Morpholine orexin receptor antagonist

Abstract

The present invention relates to compounds of formula (I) that are useful as orexin antagonists, or pharmaceutically acceptable salts, solvates, adducts, polymorphs, isomers and derivatives thereof, their preparation, their use in pharmaceutical compositions, and methods for treating or preventing diseases or disorders mediated by orexin receptor activity using orexin antagonists. JPEG2026524754000299.jpg39149

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. 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.

[0007] 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.

[0008] International Publication No. 2002090355, a patent application, and European Patent No. 1539747, a granted patent, relate 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).

[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, improved residence time, 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, hydrochloride, chloride, bromide, iodide, potassium salt, sodium salt, acetate, e.g., trifluoroacetate, sulfate, sulfonate, oxalate, maleate, malonate, nitrate, tartrate, gluconate, succinate, mesylate, citrate, phosphate, diphosphate, aluminate, enantiomer, solvate, adduct, polymorph, hydrate, tautomer, prodrug, isotope-labeled or radiolabeled derivative and isomer.

[0012] According to one aspect of the present invention, the structure of general formula I: [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. The heteroaromatic group is unsubstituted, monosubstituted, disubstituted, or trisubstituted. 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, unsubstituted (C3-C8) cycloalkyl, unsubstituted (C1-C4) alkoxy, substituted (C1-C4)-linear alkyl, substituted (C1-C4)-branched alkyl, substituted (C3-C8) cycloalkyl, cyano group, substituted (C1-C4) alkoxy, and halogen. Compounds having the property, or pharmaceutically acceptable salts and derivatives thereof, are provided.

[0013] Preferably, the substituents on the heteroaromatic group of Het are F, Cl, CHF2, CF3, methyl, ethyl, methoxy, nitrile, or cyclopropyl.

[0014] 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.

[0015] 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 a derivative thereof; a 6-membered aromatic group which is an unsubstituted aryl, substituted aryl, or a 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 any derivative thereof.

[0016] According to another aspect of the present invention, the compound of formula I is a 2S,3R stereoisomer: [ka]

[0017] According to another aspect of the present invention, the compound of formula I is a 6R-stereoisomer, a 6S-stereoisomer, or a mixture thereof: [ka]

[0018] Preferably, one or more hydrogen atoms bonded to the carbon atom of the morpholine ring in the compound of formula I are replaced by one or more deuterium atoms. Preferably, one or more hydrogen atoms bonded to the morpholine side chain of the compound of formula I are replaced by one or more deuterium atoms.

[0019] According to another aspect of the present invention, the compound of formula I has one or more hydrogen atoms 2 These are deuterated compounds that are either replaced or substituted with H (deuterium). The deuterated compounds of formula I have the following structure: [ka] (In the formula, R and Het can be independent of each other, as defined in formula I.) It may have.

[0020] According to another aspect of the present invention, the structure of formulas I(a) to I(g): [ka] (In the formula, R 1 and R 2 Each of these can be independently 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, such as fluorine, chlorine, or bromine; preferably, R1 and R 2 are each independently hydrogen, chlorine, fluorine, -CH3, or -CD3 (deuterium); R 6 and R 7 can each independently be hydrogen or deuterium; Het’ is selected from the group consisting of heteroaromatic groups selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, pyrazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole, and any derivatives thereof, wherein the heteroaromatic group is unsubstituted, mono-substituted or di-substituted, and the substituents of the heteroaromatic group, when present, are independently selected from the group consisting of unsubstituted (C1-C6)-linear or branched alkyl, substituted (C1-C6)-linear or branched alkyl, and halogen; preferably, the halogen includes fluorine, chlorine or bromine; Het can be as defined herein with respect to formula I) Compounds having, or pharmaceutically acceptable salts and derivatives thereof, are provided.

[0021] Preferably, the compounds of formulae I(a) - I(g) are the 6R,2S,3R-stereoisomer, the 6S,2S,3R-stereoisomer or mixtures thereof.

[0022] According to another aspect of the invention, the structures of formulae I(h) - I(i):

Chemical formula

[0023] Preferably, the aromatic heteroaromatic group of Y is substituted with CN, F, Br, Cl, or -O-alkyl, preferably the alkyl group contains 1 to 4 carbon atoms, and preferably the alkoxy group is -OCH3.

[0024] According to another aspect of the present invention, the structure of formula I(k): [ka] (wherein Het may be as defined herein with respect to formula I, and Y may be as defined 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) or I(m): [ka] (wherein Het may be as defined herein with respect to formula I, and Y may be as defined herein with respect to formula I(h); 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; preferably, R 5 (These are hydrogen, -CH3, or -CD3.) 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(n) is: [ka] (In the formula, R 6 and R 7 Each can independently be hydrogen or deuterium; R 3 (Het and Y can each be independently as defined in equation I(h)). Compounds having the property, or pharmaceutically acceptable salts and derivatives thereof, are provided.

[0027] Preferably, the compounds of formulas I(h) to I(n) are 6R,2S,3R stereoisomers, 6S,2S,3R stereoisomers, or mixtures thereof.

[0028] According to another aspect of the present invention, a compound of formula I or I(a-n) described herein, or a pharmaceutical composition comprising a compound of formula I or I(a-n) is provided for use as a pharmaceutical. Preferably, the pharmaceutical composition is in solid form, such as a tablet or a capsule.

[0029] 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-n) described herein or a pharmaceutically acceptable salt and derivative thereof to a subject in need of such treatment, preferably in a dose, frequency, and duration that produces the beneficial effect of a pharmaceutical composition described herein.

[0030] Another aspect of the present invention provides the use of compounds of formula I or I(a-n) described herein, or pharmaceutical compositions described herein, in the preparation of pharmaceuticals for treating diseases or disorders controlled by orexin receptor activity, and the use of such compounds for treating or preventing such diseases and disorders.

[0031] 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-n) described herein, or a pharmaceutical composition described herein.

[0032] According to another aspect of the present invention, a method for preparing the compound of the present invention is provided.

[0033] [Detailed description of the invention] [ka] According to one aspect of the present invention, compounds of formula I or pharmaceutically acceptable salts and derivatives thereof are provided. "Het" represents a heteroaromatic group, and "R" is a five-membered or six-membered aromatic or heteroaromatic group. The heteroaromatic group may be selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole, and any derivatives thereof. The heteroaromatic group may be unsubstituted, monosubstituted, disubstituted, or trisubstituted, 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, and halogens, such as fluorine, chlorine, or bromine. Preferably, the substituent of the heteroaromatic group contains CF3. The five-membered or six-membered aromatic or heteroaromatic group "R" may be unsubstituted or substituted with one or more substituents.

[0034] Preferably, the compound provided by formula I is a 2S,3R stereoisomer: [ka]

[0035] The 2S,3R stereoisomers provided by compounds of formula I or I(a-n) 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-n).

[0036] The 2S,3R,6R stereoisomer is metabolically stable compared to other stereoisomers provided by the compound of the present invention.

[0037] More preferably, the compound of formula I is a 2S,3R,6R stereoisomer, a 6S,2S,3R stereoisomer, or a mixture thereof: [ka]

[0038] In another embodiment, the compound of formula I may be a deuterated compound. Preferably, one or more hydrogen atoms are replaced or substituted by one or more deuterium atoms, for example, one or more hydrogen atoms bonded to a carbon atom of the morpholine ring, or one or more hydrogen atoms of a side chain of the morpholine ring, or one or more hydrogen atoms of any substituent of the five-membered or six-membered aromatic group or heteroaromatic group of the "R" group of formula I may be replaced by one or more deuterium atoms.

[0039] As used herein, the term "heteroaromatic" 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 "fluoroalkyl" refers to an alkyl group substituted with at least one fluorine atom.

[0042] As used herein, the term "alkoxy" refers to an alkyl group bonded to oxygen (i.e., RO).

[0043] 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.

[0044] The "halogen" can be F, Cl, Br, or I, but in preferred examples, the halogen is F, Cl, or Br.

[0045] An "isotope-labeled compound" is a chemical substance in which some of the atoms in its molecule are replaced with isotopic atoms, typically isotopic atoms different from those found in nature.

[0046] A "deuterated compound" is a compound in which one or more hydrogen atoms are replaced by one or more deuterium atoms.

[0047] As used herein, the term “deuterated alkyl” refers to an alkyl group in which one or more protons are replaced by deuterium atoms.

[0048] 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).

[0049] 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.

[0050] "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.

[0051] 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.

[0052] Preferably, when the "R" in 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. Unsubstituted or substituted pyrazoles may be fused with a five-membered ring or a six-membered ring.

[0053] Preferably, when the "R" in the compound of formula I is a six-membered aromatic group, it may include an unsubstituted aryl group, a substituted aryl group, or a derivative thereof.

[0054] Preferably, when "R" of the compound of formula I is a 6-membered heteroaromatic group, it may include unsubstituted or substituted pyridine, pyrazine, pyridazine, pyrimidine, triazine, triazole, tetrazole, imidazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole, or any derivative thereof, the heteroaromatic group may be unsubstituted, monosubstituted, disubstituted, or trisubstituted, 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 linear or branched (C1~C4)-alkyl, deuterated (C1~C6)-linear alkyl, deuterated (C1~C6)-branched alkyl, and halogen.

[0055] More preferably, if the "R" in the compound of formula I is a 6-membered aromatic group, the 6-membered aromatic group has the structure of formula II: [ka] (In the formula, R 1 This 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 halogens, such as chlorine, fluorine, and bromine; preferably, R 1 is Cl, F, CH3, or -CD3 (D = deuterium); Het' may be selected from the group consisting of heteroaromatic groups selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, pyrazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof, wherein the heteroaromatic group is unsubstituted, monosubstituted or disubstituted, and substituents on the heteroaromatic group, if present, may be independently selected from the group consisting of (C1-C4)-linear or branched alkyl, substituted linear or branched (C1-C4)-alkyl, and halogens, such as fluorine, chlorine, or bromine. It has.

[0056] Preferably, the (one or more) substituents of the heteroaromatic group of Het' may be fluorine, chlorine, or CH3.

[0057] In some cases, Het' in equation II is [ka] It can be selected from the following.

[0058] Preferably, when the "R" in the compound of formula I is a 6-membered heteroaromatic group, the 6-membered heteroaromatic group has the structure of formula III: [ka] (In the formula, R 1 This 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 halogens, such as fluorine, chlorine, or bromine; preferably, R 1 is hydrogen, chlorine, fluorine, -CH3, or -CD3 (D=deuterium); Het' may be as defined herein with respect to Equation II. It has.

[0059] In some cases, Het' in equation III is [ka] It can be selected from the following.

[0060] Preferably, when "R" in the compound of formula I is a 6-membered heteroaromatic group, the 6-membered heteroaromatic group has the structure of formulas III(a), III(b), III(c), and III(d): [ka] (In the formula, R 1 This can be as defined with respect to equation III; R 2 R 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 halogens, such as fluorine, chlorine, or bromine, preferably R 2 These are hydrogen, chlorine, fluorine, -CH3, or -CD3 (D=deuterium); Het' may be as defined herein with respect to Equation III. It has.

[0061] In some examples, Het' in equations III(a) to III(b) is [ka] It can be selected from the following.

[0062] If "R" in formula I is a 5-membered heteroaromatic group, then the 5-membered heteroaromatic group is represented by structural formula IV: [ka] (In the formula, Y may have an aromatic group (which may represent a substituted or unsubstituted aromatic group, a heteroaromatic group, or a substituted or unsubstituted heteroaromatic group). Preferably, Y may be independently selected from the group consisting of aryl, pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, nicotinonitrile, benzonitrile, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof; Y may be unsubstituted, monosubstituted or disubstituted, and the substituent may be independently selected from the group consisting of unsubstituted or substituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy, cyano group and halogen.

[0063] If Y is monosubstituted or disubstituted and (one or more) substituents are halogens, the halogen is preferably fluorine, chlorine, or bromine. If Y is monosubstituted or disubstituted and (one or more) substituents are (C1-C4)-alkoxys, the alkoxy is preferably -OCH3. Preferably, (one or more) substituents on the aromatic or heteroaromatic group of Y are selected from CN, F, Br, Cl, or -OCH3.

[0064] In some cases, Y in equation IV is, [ka] It can be selected from the following.

[0065] Furthermore, if "R" in formula I is a five-membered heteroaromatic group, then the five-membered heteroaromatic group is in structural formula V or V(a): [ka] (In the formula, R 3 and R 4 These are hydrogen, (C1~C 10 )-Linear alkyl; (C1~C 10 )-branched alkyl; (C1~C 10)-substituted or unsubstituted alkyl, optionally (C1-C4)-linear alkyl; (C1-C4)-branched alkyl; (C1-C4)-substituted or unsubstituted alkyl; deuterated (C1-C6)-linear alkyl and deuterated (C1-C6)-branched alkyl may be independently selected from the group; R 3 and R 4 R may form a substituted or unsubstituted ring; preferably, 3 and R 4 These are, independently, hydrogen, -CH3, or -CD3; Y may be as defined herein with respect to Equation IV. It may have.

[0066] In some examples, "Y" in equation V is, [ka] It is possible.

[0067] 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 is defined as defined with respect to formula IV.) It may have.

[0068] In some examples, Y in equation VI is [ka] It is possible.

[0069] Furthermore, if "R" in formula I is a five-membered heteroaromatic group, the five-membered heteroaromatic group has the structure of formula VII: [ka] (In the formula, 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-C6)-linear alkyl, deuterated (C1-C6)-branched alkyl; preferably, R 5 is hydrogen, -CH3, or -CD3; Y may be as defined herein with respect to Equation IV. It may have.

[0070] In some cases, Y in equation VII or VII(a) is [ka] It is possible.

[0071] In some examples, the "R" in the compounds of formula I described herein is [ka] It can be selected from the following.

[0072] In further examples, the "R" in the compounds of formula I described herein is [ka] It can be selected from the following.

[0073] In further examples, the "R" in the compounds of formula I described herein is [ka] It can be selected from the following.

[0074] Preferably, Het of the compound of formula I is 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. The heteroaromatic group can be unsubstituted, mono-substituted, di-substituted or tri-substituted. When present, the substituents of the heteroaromatic group are independently selected from the group consisting of unsubstituted (C1-C4)-linear alkyl, unsubstituted (C1-C4)-branched alkyl, substituted (C1-C4)-linear alkyl, substituted (C...

[0075] In some examples, "Het" of the compound of formula I described herein is

Chemical Structure

[0076] In yet another example, the compound of formula I has the following structure:

Chemical Structure

[0077] Preferably, the compounds of formulas ID(a) and ID(b) are 6R,2S,3R stereoisomers, 6S,2S,3R stereoisomers, or mixtures thereof.

[0078] In yet another example, the compounds of formula I described herein have the structures of formulas I(a) to I(n): [ka] JPEG2026524754000034.jpg225149 (In the formula, Het, Het', R 1 , R 2 , R 3 , R 4 , R 5 And Y may be independent of each other, as defined herein with respect to formulas I to VIIa; R 6 and R 7 (Each of these can be independently H or deuterium (D)). It has.

[0079] In further examples, the compounds of the present invention are [Table 1] JPEG2026524754000036.jpg171149 JPEG2026524754000037.jpg173149 JPEG2026524754000038.jpg163149 JPEG2026524754000039.jpg167149 JPEG2026524754000040.jpg207149 JPEG2026524754000041.jpg165149 JPEG2026524754000042.jpg162149 JPEG2026524754000043.jpg170149 JPEG2026524754000044.jpg211149 JPEG2026524754000045.jpg211149 JPEG2026524754000046.jpg168149 JPEG2026524754000047.jpg164149 JPEG2026524754000048.jpg174149 JPEG2026524754000049.jpg165149 JPEG2026524754000050.jpg213149 JPEG2026524754000051.jpg203149 JPEG2026524754000052.jpg165149 JPEG2026524754000053.jpg211149 JPEG2026524754000054.jpg212149 JPEG2026524754000055.jpg203149 JPEG2026524754000056.jpg210149 JPEG2026524754000057.jpg204149 JPEG2026524754000058.jpg200149 JPEG2026524754000059.jpg207149 JPEG2026524754000060.jpg211149 JPEG2026524754000061.jpg214149 JPEG2026524754000062.jpg174149 JPEG2026524754000063.jpg211149 JPEG2026524754000064.jpg196149 JPEG2026524754000065.jpg204149 JPEG2026524754000066.jpg160149 JPEG2026524754000067.jpg213149 JPEG2026524754000068.jpg103149 It may be selected from these or their pharmaceutically acceptable salts and derivatives.

[0080] According to another aspect of the present invention, the structure

Chemical formula

[0081] In some examples, R of the compound of Formula I-aa is

Chemical formula

Chemical formula

[0082] Preferably, the compound of formula I-aa is a 6R,2S,3R stereoisomer, a 6S,2S,3R stereoisomer, or a mixture thereof.

[0083] Preferably, the compound of formula I-aa is [ka] It is selected from the group consisting of the following.

[0084] 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.

[0085] Examples of "pharmaceutically acceptable salts" include, but are not limited to, hydrochloride, chloride, bromide, iodide, potassium salt, sodium salt, acetate, such as trifluoroacetate, sulfate, sulfonate, oxalate, maleate, malonate, nitrate, tartrate, gluconate, succinate, mesylate, citrate, phosphate or diphosphate, and aluminate. In some cases, a pharmaceutically acceptable salt may be trifluoroacetate.

[0086] 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.

[0087] "Pharmacologically acceptable derivatives" of the compounds of the present invention disclosed herein include, but are not limited to, enantiomers, solvates, adducts, polymorphs, hydrates, tautomers, prodrugs, isomers, isotope-labeled or radiolabeled compounds, or mixtures thereof.

[0088] Isotope labeling in the compounds described The present invention preferably further comprises all pharmaceutically acceptable isotope-labeled compounds [e.g., of formula I or I(a-e)]. 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-e)], a hydrogen atom is replaced or substituted with one or more deuterium or tritium (e.g., a hydrogen atom of (C1-C6)-alkyl or (C1-C6)-alkoxy is replaced with deuterium, e.g., d3-methoxy or 1,1,2,2-d4-3-methylbutyl).

[0089] Certain isotope-labeled compounds [e.g., compounds of formula I or I(a~e)], for example, those incorporating radioisotopes, are used in drug and / or substrate tissue distribution studies and metabolic studies, including drug or substrate tissue distribution assays (preferably, 14 Using C), reaction kinetic studies (for example), 2 H or 3 It is useful in detection or imaging techniques (e.g., positron emission tomography (PET) or single-photon emission tomography (SPECT)) or in radioactive treatment of patients. Furthermore, deuterium (i.e., 2 Substitution with heavier isotopes, such as H), may result in certain therapeutic benefits stemming from greater metabolic stability, such as an increased in vivo half-life or a reduced dose requirement.

[0090] [For example, isotope-labeled compounds of formula I or I(a-e)] 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-labeling reagents instead of previously used unlabeled reagents. Suitable isotopes that can be incorporated into the compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example. 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, 131 I, 31 P, and 32 P is one example, but it is not limited to these.

[0091] 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.

[0092] 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.

[0093] 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), 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 and depressive states. The compounds of the present invention may be useful in treating diseases or disorders associated with orexin-1 receptor dysfunction.

[0094] Preferably, the novel compounds provided by the present invention are OX1 receptor selective antagonists. OX1 receptor antagonists are useful in treating diseases and disorders such as, but are not limited to, substance abuse disorders, personality disorders, eating disorders, or anxiety-related disorders. However, antagonists that target both OX1 and OX2 receptors are known to have sleep-inducing effects; therefore, it is highly desirable to identify highly OX1-selective antagonists with a sufficient window to OX2-mediated effects in order to prevent side effects such as drowsiness or fatigue.

[0095] To demonstrate the efficiency of the compounds provided by the present invention, the half-number inhibitory concentration (IC) 50 ) can be used in the present invention. IC provided in this disclosure 50 The value indicates how much of the drug is needed to inhibit the orexin receptor by half, and thus provides a measure of the compounds provided by the present invention.

[0096] The compounds provided by the present invention have an IC500 nM of at least 500 nM for the OX1 receptor. 50 It may have the following characteristics. Preferably, the compounds provided by the present invention have an IC50 between 2nM and 500nM for the OX1 receptor. 50may have a value. The compounds provided by formula I have an IC for the OX1 receptor between 2 nM and 450 nM; between 2 nM and 400 nM; between 2 nM and 350 nM; between 2 nM and 300 nM; between 2 nM and 250 nM; between 2 nM and 200 nM; between 2 nM and 150 nM; between 2 nM and 100 nM; between 2 nM and 50 nM; between 50 nM and 500 nM; between 50 nM and 450 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 100 nM; between 100 nM and 500 nM; between 100 nM and 450 nM; between 100 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 50 may have a value.

[0097] More preferably, the compounds provided by the present invention have an IC for the OX1 receptor between 2 nM and 100 nM 50 may have a value. The compounds provided by the present invention have an IC for the OX1 receptor between 2 nM and 90 nM; between 2 nM and 70 nM; between 2 nM and 50 nM; between 2 nM and 30 nM; between 2 nM and 10 nM; between 5 nM and 90 nM; between 5 nM and 80 nM; between 5 nM and 60 nM; between 5 nM and 50 nM; between 5 nM and 30 nM; between 5 nM and 20 nM; between 5 nM and 10 nM; between 10 nM and 80 nM; between 10 nM and 60 nM; between 10 nM and 70 nM; between 10 nM and 50 nM; between 10 nM and 30 nM; or between 10 nM and 20 nM 50 may have a value.

[0098] Most preferably, the compounds provided by the present invention have an IC for the OX1 receptor between 2 nM and 50 nM 50may have a value. The compounds provided by the present invention have an IC for the OX1 receptor between 2 nM and 40 nM; between 2 nM and 30 nM; between 2 nM and 25 nM; between 2 nM and 20 nM; between 2 nM and 10 nM; between 2 nM and 5 nM; between 3 nM and 40 nM; between 3 nM and 30 nM; between 3 nM and 25 nM; between 3 nM and 20 nM; between 3 nM and 10 nM; between 3 nM and 5 nM; between 5 nM and 40 nM; between 5 nM and 30 nM; between 5 nM and 25 nM; between 5 nM and 20 nM; between 5 nM and 10 nM; between 7 nM and 40 nM; between 7 nM and 30 nM; between 7 nM and 25 nM; between 7 nM and 20 nM; or between 7 nM and 10 nM 50 may have a value.

[0099] Most preferably, the compounds provided by the present invention have an IC for the OX1 receptor of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 26, 31, 33, 34, 35, 36, 38, 39, 40, 41, 43, 48, 50, 60, 63, 65, 71, 72, 79, 88, 105, 118, 127, 133, 155, 176, 273, 283, 328, 351 or 491 nM 50 may have.

[0100] The compounds provided by the present invention have an IC for the OX2 receptor of at least 2000 nM 50 may have. Preferably, the compounds provided by the present invention have an IC for the OX2 receptor of at least 5000 nM 50 have.

[0101] The compounds provided by the present invention are at least 10 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 100 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 500 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 1000 times more effective in binding to the OX1 receptor compared to the OX2 receptor.

[0102] 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 51, 74, and 120) 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.

[0103] The compounds provided by the present invention are metabolically stable and may have improved pharmacokinetic properties required for CNS-indicated drugs, such as improved oral bioavailability, improved cellular permeability, and improved brain exposure.

[0104] 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.

[0105] 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.

[0106] The compounds of the present invention 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.

[0107] 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, including depressive states.

[0108] 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.

[0109] 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.

[0110] 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 according to the present invention (or any pharmaceutically acceptable salt, solvate, adduct, polymorph, isotope-labeled or radiolabeled derivative and isomer thereof) or at least one compound according to the present invention (or any pharmaceutically acceptable salt, solvate, adduct, polymorph, isotope-labeled or radiolabeled compound and isomer thereof).

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] According to another aspect of the present invention, the use of a pharmaceutical composition comprising a compound according to the present invention or a compound according to Formula I is provided. The compound according to the present invention or a pharmaceutical composition comprising a compound according to 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.

[0116] 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.

[0117] Preferably, the present invention provides a method for selectively regulating the activity of the OX1 receptor.

[0118] 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.

[0119] 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 TEA Triethanolamine THF (Tetrahydrofuran) Ts Tosil eq equivalent N normality V Volume

[0120] 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.

[0121] Compounds of formula I 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 can undergo nucleophilic substitution with 2-bromopropanoic acid or 2-iodopropanoic acid to form intermediate d. Intermediate d can undergo intramolecular amide coupling in the presence of a coupling reagent to form intermediate e. Preferably, the coupling reagent used to prepare intermediate e is propylphosphonic anhydride (T3P). Intermediate e can be reduced to form intermediate f. The alcohol protecting group can be removed from intermediate f to form intermediate g. The benzyl protecting group of intermediate g can be removed by Pd / C catalytic hydrogenation. A deprotected amine can be reacted with a suitable protecting group to form intermediate h. Intermediate h can be reacted with isoindoline-1,3-dione to form intermediate i. Intermediate i can be reacted with hydrazine or hydrazine hydrate to form intermediate j. Intermediate j can undergo a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of the intermediates ka~ks. Preferably, intermediates ka~ks are deprotected to form the corresponding intermediates la~ls. Intermediate la~ls can be reacted with a carboxylic acid having the general formula R-COOH to form compounds 1~57, 61, 64~82, 85~95, and 98~120.

[0122] In another aspect of the present invention, the compound of formula ID(a) can be prepared starting from compound da. Compound da can be reduced by reacting with a reducing agent to form intermediate db. Intermediate db can undergo a nucleophilic substitution reaction with 2-bromopropanoic acid or 2-iodopropanoic acid to form intermediate dc. Intermediate dc is reacted with a base to form intermediate dd. Compound dd is deuterated to form intermediate de. Removal of the amino group of intermediate de allows the deprotected group to react with a suitable protecting group to form intermediate df. Intermediate df is hydrogenated to form compound dg. Intermediate dg can undergo a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of intermediates dh and di. Preferably, intermediates dh and di are deprotected to form the corresponding intermediates dj and dk. Intermediates dj and dk can be reacted with a carboxylic acid having the general formula R-COOH to form compounds 58, 59, 60, 62, and 63.

[0123] The compound of formula ID(b) can be prepared starting from compound a. N-benzyl-L-alotreonine(a) can undergo nucleophilic substitution with 2-bromopropanoic acid or 2-iodopropanoic acid to form intermediate dl. Intermediate dl can undergo intramolecular amide coupling in the presence of a coupling reagent to form intermediate dm. Compound dm is deuterated to form intermediate dn. The carbonyl group of intermediate dn is removed to form intermediate do. Intermediate do is selectively deprotected to form intermediate dp so that it can react with a suitable protecting group. Intermediate dp is protected to form intermediate dq. Any suitable protecting group can be used. Intermediate dq can be deprotected to form compound dr. Intermediate dr can undergo nucleophilic aromatic substitution with a halo-substituted heteroaromatic compound to form one of the intermediates ds, dt, and du. Preferably, intermediates ds, dt, and du are deprotected to form the corresponding intermediates dv, dw, and dx. Intermediates dv, dw, and dx can be reacted with a carboxylic acid having the general formula R-COOH to form compounds 83, 84, 96, and 97.

[0124] The present invention provides a method for synthesizing intermediate b, as shown in the following synthetic route: [ka]

[0125] 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.

[0126] 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.

[0127] 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.

[0128] The reaction may be carried out at a temperature in the range of about 50°C to about 120°C. Preferably, the reaction is carried out at a temperature in the range of about 60°C to about 100°C. More preferably, the reaction is carried out at a temperature in the range of about 60°C to about 80°C.

[0129] The reaction may take place over a period of approximately 3 to 10 hours, preferably over a period of approximately 5 to 8 hours, and more preferably over a period of approximately 6 hours.

[0130] The present invention provides a method for synthesizing intermediate c, as shown in the following synthetic route (PG refers to a protecting group): [ka]

[0131] 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.

[0132] 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. The reagent may be used in excess of intermediate b. A 1.1 to 1.5-fold excess of the reagent may be used relative to intermediate b. Preferably, a 1.2-fold excess of the reagent relative to intermediate b is used.

[0133] 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. 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.

[0134] 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.

[0135] 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.

[0136] The present invention provides a method for synthesizing intermediate d, as shown in the following synthetic route (PG refers to a protecting group): [ka]

[0137] Intermediate c can be reacted with 2-bromopropanoic acid or 2-iodopropanoic acid to form intermediate d. Preferably, intermediate c is reacted with (2S)-2-bromopropanoic acid or (2R)-2-bromopropanoic acid to form intermediate d.

[0138] 2-bromopropanoic acid or 2-iodopropanoic acid may be used in excess of intermediate c. A 2- to 7-fold excess of 2-bromopropanoic acid or 2-iodopropanoic acid relative to intermediate c may be used. Preferably, a 3-fold excess of 2-bromopropanoic acid or 2-iodopropanoic acid relative to intermediate c is used.

[0139] 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. The Lewis base may be used in excess of intermediate c. A 4- to 10-fold excess of Lewis base may be used relative to intermediate c. Preferably, an 8-fold excess of Lewis base is used relative to intermediate c.

[0140] 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.

[0141] The reaction may be carried out at a temperature in the range of approximately -10°C to approximately 66°C. Preferably, the reaction may be carried out at a temperature in the range of approximately 0°C to approximately 60°C. The reaction may be carried out for a period of approximately 2 to approximately 10 hours. Preferably, the reaction may be carried out for a period of approximately 6 hours.

[0142] The present invention provides a method for synthesizing intermediate e, as shown in the following synthetic route (PG refers to a protecting group): [ka]

[0143] 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.

[0144] 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.

[0145] 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 may be 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 may be carried out for a period of about 2 hours.

[0146] The present invention provides a method for synthesizing intermediate f, as shown in the following synthetic route (PG refers to a protecting group): [ka]

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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 2 hours to about 8 hours. Preferably, the reaction may be carried out for a period of about 5 hours.

[0151] The present invention provides a method for synthesizing intermediate g, as shown in the following synthetic route (PG' refers to a protecting group): [ka]

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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 25°C.

[0156] The reaction may take place over a period of approximately 30 minutes to 4 hours. Preferably, the reaction takes place over a period of approximately 1 hour.

[0157] The present invention provides a method for synthesizing intermediate h as shown in the following synthetic route (PG refers to a protecting group): [ka]

[0158] 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.

[0159] The conversion of intermediate g to intermediate h may be a one-pot process.

[0160] 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.

[0161] 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.

[0162] Suitable protecting 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. The protecting reagent may be used in excess of intermediate g. A 1.1 to 2 times excess of the reagent may be used relative to intermediate g. Preferably, a 1.5 times excess of the reagent relative to intermediate g.

[0163] 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.

[0164] 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.

[0165] The present invention provides a method for synthesizing intermediate i, as shown in the following synthetic route (PG' refers to a protecting group): [ka]

[0166] 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.

[0167] Preferably, the reaction is carried out in the presence of triphenylphosphine. 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.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] The present invention provides a method for synthesizing intermediate j, as shown in the following synthetic route (PG' refers to a protecting group): [ka]

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] The present invention provides a method for synthesizing the intermediate db, as shown in the following synthetic route: [ka]

[0177] Compound da is reduced by reacting with a reducing agent such as boranetetrahydrofuran to form the intermediate db. Other suitable reducing agents, but not limited to boranedimethyl sulfide, may be used, including lithium aluminum hydride, boron trifluoride diethyl etherate, and diborane.

[0178] The reducing agent may be used in excess of the starting material da. The excess is preferably 2 to 10 times the amount of reducing agent relative to the starting material da. Preferably, a 3-fold excess of reducing agent relative to the starting material aw is used.

[0179] 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.

[0180] The reaction may take place at temperatures ranging from about -10°C to about 80°C. Preferably, the reaction takes place at temperatures ranging from about 0°C to about 70°C. More preferably, the reaction takes place at temperatures ranging from about 0°C to about 50°C.

[0181] The reaction may take place over a period of approximately 30 minutes to approximately 5 hours. Preferably, over a period of approximately 1 hour to approximately 4 hours. More preferably, the reaction takes place over a period of approximately 2.5 hours.

[0182] The present invention provides a method for synthesizing intermediate dc, as shown in the following synthetic route: [ka]

[0183] Intermediate db can be reacted with 2-bromopropanoic acid or 2-iodopropanoic acid to form intermediate dc. 2-bromopropanoic acid or 2-iodopropanoic acid may be used in excess of or in equal amounts to intermediate db.

[0184] The reaction is carried out in the presence of a base, preferably a non-nucleophilic base. Examples of bases that may be used in the synthesis of the intermediate include, but are not limited to, NN-diisopropylethylamine (DIPEA), 1,8-diazabicycloundeca-7-ene (DBU), 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN), or mixtures thereof. Preferably, the Lewis base used in the synthesis of intermediate ay is NN-diisopropylethylamine (DIPEA).

[0185] The base may be used in excess of the intermediate db. A 2- to 6-fold excess of the base may be used relative to the intermediate db. Preferably, a 3-fold excess of the base is used relative to the intermediate db.

[0186] 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.

[0187] The reaction may be carried out in the presence of a coupling reagent such as bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP). The coupling reagent may be used in excess relative to the starting material aw. The excess is preferably 0.5 to 4 times the amount of coupling agent relative to the starting material aw. Preferably, a 1-fold excess of coupling agent relative to the starting material aw is used.

[0188] The reaction may take place at temperatures ranging from approximately -10°C to approximately 60°C. Preferably, the reaction may take place at temperatures ranging from approximately 0°C to approximately 25°C.

[0189] The reaction may take place over a period of approximately 30 minutes to 4 hours. Preferably, over a period of approximately 30 minutes to 2 hours. More preferably, the reaction takes place over a period of approximately 1 hour.

[0190] The present invention provides a method for synthesizing intermediate dd, as shown in the following synthetic route: [ka]

[0191] Intermediate dc is reacted with a base to form intermediate dd. Examples of bases that can be used include, but are not limited to, lithium hydroxide, sodium hydroxide, or potassium hydroxide. Potassium hydroxide is preferably used.

[0192] The base may be used in excess of the intermediate dc. A 1:4 to 4:1 excess of the base may be used relative to the intermediate dc. Preferably, a 2:1 excess of the base is used relative to the intermediate dc.

[0193] The reaction may be carried out in solvents such as THF, DMF, DMSO, polar protic solvents such as water, methanol, ethanol, isopropanol, nonpolar solvents such as chloroform, 1,4-dioxane, or any combination thereof. Preferably, the reaction is carried out in a combination of isopropanol and water.

[0194] The solvent ratio may be in the range of about 1:1 to about 100:1, preferably in the range of about 20:1 to about 40:1; more preferably in the range of about 30:1. The ratio of isopropanol to water may be in the range of about 20:1 to about 40:1, more preferably in the range of about 30:1.

[0195] The reaction may take place at a temperature in the range of approximately 0°C to approximately 50°C. Preferably, the reaction may take place at a temperature of approximately 25°C.

[0196] The reaction may take place over a period of approximately 30 minutes to 4 hours. Preferably, over a period of approximately 30 minutes to 2 hours. More preferably, the reaction takes place over a period of approximately 1 hour.

[0197] The present invention provides a method for synthesizing the intermediate de, as shown in the following synthetic route: [ka]

[0198] The intermediate dd lactam is reduced with a deuterating agent to form the intermediate de. The deuterating agent may be lithium aluminum deuteride or sodium borode deuteride. Preferably, the deuterating agent is lithium aluminum deuteride.

[0199] The deuterating agent may be used in excess relative to the starting material dd. An excess is preferably 1 to 5 times the amount of deuterating agent relative to the starting material dd. Preferably, a 3-fold excess of deuterating agent relative to the starting material dd is used.

[0200] 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.

[0201] The reaction may be carried out at a temperature in the range of about 0°C to about 80°C. Preferably, the reaction may be carried out at a temperature in the range of about 0°C to about 25°C, and more preferably, the reaction may be carried out at a temperature of about 40°C.

[0202] The reaction may take place over a period of approximately 5 to 15 hours. Preferably, the reaction takes place over a period of approximately 10 to 14 hours. Preferably, over a period of approximately 12 hours.

[0203] The present invention provides a method for synthesizing the intermediate df, as shown in the following synthetic route: [ka]

[0204] Intermediate de is protected to form intermediate df. Any suitable protecting group can be used. Examples of suitable protecting groups that can be used include Fmoc, BOC, or benzyl. Preferably, BOC is used as the protecting group.

[0205] The protecting group reagent may be used in excess of intermediate de. A 1.1 to 2 times excess of the reagent relative to intermediate de may be used. Preferably, a 1.5 times excess of the reagent relative to intermediate de is used.

[0206] 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.

[0207] The reaction can be carried out at temperatures ranging from approximately 10°C to approximately 50°C. Preferably, the reaction is carried out at approximately 25°C.

[0208] The reaction may take place over a period of approximately 30 minutes to 3 hours. Preferably, the reaction takes place over a period of approximately 1 hour.

[0209] The present invention provides a method for synthesizing the intermediate dg as shown in the following synthetic route: [ka]

[0210] Intermediate df is reacted with hydrogen and palladium-carbon hydroxide, and then protected to form intermediate dg. 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.

[0211] The reaction may be carried out in a solvent such as trifluoroethanol, ethyl acetate, dichloromethane, THF, or a mixture thereof. Preferably, the reaction is carried out in trifluoroethanol.

[0212] Preferably, about 0.05 to about 0.5 equivalents of palladium-carbon are used. More preferably, about 0.1 equivalents of palladium-carbon are used.

[0213] The reaction can be carried out at temperatures ranging from approximately 10°C to approximately 50°C. Preferably, the reaction is carried out at approximately 25°C.

[0214] The reaction may take place over a period of approximately 1 to 4 hours. Preferably, the reaction takes place over a period of approximately 2 hours.

[0215] The present invention provides a method for synthesizing the intermediate dl, as shown in the following synthesis route: [ka]

[0216] N-benzyl-L-alotreonine (a) can be reacted with 2-bromopropanoic acid or 2-iodopropanoic acid to form the intermediate dl.

[0217] The reaction is carried out in the presence of a base, preferably a non-nucleophilic base. Examples of intermediates that may be used in the synthesis include, but are not limited to, NN-diisopropylethylamine (DIPEA), 1,8-diazabicycloundeca-7-ene (DBU), 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN), sodium tert-butoxide (t-BuONa), or mixtures thereof. Preferably, the base is sodium tert-butoxide (t-BuONa).

[0218] The base may be used in excess of compound a. A 3 to 7-fold excess of the base may be used relative to compound a. Preferably, a 5-fold excess of the base is used relative to compound a.

[0219] The reaction may be carried out in a 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.

[0220] The reaction may take place at temperatures ranging from approximately -10°C to approximately 60°C. Preferably, the reaction may take place at temperatures ranging from approximately 0°C to approximately 20°C.

[0221] The reaction may take place over a period of approximately 30 minutes to approximately 4 hours. Preferably, over a period of approximately 1 hour to approximately 3 hours. More preferably, the reaction takes place over a period of approximately 2 hours.

[0222] The present invention provides a method for synthesizing the intermediate dm, as shown in the following synthetic route: [ka]

[0223] Intermediate dl undergoes an intramolecular amide coupling reaction in the presence of an optional coupling reagent to form intermediate dm. 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, T4P, DEPBT, or CDI. Preferably, T4P is used as the coupling reagent.

[0224] 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 be carried out in the presence of a base. Examples of bases that may be used include, but are not limited to, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydride, TEA, or DIPEA. Preferably, the reaction is carried out in the presence of DIPEA.

[0226] The reaction may be carried out at temperatures ranging from about -10°C to about 153°C. Preferably, the reaction may be carried out at temperatures ranging from about 20°C to about 130°C or from about 50°C to about 100°C. More preferably, the reaction may be carried out at temperatures ranging from about 0°C to about 25°C.

[0227] The reaction may take place over a period of approximately 5 to 15 hours. Preferably, the reaction takes place over a period of approximately 12 hours.

[0228] The present invention provides a method for synthesizing the intermediate dn, as shown in the following synthesis route: [ka]

[0229] Intermediate dm is reacted with isobutylcarbonochloride d and a deuterating agent or a mixture of deuterating agents in the presence of a base to form intermediate dn. The deuterating agent may be heavy water, lithium aluminum deuteride, sodium borodeuteride, or any combination thereof. Preferably, the deuterating agent may be sodium borodeuteride or sodium borodeuteride and heavy water. The base may be triethylamine (TEA) or DIPEA. Preferably, the base is TEA.

[0230] The deuterating agent may be used in excess of the starting material dm. The excess is preferably 0.5 to 2 times the amount of deuterating agent relative to the starting material dm. Preferably, a 1.1-fold excess of deuterating agent relative to the starting material dm is used.

[0231] 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.

[0232] The reaction may be carried out at a temperature in the range of approximately -10°C to approximately 60°C. Preferably, the reaction may be carried out at a temperature in the range of approximately 0°C to approximately 25°C. The reaction may be carried out for a period of approximately 1 hour to approximately 4 hours. Preferably, the reaction may be carried out for a period of approximately 2 hours.

[0233] The present invention provides a method for synthesizing the intermediate do, as shown in the following synthetic route: [ka]

[0234] The intermediate dn is reduced by reacting with a reducing agent to form the intermediate do.

[0235] The reducing agent may be borane, borane dimethyl sulfide, lithium aluminum hydride, boron trifluoride diethyl etherate, and diborane, for example, but not limited to these. Preferably, the reducing agent is borane.

[0236] 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.

[0237] The reaction may take place at a temperature in the range of about -10°C to about 80°C. Preferably, the reaction takes place in the range of about 0°C to about 45°C. The reaction may take place over a period of about 30 minutes to about 5 hours. Preferably, over a period of about 1 hour to about 3 hours. More preferably, the reaction takes place over a period of about 2.5 hours.

[0238] The present invention provides a method for synthesizing the intermediate dp, as shown in the following synthetic route: [ka]

[0239] Intermediate do is reacted with hydrogen and palladium carbon, and then protected to form intermediate dp. 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.

[0240] 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.

[0241] An intermediate dp 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.

[0242] Suitable protecting reagents for forming the intermediate dp include, but are not limited to, fluorenylmethyloxycarbonyl chloride, 9-fluorenylmethylsuccinimidyl carbonate, 9-fluorenylmethyloxycarbonyl azide, BOC anhydride, and tosyl chloride. Preferably, BOC anhydride is used.

[0243] The protecting group reagent may be used in excess of intermediate DO. A 1.1 to 2 times excess of the reagent may be used relative to intermediate BK. Preferably, a 1.5 times excess of the reagent relative to intermediate DO is used.

[0244] 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.

[0245] 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 20°C. The reaction may take place over a period of approximately 10 to approximately 20 hours. Preferably, the reaction takes place over a period of approximately 16 hours.

[0246] The present invention provides a method for synthesizing intermediate dq, as shown in the following synthetic route: [ka]

[0247] Intermediate dp is reacted with isoindoline-1,3-dione to form intermediate dq. Isoindoline-1,3-dione may be used in excess of intermediate dp. Isoindoline-1,3-dione may be used in an excess of 1.1 to 2 times relative to intermediate bl. Preferably, isoindoline-1,3-dione is used in an excess of 1.5 times relative to intermediate dp.

[0248] Preferably, the reaction is carried out in the presence of triphenylphosphine. Triphenylphosphine may be used in excess of intermediate dp. A 1.1 to 2-fold excess of triphenylphosphine may be used relative to intermediate dp. Preferably, a 1.5-fold excess of triphenylphosphine is used relative to intermediate dp.

[0249] 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 the intermediate dp. A 1.1 to 2 times excess of the oxidizing agent relative to the intermediate dp may be used. Preferably, a 1.5 times excess of the oxidizing agent relative to the intermediate dp is used.

[0250] 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.

[0251] 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.

[0252] The present invention provides a method for synthesizing the intermediate dr as shown in the following synthetic route: [ka]

[0253] Intermediate dq is reacted with hydrazine or hydrazine hydrate to form intermediate bn. Preferably, intermediate bm is reacted with hydrazine hydrate to form intermediate dr.

[0254] Hydrazine or hydrazine hydrate may be used in excess of the intermediate dq. A 5- to 20-fold excess of hydrazine or hydrazine hydrate relative to the intermediate dq may be used. Preferably, a 10-fold excess of hydrazine or hydrazine hydrate relative to the intermediate dq is used.

[0255] 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.

[0256] 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.

[0257] The present invention also provides the following compounds: (2R,3S)-2-(benzylamino)butane-1,3-diol (intermediate b); (2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (intermediate c); (R)-2-(((2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)oxy)propanoic acid or (S)-2-(((2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)oxy)propanoic acid (intermediate d); (2R,5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine-3-one or (2S,5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine-3-one (intermediate e); (2S,3R,6R)-4-benzyl-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine or (2S,3R,6S)-4-benzyl-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine (intermediate f); ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholine-3-yl)methanol or ((2S,3R,6S)-4-benzyl-2,6-dimethylmorpholine-3-yl)methanol (intermediate g); tert-butyl(2S,3R,6R)-3-(hydroxymethyl)-2,6-dimethylmorpholine-4-carboxylate or tert-butyl(2S,3R,6S)-3-(hydroxymethyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate h); tert-butyl(2S,3R,6R)-3-((1,3-dioxoiisoindolin-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate or tert-butyl(2S,3R,6S)-3-((1,3-dioxoiisoindolin-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate i); or tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate or tert-butyl(2S,3R,6S)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate j); (2S,3R)-3-amino-4-(dibenzylamino)butan-2-ol (intermediate db); (S)-2-bromo-N-((2R,3S)-1-(dibenzylamino)-3-hydroxybutan-2-yl)propenamide (intermediate dc); (2R,5R,6S)-5-((dibenzylamino)methyl)-2,6-dimethylmorpholin-3-one (intermediate dd); tert-butyl(2S,3R,6R)-3-((dibenzylamino)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (intermediate df); tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (intermediate dg); (2S,3S,6R)-4-benzyl-2,6-dimethyl-5-oxomorpholine-3-carboxylic acid (intermediate dm); (2R,5R,6S)-4-benzyl-5-(hydroxymethyl-d2)-2,6-dimethylmorpholin-3-one (intermediate dn); ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholine-3-yl)methane-d2-ol (intermediate do); tert-butyl(2S,3R,6R)-3-(hydroxymethyl-d2)-2,6-dimethylmorpholine-4-carboxylate (intermediate dp); tert-butyl(2S,3R,6R)-3-((1,3-dioxoisoindoline-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2(intermediate dq); tert-butyl(2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4-carboxylate (intermediate dr) Preferably, intermediate j can be prepared starting from any of intermediates (a) to (i).

[0258] Preferably, tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate or (2S,3R,6S)-3-(hydroxymethyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate j) 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); Reacting intermediate (c) with (2S)-2-bromopropanoic acid, (2S)-2-iodopropanoic acid, (2R)-2-bromopropanoic acid, or (2R)-2-iodopropanoic acid in the presence of a Lewis base to form (R)-2-(((2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)oxy)propanoic acid or (S)-2-(((2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)oxy)propanoic acid (intermediate d); In the presence of a coupling reagent, intermediate (d) is subjected to an intramolecular amide coupling reaction to form (2R,5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine-3-one or (2S,5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine-3-one (intermediate e); Reacting intermediate (e) with a reducing agent to form (2S,3R,6R)-4-benzyl-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine or (2S,3R,6S)-4-benzyl-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine (intermediate f); Reacting intermediate (f) with a fluorine source to form ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholine-3-yl)methanol (intermediate g) or ((2S,3R,6S)-4-benzyl-2,6-dimethylmorpholine-3-yl)methanol (intermediate g); Reacting intermediate (g) with hydrogen, palladium carbon, and di-tert-butyl dicarbonate to form tert-butyl(2S,3R,6R)-3-(hydroxymethyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate h) or (2S,3R,6S)-3-(hydroxymethyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate h); Reacting intermediate (h) with isoindoline-1,3-dione to form tert-butyl(2S,3R,6R)-3-((1,3-dioxoiisoindoline-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate or tert-butyl(2S,3R,6S)-3-((1,3-dioxoiisoindoline-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate i); and Reacting intermediate (i) with hydrazine or hydrazine hydrate to form tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate or tert-butyl(2S,3R,6S)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate j). It is prepared by [method].

[0259] In one aspect of the present invention, a method for synthesizing compounds 1-57, 61, 64-82, 85-95, and 98-120 is provided, as shown in the following synthetic route: [ka]

[0260] The structures of compounds 1-57, 61, 64-82, 85-95, and 98-120 are as shown above in this specification.

[0261] The present invention also concerns compounds of formula I: [ka] (wherein R and Het are as defined above in this specification) A method for preparing, (a) In the presence of a base, tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate j) is reacted with a halo-substituted heteroaromatic compound to form a first intermediate compound (intermediate ka~ks); (b) The step of reacting the first intermediate compound with an acid to form a second intermediate compound (intermediates Ia to Is); (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.

[0262] Preferably, intermediate j undergoes a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of the intermediates ka~ks.

[0263] The intermediate ka~ks may be a 6R,2S,3R stereoisomer, a 6S,2S,3R stereoisomer, or a mixture thereof.

[0264] Preferably, the intermediate ka~ks is tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate or tert-butyl(2S,3R,6S)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate ka); tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate or tert-butyl(2S,3R,6S)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate kb); tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate or tert-butyl(2S,3R,6S)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate kc); tert-butyl(2S,3R,6R)-3-(((5-chloropyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate or tert-butyl(2S,3R,6S)-3-(((5-chloropyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate kd); tert-butyl(2S,3R,6R)-3-(((5-chloropyrimidine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate or tert-butyl(2S,3R,6S)-3-(((5-chloropyrimidine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate ke); tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((4-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate or tert-butyl(2S,3R,6S)-2,6-dimethyl-3-(((4-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate kf); tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((6-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate or tert-butyl(2S,3R,6S)-2,6-dimethyl-3-(((6-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate kg); tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((4-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate or tert-butyl(2S,3R,6S)-2,6-dimethyl-3-(((4-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate kh); tert-butyl(2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate ki); tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate kj); tert-butyl(2S,3R,6R)-3-(((3,5-bis(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate kk); tert-butyl(2S,3R,6R)-3-(((3-methoxy-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate kl); tert-butyl(2S,3R,6R)-3-(((3-chloro-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate km); tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate kn); tert-butyl(2S,3R,6R)-3-(((3-cyano-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate ko); tert-butyl(2S,3R,6R)-3-(((3-(difluoromethyl)-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate kp); tert-butyl(2S,3R,6R)-3-(((5-chloro-3-fluoropyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate kq); tert-butyl(2S,3R,6R)-3-(((3-fluoro-4-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate kr); or tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((4-methyl-5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate ks) That is the case.

[0265] In some cases, tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate j) is a deuterated compound. Preferably, the deuterated compound is tert-butyl(2S,3R,6R)-3-((dibenzylamino)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 or tert-butyl(2S,3R,6R)-3-((1,3-dioxoisoindolin-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2, 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 a deuterated compound of formula I.

[0266] In one aspect of the present invention, a method for synthesizing compounds 58, 59, 60, 62, and 63 is provided, as shown in the following synthetic route: [ka]

[0267] The structures of compounds 58, 59, 60, 62, and 63 are as shown above in this specification.

[0268] The present invention also relates to compounds of formula ID(a): [ka] (In the formula, R and Het are defined herein with respect to Formula I, respectively; R 6 (This is either H or deuterium (D)) A method for preparing, (a) The step of reacting tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2(dg) with a halo-substituted heteroaromatic compound in the presence of a base to form a first intermediate compound (dh,di); (b) The step of reacting the first intermediate compound with an acid to form a second intermediate compound (dj, dk); (c) The second intermediate compound is reacted 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.

[0269] Preferably, intermediate dg can be prepared starting from any of the intermediates da to df. Preferably, intermediate dg is (2S,3S)-2-amino-N,N-dibenzyl-3-hydroxybutanamide is reduced by a reducing agent to form (2S,3R)-3-amino-4-(dibenzylamino)butan-2-ol (db); In the presence of a Lewis base, intermediate db is reacted with 2-bromopropanoic acid to form intermediate dc, which in turn forms (S)-2-bromo-N-((2R,3S)-1-(dibenzylamino)-3-hydroxybutan-2-yl)propenamide (intermediate dc); Reacting intermediate dc with a base to form (2R,5R,6S)-5-((dibenzylamino)methyl)-2,6-dimethylmorpholine-3-one (intermediate dd); The intermediate dd is reduced with a deuterating agent and reacted with a protecting group to form tert-butyl(2S,3R,6R)-3-((dibenzylamino)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (intermediate df); and Intermediate df is reacted with hydrogen and palladium-carbon hydroxide, and then protected to form intermediate dg. It can be prepared by [method].

[0270] Preferably, intermediate dg undergoes a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of the intermediates dh and di.

[0271] Preferably, the intermediates dh and di are tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridine-2yl)amino)methyl)morpholine-4-carboxylate-5,5-d2(intermediate dh); or tert-butyl(2S,3R,6R)-3-(((5-chloropyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2(intermediate di) That is the case.

[0272] In one aspect of the present invention, a method for synthesizing compounds 83, 84, 96, and 97 is provided, as shown in the following synthetic route: [ka]

[0273] The structures of compounds 83, 84, 96, and 97 are as shown above in this specification.

[0274] The present invention also relates to the compound of formula ID(b): [ka] (In the formula, R and Het are defined herein with respect to Formula I, respectively; R 7 (This is either H or deuterium (D)) A method for preparing, (a) The step of reacting tert-butyl(2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4-carboxylate (dr) with a halo-substituted heteroaromatic compound in the presence of a base to form a first intermediate (ds~du); (b) The step of reacting the first intermediate with an acid to form a second intermediate (dr~dt); (c) The second intermediate 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.

[0275] Preferably, intermediate dr can be prepared starting from any of intermediates a, dm, to dq. Preferably, intermediate dr is N-benzyl-L-alotreonine (a) is reacted with 2-bromopropanoic acid or 2-iodopropanoic acid, followed by an intramolecular amide coupling reaction using a coupling reagent to form (2S,3S,6R)-4-benzyl-2,6-dimethyl-5-oxomorpholine-3-carboxylic acid (intermediate dm); The intermediate dm is reduced with a deuterating agent to form (2R,5R,6S)-4-benzyl-5-(hydroxymethyl-d2)-2,6-dimethylmorpholine-3-one (intermediate dn); The intermediate dn is reduced with a reducing agent to form ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholine-3-yl)methane-d2-ol (intermediate do); The intermediate do is reacted with hydrogen and palladium carbon, and then protected to form tert-butyl(2S,3R,6R)-3-(hydroxymethyl-d2)-2,6-dimethylmorpholine-4-carboxylate (intermediate dp); The intermediate dp is reacted with isoindoline-1,3-dione to form tert-butyl(2S,3R,6R)-3-((1,3-dioxoisoindoline-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (intermediate dq); The intermediate dq is reacted with hydrazine or hydrazine hydrate to form the intermediate dr. It is prepared by [method].

[0276] Preferably, the intermediate (dr) undergoes a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of the intermediates ds~du.

[0277] Preferably, the intermediate ds~du is tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl-d2)morpholine-4-carboxylate (intermediate ds); tert-butyl(2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)amino)methyl-d2)-2,6-dimethylmorpholine-4-carboxylate (intermediate dt); or tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl-d2)morpholine-4-carboxylate (intermediate du) That is the case.

[0278] 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; if present, further substituents of the halo-substituted heteroaromatic group 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, (C1~C4)-alkoxy, cyano, and halogen. Preferably, the further substituent of the heteroaromatic group is CHF 2、 CF3, cyclopropyl, methoxy, nitrile, or halogen, such as chlorine or fluorine.

[0279] Halo-substituted heteroaromatic compounds may be fluoro-substituted heteroaromatic compounds, chloro-substituted heteroaromatic compounds, bromo-substituted heteroaromatic compounds, or iodine-substituted heteroaromatic compounds. Preferably, halo-substituted heteroaromatic compounds may be chloro-substituted heteroaromatic compounds or fluoro-substituted heteroaromatic compounds.

[0280] The halo-substituted heteroaromatic compounds are preferably 2-chloro-5-(trifluoromethyl)pyrazine, 2-chloro-5-(trifluoromethyl)pyrimidine, 2-fluoro-5-(trifluoromethyl)pyridine, 2-chloro-5-(trifluoromethyl)pyridine, 2-chloro-5-chloropyridine, 5-chloro-2-fluoropyridine, 2,5-dichloropyrimidine, 2-chloro-4-(trifluoromethyl)pyrimidine, and 2-chloro-6-(trifluoromethyl)pyridine. Radin, 2-fluoro-4-(trifluoromethyl)pyridine, 2,3-difluoro-5-(trifluoromethyl)pyridine, 3-bromo-2-fluoro-5-(trifluoromethyl)pyridine, 2-chloro-3,5-bis(trifluoromethyl)pyridine, 2-chloro-3-methoxy-5-(trifluoromethyl)pyridine, 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine, 3-methyl-5-(trifluoromethyl)pyrazine-2-ol (in Selected from (activated in situ), 2-chloro-5-(trifluoromethyl)nicotinonitrile, 2-chloro-3-(difluoromethyl)-5-(trifluoromethyl)pyridine, 5-chloro-2,3-difluoropyridine, 2,3-difluoro-4-methyl-5-(trifluoromethyl)pyridine, 2-chloro-5-chloropyridine, 2,5-dichloropyridine, 2,3-difluoro-5-(trifluoromethyl)pyridine, and 2-chloro-3-methyl-5-(trifluoromethyl)pyridine or 2,4-dichloro-5-(trifluoromethyl)pyrimidine.

[0281] 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, nucleophilic aromatic substitution reactions are carried out in the presence of potassium carbonate (K2CO3) or DIPEA. K2CO3 or DIPEA may be used as a base to prepare a non-deuterated intermediate; DIPEA may be used as a base to prepare a deuterated intermediate.

[0282] The base may be used in excess of intermediate j, dg, or dr. A 2- to 6-fold excess of the base may be used relative to intermediate j, dg, or dr. Preferably, a 3-fold excess of the base is used relative to intermediate j, dg, or dr.

[0283] 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 DMF or DMSO. The solvent for preparing the non-deuterated intermediate may be DMF or DMSO. The solvent for preparing the deuterated intermediate may be DMSO.

[0284] Nucleophilic aromatic substitution reactions can be carried out at temperatures in the range of about 50°C to about 189°C. Preferably, the reaction is carried out at about 60°C to about 100°C. The reaction can be carried out at temperatures in the range of about 80°C to about 180°C. Preferably, the reaction is carried out at about 100°C to about 160°C, and more preferably, the reaction is carried out at about 140°C.

[0285] 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.

[0286] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0287] Preferably, the intermediates ka~ks, dh, di, ds, dt, du are deprotected by acid treatment to form the corresponding intermediates la~ls, dj, dk, dv, dw, dx.

[0288] The intermediate la~ls may be a 6R,2S,3R stereoisomer, a 6S,2S,3R stereoisomer, or a mixture thereof.

[0289] Preferably, the intermediate la~ls is N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyrazine-2-amine hydrochloride or N-(((2S,3R,6S)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyrazine-2-amine hydrochloride (intermediate la); N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyrimidine-2-amine hydrochloride or N-(((2S,3R,6S)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyrimidine-2-amine hydrochloride (intermediate lb); N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyridine-2-amine hydrochloride or N-(((2S,3R,6S)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyridine-2-amine hydrochloride (intermediate lc); 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)pyridine-2-amine hydrochloride or 5-Chloro-N-(((2S,3R,6S)-2,6-dimethylmorpholine-3-yl)methyl)pyridine-2-amine hydrochloride (intermediate ld); 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)pyrimidine-2-amine hydrochloride or 5-Chloro-N-(((2S,3R,6S)-2,6-dimethylmorpholine-3-yl)methyl)pyrimidine-2-amine hydrochloride (intermediate le); N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-4-(trifluoromethyl)pyrimidine-2-amine hydrochloride or N-(((2S,3R,6S)-2,6-dimethylmorpholine-3-yl)methyl)-4-(trifluoromethyl)pyrimidine-2-amine hydrochloride (intermediate lf); N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-6-(trifluoromethyl)pyrazine-2-amine hydrochloride or N-(((2S,3R,6S)-2,6-dimethylmorpholine-3-yl)methyl)-6-(trifluoromethyl)pyrazine-2-amine hydrochloride (intermediate lg); N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-4-(trifluoromethyl)pyridine-2-amine hydrochloride or N-(((2S,3R,6S)-2,6-dimethylmorpholine-3-yl)methyl)-4-(trifluoromethyl)pyridine-2-amine hydrochloride (intermediate lh); N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3-fluoro-5-(trifluoromethyl)pyridine-2-amine hydrochloride (intermediate li); N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyridine-2-amine (intermediate lj); N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3,5-bis(trifluoromethyl)pyridine-2-amine hydrochloride (intermediate lk) N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3-methoxy-5-(trifluoromethyl)pyridine-2-amine (intermediate II); 3-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyridine-2-amine (intermediate lm); N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyrazine-2-amine (intermediate ln); 2-((((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)amino)-5-(trifluoromethyl)nicotinonitrile hydrochloride (intermediate lo); 3-(difluoromethyl)-N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyridine-2-amine hydrochloride (intermediate lp); 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3-fluoropyridine-2-amine hydrochloride (intermediate lq); N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3-fluoro-4-methyl-5-(trifluoromethyl)pyridine-2-amine (intermediate lr); or N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-4-methyl-5-(trifluoromethyl)pyrimidine-2-amine (intermediate ls) That is the case.

[0290] Preferably, intermediates dj and dk are N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyridine-2-amine (intermediate dj); 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl-5,5-d2)methyl)pyridine-2-amine hydrochloride (intermediate dk) That is the case.

[0291] Preferably, the intermediates dv, dw, and dx are N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl-d2)-5-(trifluoromethyl)pyridine-2-amine hydrochloride (intermediate dv); N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl-d2)-3-fluoro-5-(trifluoromethyl)pyridine-2-amine hydrochloride (intermediate dw); N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl-d2)-3-methyl-5-(trifluoromethyl)pyridine-2-amine hydrochloride (intermediate dx) That is the case.

[0292] 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 the deprotection of the intermediates ka~ks, dh, di, ds, dt, and du.

[0293] 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.

[0294] The intermediates ka~ks, dh, di, ds, dt, and du are preferably reacted with 4M HCl in 1,4-dioxane.

[0295] An excess of 4M HCl in 1,4-dioxane may be used for the intermediates ka~ks, dh, di, ds, dt, and du. A 15- to 40-fold excess of 4M HCl in 1,4-dioxane may be used for the intermediates ka~ks, dh, di, ds, dt, and du. Preferably, a 30-fold excess of 4M HCl in 1,4-dioxane is used for the intermediates ka~ks, dh, di, ds, dt, and du.

[0296] Deprotection can be carried out at temperatures in the range of about 12°C to about 40°C. Preferably, the reaction is carried out at about 25°C. Deprotection can be carried out at temperatures in the range of about 10°C to about 40°C. Preferably, the reaction is carried out at about 20°C.

[0297] Deprotection may be carried out over a period of approximately 30 minutes to approximately 5 hours. Preferably, the reaction may be carried out over a period of approximately 1 hour. Deprotection may be carried out over a period of approximately 1 hour to approximately 4 hours. Preferably, the reaction may be carried out over a period of approximately 2 hours.

[0298] Preferably, intermediates Ia-Is, dj, dk, dv, dw, and dx are reacted with a carboxylic acid having the general formula R-COOH (wherein R is selected from the group consisting of a 5-membered or 6-membered aromatic or heteroaromatic group, and the aromatic or heteroaromatic group is unsubstituted or substituted with one or more substituents) to form compounds 1-120 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 a derivative thereof; or a 6-membered aromatic group which is an unsubstituted aryl, substituted aryl, or a derivative thereof.

[0299] 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-fluoropyrimidine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (CAS 2125741-56-0), 5-fluoro-2-(2H-1, 2,3-Triazole-2-yl)benzoic acid (CAS 1186050-64-5), 5-Fluoro-2-(pyrimidine-2-yl)benzoic acid (CAS 1293284-57-7), 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-1H-pyrazole-3-carboxylic acid (CAS 2044704-99-4), 4-(4-Fluorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (CAS 127919-87-3), 4 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid, 4-(5-methoxypyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (CAS 2024759-24-6), 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-fluoropyrimidine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyrimidine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid, or 4-(5-methoxypyridine-2-yl)-1,5-Dimethyl-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyridine-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyrimidine-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid, 6-methyl-3-(pyrimidine-2-yl)picolinic acid (CAS 1228188-18-8), 6-methyl-3-(2H-1,2,3-triazole-2-yl)picolinic acid (CAS 1228188-37- 1) 5-Fluoro-3-(pyrimidine-2-yl)picolinic acid (CAS 1935682-37-3), 5-Fluoro-2-(2H-1,2,3-triazole-2-yl)nicotinic acid (CAS 2138851-77-9), 5-Fluoro-2-(1H-pyrazole-1-yl)benzoic acid (CAS 1152964-04-9), 3-(pyrimidine-2-yl)picolinic acid (CAS 1228431-21-7), 3-(2H-1,2,3-triazole-2-yl)picolinic acid (CAS 1252907-8) 6-0), 3-(5-fluoropyrimidine-2-yl)-6-methylpicolinic acid (CAS 1228430-99-6), 6'-methyl-[2,3'-bipyridine]-2'-carboxylic acid (CAS 1228431-05-7), 6-methyl-[3,3'-bipyridine]-2-carboxylic acid (CAS 1228431-14-8), 6-methyl-3-(pyrazine-2-yl)picolinic acid (CAS 1228431-07-9), 6-methyl-3-(5-methylpyrimidine-2-yl)picolinic acid (CAS 122843 1-09-1), 6-methyl-3-(4-methylpyrimidine-2-yl)picolinic acid (CAS 1228431-12-6), 3-(5-fluoropyrimidine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid, 3-(5-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-4-carboxylic acid, 5-fluoro-3-(2H-1,2,3-triazole-2-yl)picolinic acid, 5,6-dimethyl-3-(pyrimidine-2-yl)picolinic acid, 4,It contains 6-dimethyl-3-(pyrimidine-2-yl)picolinic acid, 6-methyl-3-(pyrimidine-2-yl)pyrazine-2-carboxylic acid, 4-chloro-6-methyl-3-(pyrimidine-2-yl)picolinic acid, 4-(4-cyanophenyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid, 6-(methyl-d3)-3-(pyrimidine-2-yl)picolinic acid, 6-(methyl-d3)-3-(2H-1,2,3-triazole-2-yl)picolinic acid, and 4-(5-fluoropyrimidine-2-yl)-1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylic acid.

[0300] The carboxylic acid may be used in excess relative to the intermediates la~ls, dj, dk, dv, dw, and dx. A 1.2 to 3-fold excess of the carboxylic acid may be used relative to the intermediates la~ls, dj, dk, dv, dw, and dx. Preferably, a 1.5-fold excess of the carboxylic acid is used relative to the intermediates la~ls, dj, dk, dv, dw, and dx.

[0301] The reaction between intermediates Ia-Is, dj, dk, dv, dw, and dx and 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, T4P, DEPBT, or CDI. Preferably, HATU or T4P is used as the coupling reagent.

[0302] The coupling reagent may be used in excess of intermediates Ia-Is, dj, dk, dv, dw, and dx. A 1.2 to 3-fold excess of the coupling reagent may be used relative to intermediates Ia-Is, dj, dk, dv, dw, and dx. Preferably, a 1.5-fold excess of the coupling reagent relative to intermediates Ia-Is, dj, dk, dv, dw, and dx is used.

[0303] The reaction between intermediates Ia-Is, dj, dk, dv, dw, and dx 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.

[0304] The base may be used in excess of intermediates Ia-Is, dj, dk, dv, dw, and dx. A 2- to 6-fold excess of the base may be used for intermediates Ia-Is, dj, dk, dv, dw, and dx. Preferably, a 4-fold excess of the base is used for intermediates Ia-Is, dj, dk, dv, dw, and dx.

[0305] The reaction between intermediates Ia-Is, dj, dk, dv, dw, and dx 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.

[0306] The reaction between intermediates Ia-Is, dj, dk, dv, dw, and dx and carboxylic acid R-COOH can be carried out at temperatures ranging from approximately -10°C to approximately 40°C. Preferably, the reaction is carried out at approximately 0°C to approximately 20°C.

[0307] The reaction between intermediates Ia-Is, dj, dk, dv, dw, and dx and carboxylic acid R-COOH can proceed over a period of approximately 1 to 6 hours. Preferably, the reaction is carried out over a period of approximately 2 hours.

[0308] 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]

[0309] The R-COOH group may be 4-(5-methoxypyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.

[0310] 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.

[0311] 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.

[0312] (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.

[0313] 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.

[0314] 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. 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.

[0315] 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.

[0316] 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.

[0317] 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.

[0318] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0319] 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. 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.

[0320] Deprotection may be carried out at a temperature in the range of about 20°C to about 80°C. Preferably, the reaction is carried out at about 50°C. More preferably, the reaction is carried out at about 20°C. Deprotection may 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.

[0321] 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]

[0322] The R-COOH group may be 4-(5-cyanopyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid.

[0323] An intermediate can be formed by reacting a starting material (3-(tert-butoxycarbonyl)-1-methyl-1H-pyrazole-4-yl)boronic acid, 3-(tert-butoxycarbonyl)-1-methyl-5-(methyl-d3)-1H-pyrazole-4-yl)boronic acid or a derivative thereof (e.g., a boronic acid ester or an organic trifluoroborate)) with a compound selected from 6-iodopyridine-3-carbonitride, 6-bromopyridine-3-carbonitride, 6-chloropyridine-3-carbonitride, or 2-bromo-5-fluoropyrimidine via Suzuki coupling.

[0324] 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.

[0325] Compounds selected from 6-iodopyridine-3-carbonitride, 6-bromopyridine-3-carbonitride, 6-chloropyridine-3-carbonitride, or 2-bromo-5-fluoropyrimidine may be used in excess of the starting material. A 1.1 to 1.5-fold excess of the compound may be used relative to the starting material. Preferably, a 1.2-fold excess of the compound is used relative to the starting material. The reaction may be carried out in a polar aprotic solvent such as THF, DMF, or DMSO; a polar protic solvent such as water, methanol, ethanol, or isopropanol; a nonpolar solvent such as chloroform or 1,4-dioxane; or any combination thereof. Preferably, the reaction is carried out in a combination of 1,4-dioxane and water. 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. 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. The reaction may be carried out in the presence of a base. Examples of bases that can be used include K2CO3, KO t Examples of bases include, but are not limited to, Bu, Cs2CO3, K3PO4, NaOH, or NET3. Preferably, K3PO4 is used. The base may be used in excess of the starting material. A 1.1 to 5 times excess of base may be used relative to the starting material. Preferably, a 1.5 times excess of base is used relative to the starting material. The reaction may be carried out at a temperature in the range of about 50°C to about 100°C. Preferably, the reaction is carried out at about 80°C. The reaction may be carried out for a period of about 30 minutes to about 5 hours. Preferably, the reaction is carried out for a period of about 2 hours.

[0326] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0327] 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. 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. 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. Similarly, the following synthetic route shows how to synthesize carboxylic acids having the general formula R-COOH: [ka]

[0328] Preferably, R-COOH may be 4-(5-methoxypyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.

[0329] An intermediate can be formed by reacting a starting material (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazole-4-yl)boronic acid or its derivative (e.g., boronic acid ester or organic trifluoroborate)) with a compound selected from 2-iodo-5-methoxypyridine, 2-bromo-5-methoxypyridine, or 2-chloro-5-methoxypyridine via Suzuki coupling.

[0330] 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.

[0331] 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.

[0332] 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. 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.

[0333] 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 of bases include, but are not limited to, Bu, Cs2CO3, K3PO4, NaOH, or NET3. K3PO4 is preferably used. The base may be used in excess of the starting material. A 1.1 to 5 times excess of base may be used relative to the starting material. Preferably, a 1.5 times excess of base is used relative to the starting material.

[0334] 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 2 hours to approximately 16 hours. Preferably, the reaction takes place over a period of approximately 12 hours.

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

[0336] 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. 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. 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.

[0337] 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]

[0338] R-COOH may be 5-(5-fluoropyrimidine-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid.

[0339] 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.

[0340] 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.

[0341] 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.

[0342] 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. 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.

[0343] 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.

[0344] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0345] 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.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] 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. Preferably, about 0.02 to about 0.5 equivalents of catalyst are used relative to the organostannan intermediate. Preferably, about 0.1 equivalents of catalyst are used.

[0350] 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.

[0351] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0352] 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.

[0353] Deprotection can be carried out in a neat acid or base. 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.

[0354] 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.

[0355] 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]

[0356] R-COOH may be 5-(5-methoxypyridine-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid.

[0357] 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.

[0358] 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.

[0359] 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.

[0360] 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.

[0361] 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.

[0362] 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.

[0363] The reaction can 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.

[0364] The reaction may take place over a period of approximately 10 to 20 hours. Preferably, the reaction takes place over a period of approximately 16 hours.

[0365] The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.

[0366] 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.

[0367] Deprotection can be carried out in a neat acid or base.

[0368] 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.

[0369] Deprotection can be carried out at temperatures in the range of about 50°C to about 100°C. Preferably, the reaction is carried out at about 80°C.

[0370] Deprotection can be carried out over a period of approximately 6 to 22 hours. Preferably, the reaction is carried out over a period of approximately 16 hours.

[0371] 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]

[0372] R-COOH may be 4-(5-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.

[0373] 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.

[0374] 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.

[0375] 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.

[0376] 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.

[0377] 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.

[0378] 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.

[0379] 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.

[0380] 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.

[0381] 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.

[0382] 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.

[0383] 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.

[0384] 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.

[0385] The second intermediate can be reacted with 2-bromo-5-fluoropyrimidine, 2-iodo-5-fluoropyrimidine, or 2-chloro-5-fluoropyrimidine via Suzuki coupling to form a third intermediate.

[0386] Alternatively, 2-bromo-5-fluoropyrimidine, 2-iodo-5-fluoropyrimidine, or 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.

[0387] 2-bromo-5-fluoropyrimidine, 2-iodo-5-fluoropyrimidine, or 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.

[0388] 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.

[0389] 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. Preferably, about 0.02 to about 0.5 equivalents of catalyst are used relative to the second intermediate. Preferably, about 0.05 equivalents of catalyst are used.

[0390] The reaction can be carried out in the presence of a base. Examples of bases that can be used include K2CO3 and KO. tExamples of bases include, but are not limited to, Bu, Cs2CO3, K3PO4, NaOH, or NET3. Preferably, K2CO3 is used. The base may be used in excess of the second intermediate. A 1.1 to 3 times excess of base may be used for the second intermediate. Preferably, a 1.5 times excess of base is used for the second intermediate.

[0391] 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. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere.

[0392] 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. 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.

[0393] 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.

[0394] 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, as shown in the following scheme: [ka]

[0395] 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.

[0396] 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.

[0397] 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.

[0398] 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.

[0399] 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.

[0400] 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.

[0401] (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. 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.

[0402] 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.

[0403] 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 30 minutes to about 3 hours. Preferably, the reaction is carried out for a period of about 1 hour.

[0404] The present invention also provides a method for preparing 3-(5-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-4-carboxylic acid, as shown in the following scheme: [ka]

[0405] 5-Fluoro-2-pyridyl)trimethyl-stannane can be added to methyl 3-iodo-1,5-dimethyl-1H-pyrazole-4-carboxylate 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. 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.

[0406] Copper iodide and tetrakis(triphenylphosphine)palladium(0) can be added to the mixture. The reaction can 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.

[0407] The reaction mixture can be purified to obtain methyl 3-(5-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-4-carboxylate. Preferably, the reaction mixture is purified by silica gel column chromatography.

[0408] Lithium hydroxide monohydrate can be added to methyl 3-(5-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-4-carboxylate in the presence of one or more solvents to obtain 3-(5-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-4-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 THF and water. 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, the reaction is carried out for a period of about 2 hours.

[0409] The present invention also provides a method for preparing 5-fluoro-3-(2H-1,2,3-triazol-2-yl)picolinic acid, as shown in the following scheme: [ka]

[0410] 3,5-Difluoropicolinonitrile can be added to 2H-triazole in the presence of a solvent and a base. Examples of solvents include, but are not limited to, acetonitrile, DMF, DMSO, pyridine, THF, or mixtures thereof. Preferably, the solvent is acetonitrile. 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 at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 25°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.

[0411] The product can be purified to obtain 5-fluoro-3-(2H-1,2,3-triazole-2-yl)picolinonitrile. Preferably, the product is purified by flash silica gel chromatography.

[0412] 5-Fluoro-3-(2H-1,2,3-triazole-2-yl)picolinonitrile can be stirred in an acid to obtain 5-fluoro-3-(2H-1,2,3-triazole-2-yl)picolinic acid. Examples of acids include, but are not limited to, phosphoric acid, hydrochloric acid, trifluoroacetic acid, or mixtures thereof. Preferably, the acid is hydrochloric acid. The reaction may be carried out at a temperature in the range of about 80°C to about 160°C. Preferably, the reaction is carried out at about 110°C. The reaction may be carried out for a period of about 3 hours to about 7 hours. Preferably, the reaction is carried out for a period of about 5 hours.

[0413] The present invention also provides a method for preparing 5-fluoro-3-(5-fluoropyrimidine-2-yl)picolinic acid, as shown in the following scheme: [ka]

[0414] (5-Fluoropyrimidine-2-yl)-trimethyl-stannane can be added to methyl 3-bromo-5-fluoropicolinate and cesium fluoride 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 DMF.

[0415] 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 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 about 13 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 16 hours.

[0416] The reaction mixture can be purified to obtain methyl 5-fluoro-3-(5-fluoropyrimidine-2-yl)picolinate. Preferably, the reaction mixture is purified by silica gel column chromatography.

[0417] Lithium hydroxide monohydrate can be added to methyl 5-fluoro-3-(5-fluoropyrimidin-2-yl)picolinate in the presence of one or more solvents to obtain 5-fluoro-3-(5-fluoropyrimidin-2-yl)picolinic acid. Examples of solvents include, but are not limited to, THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, dioxane, or mixtures thereof. Preferably, the solvents are THF and water. 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, the reaction is carried out for a period of about 2 hours.

[0418] The present invention also provides a method for preparing 5,6-dimethyl-3-(pyrimidine-2-yl)picolinic acid, as shown in the following scheme: [ka]

[0419] 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.

[0420] 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.

[0421] 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.

[0422] 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.

[0423] 5,6-dimethyl-3-(pyrimidine-2-yl)pyridine-2-ol (1.4 g, 6.96 mmol, 1 eq) 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.

[0424] 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.

[0425] 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.

[0426] The present invention also provides a method for preparing 4,6-dimethyl-3-(pyrimidine-2-yl)picolinic acid, as shown in the following scheme: [ka]

[0427] 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.

[0428] The crude product can be purified to obtain 2-(4,6-dimethylpyridine-3-yl)pyrimidine. Preferably, purification can be carried out by silica gel column chromatography.

[0429] 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.

[0430] The reaction mixture can be quenched by the addition of sodium sulfite to obtain 2,4-dimethyl-5-(pyrimidine-2-yl)pyridine 1-oxide.

[0431] 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 14 hours to about 19 hours. Preferably, the reaction is carried out for a period of about 17 hours.

[0432] 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.

[0433] The present invention also provides a method for preparing 6-methyl-3-(pyrimidine-2-yl)pyrazine-2-carboxylic acid, as shown in the following scheme: [ka]

[0434] 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane can be added to methyl 6-bromo-3-chloropyrazine-2-carboxylate in the presence of a solvent and a base. Examples of solvents include, but are not limited to, diethyl ether, benzene, toluene, chloroform, dioxane, or mixtures thereof. Preferably, the solvent is dioxane. Examples of bases 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. Then, bis(diphenylphosphin)ferrocene)palladium(II) dichloride (Pd(dppf)Cl2) can be added under nitrogen to form methyl 3-chloro-6-methylpyrazine-2-carboxylate. 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 9 hours to about 15 hours. Preferably, the reaction is carried out over a period of about 12 hours.

[0435] Tributyl(pyrimidine-2-yl) stannane can be reacted with a mixture of methyl 3-chloro-6-methylpyrazine-2-carboxylate, 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, or DMSO. 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 100°C to about 140°C. Preferably, the reaction is carried out at about 120°C. The reaction may be carried out for a period of 3 hours to about 9 hours. Preferably, the reaction is carried out for a period of about 6 hours.

[0436] Methyl 6-methyl-3-(pyrimidine-2-yl)pyrazine-2-carboxylate can be treated with an acid to produce 6-methyl-3-(pyrimidine-2-yl)pyrazine-2-carboxylic acid. 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 30 minutes to about 4 hours. Preferably, the reaction is carried out for a period of about 2 hours.

[0437] The present invention also provides a method for preparing 4-chloro-6-methyl-3-(pyrimidine-2-yl)picolinic acid, as shown in the following scheme: [ka]

[0438] 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 acid is sulfuric 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.

[0439] Methyl 3-bromo-6-methyl picolinate can be added to tributyl(pyrimidine-2-yl) stannane, cesium fluoride, copper iodo, or tetrakis(triphenylphosphine)palladium(0) 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.

[0440] 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 50°C to about 10°C. Preferably, the reaction is carried out at 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.

[0441] The reaction mixture can be quenched by adding a saturated sodium sulfite solution.

[0442] 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.

[0443] 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.

[0444] The present invention also provides a method for preparing 6-(methyl-d3)-3-(pyrimidine-2-yl)picolinic acid, as shown in the following scheme: [ka]

[0445] 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.

[0446] The residue can be quenched with an aqueous potassium fluoride solution to obtain methyl 6-amino-3-(pyrimidine-2-yl)picolinate.

[0447] 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.

[0448] 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.

[0449] 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.

[0450] 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.

[0451] 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.

[0452] The present invention also provides a method for preparing 6-(methyl-d3)-3-(2H-1,2,3-triazol-2-yl)picolinate. [ka]

[0453] 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.

[0454] 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.

[0455] 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.

[0456] 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.

[0457] The present invention also provides a method for preparing 4-(5-fluoropyrimidine-2-yl)-1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylic acid, as shown in the following scheme: [ka]

[0458] 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid 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.

[0459] 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 2 hours.

[0460] The reaction mixture can be quenched by adding a saturated ammonium chloride solution.

[0461] 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.

[0462] 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.

[0463] 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.

[0464] Tert-butyl 4-(5-fluoropyrimidine-2-yl)-1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylate is treated with an acid to obtain 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.

[0465] The present invention also provides a method for preparing 4-(5-fluoropyridine-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid, as shown in the following scheme: [ka]

[0466] 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.

[0467] 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.

[0468] 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.

[0469] The present invention also provides a method for preparing 4-(5-fluoropyrimidine-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid, as shown in the following scheme: [ka]

[0470] A mixture can be formed by adding sodium hydride 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. 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.

[0471] 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 hours.

[0472] 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.

[0473] 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.

[0474] 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.

[0475] 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.

[0476] 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.

[0477] 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.

[0478] 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.

[0479] 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.

[0480] 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.

[0481] 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.

[0482] [Examples] The present invention is further described with reference to the following embodiments, which are not presented to limit the scope of the invention.

[0483] I. General synthesis methods and procedures [ka] 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).

[0484] 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. When the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 4 / 1), (2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (6 g, 19.38 mmol, 25.23% yield) was obtained 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).

[0485] Example 3: Synthesis of (R)-2-(((2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)oxy)propanoic acid (d) (2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (5 g, 11.53 mmol, 1 equivalent) was dissolved in tetrahydrofuran (100 mL) and (2S)-2-bromopropanoic acid (7.06 g, 46.12 mmol, 4 equivalents) was added. This solution was cooled to 0°C. NaH (4.61 g, 115.30 mmol, 60% purity, 8 equivalents) was added to this solution at 0°C. The mixture was stirred at 60°C for 6 hours. LCMS showed that all of the starting materials remained and 50% of the desired MW was detected. The reaction mixture was poured into HCl (1N) to adjust the pH to 7. The reaction product was extracted with ethyl acetate (30 mL x 3), and the combined organic layer was concentrated under reduced pressure to obtain crude (R)-2-(((2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)oxy)propanoic acid (5 g, 9.89 mmol, 85.75% yield) as a bright yellow oily substance. The product was used directly in the next step without further purification. LCMS (ESI+): m / z=506.4 (M+1), RT: 0.819 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.

[0486] Example 4: Synthesis of (2R,5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine-3-one(e) (R)-2-(((2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)oxy)propanoic acid (5 g, 9.89 mmol, 1 equivalent) was dissolved in dimethylformamide (160 mL) and T3P (12.58 g, 19.77 mmol, 11.77 mL, 50% purity, 2 equivalents) was added at 0°C. The 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 product was poured into ice water (50 mL) and extracted with ethyl acetate (50 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 (2R,5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine-3-one (2.9 g, 5.65 mmol, 57.14% yield) as a colorless oil. 1 H NMR(400 MHz, DMSO-d6): δ ppm 7.56 - 7.69 (m, 4H) 7.38 - 7.53 (m, 6 H) 7.18 - 7.38 (m, 3 H) 7.11 (br d, J=7.13 Hz, 2 H) 5.06(br d, J=15.38 Hz, 1 H) 4.27 (m, 1 H) 3.91 - 4.08 (m, 3 H) 3.71 (m, 1 H) 3.18 -3.31 (m, 1 H) 1.25 (br d, J=6.75 Hz, 3 H) 1.15 (br d, J=6.38 Hz, 3 H) 0.98 -1.05 (m, 9 H).

[0487] Example 5: Synthesis of (2S,3R,6R)-4-benzyl-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine (f) (2R,5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine-3-one (2.9 g, 5.65 mmol, 1 equivalent) was added to a solution of THF (35 mL) at 0°C with BH3-Me2S (10 M, 2.26 mL, 4 equivalents). The mixture was stirred at 30°C for 5 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 methanol (30 mL). The solution was then concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to obtain (2S,3R,6R)-4-benzyl-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine (2.1 g, 4.21 mmol, 74.55% yield) as a colorless oil. 1 H NMR(400 MHz, DMSO-d6): δ ppm 7.62 - 7.74 (m, 4H) 7.40 - 7.54 (m, 6 H) 7.15 - 7.34 (m, 5 H) 3.84 - 3.96 (m, 2 H) 3.76 - 3.83(m, 1 H) 3.71 (br d, J=14.01 Hz, 1 H) 3.48 - 3.57 (m, 2 H) 2.67 (br s, 1 H)2.27 (m, 1 H) 2.00 - 2.10 (m, 1 H) 1.06 (d, J=6.63 Hz, 3 H) 0.96 - 1.01 (m, 9H) 0.92 (d, J = 6.13 Hz, 3 H).

[0488] Example 6: Synthesis of ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholine-3-yl)methanol (g) To a solution of (2S,3R,6R)-4-benzyl-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine (2.5 g, 5.28 mmol, 1 equivalent) in tetrahydrofuran (25 mL), tetrabutylammonium fluoride trihydrate (1 M, 7.92 mL, 1.5 equivalents) 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 product was extracted with ethyl acetate (30 mL x 3), and the combined organic layer was concentrated under reduced pressure to obtain the residue. When the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 4 / 1), ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholine-3-yl)methanol (0.9 g, 3.44 mmol, 65.22% yield) was obtained as a colorless oil. 1 H NMR(400 MHz, DMSO-d6): δ ppm 7.27 - 7.39 (m, 4H) 7.17 - 7.24 (m, 1 H) 4.26 (t, J=4.75 Hz, 1 H) 3.88 (d, J=13.88 Hz, 1 H) 3.72- 3.83 (m, 2 H) 3.53 - 3.70 (m, 3 H) 2.31 (m, 1 H) 2.12 - 2.22 (m, 1 H) 1.07(d, J=6.75 Hz, 3 H) 0.97 (d, J=6.13 Hz, 3 H).

[0489] Example 7: Synthesis of tert-butyl(2S,3R,6R)-3-(hydroxymethyl)-2,6-dimethylmorpholine-4-carboxylate(h) To a solution of ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholine-3-yl)methanol (900 mg, 3.44 mmol, 1 equivalent) in ethyl acetate (18 mL), Pd / C (183.15 mg, 172.11 μmol, 10% Pd (w / w), 0.05 equivalents on activated carbon) and (Boc)2O (1.13 g, 5.16 mmol, 1.19 mL, 1.5 equivalents) were added. This mixture was stirred under H2 (15 Psi) at 25°C for 12 hours. LC-MS showed that all of the starting materials were consumed. When this reaction product was filtered and concentrated, crude tert-butyl(2S,3R,6R)-3-(hydroxymethyl)-2,6-dimethylmorpholine-4-carboxylate (0.63 g, 2.31 mmol, 67.15% yield) was obtained as a colorless oil. The product was used directly in the next step without further purification. 1 H NMR(400 MHz, DMSO-d6): δ ppm 4.40 - 4.51 (m, 1H) 3.71 - 3.99 (m, 1 H) 3.56 - 3.69 (m, 3 H) 3.38 - 3.48 (m, 1 H) 2.59 (m, 1 H)1.39 (d, J=3.88 Hz, 9 H) 0.97 - 1.16 (m, 6 H).

[0490] Example 8: Synthesis of tert-butyl(2S,3R,6R)-3-((1,3-dioxoisoindoline-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate(i) To a solution of tert-butyl(2S,3R,6R)-3-(hydroxymethyl)-2,6-dimethylmorpholine-4-carboxylate (630 mg, 2.57 mmol, 1 equivalent) in tetrahydrofuran (6.50 mL), isoindoline-1,3-dione (566.78 mg, 3.85 mmol, 1.5 equivalent) and PPh3 (1.01 g, 3.85 mmol, 1.5 equivalent) were added at 0°C. Next, DIAD (778.95 mg, 3.85 mmol, 746.84 μL, 1.5 equivalent) was added to this mixture at 0°C. This mixture was stirred at 20°C for 16 hours. LC-MS showed that all of the starting materials were consumed and the desired MW was detected. The reaction product was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were 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 4 / 1) to obtain tert-butyl(2S,3R,6R)-3-((1,3-dioxoisoindolin-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate (650 mg, 1.74 mmol, 67.60% yield) as a white solid. LCMS (ESI+): m / z=375.2 (M+1), RT: 0.767 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.

[0491] Example 9: Synthesis of tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate(j) To a solution of tert-butyl(2S,3R,6R)-3-((1,3-dioxoisoindolin-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate (650 mg, 1.74 mmol, 1 equivalent) in methanol (26 mL), NH2NH2.H2O (869.03 mg, 17.36 mmol, 842.08 μL, 10 equivalents) was added. This mixture was stirred at 60°C for 2 hours. LC-MS showed that all of the starting material was consumed and the desired MW was detected. The reaction product was filtered to remove impurities. The filtrate was concentrated under vacuum to obtain crude tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate (0.35 g, 1.43 mmol, 82.52% yield) as a white solid. The product was used directly in the next step without further purification. LCMS (ESI+): m / z=245.2 (M+1), RT: 0.510 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.

[0492] Example 10: Synthesis of tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (ka), general procedure To a solution of tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate (200 mg, 736.71 μmol, 1 equivalent) in dimethylformamide (4 mL), K2CO3 (203.63 mg, 1.47 mmol, 2 equivalents) and 2-chloro-5-(trifluoromethyl)pyrazine (201.71 mg, 1.11 mmol, 1.5 equivalents) were added at 25 °C. The mixture was then stirred at 100 °C for 2 hours. LC-MS indicated that all of the starting materials were consumed and the desired MW was detected. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layer was 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(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (150 mg, 46.94% yield) as a white solid. 1 H NMR(400 MHz, DMSO-d6): δ 8.45 - 8.33 (m,0.86H), 8.12 - 7.96 (m, 1.28H), 7.96 - 7.74 (m, 0.55H), 4.17 - 4.06 (m, 0.92H),3.79 (dd, J = 2.7, 13.6 Hz, 0.69H), 3.74 - 3.63 (m, 1.81H), 3.60 - 3.36 (m,2.25H), 2.90 - 2.63 (m, 1.09H), 1.29 - 1.18 (m, 2.92H), 1.18 - 1.08 (m, 5.91H),1.04 (s, 6H).

[0493] Example 11: Synthesis of tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate (kb), general procedure To a DMSO (5 mL) solution of tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate (250 mg, 1.02 mmol, 1 equivalent), 2-chloro-5-(trifluoromethyl)pyrimidine (280.15 mg, 1.53 mmol, 1.5 equivalents) and DIPEA (396.72 mg, 3.07 mmol, 534.66 μL, 3 equivalents) were added at 25°C. The mixture was then stirred at 80°C for 2 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete and the desired MW was detected. The residue was quenched with ice water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic matter was dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1:1). The compound tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate (360 mg, 81.11% yield) was obtained as a colorless oil. LCMS (ESI+): m / z=391.3 (M+1), RT: 0.803 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. Similarly, the following intermediates were prepared.

[0494] Example 12: Synthesis of tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate (kc) The general procedure used to prepare compound (ka) (see Example 10) was repeated using tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2-fluoro-5-(trifluoromethyl)pyridine. Yield 88%, colorless oil. 1 H NMR(400 MHz, DMSO-d6): δ 8.89 (s, 0.18 H) 8.25- 8.32 (m, 0.84 H) 7.51 - 7.66 (m, 0.87 H) 7.41 (br s, 0.66 H) 7.07 - 7.17 (m,0.18 H) 6.57 (d, J=8.88 Hz, 0.68 H) 6.49 (d, J=9.01 Hz, 0.18 H) 4.77 (dt,J=12.38, 6.07 Hz, 0.22 H) 4.09 - 4.17 (m, 0.78 H) 3.77 (dd, J=13.51, 2.75Hz,0.74H) 3.62 - 3.72 (m, 1.54 H) 3.52 - 3.59 (m, 0.34 H) 3.47 (ddd, J=10.63, 6.25,2.75 Hz, 0.97 H) 3.30 (br d, J=5.88 Hz, 1.14 H) 2.85 (dd, J=13.01, 11.01 Hz,0.21 H) 2.68 (dd, J=13.20, 11.32 Hz, 0.73 H) 1.26 (s, 2.00 H) 1.16 - 1.19 (m,3.24 H) 1.09 - 1.14 (m, 2.71 H) 1.05 (s, 6.59 H).

[0495] Example 13: Synthesis of tert-butyl(2S,3R,6R)-3-(((5-chloropyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (kd) Using tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 5-chloro-2-fluoropyridine, the general procedure used to prepare compound (ka) (see Example 10) was repeated. Yield 43%, colorless oil. 1 HNMR(400 MHz, DMSO-d6): δ ppm 7.92 - 8.00 (m,0.76 H) 7.33 - 7.45 (m, 0.78 H) 6.83 (br t, J=5.75 Hz, 0.60 H) 6.40 - 6.55 (m,1.00 H) 4.06 - 4.15 (m, 0.82 H) 3.67 - 3.80 (m, 1.37 H) 3.41 - 3.63 (m, 2.28 H)3.21 - 3.32 (m, 2.19 H) 2.60 - 2.73 (m, 0.83 H) 1.03 - 1.35 (m, 15.00 H).

[0496] Example 14: Synthesis of tert-butyl(2S,3R,6R)-3-(((5-chloropyrimidine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (ke) Using tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2,5-dichloropyrimidine, the general procedure used to prepare compound (kb) (see Example 11) was repeated. Yield 68%, white solid. 1 H NMR(400 MHz, DMSO-d6): δ 8.98 - 8.15 (m,2.11H), 7.52 - 7.03 (m, 1.02H), 4.83 - 4.71 (m, 0.25H), 4.10 (br d, J = 11.1Hz, 0.97H), 3.80 - 3.60 (m, 1.86H), 3.55 - 3.37 (m, 2.73H), 2.90 - 2.68 (m,1.04H), 1.20 - 1.06 (m, 15.00H).

[0497] Example 15: Synthesis of tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((4-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate (kf) Using tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2-chloro-4-(trifluoromethyl)pyrimidine, the general procedure used to prepare compound (kb) (see Example 11) was repeated. Yield 59%, white solid. LCMS (ESI+): m / z=391.2 (M+1), RT: 0.789 min.

[0498] Example 16: Synthesis of tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((6-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (kq) The general procedure used to prepare tert-butyl(2S,3R,6R)-2,6-dimethylmorpholine-4-carboxylate and 2-chloro-6-(trifluoromethyl)pyrazine (see Example 10) was repeated. Yield 56%, colorless oil. LCMS (ESI+): m / z=335.2 (M-55), RT=0.784 min.

[0499] Example 17: Synthesis of tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((4-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate (KH) Using tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2-fluoro-4-(trifluoromethyl)pyridine, the general procedure used to prepare compound (ka) (see Example 10) was repeated. Yield 63%, colorless oil. LCMS (ESI+): m / z=390.2(M+1), RT=0.682 min.

[0500] Example 18: Synthesis of tert-butyl(2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (ki) Using tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2,3-difluoro-5-(trifluoromethyl)pyridine, the general procedure used to prepare compound (kb) (see Example 11) was repeated. Yield 36%, yellow solid. 1 HNMR(400 MHz, DMSO-d6): δ ppm 8.13 - 8.27 (m, 1H), 7.76 (br d, J=11.38 Hz, 1 H), 7.54 (br s, 1 H), 7.15 (br d, J=1.00 Hz, 1H), 4.09 - 4.25 (m, 1 H), 3.62 - 3.80 (m, 3 H), 3.37 - 3.58 (m, 2 H), 2.73 -2.85 (m, 1 H), 1.23 (s, 3 H), 1.07 - 1.20 (m, 6 H), 1.03 (s, 6 H).

[0501] Example 19: Synthesis of tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate (kJ) Using tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 3-bromo-2-fluoro-5-(trifluoromethyl)pyridine, the general procedure used to prepare compound (kb) (see Example 11) was repeated to obtain the title compound. Yield 75%, yellow solid. 1HNMR(400 MHz, DMSO-d6): δ ppm 8.33 - 8.39 (m,0.90 H), 7.99 - 8.11 (m, 0.90 H), 7.13 (br t, J=5.63 Hz, 0.70 H), 6.72 - 6.79(m, 0.30 H), 4.14 - 4.26 (m, 1.00 H), 3.84 (ddd, J=13.26, 11.13, 7.00 Hz, 0.30H), 3.60 - 3.78 (m, 2.50H), 3.41 - 3.60 (m, 2.30 H), 2.81 - 3.02 (m, 1.00 H),1.99 (s, 0.70 H), 1.25 (s, 2.50 H), 1.08 - 1.20 (m, 6.70 H), 1.03 (s, 6.00 H). To a solution of tert-butyl(2S,3R,6R)-3-(((3-bromo-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (1.55 g, 3.31 mmol, 1 equivalent) in THF (62 mL) and H2O (15.5 mL), K3PO4 (2.11 g, 9.93 mmol, 3 equivalents), MeB(OH)2 (297.19 mg, 4.96 mmol, 1.5 equivalents) and Pd(dtbpf)Cl2 (215.71 mg, 330.98 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(2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate (1.1 g, 74.14% yield) was obtained as a yellow solid. 1HNMR(400 MHz, DMSO-d6): δ ppm 8.12 - 8.29 (m,0.90 H), 7.39 - 7.63 (m, 0.95 H), 6.54 - 6.73 (m, 0.70 H), 6.31 (br t, J=5.44Hz, 0.30 H), 4.13 - 4.29 (m, 0.95 H), 4.03 (q, J=7.13 Hz, 0.2 H), 3.63 - 3.91(m, 2.70H), 3.36 - 3.59 (m, 2.30 H), 2.78 - 3.00 (m, 0.90 H), 1.97 - 2.07 (m,3.00H), 1.04 - 1.27 (m, 9.40 H), 0.98 (s, 6.00 H).

[0502] Example 20: Synthesis of tert-butyl(2S,3R,6R)-3-(((3,5-bis(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (kk) Using tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2-chloro-3,5-bis(trifluoromethyl)pyridine, the general procedure used to prepare compound (kb) (see Example 11) was repeated. Yield 94%, yellow oily substance. 1H NMR(400 MHz, DMSO-d6): δ ppm 8.55 - 8.69 (m,1.00 H), 7.91 - 8.06 (m, 1.00 H), 6.93 - 7.32 (m, 1.00 H), 4.22 - 4.30 (m, 1.00H), 3.80 - 4.06 (m, 0.40 H), 3.63 - 3.78 (m, 2.00 H), 3.52 - 3.62 (m, 1.00 H),3.46 (ddd, J=10.64, 6.25, 3.15 Hz, 1.00 H), 3.39 (br d, J=2.10 Hz, 0.70 H),2.85 - 3.06 (m, 1.00 H), 1.21 (s, 3.00 H), 1.08 - 1.19 (m, 6.00 H), 1.00 (s,6.00 H).

[0503] Example 21: Synthesis of tert-butyl(2S,3R,6R)-3-(((3-methoxy-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (kl) Using tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2-chloro-3-methoxy-5-(trifluoromethyl)pyridine, the general procedure used to prepare compound (kb) (see Example 11) was repeated. Yield 34%, white solid. 1 HNMR(400 MHz, DMSO-d6): δ ppm 7.90 - 7.98 (m, 1H), 7.05 - 7.17 (m, 1 H), 6.32 - 6.87 (m, 1 H), 4.13 - 4.22 (m, 1 H), 3.75 -3.89 (m, 3 H), 3.60 - 3.75 (m, 2 H), 3.41 - 3.57 (m, 2 H), 2.76 - 2.93 (m, 1H), 1.06 - 1.31 (m, 9 H), 1.01 (s, 6 H).

[0504] Example 22: Synthesis of tert-butyl(2S,3R,6R)-3-(((3-chloro-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (km) The general procedure used to prepare compound (ka) (see Example 10) was repeated using tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine. Yield 77%, yellow solid. 1 HNMR(400 MHz, DMSO-d6): δ ppm 8.30 - 8.37 (m,0.90 H), 7.87 - 7.99 (m, 0.90 H), 6.90 - 7.37 (m, 1.00 H), 4.14 - 4.25 (m, 1.00H), 3.62 - 3.78 (m, 2.40 H), 3.41 - 3.60 (m, 2.30 H), 2.81 - 3.01 (m, 1.00 H),1.08 - 1.26 (m, 9.05 H), 1.02 (s, 6.00 H).

[0505] Example 23: Synthesis of tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (kn) [ka] To a solution of 3-methyl-5-(trifluoromethyl)pyrazine-2-ol (218.69 mg, 1.23 mmol, 1.5 equivalents) in DMF (2 mL), DBU (373.85 mg, 2.46 mmol, 370.14 μL, 3 equivalents) was added. Then, BOP (543.05 mg, 1.23 mmol, 1.5 equivalents) was added in small amounts at 0°C, and the mixture was stirred at 0°C for 0.5 hours. Next, tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate (0.2 g, 818.57 μmol, 1 equivalent) was added 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 layers were 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 to which ethyl acetate from petroleum ether was eluted from 0% to 11%, yielding tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (0.18 g, 54.37% yield) as a yellow solid. 1 H NMR(400 MHz, DMSO-d6): δ ppm 8.20 - 8.36 (m, 1H), 7.01 - 7.44 (m, 1 H), 4.10 - 4.26 (m, 1 H), 3.39 - 3.90 (m, 5 H), 2.74 -3.03 (m, 1 H), 2.22 - 2.33 (m, 3 H), 0.92 - 1.22 (m, 15 H).

[0506] Example 24: Synthesis of tert-butyl(2S,3R,6R)-3-(((3-cyano-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (ko) The general procedure used to prepare compound (kb) (see Example 11) was repeated using tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2-chloro-5-(trifluoromethyl)nicotinonitrile. Yield 55%, yellow solid. 1 H NMR (400 MHz, methanol-d4): δ = 8.53 (dd, J=7.50, 1.63 Hz, 1 H), 8.02 - 8.16 (m, 1 H), 4.24 -4.34 (m, 1 H), 3.51 - 3.98 (m, 4 H), 2.88 - 3.06 (m, 1H), 1.15 - 1.37 (m, 12H).

[0507] Example 25: Synthesis of tert-butyl(2S,3R,6R)-3-(((3-(difluoromethyl)-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (kp) Using tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2-chloro-3-(difluoromethyl)-5-(trifluoromethyl)pyridine, the general procedure used to prepare compound (kb) (see Example 11) was repeated. Yield 80%, yellow solid. 1 H NMR(400 MHz, DMSO-d6): δ = 7.79 - 8.56 (m, 2H), 6.74 - 7.28 (m, 2 H), 4.15 - 4.29 (m, 1 H), 3.41 - 3.88 (m, 5 H), 2.77 -3.00 (m, 1 H), 0.97 - 1.27 (m, 15 H).

[0508] Example 26: Synthesis of tert-butyl(2S,3R,6R)-3-(((5-chloro-3-fluoropyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (kq) Using tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 5-chloro-2,3-difluoropyridine, the general procedure used to prepare compound (kb) (see Example 11) was repeated. Yield 85%, white solid. 1 H NMR(400 MHz, DMSO-d6): δ = 7.83 - 7.92 (m, 1H), 7.50 - 7.68 (m, 1 H), 6.47 - 6.98 (m, 1 H), 4.09 - 4.20 (m, 1 H), 3.57 -3.76 (m, 3 H), 3.38 - 3.57 (m, 2 H), 2.71 - 2.93 (m, 1 H), 1.27 (s, 2.40 H),1.12 - 1.18 (m, 3 H), 1.08 - 1.12 (m, 3 H), 1.05 (s, 6.60 H).

[0509] Example 27: Synthesis of tert-butyl(2S,3R,6R)-3-(((3-fluoro-4-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (kr) The general procedure used to prepare compound (ka) (see Example 10) was repeated using tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2,3-difluoro-4-methyl-5-(trifluoromethyl)pyridine. Yield 57%, white solid. 1H NMR(400 MHz, DMSO-d6): δ = 8.06 - 8.14 (m, 1H), 7.43 (br t, J=5.14 Hz, 0.85 H), 7.06 (br s, 0.25 H), 4.09 - 4.21 (m, 1 H),3.62 - 3.81 (m, 2.70 H), 3.38 - 3.56 (m, 2.30 H), 2.75 - 3.00 (m, 1 H), 2.14 -2.26 (m, 3 H), 1.22 (s, 2.40 H), 1.13 - 1.19 (m, 3 H), 1.07 - 1.13 (m, 3 H),1.02 (s, 6.60 H).

[0510] Example 28: Synthesis of tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((4-methyl-5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate (ks) Using tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2,4-dichloro-5-(trifluoromethyl)pyrimidine, the general procedure used to prepare compound (kb) (see Example 11) was repeated to obtain tert-butyl(2S,3R,6R)-3-(((4-chloro-5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate. Yield 38%, yellow solid. 1 HNMR(400 MHz, DMSO-d6): δ ppm 8.23 ​​- 8.70 (m,1.90 H), 4.05 - 4.21 (m, 0.90 H), 3.34 - 3.81 (m, 4.80 H), 2.64 - 3.07 (m, 1.00H), 1.04 - 1.28 (m, 15.00 H). Dioxane (12 mL) was used to contain tert-butyl(2S,3R,6R)-3-(((4-chloro-5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (600 mg, 1.41 mmol, 1 equivalent), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatrivolinane (1.06 g, 4.24 mmol, 1.18 mL, 3 equivalents), Cs2CO3 (1.38 g, 4.24 mmol, 3 equivalents), and Pd(dppf)Cl2 (103.34 mg, 141.23 μmol, 0.1 equivalent), which were then placed in a microwave tube. The mixture was then degassed and purged three times with N2. 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 (15 mL) and extracted with ethyl acetate (3 × 15 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 residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~1 / 100) to obtain the title compound (0.4 g, 70.03% yield) as a yellow oily substance. 1 HNMR (400 MHz, chloroform-d): δ ppm 8.17- 8.51 (m, 1.00 H), 5.31 - 5.81 (m, 1.10 H), 4.08 - 4.29 (m, 1.30 H), 3.90 -4.07 (m, 1.20 H), 3.77 - 3.86 (m, 1.20 H), 3.45 - 3.76 (m, 3.20 H), 2.60 - 2.86(m, 1.15 H), 2.37 - 2.54 (m, 3.00 H), 1.40 (s, 4.10 H), 1.26 - 1.34 (m, 8.00H), 1.20 (d, J=6.13 Hz, 3.35 H).

[0511] Example 29: Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyrazine-2-amine hydrochloride (la), general procedure To a solution of tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (150 mg, 345.80 μmol, 1 equivalent) in dioxane (0.5 mL), HCl / dioxane (4 M, 2.60 mL, 30.11 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 reaction mixture was concentrated under reduced pressure to obtain crude N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyrazine-2-amine hydrochloride (100 mg, 79.65% yield) as a white solid. LCMS (ESI+): m / z=291.2 (M+1), RT: 0.558 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. Similarly, the following intermediates were prepared.

[0512] Example 30: Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyrimidine-2-amine hydrochloride (lb) Using tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate(l), the general procedure used to prepare compound (la) (see Example 29) was repeated. Yield 99%, white solid. LCMS (ESI+): m / z=291.2 (M+1), RT: 0.351 min (Column Halo C18 3.0 * 30 mm, 5 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% TFA in water, and mobile phase B was 0.02% TFA in acetonitrile (HPLC grade). The gradient was 10–100% B over 0.90 minutes, 10% B over 0.01 minutes, 10–100% B over 0.01–0.50 minutes, and B was maintained at 100% for 0.40 minutes. The flow rate was 2.0 mL / min.

[0513] Example 31: Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyridine-2-amine hydrochloride (lc) Using tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate (kc), the general procedure used to prepare compound (la) (see Example 29) was repeated. Yield 96%, yellow solid. LCMS (ESI+): m / z=290.2 (M+1), RT: 0.368 min (Column Halo C18 3.0 *30 mm, 5 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% TFA in water, and mobile phase B was 0.02% TFA in acetonitrile (HPLC grade). The gradient was 10–100% B over 0.90 minutes, 10% B over 0.01 minutes, 10–100% B over 0.01–0.50 minutes, and B was maintained at 100% for 0.40 minutes. The flow rate was 2.0 mL / min.

[0514] Example 32: Synthesis of 5-chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)pyridine-2-amine hydrochloride (ld) Using tert-butyl(2S,3R,6R)-3-(((5-chloropyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (kd), the general procedure used to prepare compound (la) (see Example 29) was repeated. Yield 99%, yellow solid. LCMS (ESI+): m / z=256.3 (M+1), RT: 0.328 min (column Halo C18 3.0 * 30 mm, 5 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% TFA in water, and mobile phase B was 0.02% TFA in acetonitrile (HPLC grade). The gradient was 10–100% B over 0.90 minutes, 10% B over 0.01 minutes, 10–100% B over 0.01–0.50 minutes, and B was maintained at 100% for 0.40 minutes. The flow rate was 2.0 mL / min.

[0515] Example 33: Synthesis of 5-chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)pyrimidine-2-amine hydrochloride (le) The general procedure used to prepare compound (la) (see Example 29) was repeated using tert-butyl(2S,3R,6R)-3-(((5-chloropyrimidine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (ke). Yield 85%, white solid. 1 H NMR(400 MHz, DMSO-d6): δ 10.32 - 10.11 (m,0.74H), 8.88 (s, 0.14H), 8.68 (br d, J = 10.4 Hz, 0.73H), 8.41 (s, 1.31H), 7.50(br t, J = 5.9 Hz, 0.74H), 4.76 (td, J = 6.2, 12.3 Hz, 0.20H), 4.10 (dq, J =2.3, 6.6 Hz, 0.75H), 3.90 (ddd, J = 2.7, 6.2, 11.1 Hz, 0.79H), 3.65 (t, J = 6.6Hz, 1.61H), 3.49 (br d, J = 6.6 Hz, 0.76H), 3.08 - 2.97 (m, 0.77H), 2.90 (q, J= 11.0 Hz, 0.74H), 1.27 - 1.08 (m, 6.00H).

[0516] Example 34: Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-4-(trifluoromethyl)pyrimidine-2-amine hydrochloride (lf) The general procedure used to prepare compound (la) (see Example 29) was repeated using tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((4-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate (kf). Yield 97%, white solid. LCMS (ESI+): m / z=291.3 (M+1), RT: 0.476 min.

[0517] Example 35: Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-6-(trifluoromethyl)pyrazine-2-amine hydrochloride (1g) Using tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((6-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (kg), the general procedure used to prepare compound (la) (see Example 29) was repeated. Yield 81%, white solid. LCMS (ESI+): m / z=291.2(M+1), RT=0.539 min.

[0518] Example 36: Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-4-(trifluoromethyl)pyridine-2-amine hydrochloride (lh) The general procedure used to prepare compound (la) (see Example 29) was repeated using tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((4-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate (kh). Yield 94%, colorless oil. LCMS (ESI+): m / z=290.3(M+1), RT=0.541 min.

[0519] Example 37: Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3-fluoro-5-(trifluoromethyl)pyridine-2-amine hydrochloride (li) Using tert-butyl(2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (ki), the general procedure used to prepare compound (la) (see Example 29) was repeated. Yield 99%, yellow solid. 1HNMR(400 MHz, DMSO-d6): δ ppm 8.23 ​​(s, 1 H),7.81 (dd, J=11.32, 1.81 Hz, 1 H), 7.52 (br t, J=4.82 Hz, 1 H), 4.06 - 4.16 (m,1 H), 3.67 - 3.94 (m, 3 H), 3.50 (td, J=4.91, 2.31 Hz, 1 H), 2.86 - 3.04 (m, 2H), 1.16 (dd, J=10.69, 6.44 Hz, 6 H).

[0520] Example 38: Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyridine-2-amine(lj), general procedure Tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate (1.1 g, 2.73 mmol, 1 equivalent) was dissolved in HCl / dioxane (4 M, 11 mL, 16.14 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) (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate (0.77 g, 82.86% yield) as a brown solid. The crude product was used directly in the next step without purification. 1H NMR(400 MHz, DMSO-d6): δ ppm 8.20 (s, 0.90 H),7.50 (s, 0.90 H), 6.34 (br t, J=4.88 Hz, 0.90 H), 3.80 (qd, J=6.63, 2.75 Hz,1.00 H), 3.44 - 3.64 (m, 3.20 H), 2.82 (ddd, J=9.91, 4.60, 3.00 Hz, 1.00 H),2.53 (s, 0.50 H), 2.42 - 2.49 (m, 1.50 H), 2.11 (s, 2.80 H), 0.94 - 1.13 (m, 6.00H).

[0521] Example 39: N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3,5-bis(trifluoromethyl)pyridine-2-amine hydrochloride (lk) Using tert-butyl(2S,3R,6R)-3-(((3,5-bis(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (kk), the general procedure used to prepare compound (la) (see Example 29) was repeated. Yield 82%, yellow solid. 1 H NMR(400 MHz, DMSO-d6): δ ppm 8.65 (s, 1 H),8.03 (d, J=1.38 Hz, 1 H), 6.99 (br s, 1 H), 3.78 (qd, J=6.61, 2.94 Hz, 1 H),3.43 - 3.62 (m, 3 H), 2.81 (ddd, J=10.51, 5.38, 2.88 Hz, 2 H), 2.47 (br d,J=2.63 Hz, 1 H), 2.35 (dd, J=13.38, 10.63 Hz, 1 H), 0.91 - 1.09 (m, 6 H).

[0522] Example 40: N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3-methoxy-5-(trifluoromethyl)pyridine-2-amine(II) Using tert-butyl(2S,3R,6R)-3-(((3-methoxy-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (kl), the general procedure used to prepare compound (lj) (see Example 38) was repeated. Yield 95%, yellow solid. 1 HNMR(400 MHz, DMSO-d6): δ ppm 7.94 (s, 1 H),7.13 (d, J=1.75 Hz, 1 H), 6.52 (br t, J=4.75 Hz, 1 H), 3.87 (s, 3 H), 3.77 (qd,J=6.65, 2.94 Hz, 1 H), 3.41 - 3.56 (m, 3 H), 2.76 (ddd, J=10.07, 5.25, 2.94 Hz,1 H), 2.36 - 2.47 (m, 2 H), 0.95 - 1.08 (m, 6 H).

[0523] Example 41: 3-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyridine-2-amine(lm) Using tert-butyl(2S,3R,6R)-3-(((3-chloro-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (km), the general procedure used to prepare compound (lj) (see Example 38) was repeated. Yield 99%, yellow solid. 1 HNMR(400 MHz, DMSO-d6): δ ppm 8.35 (d, J=0.88Hz, 1 H), 7.98 (d, J=2.00 Hz, 1 H), 6.95 (br t, J=4.69 Hz, 1 H), 3.80 (qd,J=6.63, 2.88 Hz, 1 H), 3.41 - 3.63 (m, 4 H), 2.81 - 2.90 (m, 1 H), 2.46 (s, 1H), 0.96 - 1.11 (m, 6 H).

[0524] Example 42: N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyrazine-2-amine(ln) Using tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (kn), the general procedure used to prepare compound (lj) (see Example 38) was repeated. Yield 96%, yellow oily substance. LCMS(ESI+):m / z=305.3(M+1), RT:0.570min

[0525] Example 43: 2-((((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)amino)-5-(trifluoromethyl)nicotinonitrile hydrochloride (lo) Using tert-butyl(2S,3R,6R)-3-(((3-cyano-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (ko), the general procedure used to prepare compound (la) (see Example 29) was repeated. Yield 94%, yellow solid. LCMS: (ESI+): m / z=315.2(M+1), RT: 0.366 min.

[0526] Example 44: 3-(difluoromethyl)-N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyridine-2-amine hydrochloride (lp) Using tert-butyl(2S,3R,6R)-3-(((3-(difluoromethyl)-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (kp), the general procedure used to prepare compound (la) (see Example 29) was repeated. Yield 96%, yellow solid. LCMS:(ESI+):m / z=340.2(M+1), RT:0.388min

[0527] Example 45: 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3-fluoropyridine-2-amine hydrochloride (lq) Using tert-butyl(2S,3R,6R)-3-(((5-chloro-3-fluoropyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (kq), the general procedure used to prepare compound (la) (see Example 29) was repeated. Yield 99%, light brown solid. LCMS (ESI+): m / z=274.1 (M+1), RT: 0.331 min.

[0528] Example 46: N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3-fluoro-4-methyl-5-(trifluoromethyl)pyridine-2-amine(lr) Using tert-butyl(2S,3R,6R)-3-(((3-fluoro-4-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (kr), the general procedure used to prepare compound (lj) (see Example 38) was repeated. Yield 98%, yellow oily substance. LCMS (ESI+): m / z=322.1 (M+1), RT: 0.377 min.

[0529] Example 47: N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-4-methyl-5-(trifluoromethyl)pyrimidine-2-amine(ls) Using tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((4-methyl-5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate (ks), the general procedure used to prepare compound (lj) (see Example 38) was repeated. Yield 73%, yellow oily substance. 1HNMR(400 MHz, DMSO-d6): δ ppm 8.28 - 8.54 (m,0.80 H), 7.54 - 7.73 (m, 0.90 H), 3.77 (qd, J=6.59, 2.63 Hz, 0.90 H), 3.35 -3.66 (m, 2.80 H), 2.74 (dt, J=9.88, 3.50 Hz, 0.90 H), 2.35 - 2.48 (m, 4.70 H),0.77 - 1.09 (m, 6.00 H). [ka]

[0530] Example 48: Synthesis of (2S,3R)-3-amino-4-(dibenzylamino)butan-2-ol (db). To a solution of (2S,3S)-2-amino-N,N-dibenzyl-3-hydroxybutanamide (32 g, 101.88 mmol, 1 equivalent) in THF (320 mL), BH3.THF (1 M, 305.65 mL, 3 equivalents) was added dropwise under N2 at 0°C. The reaction mixture was degassed three times with N2. The reaction mixture was stirred at 25°C for 0.5 hours, and then heated to 50°C and stirred for 2 hours. LCMS showed that the starting material had been consumed and the desired mass had been detected. The reaction mixture was slowly quenched with methanol (500 mL) at 0°C, and then stirred at 50°C for 0.5 hours. When the reaction mixture was concentrated under vacuum, (2S,3R)-3-amino-4-(dibenzylamino)butan-2-ol (31 g, yield 85.59%) was obtained as a yellow oily substance. This product was used in the next step without further purification. LCMS(ESI+): m / z=285.3(M+1), RT: 0.568 min

[0531] Example 49: Synthesis of (S)-2-bromo-N-((2R,3S)-1-(dibenzylamino)-3-hydroxybutan-2-yl)propanamide (dc) To a solution of (2S,3R)-3-amino-4-(dibenzylamino)butan-2-ol (31 g, 87.20 mmol, 1 equivalent) in THF (310 mL), (2S)-2-bromopropanoic acid (13.33 g, 87.20 mmol, 1 equivalent) and DIPEA (33.79 g, 261.64 mmol, 45.5 mL, 3 equivalents) were added. Next, PyBrOP (44.72 g, 95.94 mmol, 1.1 equivalents) was added at 0°C, and the reaction mixture was stirred at 25°C for 1 hour. LC-MS showed that the starting materials had been consumed and the desired mass had been detected. The combined solution was diluted with water (700 mL) and extracted with ethyl acetate (3 × 700 mL). The combined organic phase was washed with brine (500 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum to obtain the residue. This residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3 to 2 / 1) to obtain (S)-2-bromo-N-((2R,3S)-1-(dibenzylamino)-3-hydroxybutan-2-yl)propanamide (36 g, yield 88.60%) as a yellow oily substance. 1 H NMR(400 MHz, DMSO-d6): δ ppm 7.31 (d, J=4.50Hz, 8.00 H), 7.21 - 7.26 (m, 1.95 H), 4.86 (d, J=4.88 Hz, 0.95 H), 4.53 (q,J=6.67 Hz, 1.00 H), 3.89 - 3.97 (m, 1.00 H), 3.53 - 3.58 (m, 2.00 H), 3.45 -3.49 (m, 1.95 H), 2.64 - 2.69 (m, 1.00 H), 2.39 - 2.44 (m, 1.00 H), 1.68 (d,J=6.63 Hz, 2.95 H), 0.96 (d, J=6.25 Hz, 3.00 H).

[0532] Example 50: Synthesis of (2R,5R,6S)-5-((dibenzylamino)methyl)-2,6-dimethylmorpholine-3-one (dd) To a solution of (S)-2-bromo-N-((2R,3S)-1-(dibenzylamino)-3-hydroxybutan-2-yl)propanamide (36 g, 77.26 mmol, 1 equivalent) in IPA (1100 mL), KOH (8.69 g, 154.52 mmol, 2 equivalents) in H2O (37 mL) was added. This reaction mixture was stirred at 25°C for 1 hour. LC-MS showed that most of the starting material had been consumed and the desired mass was detected. This reaction mixture was diluted with water (2 L) and extracted with ethyl acetate (3 × 1.5 L). The combined organic phase was washed with brine (3 × 700 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was then subjected to preparative HPLC (column: Phenomenex luna C18 (250)). * When B was purified by a 70 mm, 15 μm (mobile phase: [H2O (0.04% HCl)-CAN]) gradient over 20.0 minutes (15% to 50%), (2R,5R,6S)-5-((dibenzylamino)methyl)-2,6-dimethylmorpholine-3-one (16 g, yield 58.16%) was obtained as a white solid. 1 H NMR(400 MHz, DMSO-d6): δ ppm 7.86 (br d, J=4.38Hz, 0.90 H), 7.35 - 7.41 (m, 3.75 H), 7.30 (t, J=7.38 Hz, 3.90 H), 7.20 - 7.25(m, 1.95 H), 3.87 - 4.01 (m, 1.95 H), 3.72 (d, J=13.63 Hz, 1.90 H), 3.37 (br d,J=13.63 Hz, 2.95 H), 2.50 (br s, 1.95 H), 0.87 - 1.06 (m, 6.00 H).

[0533] Example 51: Synthesis of tert-butyl(2S,3R,6R)-3-((dibenzylamino)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2(df) (2R,5R,6S)-5-((dibenzylamino)methyl)-2,6-dimethylmorpholine-3-one (8.5 g, 23.86 mmol, 1 equivalent) was added dropwise to a THF (85 mL) solution under N2 at 0°C with LiAlD4 (3.01 g, 71.58 mmol, 4.09 mL, 3 equivalents). The reaction mixture was then stirred at 40°C for 12 hours. LC-MS showed that the starting material had been consumed and the desired mass had been detected. The reaction mixture was quenched with water (20 mL) under N2.

[0534] To the residual solution, TEA (7.24 g, 71.58 mmol, 9.96 mL, 3 equivalents) and Boc₂O (7.81 g, 35.79 mmol, 8.22 mL, 1.5 equivalents) were added at 0°C. The reaction mixture was stirred at 25°C for 1 hour. LC-MS indicated that the starting materials had been consumed and that the desired mass had been detected. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 × 300 mL). The combined organic phases were washed with brine (300 mL), dehydrated with Na₂SO₄, filtered, and concentrated under vacuum to obtain the residue. When the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 16 / 1~14 / 1), tert-butyl(2S,3R,6R)-3-((dibenzylamino)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (10.3g, yield 96.13%) was obtained as a colorless oil. 1H NMR(400 MHz, DMSO-d6): δ ppm 7.21 - 7.36 (m,10.00 H), 4.17 (dt, J=10.69, 3.35 Hz, 0.60 H), 4.03 - 4.07 (m, 0.45 H), 3.77(dd, J=13.26, 6.38 Hz, 2.00 H), 3.52 - 3.61 (m, 1.05 H), 3.26 - 3.32 (m, 1.95H), 3.14 (d, J=13.01 Hz, 1.15 H), 2.65 - 2.77 (m, 1.05 H), 2.34 (dd, J=13.26, 4.38Hz, 0.45H), 2.27 (dd, J=13.32, 3.81 Hz, 0.55 H), 1.46 (s, 5.35 H), 1.28 (s,3.65 H), 0.99 (dd, J=15.63, 6.63 Hz, 3.00 H), 0.74 (dd, J=10.38, 6.13 Hz, 3.00H).

[0535] Example 52: Synthesis of tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2(dg) To a solution of tert-butyl(2S,3R,6R)-3-((dibenzylamino)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (10 g, 22.27 mmol, 1 equivalent) in trifluoroethanol (300 mL), Pd(OH)2 (1.56 g, 2.23 mmol, 20% purity, 0.1 equivalent) was added under argon. Next, the mixture was degassed and purged three times with H2, and then stirred at 25°C for 2 hours under an H2 (15 psi) atmosphere. LCMS showed that the starting material was completely consumed. The solution was filtered through a Celite pad, and the filter cake was washed with ethyl acetate (300 mL). When the combined filtrate was concentrated, tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (5.9g, yield 96.79%) was obtained as a colorless oil. 1H NMR(400 MHz, DMSO-d6): δ ppm 3.77 - 3.82 (m,0.45 H), 3.64 - 3.70 (m, 0.55 H), 3.61 (td, J=6.13, 2.88 Hz, 0.95 H), 3.39 -3.46 (m, 1.05 H), 2.68 - 2.77 (m, 1.95 H), 1.40 (s, 9.00 H), 1.05 (dd, J=6.38,2.75 Hz, 6.20 H).

[0536] Example 53: Synthesis of tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate-5,5-d2(dh) [ka] To a DMSO (20 mL) solution of tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (1 g, 3.65 mmol, 1 equivalent), DIPEA (1.42 g, 10.96 mmol, 1.91 mL, 3 equivalents) and 2-fluoro-5-(trifluoromethyl)pyridine (723.77 mg, 4.38 mmol, 1.2 equivalents) were added. This mixture was stirred at 140°C for 12 hours. 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 quenched by adding water (15 mL) and extracted with ethyl acetate (3 × 15 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 to 1 / 100). The compound tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate-5,5-d2 (1.1 g, 76.92% yield) was obtained as a yellow oily substance. 1 HNMR(400 MHz, DMSO-d6): δ ppm 8.23 ​​- 8.32 (m,0.90 H), 7.52 - 7.64 (m, 0.90 H), 7.38 (br s, 0.70 H), 7.10 (br s, 0.20 H),6.45 - 6.61 (m, 1.00 H), 4.13 (br d, J=10.88 Hz, 0.90 H), 3.61 - 3.74 (m, 1.80H), 3.46 (q, J=5.63 Hz, 1.20 H), 1.26 (s, 2.10 H), 1.07 - 1.20 (m, 7.00 H), 1.05(s, 6.00 H). Similarly, the following compounds were prepared.

[0537] Example 54: tert-butyl(2S,3R,6R)-3-(((5-chloropyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2(di) [ka] The title compound (di) was prepared using 5-chloro-2-fluoropyridine in the same manner as described for compound (dh). The yield was 58%, and it was a colorless oil. 1HNMR(400 MHz, DMSO-d6): δ ppm 7.86 - 8.00 (m,0.90 H), 7.31 - 7.45 (m, 1.00 H), 6.80 (br t, J=6.00 Hz, 0.75 H), 6.39 - 6.52(m, 1.20 H), 4.03 - 4.14 (m, 1.00 H), 3.63 - 3.72 (m, 1.00 H), 3.52 - 3.62 (m,0.80 H), 3.41 - 3.51 (m, 1.50 H), 3.23 - 3.30 (m, 0.80 H), 1.30 (s, 2.05 H),1.24 (br s, 0.60 H), 1.15 (d, J=6.75 Hz, 2.65 H), 1.10 - 1.12 (m, 3.25 H), 1.07- 1.09 (m, 7.15 H).

[0538] Example 55: Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyridine-2-amine(dj) [ka] A solution of tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate-5,5-d2 (1.1 g, 2.81 mmol, 1 equivalent) in HCl / dioxane (4 M, 11 mL, 15.66 equivalents) was stirred at 20°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 reaction mixture was neutralized with NaHCO3 (aqueous solution) (15 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (15 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyridine-2-amine (0.75 g, 84.29% yield) as a yellow solid. 1 HNMR(400 MHz, DMSO-d6): δ ppm 8.28 (s, 0.90 H),7.60 (dd, J=8.88, 1.88 Hz, 0.95 H), 7.05 (br s, 1.00 H), 6.64 (d, J=9.01 Hz,1.00 H), 3.78 (qd, J=6.65, 2.69 Hz, 1.00 H), 3.39 - 3.56 (m, 3.20 H), 2.65 -2.80 (m, 1.20 H), 0.95 - 1.11 (m, 6.00 H). Similarly, the following compounds were prepared.

[0539] Example 56: 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl-5,5-d2)methyl)pyridine-2-amine hydrochloride (dk) [ka] The title compound was prepared using (2S,3R,6R)-3-(((5-chloropyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2, in the same manner as described for compound (dj). Yield 95%, yellow solid. 1 HNMR(400 MHz, DMSO-d6): δ ppm 10.34 (br d,J=11.13 Hz, 0.95 H), 9.01 (br d, J=11.63 Hz, 0.95 H), 8.06 (d, J=2.38 Hz, 1.20H), 7.70 (dd, J=9.19, 2.31 Hz, 1.00 H), 6.86 (d, J=9.13 Hz, 0.95 H), 4.06 -4.16 (m, 1.00 H), 3.90 (q, J=6.25 Hz, 1.00 H), 3.64 - 3.81 (m, 2.10 H), 3.58 -3.60 (m, 0.40 H), 3.43 - 3.55 (m, 0.60 H), 1.16 (dd, J=14.07, 6.44 Hz, 6.00 H). [ka]

[0540] Example 57: Synthesis of (2S,3S,6R)-4-benzyl-2,6-dimethyl-5-oxomorpholine-3-carboxylic acid (dm) To a solution of t-BuONa (43.63 g, 454.02 mmol, 5 equivalents) in dioxane (400 mL), benzyl-L-alotreonine (20 g, 90.80 mmol, 1 equivalent) and (2S)-2-bromopropanoic acid (41.67 g, 272.41 mmol, 3 equivalents) were added at 0°C. The reaction mixture was stirred at 20°C for 2 hours. LC-MS indicated that the starting materials had been consumed. Next, the reaction mixture was quenched with HCl / dioxane (4N) to adjust the pH to 3 and concentrated. The residue was dissolved in ethyl acetate (400 mL), and DIPEA (35.21 g, 272.41 mmol, 47.45 mL, 3 equivalents) was added to this solution at 0°C, followed by T4P (130.85 g, 181.61 mmol, 50% purity, 2 equivalents). This mixture was stirred at 25°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 poured into aqueous HCl (1N), adjusted to pH 7, and extracted with ethyl acetate (1000 mL x 3). The combined organic layers were washed with brine (500 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) to obtain (2S,3S,6R)-4-benzyl-2,6-dimethyl-5-oxomorpholine-3-carboxylic acid (4 g, 16.73% yield) as a yellow oil. LCMS (ESI+): m / z=264.3 (M+1), RT: 0.577 min.

[0541] Example 58: Synthesis of (2R,5R,6S)-4-benzyl-5-(hydroxymethyl-d2)-2,6-dimethylmorpholine-3-one (dn) (2S,3S,6R)-4-benzyl-2,6-dimethyl-5-oxomorpholine-3-carboxylic acid (4 g, 15.19 mmol, 1 equivalent) was dissolved in THF (80 mL) and TEA (2.31 g, 22.79 mmol, 3.17 mL, 1.5 equivalents) was added. This solution was cooled to 0°C, and isobutyl chloroformate (3.11 g, 22.79 mmol, 2.98 mL, 1.5 equivalents) was added to the solution at 0°C. This mixture was stirred at 25°C for 30 minutes, then filtered, and sodium borode deuterate (632.25 mg, 16.71 mmol, 1.1 equivalents) was dissolved in D2O (2 mL) and added to the above filtrate at 0°C. The reaction mixture was then stirred at 25°C for 1.5 hours. LCMS showed that all of the starting materials were consumed and the desired mass was detected. The reaction mixture was poured into aqueous HCl (1N), adjusted to pH 7, and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (100 mL x 2), dehydrated with Na2SO4, filtered, and concentrated to obtain the crude product. This was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain (2R,5R,6S)-4-benzyl-5-(hydroxymethyl-d2)-2,6-dimethylmorpholine-3-one (1.5 g, 39.29% yield) as a colorless oil. LCMS (ESI+): m / z=252.4 (M+1), RT: 0.559 min.

[0542] Example 59: Synthesis of ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholine-3-yl)methane-d2-ol (do) To a stirred solution of BH3.THF (1M, 14.21 mL, 2.55 equivalents), (2R,5R,6S)-4-benzyl-5-(hydroxymethyl-d2)-2,6-dimethylmorpholine-3-one (1.4 g, 5.57 mmol, 1 equivalent) in THF (2.8 mL) was added 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 materials were consumed and the desired mass was detected. The reaction mixture was quenched with MeOH (10 mL) and concentrated under reduced pressure to obtain the crude product. This residue was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dehydrated with Na2SO4, filtered, and concentrated to obtain the crude product. When the crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1), ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholine-3-yl)methane-d2-ol (0.6 g, 43.11% yield) was obtained as a colorless oil. 1 H NMR(400 MHz, DMSO-d6): δ ppm 7.28 - 7.39 (m, 4H), 7.19 - 7.26 (m, 1 H), 4.22 (s, 1 H), 3.89 (d, J=13.88 Hz, 1 H), 3.79 (m, 1H), 3.68 (d, J=13.88 Hz, 1 H), 3.52 - 3.64 (m, 1 H), 2.49 (d, J=2.25 Hz, 1 H),2.32 (m, 1 H), 2.09 - 2.22 (m, 1 H), 1.08 (d, J=6.75 Hz, 3 H), 0.98 (d, J=6.13Hz, 3H).

[0543] Example 60: Synthesis of tert-butyl(2S,3R,6R)-3-(hydroxymethyl-d2)-2,6-dimethylmorpholine-4-carboxylate (dp) To a solution of ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholine-3-yl)methane-d2-ol (0.6 g, 2.53 mmol, 1 equivalent) in SiO (12 mL), Pd / C (134.52 mg, 126.40 μmol, 10% purity, 0.05 equivalent) and (Boc)2O (827.61 mg, 3.79 mmol, 871.17 μL, 1.5 equivalent) were added. This mixture was stirred under H2 (15 Psi) at 20°C for 16 hours. TLC showed that all of the starting materials were consumed. When this reaction product was filtered and the filtrate was concentrated, a crude product was obtained. This was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to yield tert-butyl(2S,3R,6R)-3-(hydroxymethyl-d2)-2,6-dimethylmorpholine-4-carboxylate (0.6 g, 91.16% yield) as a colorless oil. 1 H NMR(400 MHz, DMSO-d6): δ ppm 4.42 (d, J=4.50Hz, 1 H), 3.76 (d, J=2.50 Hz, 1 H), 3.57 - 3.70 (m, 2 H), 3.38 - 3.52 (m, 1 H),2.60 (m, 1 H), 1.40 (d, J=4.00 Hz, 9 H), 1.02 - 1.13 (m, 6 H).

[0544] Example 61: Synthesis of tert-butyl(2S,3R,6R)-3-((1,3-dioxoisoindolin-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2(dq) To a solution of tert-butyl(2S,3R,6R)-3-(hydroxymethyl-d2)-2,6-dimethylmorpholine-4-carboxylate (0.6 g, 2.30 mmol, 1 equivalent) in THF (6 mL), isoindoline-1,3-dione (508.63 mg, 3.46 mmol, 1.5 equivalents) and PPh3 (906.73 mg, 3.46 mmol, 1.5 equivalents) were added at 0°C. Then, DIAD (699.03 mg, 3.46 mmol, 670.21 μL, 1.5 equivalents) was added to this mixture at 0°C. This mixture was stirred at 20°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 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 mixture was then concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to obtain tert-butyl(2S,3R,6R)-3-((1,3-dioxoisoindoline-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (0.9 g, 1.60 mmol, 69.50% yield, 67% purity) as a white solid. 1 H NMR(400 MHz, DMSO-d6): δ ppm 4.01 - 4.21 (m, 1H), 3.46 - 3.80 (m, 3 H), 2.78 - 3.01 (m, 1 H), 1.23 (d, J=6.63 Hz, 3 H), 1.11- 1.18 (m, 3 H), 0.84 - 1.05 (m, 9 H).

[0545] Example 62: Synthesis of tert-butyl(2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4-carboxylate (dr) To a solution of tert-butyl(2S,3R,6R)-3-((1,3-dioxoisoindolin-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (0.9 g, 1.60 mmol, 1 equivalent) in MeOH (18 mL), NH2NH2.H2O (801.88 mg, 16.02 mmol, 777.02 μL, 10 equivalents) was added. This mixture was stirred at 60°C for 2 hours. LC-MS showed that all of the starting material was consumed and the desired mass was detected. The reaction product was filtered to remove insoluble substances. The filtrate was concentrated under vacuum and diluted with ethyl acetate (50 mL). It was then washed with saturated aqueous solution NaHCO3 (10 mL), water (10 mL), and then brine (10 mL). After dehydration with Na2SO4, the solution was filtered and concentrated under high vacuum to obtain tert-butyl(2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4-carboxylate (400 mg, 81.09% yield) as a colorless oil. 1 H NMR(400 MHz, DMSO-d6): δ ppm 4.13 (br s, 1 H),3.59 - 3.72 (m, 2 H), 3.41 - 3.49 (m, 1 H), 2.57 - 2.71 (m, 1 H), 1.34 - 1.50(m, 9 H), 1.06 (br d, J=5.50 Hz, 6 H).

[0546] Example 63: tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl-d2)morpholine-4-carboxylate(ds), general procedure [ka] To a 3 mL solution of tert-butyl(2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4-carboxylate (140 mg, 454.65 μmol, 1 equivalent) in DMSO, DIPEA (176.28 mg, 1.36 mmol, 237.57 μL, 3 equivalents) and 2-fluoro-5-(trifluoromethyl)pyridine (90.07 mg, 545.58 μmol, 1.2 equivalents) were added. This mixture was stirred at 140°C for 2 hours. LC-MS showed that all of the starting materials were consumed. The reaction product was filtered and concentrated to obtain the crude product. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1). tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl-d2)morpholine-4-carboxylate (140 mg, 78.67% yield) was obtained as a bright yellow oily substance. 1 HNMR(400 MHz, DMSO-d6): δ ppm 8.19 - 8.40 (m, 1H), 7.51 - 7.66 (m, 1 H), 7.07 - 7.44 (m, 1 H), 6.43 - 6.61 (m, 1 H), 4.07 -4.19 (m, 1 H), 3.78 (m, 1 H), 3.64 - 3.73 (m, 1 H), 3.57 (m, 1 H), 3.42 - 3.53(m, 1 H), 2.63 - 2.94 (m, 1 H), 1.27 (s, 2 H), 1.15 - 1.20 (m, 3 H), 1.09 -1.14 (m, 3 H), 1.05 (s, 6 H). Similarly, the following compounds were obtained.

[0547] Example 64: tert-butyl(2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)amino)methyl-d2)-2,6-dimethylmorpholine-4-carboxylate(dt) [ka] The title compound (dt) was prepared using tert-butyl(2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4-carboxylate and 2,3-difluoro-5-(trifluoromethyl)pyridine in the same manner as described for compound (dt). Yield 86%, bright yellow oily substance. 1 HNMR(400 MHz, DMSO-d6): δ ppm 8.13 - 8.34 (m, 1H), 7.64 - 7.85 (m, 1 H), 7.09 - 7.58 (m, 1 H), 4.14 - 4.20 (m, 1 H), 3.55 -3.78 (m, 2 H), 3.44 - 3.53 (m, 1 H), 2.92 - 3.00 (m, 1 H), 2.76 - 2.84 (m, 1H), 1.24 (s, 3 H), 1.16 - 1.21 (m, 3 H), 1.12 (br d, J=5.75 Hz, 3 H), 1.03 (s,6 H).

[0548] Example 65: tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl-d2)morpholine-4-carboxylate(du) [ka] The title compound was obtained by repeating the general procedure used to prepare compound (kJ) (see Example 19) using tert-butyl(2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4-carboxylate and 3-bromo-2-fluoro-5-(trifluoromethyl)pyridine. Yield 87%, colorless oil. 1HNMR(400 MHz, DMSO-d6): δ ppm 8.12 - 8.33 (m,0.90 H), 7.28 - 7.63 (m, 1.00 H), 6.21 - 6.73 (m, 1.00 H), 4.13 - 4.25 (m, 0.90H), 3.41 - 3.80 (m, 3.10 H), 2.74 - 3.02 (m, 1.00 H), 1.93 - 2.10 (m, 2.90 H),1.23 (s, 2.60 H), 1.08 - 1.20 (m, 6.00 H), 0.97 (s, 6.40 H).

[0549] Example 66: N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl-d2)-5-(trifluoromethyl)pyridine-2-amine hydrochloride (dv) [ka] A solution of tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl-d2)morpholine-4-carboxylate (140 mg, 357.67 μmol, 1 equivalent) in HCl / dioxane (4 M, 2.79 mL, 31.23 equivalents). This mixture was stirred at 25°C for 1 hour. LC-MS showed that all of the starting material was consumed. The reaction product was filtered and concentrated to obtain crude N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl-d2)-5-(trifluoromethyl)pyridine-2-amine hydrochloride (100 mg, 95.98% yield) as a white solid. 1HNMR(400 MHz, DMSO-d6): δ ppm 8.29 (s, 1 H),7.61 (m, 1 H), 7.05 (br s, 1 H), 6.65 (d, J=8.88 Hz, 1 H), 3.79 (m, 1 H), 3.50(m, 1 H), 3.31 (s, 1 H), 2.72 (d, J=2.50 Hz, 1 H), 2.45 (br d, J=10.13 Hz, 2H), 1.06 (d, J=6.63 Hz, 3 H), 1.01 (d, J=6.13 Hz, 3 H). Similarly, the following compounds were prepared.

[0550] Example 67: N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl-d2)-3-fluoro-5-(trifluoromethyl)pyridine-2-amine hydrochloride (dw) [ka] The title compound (dw) was prepared using tert-butyl(2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)amino)methyl-d2)-2,6-dimethylmorpholine-4-carboxylate, in the same manner as described for compound (dv). Yield 83%, white solid. 1 HNMR(400 MHz, DMSO-d6): δ ppm 8.20 (s, 1 H),7.73 (m, 1 H), 7.07 (s, 1 H), 3.80 (m, 1 H), 3.45 - 3.56 (m, 2 H), 3.31 (s, 1H), 2.81 (d, J=2.75 Hz, 1 H), 2.41 - 2.49 (m, 2 H), 1.07 (d, J=6.75 Hz, 3 H),1.01 (d, J=6.13 Hz, 3 H).

[0551] Example 68: N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl-d2)-3-methyl-5-(trifluoromethyl)pyridine-2-amine hydrochloride (dx) [ka] The title compound (dx) was prepared using tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl-d2)morpholine-4-carboxylate, in the same manner as described for compound (dv). Yield 90%, white solid. 1 HNMR(400 MHz, DMSO-d6): δ ppm 8.20 (s, 0.90 H),7.50 (d, J=1.25 Hz, 0.90 H), 6.09 - 6.69 (m, 1.00 H), 3.80 (qd, J=6.65, 2.81Hz, 1.00 H), 3.43 - 3.57 (m, 1.10 H), 2.80 (d, J=2.75 Hz, 0.90 H), 2.46 - 2.48(m, 1.30 H), 2.11 (s, 2.80 H), 0.96 - 1.11 (m, 6.00 H).

[0552] Example 69: 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. 1H 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).

[0553] Example 70: 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. 1¹H 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).

[0554] Example 71: 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

[0555] Example 72: 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).

[0556] Example 73: 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).

[0557] Example 74: 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.

[0558] Example 75: 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.

[0559] Example 76: 3-(5-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-4-carboxylic acid [ka] To a 12 mL solution of methyl 3-iodo-1,5-dimethyl-1H-pyrazole-4-carboxylate (0.6 g, 2.08 mmol, 1 equivalent) and (5-fluoro-2-pyridyl)-trimethyl-stannane (2.91 g, 7.27 mmol, 3.5 equivalents) in dioxane (12 mL), CsF (631.33 mg, 4.16 mmol, 153.42 μL, 2 equivalents) was added at 20 °C. This mixture was degassed and purged three times with N2. Next, Pd(PPh3)4 (240.14 mg, 207.81 μmol, 0.1 equivalent) and CuI (39.58 mg, 207.81 μmol, 0.1 equivalent) were added to this mixture at 20 °C. This mixture was degassed and purged three times with N2, and stirred at 120 °C for 12 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 filtered through a Celite pad and washed with ethyl acetate (20 mL x 3). The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel (eluting 0% to 30% of ethyl acetate in petroleum ether) to obtain methyl 3-(5-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-4-carboxylate (0.35 g, 58.79% yield) as a yellow solid. 1 H NMR(400 MHz, DMSO-d6): δ = 8.57 (d, J=2.88 Hz,1 H), 7.70 - 7.82 (m, 1 H), 7.66 (br d, J=4.63 Hz, 1 H), 3.81 (s, 3 H), 3.60(s, 3 H), 2.47 (s, 3 H). To a solution of methyl 3-(5-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-4-carboxylate (0.35 g, 1.22 mmol, 1 equivalent) in THF (3.5 mL) and H2O (1.75 mL), LiOH.H2O (76.90 mg, 1.83 mmol, 1.5 equivalents) was added at 20°C. This mixture was stirred at 20°C for 2 hours. LC-MS showed that the starting material had been consumed and that a product with the desired mass was detected. This reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 × 3 mL). The pH of the aqueous layer was adjusted to 5 with 1N aqueous HCl at 0°C, filtered, and the filter cake was dehydrated under high pressure to obtain 3-(5-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-4-carboxylic acid (0.2 g, 68.90% yield, 99% purity) as a white solid. 1 H NMR(400 MHz, DMSO-d6): δ = 16.00 (br d, J=1.75Hz, 1 H), 8.75 (d, J=2.75 Hz, 1 H), 8.22 (dd, J=9.01, 4.63 Hz, 1 H), 8.04 (td,J=8.75, 2.88 Hz, 1 H), 3.87 (s, 3 H), 2.59 (s, 3 H).

[0560] Example 77: 5-Fluoro-3-(2H-1,2,3-triazol-2-yl)picolinic acid [ka] 3,5-difluoropicolinonitrile (2.2 g, 15.70 mmol, 1 equivalent) and 2H-triazole (1.08 g, 15.70 mmol, 909.91 μL, 1 equivalent) were dissolved in ACN (110 mL) and K2CO3 (5.43 g, 39.26 mmol, 2.5 equivalents) were added. This mixture was stirred at 25°C for 12 hours. TLC showed that the starting materials were completely consumed and that numerous new spots had formed. For workup, the crude reaction mixtures from the four experiments were combined. This reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The crude product was purified by flash silica gel chromatography (Biotage®; 40 g SepaFlash® silica flash column, gradient of 0-50% ethyl acetate / petroleum ether eluent, 100 mL / min) to obtain the residue. The residue was purified twice by preparative HPLC (TFA conditions) to obtain 5-fluoro-3-(2H-1,2,3-triazole-2-yl)picolinonitrile (2.5 g, yield 21.04%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.90 (d, J=2.50Hz, 1 H), 8.59 (dd, J=9.13, 2.50 Hz, 1 H), 8.41 (s, 2 H). A solution of 5-fluoro-3-(2H-1,2,3-triazole-2-yl)picolinonitrile (0.9 g, 4.76 mmol, 1 equivalent) in HCl (12 M, 81 mL) was stirred at 110 °C for 5 hours. LC-MS showed that the starting material was completely consumed and that one major peak with the desired mass was detected. For workup, the crude reaction mixtures from the four parallel reactions were combined. The reaction mixture was concentrated under reduced pressure to obtain a residue. Purification of the residue by preparative HPLC (HCl conditions) yielded 5-fluoro-3-(2H-1,2,3-triazole-2-yl)picolinic acid (1.84 g, yield 57.07%) as a white solid. 1H NMR(400 MHz, DMSO-d6): δ ppm 13.33 - 13.94 (m,1 H), 8.75 (d, J=2.50 Hz, 1 H), 8.36 (dd, J=9.13, 2.50 Hz, 1 H), 8.23 ​​(s, 2 H).

[0561] Example 78: 5-Fluoro-3-(5-Fluoropyrimidine-2-yl)picolinic acid [ka] To a 10 mL solution of methyl 3-bromo-5-fluoropicolinate (500 mg, 2.14 mmol, 1 equivalent) in DMF (10 mL), (5-fluoropyrimidine-2-yl)-trimethyl-stannan (3.19 g, 8.55 mmol, 4 equivalents) and CsF (649.10 mg, 4.27 mmol, 157.74 μL, 2 equivalents) were added. This mixture was degassed and purged three times with argon. Then, palladium triphenylphosphine (246.89 mg, 213.65 μmol, 0.1 equivalent) and CuI (40.69 mg, 213.65 μmol, 0.1 equivalent) were added to the mixture at 20 °C. The mixture was stirred under argon at 110 °C for 16 hours. LC-MS 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 crude product was purified by column chromatography on silica gel (eluting 0% to 15% of ethyl acetate in petroleum ether) to obtain methyl 5-fluoro-3-(5-fluoropyrimidine-2-yl)picolinate (199 mg, 37.08% yield) as a yellow oily substance. 1 H NMR (400 MHz, DMSO-d6): δ = ppm 9.09 (d, J=0.88Hz, 2 H), 8.79 (d, J=2.75 Hz, 1 H), 8.38 (dd, J=9.38, 2.75 Hz, 1 H), 3.77 (s, 3H). To a solution of methyl 5-fluoro-3-(5-fluoropyrimidine-2-yl)picolinate (199 mg, 792.23 μmol, 1 equivalent) in THF (1 mL) and H2O (1 mL), LiOH·H2O (66.49 mg, 1.58 mmol, 2 equivalents) was added at 20°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 MS was detected. The reaction product was diluted with water (10 mL) and extracted with 10 mL (10 mL x 3) of ethyl acetate. The phase layer was adjusted to pH=2 with 1N HCl at 0°C, and the reaction product was diluted with water (5 mL) and extracted with (dichloromethane:MeOH) = (5:1, 10 mL x 5). The combined organic layers were dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-fluoro-3-(5-fluoropyrimidine-2-yl)picolinic acid (87 mg, 46.30% yield) as a white solid. LCMS (ESI+): m / z=238.1 (M+1), RT: 0.490 min.

[0562] Example 79: 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 indicated 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).

[0563] Example 80: 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).

[0564] Example 81: 6-Methyl-3-(pyrimidine-2-yl)pyrazine-2-carboxylic acid [ka] To a solution of methyl 6-bromo-3-chloropyrazine-2-carboxylate (1.5 g, 5.97 mmol, 1 equivalent) in dioxane (15 mL), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (748.82 mg, 5.97 mmol, 833.87 μL, 1 equivalent), K2CO3 (1.65 g, 11.93 mmol, 2 equivalents), and Pd(dppf)Cl2.CH2Cl2 (487.13 mg, 596.50 μmol, 0.1 equivalent) were added under N2. The reaction mixture was stirred at 100°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 (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with brine (20 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 8:1~6:1) to obtain methyl 3-chloro-6-methylpyrazine-2-carboxylate (600 mg, yield 53.91%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.62 (s, 0.85 H), 3.93 (s, 3.00 H), 2.54 (s, 3.00 H). To a solution of methyl 3-chloro-6-methylpyrazine-2-carboxylate (600 mg, 3.22 mmol, 1 equivalent) in DMF (9 mL), tributyl(pyrimidine-2-yl) stannan (1.78 g, 4.82 mmol, 1.5 equivalents), CsF (976.87 mg, 6.43 mmol, 2 equivalents), CuI (61.24 mg, 321.55 μmol, 0.1 equivalent), and Pd(PPh3)4 (371.57 mg, 321.55 μmol, 0.1 equivalent) were added under N2. The reaction mixture was stirred at 120°C for 6 hours. LC-MS indicated that the reaction was complete. The reaction mixture was diluted with water (10 mL) and aqueous KF (20 mL) was added. The residual mixture was stirred at 25°C for 30 minutes and filtered. The filtrate was extracted with dichloromethane:methanol (10:1, 3 × 20 mL). The combined organic phase was washed with brine (3 × 10 mL), dehydrated with Na₂SO₄, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 8 to 0 / 1) to obtain methyl 6-methyl-3-(pyrimidine-2-yl)pyrazine-2-carboxylate (700 mg, yield 70.92%, 75% purity) as a yellow solid. 1 H NMR(400 MHz, DMSO-d6): δ ppm 8.98 (d, J=4.88Hz, 1.90 H), 8.85 (s, 1.00 H), 7.62 (t, J=4.88 Hz, 1.00 H), 3.74 (s, 3.00 H),2.89 (s, 3.00 H). A solution of methyl 6-methyl-3-(pyrimidine-2-yl)pyrazine-2-carboxylate (700 mg, 2.28 mmol, 1 equivalent) in hydrochloric acid (10 mol / L, 10V) was stirred at 80°C for 2 hours. LC-MS showed that all of the starting material was consumed and the desired mass was detected. When the reaction was concentrated under vacuum, 6-methyl-3-(pyrimidine-2-yl)pyrazine-2-carboxylic acid (200 mg, yield 40.57%) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.95 (d, J=4.88Hz, 2.00 H), 8.79 (s, 0.90 H), 7.59 (t, J=4.94 Hz, 0.95 H), 2.63 (s, 3.00 H).

[0565] Example 82: 4-Chloro-6-methyl-3-(pyrimidine-2-yl)...

Claims

1. Compounds of formula I, or pharmaceutically acceptable salts and derivatives thereof. 【Chemistry 1】 (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 derivatives thereof, and the heteroaromatic group is unsubstituted, monosubstituted, disubstituted, or trisubstituted. When present, the substituents of the heteroaromatic group are independently selected from the group consisting of unsubstituted (C １ , ４ , ４ , ８ , １ , ４ , ３ , ４ , １ ~C ４ )-linear alkyl, unsubstituted (C １ ~C ４ )-branched alkyl, unsubstituted (C ３ ~C ８ )-cycloalkyl, unsubstituted (C １ ~C ４ )-alkoxy, substituted (C １ ~C ４ )-linear alkyl, substituted (C １ ~C ４ )-branched alkyl, substituted (C ３ ~C ８ )-cycloalkyl, cyano group, substituted (C １ ~C<​ R is selected from the group consisting of five-membered or six-membered aromatic or heteroaromatic groups, wherein the aromatic or heteroaromatic group is unsubstituted or substituted with one or more substituents.

2. The compound of formula I is a 2S,3R stereoisomer: 【Chemistry 2】 The compound according to claim 1, wherein the compound of formula I is preferably a 6R-stereoisomer, a 6S-stereoisomer, or a mixture thereof.

3. The compound of formula I is a deuterated compound in which one or more hydrogen atoms are replaced by one or more deuterium atoms, and preferably the deuterated compound of formula I has the following structure: 【Transformation 3】 (In the formula, Het and R are each independently defined as in claims 1 to 3; R ６ and R ７ (Each of these is independently either H or deuterium (D)). A compound according to claim 1 or 2, having the following characteristics.

4. The substituents of the heteroaromatic group of Het are (C １ ~C ４ )-alkyl, (C １ ~C ４ )-Fluoroalkyl, (C ３ ~C ８ )-cycloalkyl, cyano, (C １ ~C ４ ) -alkoxy or halogen, preferably the substituent of the heteroaromatic group of Het is Cl, F, -CHF ２ , -CF ３ ien-CH ３ , -C ２ H ５ 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; 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 any derivative thereof; or a six-membered aromatic group which is an unsubstituted aryl, substituted aryl, or a derivative thereof.

6. R is, 【Chemistry 4】 (In the formula, R ３ , R ４ and R ５ 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; (C １ ~C ４ ) - Substituted or unsubstituted alkyl; deuterated (C １ ~C ６ )-Linear alkyl, deuterated (C １ ~C ６ ) - Independently selected from branched alkyl groups; R ３ and R ４ R may form a substituted or unsubstituted ring; preferably, ３ , R ４ and R ５ is hydrogen, -CH ３ or -CD ３ Each (deuterated form) is independently selected; 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, unsubstituted or substituted (C １ ~C ４ ) - Independently selected from the group consisting of alkoxy groups, cyano groups, and halogens, such as fluorine, bromine, or chlorine. A compound selected from any one of claims 1 to 5.

7. The substituent of the aromatic or heteroaromatic group of Y is selected from CN, F, Br, Cl, or -O-alkyl, the alkyl group contains 1 to 4 carbon atoms, and preferably the alkoxy 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, unsubstituted (C １ ~C ６ ) - Branched alkyl, substituted (C １ ~C ６ ) - Linear alkyl, substituted (C １ ~C ６ ) - Branched alkyl, deuterated (C １ ~C ６ )-Linear alkyl, deuterated (C １ ~C ６ ) - Independently selected from the group consisting of branched alkyls and halogens; Het' is selected from the group consisting of heteroaromatic groups selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, pyrazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivative thereof, wherein the heteroaromatic group is unsubstituted, monosubstituted or disubstituted, and substituents on the heteroaromatic group are present, if any, (C １ ~C ４ ) - Linear or branched alkyl, substituted linear or branched (C １ ~C ４ ) -Alkyl and halogen are independently selected from the group consisting of these, and preferably the substituents of the heteroaromatic group are, if present, fluorine, chlorine, and -CH ３ (Selected independently from the group consisting of) The compound according to any one of claims 1 to 5.

11. R １ and R ２ However, hydrogen, chlorine, fluorine, -CH ３ , and -CD ３ The compound according to claim 10, each independently selected from the group consisting of the following.

12. The aforementioned Het' is, 【Transformation 8】 A compound according to any one of claims 1 to 5, 10, and 11, selected from the group consisting of the following.

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

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

15. Structures of formulas 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): 【Chemistry 11】 (wherein R １ , R ２ , R ３ , R ４ , R ５ , Het, Het' and Y are each independently as defined in any one of claims 1 to 14; R ６ and R ７ are, when present, each independently hydrogen or deuterium) A compound according to any one of claims 1 to 14, having the following characteristics. 【Request Item 16】 【Chemistry 12】 【change】 【change】 Or a compound according to any one of claims 1 to 9, 14, and 15, selected from the group consisting of pharmaceutically acceptable salts and derivatives thereof. 【Request Item 17】 【Chemistry 13】 【change】 【change】 【change】 Or a compound according to any one of claims 1 to 5 and 10 to 15, selected from the group consisting of pharmaceutically acceptable salts and derivatives thereof.

18. Compounds of formula I-aa, or pharmaceutically acceptable salts and derivatives thereof: 【Chemistry 14】 (In the formula, R ８ CF ３ or a halogen, preferably the halogen being Cl; W １ is selected from the group consisting of -CH, N, -C-CH ３ , -C-CH ２ CH ３ , -C-F, -C-Cl, -C-CN, -C-CHF ２ , and -C-OMe; W ２ -CH, N, -C-CH ３ and -C-CH ２ CH ３ Selected from the group consisting of; R is a five-membered heteroaromatic group that is an unsubstituted pyrazole, unsubstituted oxazole, unsubstituted thiazole, unsubstituted imidazole, substituted pyrazole, substituted oxazole, substituted thiazole, substituted imidazole, or a derivative thereof; or a six-membered heteroaromatic group that is an unsubstituted pyridine, unsubstituted pyrimidine, unsubstituted pyridazine, unsubstituted pyrazine, substituted pyridine, substituted pyrimidine, substituted pyridazine, substituted pyrazine, or any derivative thereof.

19. R is, 【Chemistry 15】 (In the formula, R １ and R ３ These are, independently of each other, hydrogen and -CH. ３ or -CD ３ And; preferably, R １ ha-CH ３ or -CD ３ And; preferably, R ３ Ha-CD ３ And; Het' and Y are, 【Chemistry 16】 (Each is selected independently.) A compound according to claim 18, selected from the above. 【Request Item 20】 【Chemistry 17】 A compound according to claim 18 or 19, selected from the group consisting of the following.

21. 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 radiolabeled compound, and mixtures thereof; preferably, the pharmaceutically acceptable salts and derivatives are trifluoroacetate, the compound according to any one of claims 1 to 20.

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 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, drug abuse or addiction, opioid dependence, 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 18] (In the formula, R and Het are each independently defined as in any one of claims 1 to 20.) A method for preparing, (a) The step of reacting tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-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(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate is a deuterated compound, and preferably the deuterated tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate is tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 or tert-butyl(2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4-carboxylate.

31. The compound of formula I has the following structure: 【Chemistry 19】 (wherein R and Het are each independently defined as in any one of claims 1 to 20; 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) The step of reacting tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 or tert-butyl(2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-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 a deuterated compound of formula I. 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, substituted (C １ ~C ４ ) - Linear alkyl, substituted (C １ ~C ４ ) - Branched alkyl, substituted or unsubstituted (C ３ ~C ８ )-Cycloalkyl, cyano group, substituted or unsubstituted (C １ ~C ４ ) The method according to claim 29, 30, or 31, independently selected from the group consisting of alkoxys and halogens.

33. The further substituents of the heteroaromatic group are (C １ ~C ４ )-alkyl, (C １ ~C ４ )-Fluoroalkyl, (C ３ ~C ８ )-cycloalkyl, cyano group, (C １ ~C ４ ) - Selected from the group consisting of alkoxys and halogens; preferably, the further substituent of the heteroaromatic group is Cl, F, -CHF ２ , -CF ３ ien-CH ３ , -C ２ H ５ The method according to claim 31, selected from the group consisting of methoxy, nitrile, and cyclopropyl.

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-fluoro-5-(trifluoromethyl)pyridine, 5-chloro-2-fluoropyridine, 2,5-dichloropyrimidine, 2-chloro-4-(trifluoromethyl)pyrimidine, 2-chloro-6-(trifluoromethyl)pyrazine, and 2-fluoro-4-(trifluoromethyl)pyridine, 2,3-difluoro-5-(trifluoromethyl)pyridine, 3-bromo-2-fluoro-5-(trifluoromethyl)pyridine, 2-chloro-3,5-bis(trifluoromethyl)pyridine, 2-chloro-3-methoxy-5-(trifluoromethyl)pyridine, 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine, and 3-methyl-5-(trifluoromethyl)pyrazine-2-ol (in The method according to any one of claims 29 to 34, selected from the group consisting of 2-chloro-5-(trifluoromethyl)nicotinonitrile, 2-chloro-3-(difluoromethyl)-5-(trifluoromethyl)pyridine, 5-chloro-2,3-difluoropyridine, 2,3-difluoro-4-methyl-5-(trifluoromethyl)pyridine, and 2,4-dichloro-5-(trifluoromethyl)pyrimidine, which is activated by situ.

36. The method according to any one of claims 29 to 35, wherein the base is potassium carbonate or DIPEA.

37. The method according to any one of claims 29 to 36, wherein steps (a), (b), and (c) are 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 preferably, the solvent is DMF or DMSO.

38. The following features: (i) Step (a) is carried out at a temperature in the range of about 50°C to about 189°C, preferably about 80°C; (ii) Step (b) is carried out at a temperature in the range of about 12°C to about 40°C, preferably about 20°C. The method according to any one of claims 29 to 37, comprising at least one of the following.

39. The following features: (i) Step (a) is carried out over a period of about 6 to about 18 hours, preferably about 12 hours; (ii) Step (b) is performed for a period of about 30 minutes to about 5 hours, preferably about 2 hours. The method according to any one of claims 29 to 38, comprising at least one of the above.

40. The method according to any one of claims 29 to 39, wherein the acid is selected from the group consisting of an aqueous solution of phosphoric acid, hydrochloric acid, trifluoroacetic acid, and mixtures thereof; preferably, the acid is hydrochloric acid.

41. The method according to any one of claims 29 to 40, 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.

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; 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 any derivative thereof; or a six-membered aromatic group which is an unsubstituted aryl or substituted aryl or a derivative thereof.

43. The carboxylic acid R-COOH is 4-(4-chlorophenyl)-1-methylpyrazole-3-carboxylic acid (CAS1534651-22-3), 5-methyl-2-(2H-1,2,3-triazole-2-yl)benzoic acid (CAS956317-36-5), 3-fluoro-2-(pyrimidine-2-yl)benzoic acid (CAS1293285-04-7), 4-(5-chloropyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (CAS2125741-28-6), 4-(5-fluoropyrimidine-2-yl)- 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (CAS2125741-56-0), 5-fluoro-2-(2H-1,2,3-triazole-2-yl)benzoic acid (CAS1186050-64-5), 5-fluoro-2-(pyrimidine-2-yl)benzoic acid (CAS1293284-57-7), 5-methyl-2-(2-methyl-2H-tetrazole-5-yl)benzoic acid (CAS1861694-01-0), 5-chloro-2-(2-methyl-2H-tetrazole-5-yl)benzoic acid (CAS1858774-05-6) ), 4-(5-fluoropyrimidine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (CAS2044704-99-4), 4-(4-fluorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (CAS127919-87-3), 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid, 4-(5-methoxypyridine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (CAS2024759-24-6), 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, 4-(5-fluoropyrimidine-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid, 4-(5-methoxypyridine-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid, 6-methyl-3-(pyrimidine-2-yl)picolinic acid (CAS1228188-18-8);6-Methyl-3-(2H-1,2,3-triazole-2-yl) picolinic acid (CAS1228188-37-1); 5-Fluoro-3-(pyrimidine-2-yl) picolinic acid (CAS1935682-37-3); 5-Fluoro-2-(2H-1,2,3-triazole-2-yl) nicotinic acid (CAS2138851-77-9); 5-Fluoro-2-(1H-pyrazole-1-yl) benzoic acid (CAS1152964-04-9); 3-(pyrimidine-2-yl) ) picolinic acid (CAS1228431-21-7); 3-(2H-1,2,3-triazole-2-yl) picolinic acid (CAS1252907-86-0); 3-(5-fluoropyrimidine-2-yl)-6-methylpicolinic acid (CAS1228430-99-6); 6'-methyl-[2,3'-bipyridine]-2'-carboxylic acid (CAS1228431-05-7); 6-methyl-[3,3'-bipyridine]-2-carboxylic acid (CAS1228431-14-8);6-methyl-3-(pyrazine-2-yl) picolinic acid (CAS1228431-07-9), 6-methyl-3-(5-methylpyrimidine-2-yl) picolinic acid (CAS1228431-09-1), 6-methyl-3-(4-methylpyrimidine-2-yl) picolinic acid (CAS1228431-12-6), 3-(5-fluoropyrimidine-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid, 3-(5-fluoropyridine-2-yl)-1,5-dimethyl-1H-pyrazole-4-carboxylic acid, 5-fluoro-3-(2H-1,2,3-triazole-2-yl) picolinic acid, 5,6-dimethyl-3-(pyrimidine-2-yl) picolinic acid, 4,6-dimethyl- The method according to any one of claims 29 to 42, comprising 3-(pyrimidine-2-yl)picolinic acid, 6-methyl-3-(pyrimidine-2-yl)pyrazine-2-carboxylic acid, 4-(5-fluoropyridine-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyrimidine-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid, 6-(methyl-d3)-3-(pyrimidine-2-yl)picolinic acid, 6-(methyl-d3)-3-(2H-1,2,3-triazole-2-yl)picolinic acid, or 4-(5-fluoropyrimidine-2-yl)-1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylic acid.

44. The following features: Step (c) is carried out in the presence of a coupling reagent, preferably the coupling reagent is HATU or T ４ Being P; 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; 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; and Step (c) is performed for a period of approximately 1 to 6 hours, preferably approximately 2.5 hours. The method according to any one of claims 29 to 43, comprising at least one of the following.

45. The first intermediate compound is tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate; tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate; tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate; tert-butyl(2S,3R,6R)-3-(((5-chloropyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate; tert-butyl(2S,3R,6R)-3-(((5-chloropyrimidine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate; tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((4-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate; tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((6-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate; tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((4-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate; tert-butyl(2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate; tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate; tert-butyl(2S,3R,6R)-3-(((3,5-bis(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate; tert-butyl(2S,3R,6R)-3-(((3-methoxy-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate; tert-butyl(2S,3R,6R)-3-(((3-chloro-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate; tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyrazine-2-yl)amino)methyl)morpholine-4-carboxylate; tert-butyl(2S,3R,6R)-3-(((3-cyano-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate; tert-butyl(2S,3R,6R)-3-(((3-(difluoromethyl)-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate; tert-butyl(2S,3R,6R)-3-(((5-chloro-3-fluoropyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate; tert-butyl(2S,3R,6R)-3-(((3-fluoro-4-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate; or tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((4-methyl-5-(trifluoromethyl)pyrimidine-2-yl)amino)methyl)morpholine-4-carboxylate The method according to any one of claims 29, 32 to 44.

46. The first intermediate compound is tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl)morpholine-4-carboxylate-5,5-d2; tert-butyl(2S,3R,6R)-3-(((5-chloropyridine-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2; tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl-d2)morpholine-4-carboxylate; tert-butyl(2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridine-2-yl)amino)methyl-d2)-2,6-dimethylmorpholine-4-carboxylate; or tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridine-2-yl)amino)methyl-d2)morpholine-4-carboxylate The method according to any one of claims 30 to 44.

47. The second intermediate compound is N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyrazine-2-amine hydrochloride; N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyrimidine-2-amine hydrochloride; N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyridine-2-amine hydrochloride; 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)pyridine-2-amine hydrochloride; 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)pyrimidine-2-amine hydrochloride; N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-4-(trifluoromethyl)pyrimidine-2-amine hydrochloride; N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-6-(trifluoromethyl)pyrazine-2-amine hydrochloride; or N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-4-(trifluoromethyl)pyridine-2-amine hydrochloride; N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3-fluoro-5-(trifluoromethyl)pyridine-2-amine hydrochloride; N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyridine-2-amine; N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3,5-bis(trifluoromethyl)pyridine-2-amine hydrochloride; N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3-methoxy-5-(trifluoromethyl)pyridine-2-amine; 3-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyridine-2-amine; N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyrazine-2-amine; 2-((((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)amino)-5-(trifluoromethyl)nicotinonitrile hydrochloride; 3-(difluoromethyl)-N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-5-(trifluoromethyl)pyridine-2-amine hydrochloride; 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3-fluoropyridine-2-amine hydrochloride; N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-3-fluoro-4-methyl-5-(trifluoromethyl)pyridine-2-amine; or N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl)-4-methyl-5-(trifluoromethyl)pyrimidine-2-amine The method according to any one of claims 29, 32 to 45.

48. The second intermediate compound is N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyridine-2-amine; 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl-5,5-d2)methyl)pyridine-2-amine hydrochloride; N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl-d2)-5-(trifluoromethyl)pyridine-2-amine hydrochloride; N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl-d2)-3-fluoro-5-(trifluoromethyl)pyridine-2-amine hydrochloride; or N-(((2S,3R,6R)-2,6-dimethylmorpholine-3-yl)methyl-d2)-3-methyl-5-(trifluoromethyl)pyridine-2-amine hydrochloride The method according to any one of claims 30 to 44 or 46.

49. tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate or (2S,3R,6S)-3-(hydroxymethyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate j) Reducing N-benzyl-L-alotreonine a 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); Reacting intermediate c with (2S)-2-bromopropanoic acid, (2S)-2-iodopropanoic acid, (2R)-2-bromopropanoic acid, or (2R)-2-iodopropanoic acid in the presence of a Lewis base to form (R)-2-(((2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)oxy)propanoic acid or (S)-2-(((2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)oxy)propanoic acid (intermediate d); In the presence of a coupling reagent, intermediate d is subjected to an intramolecular amide coupling reaction to form (2R,5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine-3-one or (2S,5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine-3-one (intermediate e); Reacting intermediate e with a reducing agent to form (2S,3R,6R)-4-benzyl-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine or (2S,3R,6S)-4-benzyl-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine (intermediate f); Reacting intermediate f with a fluorine source to form ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholine-3-yl)methanol (intermediate g) or ((2S,3R,6S)-4-benzyl-2,6-dimethylmorpholine-3-yl)methanol (intermediate g); Intermediate g is reacted with hydrogen, palladium carbon, and di-tert-butyl dicarbonate to form tert-butyl (2S,3R,6R)-3-(hydroxymethyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate h) or (2S,3R,6S)-3-(hydroxymethyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate h); Reacting intermediate h with isoindoline-1,3-dione to form tert-butyl(2S,3R,6R)-3-((1,3-dioxoisoindoline-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate or tert-butyl(2S,3R,6S)-3-((1,3-dioxoisoindoline-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate i); and Intermediate i is reacted with hydrazine or hydrazine hydrate to form tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate or tert-butyl(2S,3R,6S)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate j). The method according to claim 29, which is prepared by...

50. tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 is Reducing (2S,3S)-2-amino-N,N-dibenzyl-3-hydroxybutanamide by reacting it with a reducing agent to form (2S,3R)-3-amino-4-(dibenzylamino)butan-2-ol (d-b); In the presence of a Lewis base, intermediate d-b is reacted with 2-bromopropanoic acid to form intermediate d-c, thereby forming (S)-2-bromo-N-((2R,3S)-1-(dibenzylamino)-3-hydroxybutan-2-yl)propenamide (intermediate d-c); Reacting intermediate d-c with a base to form (2R,5R,6S)-5-((dibenzylamino)methyl)-2,6-dimethylmorpholine-3-one (intermediate d-d); Reducing intermediate d-d with a deuterating agent and reacting it with a protecting group to form tert-butyl(2S,3R,6R)-3-((dibenzylamino)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 or tert-butyl(2S,3R,6S)-3-((dibenzylamino)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (intermediate d-f); and Intermediate d-f is reacted with hydrogen and palladium-carbon hydroxide, and then protected to form intermediate d-g. The method according to claim 30 or 31, which is prepared by...

51. tert-butyl(2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4-carboxylate (intermediate d-r) Reacting N-benzyl-L-alotreonine (a) with 2-bromopropanoic acid or 2-iodopropanoic acid, followed by an intramolecular amide coupling reaction using a coupling reagent, to form (2S,3S,6R)-4-benzyl-2,6-dimethyl-5-oxomorpholine-3-carboxylic acid (intermediate d-m); The intermediate d-m is reduced with a deuterating agent to form (2R,5R,6S)-4-benzyl-5-(hydroxymethyl-d2)-2,6-dimethylmorpholine-3-one (intermediate d-n); The intermediate d-n is reduced with a reducing agent to form ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholine-3-yl)methane-d2-ol (intermediate d-o); Reacting intermediate d-o with hydrogen and palladium carbon, and then protecting it, to form tert-butyl(2S,3R,6R)-3-(hydroxymethyl-d2)-2,6-dimethylmorpholine-4-carboxylate (intermediate d-p); Reacting intermediate d-p with isoindoline-1,3-dione to form tert-butyl(2S,3R,6R)-3-((1,3-dioxoisoindoline-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (intermediate d-q); The intermediate d-q is reacted with hydrazine or hydrazine hydrate to form the intermediate d-r. The method according to claim 43, which is prepared by

52. (2R,3S)-2-(benzylamino)butane-1,3-diol (intermediate b); (2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (intermediate c); (R)-2-(((2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)oxy)propanoic acid or (S)-2-(((2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)oxy)propanoic acid (intermediate d); (2R,5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine-3-one or (2S,5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine-3-one (intermediate e); (2S,3R,6R)-4-benzyl-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine or (2S,3R,6S)-4-benzyl-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine (intermediate f); ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholine-3-yl)methanol or ((2S,3R,6S)-4-benzyl-2,6-dimethylmorpholine-3-yl)methanol (intermediate g); tert-butyl(2S,3R,6R)-3-(hydroxymethyl)-2,6-dimethylmorpholine-4-carboxylate or tert-butyl(2S,3R,6S)-3-(hydroxymethyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate h); tert-butyl(2S,3R,6R)-3-((1,3-dioxoiisoindoline-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate or tert-butyl(2S,3R,6S)-3-((1,3-dioxoiisoindoline-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate i); or tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate or tert-butyl(2S,3R,6S)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate j); (2S,3R)-3-amino-4-(dibenzylamino)butan-2-ol (intermediate d-b); (S)-2-bromo-N-((2R,3S)-1-(dibenzylamino)-3-hydroxybutan-2-yl)propenamide (intermediate d-c); (2R,5R,6S)-5-((dibenzylamino)methyl)-2,6-dimethylmorpholin-3-one (intermediate d-d); tert-butyl(2S,3R,6R)-3-((dibenzylamino)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (intermediate d-f); tert-butyl(2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (intermediate d-g); (2S,3S,6R)-4-benzyl-2,6-dimethyl-5-oxomorpholine-3-carboxylic acid (intermediate d-m); (2R,5R,6S)-4-benzyl-5-(hydroxymethyl-d2)-2,6-dimethylmorpholine-3-one (intermediate d-n); ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholine-3-yl)methane-d2-ol (intermediate d-o); tert-butyl(2S,3R,6R)-3-(hydroxymethyl-d2)-2,6-dimethylmorpholine-4-carboxylate (intermediate d-p); tert-butyl(2S,3R,6R)-3-((1,3-dioxoisoindoline-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (intermediate d-q); tert-butyl(2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4-carboxylate(intermediate d-r) A compound that is

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