can be carried out at a temperature in the range of about 50°C to about 100°C. Preferably, the reaction is carried out at about 80°C. Deprotection can be carried out for a period of about 6 hours to about 22 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0360] The present invention also provides yet another alternative method for synthesizing carboxylic acids having the general formula R-COOH, as shown in the following synthetic route (PG refers to the protecting group): [ka]

[0361] Preferably, R-COOH is 4-(5-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.

[0362] A starting material selected from 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid, 4-iodo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid, or 4-chloro-1,5-dimethyl-1H-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.

[0363] Suitable reagents for forming the first intermediate include, but are not limited to, BOC anhydrous, MeOH, benzyl alcohol, or 2-benzyloxy-1-methylpyridinium triflate. Preferably, BOC anhydrous is used.

[0364] The reagent may be used in excess of the first intermediate. A 1.5 to 5-fold excess of the reagent may be used relative to the first intermediate. Preferably, a 3-fold excess of the reagent relative to the first intermediate.

[0365] The reaction may be carried out in the presence of a catalyst such as DMAP, imidazole, or a mixture thereof. Preferably, imidazole is used as the catalyst.

[0366] The reaction may be carried out in polar aprotic solvents such as THF, DMF, and DMSO; polar protic solvents such as water, methanol, ethanol, isopropanol, and tert-butyl alcohol; nonpolar solvents such as chloroform and 1,4-dioxane; or any combination thereof. Preferably, the reaction is carried out in a combination of THF and tert-butyl alcohol.

[0367] The reaction may take place at a temperature in the range of approximately 10°C to approximately 50°C. Preferably, the reaction takes place at approximately 20°C. The reaction may take place over a period of approximately 6 to approximately 18 hours. Preferably, the reaction takes place over a period of approximately 12 hours.

[0368] The first intermediate can be converted to a boronic acid or its derivative (e.g., a boronic acid ester or an organic trifluoroborate) to form a second intermediate. The first intermediate can be reacted with a tri(alkyl)borate such as trimethylborate, tributylborate, or triisopropylborate to form a second intermediate.

[0369] Tri(alkyl)borate may be used in excess of the first intermediate. A 1.2 to 3-fold excess of tri(alkyl)borate may be used relative to the first intermediate. Preferably, a 1.5-fold excess of tri(alkyl)borate is used relative to the first intermediate.

[0370] The reaction may 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.

[0371] The reaction is carried out in the presence of a Lewis base. Examples of Lewis bases that may be used in the synthesis of the second intermediate include, but are not limited to, butyllithium, lithium diisopropylamide (LDA), lithium diethylamide (LDEA), sodium amide (NaNH2), sodium hydride (NaH), lithium bis(trimethylsilyl)amide, or mixtures thereof. Preferably, the Lewis base used in the synthesis of the second intermediate is butyllithium.

[0372] Lewis bases may be used in excess of the first intermediate. A 1.2 to 3 times excess of Lewis base may be used relative to the first intermediate. Preferably, a 1.5 times excess of Lewis base is used relative to the first intermediate.

[0373] The reaction may take place at a temperature in the range of approximately -78°C to approximately 60°C. Preferably, the reaction takes place at approximately -78°C to approximately 20°C. The reaction may take place over a period of approximately 1 hour to approximately 8 hours. Preferably, the reaction takes place over a period of approximately 3 hours.

[0374] The second intermediate can be reacted with 2-bromo-5-fluoropyrimidine / 2-iodo-5-fluoropyrimidine / 2-chloro-5-fluoropyrimidine via Suzuki coupling to form a third intermediate.

[0375] Alternatively, 2-bromo-5-fluoropyrimidine / 2-iodo-5-fluoropyrimidine / 2-chloro-5-fluoropyrimidine can be reacted with a (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazole-4-yl) derivative suitable for Hiyama coupling, Still coupling, Heck coupling, Kumada coupling, or Negishi coupling.

[0376] 2-bromo-5-fluoropyrimidine / 2-iodo-5-fluoropyrimidine / 2-chloro-5-fluoropyrimidine may be used in excess of the second intermediate. 1.1 to 3 times excess of 2-bromo-5-fluoropyrimidine, 2-iodo-5-fluoropyrimidine, or 2-chloro-5-fluoropyrimidine may be used for the second intermediate. Preferably, 1.5 times excess of 2-bromo-5-fluoropyrimidine, 2-iodo-5-fluoropyrimidine, or 2-chloro-5-fluoropyrimidine is used for the second intermediate.

[0377] The reaction may 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-butyl alcohol, or any combination thereof. Preferably, the reaction is carried out in a combination of DMF and water.

[0378] The reaction may be carried out in the presence of a catalyst. Preferably, the catalyst is a palladium compound. Examples of such palladium compounds include, but are not limited to, Pd(dtbpf)Cl2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2, or Pd(dppp)Cl2. More preferably, Pd(PPh3)4 is used as the catalyst.

[0379] Preferably, about 0.02 to about 0.5 equivalents of catalyst are used for the second intermediate. Preferably, about 0.05 equivalents of catalyst are used.

[0380] The reaction can be carried out in the presence of a base. Examples of bases that can be used include K2CO3 and KO. t Examples include, but are not limited to, Bu, Cs2CO3, K3PO4, NaOH, or NEt3. Preferably, K2CO3 is used.

[0381] The base may be used in excess of the second intermediate. A 1.1 to 3 times excess of the base may be used for the second intermediate. Preferably, a 1.5 times excess of the base is used for the second intermediate.

[0382] The reaction may be carried out at a temperature in the range of approximately 50°C to approximately 153°C. Preferably, the reaction is carried out at approximately 80°C. The reaction may be carried out for a period of approximately 8 hours to approximately 20 hours. Preferably, the reaction is carried out for a period of approximately 12 hours.

[0383] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere.

[0384] The formed third intermediate can be deprotected by reacting it with an acid. Examples of acids that can be used include, but are not limited to, hydrochloric acid, trifluoroacetic acid, or phosphoric acid. Hydrochloric acid is preferably used.

[0385] Deprotection can be carried out in a nonpolar 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.

[0386] Deprotection can be carried out at a temperature in the range of about 20°C to about 80°C. Preferably, the reaction is carried out at about 20°C. Deprotection can be carried out for a period of about 8 hours to about 20 hours. Preferably, the reaction is carried out for a period of about 12 hours.

[0387] The present invention also provides another method for synthesizing carboxylic acids having the general formula R-COOH, as shown in the following synthetic route: [ka]

[0388] Preferably, R-COOH is 4-(5-methoxypyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.

[0389] An intermediate can be formed by reacting a starting material selected from 2-bromo-5-methoxypyridine, 2-iodo-5-methoxypyridine, or 2-chloro-5-methoxypyridine with 3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazole-4-yl)boronic acid or its derivatives (e.g., boronic acid esters or organic trifluoroborates) via Suzuki coupling.

[0390] Alternatively, the starting material can be reacted with a 3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazole-4-yl derivative suitable for Hiyama coupling, Still coupling, Heck coupling, Kumada coupling, or Negishi coupling.

[0391] The reaction may be carried out in polar aprotic solvents such as THF, DMF, and DMSO; polar protic solvents such as water, methanol, ethanol, and isopropanol; nonpolar solvents such as chloroform and 1,4-dioxane; or any combination thereof. Preferably, the reaction is carried out in a combination of DMF and water.

[0392] The reaction may be carried out in the presence of a catalyst. Preferably, the catalyst is a palladium compound. Examples of such palladium compounds include, but are not limited to, Pd(dtbpf)Cl2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dppf)Cl2, or Pd(dppp)Cl2. More preferably, Pd(PPh3)4 is used as the catalyst.

[0393] Preferably, about 0.02 to about 0.5 equivalents of catalyst are used relative to the starting material. Preferably, about 0.05 equivalents of catalyst are used.

[0394] The reaction can be carried out in the presence of a base. Examples of bases that can be used include K2CO3 and KO. t Examples include, but are not limited to, Bu, Cs2CO3, K3PO4, NaOH, or NEt3. Preferably, K2CO3 is used.

[0395] The base may be used in excess of the starting material. A 1.1 to 5 times excess of the base may be used relative to the starting material. Preferably, a 1.5 times excess of the base is used relative to the starting material.

[0396] The reaction may take place at a temperature in the range of approximately 50°C to approximately 100°C. Preferably, the reaction takes place at approximately 80°C. The reaction may take place over a period of approximately 6 hours to approximately 18 hours. Preferably, the reaction takes place over a period of approximately 12 hours.

[0397] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0398] The formed intermediate can be deprotected by reacting it with an acid. Examples of acids that can be used include, but are not limited to, hydrochloric acid, trifluoroacetic acid, or phosphoric acid. Hydrochloric acid is preferably used.

[0399] Deprotection can be carried out in a nonpolar 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.

[0400] Deprotection can be carried out at a temperature in the range of about 10°C to about 50°C. Preferably, the reaction is carried out at about 20°C. Deprotection can be carried out for a period of about 6 hours to about 18 hours. Preferably, the reaction is carried out for a period of about 12 hours.

[0401] The present invention also provides a method for preparing 3-(5-fluoropyrimidine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid: [ka]

[0402] Bromine can be added to a solvent solution of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid. Examples of solvents include, but are not limited to, THF, dichloromethane, ethyl acetate, DMF, DMSO, or mixtures thereof. Preferably, the reaction is carried out in dichloromethane. The reaction may be carried out at a temperature in the range of about -10°C to about 10°C. Preferably, the reaction is carried out at about 0°C. The reaction may be carried out for a period of about 30 minutes to about 4 hours. Preferably, the reaction may be carried out for a period of about 2 hours.

[0403] The reaction mixture can be quenched by adding a saturated sodium thiosulfate aqueous solution to obtain 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid.

[0404] 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid can be reacted with 2-tert-butyl-3-isopropyl-1,1-dimethyl-isourea in a solvent. Examples of solvents include, but are not limited to, THF, DMF, DMSO, or mixtures thereof. Preferably, the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about -10°C to about 40°C. Preferably, the reaction is carried out at a temperature in the range of about 0°C to about 20°C. The reaction may be carried out for a period of about 10 hours to about 20 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0405] The reaction mixture can be quenched by adding an aqueous saturated ammonium chloride solution to obtain tert-butyl3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate.

[0406] Tert-butyl 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate can be reacted with triisopropyl borate in a solvent. Examples of solvents include, but are not limited to, THF, DMF, DMSO, or mixtures thereof. Preferably, the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about -10°C to about 40°C. Preferably, the reaction is carried out at a temperature in the range of about 0°C to about 20°C. Then, n-BuLi can be added. The reaction may be carried out at a temperature in the range of about -100°C to about -50°C. Preferably, the reaction is carried out at about -78°C. The reaction may be carried out for a period of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a period of about 2 hours.

[0407] Next, the reaction mixture is quenched by adding a saturated ammonium chloride aqueous solution as described above to obtain (2-(tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)boronic acid.

[0408] (2-(tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)boronic acid can be added to 2-bromo-5-fluoropyrimidine 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 may be carried out in a solvent such as THF, DMF, DMSO, water, or a mixture thereof. Preferably, the solvents are DMF and water. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C.

[0409] Tetrakis(triphenylphosphine)palladium(0)(Pd(PPh3)4) can be added to obtain tert-butyl3-(5-fluoropyrimidine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere. The reaction may be carried out at a temperature in the range of about 50°C to about 150°C. Preferably, the reaction is carried out at about 80°C. The reaction may be carried out for a period of about 10 hours to about 16 hours. Preferably, the reaction is carried out for a period of about 12 hours.

[0410] 3-(5-fluoropyrimidine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate can be treated with an acid to produce 3-(5-fluoropyrimidine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-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. Hydrochloric acid is preferably used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane, or mixtures thereof. Dioxane is preferably the solvent. The reaction may be carried out at a temperature in the range of about 10°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of about 1 hour to about 4 hours. Preferably, the reaction is carried out for a period of about 2 hours.

[0411] The present invention also provides a method for preparing 5,6-dimethyl-3-(pyrimidine-2-yl)picolinic acid: [ka]

[0412] 3-Bromo-5,6-dimethylpyridine-2-amine can be added to tributyl(pyrimidine-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.

[0413] Copper iodide and palladium triphenylphosphine can be added to the mixture. The reaction may be carried out at a temperature in the range of about 70°C to about 130°C. Preferably, the reaction is carried out at about 100°C. The reaction may be carried out for a period of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0414] The residue can be purified to obtain 5,6-dimethyl-3-(pyrimidine-2-yl)pyridine-2-amine. Preferably, the residue is purified by silica gel column chromatography.

[0415] 5,6-dimethyl-3-(pyrimidine-2-yl)pyridine-2-amine can be added to an acid or a combination of acids. Examples of acids may be sulfuric acid, acetic acid, phosphoric acid, hydrochloric acid, trifluoroacetic acid, or mixtures thereof. Preferably, the acids are sulfuric acid and acetic acid. By adding an aqueous solution of sodium nitrite, 5,6-dimethyl-3-(pyrimidine-2-yl)pyridine-2-ol can be obtained. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a period of about 2 hours.

[0416] 5,6-dimethyl-3-(pyrimidine-2-yl)pyridine-2-ol can be added to trifluoromethylsulfonyl trifluoromethanesulfonate in the presence of a solvent and a base to obtain the residue 5,6-dimethyl-3-(pyrimidine-2-yl)pyridine-2-yltrifluoromethanesulfonate. Examples of solvents that can be used include, but are not limited to, THF, dichloromethane, ethyl acetate, DMF, or DMSO, or mixtures thereof. Preferably, the solvent is dichloromethane. Examples of bases that 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 DIPEA. The reaction can be carried out at a temperature in the range of about 0°C to about 60°C. Preferably, the reaction is carried out at about 30°C. The reaction can be carried out for a period of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0417] Methyl 5,6-dimethyl-3-(pyrimidine-2-yl)picolinate can be obtained by adding bis(diphenylphosphin)ferrocene)palladium(II) dichloride (Pd(dppf)Cl2) to 5,6-dimethyl-3-(pyrimidine-2-yl)pyridine-2-yltrifluoromethanesulfonate in the presence of a solvent and a base. 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 may be carried out at a temperature in the range of about 50°C to about 100°C. Preferably, the reaction is carried out at about 70°C. The reaction may be carried out for a period of about 13 hours to about 19 hours. Preferably, the reaction is carried out over a period of about 16 hours. The reaction may be carried out at a pressure of 50 psi in the presence of carbon monoxide.

[0418] Lithium hydroxide monohydrate can be added to methyl 5,6-dimethyl-3-(pyrimidine-2-yl)picolinate in the presence of one or more solvents. Examples of solvents include, but are not limited to, THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, dioxane, or mixtures thereof. Preferably, the solvents are methanol and THF. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of about 1 hour to about 5 hours. Preferably, the reaction is carried out for a period of about 3 hours.

[0419] The present invention also provides a method for preparing 4,6-dimethyl-3-(pyrimidine-2-yl)picolinic acid: [ka]

[0420] 5-Bromo-2,4-dimethylpyridine can be reacted with a mixture of tributyl(pyrimidine-2-yl) stannane, cesium fluoride, copper iodo, and tetrakis(triphenylphosphine)palladium(O)(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 may be carried out at a temperature in the range of about 70°C to about 130°C. Preferably, the reaction is carried out at about 100°C. The reaction may be carried out for a period of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0421] The crude product can be purified to obtain 2-(4,6-dimethylpyridine-3-yl)pyrimidine. Preferably, the purification is carried out by silica gel column chromatography.

[0422] Meta-chloroperbenzoic acid is added to a solution of 2-(4,6-dimethylpyridine-3-yl)pyrimidine in the presence of a solvent. Examples of solvents include, but are not limited to, THF, dichloromethane, ethyl acetate, DMF, DMSO, or mixtures thereof. Preferably, the reaction is carried out in dichloromethane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a period of about 2 hours.

[0423] The reaction mixture can be quenched by the addition of sodium sulfite to obtain 2,4-dimethyl-5-(pyrimidine-2-yl)pyridine 1-oxide.

[0424] Trimethylsilyl cyanide can be added to 2,4-dimethyl-5-(pyrimidine-2-yl)pyridine 1-oxide in a solvent. Examples of solvents include, but are not limited to, THF, dichloromethane, ethyl acetate, DMF, DMSO, or mixtures thereof. Preferably, the solvent is dichloromethane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of about 30 minutes to about 3 hours. Preferably, the reaction is carried out for a period of about 1 hour. N,N-dimethylcarbamoyl chloride can then be added. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of 13 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0425] 4,6-dimethyl-3-(pyrimidine-2-yl)picolinic acid can be obtained by adding sodium hydroxide to 4,6-dimethyl-3-(pyrimidine-2-yl)picolinonitrile in the presence of one or more solvents. Examples of solvents include, but are not limited to, THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, dioxane, or mixtures thereof. Preferably, the solvents are methanol and water. The reaction may be carried out at a temperature in the range of about 30°C to about 90°C. Preferably, the reaction is carried out at about 60°C. The reaction may be carried out for a period of 36 hours to about 60 hours. Preferably, the reaction is carried out for a period of about 48 hours.

[0426] The present invention also provides a method for preparing 4-chloro-6-methyl-3-(pyrimidine-2-yl)picolinic acid: [ka]

[0427] Acids and solvents 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 mixtures thereof. Preferably, the acids are sulfuric acid and acetic acid. Examples of solvents include, but are not limited to, THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, 1,4-dioxane, or mixtures thereof. Preferably, the solvent is methanol. The reaction may be carried out at a temperature in the range of about 40°C to about 100°C. Preferably, the reaction is carried out at about 70°C. The reaction may be carried out for a period of 13 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0428] Methyl 3-bromo-6-methyl picolinate can be added to tributyl(pyrimidine-2-yl) stannane, cesium fluoride, copper iodo, or palladium triphenylphosphine 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 solvent is dioxane. The reaction may be carried out at a temperature in the range of about 60°C to about 140°C. Preferably, the reaction is carried out at about 100°C. The reaction may be carried out for a period of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0429] 3-Chlorobenzenecarboperoxoic acid can be added to methyl 6-methyl-3-(pyrimidine-2-yl)picolinate in a solvent. Examples of solvents include, but are not limited to, THF, dichloromethane, ethyl acetate, DMF, DMSO, or mixtures thereof. Preferably, the reaction is carried out in dichloromethane. The reaction may be carried out at a temperature in the range of about -20°C to about 50°C. Preferably, the reaction is carried out at a temperature in the range of about 0°C to about 30°C. The reaction may be carried out for a period of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0430] The reaction mixture can be quenched by adding a saturated sodium sulfite solution.

[0431] By adding phosphoryl chloride to 2-(methoxycarbonyl)-6-methyl-3-(pyrimidine-2-yl)pyridine 1-oxide, methyl 4-chloro-6-methyl-3-(pyrimidine-2-yl)picolinate can be formed. The reaction may be carried out at a temperature in the range of about 90°C to about 150°C. Preferably, the reaction is carried out at about 120°C. The reaction may be carried out for a period of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a period of about 2 hours.

[0432] Lithium hydroxide monohydrate can be added to methyl 4-chloro-6-methyl-3-(pyrimidine-2-yl)picolinate in the presence of one or more solvents. Examples of solvents include, but are not limited to, THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, 1,4-dioxane, or mixtures thereof. Preferably, the solvents are methanol and THF. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0433] The present invention also provides a method for preparing 4-(5-fluoropyrimidine-2-yl)-1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylic acid: [ka]

[0434] 5-Bromo-1-methyl-1H-pyrazole-3-carboxylic acid (5 g, 24.39 mmol, 1 equivalent) can be added to di-tert-butyl dicarbonate, tert-butyl alcohol, and 4-dimethylaminopyridine in the presence of a solvent. Examples of solvents include, but are not limited to, water, acetonitrile, DMF, DMSO, pyridine, THF, or mixtures thereof. Preferably, the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about 00°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a period of about 12 hours.

[0435] Tert-butyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate can be reacted with n-BuLi and triduterio(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 may be carried out at a temperature in the range of about -10°C to about 40°C. Preferably, the reaction is carried out at a temperature in the range of about 0°C to about 20°C. Then, n-BuLi can be added. The reaction may be carried out at a temperature in the range of about -100°C to about -50°C. Preferably, the reaction is carried out at about -78°C. The reaction may be carried out for a period of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a period of about 3 hours.

[0436] The reaction mixture can be quenched by adding a saturated ammonium chloride solution.

[0437] N-bromosuccinimide can be added to a solvent solution of tert-butyl 1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylate. Examples of solvents include, but are not limited to, THF, DMF, DMSO, or mixtures thereof. Preferably, the reaction is carried out in DMF. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a period of about 12 hours.

[0438] Isopropyl magnesium chloride lithium chloride can be added to tert-butyl 4-bromo-1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylate in a solvent. Examples of solvents include, but are not limited to, THF, DMF, DMSO, or mixtures thereof. Preferably, the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about -80°C to about -20°C. Preferably, the reaction is carried out at about -50°C. The reaction may be carried out for a period of about 30 minutes to about 2 hours. Preferably, the reaction is carried out for a period of about 1 hour. Triisopropyl borate can then be added to the reaction mixture. The reaction may be carried out at a temperature in the range of about -80°C to about -20°C. Preferably, the reaction is carried out at about -50°C. The reaction may be carried out for a period of about 1 hour to about 5 hours. Preferably, the reaction is carried out for a period of about 3 hours.

[0439] 2-bromo-5-fluoropyrimidine and potassium carbonate can be added to (3-(tert-butoxycarbonyl)-1-methyl-5-(methyl-d3)-1H-pyrazole-4-yl)boronic acid in a solvent. Examples of solvents include, but are not limited to, water, THF, DMF, DMSO, or mixtures thereof. Preferably, the reaction is carried out in THF and water. Tetrakis(triphenylphosphine)palladium(0)(Pd(PPh3)4) can then be added. The reaction may be carried out at a temperature in the range of about 60°C to about 120°C. Preferably, the reaction is carried out at about 90°C. The reaction may be carried out for a period of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a period of about 12 hours.

[0440] 4-(5-fluoropyrimidine-2-yl)-1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylate can be treated with an acid to produce 4-(5-fluoropyrimidine-2-yl)-1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylic acid. Examples of acids include, but are not limited to, aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid, or mixtures thereof. Hydrochloric acid is preferably used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane, or mixtures thereof. Preferably, the reaction is carried out in dioxane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of about 5 hours to about 11 hours. Preferably, the reaction is carried out for a period of about 8 hours.

[0441] The present invention also provides a method for preparing 4-(5-fluoropyrimidine-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid: [ka]

[0442] Sodium hydride can be added to ethyl 4-bromo-5-methyl-1H-pyrazole-3-carboxylate in a solvent. Examples of solvents include, but are not limited to, water, acetonitrile, DMF, DMSO, pyridine, THF, or mixtures thereof. Preferably, the solvent is THF. The reaction may be carried out at a temperature in the range of about -20°C to about 20°C. Preferably, the reaction is carried out at about 0°C. The reaction may be carried out for a period of about 15 minutes to about 1 hour. Preferably, the reaction is carried out for a period of about 30 minutes.

[0443] Triduterio(iodo)methane can be added to the mixture. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of about 2 hours to about 4 hours. Preferably, the reaction is carried out for a period of about 3.5 hours.

[0444] The mixture can be quenched with a saturated ammonium chloride solution. The product can be purified to obtain ethyl 4-bromo-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate. Preferably, the product is purified by silica gel column chromatography.

[0445] Lithium hydroxide monohydrate can be added to ethyl 4-bromo-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate in the presence of one or more solvents to obtain 4-bromo-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid. Examples of solvents include, but are not limited to, THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, dioxane, or mixtures thereof. Preferably, the solvents are methanol and water. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of about 1 hour to about 3 hours. Preferably, the reaction is carried out for a period of about 2 hours.

[0446] 2-tert-butyl-1,3-diisopropyl-isourea can be added to 4-bromo-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid in the presence of a solvent to obtain tert-butyl 4-bromo-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate. Examples of solvents include, but are not limited to, THF, dichloromethane, ethyl acetate, DMF, DMSO, or combinations thereof. Preferably, the reaction is carried out in dichloromethane. The reaction may be carried out at a temperature in the range of about 20°C to about 80°C. Preferably, the reaction is carried out at about 50°C. The reaction may be carried out for a period of 13 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0447] Triisopropyl borate can be added to tert-butyl 4-bromo-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate in the presence of a solvent. Examples of solvents include, but are not limited to, THF, DMF, DMSO, or mixtures thereof. Preferably, the solvent is THF.

[0448] Next, n-BuLi is added to obtain (3-(tert-butoxycarbonyl)-5-methyl-1-(methyl-d3)-1H-pyrazole-4-yl)boronic acid. The reaction may be carried out at a temperature in the range of about -100°C to about -50°C. Preferably, the reaction is carried out at about -78°C. The reaction may be carried out for a period of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a period of about 2 hours. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0449] The reaction mixture can be quenched by adding a saturated ammonium chloride solution to obtain (3-(tert-butoxycarbonyl)-5-methyl-1-(methyl-d3)-1H-pyrazole-4-yl)boronic acid.

[0450] 2-bromo-5-fluoropyrimidine and potassium carbonate can be added to 3-(tert-butoxycarbonyl)-5-methyl-1-(methyl-d3)-1H-pyrazole-4-yl)boronic acid in the presence of one or more solvents. Examples of solvents include, but are not limited to, water, THF, DMF, DMSO, or mixtures thereof. Preferably, the solvents are DMF and water. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere.

[0451] Next, tetrakis(triphenylphosphine)palladium(0)(Pd(PPh3)4) can be added. The reaction may be carried out at a temperature in the range of about 40°C to about 120°C. Preferably, the reaction is carried out at about 80°C. The reaction may be carried out for a period of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a period of about 12 hours. The mixture was stirred at 80°C for 12 hours.

[0452] The product can be purified to obtain tert-butyl 4-(5-fluoropyrimidine-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate. Preferably, the product is purified by silica gel column chromatography.

[0453] 4-(5-fluoropyrimidine-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate can be treated with an acid to produce 4-(5-fluoropyrimidine-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 mixtures thereof. Hydrochloric acid is preferably used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane, or mixtures thereof. Preferably, the reaction is carried out in dioxane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0454] The present invention also provides a method for preparing 4-(5-fluoropyridine-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid. [ka]

[0455] 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-pyrazole-4-yl)boronic acid in the presence of one or more solvents. Examples of solvents include, but are not limited to, water, acetonitrile, DMF, DMSO, pyridine, THF, or mixtures thereof. Preferably, the reaction is carried out in DMF and water. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere. The reaction may be carried out at a temperature in the range of about 50°C to about 150°C. Preferably, the reaction is carried out at about 80°C. The reaction may be carried out for a period of about 10 hours to about 16 hours. Preferably, the reaction is carried out for a period of about 12 hours.

[0456] The product can be purified to obtain tert-butyl 4-(5-fluoropyridine-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate. Preferably, the product is purified by silica gel column chromatography.

[0457] 4-(5-fluoropyridine-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate can be treated with an acid to produce 4-(5-fluoropyridine-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 mixtures thereof. Hydrochloric acid is preferably used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane, or mixtures thereof. Preferably, the reaction is carried out in dioxane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0458] The present invention also provides a method for preparing 6-(methyl-d3)-3-(pyrimidine-2-yl)picolinic acid. [ka]

[0459] Tributyl(pyrimidine-2-yl) stannane can be reacted with a mixture of methyl 6-amino-3-bromopicolinate, cesium fluoride, copper iodo, and tetrakis(triphenylphosphine)palladium(0)(Pd(PPh3)4) in the presence of a solvent. Examples of solvents include, but are not limited to, THF, dichloromethane, ethyl acetate, DMF, DMSO, or combinations thereof. Preferably, the reaction is carried out in dichloromethane. The reaction may be carried out under nitrogen. The reaction may be carried out at a temperature in the range of about 80°C to about 140°C. Preferably, the reaction is carried out at about 110°C. The reaction may be carried out for a period of 9 hours to about 15 hours. Preferably, the reaction is carried out for a period of about 12 hours.

[0460] The residue can be quenched with an aqueous potassium fluoride solution to obtain methyl 6-amino-3-(pyrimidine-2-yl)picolinate.

[0461] Tert-butyl nitrite and copper bromide can be added to methyl 6-amino-3-(pyrimidine-2-yl)picolinate in the presence of a solvent. Examples of solvents include, but are not limited to, acetonitrile, DMF, DMSO, pyridine, THF, or mixtures thereof. Preferably, the reaction is carried out in acetonitrile. The reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a period of 9 hours to about 15 hours. Preferably, the reaction is carried out for a period of about 12 hours.

[0462] Triduterio(duteriooxy)methane is added to 5,7-ditert-butyl-3-phenyl-1,3-benzoxazole-3-iumtetrafluoroborate in methyl tert-butyl ether. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere. The reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction is carried out at about 25°C.

[0463] Pyridine can be added to the mixture under an argon atmosphere. The reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a period of about 15 minutes to about 1 hour. Preferably, the reaction is carried out for a period of about 30 minutes.

[0464] Bis[2-(2-pyridyl)phenyl]iridium(1+)4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridinehexafluorophosphate, 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridinedibromonickel, and quinuclidine can be added to the mixture. Then, methyl 6-bromo-3-(pyrimidine-2-yl)picolinate can be added to the mixture in dimethylacetamide under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere. The reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a period of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a period of about 2 hours.

[0465] Next, methyl 6-(methyl-d3)-3-(pyrimidine-2-yl)picolinate can be added to the acid and water. Examples of acids include, but are not limited to, aqueous phosphoric acid, hydrochloric acid, and trifluoroacetic acid. Hydrochloric acid is preferably used. The reaction may be carried out at a temperature in the range of about 40°C to about 120°C. Preferably, the reaction is carried out at about 80°C. The reaction may be carried out for a period of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a period of about 12 hours.

[0466] The present invention also provides a method for preparing 6-(methyl-d3)-3-(2H-1,2,3-triazol-2-yl)picolinate. [ka]

[0467] 2H-triazole, cesium carbonate, N1,N2-dimethylcyclohexane-1,2-diamine, and copper iodo can be added to a solvent solution of 3-bromo-6-chloropicolinic acid. Examples of solvents include, but are not limited to, diethyl ether, benzene, toluene, chloroform, dioxane, methanol, or mixtures thereof. Preferably, the solvents are dioxane and water. The reaction may be carried out at a temperature in the range of about 80°C to about 120°C. Preferably, the reaction is carried out at about 100°C. The reaction may be carried out for a period of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a period of about 12 hours.

[0468] 2-tert-butyl-1,3-diisopropyl-isourea can be added to 6-chloro-3-(2H-1,2,3-triazole-2-yl)picolinic acid in the presence of a solvent. Examples of solvents include, but are not limited to, acetonitrile, DMF, DMSO, pyridine, THF, or mixtures thereof. Preferably, the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a period of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a period of about 12 hours.

[0469] Methyl 5,6-dimethyl-3-(pyrimidine-2-yl)picolinate can be obtained by adding bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)Cl2), tripotassium phosphate, and tert-butyl 6-chloro-3-(2H-1,2,3-triazole-2-yl)picolinate to (methyl-d3)boronic acid in the presence of a solvent. Examples of solvents include, but are not limited to, water, acetonitrile, DMF, DMSO, pyridine, THF, or mixtures thereof. Preferably, the reaction is carried out in THF and water. The reaction may be carried out at a temperature in the range of about 40°C to about 120°C. Preferably, the reaction is carried out at about 80°C. The reaction may be carried out for a period of about 2 hours to about 6 hours. Preferably, the reaction is carried out for a period of about 4 hours.

[0470] Tert-butyl 6-(methyl-d3)-3-(2H-1,2,3-triazole-2-yl)picolinate is treated with an acid in the presence of a solvent to produce 6-(methyl-d3)-3-(2H-1,2,3-triazole-2-yl)picolinate. Examples of acids include, but are not limited to, aqueous phosphoric acid, hydrochloric acid, and trifluoroacetic acid. Hydrochloric acid is preferably 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 may be carried out at a temperature in the range of about 30°C to about 90°C. Preferably, the reaction is carried out at about 60°C. The reaction may be carried out for a period of about 1 hour to about 4 hours. Preferably, the reaction is carried out for a period of about 2 hours.

[0471] The present invention also provides a method for preparing 1,5-dimethyl-4-(pyrazine-2-yl)-1H-pyrazole-3-carboxylic acid. [ka]

[0472] 2-chloropyrazine, a base, and a solvent can be added to (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazole-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 may be carried out in a solvent such as THF, DMF, DMSO, water, or a mixture thereof. Preferably, the solvents are DMF and water.

[0473] Tetrakis(triphenylphosphine)palladium(O)(Pd(PPh3)4) can be added to the reaction mixture. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere. The reaction may be carried out at a temperature in the range of about 50°C to about 150°C. Preferably, the reaction is carried out at about 80°C. The reaction may be carried out for a period of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 16 hours. The reaction mixture can be purified to obtain tert-butyl1,5-dimethyl-4-(pyrazine-2-yl)-1H-pyrazole-3-carboxylate. Preferably, the purification is performed by silica gel column chromatography.

[0474] 1,5-dimethyl-4-(pyrazine-2-yl)-1H-pyrazole-3-carboxylate can be treated with an acid to produce 1,5-dimethyl-4-(pyrazine-2-yl)-1H-pyrazole-3-carboxylic acid. Examples of acids include, but are not limited to, aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid, or mixtures thereof. Hydrochloric acid is preferably used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane, or mixtures thereof. Preferably, the reaction is carried out in dioxane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0475] The present invention also provides a method for preparing 4-(5-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. [ka]

[0476] 3-chloro-5-fluoropyridine, a base, and a solvent can be added to (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazole-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 may be carried out in a solvent such as THF, DMF, DMSO, water, or a mixture thereof. Preferably, the solvents are DMF and water.

[0477] Tetrakis(triphenylphosphine)palladium(0)(Pd(PPh3)4) can be added to the reaction mixture. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere. The reaction may be carried out at a temperature in the range of about 50°C to about 150°C. Preferably, the reaction is carried out at about 80°C. The reaction may be carried out for a period of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0478] The reaction mixture can be purified to obtain tert-butyl 4-(5-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate. Preferably, purification is performed by silica gel column chromatography.

[0479] 4-(5-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate can be treated with an acid to produce 4-(5-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Examples of acids include, but are not limited to, aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid, or mixtures thereof. Hydrochloric acid is preferably used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane, or mixtures thereof. Preferably, the reaction is carried out in dioxane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0480] The present invention also provides a method for preparing 4-(4-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. [ka]

[0481] (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazole-4-yl)boronic acid, 3-chloro-4-fluoropyridine, [2-(2-aminophenyl)phenyl]-chloropalladium dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane, tripotassium phosphate, and butan-1-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 mixtures thereof. Preferably, the solvent is water. The reaction may be carried out under an inert atmosphere. Preferably, the reaction may be carried out under an argon atmosphere. The reaction may be carried out at a temperature in the range of about 50°C to about 150°C. Preferably, the reaction may be carried out at about 100°C. The reaction may be carried out for a period of about 1 hour to about 5 hours. Preferably, the reaction may be carried out for a period of about 3 hours.

[0482] The reaction mixture can be purified to obtain tert-butyl 4-(4-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate. Preferably, purification is performed by silica gel column chromatography.

[0483] 4-(4-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate can be treated with an acid to produce 4-(4-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Examples of acids include, but are not limited to, aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid, or mixtures thereof. Hydrochloric acid is preferably used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane, or mixtures thereof. Preferably, the reaction is carried out in dioxane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a period of about 12 hours.

[0484] The present invention also provides a method for preparing 4-(4-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. [ka]

[0485] 2-chloro-4-fluoropyridine, a base, and a solvent can be added to (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazole-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 may be carried out in a solvent such as THF, DMF, DMSO, water, or a mixture thereof. Preferably, the solvents are DMF and water.

[0486] Tetrakis(triphenylphosphine)palladium(0)(Pd(PPh3)4) can be added to the reaction mixture. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere. The reaction may be carried out at a temperature in the range of about 50°C to about 150°C. Preferably, the reaction is carried out at about 80°C. The reaction may be carried out for a period of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0487] The reaction mixture can be purified to obtain tert-butyl 4-(4-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate. Preferably, purification is performed by silica gel column chromatography.

[0488] 4-(4-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate can be treated with an acid to produce 4-(4-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Examples of acids include, but are not limited to, aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid, or mixtures thereof. Hydrochloric acid is preferably used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane, or mixtures thereof. Preferably, the reaction is carried out in dioxane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a period of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0489] [Examples] The present invention is further described with reference to the following embodiments, which are not presented to limit the scope of the invention.

[0490] I. General synthesis methods and procedures [ka]

[0491] Example 1: Synthesis of (2R,3S)-2-(benzylamino)butane-1,3-diol (b) To a solution of N-benzyl-L-alotreonine (15 g, 68.10 mmol, 1 equivalent) in tetrahydrofuran (300 mL), BH3.DMS (10 M, 34.05 mL, 5 equivalents) was added under N2 at 0°C. This mixture was stirred at 80°C for 6 hours. LC-MS showed that all of the starting material was consumed and the desired MW was detected. The reaction mixture was cooled to 0°C and then quenched with methyl alcohol (100 mL). The solution was then concentrated under reduced pressure to obtain a crude product (14 g, 64.53 mmol, 94.75% yield) as a colorless oil, which was used without further purification. 1 H NMR(400 MHz, DMSO-d6): δ ppm 7.32 (br d, J=1.25Hz, 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).

[0492] Example 2: Synthesis of (2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol(c) To a solution of (2R,3S)-2-(benzylamino)butane-1,3-diol (15 g, 76.82 mmol, 1 equivalent) in dimethyl sulfoxide (300 mL), imidazole (7.85 g, 115.23 mmol, 1.5 equivalents) and TBDPSCl (25.34 g, 92.19 mmol, 23.59 mL, 1.2 equivalents) were added. This mixture was stirred at 25°C for 12 hours. LC-MS showed that all of the starting material was consumed and the desired MW was detected. This reaction mixture was quenched by adding water (1000 mL) at 0°C, and then the mixture was extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with brine (2 × 1000 mL), dehydrated with Na₂SO₄, filtered, and concentrated to obtain the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate, 1 / 0~4 / 1) to obtain (2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (6g, 19.38 mmol, 25.23% yield) as a colorless oil. 1 H NMR(400 MHz, DMSO-d6): δ ppm 7.57 - 7.68 (m, 4H) 7.37 - 7.50 (m, 6 H) 7.15 - 7.31 (m, 5 H) 4.43 (d, J=4.88 Hz, 1 H) 3.60 -3.85 (m, 5 H) 2.54 (m, 1 H) 1.05 (d, J=6.38 Hz, 3 H) 0.98 (s, 9 H).

[0493] Example 3: Synthesis of 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 equivalent) in dioxane (68 mL), 2-bromo-2,2-difluoroacetic acid (4.11 g, 23.52 mmol, 3 equivalents) was added. This solution was cooled to 0°C. To this solution, NaH (1.41 g, 35.28 mmol, 60% purity, 4.5 equivalents) was added at 0°C. This mixture was stirred at 20°C for 12 hours. LC-MS showed that all of the starting material was consumed and the desired MW was detected. The reaction product was poured into 1N HCl at 0°C, adjusted to pH 7, and then extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (40 mL x 2), dehydrated with Na2SO4, filtered, and concentrated to obtain a crude product (5 g, 7.58 mmol, 96.69% yield) as a yellow oily substance. The product was used directly in the next step without further purification. 1 H NMR(400 MHz, DMSO-d6): δ ppm 7.55 - 7.73 (m, 5H) 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, 2H) 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).

[0494] Example 4: Synthesis of (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholin-3-one(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 equivalent) in dimethylformamide (164 mL), T3P (4.94 g, 7.77 mmol, 4.63 mL, 50% purity, 1 equivalent) was added at 0°C. This mixture was stirred at 20°C for 2 hours. LC-MS showed that all of the starting material was consumed and the desired MW was detected. The reaction mixture was poured into ice water (150 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layer was dried over Na2SO4 and filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to obtain (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine-3-one (3.1 g, 5.47 mmol, 70.45% yield) as a colorless oil. 1 H NMR(400 MHz, DMSO-d6): δ ppm 7.55 - 7.67 (m, 4H) 7.40 - 7.55 (m, 6 H) 7.25 - 7.36 (m, 3 H) 7.21 (br d, J=6.75 Hz, 2 H) 4.97(d, J=15.13 Hz, 1 H) 4.62 - 4.73 (m, 1 H) 4.09 (d, J=15.13 Hz, 1 H) 3.88 (m, 1H) 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, 9H).

[0495] Example 5: Synthesis of (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine (f) To a solution of (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine-3-one (3.3 g, 5.83 mmol, 1 equivalent) in tetrahydrofuran (33 mL), BH3.DMS (10 M, 2.33 mL, 4 equivalents) was added at 25 °C. The mixture was then stirred at 30 °C for 3 hours. LC-MS showed that all of the starting material had been consumed and the desired MW was detected. The reaction mixture was quenched by adding methanol (30 mL) at 20 °C, and the mixture was stirred at 40 °C for 1 hour. The crude product was then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to obtain (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine (1.9 g, 3.45 mmol, 59.20% yield) as a white solid. 1 H NMR(400 MHz, DMSO-d6): 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 = 6.1 Hz, 2H), 2.99 - 2.75 (m, 3H), 1.22 (d, J = 6.8 Hz, 3H),1.00 (s, 9H).

[0496] Example 6: Synthesis of ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholine-3-yl)methanol (g) (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine (1.8 g, 3.27 mmol, 1 equivalent) was dissolved in tetrahydrofuran (36 mL) and TBAF (1 M, 4.90 mL, 1.5 equivalents) was added at 25 °C. The mixture was then stirred at 25 °C for 1 hour. LC-MS showed that all of the starting material was consumed and the desired MW was detected. The residue was quenched with water (40 mL) and extracted with ethyl acetate (2 × 40 mL). The combined organic matter was washed with brine (40 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification of the crude product by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) yielded ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholine-3-yl)methanol (0.9 g, 3.15 mmol, 96.33% yield) as a white solid. 1 H NMR(400 MHz, DMSO-d6): 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= 6.8Hz, 3H).

[0497] Example 7: Synthesis of tert-butyl(5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylate(h) To a solution of ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholine-3-yl)methanol (0.9 g, 3.15 mmol, 1 equivalent) in ethyl acetate (30 mL), Pd / C (410 mg, 10% purity, 0.05 equivalent) and Boc2O (1.03 g, 4.72 mmol, 1.08 mL, 1.5 equivalent) were added at 25°C under an H2 (15 Psi) atmosphere. The mixture was then stirred at 25°C for 16 hours. LC-MS showed that all of the starting materials were consumed and the desired MW was detected. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude product. Purification of the crude product by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) yielded tert-butyl(5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylate (0.73 g, 2.46 mmol, 78.08% yield) as a white solid. 1 H NMR(400 MHz, DMSO-d6): δ ppm 4.77 (t, J=5.57Hz, 1 H) 4.29 (br s, 1 H) 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).

[0498] Example 8: Synthesis of tert-butyl(5R,6S)-5-((1,3-dioxoisoindoline-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 equivalent) in tetrahydrofuran (5 mL), isoindoline-1,3-dione (371.59 mg, 2.53 mmol, 1.5 equivalents) was added at 25°C. This reaction mixture was degassed and purged three times with N2. PPh3 (662.43 mg, 2.53 mmol, 1.5 equivalents) was added to the reaction mixture at 20°C. DIAD (510.69 mg, 2.53 mmol, 489.64 μL, 1.5 equivalents) was added to this mixture at 0°C. Next, this mixture was stirred at 20°C for 12 hours under an N2 atmosphere. LCMS showed that all of the starting materials were consumed and the desired MW was detected. The residue was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic matter was washed with brine (30 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated 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). 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. 1 H NMR(400 MHz, DMSO-d6): δ ppm 7.75 - 8.04 (m, 4H) 4.04 - 4.52 (m, 3 H) 3.94 (m, 1 H) 3.75 (br d, J=14.38 Hz, 1 H) 3.37 - 3.62(m, 1 H) 1.38 (d, J=6.50 Hz, 3 H) 0.87 - 1.10 (m, 9 H).

[0499] Example 9: Synthesis of tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate(j) To a solution of tert-butyl(5R,6S)-5-((1,3-dioxoisoindolin-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (720.00 mg, 1.63 mmol, 1 equivalent) in methyl alcohol (7 mL), hydrazine hydrate (818.37 mg, 16.35 mmol, 793.00 μL, 10 equivalents) was added at 25°C. The mixture was then stirred at 60°C for 2 hours under an N2 atmosphere. LC-MS indicated that all of the starting material was consumed and the desired MW was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (420 mg, 86.83% yield) as a white solid. The crude product was used in the next step without further purification. 1 H NMR(400 MHz, DMSO-d6): 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).

[0500] Example 10: Synthesis of tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (k), general procedure A mixture of tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (210 mg, 788.63 μmol, 1 equivalent) and K2CO3 (217.99 mg, 1.58 mmol, 2 equivalents) in dimethylformamide (5 mL) was mixed with 2-chloro-5-(trifluoromethyl)pyrazine (215.92 mg, 1.18 mmol, 1.5 equivalents) at 25 °C. The mixture was stirred at 80 °C for 12 hours. LC-MS indicated that the reaction was complete and the desired MW was detected. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO2, PE:EA = 1:1) to obtain tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (105 mg, 29.20% yield) as a colorless oil. 1 H NMR(400 MHz, DMSO-d6): δ ppm 8.37 - 8.47 (m, 1H) 7.87 - 8.13 (m, 2 H) 3.99 - 4.40 (m, 3 H) 3.67 - 3.82 (m, 1 H) 3.36 - 3.65(m, 2 H) 1.31 (br d, J=6.38 Hz, 3 H) 1.02 - 1.26 (m, 9 H). Similarly, the following intermediates were prepared.

[0501] Example 11: Synthesis of tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate(l) Using tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2-chloro-5-(trifluoromethyl)pyrimidine, the general procedure used to prepare compound (k) (see Example 10) was repeated. Yield 65%, white solid. LCMS (ESI+): m / z=413.3 (M+1), RT: 0.573 min (Column Agilent Poroshell SB-C18 3.0 * 30 mm, 4 μm. The detection method was a diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 50–2000. Mobile phase A was 0.04% trifluoroacetic acid in water, and mobile phase B was 0.02% trifluoroacetic acid in acetonitrile (HPLC grade). The gradient was 5–95% B over 1.50 mins, 5% B over 0.01 mins, 5–95% B over 0.01 mins (0.01–0.70 mins), 95% B over 0.70 mins (0.70–1.16 mins), 95–5% B over 1.16–1.17 mins (1.16–1.17 mins), and B was maintained at 5% for 0.33 mins. The flow rate was 1.5 mL / min.

[0502] Example 12: Synthesis of tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate (m) The general procedure used to prepare compound (k) (see Example 10) was repeated using tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2-chloro-5-(trifluoromethyl)pyridine. Yield 43%, yellow oily substance. 1H NMR(400 MHz, DMSO-d6): 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).

[0503] Example 13: Synthesis of tert-butyl(5R,6S)-5-(((5-chloropyridine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate(n), general procedure To a mixture consisting of DIPEA (135.90 mg, 1.05 mmol) in DMSO (1.5 mL), tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (0.07 g, 262.88 μmol) and 5-chloro-2-fluoropyridine (69.16 mg, 525.75 μmol) were added at 20°C, and the reaction mixture was stirred at 140°C for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was poured into NH4Cl (2 mL) at 0°C and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water (5 mL x 3) and brine (3 mL x 1), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by column chromatography on silica gel in which ethyl acetate from petroleum ether was eluted from 0% to 40%, yielding tert-butyl(5R,6S)-5-(((5-chloropyridine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (50 mg, 25.17% yield) as a brown solid. 1H NMR(400 MHz, DMSO-d6): 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, 5 H) 1.10 (s, 7 H). Similarly, the following intermediates were prepared.

[0504] Example 14: Synthesis of tert-butyl(5R,6S)-5-(((5-chloropyrimidine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate(o) Using tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 5-chloro-2-fluoropyrimidine, the general procedure used to prepare compound (n) (see Example 13) was repeated. Yield 49%, white solid. 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, 0.57 H) 3.70 (br t, J=6.82 Hz, 0.85 H) 3.56 (dt,J=14.13, 4.19 Hz, 0.57 H) 3.10 - 3.40 (m, 1 H) 1.27 - 1.46 (m, 12 H).

[0505] Example 15: Synthesis of tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate(p) Using tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 5-chloro-2-fluoropyrimidine, the general procedure used to prepare compound (n) (see Example 13) was repeated. Yield 46%, white solid. 1 ¹H NMR (400 MHz, chloroform-d): δ ppm 8.35-8.60 (m, 0.81 H) 6.87 (dd, J=15.51, 4.88 Hz, 0.83 H) 5.33-5.57 (m, 0.85 H) 4.21-4.51 (m, 2.22 H) 3.90-4.20 (m, 1.14 H) 3.15-3.85 (m, 2.29 H) 1.18-1.45 (m, 12 H).

[0506] Example 16. Synthesis of tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((6-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate(q) The general procedure used to prepare 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. 1 ¹H NMR (400 MHz, chloroform-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).

[0507] Example 17. Synthesis of tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate(r) The general procedure used to prepare compound (n) (see Example 13) was repeated using tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2-fluoro-4-(trifluoromethyl)pyridine. Yield 39%, bright yellow solid. 1 H NMR(400 MHz, DMSO-d6) δ ppm 8.16 - 8.25 (m, 1H) 7.00 - 7.27 (m, 1 H) 6.65 - 6.78 (m, 2 H) 4.01 - 4.40 (m, 3 H) 3.34 - 3.82(m, 3 H) 1.31 (d, J=6.63 Hz, 3 H) 1.00 - 1.26 (m, 9 H).

[0508] Example 18: Synthesis of tert-butyl(5R,6S)-2,2-difluoro-5-(((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-6-methylmorpholine-4-carboxylate(s) The general procedure used to prepare compound (n) (see Example 13) was repeated using tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2,3-difluoro-5-(trifluoromethyl)pyridine. Yield 65%, white solid. 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, 2.00H), 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).

[0509] Example 19: Synthesis of tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate(t) 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 to prepare compound (n) (see Example 13) was repeated to obtain tert-butyl(5R,6S)-5-(((3-bromo-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate. Yield 65%, yellow solid. 1 HNMR(400 MHz, DMSO-d6): 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, 1.20H), 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)pyridine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (550 mg, 1.12 mmol, 1 equivalent) in THF (22 mL) and H2O (5.5 mL), K3PO4 (714.39 mg, 3.37 mmol, 3 equivalents), MeB(OH)2 (100.73 mg, 1.68 mmol, 1.5 equivalents) and Pd(dtbpf)Cl2 (73.12 mg, 112.18 μmol, 0.1 equivalent) were added. This mixture was stirred under N2 at 80°C for 2 hours. LCMS showed that the starting materials were completely consumed and that one major peak with the desired mass was detected. The reaction mixture was quenched by adding water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layer was washed with brine (100 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~1 / 100). Tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate (0.42 g, 83.61% yield) was obtained as a yellow solid. 1HNMR(400 MHz, DMSO-d6): 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, 0.40H), 3.46 - 3.59 (m, 0.80 H), 3.40 (ddd, J=13.70, 11.32, 6.13 Hz, 0.70 H), 1.97- 2.10 (m, 2.90 H), 1.33 (br d, J=6.50 Hz, 3.00 H), 1.21 (s, 2.60 H), 0.99 (s,6.60 H).

[0510] Example 20: Synthesis of tert-butyl(5R,6S)-5-(((5-cyclopropylpyrimidine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate(u) Using tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2-chloro-5-cyclopropylpyrimidine, the general procedure used to prepare compound (n) (see Example 13) was repeated.

[0511] Yield 84%, white solid. 1H NMR(400 MHz, DMSO-d6): δ = 8.01 - 8.17 (m, 2H), 7.00 (br t, J=6.19 Hz, 0.80 H), 6.73 (br t, J=5.88 Hz, 0.20 H), 4.27 - 4.41(m, 2 H), 4.21 (br dd, J=14.20, 4.44 Hz, 1 H), 3.58 - 3.71 (m, 1 H), 3.52 (brd, J=6.50 Hz, 0.50 H), 3.36 - 3.49 (m, 1 H), 3.22 - 3.30 (m, 0.50 H), 1.67 -1.81 (m, 1 H), 1.24 - 1.32 (m, 5 H), 1.08 (s, 7 H), 0.79 - 0.89 (m, 2 H), 0.52- 0.63 (m, 2 H).

[0512] Example 21: Synthesis of tert-butyl(5R,6S)-2,2-difluoro-5-(((3-methoxy-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-6-methylmorpholine-4-carboxylate(v) The general procedure used to prepare compound (n) (see Example 13) was repeated using tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2-chloro-3-methoxy-5-(trifluoromethyl)pyridine. Yield 49%, colorless oil. 1HNMR(400 MHz, DMSO-d6): 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, 2.00 H), 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,3.00H), 1.23 (s, 1.95 H), 1.00 (s, 6.50 H).

[0513] Example 22: Synthesis of tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (w) [ka] To a solution of 3-methyl-5-(trifluoromethyl)pyrazine-2-ol (200.66 mg, 1.13 mmol, 1.5 equivalents) in DMF (5 mL), DBU (343.02 mg, 2.25 mmol, 339.63 μL, 3 equivalents) was added. Then, BOP (498.28 mg, 1.13 mmol, 1.5 equivalents) was added in fractions at 0°C, and the mixture was stirred at 0°C for 0.5 hours. Next, tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate(j) (0.2 g, 751.08 μmol, 1 equivalent) was added to the mixture at 0°C. The mixture was stirred at 20°C for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was quenched by adding water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layer was washed with brine (5 mL x 3), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by column chromatography on silica gel in which ethyl acetate was eluted from 0% to 11% in petroleum ether, yielding tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (0.2 g, 62.45% yield) as a yellow oily substance. 1 H NMR(400 MHz, DMSO-d6): δ ppm 8.23 ​​- 8.42 (m, 1H), 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).

[0514] Example 23: Synthesis of tert-butyl(5R,6S)-5-(((3-cyano-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate(x) The general procedure used to prepare compound (n) (see Example 13) was repeated using tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2-chloro-5-(trifluoromethyl)nicotinonitrile. Yield 59%, yellow solid. 1 ¹H NMR (400 MHz, methanol-d4): δ = 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).

[0515] Example 24: Synthesis of tert-butyl(y) The general procedure used to prepare compound (n) (see Example 13) was repeated using tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 5-chloro-2,3-difluoropyridine. Yield 94%, colorless oil. 1 ¹H NMR (400 MHz, chloroform-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, 1 H), 1.29-1.46 (m, 12 H).

[0516] Example 25: Synthesis of tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((4-methyl-5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-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 used to prepare compound (n) (see Example 13) was repeated to obtain tert-butyl(5R,6S)-5-(((4-chloro-5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate. Yield 33%, yellow solid. 1 HNMR(400 MHz, DMSO-d6): 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, 6.00H), 1.12 (d, J=3.00 Hz, 6.45 H). Dioxane (10.8 mL) was mixed with tert-butyl(5R,6S)-5-(((4-chloro-5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (0.54 g, 1.21 mmol, 1 equivalent), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatrivolinane (606.88 mg, 2.42 mmol, purity = 50%, 2 equivalents), Cs2CO3 (1.18 g, 3.63 mmol, 3 equivalents), and Pd(dppf)Cl2 (88.43 mg, 120.86 μmol, 0.1 equivalent) in a microwave tube. Next, the mixture was degassed and purged with N2 three times. The sealed tube was heated under microwave at 140°C for 4 hours. LC-MS indicated that the starting material had been completely consumed and that a single major peak with the desired mass was detected. After cooling to 25°C, the reaction mixture was quenched by adding water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine (30 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~1 / 100) to obtain tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((4-methyl-5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate (0.32 g, 62.10% yield) as a yellow oily substance. 1 1H NMR (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).

[0517] Example 26: Synthesis of tert-butyl(5R,6S)-5-(((5-(difluoromethyl)pyrimidine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (z1) The general procedure used to prepare compound (n) (see Example 13) was repeated using tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2-chloro-5-(difluoromethyl)pyrimidine. Yield 88%, yellow solid. 1 H NMR(400 MHz, DMSO-d6): δ = 8.37 - 8.58 (m, 2H), 7.79 (br t, J=6.00 Hz, 0.70 H), 7.48 - 7.66 (m, 0.25 H), 6.76 - 7.17 (m, 1H), 4.28 - 4.43 (m, 2 H), 4.23 (br dd, J=14.10, 4.82 Hz, 0.70 H), 3.99 - 4.11(m, 0.30 H), 3.68 (td, J=9.74, 4.76 Hz, 1 H), 3.53 - 3.63 (m, 0.60 H), 3.47 (brd, J=13.73 Hz, 0.40 H), 3.34 - 3.43 (m, 1 H), 1.30 (br d, J=6.43 Hz, 3 H), 1.03- 1.27 (m, 9 H).

[0518] Example 27: Synthesis of tert-butyl(5R,6S)-5-(((5-(difluoromethyl)pyrazine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (z2) The general procedure used to prepare compound (n) (see Example 13) was repeated using tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2-chloro-5-(difluoromethyl)pyrazine. Yield 95%, colorless oil. 1H NMR(400 MHz, DMSO-d6): δ = 8.19 - 8.28 (m, 1H), 7.88 - 8.04 (m, 1 H), 7.76 (br s, 0.70 H), 7.61 (br s, 0.30 H), 6.62 - 7.06(m, 1 H), 4.06 - 4.44 (m, 3 H), 3.35 - 3.79 (m, 3 H), 1.32 (br d, J=6.50 Hz, 3H), 1.00 - 1.28 (m, 9 H).

[0519] Example 28: Synthesis of 5-chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)pyridine-2-amine hydrochloride (aa), general procedure To a solution of tert-butyl(5R,6S)-5-(((5-chloropyridine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (50 mg, 92.64 μmol) in dioxane (0.5 mL), HCl / dioxane (4N, 0.5 mL) was added, and the reaction mixture was stirred at 20°C for 2 hours. LC-MS indicated that the reaction was complete. When the reaction mixture was concentrated under reduced pressure, 5-chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)pyridine-2-amine hydrochloride (40 mg, 96.2% yield) was obtained as a brown solid. 1 H NMR(400 MHz, DMSO-d6): 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, 2H) 4.63 (br dd, J=6.69, 2.31 Hz, 1 H) 3.68 - 3.85 (m, 4 H) 3.58 - 3.67 (m, 1 H)1.37 (d, J=6.75 Hz, 3 H). Similarly, the following intermediates were prepared.

[0520] Example 29: Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyrazine-2-amine hydrochloride (ab) Using tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (k), the general procedure used to prepare compound (aa) (see Example 28) was repeated. Yield 99%, white solid. LCMS (ESI+): m / z=313.1 (M+1), RT: 0.669 min (column Kinetex EVO C18 2.1 * 30 mm, 5 μm. The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100 to 1000. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in acetonitrile (HPLC grade). The gradient was 5-95% B over 1.50 minutes, 5% B over 0.01 minutes, 5-95% B over 0.01-0.70 minutes, 95% B over 0.70-1.16 minutes, and 95-5% B over 1.16-1.5 minutes. The flow rate was 1.5 mL / min.

[0521] Example 30: Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyrimidine-2-amine hydrochloride (ac) Using tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate, the general procedure used to prepare compound (aa) (see Example 28) was repeated. Yield 89%, yellow solid. LCMS (ESI+): m / z=313.2 (M+1), RT: 0.361 min (Column Agilent Poroshell SB-C18 3.0 *30 mm, 4 μm. The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 50–2000. Mobile phase A was 0.04% trifluoroacetic acid in water, and mobile phase B was 0.02% trifluoroacetic acid in acetonitrile (HPLC grade). The gradient was 5–95% B over 1.50 mins, 5% B over 0.01 mins, 5–95% B over 0.01 mins, 95% B over 0.70 mins, 95% B over 0.70 mins, and 95–5% B over 1.16 mins (1.16–1.17 mins), with B held at 5% for 0.33 mins. The flow rate was 1.5 mL / min.

[0522] Example 31: Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyridine-2-amine hydrochloride (ad) Using tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate, the general procedure used to prepare compound (aa) (see Example 28) was repeated. Yield 89%, yellow solid. LCMS (ESI+): m / z=312.2 (M+1), RT: 0.602 min (Column Agilent Poroshell SB-C18 3.0 * 30 mm, 4 μm. The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 50–2000. Mobile phase A was 0.04% trifluoroacetic acid in water, and mobile phase B was 0.02% trifluoroacetic acid in acetonitrile (HPLC grade). The gradient was 5–95% B over 1.50 mins, 5% B over 0.01 mins, 5–95% B over 0.01 mins, 95% B over 0.70 mins, 95% B over 0.70 mins, and 95–5% B over 1.16 mins (1.16–1.17 mins), with B held at 5% for 0.33 mins. The flow rate was 1.5 mL / min.

[0523] Example 32: Synthesis of 5-chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)pyrimidine-2-amine hydrochloride (ae) Using tert-butyl(5R,6S)-5-(((5-chloropyrimidine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate, the general procedure used to prepare compound (aa) (see Example 28) was repeated. Yield 98%, white solid. 1 H NMR(400 MHz, DMSO-d6): 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).

[0524] Example 33. Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-4-(trifluoromethyl)pyrimidine-2-amine hydrochloride (af) Using tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate, the general procedure used to prepare compound (aa) (see Example 28) was repeated. Yield 79%, bright yellow solid. 1 H NMR(400 MHz, DMSO-d6) δ ppm 8.69 (br d, J=4.00Hz, 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).

[0525] Example 34. Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-6-(trifluoromethyl)pyrazine-2-amine hydrochloride (ag) Using tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((6-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate, the general procedure used to prepare compound (aa) (see Example 28) was repeated. Yield 97%, yellow solid. 1 H NMR(400 MHz, DMSO-d6): δ 7.84 - 8.40 (m, 1.64H) 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).

[0526] Example 35. Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-4-(trifluoromethyl)pyridine-2-amine hydrochloride (ah) Using tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate, the general procedure used to prepare compound (aa) (see Example 28) was repeated. Yield 89%, bright yellow solid. 1 H NMR(400 MHz, DMSO-d6): δ ppm 8.25 (d, J=5.38Hz, 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).

[0527] Example 36. Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-3-fluoro-5-(trifluoromethyl)pyridine-2-amine hydrochloride (ai) Using tert-butyl(5R,6S)-2,2-difluoro-5-(((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-6-methylmorpholine-4-carboxylate, the general procedure used to prepare compound (aa) (see Example 28) was repeated. Yield 94%, white solid. 1 HNMR(400 MHz, DMSO-d6): 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).

[0528] Example 37. Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyridine-2-amine (aj), general procedure Tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate (0.42 g, 987.32 μmol, 1 equivalent) was dissolved in HCl / dioxane (4 M, 4.2 mL, 17.02 equivalents). This mixture was stirred at 25°C for 1 hour. LC-MS showed that the starting material was completely consumed and that one major peak with the desired mass was detected. The mixture was adjusted to pH 9 with NaHCO3 (aqueous solution) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (30 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyridine-2-amine (0.27 g, 79.03% yield) as a yellow solid. 1 H NMR(400 MHz, DMSO-d6): 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).

[0529] Example 38. Synthesis of 5-Cyclopropyl-N-(((2S,3R)-6,6-Difluoro-2-methylmorpholine-3-yl)methyl)pyrimidine-2-amine hydrochloride (ak) Using tert-butyl(5R,6S)-5-(((5-cyclopropylpyrimidine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate, the general procedure used to prepare compound (aa) (see Example 28) was repeated. Yield 85%, brown oily substance. 1 H NMR(400 MHz, DMSO-d6): 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, 3 H), 0.86 - 0.98 (m, 2 H), 0.64 - 0.76 (m, 2 H).

[0530] Example 39. Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-3-methoxy-5-(trifluoromethyl)pyridine-2-amine(al) Using tert-butyl(5R,6S)-2,2-difluoro-5-(((3-methoxy-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-6-methylmorpholine-4-carboxylate, the general procedure used to prepare compound (aj) (see Example 37) was repeated. Yield 64%, yellow solid. LCMS: m / z=342.2(M+1), RT: 0.621 min.

[0531] Example 40. Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyrazine-2-amine hydrochloride (am) Using tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate, the general procedure used to prepare compound (aa) (see Example 28) was repeated. Yield 99%, bright yellow solid. 1H NMR(400 MHz, DMSO-d6): 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, 2.19Hz, 1 H), 3.65 - 3.93 (m, 5 H), 2.43 (s, 3 H), 1.39 (d, J=6.75 Hz, 3 H).

[0532] Example 41. Synthesis of 2-((((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)amino)-5-(trifluoromethyl)nicotinonitrile hydrochloride (an) Using tert-butyl(5R,6S)-5-(((3-cyano-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate, the general procedure used to prepare compound (aa) (see Example 28) was repeated. Yield 95%, yellow solid. LCMS: (ESI+): m / z=337.2(M+1), RT: 0.404 min.

[0533] Example 42. Synthesis of 5-chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-3-fluoropyridine-2-amine hydrochloride (ao) Using tert-butyl(5R,6S)-5-(((5-chloro-3-fluoropyridine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate, the general procedure used to prepare compound (aa) (see Example 28) was repeated. Yield 94%, white solid. 1H NMR(400 MHz, DMSO-d6): δ ppm 7.93 (d, J=2.00Hz, 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).

[0534] Example 43. Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-4-methyl-5-(trifluoromethyl)pyrimidine-2-amine (ap) Using tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((4-methyl-5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate, the general procedure used to prepare compound (aj) (see Example 37) was repeated. Yield 82%, yellow oily substance. 1 HNMR(400 MHz, DMSO-d6): 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, 1.30H), 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).

[0535] Example 44: Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-5-(difluoromethyl)pyrimidine-2-amine hydrochloride (aq) Using tert-butyl(5R,6S)-5-(((5-(difluoromethyl)pyrimidine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate, the general procedure used to prepare compound (aa) (see Example 28) was repeated. Yield 92%, yellow solid. 1 H NMR(400 MHz, DMSO-d6): 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, 5H), 1.37 (br d, J=6.68 Hz, 3 H).

[0536] Example 45: Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl)-5-(difluoromethyl)pyrazine-2-amine hydrochloride (ar) Using tert-butyl(5R,6S)-5-(((5-(difluoromethyl)pyrazine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate, the general procedure used to prepare compound (aa) (see Example 28) was repeated. Yield 87%, yellow solid. 1 H NMR(400 MHz, DMSO-d6): δ = 8.19 (d, J=1.00 Hz,1 H), 8.00 (d, J=1.13 Hz, 1 H), 7.93 (br s, 1 H), 6.83 (t, J=54.84 Hz, 1 H),4.52 - 4.70 (m, 1 H), 3.57 - 3.84 (m, 5 H), 1.32 (d, J=6.75 Hz, 3 H). [ka]

[0537] Example 46: Synthesis of (5R,6S)-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-methylmorpholine-3-one (2.3 g, 4.51 mmol, 1 equivalent) was dissolved in triduterioborane (1 M in THF, 23.00 mL, 5.10 equivalents) at 20°C. The mixture was then stirred at 40°C for 1.5 hours. LC-MS showed that 30% of the starting material remained and 60% of the desired mass was detected. The reaction mixture was quenched by adding MeOH (30 mL) at 20°C. The mixture was stirred at 40°C for 1 hour and then concentrated under reduced pressure to obtain the crude product. Purification of the crude product by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) yielded (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine-3,3-d2 (1.1 g, 1.99 mmol, 44.08% yield, 90% purity) as a colorless oil. 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).

[0538] Example 47: Synthesis of ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholine-3-yl-5,5-d2)methanol (g1). (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine-3,3-d2 (0.7 g, 1.41 mmol, 1 equivalent) was dissolved in tetrahydrofuran (14 mL) and TBAF (1 M, 2.81 mL, 2 equivalents) was added at 20 °C. The mixture was then stirred at 20 °C for 12 hours. LC-MS showed that all of the starting material had been consumed and the desired mass had been detected. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic matter was washed with brine (30 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. When the crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1), ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholine-3-yl-5,5-d2)methanol (150 mg, 549.58 μmol, 39.07% yield, 95% purity) was obtained as a colorless oil. 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).

[0539] Example 48: Synthesis of tert-butyl(5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylate-3,3-d2(h1). ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholine-3-yl-5,5-d2)methanol (0.5 g, 1.93 mmol, 1 equivalent) in ethyl acetate (20 mL) was mixed with Pd / C (410.43 mg, 385.67 μmol, 10% purity, 0.05 equivalent), (Boc)2O (631.28 mg, 2.89 mmol, 664.51 μL, 1.5 equivalent), and TEA (390.26 mg, 3.86 mmol, 536.81 μL, 2 equivalents) under N2. This suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 20°C for 12 hours under H2 (15 psi). LCMS showed that all of the starting material was consumed and the desired mass was detected. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was used directly in the next step. Tert-butyl(5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylate-3,3-d2 (519 mg, 1.93 mmol, 99.95% yield) was obtained as a colorless oil. 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).

[0540] Example 49: Synthesis of tert-butyl(5R,6S)-5-((1,3-dioxoisoindoline-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2(i1). To a 5 mL solution of tetrahydrofuran (519 mg, 1.93 mmol, 1 equivalent), isoindoline-1,3-dione (425.36 mg, 2.89 mmol, 1.5 equivalents) was added at 25°C. This reaction mixture was degassed and purged three times with N2. PPh3 (758.29 mg, 2.89 mmol, 1.5 equivalents) was added to the reaction mixture at 20°C. DIAD (584.59 mg, 2.89 mmol, 560.49 μL, 1.5 equivalents) was added to this mixture at 0°C. Next, the mixture was stirred at 20°C for 12 hours under an N2 atmosphere. LC-MS showed that all of the starting material was consumed and the desired mass was detected. The residue was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic matter was washed with brine (30 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated 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). The compound tert-butyl(5R,6S)-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. 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, 14.4Hz, 1H), 1.38 (d, J = 6.6 Hz, 3H), 1.05 - 0.91 (m, 9H).

[0541] Example 50: Synthesis of tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2(j1). 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 equivalent) in MeOH (24 mL), hydrazine hydrate (723.77 mg, 14.46 mmol, 701.33 μL, 10 equivalents) was added at 25°C. The mixture was then stirred at 60°C for 4 hours under an N2 atmosphere. LC-MS indicated that all of the starting material had been consumed and the desired mass had been detected. The reaction mixture was filtered to obtain a filtrate, which was concentrated under reduced pressure to obtain the crude product. The crude product was used directly in the next step. tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (450 mg, 1.34 mmol, 92.81% yield, 80% purity) was obtained as a white solid. 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).

[0542] Example 51: Synthesis of tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate-3,3-d2(k1) [ka] To a solution of 2-chloro-5-(trifluoromethyl)pyrazine (187.77 mg, 1.03 mmol, 1.5 equivalents) in DMF (4.6 mL), tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (230.00 mg, 685.81 μmol, 1 equivalent) was added at 25°C. K2CO3 (189.57 mg, 1.37 mmol, 2 equivalents) was added to the reaction mixture at 25°C. The mixture was then stirred at 80°C for 2 hours. LCMS showed that all of the starting material was consumed and the desired mass was detected. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to obtain the compound tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate-3,3-d2 (90 mg, yield 25.34%) as a yellow solid. 1 H NMR(400 MHz, DMSO-d6): 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, 0.80H), 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).

[0543] Example 52: Synthesis of tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate-3,3-d2(m1) [ka] To a 1.6 mL solution of tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (80.00 mg, 238.54 μmol, 1 equivalent) in DMSO (1.6 mL), DIPEA (61.66 mg, 477.08 μmol, 83.10 μL, 2 equivalents) and 2-fluoro-5-(trifluoromethyl)pyridine (59.07 mg, 357.81 μmol, 1.5 equivalents) were added at 25 °C. The mixture was then stirred at 140 °C for 16 hours. LC-MS showed that all of the starting material was consumed and the desired mass was detected. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification of the crude product by preparative TLC (petroleum ether:ethyl acetate = 1:1) yielded tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate-3,3-d2 (40 mg, yield 32.45%) as a yellow solid. LCMS (ESI+): m / z=414.2 (M+1), RT: 0.564 min. Similarly, the following compounds were prepared.

[0544] Example 53: tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate-3,3-d2(l1) [ka] Using tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 and 2-chloro-5-(trifluoromethyl)pyrimidine, the general procedure used to prepare compound (m1) (see Example 52) was repeated. Yield 85%, colorless oil. 1 HNMR(400 MHz, DMSO-d6): δ ppm 8.46 - 8.78 (m, 2H), 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, 9H).

[0545] Example 54: Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyrazine-2-amine hydrochloride (ab1) [ka] 90 mg, 173.76 μmol, 1 equivalent) of tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate-3,3-d2 (40 mg, 173.76 μmol, 1 equivalent) was added to a HCl / dioxane (4 M, 2 mL, 46.04 equivalents) solution at 20°C. The mixture was then stirred at 20°C for 1 hour. LC-MS indicated that all of the starting material had been consumed and the desired mass had been detected. The reaction mixture was concentrated under reduced pressure to obtain crude N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyrazine-2-amine hydrochloride (60 mg, yield 98.46%) as a yellow solid. LCMS (ESI+): m / z=315.1 (M+1), RT: 0.584 min. Similarly, the following compounds were prepared.

[0546] Example 55: N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyrimidine-2-amine hydrochloride (ac1) [ka] Using tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate-3,3-d2, the general procedure used to prepare compound (ab1) (see Example 54) was repeated. Yield 97%, white solid. LCMS (ESI+): m / z=315.2 (M+1), RT: 0.574 min.

[0547] Example 56: N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyridine-2-amine hydrochloride (ad1) [ka] Using tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate-3,3-d2, the general procedure used to prepare compound (ab1) (see Example 54) was repeated. 99% yield, yellow solid. LCMS (ESI+): m / z=314.2 (M+1), RT: 0.380 min. [ka]

[0548] Example 57: Synthesis of (2S,3S)-4-benzyl-6,6-difluoro-2-methyl-5-oxomorpholine-3-carboxylic acid (e2'). Dioxane (20 L, 20V) was added to a 50 L reactor equipped with a stirrer, dropping funnel, and thermometer. Then, t-BuONa (1.09 kg, 11.35 mol, 5 equivalents) was added to this suspension in four separate additions at 25°C. After cooling to 10°C, benzyl-L-alotreonine (CAS 1932485-18-1) (500.00 g, 2.27 mol, 1 equivalent) and (2-bromo-2,2-difluoroacetyl)oxysodium (1.34 kg, 6.81 mol, 3 equivalents) were added to the reactor in five separate additions at 10°C: benzyl-L-alotreonine (100 g, 0.2 equivalents) and (2-bromo-2,2-difluoroacetyl)oxysodium (268 g, 0.6 equivalents) were added alternately, with the temperature allowed to drop to 10°C after each addition until all of these had been added. Finally, a yellow suspension was formed. This suspension was stirred under N2 at 25°C for 1 hour. LCMS showed that benzyl-L-alotreonine had been consumed and the desired mass was detected. The reactants were quenched with an aqueous hydrochloric acid solution (5 L, 10V, 4 mol / L) at 0°C to adjust the pH of the solution to 2. Next, ethyl acetate (5 L, 10V) was added to the reactants at 25°C. The solution was stirred under N2 at 25°C for 12 hours. LC-MS indicated that the intermediate had been consumed and that the desired mass had been detected. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (3 × 5 L). The combined organic layers were dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~3 / 1) to obtain (2S,3S)-4-benzyl-6,6-difluoro-2-methyl-5-oxomorpholine-3-carboxylic acid (250 g, 37% yield) as a gray solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 13.64 (br s, 1H),7.25 - 7.34 (m, 5 H), 4.75 - 4.83 (m, 2H), 4.13 - 4.16 (m, 2H), 1.28 (d, J=6.50Hz, 3 H).

[0549] Example 58: Synthesis of (5R,6S)-4-benzyl-2,2-difluoro-5-(hydroxymethyl-d2)-6-methylmorpholine-3-one (e2''). (2S,3S)-4-benzyl-6,6-difluoro-2-methyl-5-oxomorpholine-3-carboxylic acid (10 g, 35.06 mmol, 1 equivalent) was dissolved in THF (200 mL) and TEA (5.32 g, 52.59 mmol, 7.32 mL, 1.5 equivalents) was added. This solution was cooled to 0°C. Isobutyl chloroformate (7.18 g, 52.59 mmol, 6.88 mL, 1.5 equivalents) was added to this solution at 0°C. The mixture was stirred at 25°C for 30 minutes. LC-MS showed that (2S,3S)-4-benzyl-6,6-difluoro-2-methyl-5-oxomorpholine-3-carboxylic acid was consumed and the desired mass was detected. This reaction mixture was filtered. Sodium borodeuteride (1.46 g, 38.56 mmol, 1.1 equivalents) was dissolved in D2O (6 mL), and this solution was added to the filtrate at 0°C. The reaction mixture was then stirred at 25°C for 2 hours. LC-MS showed that all of the starting material had been consumed and the desired mass had been detected. Next, the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dehydrated with Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~3 / 1). The compound obtained as a colorless oil was (5R,6S)-4-benzyl-2,2-difluoro-5-(hydroxymethyl-d2)-6-methylmorpholine-3-one (6 g, 62.63% yield). 1H NMR(400 MHz, DMSO-d6): δ ppm 7.21 - 7.48 (m, 5H), 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).

[0550] Example 59: Synthesis of ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholine-3-yl)methane-d2-ol (g2). A solution of (5R,6S)-4-benzyl-2,2-difluoro-5-(hydroxymethyl-d2)-6-methylmorpholine-3-one (6 g, 21.96 mmol, 1 equivalent) in THF (12 mL) was added to a stirred solution of BH3.THF (1 M, 60.38 mL, 2.75 equivalents) at 0°C. The reaction mixture was heated to 45°C and stirred for 2.5 hours. LC-MS showed that all of the starting material was consumed and the desired mass was detected. The reaction mixture was poured into HCl (1 N), adjusted to pH 7, and then extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dehydrated with Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~3 / 1). ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholine-3-yl)methane-d2-ol (4.2 g, 73.78% yield) was obtained as a colorless oil. 1 H NMR(400 MHz, DMSO-d6): δ ppm 7.19 - 7.49 (m, 5H), 4.58 (s, 1 H), 4.45 (m, 1 H), 3.89 (s, 2 H), 2.78 - 3.02 (m, 2 H), 2.67 (brs, 1 H), 1.24 (d, J=6.75 Hz, 3 H).

[0551] 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-methylmorpholine-3-yl)methane-d2-ol (4.2 g, 16.20 mmol, 1 equivalent) in SiO (84 mL), Pd / C (861.91 mg, 10% purity, 0.05 equivalent) and (Boc)2O (4.95 g, 5.21 mL, 1.4 equivalent) were added. This mixture was stirred under H2 (15 Psi) at 20°C for 12 hours. TLC showed that all of the starting materials were consumed. The reaction product was filtered and concentrated to obtain the crude product. When the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 4 / 1), tert-butyl(2S,3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3-methylpiperidine-1-carboxylate (3.6 g, 82.53% yield) was obtained as a white solid. 1 H NMR(400 MHz, DMSO-d6): 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 (brd, J=13.88 Hz, 1 H), 3.13 - 3.29 (m, 1 H), 1.42 (s, 9 H), 1.23 (br d, J=6.75Hz, 3 H).

[0552] Example 61: Synthesis of tert-butyl(5R,6S)-5-((1,3-dioxoisoindoline-2-yl)methyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate(i2) To a solution of tert-butyl(2S,3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3-methylpiperidine-1-carboxylate (3.6 g, 1 equivalent) in THF (36 mL), isoindoline-1,3-dione (2.80 g, 19.05 mmol, 1.5 equivalents) and PPh3 (5.00 g, 1.5 equivalents) were added at 0°C. Next, DIAD (3.85 g, 1.5 equivalents) was added to this mixture. This mixture was stirred at 20°C for 16 hours. LCMS showed that all of the starting materials were consumed and the desired mass was detected. The reaction mixture was poured into ice water (50 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic layer was dried over Na2SO4 and filtered. The residue was concentrated under reduced pressure to obtain the final product. When the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 4 / 1), 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) was obtained as a white solid. 1 H NMR(400 MHz, DMSO-d6): δ ppm 7.74 - 8.02 (m, 4H), 4.42 (m, 1 H), 4.06 - 4.38 (m, 2 H), 3.37 - 3.67 (m, 1 H), 1.39 (d, J=6.63Hz, 3 H), 0.90 - 1.08 (m, 9 H).

[0553] Example 62: Synthesis of tert-butyl(5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate(j2). To a solution of tert-butyl(5R,6S)-5-((1,3-dioxoisoindolin-2-yl)methyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (3.4 g, 1 equivalent) in methyl alcohol (68 mL), hydrazine hydrate (4.06 g, 3.93 mL, 10 equivalents) was added at 25 °C. The mixture was then stirred at 60 °C for 2 hours under an N2 atmosphere. LC-MS indicated that all of the starting material had been consumed and the desired mass had been detected. The reaction mixture was filtered to obtain a filtrate, which was concentrated under reduced pressure to obtain the crude product. The crude product was used directly in 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. 1 H NMR(400 MHz, DMSO-d6): δ ppm 4.27 (br s, 1 H),4.14 (br t, J=15.01 Hz, 1 H), 3.82 - 4.03 (m, 1 H), 3.11 - 3.32 (m, 1 H), 1.43(s, 9 H), 1.20 (d, J=6.63 Hz, 3H).

[0554] Example 63: tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl-d2)morpholine-4-carboxylate(k2) [ka] To a solution of tert-butyl(5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (100 mg, 372.72 μmol, 1 equivalent) in DMSO (2 mL), DIPEA (96.34 mg, 745.44 μmol, 129.84 μL, 2 equivalents) and 2-chloro-5-(trifluoromethyl)pyrazine (81.64 mg, 447.27 μmol, 1.2 equivalents) were added at 25 °C. The mixture was then stirred at 80 °C for 2 hours. LC-MS indicated that all of the starting materials were consumed and the desired mass was detected. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic matter was washed with brine (30 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification of the crude product by preparative TLC (petroleum ether:ethyl acetate = 3:1) yielded tert-butyl(2S,3R)-5,5-difluoro-3-methyl-2-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl-d2)piperidine-1-carboxylate (115 mg, 67.01% yield) as a yellow oil. 1 HNMR(400 MHz, DMSO-d6): δ ppm 8.36 - 8.51 (m, 1H), 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).

[0555] Example 64: Synthesis of tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl-d2)morpholine-4-carboxylate(l2) [ka] To a DMSO (2.5 mL) solution of tert-butyl(5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (250 mg, 931.80 μmol, 1 equivalent) and 2-chloro-5-(trifluoromethyl)pyrimidine (204.10 mg, 1.12 mmol, 1.2 equivalents), DIPEA (240.85 mg, 1.86 mmol, 324.60 μL, 2 equivalents) was added. This mixture was stirred at 140°C for 5 hours. LCMS showed that the starting materials were consumed and the desired mass was detected. The reaction mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layer was washed with brine (10 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 5% ethyl acetate / petroleum ether gradient, 50 mL / min) to obtain tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl-d2)morpholine-4-carboxylate (650 mg, yield 84.17%) as a yellow oily substance. LCMS (ESI+): m / z=415.2 (M+1), RT: 0.586 min. Similarly, the following compounds were prepared.

[0556] Example 65: tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl-d2)morpholine-4-carboxylate(m2) [ka] The title compound (m2) was prepared using tert-butyl(5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 2-fluoro-5-(trifluoromethyl)pyridine in the same manner as described for compound (l2). Yield 42%, yellow oily substance. 1 H NMR(400 MHz, DMSO-d6): δ ppm 8.26 - 8.34 (m, 1H), 7.64 (br d, J=8.63 Hz, 1 H), 7.42 (s, 1 H), 6.60 (br d, J=8.88 Hz, 1 H),4.19 - 4.42 (m, 4 H), 1.31 (br d, J=6.38 Hz, 3 H), 1.07 (s, 9 H).

[0557] Example 66: tert-butyl(5R,6S)-5-(((5-chloropyridine-2-yl)amino)methyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate(n2) [ka] The title compound (n2) was prepared using tert-butyl(5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate and 5-chloro-2-fluoropyridine in the same manner as described for compound (l2). Yield 45%, yellow oil. 1 HNMR(400 MHz, DMSO-d6): δ ppm 7.91 - 8.01 (m, 1H), 7.32 - 7.48 (m, 1 H), 6.64 - 6.90 (m, 1 H), 6.40 - 6.54 (m, 1 H), 4.05 -4.40 (m, 3 H), 3.36 - 3.62 (m, 1 H), 1.30 (br s, 2 H), 1.29 (s, 3 H), 1.10 (s,7 H).

[0558] Example 67: Synthesis of N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl-d2)-5-(trifluoromethyl)pyrimidine-2-amine (ac2). [ka] A solution of tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl-d2)morpholine-4-carboxylate (200 mg, 482.66 μmol, 1 equivalent) in HCl / dioxane (2 mL) was stirred at 25°C for 1 hour. LC-MS showed that the starting material was completely consumed and the desired mass was detected. This reaction mixture was neutralized with aqueous Na2CO3 (5 mL) to pH 9 and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (10 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl-d2)-5-(trifluoromethyl)pyrimidine-2-amine (500 mg, yield 76.36%) as a yellow solid. LCMS (ESI+): m / z=315.2 (M+1), RT: 0.349 min. Similarly, the following compounds were prepared.

[0559] Example 68: N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl-d2)-5-(trifluoromethyl)pyridine-2-amine(ad2) [ka] The title compound (ad2) was prepared using tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl-d2)morpholine-4-carboxylate (m2), in the same manner as described for compound (ac2). Yield 70%, white solid. 1 H NMR(400 MHz, DMSO-d6): δ 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).

[0560] Example 69: N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl-d2)-5-(trifluoromethyl)pyrazine-2-amine hydrochloride (ab2) [ka] The title compound (ab2) was prepared using tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl-d2)morpholine-4-carboxylate (k2), in the same manner as described for compound (ac2). Yield 92%, yellow solid. 1 HNMR(400 MHz, DMSO-d6): 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).

[0561] Example 70: 5-Chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl-d2)pyridine-2-amine hydrochloride (aa2) [ka] The title compound (aa2) was prepared using tert-butyl(5R,6S)-5-(((5-chloropyridine-2-yl)amino)methyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (n2), in the same manner as described for compound (ac2). Yield 94%, yellow solid. 1 HNMR(400 MHz, DMSO-d6): δ ppm 8.05 (d, J=2.50Hz, 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).

[0562] Example 71: Synthesis of 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid [ka] To a solution of tert-butyl 4-iodo-1-methyl-1H-pyrazole-3-carboxylate (1.5 g, 4.87 mmol, 1 equivalent) in THF (60 mL) and H2O (15 mL), (4-cyanophenyl)boronic acid (929.95 mg, 6.33 mmol, 1.3 equivalents), K3PO4 (3.10 g, 14.60 mmol, 3 equivalents), and Pd(dtbpf)Cl2 (158.65 mg, 243.42 μmol, 0.05 equivalents) were added. This mixture was stirred at 80°C for 2 hours under N2. LC-MS showed that the starting materials were completely consumed and that one major peak with the desired mass was detected. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. When this residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1 to 30 / 1), tert-butyl 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylate (1.4 g, 4.94 mmol, 72.50% yield) was obtained as a brown solid. LCMS (ESI+): m / z=284.5 (M+1), RT: 0.718 min. 1 H NMR (400 MHz, DMSO-d6): 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 equivalent) in HCl / dioxane (15 mL) was stirred at 50°C for 2 hours. LC-MS showed that the starting material was completely consumed and that one major peak with the desired mass was detected. The reaction mixture was filtered, and the filter cake was dried to obtain 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (0.9 g, 3.96 mmol, 86.33% yield) as a brown solid. 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).

[0563] Example 72: Synthesis of 4-(5-cyanopyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid [ka] (3-(tert-butoxycarbonyl)-1-methyl-1H-pyrazole-4-yl)boronic acid (500 mg, 2.21 mmol, 1 equivalent) was dissolved in H2O (0.1 mL) and dioxane (0.5 mL). At 25°C, 6-bromopyridine-3-carbonitrile (485.78 mg, 2.65 mmol, 1.2 equivalents) and K3PO4 (1.41 g, 6.64 mmol, 3 equivalents) were added. This mixture was degassed and purged three times with N2. Next, ditert-butyl(cyclopentyl)phosphine dichloropalladium iron (72.08 mg, 110.60 μmol, 0.05 equivalents) was added to this reaction mixture at 25°C. This mixture was degassed and purged three times with N2 and stirred at 80°C for 2 hours. LC-MS showed that all of the starting material was consumed and the desired MS was detected. The reaction mixture was poured into H2O (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic matter was washed with brine (100 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification of this residue by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~1 / 2) yielded tert-butyl 4-(5-cyanopyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylate (520 mg, 82.68% yield) as a yellow solid. 1 ¹H 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-cyanopyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylate (520 mg, 1.83 mmol, 1 equivalent) in 4N / HCl dioxane (10 mL) was stirred at 20°C for 12 hours. LC-MS showed that all of the starting material was consumed and the desired MS was detected. The reaction mixture was filtered to obtain a filter cake, and the filter cake was dried under vacuum to obtain 4-(5-cyanopyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (470 mg, 97.09% yield, HCl) as a white solid. 1 H NMR:(400 MHz, DMSO-d6): 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).

[0564] Example 73: Synthesis of 1,5-dimethyl-4-(pyrazine-2-yl)-1H-pyrazole-3-carboxylic acid [ka] (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazole-4-yl)boronic acid (300 mg, 1.25 mmol, 1 equivalent) was dissolved in DMF (4.5 mL) and H2O (0.9 mL) at 20°C. K2CO3 (259.08 mg, 1.87 mmol, 1.5 equivalents) and 2-chloropyrazine (214.69 mg, 1.87 mmol, 167.34 μL, 1.5 equivalents) were added. The container was evacuated and backfilled with argon (this process was repeated three times). Palladium triphenylphosphine (23.04 mg, 62.48 μmol, 0.05 equivalents) was added to the mixture under argon, the container was evacuated, and backfilled with argon (this process was repeated three times). The mixture was stirred at 80°C for 16 hours. LC-MS showed that all of the starting material was consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in ethyl acetate (10 mL) and filtered; the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel (eluting ethyl acetate in petroleum ether from 0% to 100%) to obtain tert-butyl 1,5-dimethyl-4-(pyrazine-2-yl)-1H-pyrazole-3-carboxylate (270 mg, 78.76% yield) as a yellow oily substance. 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-(pyrazine-2-yl)-1H-pyrazole-3-carboxylate (270 mg, 984.26 μmol, 1 equivalent) in HCl / dioxane (4N, 6 mL) was stirred at 20°C for 16 hours. LC-MS indicated that all of the starting material was consumed and the desired mass was detected. When this reaction mixture was concentrated under reduced pressure, 1,5-dimethyl-4-(pyrazine-2-yl)-1H-pyrazole-3-carboxylic acid (210 mg, 97.78% yield) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.72 (d, J=1.00Hz, 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).

[0565] Example 74: Synthesis of 4-(5-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid [ka] (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazole-4-yl)boronic acid (300 mg, 1.25 mmol, 1 equivalent) was dissolved in DMF (4.5 mL) and H2O (0.9 mL). At 20°C, K2CO3 (259.08 mg, 1.87 mmol, 1.5 equivalents) and 3-chloro-5-fluoropyridine (246.56 mg, 1.87 mmol, 1.5 equivalents) were added. The container was evacuated and backfilled with argon (this process was repeated three times). Palladium triphenylphosphan (23.04 mg, 62.48 μmol, 0.05 equivalents) was added to the mixture under argon, the container was evacuated, and backfilled with argon (this process was repeated three times). The mixture was stirred at 80°C for 16 hours. LC-MS indicated that all of the starting material had been consumed and the desired mass had been detected. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in ethyl acetate (10 mL) and filtered; the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel (eluting ethyl acetate in petroleum ether from 0% to 100%) to obtain tert-butyl 4-(5-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (110 mg, 30.22% yield) as a yellow oily substance. 1 ¹H 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, 9 H). A solution of tert-butyl 4-(5-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (110 mg, 377.59 μmol, 1 equivalent) in HCl / dioxane (4N, 2.5 mL) was stirred at 20°C for 16 hours. LC-MS indicated that all of the starting material was consumed and the desired MS was detected. When this reaction mixture was concentrated under reduced pressure, 4-(5-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (87 mg, 97.96% yield) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.55 (d, J=2.75Hz, 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).

[0566] Example 75: Synthesis of 4-(4-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid [ka] A mixture consisting of (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazole-4-yl)boronic acid (0.3 g, 1.25 mmol, 1 equivalent), 3-chloro-4-fluoropyridine (164.38 mg, 1.25 mmol, 1 equivalent), K3PO4 (530.53 mg, 2.50 mmol, 128.17 μL, 2 equivalents), and [2-(2-aminophenyl)phenyl]-chloropalladium dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (98.32 mg, 124.97 μmol, 0.1 equivalent) in H2O (0.225 mL) and butan-1-ol (0.9 mL) was degassed and purged three times with argon, and then the mixture was stirred at 100°C for 3 hours under an argon atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic matter was washed with brine (20 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether at 0% to 60%, yielding tert-butyl 4-(4-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (0.27 g, 74.16% yield) as a colorless oil. 1 H NMR(400 MHz, DMSO-d6): 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-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (0.27 g, 926.82 μmol, 1 equivalent) in HCl / dioxane (4N, 3 mL) was stirred at 20°C for 12 hours. LC-MS indicated that the reaction was complete. When this reaction mixture was concentrated under reduced pressure, 4-(4-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (0.21 g, 96.33% yield) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.75 - 9.02 (m, 2H), 7.93 (dd, J=8.69, 6.32 Hz, 1 H), 3.90 (s, 3 H), 2.22 (s, 3 H).

[0567] Example 76: Synthesis of 4-(4-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid [ka] (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazole-4-yl)boronic acid (300 mg, 1.25 mmol, 1 equivalent) was dissolved in DMF (4.5 mL) and H2O (0.9 mL). At 20°C, K2CO3 (259.08 mg, 1.87 mmol, 1.5 equivalent) and 2-chloro-4-fluoropyridine (246.56 mg, 1.87 mmol, 1.5 equivalent) were added. The container was evacuated and backfilled with argon (this process was repeated three times). Palladium triphenylphosphine (23.04 mg, 62.48 μmol, 0.05 equivalent) was added to the mixture under argon, the container was evacuated, and backfilled with argon (this process was repeated three times). The mixture was stirred at 80°C for 16 hours. LC-MS indicated that all of the starting material had been consumed and the desired mass had been detected. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in ethyl acetate (10 mL) and filtered; the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel (eluting ethyl acetate in petroleum ether from 0% to 100%) to obtain tert-butyl 4-(4-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (90 mg, 24.72% yield) as a yellow oily substance. 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, 3H), 2.32 (s, 3H), 1.45 (s, 9H). A solution of tert-butyl 4-(4-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (90 mg, 308.94 μmol, 1 equivalent) in HCl / dioxane (4N, 2 mL) was stirred at 20°C for 16 hours. LC-MS indicated that all of the starting material was consumed and the desired mass was detected. When this reaction mixture was concentrated under reduced pressure, 4-(4-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (70 mg, 96.33% yield) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.86 (t, J=6.88Hz, 1 H), 7.71 - 7.97 (m, 1 H), 7.61 - 7.69 (m, 1 H), 3.89 (s, 3 H), 2.34 (s, 3H).

[0568] Example 77: Synthesis of 5-(5-fluoropyrimidine-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid [ka] A suspension of methyl 5-bromo-1-methyl-1H-imidazole-4-carboxylate (2 g, 9.13 mmol, 1 equivalent) in toluene (20 mL) at 20°C was degassed and purged three times with N2. To this reaction mixture, Pd(PPh3)4 (1.06 g, 913.09 μmol, 0.1 equivalent) and trimethyl(trimethylstanyl) stannan (5.98 g, 18.26 mmol, 3.79 mL, 2 equivalents) were added at 20°C. This suspension was degassed and purged three times with N2, and then the mixture was stirred under N2 at 120°C for 6 hours. LC-MS showed that all of the starting materials were consumed and the desired Ms was detected. The reaction mixture was concentrated under reduced pressure to obtain the crude product. When this residue was purified by column chromatography (Al2O3, petroleum ether / ethyl acetate = 1 / 0~0 / 1), methyl 1-methyl-5-(trimethylstanyl)-1H-imidazole-4-carboxylate (1.7g, yield 49.17%) was obtained as a yellow oily substance. 1 H NMR(400 MHz, DMSO-d6): 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). To a solution of methyl-1-methyl-5-(trimethylstanyl)-1H-imidazole-4-carboxylate (1 g, 2.64 mmol, 1 equivalent) in xylene (20 mL), 2-bromo-5-fluoropyrimidine (701.02 mg, 3.96 mmol, 1.5 equivalents) was added at 20 °C. This suspension was degassed and purged three times with N2. Pd(PPh3)4 (305.15 mg, 264.07 μmol, 0.1 equivalent) was added to this reaction mixture at 20 °C. This suspension was degassed and purged three times with N2. Next, the mixture was stirred under N2 at 140 °C for 16 hours. LC-MS showed that all of the starting material was consumed and the desired Ms was detected. The residue was quenched with water (20 mL) and extracted with dichloromethane (5 × 30 mL). The combined organic matter was washed with brine (30 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1). Crude methyl 5-(5-fluoropyrimidine-2-yl)-1-methyl-1H-imidazole-4-carboxylate (600 mg, yield 67.33%) was obtained as a brown solid. LCMS (ESI+): m / z=237.3 (M+1), RT: 0.186 min. Methyl 5-(5-fluoropyrimidine-2-yl)-1-methyl-1H-imidazole-4-carboxylate (600 mg, 1.78 mmol, 1 equivalent) was dissolved in 6N HCl (12 mL) at 20°C, and the mixture was stirred at 80°C for 2 hours. LC-MS showed that all of the starting material was consumed and the desired Ms was detected. The residue was quenched with water (10 mL) and extracted with ethyl acetate (3 × 30 mL). The aqueous phase was concentrated under reduced pressure to obtain the crude product. The crude product was used directly in the next step. Crude 5-(5-fluoropyrimidine-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid (400 mg, yield 69.58%) was obtained as a yellow solid and was used without further purification. LCMS(ESI+): m / z=223.2(M+1), RT: 0.255 min

[0569] Example 78: Synthesis of 5-(5-methoxypyridine-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid [ka] To a solution of methyl 5-bromo-1-methyl-1H-imidazole-4-carboxylate (500 mg, 2.28 mmol, 1 equivalent) in xylene (10 mL), Pd(PPh3)4 (263.78 mg, 228.27 μmol, 0.1 equivalent) was added at 20 °C. This suspension was degassed and purged three times with N2. Tributyl-(5-methoxy-2-pyridyl) stannane (1.09 g, 2.74 mmol, 1.2 equivalents) was added to this reaction mixture at 20 °C. This suspension was degassed and purged three times with N2. Next, the mixture was stirred under N2 at 140 °C for 16 hours. LC-MS showed that all of the starting material was consumed and the desired Ms was detected. The residue was quenched with water (20 mL) and extracted with ethyl acetate (4 × 20 mL). The combined organic matter was washed with brine (30 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 4 to 0 / 1). The compound methyl 5-(5-methoxypyridine-2-yl)-1-methyl-1H-imidazole-4-carboxylate (400 mg, yield 67.33%) was obtained as a bright yellow solid. 1 H NMR(400 MHz, DMSO-d6): δ ppm 8.40 (d, J=2.63Hz, 0.95 H) 7.81 (s, 1.00 H) 7.63 (d, J=8.25 Hz, 1.05 H) 7.49 (dd, J=8.76, 3.10Hz, 1.00 H) 3.90 (s, 3.00 H) 3.63 (s, 3 H) 3.56 (s, 3.00 H). A solution of methyl 5-(5-methoxypyridine-2-yl)-1-methyl-1H-imidazole-4-carboxylate (200 mg, 768.45 μmol, 1 equivalent) in 6N HCl (4 mL) was stirred at 80°C for 24 hours. LC-MS indicated that all of the starting material was consumed and the desired Ms was detected. Concentration of this reaction mixture under reduced pressure yielded crude 5-(5-methoxypyridine-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid (220 mg, 95.54% yield) as a yellow solid. The crude product was used directly in the next step. 1 H NMR(400 MHz, DMSO-d6): δ ppm 9.35 (s, 0.95 H)8.48 (d, J=2.75 Hz, 0.95 H) 7.82 (d, J=8.75 Hz, 1.00 H) 7.62 (dd, J=8.76, 3.00Hz, 1.15 H) 3.93 (s, 3.05 H) 3.74 (s, 3.00 H).

[0570] Example 79: Synthesis of 4-(5-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid [ka] To a solution of 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (10 g, 46.65 mmol, 1 equivalent) in THF (50 mL) and t-BuOH (50 mL), DMAP (557.75 mg, 4.57 mmol, 0.1 equivalent) and tert-butoxycarbonyl tert-butyl carbonate (29.89 g, 136.96 mmol, 3 equivalents) were added at 20°C, and the mixture was stirred at 20°C for 12 hours. LC-MS showed that all of the starting material was consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. This 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), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. When the crude product was purified by column chromatography on silica gel (eluting 0% to 20% of ethyl acetate in petroleum ether), tert-butyl 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylate (3.5 g, yield 27.86%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ ppm 3.84 (s, 3.00 H)2.25 (s, 3.00 H) 1.51 (s, 9.00 H). To a solution of tert-butyl 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylate (3.5 g, 12.72 mmol, 1 equivalent) and triisopropyl borate (3.59 g, 19.08 mmol, 4.39 mL, 1.5 equivalents) in THF (70 mL), n-BuLi (1.22 g, 19.08 mmol, 1.5 equivalents) was added dropwise at -78°C, and the mixture was stirred at -78°C for 1 hour. LC-MS showed that all of the starting materials were consumed and the desired mass was detected. The reaction mixture was quenched by adding saturated ammonium chloride solution (50 mL) at 0°C, then diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (100 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was triturated at 20°C with petroleum ether:ethyl acetate (50 mL, 10:1) 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-pyrazole-4-yl)boronic acid (2.52 g, yield 82.52%) as a white solid. 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). A mixture consisting of (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazole-4-yl)boronic acid (2.5 g, 10.41 mmol, 1 equivalent) in DMF (37.5 mL) was mixed with 2-bromo-5-fluoropyridine (2.75 g, 15.62 mmol, 1.5 equivalents), and then a solution of K2CO3 (2.16 g, 15.62 mmol, 1.5 equivalents) in H2O (7.5 mL) was added at 20°C. The container was evacuated and backfilled with argon (this process was repeated three times), and then palladium triphenylphosphine (601.70 mg, 520.70 μmol, 0.05 equivalents) was added to the mixture under argon. The container was evacuated and backfilled with argon (this process was repeated three times), and then the mixture was stirred at 80°C for 12 hours. LC-MS showed that all of the starting materials were consumed and the desired mass was detected. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (100 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel (eluting ethyl acetate in petroleum ether at 0% to 20%) to obtain tert-butyl 4-(5-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (2.51 g, yield 82.73%) as a bright yellow solid. LCMS (ESI+): m / z=292.0 (M+1), RT: 0.417 min. A solution of tert-butyl 4-(5-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (2.5 g, 8.58 mmol, 1 equivalent) in HCl / dioxane (4 M, 50 mL) was stirred at 20°C for 12 hours. LC-MS indicated that all of the starting material was consumed and the desired mass was detected. When this reaction mixture was concentrated under reduced pressure, 4-(5-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (2.3 g, yield 98.65%, HCl) was obtained as a white solid. 1H NMR(400 MHz, DMSO-d6): δ ppm 8.62 (d, J=2.88Hz, 1.00 H) 7.79 (td, J=8.76, 3.00 Hz, 1.00 H) 7.58 (dd, J=8.82, 4.57 Hz, 1.00H) 3.85 (s, 3.00 H) 2.27 (s, 3.00 H).

[0571] Example 80: Synthesis of 4-(5-methoxypyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid [ka] To a solution of (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazole-4-yl)boronic acid (1 g, 3.04 mmol, 1 equivalent) in DMF (7.2 mL), a solution of 2-bromo-5-methoxypyridine (571.75 mg, 3.04 mmol, 1 equivalent) and K2CO3 (630.42 mg, 4.56 mmol, 1.5 equivalents) in H2O (1.44 mL) was added at 20°C, followed by evacuating the container and backfilling with N2 (this process was repeated three times). Next, under N2 conditions, Pd(PPh3)4 (175.70 mg, 152.04 μmol, 0.05 equivalents) was added to this mixture, followed by evacuating the container and backfilling with N2 (this process was repeated three times). Finally, this mixture was stirred at 80°C for 12 hours. LC-MS indicated that the starting materials had been consumed and that a product with the desired mass had been detected. The reaction solution was poured into ice water (20 mL), extracted with ethyl acetate (3 × 30 mL), the combined organic layer was washed with brine (20 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel (eluting 0% to 50% of ethyl acetate in petroleum ether) to obtain tert-butyl 4-(5-methoxypyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (0.5 g, 50.95% yield) as a white solid. 1H NMR(400 MHz, DMSO-d6): 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-methoxypyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (0.5 g, 1.55 mmol, 1 equivalent) in dioxane / HCl(4N) (10 mL) was stirred at 20°C for 12 hours. LC-MS indicated that the starting material had been consumed and that a product with the desired mass was detected. The reaction mixture was filtered, and the filter cake was dried under high vacuum to obtain 4-(5-methoxypyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (0.37 g, 76.79% yield) as a white solid. 1 H NMR(400 MHz, DMSO-d6): 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.

[0572] Example 81: 3-(5-fluoropyrimidine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid [ka] To a solution of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (25 g, 164.31 mmol, 1 equivalent) in DCM (370 mL), Br2 (52.52 g, 328.62 mmol, 16.93 mL, 2 equivalents) was added dropwise at 0°C. The reaction mixture was then stirred at 0°C for 2 hours. LC-MS indicated that the starting material had been consumed and that a product with the desired mass had been detected. The reaction mixture was quenched by adding saturated sodium thiosulfate aqueous solution (100 mL), the reaction solution was filtered, and the filter cake was dehydrated under high pressure to obtain 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (36.5 g, 95.18% yield) as a yellow solid. 1 H NMR(400 MHz, DMSO-d6): δ = 4.13 - 4.24 (m, 2H), 2.82 (t, J=7.32 Hz, 2 H), 2.55 (dt, J=14.85, 7.52 Hz, 2 H). 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (10 g, 42.85 mmol, 1 equivalent) was dissolved in THF (200 mL) and 2-tert-butyl-3-isopropyl-1,1-dimethyl-isourea (23.95 g, 128.55 mmol, 3 equivalents) was added at 0°C. The mixture was stirred at 20°C for 16 hours. TLC showed that the starting material had been completely consumed and that new spots had been detected. The reaction mixture was quenched by adding saturated ammonium chloride aqueous solution (500 mL), extracted with ethyl acetate (2 × 300 mL), washed with brine (200 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. When the residue was purified by column chromatography on silica gel (eluting 0% to 50% of ethyl acetate in petroleum ether), tert-butyl 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (10 g, 77.21% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6): 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[1,2-b]pyrazole-2-carboxylate (2.5 g, 8.27 mmol, 1 equivalent) in THF (40 mL), triisopropyl borate (2.33 g, 12.41 mmol, 2.85 mL, 1.5 equivalents) was added at 20 °C. Next, n-BuLi (2.5 M, 4.96 mL, 1.5 equivalents) was added dropwise to this mixture at -78 °C, and the mixture was stirred at -78 °C for 2 hours. LC-MS showed that a product with the desired mass was detected. This reaction mixture was quenched by adding saturated ammonium chloride aqueous solution (100 mL) and then extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by column chromatography on silica gel (eluting 0% to 50% methanol in ethyl acetate) to yield (2-(tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl)boronic acid (0.9 g, 35.40% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ = 4.08 - 4.15 (m, 2H), 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[1,2-b]pyrazole-3-yl)boronic acid (0.9 g, 2.93 mmol, 1 equivalent) in DMF (13.5 mL), a solution of 2-bromo-5-fluoropyrimidine (518.13 mg, 2.93 mmol, 1 equivalent) and K2CO3 (606.94 mg, 4.39 mmol, 1.5 equivalents) in H2O (3 mL) was added at 20°C, and the container was evacuated and backfilled with N2 (this process was repeated 3 times). Next, under N2 conditions, Pd(PPh3)4 (53.97 mg, 146.39 μmol, 0.05 equivalents) was added to this mixture, and the container was evacuated and backfilled with N2 (this process was repeated 3 times). Next, the mixture was stirred at 80°C for 12 hours. LC-MS indicated that the starting materials had been consumed and that a product with the desired mass had been detected. The reaction solution was poured into ice water (50 mL), extracted with ethyl acetate (3 × 30 mL), washed with brine (20 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel (eluting 0% to 30% of ethyl acetate in petroleum ether) to obtain tert-butyl 3-(5-fluoropyrimidine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (0.78 g, 73.54% yield) as a yellow solid. 1 H NMR(400 MHz, DMSO-d6): 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 (quintet, J=7.33 Hz, 2 H), 1.45 (s, 9 H). A solution of tert-butyl 3-(5-fluoropyrimidine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (0.78 g, 2.15 mmol, 1 equivalent) in 4N HCl / dioxane (16 mL) was stirred at 20°C for 1 hour. LC-MS indicated that the starting material had been consumed and that a product with the desired mass was detected. When this reaction solution was concentrated under reduced pressure, 3-(5-fluoropyrimidine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (0.45 g, 82.52% yield, 98% purity) was obtained as a white solid. 1 H NMR(400 MHz, DMSO-d6): δ = 14.44 - 15.49 (m, 1H), 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, 2H). LCMS (ESI+): m / z=249.1 (M+1), RT: 0.322 min.

[0573] Example 82: 5,6-Dimethyl-3-(pyrimidine-2-yl)picolinic acid [ka] To a solution of 3-bromo-5,6-dimethylpyridine-2-amine (4.2 g, 20.89 mmol, 1 equivalent) in dioxane (85 mL), tributyl(pyrimidine-2-yl) stannane (9.25 g, 25.07 mmol, 1.2 equivalents) and CsF (6.35 g, 41.78 mmol, 2 equivalents) were added. This mixture was degassed and purged with argon three times. Next, CuI (397.83 mg, 2.09 mmol, 0.1 equivalent) and palladium triphenylphosphane (770.17 mg, 2.09 mmol, 0.1 equivalent) were added to this mixture at 20°C, and this mixture was degassed and purged with argon three times. This mixture was stirred at 100°C for 16 hours. LCMS showed that all of the starting material was consumed and the desired mass was detected. This mixture was filtered, and the filtrate was then concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography on silica gel (eluting 0% to 40% of ethyl acetate in petroleum ether) to obtain 5,6-dimethyl-3-(pyrimidine-2-yl)pyridine-2-amine (3.6 g, 86.07% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.86 (d, J=4.88Hz, 2 H), 8.37 (s, 1 H), 7.33 (t, J=4.88 Hz, 1 H), 2.30 (s, 3 H), 2.16 (s, 3H). To a solution of 5,6-dimethyl-3-(pyrimidine-2-yl)pyridine-2-amine (2 g, 9.99 mmol, 1 equivalent) in AcOH (20 mL), H2SO4 (3.2 mL) was added dropwise at 0°C. Next, a solution of NaNO2 (1.38 g, 19.98 mmol, 2 equivalents) in H2O (10 mL) was added dropwise at 0°C. This mixture was stirred at 20°C for 2 hours. LC-MS showed that all of the starting material was consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC. 5,6-dimethyl-3-(pyrimidine-2-yl)pyridine-2-ol (1.62 g, 80.60% yield) was obtained as a yellow solid. 1H NMR(400 MHz, DMSO-d6): 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 28 mL solution of 5,6-dimethyl-3-(pyrimidine-2-yl)pyridine-2-ol (1.4 g, 6.96 mmol, 1 equivalent) in DCM, DIPEA (3.60 g, 27.83 mmol, 4.85 mL, 4 equivalents) was added at 20°C. Then, trifluoromethylsulfonyl trifluoromethanesulfonate (2.94 g, 10.44 mmol, 1.72 mL, 1.5 equivalents) was added dropwise at 0°C. The mixture was stirred at 30°C for 16 hours. LC-MS showed that all of the starting material had been consumed and the desired mass had been 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), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography on silica gel (eluting 0% to 20% of ethyl acetate in petroleum ether) to obtain the residue. 5,6-dimethyl-3-(pyrimidine-2-yl)pyridine-2-yl trifluoromethanesulfonic acid (1.9 g, 81.94% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.98 (d, J=4.88Hz, 2 H), 8.48 (s, 1 H), 7.58 (t, J=4.88 Hz, 1 H), 2.50 (s, 3 H), 2.40 (s, 3H). To a methanol (40 mL) solution of 5,6-dimethyl-3-(pyrimidine-2-yl)pyridin-2-yl trifluoromethanesulfonic acid, Pd(dppf)Cl2 (417.13 mg, 570.08 μmol, 0.1 equivalent) and TEA (1.73 g, 17.10 mmol, 2.38 mL, 3 equivalents) were added at 20°C. This mixture was stirred at 70°C for 16 hours under CO (50 psi). LC-MS showed that all of the starting materials were consumed and the desired mass was detected. The reaction mixture was filtered, and 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), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. When the residue was purified by column chromatography on silica gel (eluting 0% to 20% of ethyl acetate in petroleum ether), methyl 5,6-dimethyl-3-(pyrimidine-2-yl)picolinate (500 mg, 36.05% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.90 (d, J=4.88Hz, 2 H), 8.29 (s, 1 H), 7.49 (t, J=4.94 Hz, 1 H), 3.72 (s, 3 H), 2.50 (s, 3H), 2.37 (s, 3 H). To a solution of methyl 5,6-dimethyl-3-(pyrimidine-2-yl)picolinate (100 mg, 411.08 μmol, 1 equivalent) in methanol (0.5 mL), THF (0.5 mL), and H2O (0.5 mL), LiOH.H2O (34.50 mg, 822.16 μmol, 2 equivalents) was added at 20°C. This mixture was stirred at 20°C for 3 hours. LC-MS showed that all of the starting material was consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. The phase was adjusted to pH=3 with 1N HCl 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 layers were washed with saturated sodium chloride solution (10 mL x 1), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5,6-dimethyl-3-(pyrimidine-2-yl)picolinic acid (90 mg, 95.51% yield) as a yellow solid. 1 H NMR(400 MHz, DMSO-d6): 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, 3 H).

[0574] Example 83: 4,6-Dimethyl-3-(pyrimidine-2-yl)picolinic acid [ka] A mixture consisting of 5-bromo-2,4-dimethylpyridine (1.00 g, 5.37 mmol, 1 equivalent), tributyl(pyrimidine-2-yl) stannan (2.38 g, 6.45 mmol, 1.2 equivalents), CsF (1.63 g, 10.75 mmol, 2 equivalents), Pd(PPh3)4 (621.11 mg, 537.49 μmol, 0.1 equivalent), and CuI (102.37 mg, 537.49 μmol, 0.1 equivalent) in 20 mL of dioxane was degassed and purged three times with argon. The mixture was then stirred at 100°C for 16 hours under an argon atmosphere. LC-MS indicated that the reaction was complete. The reaction product was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. When the crude product was purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether at concentrations of 0% to 60%, 2-(4,6-dimethylpyridine-3-yl)pyrimidine (0.5 g, 50.22% yield) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.95 (d, J=4.88Hz, 2 H), 8.84 (s, 1 H), 7.49 (t, J=4.88 Hz, 1 H), 7.23 (s, 1 H), 2.52 (s, 3H), 2.49 (s, 3 H). To a 10 mL solution of 2-(4,6-dimethylpyridine-3-yl)pyrimidine (0.5 g, 2.70 mmol, 1 equivalent) in DCM, m-CPBA (822.05 mg, 4.05 mmol, 85% purity, 1.5 equivalents) was added in small portions at 0°C. This mixture was stirred at 20°C for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was quenched at 0°C by adding Na2SO3 (20 mL), then the pH was adjusted to 8 with NaHCO3 at 0°C, and finally 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), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain 2,4-dimethyl-5-(pyrimidine-2-yl)pyridine 1-oxide (0.5 g, 92.05% yield) as a white solid. 1H NMR(400 MHz, DMSO-d6): δ ppm 8.97 (d, J=5.02Hz, 2 H), 8.61 (s, 1 H), 7.55 (t, J=4.89 Hz, 1 H), 7.44 - 7.51 (m, 1 H), 2.50(s, 3 H), 2.39 (s, 3 H). To a 10 mL solution of 2,4-dimethyl-5-(pyrimidine-2-yl)pyridine 1-oxide (0.5 g, 2.48 mmol, 1 equivalent) in DCM, TMSCN (739.55 mg, 7.45 mmol, 932.60 μL, 3 equivalents) was added, and the mixture was stirred at 20°C for 1 hour. Next, N,N-dimethylcarbamoyl chloride (400.82 mg, 3.73 mmol, 341.99 μL, 1.5 equivalents) was added to the mixture, and the mixture was stirred at 20°C for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was diluted with water (20 mL), adjusted to pH=8 with aqueous NaHCO3 at 0°C, and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 1), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by column chromatography on silica gel eluted with 0% to 30% ethyl acetate in petroleum ether to obtain 4,6-dimethyl-3-(pyrimidine-2-yl)picolinonitrile (0.4 g, 76.57% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ ppm 9.06 (d, J=4.88Hz, 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-(pyrimidine-2-yl)picolinonitrile (0.3 g, 1.43 mmol, 1 equivalent) in methanol (3 mL) and H2O (3 mL), NaOH (171.23 mg, 4.28 mmol, 3 equivalents) was added, and the mixture was stirred at 60°C for 48 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in water (10 mL), and the pH was adjusted to 5 with 1N HCl at 0°C. The mixture was then freeze-dried to obtain 4,6-dimethyl-3-(pyrimidine-2-yl)picolinic acid (0.8 g, 85.60% yield, 35% purity) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.89 (d, J=5.00Hz, 2 H), 7.49 (t, J=4.88 Hz, 1 H), 7.45 (s, 1 H), 2.54 (s, 3 H), 2.20 (s, 3H).

[0575] Example 84: 4-Chloro-6-methyl-3-(pyrimidine-2-yl)picolinic acid [ka] To a solution of 3-bromo-6-methylpicolinic acid (5 g, 23.14 mmol, 1 equivalent) in MeOH (50 mL), H2SO4 (2.27 g, 23.14 mmol, 1.23 mL, 1 equivalent) was added at 20 °C and stirred at 70 °C for 16 hours. LC-MS showed that all the starting materials were consumed and that a product with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. This residue was diluted with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with saturated sodium chloride aqueous solution (40 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl 3-bromo-6-methylpicolinate (5 g, 93.90% yield) as a yellow oil. 1¹H 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). To a solution of methyl 3-bromo-6-methyl picolinate (4 g, 17.39 mmol, 1 equivalent), tributyl(pyrimidine-2-yl) stannan (7.70 g, 20.86 mmol, 1.2 equivalents), and cesium fluoride (5.28 g, 34.77 mmol, 2 equivalents) in dioxane (80 mL), copper iodide (331.13 mg, 1.74 mmol, 0.1 equivalent) and palladium triphenylphosphane (2.01 g, 1.74 mmol, 0.1 equivalent) were added under N2 at 20°C. This mixture was stirred at 100°C for 16 hours. LC-MS showed th...

Claims

1. Compounds of formula I, or pharmaceutically acceptable salts and derivatives thereof. 【Chemistry 1】 (In the formula, X and X' are halogens, such as fluorine; Het represents a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof, and the heteroaromatic group is unsubstituted, mono-substituted, or di-substituted, and the substituent of the heteroaromatic group, when present, is unsubstituted (C １ , ８ , ８ , ４ , ３ , ４ , １ , ４ , １ ~C ４ )-linear alkyl, unsubstituted (C １ ~C ４ )-branched alkyl, unsubstituted (C １ ~C ４ )-alkoxy group, unsubstituted (C<1000007>~C ８ )-cycloalkyl, substituted (C １ ~C ４ )-linear alkyl, substituted (C １ ~C ４ )-branched alkyl, substituted (C １ ~C ４ )-alkoxy group, substituted (C ３ ~C ８ )-cycloalkyl, and is independently selected from the group consisting of a cyano group and a halogen; R is selected from the group consisting of five-membered or six-membered aromatic groups or heteroaromatic groups, and the aromatic group or heteroaromatic group is either unsubstituted or substituted with one or more substituents.

2. The compound of formula I is a 5R,6S stereoisomer: 【Chemistry 2】 The compound according to claim 1.

3. The compound of formula I has the following structure: 【Transformation 3】 (wherein X, X', Het, and R are each independently as defined herein with respect to Formula I; R ６ and R ７ (Each is independently hydrogen or deuterium.) The compound according to claim 1, which is a deuterated compound having one or more hydrogen atoms replaced by one or more deuterium atoms.

4. The substituents of the heteroaromatic group of Het are (C １ ~C ４ )-Fluoroalkyl, (C ３ ~C ８ )-cycloalkyl, cyano group, (C １ ~C ４ ) - Alkoxy or halogen; preferably, the substituent of the heteroaromatic group of Het is Cl, F, CHF ２ CF ３ ,CH ３ The compound according to any one of claims 1 to 3, wherein the compound is methoxy, nitrile, or cyclopropyl.

5. The compound according to any one of claims 1 to 4, wherein R is a five-membered heteroaromatic group which is an unsubstituted pyrazole, unsubstituted oxazole, unsubstituted thiazole, unsubstituted imidazole, substituted pyrazole, substituted oxazole, substituted thiazole, substituted imidazole or a derivative thereof; an unsubstituted aryl or substituted aryl or a derivative thereof, which is a six-membered heteroaromatic group; or an unsubstituted pyridine, unsubstituted pyrimidine, unsubstituted pyridazine, unsubstituted pyrazine, substituted pyridine, substituted pyrimidine, substituted pyridazine, substituted pyrazine or a derivative thereof, which is a six-membered heteroaromatic group.

6. R is, 【Chemistry 4】 (In the formula, R ３ and R ４ is hydrogen, (C １ ~C １０ ) - Linear alkyl; (C １ ~C １０ ) - branched alkyl; (C １ ~C １０ ) - Substituted or unsubstituted alkyl, optionally (C １ ~C ４ ) - Linear alkyl; (C １ ~C ４ ) - branched alkyl; and (C １ ~C ４ )-substituted or unsubstituted alkyl, deuterated (C １ ~C ４ ) - Linear alkyl; deuterated (C １ ~C ４ ) - Independently selected from the group consisting of branched alkyl groups; R ３ and R ４ The ring may form a condensation substitution or an unsubstituted ring; preferably, R ３ and R ４ Each is independent of the other, -CH ３ or -CD ３ And; Y represents an aromatic group or a heteroaromatic group; a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, and Y is independently selected from the group consisting of aryl, pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, nicotinonitrile, benzonitrile, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof, and the substituent is unsubstituted or substituted (C １ ~C ４ ) - alkyl group, unsubstituted or substituted (C １ ~C ４ ) - Independently selected from the group consisting of alkoxy groups, cyano groups, and halogens; preferably, the halogen is fluorine, bromine, or chlorine. The compound according to any one of claims 1 to 5.

7. The aromatic group or heteroaromatic group of Y is CN, F, Cl, CH ３ Alternatively, it is substituted with an -O-alkyl group, where the alkyl group contains 1 to 4 carbon atoms, and preferably the O-alkyl group is -OCH ３ The compound according to claim 6.

8. Y, 【Transformation 5】 A compound according to claim 6 or 7, selected from the group consisting of the following.

9. R is, 【Transformation 6】 A compound according to any one of claims 1 to 8, selected from the group consisting of the following.

10. R is, 【Transformation 7】 (In the formula, R １ and R ２ is hydrogen, unsubstituted (C １ ~C ６ ) - Linear alkyl group; unsubstituted (C １ ~C ６ ) - Branched alkyl group; substitution (C １ ~C ６ ) - Linear alkyl group; substitution (C １ ~C ６ ) - Branched alkyl group; Deuterated (C １ ~C ６ )-Linear alkyl, deuterated (C １ ~C ６ ) - Each is independently selected from the group consisting of branched alkyls and halogens; preferably, the halogen includes fluorine, chlorine or bromine; preferably, R １ H, Cl, F, CH ３ or CD ３ And; Het' is a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof, wherein the heteroaromatic group is unsubstituted, monosubstituted, or disubstituted, and the substituents of the heteroaromatic group, if present, are (C １ ~C ４ ) - Linear or branched alkyl, substituted linear or branched (C １ ~C ４ ) - Independently selected from the group consisting of alkyl and halogen; preferably, the substituent is F, Cl or CH ３ (is) The compound according to any one of claims 1 to 5.

11. The aforementioned Het' is, 【Transformation 8】 A compound according to any one of claims 1 to 5 and 10, selected from among them.

12. R is, 【Chemistry 9】 A compound according to any one of claims 1 to 5 and 10 and 11, selected from the group consisting of the above.

13. Het, 【Chemistry 10】 A compound according to any one of claims 1 to 12, selected from the group consisting of the following.

14. Structure of equations I(a) to I(q): 【Chemistry 11】 【change】 【change】 (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ (Het, Het', and Y are each independently defined in any one of claims 1 to 13.) A compound having the following properties. 【Request Item 15】 【Chemistry 12】 【change】 【change】 【change】 【change】 Or a compound according to any one of claims 1 to 9, 13, and 14, selected from the group consisting of pharmaceutically acceptable salts and derivatives thereof. 【Request Item 16】 【Chemistry 13】 【change】 or a compound according to any one of claims 1 to 5 and 10 to 14, selected from the group consisting of pharmaceutically acceptable salts and derivatives thereof.

17. Compounds of formula I-aa, or pharmaceutically acceptable salts and derivatives thereof. 【Chemistry 14】 (In the formula, R ６ and R ７ Each is independently either H or deuterium; R ８ is CF ３ ; and W １ is -CH, N, or -C-O-CH ３ Selected from; W ２ -CH, N, -C-CH ３ Selected from; R is selected from a five-membered heteroaromatic group comprising an unsubstituted pyrazole, an unsubstituted oxazole, an unsubstituted thiazole, an unsubstituted imidazole, a substituted pyrazole, a substituted oxazole, a substituted thiazole, a substituted imidazole, or a derivative thereof; or a six-membered heteroaromatic group comprising an unsubstituted pyridine, an unsubstituted pyrimidine, an unsubstituted pyridazine, an unsubstituted pyrazine, a substituted pyridine, a substituted pyrimidine, a substituted pyridazine, or a derivative thereof.

18. R is, 【Chemistry 15】 (In the formula, R ３ and R ４ are each independently, -CH ３ or -CD ３ ; Y is, 【Chemistry 16】 And; Het' is, 【Chemistry 17】 (is) A compound according to claim 17, selected from the above.

19. The compound of formula I-aa is [Chemistry 18] A compound according to claim 17 or 18, selected from the above.

20. The compound according to any one of claims 1 to 19, wherein the pharmaceutically acceptable salts and derivatives are selected from the group consisting of hydrochloride, chloride, bromide, iodide, potassium salt, sodium salt, acetate, trifluoroacetate, sulfate, sulfonate, oxalate, maleate, malonate, nitrate, tartrate, gluconate, succinate, mesylate, citrate, phosphate or diphosphate, aluminate, enantiomer, solvate, adduct, polymorph, hydrate, tautomer, isomer, prodrug, isotope-labeled or radioactively labeled derivative, and mixtures thereof.

21. The compound according to any one of claims 1 to 20, wherein the compounds of formulas I and I(a to q) are deuterated, and at least one hydrogen atom is replaced by 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 in the form of a tablet or a capsule.

23. A compound according to any one of claims 1 to 21 or a pharmaceutical composition according to claim 22, for use as a pharmaceutical.

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

25. The method according to claim 24, wherein the disease or disorder is selected from the group consisting of eating disorders, obesity, bulimia nervosa (BED), schizophrenia (negative symptoms and CIAS), addiction to psychomotor stimulants such as cocaine, opioids, nicotine and alcohol, opioid use disorder, opioid dependence, drug abuse or addiction, sleep disorders, cognitive impairment in psychiatric or neurological disorders, depression, anxiety, panic disorder, post-traumatic stress disorder, behavioral disorders and mood disorders (depressive states).

26. The use of a compound according to any one of claims 1 to 21 or a pharmaceutical composition according to claim 22 in the preparation of a pharmaceutical for treating a disease or disorder controlled by orexin receptor activity, and the use of such compounds for treating or preventing such diseases and disorders.

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

28. The method according to claim 27, wherein the step of bringing the cells into contact is in vivo, in vitro, or ex vivo.

29. Compound of formula I as described in claim 1 【Chemistry 19】 (wherein X, X', R, and Het are as defined in any one of claims 1 to 21) A method for preparing, (a) The step of reacting tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate with a halo-substituted heteroaromatic compound in the presence of a base to form a first intermediate compound; (b) The step of reacting the first intermediate compound with an acid to form a second intermediate compound; (c) The step of reacting the second intermediate compound with a carboxylic acid having the general formula R-COOH to obtain the compound of formula I. A method that includes this.

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

31. The compound of formula I has the following structure: 【Chemistry 20】 (wherein R and Het are each independently defined as in any one of claims 1 to 21; R ６ and R ７ (Each is independently either H or deuterium.) The method according to claim 29 or 30, wherein the deuterated compound is having the following characteristics: (a) In the presence of a base, react tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (intermediate j1) or tert-butyl(5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2) with a halo-substituted heteroaromatic compound to form a first intermediate compound; (b) The step of reacting the first intermediate compound with an acid to form a second intermediate compound; (c) The step of reacting 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. A method that includes this.

32. The halo-substituted heteroaromatic compound is selected from the group consisting of halo-substituted pyridine, halo-substituted pyridazine, halo-substituted pyrazine, halo-substituted pyrimidine, halo-substituted triazole, halo-substituted tetrazole, halo-substituted pyrazole, halo-substituted furan, halo-substituted thiophene, halo-substituted pyrrole, halo-substituted imidazole, halo-substituted isoxazole, halo-substituted oxazole, halo-substituted isothiazole, halo-substituted thiazole and any derivative thereof, and the halo-substituted heteroaromatic group may be further substituted; if further substituents of the halo-substituted heteroaromatic group are present, unsubstituted (C １ ~C ４ )-Linear alkyl, unsubstituted (C １ ~C ４ ) - Branched alkyl, unsubstituted (C １ ~C ４ )-alkoxy group, unsubstituted (C ３ ~C ８ )-cycloalkyl, substituted (C １ ~C ４ ) - Linear alkyl, substituted (C １ ~C ４ ) - Branched alkyl, substituted (C １ ~C ４ )-alkoxy group, substituted (C ３ ~C ８ The method according to any one of claims 29 to 31, independently selected from the group consisting of cycloalkyl, cyano groups, and halogens.

33. The further substituents of the heteroaromatic group are Cl, F, CHF ２ CF ３ ,CH ３ The method according to claim 32, wherein the methoxy, nitrile, or cyclopropyl is used.

34. The method according to any one of claims 29 to 33, wherein the halo-substituted heteroaromatic compound is selected from the group consisting of fluoro-substituted heteroaromatic compounds, chloro-substituted heteroaromatic compounds, bromo-substituted heteroaromatic compounds, and iodo-substituted heteroaromatic compounds.

35. The halo-substituted heteroaromatic compounds include 2-chloro-5-(trifluoromethyl)pyrazine, 2-chloro-5-(trifluoromethyl)pyrimidine, 2-chloro-5-(trifluoromethyl)pyridine, 5-chloro-2-fluoropyridine, 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, and 2-chloro-3-methoxy-5-(trifluoromethyl) The method according to any one of claims 29 to 34, selected from (Tyl)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)pyridine, 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 the solvent is a polar aprotic solvent selected from the group consisting of THF, DMF, DMSO and mixtures thereof, and more preferably the solvent is DMSO.

38. The following features: Step (a) is carried out at a temperature in the range of about 50°C to about 189°C, preferably at a temperature of about 80°C; Step (a) is performed for a period of about 6 to about 18 hours, preferably about 12 hours. The method according to any one of claims 29 to 37, further comprising at least one of the above.

39. The method according to any one of claims 29 to 38, wherein the acid is selected from the group consisting of an aqueous solution of phosphoric acid, hydrochloric acid, trifluoroacetic acid, and mixtures thereof, and 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 the group consisting of diethyl ether, benzene, toluene, chloroform, 1,4-dioxane, or a mixture thereof, preferably the nonpolar solvent being 1,4-dioxane.

41. The following features: Step (b) is performed at a temperature in the range of about 12°C to about 40°C, preferably about 20°C. Step (b) is performed for a period of about 30 minutes to about 5 hours, preferably for about 2 hours. The method according to any one of claims 29 to 40, further comprising at least one of the following.

42. The method according to any one of claims 29 to 41, wherein R of the R-COOH group is selected from the group consisting of five-membered or six-membered aromatic or heteroaromatic groups, and the aromatic or heteroaromatic group is unsubstituted or substituted with one or more substituents, preferably R is a five-membered heteroaromatic group which is an unsubstituted pyrazole, oxazole, thiazole, imidazole, substituted pyrazole, oxazole, thiazole, imidazole or a derivative thereof; a six-membered aromatic group which is an unsubstituted aryl or substituted aryl or a derivative thereof; or a six-membered heteroaromatic group which is an unsubstituted pyridine, unsubstituted pyrimidine, unsubstituted pyridazine, unsubstituted pyrazine, substituted pyridine, substituted pyrimidine, substituted pyridazine, substituted pyrazine or a derivative thereof; optionally, at least one hydrogen of R is replaced with deuterium.

43. The carboxylic acid R-COOH is 4-(4-chlorophenyl)-1-methylpyrazole-3-carboxylic acid, 5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoic acid, 3-fluoro-2-(pyrimidine-2-yl)benzoic acid, 4-(5-chloropyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyrimidine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid, 5-methyl-2-(pyrimidine-2-yl)benzoic acid, 5-methyl-2-(2-methyl-2 H-tetrazole-5-yl)benzoic acid, 5-chloro-2-(2-methyl-2H-tetrazole-5-yl)benzoic acid, 4-(5-fluoropyrimidine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid, 1-methyl-4-(pyrimidine-2-yl)-1H-pyrazole-3-carboxylic acid, 4-(5-methoxypyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid, 4-(4-fluorophenyl)-1-methyl Tyl-1H-pyrazole-3-carboxylic acid, 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid, 4-(5-cyanopyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid, 5-(5-fluoropyrimidine-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid, 5-(5-methoxypyridine-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid, 4-(5-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid, 2-methyl- 5-(pyridin-2-yl)thiazole-4-carboxylic acid, 2-methyl-5-(pyrimidine-2-yl)thiazole-4-carboxylic acid, 2-methyl-5-(pyrimidine-2-yl)oxazole-4-carboxylic acid, 6-methyl-3-(2H-1,2,3-triazole-2-yl)picolinic acid, 5-fluoro-2-(2H-1,2,3-triazole-2-yl)benzoic acid, 4-(5-methoxypyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid, or 6-methyl-3-(pyrimidine-2-yl)picolinic acid;3-(5-fluoropyrimidine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid, 5,6-dimethyl-3-(pyrimidine-2-yl)picolinic acid, 4,6-dimethyl-3-(pyrimidine-2-yl)picolinic acid, 4-chloro-6-methyl-3-(pyrimidine-2-yl)picolinic acid, 1-methyl-4-(pyridine-2-yl)-1H-pyrazole-3-carboxylic acid, 2-(2H-1,2,3-triazole-2-yl)benzoic acid; The method according to any one of claims 29 to 42, selected from the group consisting of 1,5-dimethyl-4-(pyrazine-2-yl)-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-carboxylic acid, 4-(4-fluoropyridine-3-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid, and 4-(4-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.

44. The method according to claim 30 or 31, wherein the carboxylic acid comprises 4-(5-fluoropyrimidine-2-yl)-1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyrimidine-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyridine-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid, 6-(methyl-d3)-3-(pyrimidine-2-yl)picolinic acid, or 6-(methyl-d3)-3-(2H-1,2,3-triazole-2-yl)picolinate salt.

45. The following features: Step (c) is carried out in the presence of a coupling reagent, preferably the coupling reagent being HATU; Step (c) is carried out in the presence of a base, preferably the base being DIPEA; Step (c) is carried out in the presence of a polar aprotic solvent selected from the group consisting of THF, dichloromethane, ethyl acetate, DMF, DMSO, and combinations thereof, preferably the polar aprotic solvent being dichloromethane. The method according to any one of claims 29 to 44, further comprising at least one of the above.

46. The following features: Step (c) is carried out at a temperature in the range of about -10°C to about 40°C, preferably in the range of about 0°C to about 20°C; Step (c) is performed for a period of about 1 to 6 hours, preferably about 2.5 hours. The method according to any one of claims 29 to 45, further comprising at least one of the above.

47. The first intermediate compound is tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate; tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate; tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate; tert-butyl(5R,6S)-5-(((5-chloropyridine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate; tert-butyl(5R,6S)-5-(((5-chloropyrimidine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate; tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate; tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((6-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate; tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((4-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate; tert-butyl(5R,6S)-2,2-difluoro-5-(((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-6-methylmorpholine-4-carboxylate; tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate; tert-butyl(5R,6S)-5-(((5-cyclopropylpyrimidine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate; tert-butyl(5R,6S)-2,2-difluoro-5-(((3-methoxy-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-6-methylmorpholine-4-carboxylate; tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((3-methyl-5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate; tert-butyl(5R,6S)-5-(((3-cyano-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate; tert-butyl(5R,6S)-5-(((5-chloro-3-fluoropyridine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate; tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((4-methyl-5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate; tert-butyl(5R,6S)-5-(((5-(difluoromethyl)pyrimidine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate; or tert-butyl(5R,6S)-5-(((5-(difluoromethyl)pyrazine-2-yl)amino)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate The method according to any one of claims 29, 32 to 46.

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

49. The first intermediate compound is tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate-3,3-d2; tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate-3,3-d2; tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate-3,3-d2; tert-butyl(5R,6S)-5-(((5-chloropyridine-2-yl)amino)methyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate; tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl-d2)morpholine-4-carboxylate; (5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl-d2)morpholine-4-carboxylate; or tert-butyl(5R,6S)-2,2-difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl-d2)morpholine-4-carboxylate The method according to any one of claims 30 to 46.

50. The second intermediate compound is N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyrazine-2-amine hydrochloride; N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyrimidine-2-amine hydrochloride; N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyridine-2-amine hydrochloride; 5-Chloro-N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl-d2)pyridine-2-amine hydrochloride; N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl-d2)-5-(trifluoromethyl)pyrazine-2-amine hydrochloride; N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl-d2)-5-(trifluoromethyl)pyrimidine-2-amine; or N-(((2S,3R)-6,6-difluoro-2-methylmorpholine-3-yl)methyl-d2)-5-(trifluoromethyl)pyridine-2-amine The method according to any one of claims 30 to 46.

51. tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate, Reducing N-benzyl-L-alotreonine (a) by reacting it 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); In the presence of a coupling reagent, intermediate (d) is subjected to an intramolecular amide coupling reaction to form (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine-3-one (intermediate e); Reacting intermediate (e) with a reducing agent to form (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine (intermediate f); Reacting intermediate (f) with a fluorine source to form ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholine-3-yl)methanol (intermediate g); Intermediate (g) is reacted with hydrogen, palladium 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-dioxoisoindoline-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate i); and The intermediate (i) is reacted with hydrazine or hydrazine hydrate to form tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j). The method according to claim 29, which is prepared by...

52. tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (intermediate j1) (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine-3-one (intermediate e) is reduced with a deuterating reagent to form (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine-3,3-d2 (intermediate f1); The intermediate (f1) is reacted with a fluorine source to form ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholine-3-yl-5,5-d2)methanol (intermediate g1); The intermediate (g1) is reacted with hydrogen, palladium 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-dioxoisoindoline-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (intermediate i1); and The intermediate (i1) is reacted 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). The method according to claim 30 or 31, which is prepared by...

53. tert-butyl(5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2) Reacting N-benzyl-L-alotreonine (a) with 2-bromo-2,2-difluoroacetyl)oxysodium, followed by a suitable acid, to form (2S,3S)-4-benzyl-6,6-difluoro-2-methyl-5-oxomorpholine-3-carboxylic acid (intermediate e2'); The intermediate e2' is reduced with a deuterating agent to form (5R,6S)-4-benzyl-2,2-difluoro-5-(hydroxymethyl-d2)-6-methylmorpholine-3-one (intermediate e2''); The intermediate (e2'') is reduced with a reducing agent to form ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholine-3-yl)methane-d2-ol (intermediate g2); The intermediate (g2) is reacted with hydrogen, palladium carbon, and di-tert-butyl dicarbonate to form tert-butyl(2S,3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3-methylpiperidine-1-carboxylate (intermediate h2); Reacting intermediate (h2) with isoindoline-1,3-dione to form tert-butyl(5R,6S)-5-((1,3-dioxoisoindoline-2-yl)methyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate i2); and The intermediate (i2) is reacted with hydrazine or hydrazine hydrate to form tert-butyl(5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2). The method according to claim 30 or 31, which is prepared by...

54. (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-methylmorpholine-3-yl)methanol (intermediate g); tert-butyl(5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylate (intermediate h); tert-butyl(5R,6S)-5-((1,3-dioxoisoindoline-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate i); tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j); (5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-difluoro-6-methylmorpholine-3,3-d2 (intermediate f1); ((2S,3R)-4-benzyl-6,6-difluoro-2-methylmorpholine-3-yl-5,5-d2)methanol (intermediate g1); tert-butyl(5R,6S)-2,2-difluoro-5-(hydroxymethyl)-6-methylmorpholine-4-carboxylate-3,3-d2 (intermediate h1); tert-butyl(5R,6S)-5-((1,3-dioxoisoindoline-2-yl)methyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (intermediate i1); tert-butyl(5R,6S)-5-(aminomethyl)-2,2-difluoro-6-methylmorpholine-4-carboxylate-3,3-d2 (intermediate j1); (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-methylmorpholine-3-yl)methane-d2-ol (intermediate g2); tert-butyl(2S,3R)-5,5-difluoro-2-(hydroxymethyl-d2)-3-methylpiperidine-1-carboxylate (intermediate h2); tert-butyl(5R,6S)-5-((1,3-dioxoisoindoline-2-yl)methyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate i2); or tert-butyl(5R,6S)-5-(aminomethyl-d2)-2,2-difluoro-6-methylmorpholine-4-carboxylate (intermediate j2) A compound that is

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