EP4688155A1 - Morpholine orexin receptor antagonists - Google Patents

Morpholine orexin receptor antagonists

Info

Publication number
EP4688155A1
EP4688155A1 EP24754433.1A EP24754433A EP4688155A1 EP 4688155 A1 EP4688155 A1 EP 4688155A1 EP 24754433 A EP24754433 A EP 24754433A EP 4688155 A1 EP4688155 A1 EP 4688155A1
Authority
EP
European Patent Office
Prior art keywords
methyl
tert
substituted
carboxylate
butyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24754433.1A
Other languages
German (de)
French (fr)
Inventor
László Erno KISS
Alexandre BELIAEV
Marco André Coelho das NEVES
Tomislav Karoli
Joerg Holenz
Soraia Patrícia PINTO DOS SANTOS
Ana Catarina Gomes OLIVEIRA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bial Portela and Cia SA
Original Assignee
Bial Portela and Cia SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bial Portela and Cia SA filed Critical Bial Portela and Cia SA
Publication of EP4688155A1 publication Critical patent/EP4688155A1/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds, or pharmaceutically acceptable salts and derivatives thereof, that are useful as orexin antagonists; pharmaceutical compositions comprising such compounds, salts or derivatives thereof and, methods of using such compounds to treat or prevent a disease or disorder mediated by orexin receptor activity.
  • Diseases or disorders mediated by orexin receptors include, but are not limited, to central nervous system (CNS) disorders, neurological diseases or eating disorders such as obesity, binge eating disorder (BED), schizophrenia (negative symptoms and CIAS), addiction to psychomotor stimulants such as cocaine, opiates, nicotine and alcohol, opioid use disorder, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, behaviour disorder and mood disorder depression.
  • Orexins have been found to stimulate food consumption, regulate states of sleep and wakefulness, and may be involved in neural mechanisms of drug abuse and addiction.
  • the neuronal pathways and receptors via which orexins are involved in these processes seem to be partly overlapping and partly distinct.
  • findings have suggested that the arousal-promoting function of orexins is mainly promoted by 0X2 receptor whereas the role of orexin in regulating reward and feeding is predominantly mediated by 0X1 receptor.
  • Orexin receptors are suitable targets for the development of drug candidates for the treatment of a variety of orexin-related pathologies and symptoms, such as, but not limited to, central nervous system (CNS) disorders, sleep/wake disorders, anxiety, and obesity.
  • Orexin receptor antagonists have been developed as potential treatments for sleep disorders such as insomnia and narcolepsy. These antagonists block the binding of orexins to their receptors, thereby reducing orexin signalling and promoting sleep.
  • the development of orexin receptor antagonists has focused primarily on OX2 receptor antagonists, for the regulation of arousal and wakefulness. However, there is also interest in the development of OX1 receptor antagonists for the treatment of substance addiction, obesity and other metabolic disorders.
  • Patent application WO2020247447A1 is directed towards substituted pyrazole and imidazole derivatives of compounds that are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved or implicated. It also relates to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.
  • Patent application WO2002090355A1 and granted patent EP1539747 relates to N-aroyl cyclic amine derivatives as orexin receptor antagonists and their potential use in the treatment of obesity, including obesity observed in Type 2 (non-insulin-dependent) diabetes patients, and/or sleep disorders, stroke, particularly ischemic or haemorrhagic stroke, and/or blocking the emetic response, i.e. useful in the treatment of nausea and vomiting.
  • Patent application WO2013068935A1 relates to derivatives of 2-(1,2,3-triazol-2-yl)benzamide and 3-(1,2,3-triazol-2-yl)picolinamide and their use as orexin receptor antagonists in pharmaceutical compositions.
  • a compound, or pharmaceutically acceptable salts and derivatives thereof wherein the compound has the structure of general Formula I: wherein: Het represents a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof, wherein said heteroaromatic group is unsubstituted, mono-, di-substituted, or tri-substituted, wherein the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (C 1 -C 4 ) straight chain alkyl, unsubstituted (C 1 -C 4 )-branched alkyl, unsubstit
  • the substituent of the heteroaromatic group in Het is F, Cl, CHF 2 , CF 3 , methyl, ethyl, methoxy, nitrile or cyclopropyl.
  • R is selected from the group consisting of a five or a six membered aromatic group or heteroaromatic group, wherein the aromatic group or heteroaromatic group is either unsubstituted or is substituted with one or more substituents.
  • R in the compound of Formula I comprises a five membered heteroaromatic group which is an unsubstituted pyrazole, an unsubstituted oxazole, an unsubstituted thiazole, an unsubstituted imidazole, a substituted pyrazole, a substituted oxazole, a substituted thiazole, a substituted imidazole or a derivative thereof; a six membered aromatic group which is an unsubstituted aryl, or substituted aryl, or a derivative thereof; or a six membered heteroaromatic group, which is an unsubstituted pyridine, an unsubstituted pyrimidine, an unsubstituted pyridazine, an unsubstituted pyrazine, a substituted pyridine, a substituted pyrimidine, a substituted pyridazine, a substituted pyrazine or
  • the compound of Formula I is a 2S,3R- stereoisomer: .
  • the compound of Formula I is a 6R- stereoisomer, a 6S-stereoisomer or mixtures thereof: .
  • one or more of the hydrogen atom attached to the carbon atom in the morpholine ring of the compound of Formula I is replaced with one or more deuterium.
  • one or more of the hydrogen atom attached to the side chain in the morpholine of the compound of Formula I is replaced with one or more deuterium.
  • the compound of Formula I is a deuterated compound, in which one or more hydrogen atoms is replaced or substituted by one or more 2 H (deuterium).
  • the deuterated compound of Formula I may have the following structure: ; wherein R and Het may be each independently as defined in Formula I.
  • a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of Formula I(a) - (g):
  • R 1 and R 2 may be each independently selected from the group consisting of: hydrogen, unsubstituted (C 1 -C6)-straight chain alkyl; unsubstituted (C 1 -C6)-branched alkyl; substituted (C 1 -C6)-straight chain alkyl; substituted (C 1 -C6)-branched alkyl; deuterated (C 1 -C6)-straight chain alkyl; deuterated (C 1 -C 6 )-branched chain alkyl and halogen such as fluorine, chlorine or bromine; preferably R 1 and R 2 are each independently hydrogen, chlorine, fluorine, -CH 3 , or - CD 3 (deuterium); R 6 and R 7 may be each independently hydrogen or deuterium; Het’ is selected from the group consisting of: a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole,
  • the compound of Formula I(a)-(g) is a 6R,2S,3R-stereoisomer, 6S,2S,3R- stereoisomer or mixtures thereof.
  • a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of Formula I(h) –I(i): wherein: R 3 and R 4 may be each independently selected from the group consisting of: hydrogen, (C 1 - C 10 )-straight chain alkyl; (C 1 -C 10 )-branched alkyl; (C 1 -C 10 )-substituted or unsubstituted alkyl, optionally (C 1 -C 4 )-straight chain alkyl; (C 1 -C 4 )-branched alkyl; and (C 1 -C 4 )-substituted or unsubstituted alkyl; R 3 and R 4 may form a substituted or un
  • the aromatic heteroaromatic group in Y is substituted with CN, F, Br, Cl, -O-alkyl, preferably the alkyl group comprises 1-4 carbon atoms, preferably the alkoxy is -OCH 3 .
  • a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of Formula I(k): 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).
  • the pharmaceutical composition is in a solid form such as a tablet or a capsule.
  • a method of treating or preventing a disease or disorder mediated by orexin receptor activity comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula I or I(a-n) described herein or pharmaceutically acceptable salts, and derivatives thereof, preferably in a dose, at a frequency, and for a duration to provide a beneficial effect a pharmaceutical composition described herein.
  • a compound of Formula I or I(a-n) described herein, or a pharmaceutical composition described therein in the preparation of a medicament for the treatment of diseases or disorders regulated by orexin receptor activity, and the use of such compounds for treatment or prevention of such diseases and disorders.
  • a method of modulating the activity of orexin receptors OX1, OX2, or both comprising contacting a cell comprising the orexin receptor with an effective amount of at least one compound of Formula I or I(a-n) described herein, or a pharmaceutical composition described herein.
  • a method for the preparation of the compounds of the present invention is provided.
  • a compound of Formula I or pharmaceutically acceptable salts and derivatives thereof is provided.
  • ‘Het’ represents a heteroaromatic group and ‘R’ is a five 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, mono-, di-, or tri-substituted, wherein the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (C 1 -C 4 )-straight chain alkyl, unsubstituted (C 1 -C 4 )-branched alkyl, substituted (C 1 -C 4 )-straight chain alkyl, substituted (C 1 -C 4 )-branched alkyl, and halogen such as fluorine, chlorine or bromine.
  • the substituents of the heteroaromatic group comprises CF 3 .
  • the five or six membered aromatic or heteroaromatic group ‘R’ may either be unsubstituted or substituted with one or more substituents.
  • the compound provided by Formula I is a 2S,3R-stereoisomer:
  • the 2S,3R stereoisomer provided by the compound of Formula I or I(a-n) may bind stronger to the orexin receptors and may be more selective at binding to the OX1 receptor in comparison to other stereoisomers provided by compounds of Formula I or I(a-n).
  • the 2S,3R,6R- stereoisomer are metabolically more stable in comparison to other stereoisomers provided by compounds of the present invention.
  • the compound of Formula I is a 2S,3R,6R-stereoisomer, a 6S,2S,3R- stereoisomer or mixtures thereof: .
  • the compound of Formula I may be a deuterated compound.
  • one or more hydrogen atom is replaced or substituted by one or more deuterium, for example one or more hydrogen atom attached to the carbon atom of the morpholine ring, or one or more hydrogen atom in the side chain of the morpholine ring or one or more hydrogen atom in any of the substituents of the five or a six membered aromatic group or heteroaromatic group of ‘R’ group of Formula I may be replaced with one or more deuterium.
  • heteromatic refers to an aromatic compound which contains heteroatoms such as oxygen, nitrogen or sulfur as part of the cyclic conjugated ⁇ system.
  • alkyl refers to univalent groups derived from alkanes by removal of a hydrogen atom from any carbon atom –C n H 2n+1 .
  • substituted alkyl refers to an alkyl wherein one or more hydrogen atoms of the alkyl group are replaced with one or more substituents selected from but not limited to halogen (such as fluorine, chlorine, or bromine), -OH, -CN.
  • fluoroalkyl refers to an alkyl substituted by at least one fluorine atom.
  • alkoxy refers to an alkyl bonded to oxygen (i.e. R-O).
  • 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.
  • Halogen can be F, Cl, Br or I, however, in preferred examples the halogen is F, Cl or Br.
  • “Isotopically labelled compound” are chemical substances in which some atoms in their molecules are replaced by isotope atoms, typically different from naturally occurring isotopes.
  • “Deuterated compounds” are compounds in which one or more hydrogen atom in the compound have been replaced by one or more deuterium atom.
  • the term “deuterated alkyl” used herein refers to an alkyl group with one or more protons replaced with deuterium atoms.
  • substituted refers to, for a particular group (e.g, alkyl, aryl, heteroaryl, aromatic), the replacement of one functional group by another (e.g., the substitution of an alkyl hydrogen by fluorine to provide fluoroalkyl).
  • solvate is used herein to describe a compound in this invention that contains stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule such as ethanol.
  • solvent molecule such as ethanol.
  • hydrate refers to when the said solvent is water.
  • pharmaceutically acceptable is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the subject to which it is administered.
  • therapeutically effective amount (or more simply an “effective amount”) as used herein means the amount of active agent or active ingredient that is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which/whom it is administered.
  • the “R” in the compound of Formula I is a five-membered heteroaromatic group, it may comprise an unsubstituted pyrazole, oxazole, thiazole, imidazole; a substituted pyrazole, oxazole, thiazole, imidazole; or a derivative thereof.
  • the unsubstituted or substituted pyrazole may be a fused with a five or six membered ring.
  • the “R” in the compound of Formula I is a six-membered aromatic group, it may comprise an unsubstituted aryl, or substituted aryl, or a derivative thereof.
  • Het’ of Formula III(a) –(b) may be selected from: .
  • the “R” in Formula I is a five-membered heteroaromatic group
  • the five-membered heteroaromatic group may have the structure Formula IV: wherein: Y may represent an aromatic group; a substituted or unsubstituted aromatic group, a heteroaromatic group, a substituted or unsubstituted heteroaromatic group.
  • the halogen may preferably be fluorine, chlorine or bromine.
  • the substituent(s) is a (C 1 -C 4 )-alkoxy
  • the alkoxy may preferably be -OCH 3 .
  • the substituent(s) of the aromatic or heteroaromatic group in Y is selected from CN, F, Br, Cl , or - OCH 3 .
  • Y of Formula IV may be selected from: Further, where the “R” in Formula I is a five-membered heteroaromatic group, the five- membered heteroaromatic group may have the structure Formula V or V(a) wherein: R 3 and R 4 may each be independently selected from the group consisting of: hydrogen, (C 1 - C10)-straight chain alkyl; (C 1 -C10)-branched alkyl; (C 1 -C10)-substituted or unsubstituted alkyl, optionally (C 1 -C 4 )-straight chain alkyl; (C 1 -C 4 )-branched alkyl; (C 1 -C 4 )-substituted or unsubstituted alkyl; deuterated (C 1 -C6)-straight chain alkyl and deuterated (C 1 -C6)-branched chain alkyl; R 3 and R 4 may form a substituted or unsubstituted ring; preferably
  • the present invention preferably further includes all pharmaceutically acceptable isotopically labelled compound [e.g., of Formula I or I(a-e)]
  • An "isotopically" or “radio-labelled” compound is a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • compounds provided by the present invention may have an IC 50 value between 2 nM to 50 nM for OX1 receptors.
  • Compounds provided by the present invention may have an IC 50 value between 2 nM to 40 nM; between 2 nM to 30 nM; between 2 nM to 25 nM; between 2 nM to 20 nM; between 2 nM to 10 nM; between 2 nM to 5 nM; 3 nM to 40 nM; between 3 nM to 30 nM; between 3 nM to 25 nM; between 3 nM to 20 nM; between 3 nM to 10 nM; between 3 nM to 5 nM; 5 nM to 40 nM; between 5 nM to 30 nM; between 5 nM to 25 nM; between 5 nM to 20 nM; between 5 nM to 10 nM; 7 nM to 40 nM; between 7 nM to 30 nM;
  • Orexin A was incubated with human OX1 receptor membranes for different incubation times in the presence or absence of 6 different concentrations of compounds.
  • the non-specific binding was assessed in presence of unlabeled SB 334867 (1-(2-methylbenzo[d]oxazol-6-yl)-3-(1,5-naphthyridin-4-yl)urea, which is commercially available OX1R-ANT) for each incubation time.
  • Kinetic parameters (kon, koff, residence time) were calculated by applying the Motulsky Mahan equation. Compounds of the present invention were found to show a higher residence time compared to reference compounds, suggesting a higher ligand-OX1R complex half-life which positively impacts the therapeutic dose in humans.
  • compounds of present invention (such as compounds 51, 74, 120) showed higher ranking compared to known compounds such as those in WO2017129829, WO2017139603, JNJ-61393215 and ACT-539313.
  • Improved drug residence time is advantageous, as longer drug-target residence time are generally more efficacious in vivo. As a result, lower therapeutic doses are needed.
  • drugs with longer residence times have increased efficacy and fewer side effects because they occupy a higher fraction of their target over a longer period of time, even after clearance from systemic circulation.
  • a pharmaceutical composition comprising a compound of present invention described herein and one or more pharmaceutically acceptable excipients.
  • Pharmaceutically acceptable excipients may be added to streamline the manufacture of the pharmaceutical composition and ultimately facilitate physiological absorption of the drug.
  • pharmaceutically acceptable excipients used in the present invention may provide key benefits such as solubilisation, stabilisation, delivery enhancement, and formulation preservation.
  • Non-limiting examples of types of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersing agents, disintegration agents, emulsifying agents, wetting agents, suspending agents, thickeners, solvents, isotonic agents, buffers, pH adjusters, absorption-delaying agents, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweetening agents, flavoring agents, coloring agents, encapsulating materials and coating materials.
  • the use of such excipients in pharmaceutical formulations is known in the art.
  • the compounds of the present invention may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein.
  • the additional active ingredients may include other active agents that are effective in treating the diseases and disorders described herein.
  • additional active ingredients include those that are known to be useful for enhancing sleep quality and preventing and treating sleep disorders and sleep disturbances, anti-diabetic agents, cardiovascular therapies, anti-obesity agents, other orexin receptor antagonists, pain medications, anti-depressants, anti-anxiety agents, cognition-enhancing agents, anti- Alzheimer’s Disease therapies, and other active ingredients.
  • the pharmaceutical composition or the compound provided by the present invention may be used as a medicament.
  • the pharmaceutical composition provided by the present invention is in the form of tablets or capsules.
  • the pharmaceutical composition provided by the present invention may be administered through oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intra-arterial, intraperitoneal, intracavitary and topical), topical (including transdermal, transmucosal, intranasal (e.g., by nasal spray or drop), ocular (e.g., by eye drop), pulmonary (e.g., by oral or nasal inhalation), and/or other suitable routes.
  • the pharmaceutical composition provided by the present invention is administered orally.
  • a method of treating or preventing a disease or disorder mediated by orexin receptor activity comprising administering to a subject in need of such treatment an effective amount of at least one compound in accordance with the present invention (or any pharmaceutically acceptable salts, solvates, adducts, polymorphs, isotopically or radio-labelled derivatives and isomers thereof) or a pharmaceutical composition comprising of at least one compound in accordance with the present invention (or any pharmaceutically acceptable salts, solvates, adducts, polymorphs, isotopically or radio-labelled compounds and isomers thereof).
  • the method provided by the present invention may be used for the treatment or for the prevention of diseases or disorders selected from but not limited to eating disorders, obesity, binge eating disorder (BED), schizophrenia (negative symptoms and CIAS), addiction to psychomotor stimulants such as cocaine, opiates, nicotine and alcohol, opioid use disorder, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, behaviour disorder and mood disorder depression.
  • Dosage regimens may be adjusted to provide the optimum desired response. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses.
  • the use of a compound in accordance with the present invention or a pharmaceutical composition comprising a compound in accordance with Formula I is provided.
  • the compound in accordance with the present invention or the pharmaceutical composition comprising the compound in accordance with the present invention is used in the preparation of a medicament for the treatment of diseases or disorders regulated by orexin receptor activity and is used for treatment or prevention of such diseases and disorders.
  • a method of modulating the activity of orexin receptors OX1, OX2, or both comprising contacting a cell comprising the orexin receptor with an effective amount of at least one compound in accordance with the present invention or a pharmaceutical composition comprising a compound in accordance with the present invention.
  • hexaalkylditin examples include but are not limited to hexamethylditin or hexabutylditin.
  • Compounds of Formula I may be prepared by starting with commercially available starting material N-benzyl-L-allothreonine (a). N-benzyl-L-allothreonine (a) may be reduced by reacting with a reducing agent to form intermediate b. The primary alcohol of intermediate b may be selectively protected by reacting with a suitable protecting group to form intermediate c. Intermediate c may undergo a nucleophilic substitution reaction with 2-bromopropanoic acid or 2-iodopropanoic acid to form intermediate d.
  • Intermediate i may be reacted with hydrazine or hydrazine hydrate to form intermediate j.
  • Intermediate j may undergo a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of intermediate k-a to k-s.
  • intermediates k-a to k-s are deprotected to form corresponding intermediates l-a to l-s.
  • Intermediates l-a to l-s may be reacted with a carboxylic acid having general formula R-COOH to form compounds 1-57, 61, 64-82, 85-95, 98-120.
  • compounds of Formula ID(a) may be prepared by starting with compound d-a.
  • Compound d-a may be reduced by reacting with a reducing agent to form intermediate d-b.
  • Intermediate d-b may undergo a nucleophilic substitution reaction with 2-bromopropanoic acid or 2-iodopropanoic acid to form intermediate d-c.
  • Intermediate d- c is reacted with a base to form intermediate d-d.
  • Compound d-d is deuterated to form intermediate d-e.
  • the amino group from intermediate d-e is removed and the deprotected group may react with a suitable protecting group to form intermediate d-f.
  • Intermediate d-f is hydrogenated to form compound d-g.
  • Intermediate d-g may undergo a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of intermediate d-h and d-i.
  • intermediate d-h and d-i is deprotected to form corresponding intermediates d-j and dk.
  • Intermediates d-j and dk may be reacted with a carboxylic acid having general formula R-COOH to form compounds 58, 59, 60, 62 and 63.
  • Compounds of Formula ID(b) may be prepared by starting with compound a.
  • Intermediate d-q may be deprotected to form compound d-r.
  • Intermediate d-r may undergo a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of intermediate d-s, d-t, and d-u.
  • intermediate d-s, d-t, and d-u are deprotected to form corresponding intermediates d-v, d-w, and d-x.
  • Intermediates d-v, d-w, and d-x may be reacted with a carboxylic acid having general formula R-COOH to form compounds 83, 84, 96 and 97.
  • N-benzyl-L-allothreonine a is reduced by reacting with a reducing agent such as borane dimethyl sulfide to form intermediate b.
  • a reducing agent such as borane dimethyl sulfide
  • suitable reducing agents may be used instead of borane dimethyl sulfide such as but not limited to lithium aluminum hydride, boron trifluoride diethyl etherate and diborane.
  • the reducing agent may be used in excess with respect to starting material a.
  • the excess is preferably 2-times to 10-times of the reducing agent with respect to starting material a.
  • a 5-times excess of the reducing agent is used with respect to starting material a.
  • the reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF.
  • the reaction may be carried out at a temperature in the range of about 50°C to about 120°C. Preferably, the reaction is carried out in the range of about 60°C to about 100°C. More preferably, the reaction is carried out in the range of about 60°C to about 80°C.
  • the reaction may be carried out for a duration of about 3 to about 10 hours. Preferably, for a duration of about 5 to about 8 hours. More preferably, the reaction is carried out for a duration of about 6 hours.
  • the present invention provides a method for synthesizing intermediate c as shown in the synthetic pathway below, where PG refers to protecting group:
  • the primary alcohol of intermediate b may be selectively protected using a suitable reagent such as tert-butyldiphenylsilyl to form intermediate c.
  • suitable protecting groups may be used including but not limited to tert-butyldimethylsilyl, triisopropylsilyl or trimethylsilyl protecting group.
  • Intermediate b may be reacted with tert-butyl(chloro)diphenylsilane to form intermediate c.
  • intermediate b may be reacted with reagents such as tert-butyldimethylsilyl chloride, triisopropylsilyl chloride or trimethylsilyl chloride to form intermediate c.
  • reagents such as tert-butyldimethylsilyl chloride, triisopropylsilyl chloride or trimethylsilyl chloride to form intermediate c.
  • the reagent may be used in excess with respect to intermediate b.
  • a 1.1-times to 1.5-times excess of the reagent may be used with respect to intermediate b.
  • a 1.2-times excess of the reagent is used with respect to intermediate b.
  • the reaction may be carried out in the presence of a catalyst such as DMAP, imidazole or mixtures thereon.
  • imidazole is used as the catalyst.
  • the catalyst may be used in excess with respect to intermediate b.
  • a 1.1-times to 2-times excess of the catalyst may be used with respect to intermediate b.
  • a 1.5-times excess of the catalyst is used with respect to intermediate b.
  • the reaction may be carried out in polar solvents such as acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof.
  • the reaction is carried out in THF.
  • the reaction may be carried out at a temperature in the range of about 20°C to about 66°C.
  • the reaction is carried out at about 25°C.
  • the reaction may be carried out for a duration of about 5 to about 18 hours.
  • the reaction is carried out for a duration of about 12 hours.
  • the present invention provides a method for synthesizing intermediate d as shown in the synthetic pathway below, where PG refers to protecting group:
  • Intermediate c may be reacted with 2-bromopropanoic acid or 2-iodopropanoic acid to form intermediate d.
  • intermediate c is reacted with (2S)-2-bromopropanoic acid or (2R)- 2-bromopropanoic acid to form intermediate d.
  • 2-bromopropanoic acid or 2-iodopropanoic acid may be used in excess with respect to intermediate c.
  • a 2-times to 7-times excess of 2-bromopropanoic acid or 2-iodopropanoic acid may be used with respect to intermediate c.
  • a 3-times excess of 2-bromopropanoic acid or 2-iodopropanoic acid is used with respect to intermediate c.
  • the reaction is carried out in the presence of a Lewis base.
  • Lewis bases that may be used for the synthesis of intermediate d include but are not limited to butyl lithium, lithium diisopropylamide (LDA), lithium diethylamide (LDEA), sodium amide (NaNH 2 ), sodium hydride (NaH), lithium bis(trimethylsilyl)amide, or mixtures thereof.
  • the Lewis base used in the synthesis of intermediate d is sodium hydride. The Lewis base may be used in excess with respect to intermediate c.
  • a 4-times to 10-times excess of the Lewis base may be used with respect to intermediate c.
  • an 8-times excess of the Lewis base is used with respect to intermediate c.
  • the reaction may be carried out in polar solvents such as acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof.
  • 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 66°C.
  • the reaction may be carried out at a temperature in the range of about 0°C to about 60°C.
  • the reaction may be carried out for a duration of about 2 to about 10 hours.
  • the reaction is carried out for a duration of about 6 hours.
  • the present invention provides a method for synthesizing intermediate e as shown in the synthetic pathway below, where PG refers to protecting group:
  • Intermediate d undergoes an intramolecular amide coupling reaction, optionally in the presence of a coupling reagent to form intermediate e.
  • Suitable coupling reagents include, but are not limited to, DCC, DIC, EDC-HCl, BOP, PyBOP, PyAOP, PyBrOP, BOP-Cl, HATU, HBTU, HCTU, TATU, TBTU, T3P, DEPBT or CDI.
  • T3P is used as the coupling reagent.
  • the reaction may be carried out in a polar aprotic solvent such as DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in DMF.
  • the reaction may be carried out at a temperature in the range of about 15°C to about 153°C.
  • the reaction may be carried out at a temperature in the range of about 20°C to about 130°C or about 50°C to about 100°C. More preferably, the reaction is carried out at about 20°C.
  • the reaction may be carried out for a duration of about 1 hour to about 5 hours. Preferably, the reaction is carried out for a duration of about 2 hours.
  • the present invention provides a method for synthesizing intermediate f as shown in the synthetic pathway below, where PG refers to protecting group:
  • Intermediate e is reduced by reacting with a reducing agent such as borane dimethyl sulfide to form intermediate f.
  • a reducing agent such as borane dimethyl sulfide
  • suitable reducing agents may be used instead of borane dimethyl sulfide such as but not limited to lithium aluminum hydride, boron trifluoride diethyl etherate and diborane.
  • the reducing agent may be used in excess with respect to intermediate e.
  • a 2-times to 10- times excess of the reducing agent may be used with respect to intermediate e.
  • a 4-times excess of the reducing agent is used with respect to intermediate e.
  • the reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof.
  • a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof.
  • the reaction is carried out in THF.
  • the reaction may be carried out at a temperature in the range of about 20°C to about 66°C.
  • the reaction may be carried out at a temperature in the range of about 30°C to about 50°C. More preferably, the reaction is carried out at about 30°C.
  • the reaction may be carried out for a duration of about 2 hours to about 8 hours.
  • the reaction is carried out for a duration of about 5 hours.
  • the present invention provides a method for synthesizing intermediate g as shown in the synthetic pathway below, where PG’ refers to protecting group:
  • the tert-butyl-diphenylsilane protecting group may be removed from intermediate f by reacting with a source of fluorine to form intermediate g.
  • Suitable reagents as a source of fluorine include but are not limited to tetra-n-butylammonium fluoride (TBAF) or triethylamine trihydrofluoride.
  • TBAF tetra-n-butylammonium fluoride
  • TBAF triethylamine trihydrofluoride.
  • TBAF tetra-n-butylammonium fluoride
  • the reagent may be used in excess with respect to intermediate f. A 1.1-times to 2-times excess of the reagent may be used with respect to intermediate f.
  • a 1.5-times excess of the reagent is used with respect to intermediate f.
  • the reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof.
  • the reaction is carried out in THF.
  • the reaction may be carried out at a temperature in the range of about 15°C to about 66°C.
  • the reaction is carried out at about 20°C to about 50°C. More preferably, the reaction is carried out at about 25°C.
  • the reaction may be carried out for a duration of about 30 mins to about 4 hours.
  • the reaction is carried out for a duration of about 1 hour.
  • the present invention provides a method for synthesizing intermediate h as shown in the synthetic pathway below, where PG refers to protecting group:
  • Intermediate g is reacted with hydrogen and palladium over carbon and is subsequently protected to form intermediate h.
  • the reaction is carried out under a hydrogen atmosphere at a pressure in the range of about 10 Psi to about 30 Psi.
  • the reaction is carried out at about 15 Psi.
  • the conversion of intermediate g to intermediate h may be a one-pot process.
  • about 0.02 to about 0.5 equivalents of palladium over carbon is used. More preferably, about 0.05 equivalents of palladium over carbon is used.
  • Any suitable protecting group may be used form intermediate h.
  • suitable protecting groups include Fmoc, BOC or Ts.
  • BOC is used as the protecting group.
  • suitable protecting group reagents to form intermediate h include but are not limited to fluorenylmethyloxycarbonyl chloride, 9-fluorenylmethylsuccinimidyl carbonate, 9- fluorenylmethyloxycarbonyl azide, BOC-anhydride, tosylchloride.
  • BOC-anhydride is used.
  • the protecting group reagent may be used in excess with respect to intermediate g. A 1.1-times to 2-times excess of the reagent may be used with respect to intermediate g.
  • the reaction may be carried out in a polar aprotic solvent such as ethyl acetate, dichloromethane, THF, or mixtures thereof.
  • a polar aprotic solvent such as ethyl acetate, dichloromethane, THF, or mixtures thereof.
  • the reaction is carried out in ethyl acetate.
  • the reaction may be carried out at a temperature in the range of about 15°C to about 77°C.
  • the reaction is carried out at about 25°C.
  • the reaction may be carried out for a duration of about 6 to about 18 hours.
  • the reaction is carried out for a duration of about 12 hours.
  • the present invention provides a method for synthesizing intermediate i as shown in the synthetic pathway below, where PG’ refers to protecting group:
  • Intermediate h is reacted with isoindoline-1,3-dione to form intermediate i.
  • Isoindoline-1,3- dione may be used in excess with respect to intermediate h.
  • a 1.1-times to 2-times excess of isoindoline-1,3-dione may be used with respect to intermediate h.
  • a 1.5-times excess of isoindoline-1,3-dione is used with respect to intermediate h.
  • the reaction is carried out in the presence of triphenylphosphine.
  • the reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof.
  • a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof.
  • 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 66°C.
  • the reaction is carried out at about 0°C to about 20°C.
  • the reaction may be carried out for a duration of about 5 to about 20 hours.
  • the reaction is carried out for a duration of about 16 hours.
  • the present invention provides a method for synthesizing intermediate j as shown in the synthetic pathway below, where PG’ refers to protecting group: Intermediate i is reacted with hydrazine or hydrazine hydrate to form intermediate j.
  • intermediate i is reacted with hydrazine hydrate to form intermediate j.
  • Hydrazine or hydrazine hydrate may be used in excess with respect to intermediate i.
  • a 5- times to 20-times excess of hydrazine or hydrazine hydrate may be used with respect to intermediate i.
  • a 10-times excess of hydrazine or hydrazine hydrate is used with respect to intermediate i.
  • the reaction may be carried out in a polar protic solvent such as alcohols including but not limited to methanol, ethanol, isopropanol or mixtures thereof.
  • the reaction is carried out in methanol.
  • the reaction may be carried out at a temperature in the range of about 40°C to about 65°C. Preferably, the reaction is carried out at about 60°C. The reaction may be carried out for a duration of about 1 to about 5 hours. Preferably, the reaction is carried out for a duration of about 2 hours.
  • the present invention provides a method for synthesizing intermediate d-b shown in the synthetic pathway below: Compound d-a is reduced by reacting with a reducing agent such as borane tetrahydrofuran to form intermediate d-b.
  • a reducing agent such as borane tetrahydrofuran
  • Other suitable reducing agents may be used instead of borane dimethyl sulfide such as but not limited to lithium aluminum hydride, boron trifluoride diethyl etherate and diborane.
  • the reducing agent may be used in excess with respect to starting material d-a.
  • the excess is preferably 2-times to 10-times of the reducing agent with respect to starting material d-a.
  • a 3-times excess of the reducing agent is used with respect to starting material aw.
  • the reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof.
  • 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 80°C.
  • the reaction is carried out in the range of about 0°C to about 70°C. More preferably, the reaction is carried out in the range of about 0°C to about 50°C.
  • the reaction may be carried out for a duration of about 30 minutes to about 5 hours. Preferably, for a duration of about 1 hour to about 4 hours. More preferably, the reaction is carried out for a duration of about 2.5 hours.
  • the present invention provides a method for synthesizing intermediate d-c as shown in the synthetic pathway below: Intermediate d-b may be reacted with 2-bromopropanoic acid or 2-iodopropanoic acid to form intermediate d-c.2-bromopropanoic acid or 2-iodopropanoic acid may be used in excess with respect to intermediate d-b or may be used in equal quantities.
  • the reaction is carried out in the presence of a base, preferably a non-nucleophilic base.
  • Examples that may be used for the synthesis of intermediate may include, but are not limited to N-N-Diisopropylethylamine (DIPEA), 1,8-Diazabicycloundec-7-ene (DBU), 1,5- Diazabicyclo(4.3.0)non-5-ene (DBN), or mixtures thereof.
  • the Lewis base used in the synthesis of intermediate ay is N-N-Diisopropylethylamine (DIPEA).
  • the base may be used in excess with respect to intermediate d-b.
  • a 2-times to 6-times excess of the base may be used with respect to intermediate d-b.
  • a 3-times excess of the base is used with respect to intermediate d-b.
  • the reaction may be carried out in polar solvents such as acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in THF.
  • 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 with respect to starting material aw.
  • the excess is preferably 0.5-times to 4-times of the coupling agent with respect to starting material aw.
  • a 1-times excess of the coupling agent is used with respect to starting material aw.
  • the reaction may be carried out at a temperature in the range of about -10°C to about 60°C. Preferably, the reaction may be carried out at a temperature in the range of about 0°C to about 25°C.
  • the reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, for a duration of about 30 minutes to about 2 hours. More preferably, the reaction is carried out for a duration of about 1 hour.
  • the present invention provides a method for synthesizing intermediate d-d as shown in the synthetic pathway below: Intermediate d-c is reacted with a base to form intermediate d-d. Examples of bases that may be used include but are not limited to lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • potassium hydroxide is used.
  • the base may be used in excess with respect to intermediate d-c.
  • a 1-times to 4-times excess of the base may be used with respect to intermediate d-c.
  • a 2-times excess of the base is used with respect to intermediate d-c.
  • the reaction may be carried out in a solvent such as THF, DMF, DMSO, a polar protic solvent such as water, methanol, ethanol, isopropanol, a non-polar solvent such as chloroform, 1,4- dioxane or any combination thereof.
  • the reaction is carried out in a combination of isopropanol and water.
  • the ratio of solvents 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 about 30:1.
  • the ratio of isopropanol and water may be in the range of about 20:1 to about 40:1, more preferably about 30:1.
  • the reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction may be carried out at a temperature of about 25°C.
  • the reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, for a duration of about 30 minutes to about 2 hours. More preferably, the reaction is carried out for a duration of about 1 hour.
  • the present invention provides a method for synthesizing intermediate d-e as shown in the synthetic pathway below:
  • Intermediate d-d lactam is reduced with a deuterated reagent to form intermediate d-e.
  • the deuterated reagent may be lithium aluminium deuteride or sodium borodeuteride.
  • the deuterated agent may be lithium aluminium deuteride.
  • the deuterated reagent may be used in excess with respect to starting material d-d. The excess is preferably 1-times to 5-times of the deuterated reagent with respect to starting material d-d.
  • a 3-times excess of the deuterated reagent is used with respect to starting material d-d.
  • the reaction may be carried out in polar solvents such as acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in THF.
  • the reaction may be carried out at a temperature in the range of about 0°C to about 80°C.
  • the reaction may be carried out at a temperature in the range of about 0°C to about 25°C, more preferably the reaction may be carried out at a temperature of about 40°C.
  • the reaction may be carried out for a duration of about 5 hours to about 15 hours.
  • the reaction is carried out for a duration of about 10 hours to about 14 hours.
  • the present invention provides a method for synthesizing intermediate d-f as shown in the synthetic pathway below:
  • Intermediate d-e is protected to form intermediate d-f.
  • Any suitable protecting group may be used.
  • suitable protecting groups include Fmoc, BOC, or benzyl.
  • BoC is used as the protecting group.
  • the protecting group reagent may be used in excess with respect to intermediate d-e. A 1.1- times to 2-times excess of the reagent may be used with respect to intermediate d-e. Preferably, a 1.5-times excess of the reagent with respect to intermediate d-e.
  • the reaction may be carried out in a polar aprotic solvent such as ethyl acetate, dichloromethane, THF, or mixtures thereof.
  • a polar aprotic solvent such as ethyl acetate, dichloromethane, THF, or mixtures thereof.
  • the reaction is carried out in ethyl acetate.
  • the reaction may be carried out at a temperature in the range of about 10°C to about 50°C.
  • the reaction is carried out at about 25°C.
  • the reaction may be carried out for a duration of about 30 minutes to about 3 hours.
  • the reaction is carried out for a duration of about 1 hour.
  • the present invention provides a method for synthesizing intermediate d-g as shown in the synthetic pathway below:
  • Intermediate d-f is reacted with hydrogen and palladium hydroxide over carbon and is subsequently protected to form intermediate d-g.
  • the reaction is carried out under a hydrogen atmosphere at a pressure in the range of about 10 Psi to about 30 Psi.
  • the reaction is carried out at about 15 Psi.
  • the reaction may be carried out in a solvent such as trifluoroethanol, ethyl acetate, dichloromethane, THF, or mixtures thereof.
  • the reaction is carried out in trifluoroethanol.
  • about 0.05 to about 0.5 equivalents of palladium over carbon is used.
  • the reaction may be carried out at a temperature in the range of about 10°C to about 50°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a duration of about 1 hours to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours.
  • the present invention provides a method for synthesizing intermediate d-l as shown in the synthetic pathway below: N-benzyl-L-allothreonine (a) may be reacted with 2-bromopropanoic acid or 2-iodopropanoic acid to form intermediate d-l.
  • the reaction is carried out in the presence of a base, preferably a non-nucleophilic base.
  • a base preferably a non-nucleophilic base.
  • Examples that may be used for the synthesis of intermediate may include but are not limited to N-N-Diisopropylethylamine (DIPEA), 1,8-Diazabicycloundec-7-ene (DBU), 1,5- Diazabicyclo(4.3.0)non-5-ene (DBN), sodium tert-butoxide (t-BuONa) or mixtures thereof.
  • the base is sodium tert-butoxide (t-BuONa).
  • the base may be used in excess with respect to compound a. A 3-times to 7-times excess of the base may be used with respect to compound a.
  • an 5-times excess of the base is used with respect to compound a.
  • the reaction may be carried out in solvents such as solvent such as diethyl ether, benzene, toluene, chloroform, 1,4 dioxane or mixtures thereof.
  • the reaction is carried out in 1,4 dioxane.
  • the reaction may be carried out at a temperature in the range of about -10°C to about 60°C.
  • the reaction may be carried out at a temperature in the range of about 0°C to about 20°C.
  • the reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, for a duration of about 1 hours to about 3 hours.
  • the reaction is carried out for a duration of about 2 hours.
  • the present invention provides a method for synthesizing intermediate d-m as shown in the synthetic pathway below:
  • Intermediate d-l undergoes an intramolecular amide coupling reaction, optionally in the presence of a coupling reagent to form intermediate d-m.
  • Suitable coupling reagents include, but are not limited to, DCC, DIC, EDC-HCl, BOP, PyBOP, PyAOP, PyBrOP, BOP-Cl, HATU, HBTU, HCTU, TATU, TBTU, T 3 P, T 4 P, DEPBT or CDI.
  • T 4 P is used as the coupling reagent.
  • the reaction may be carried out in a polar aprotic solvent such as ethyl acetate, dichloromethane, THF, or mixtures thereof. Preferably, the reaction is carried out in ethyl acetate.
  • 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, caesium carbonate, sodium carbonate, sodium hydride, TEA or DIPEA. Preferably, the reaction is carried out in the presence of DIPEA.
  • the reaction may be carried out at a temperature in the range of about -10°C to about 153°C.
  • the reaction may be carried out at a temperature in the range of about 20°C to about 130°C or about 50°C to about 100°C. More preferably, the reaction is carried out in the range of about 0°C to about 25°C. The reaction may be carried out for a duration of about 5 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours.
  • the present invention provides a method for synthesizing intermediate d-n as shown in the synthetic pathway below: Intermediate d-m is reacted with isobutyl carbonochloridate d in the presence of a base, and a deuterated reagent or a mixture of deuterated reagents form intermediate d-n.
  • the deuterated reagent may be deuterium oxide, lithium aluminium deuteride or sodium borodeuteride or any combination thereof.
  • the deuterated reagent may be sodium borodeuteride or sodium borodeuteride and deteurium oxide.
  • the base may be triethylamine (TEA) or DIPEA.
  • the base is TEA.
  • the deuterated reagent may be used in excess with respect to starting material d-m. The excess is preferably 0.5-times to 2-times of the deuterated reagent with respect to starting material d-m. Preferably, a 1.1-times excess of the deuterated reagent is used with respect to starting material d-m.
  • the reaction may be carried out in polar solvents such as acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in THF.
  • the reaction may be carried out at a temperature in the range of about -10°C to about 60°C. Preferably, the reaction may be carried out at a temperature in the range of about 0°C to about 25°C.
  • the reaction may be carried out for a duration of about 1 hours to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours.
  • the present invention provides a method for synthesizing intermediate d-o as shown in the synthetic pathway below: Intermediate d-n is reduced by reacting with a reducing agent to form intermediate d-o.
  • the reducing agent may be borane, borane dimethyl sulfide such as but not limited to lithium aluminum hydride, boron trifluoride diethyl etherate and diborane.
  • the reducing agent is borane.
  • the reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof.
  • 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 80°C.
  • the reaction is carried out in the range of about 0°C to about 45°C.
  • the reaction may be carried out for a duration of about 30 minutes to about 5 hours.
  • the reaction is carried out for a duration of about 1 hours to about 3 hours. More preferably, the reaction is carried out for a duration of about 2.5 hours.
  • the present invention provides a method for synthesizing intermediate d-p as shown in the synthetic pathway below: Intermediate d-o is reacted with hydrogen and palladium over carbon and is subsequently protected to form intermediate d-p.
  • the reaction is carried out under a hydrogen atmosphere at a pressure in the range of about 10 Psi to about 30 Psi.
  • the reaction is carried out at about 15 Psi.
  • about 0.02 to about 0.5 equivalents of palladium over carbon is used. More preferably, about 0.05 equivalents of palladium over carbon is used.
  • Any suitable protecting group may be used form intermediate d-p.
  • suitable protecting groups that may be used include Fmoc, BOC or Ts.
  • BOC is used as the protecting group.
  • suitable protecting group reagents to form intermediate d-p include, but are not limited to, fluorenylmethyloxycarbonyl chloride, 9-fluorenylmethylsuccinimidyl carbonate, 9- fluorenylmethyloxycarbonyl azide, BOC-anhydride, tosyl chloride.
  • BOC-anhydride is used.
  • the protecting group reagent may be used in excess with respect to intermediate d-o. A 1.1- times to 2-times excess of the reagent may be used with respect to intermediate bk.
  • the reaction may be carried out in a polar aprotic solvent such as ethyl acetate, dichloromethane, THF, or mixtures thereof.
  • a polar aprotic solvent such as ethyl acetate, dichloromethane, THF, or mixtures thereof.
  • the reaction is carried out in ethyl acetate.
  • the reaction may be carried out at a temperature in the range of about 15°C to about 77°C.
  • the reaction is carried out at about 20°C.
  • the reaction may be carried out for a duration of about 10 to about 20 hours.
  • the reaction is carried out for a duration of about 16 hours.
  • the present invention provides a method for synthesizing intermediate d-q as shown in synthetic pathway below:
  • Intermediate d-p is reacted with isoindoline-1,3-dione to form intermediate d-q.
  • Isoindoline- 1,3-dione may be used in excess with respect to intermediate d-p.
  • a 1.1-times to 2-times excess of isoindoline-1,3-dione may be used with respect to intermediate bl.
  • a 1.5- times excess of isoindoline-1,3-dione is used with respect to intermediate d-p.
  • the reaction is carried out in the presence of triphenylphosphine.
  • Triphenylphosphine may be used in excess with respect to intermediate d-p.
  • a 1.1-times to 2- times excess of triphenylphosphine may be used with respect to intermediate d-p.
  • a 1.5-times excess of triphenylphosphine is used with respect to intermediate d-p.
  • the reaction is carried out in the presence of an oxidizer such as DIAD or DEAD.
  • the oxidizer DIAD is used.
  • the oxidiser may be used in excess with respect to intermediate d- p.
  • a 1.1-times to 2-times excess of the oxidiser may be used with respect to intermediate d-p.
  • a 1.5-times excess of the oxidiser is used with respect to intermediate d-p.
  • the reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof.
  • a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof.
  • 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 66°C.
  • the reaction is carried out at about 0°C to about 20°C.
  • the reaction may be carried out for a duration of about 5 to about 20 hours.
  • the reaction is carried out for a duration of about 16 hours.
  • the present invention provides a method for synthesizing intermediate d-r as shown in the synthetic pathway below: Intermediate d-q is reacted with hydrazine or hydrazine hydrate to form intermediate bn.
  • intermediate bm is reacted with hydrazine hydrate to form intermediate d-r.
  • Hydrazine or hydrazine hydrate may be used in excess with respect to intermediate d-q.
  • a 5- times to 20-times excess of hydrazine or hydrazine hydrate may be used with respect to intermediate d-q.
  • a 10-times excess of hydrazine or hydrazine hydrate is used with respect to intermediate d-q.
  • the reaction may be carried out in a polar protic solvent such as alcohols including but not limited to methanol, ethanol, isopropanol or mixtures thereof.
  • the reaction is carried out in methanol.
  • the reaction may be carried out at a temperature in the range of about 40°C to about 65°C. Preferably, the reaction is carried out at about 60°C.
  • the reaction may be carried out for a duration of about 1 to about 5 hours. Preferably, the reaction is carried out for a duration of about 2 hours.
  • 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-
  • intermediate j can be prepared starting from any of the intermediates (a) – (i).
  • 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) is prepared by: - reducing N-benzyl-L-allothreonine (a) by reacting with a reducing agent to form 2R,3S)-2-(Benzylamino)butane-1,3-diol (intermediate b); - reacting intermediate (b) with tert-butyl(chloro)diphenylsilane to form (2S,3R)-3- (Benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (intermediate c);
  • the present invention also provides a method for preparing a compound of Formula I: wherein R and Het are as herein defined above; said method comprising the steps of: (a) reacting tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate j) with a halo-substituted heteroaromatic compound in the presence of a base to form a first intermediate compound (intermediates k-a to k-s); (b) reacting the first intemediate compound with an acid to form a second intermediate compound (intermediates I-a to I-s); and (c) reacting the second intemediate compound with a carboxylic acid having a general formula R-COOH to obtain a compound of Formula I.
  • intermediate j undergoes a nucleophilic aromatic substitution reaction with a halo- substituted heteroaromatic compound to form one of intermediates k-a to k-s.
  • the intermediates k-a to k-s may be 6R,2S,3R-stereoisomer, 6S,2S,3R-stereoisomer or mixtures thereof.
  • intermediates k-a to k-s are: tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate or tert-Butyl (2S,3R,6S)-2,6-dimethyl-3-(((5- (trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate k-a); tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylate or tert-Butyl (2S,3R,6S)-2,6-dimethyl-3-(((5- (trifluoromethyl)pyrimidin-2-yl)amino
  • tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4- carboxylate is a deuterated compound.
  • 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 with a halo-substituted heteroaromatic compound in the presence of a base in step (a) to form the first intermediate compound.
  • the first intemediate compound may be reacted with an acid to form the second intermediate compound; and the second intemediate compound may be reacted with a carboxylic acid having a general formula R-COOH to obtain a deuterated compound of Formula I.
  • the present invention also provides a method for preparing compounds of Formula ID (a): wherein: R and Het are each as defined herein with respect to Formula I; and R 6 is H or deuterium (D), the method comprising the steps of: (a) reacting tert-butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4- carboxylate-5,5-d2 (d-g) with a halo-substituted heteroaromatic compound in the presence of a base to form a first intermediate compound (d-h, d-i); (b) reacting the first intermediate compound with an acid to form a second intermediate compound (d-j, d-k); and (c) reacting the second intermediate compound with a carboxylic acid having a general formula R-COOH to obtain a compound of Formula ID(a).
  • intermediate d-g may be prepared starting from any of the intermediates d-a to d- f.
  • intermediate d-g may be prepared by: - reducing (2S,3S)-2-amino-N,N-dibenzyl-3-hydroxybutanamide by reacting with a reducing agent to form (2S,3R)-3-amino-4-(dibenzylamino)butan-2-ol (d-b); - reacting intermediate d-b with 2-bromopropanoic acid to form intermediate d-c in the presence of a Lewis base to form (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-dimethylmorpholin-3
  • intermediate d-g undergoes a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of intermediates d-h and d-i.
  • intermediates d-h and d-i are: tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridin-2 yl)amino) methyl) morpholine-4-carboxylate-5,5-d2 (intermediate d-h); or tert-Butyl (2S,3R,6R)-3-(((5-chloropyridin-2-yl)amino)methyl)-2,6-dimethylmorpholine- 4-carboxylate-5,5-d2 (intermediate d-i).
  • a method for synthesizing compounds 83, 84, 96 and 97 as shown in the synthetic
  • the structure of compounds 83, 84, 96 and 97 are as shown herein above.
  • the present invention also provides a method for preparing compounds of Formula ID(b): wherein: R and Het are each as defined herein with respect to Formula I; and R 7 is H or deuterium (D); The method comprising the steps of: (a) reacting tert-butyl (2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4- carboxylate (d-r) with a halo-substituted heteroaromatic compound in the presence of a base to form a first intermediate (d-s to d-u); (b) reacting the first intermediates with an acid to form a second intermediate (d-r to d-t); and (c) reacting the second intermediates with a carboxylic acid having a general formula R- COOH to obtain a compound of Formula ID(b).
  • intermediate d-r can be prepared starting from any of the intermediates a, d-m to d-q.
  • intermediate d-r is prepared by: - reacting N-benzyl-L-allothreonine (a) with 2-bromopropanoic acid or 2- iodopropanoic, followed by an intramolecular amide coupling reaction with a coupling reaction to form (2S,3S,6R)-4-benzyl-2,6-dimethyl-5-oxomorpholine-3- carboxylic acid (intermediate d-m); - reducing intermediate d-m with a deuterated agent to form (2R,5R,6S)-4-benzyl- 5-(hydroxymethyl-d2)-2,6-dimethylmorpholin-3-one (intermediate d-n); - reducing intermediate d-n with a reducing agent to form ((2S,3R,6R)-4-benzyl-2,6- dimethylmorpholin-3
  • intermediates d-s to d-u are: tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl- d2)morpholine-4-carboxylate (intermediate d-s); tert-Butyl (2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl-d2)- 2,6-dimethylmorpholine-4-carboxylate (intermediate d-t); or tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl-d2)morpholine-4-carboxylate (intermediate d-u).
  • the halo-substituted heteroaromatic compound may be selected from the group consisting of halo-substituted pyridine, halo-substituted pyridazine, halo-substituted pyrazine, halo- substituted pyrimidine, halo-substituted triazole, halo-substituted tetrazole, halo-substituted pyrazole, halo-substituted furan, halo-substituted thiophene, halo-substituted pyrrole, halo- substituted imidazole, halo-substituted isoxazole, halo-substituted oxazole, halo-substituted isothiazole, halo-substituted thiazole and any derivatives thereof, wherein said halo- substituted heteroaromatic group may
  • the further substituents of the heteroaromatic group is CHF 2, CF 3 , cyclopropyl, methoxy, nitrile or a halogen such as chlorine, flourine.
  • the halo-substituted heteroaromatic compound may be a fluoro-substituted heteroaromatic compound, chloro-substituted heteroaromatic compound, bromo-substituted heteroaromatic compound or iodo-substituted heteroaromatic compound.
  • the halo-substituted heteroaromatic compound may be a chloro-substituted heteroaromatic compound or a fluoro- substituted heteroaromatic compound.
  • the halo-substituted heteroaromatic compound is preferably selected from 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, 2-chloro-6- (trifluoromethyl)pyrazine, 2-fluoro-4-(trifluoromethyl)pyridine, 2,3-difluoro-5- (trifluoromethyl)pyridine,3-bromo-2-fluoro-5-(trifluoromethyl)pyridine, 2-chloro-3,5- bis(trifluoromethyl)pyridine, 2-chloro-3-methoxy-5-(trifluoromethyl)pyr
  • the nucleophilic aromatic substitution reaction is carried out in the presence of a base.
  • bases that may be used include but are not limited to potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA or DIPEA.
  • the nucleophilic aromatic substitution reaction is carried out in the presence of potassium carbonate (K2CO3) or DIPEA.
  • K2CO3 or DIPEA may be used as a base for preparing non- deuterated intermediates; and DIPEA may be used as a base for preparing deuterated intermediates.
  • the base may be used in excess with respect to intermediate j, d-g or d-r.
  • a 2-times to 6-times excess of the base may be used with respect to intermediate j, d-g or d-r.
  • a 3-times excess of the base is used with respect to intermediate j, d-g or d-r .
  • the reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof.
  • the reaction is carried out in DMF or DMSO.
  • the solvent may be DMF or DMSO for preparing non-deuterated intermediates.
  • the solvent may be DMSO for preparing deuterated intermediates
  • the nucleophilic aromatic substitution reaction may be carried out at a temperature in the range of about 50°C to about 189°C.
  • the reaction is carried out at about 60 °C to about 100°C.
  • the reaction may be carried out at a temperature in the range of about 80°C to about 180°C.
  • the reaction is carried out at about 100°C to about 160°C, more preferably the reaction is carried out at about 140°C.
  • the reaction may be carried out for a duration of about 1 hour to about 5 hours.
  • the reaction is carried out for a duration of about 2 hours.
  • the reaction may be carried out under an inert atmosphere.
  • the reaction is carried out under a nitrogen atmosphere.
  • intermediates k-a to k-s, d-h, d-i, d-s, dt, d-u are deprotected by treatment with an acid to form corresponding intermediates l-a to l-s, d-j, d-k, d-v, d-w, d-x.
  • the intermediates l-a to l-s may be 6R,2S,3R-stereoisomer, 6S,2S,3R-stereoisomer or mixtures thereof.
  • intermediates l-a to l-s are: N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2- amine hydrochloride or N-(((2S,3R,6S)-2,6-Dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyrazin-2-amine hydrochloride (intermediate l-a); N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2- amine hydrochloride or N-(((2S,3R,6S)-2,6-dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyrimidin-2-amine hydrochloride (intermediate l-b); N-(((2S,3R,6R)-2,6-Dimethylmorpholin
  • intermediates d-j and d-k are: N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyridin- 2-amine (intermediate d-j); 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl-5,5-d2)methyl)pyridin-2-amine hydrochloride (intermediate d-k).
  • intermediates d-v, d-w, and d-x are: N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl)pyridin-2- amine hydrochloride (intermediate d-v); N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl-d2)-3-fluoro-5-(trifluoromethyl) pyridin-2-amine hydrochloride (intermediate d-w); N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl-d2)-3-methyl-5-(trifluoromethyl) pyridin-2-amine hydrochloride (intermediate d-x).
  • hydrochloric acid is used for the deprotection of intermediates k-a to k-s, d-h, d-i, d-s, d-t, d-u.
  • the deprotection may be carried out in a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1,4-dioxane or mixtures thereof.
  • the reaction is carried out in 1,4-dioxane.
  • Intermediates k-a to k-s, d-h, d-i, d-s, d-t, d-u is preferably reacted with 4M HCl in 1,4 dioxane.
  • An excess of 4M HCl in 1,4-dioxane may be used with respect to intermediates k-a to k-s, d- h, d-i, d-s, d-t, d-u.
  • a 15-times to 40-times excess of 4M HCl in 1,4-dioxane may be used with respect to intermediates k-a to k-s, d-h, d-i, d-s, d-t, d-u.
  • a 30-times excess of 4M HCl in 1,4-dioxane is used with respect to intermediates k-a to k-s, d-h, d-i, d-s, d-t, d- u.
  • the deprotection may be carried out at a temperature in the range of about 12°C to about 40°C.
  • the reaction is carried out at about 25 °C.
  • the deprotection may be carried out at a temperature in the range of about 10°C to about 40°C.
  • the reaction is carried out at about 20 °C.
  • the deprotection may be carried out for a duration of about 30 mins to about 5 hours.
  • the reaction is carried out for a duration of about 1 hour.
  • the deprotection may be carried out for a duration of about 1 hours to about 4 hours.
  • the reaction is carried out for a duration of about 2 hours.
  • intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x are reacted with carboxylic acid having the general formula R-COOH to form compounds 1-120 disclosed herein; wherein R is selected from the group consisting of a five or a six membered aromatic or heteroaromatic group, wherein the aromatic group or heteroaromatic group is either unsubstituted or is substituted with one or more substituents.
  • R in the compound of Formula I comprises a five membered heteroaromatic group which is an unsubstituted pyrazole, an unsubstituted oxazole, an unsubstituted thiazole, an unsubstituted imidazole, a substituted pyrazole, a substituted oxazole, a substituted thiazole, a substituted imidazole or a derivative thereof; or a six membered aromatic group which is unsubstituted aryl, or substituted aryl, or a derivative thereof.
  • the carboxylic acid R-COOH preferably comprises 4-(4-chlorophenyl)-1-methyl-pyrazole-3- carboxylic acid (CAS 1534651-22-3), 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS 956317-36-5), 3-fluoro-2-(pyrimidin-2-yl)benzoic acid (CAS 1293285-04-7), 4-(5- chloropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (CAS 2125741-28-6), 4-(5- fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (CAS 2125741-56-0), 5- fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS 1186050-64-5), 5-fluoro-2-(pyrimidin-2- yl)benzoic acid (CAS 1293284-57-7), 5-methyl
  • the carboxylic acid may be used in excess with respect to intermediates l-a to l-s, d-j, d-k, d-v, d-w, d-x.
  • a 1.2-times to 3-times excess of the carboxylic acid may be used with respect to intermediates l-a to l-s, d-j, d-k, d-v, d-w, d-x.
  • a 1.5-times excess of the carboxylic acid is used with respect to intermediates l-a to l-s, d-j, d-k, d-v, d-w, d-x.
  • the reaction of intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x with carboxylic acid R-COOH may be carried out in the presence of a coupling reagent.
  • Suitable coupling reagents include but are not limited to DCC, DIC, EDC-HCl, BOP, PyBOP, PyAOP, PyBrOP, BOP-Cl, HATU, HBTU, HCTU, TATU, TBTU, T3P, T4P, DEPBT or CDI.
  • HATU or T4P is used as the coupling reagent.
  • the coupling reagent may be used in excess with respect to intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x.
  • a 1.2-times to 3-times excess of the coupling reagent may be used with respect to intermediates I-a to I-s, d-j, d-k,d-v, d-w,d-x.
  • a 1.5-times excess of the coupling reagent is used with respect to intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x.
  • the reaction of intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x with carboxylic acid R-COOH may be carried out in the presence of a base.
  • a base Any suitable base may be used for this reaction.
  • suitable bases include but are not limited DIPEA or TEA.
  • DIPEA is used as the base in the reaction.
  • the base may be used in excess with respect to intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x.
  • a 2-times to 6-times excess of the base may be used with respect to intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x.
  • a 4-times excess of the base is used with respect to intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x.
  • the reaction of intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x with carboxylic acid R-COOH may be carried out in a polar aprotic solvent such as THF, dichloromethane, ethyl acetate, DMF or DMSO. Preferably the reaction is carried out in dichloromethane.
  • the reaction of intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x with carboxylic acid R-COOH may be carried out at a temperature in the range of about -10°C to about 40°C. Preferably, the reaction is carried out from about 0°C to about 20°C.
  • the reaction of intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x with carboxylic acid R-COOH may be carried out for a duration of about 1 hours to about 6 hours. Preferably, the reaction is carried out for a duration of about 2 hours.
  • the present invention also provides a method for synthesizing carboxylic acid with general formula R-COOH as shown in the synthetic pathway below:
  • the R-COOH group may be 4-(5-Methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.
  • the starting material selected from tert-butyl 4-iodo-1-methyl-1H-pyrazole-3-carboxylate, tert- butyl 4-bromo-1-methyl-1H-pyrazole-3-carboxylate, or tert-butyl 4-chloro-1-methyl-1H- pyrazole-3-carboxylate may be reacted with (4-cyanophenyl)boronic acid or derivatives thereof (for example boronic esters or organotrifluoroborate salts), via Suzuki coupling to form an intermediate.
  • the starting material selected from tert-butyl 4-iodo-1-methyl-1H-pyrazole-3- carboxylate, tert-butyl 4-bromo-1-methyl-1H-pyrazole-3-carboxylate, or tert-butyl 4-chloro-1- methyl-1H-pyrazole-3-carboxylate may be reacted with 4-cyanophenyl derivatives that are suitable for Hiyama coupling, Stille coupling, Heck coupling, Kumada coupling or Negishi coupling. (4-cyanophenyl)boronic acid or derivatives thereof may be used in excess with respect to the starting material.
  • a 1.1-times to 1.5-times excess of (4-cyanophenyl)boronic acid or derivatives thereof may be used with respect to the starting material.
  • a 1.2-times excess of (4- cyanophenyl)boronic acid or derivatives thereof is used with respect to the starting material.
  • the reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO, a polar protic solvent such as water, methanol, ethanol, isopropanol, a non-polar solvent such as chloroform, 1,4-dioxane or any combination thereof.
  • the reaction is carried out in a combination of THF and water.
  • the reaction may be carried out in the presence of a catalyst.
  • the catalyst is a palladium compound.
  • palladium compounds include but are not limited to Pd(dtbpf)Cl 2 , Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd(dppf)Cl 2 , or Pd(dppp)Cl 2 .
  • Pd(dtbpf)Cl 2 is used as the catalyst.
  • about 0.02 to about 0.5 equivalents of the catalyst is used with respect to the starting material. More preferably, about 0.05 equivalents of the catalyst is used.
  • the reaction may be carried out in the presence of a base.
  • bases examples include but are not limited to K2CO3, KO t Bu, Cs2CO3, K3PO4, NaOH, or NEt3.
  • K3PO4 is used.
  • the base may be used in excess with respect to the starting material.
  • a 2-times to 6-times excess of the base may be used with respect to the starting material.
  • Preferably, a 3-times excess of the base is used with respect to the starting material.
  • the reaction may be carried out at a temperature in the range of about 50 °C to about 100 °C.
  • the reaction is carried out at about 80 °C.
  • the reaction may be carried out for a duration of about 30 mins to about 5 hours.
  • the reaction is carried out for a duration of about 2 hours.
  • the reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.
  • the intermediate formed may be deprotected by reacting with an acid. Examples of acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid. Preferably, hydrochloric acid is used.
  • the deprotection may be carried out in a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1,4-dioxane or mixtures thereof. Preferably the reaction is carried out in 1,4-dioxane.
  • the deprotection may be carried out at a temperature in the range of about 20°C to about 80°C.
  • the reaction is carried out at about 50°C.More preferably, the reaction is carried out at about 20°C.
  • the deprotection may be carried out for a duration of about 30 mins to about 5 hours. Preferably, the reaction is carried out for a duration of about 2 hours.
  • the present invention also provides an alternative method for synthesizing carboxylic acid with general formula R-COOH as shown in the synthetic pathway below:
  • the R-COOH group may be 4-(5-Cyanopyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid.
  • the starting material (3-(tert-butoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)boronic acid, 3-(tert- butoxycarbonyl)-1-methyl-5-(methyl-d3)-1H-pyrazol-4-yl)boronic acid or derivatives thereof (for example boronic esters or organotrifluoroborate salts) may be reacted with compounds selected from 6-iodopyridine-3-carbonitrile, 6-bromopyridine-3-carbonitrile, 6-chloropyridine- 3-carbonitrile or 2-bromo-5-fluoro-pyrimidine, via Suzuki coupling to form an intermediate.
  • the starting material may be reacted with (3-(tert-butoxycarbonyl)-1-methyl-1H- pyrazol-4-yl) derivatives that are suitable for Hiyama coupling, Stille coupling, Heck coupling, Kumada coupling or Negishi coupling.
  • the compounds selected from 6-iodopyridine-3-carbonitrile, 6-bromopyridine-3-carbonitrile, 6-chloropyridine-3-carbonitrile or 2-bromo-5-fluoro-pyrimidine may be used in excess with respect to the starting material.
  • a 1.1-times to 1.5-times excess of may be used with respect to the starting material.
  • a 1.2-times excess of is used with respect to the starting material.
  • the reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO, a polar protic solvent such as water, methanol, ethanol, isopropanol, a non-polar solvent such as chloroform, 1,4-dioxane or any combination thereof.
  • a polar aprotic solvent such as THF, DMF, DMSO
  • a polar protic solvent such as water, methanol, ethanol, isopropanol
  • a non-polar solvent such as chloroform, 1,4-dioxane or any combination thereof.
  • 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.
  • the catalyst is a palladium compound.
  • Examples of such palladium compounds include but are not limited to Pd(dtbpf)Cl 2 , Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd(dppf)Cl 2 , or Pd(dppp)Cl 2 . More preferably, Pd(dtbpf)Cl 2 is used as the catalyst. Preferably, about 0.02 to about 0.5 equivalents of the catalyst is used with respect to the starting material. Preferably, about 0.05 equivalents of the catalyst is used. The reaction may be carried out in the presence of a base.
  • the reaction is carried out for a duration of about 2 hours.
  • the reaction may be carried out under an inert atmosphere.
  • the reaction is carried out under a nitrogen atmosphere.
  • the intermediate formed may be deprotected by reacting with an acid.
  • acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid.
  • hydrochloric acid is used.
  • the deprotection may be carried out in a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1,4-dioxane or mixtures thereof.
  • the reaction is carried out in 1,4-dioxane.
  • the deprotection may be carried out at a temperature in the range of about 10°C to about 50°C. Preferably, the reaction is carried out at about 20°C. The deprotection may be carried out for a duration of about 6 hours to about 18 hours. Preferably, the reaction is carried out for a duration of about 12 hours.
  • the method for synthesizing carboxylic acid with general formula R-COOH is shown in the synthetic pathway below: Preferably the R-COOH may be 4-(5-Methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3- carboxylic acid.
  • the starting material (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazol-4-yl)boronic acid or derivatives thereof (for example boronic esters or organotrifluoroborate salts) may be reacted with compounds selected from 2-iodo-5-methoxy-pyridine, 2-bromo-5-methoxy-pyridine or 2- chloro-5-methoxy-pyridine, via Suzuki coupling to form an intermediate.
  • the starting material may be reacted with (3-(tert-butoxycarbonyl)-1,5-dimethyl- 1H-pyrazol-4-yl) derivatives that are suitable for Hiyama coupling, Stille coupling, Heck coupling, Kumada coupling or Negishi coupling.
  • the reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO, a polar protic solvent such as water, methanol, ethanol, isopropanol, a non-polar solvent such as chloroform, 1,4-dioxane or any combination thereof.
  • a polar aprotic solvent such as THF, DMF, DMSO
  • a polar protic solvent such as water, methanol, ethanol, isopropanol
  • a non-polar solvent such as chloroform, 1,4-dioxane or any combination thereof.
  • the reaction is carried out in a combination of DMF and water.
  • the reaction may be carried out in the presence of a catalyst.
  • 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 P
  • Pd(PPh3)4 is used as the catalyst.
  • about 0.02 to about 0.5 equivalents of the catalyst is used with respect to the starting material.
  • about 0.05 equivalents of the catalyst is used.
  • the reaction may be carried out in the presence of a base.
  • bases include but are not limited to K2CO3, KO t Bu, Cs2CO3, K3PO4, NaOH, or NEt3.
  • K3PO4 is used.
  • the base may be used in excess with respect to the starting material. A 1.1- times to 5-times excess of the base may be used with respect to the starting material. Preferably, a 1.5-times excess of the base is used with respect to the starting material.
  • the reaction may be carried out at a temperature in the range of about 50°C to about 100°C. Preferably, the reaction is carried out at about 80°C.The reaction may be carried out for a duration of 2 hours to about 16 hours. Preferably, the reaction is carried out for a duration of about 12 hours.
  • the reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.
  • the intermediate formed may be deprotected by reacting with an acid. Examples of acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid. Preferably. hydrochloric acid is used.
  • the deprotection may be carried out in a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1,4-dioxane or mixtures thereof.
  • a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1,4-dioxane or mixtures thereof.
  • the reaction is carried out in 1,4-dioxane.
  • the deprotection may be carried out at a temperature in the range of about 10°C to about 50°C.
  • the reaction is carried out at about 20°C.
  • the deprotection may be carried out for a duration of about 6 hours to about 18 hours.
  • the reaction is carried out for a duration of about 12 hours.
  • the present invention also provides another alternative method for synthesizing carboxylic acid with general formula R-COOH as shown in the synthetic pathway below:
  • the R-COOH may be 5-(5-fluoropyrimidin-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid.
  • the 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 may be converted to an organostannane intermediate by reacting with hexaalkylditin such as hexamethylditin or hexabutylditin.
  • the hexaalkylditin may be used in excess with respect to the starting material.
  • a 1.2-times to 5-times excess of may be used with respect to the starting material.
  • Preferably, a 2-times excess of is used with respect to the starting material.
  • the reaction may be carried out in a non-polar solvent such as chloroform, 1,4-dioxane, or toluene.
  • a non-polar solvent such as chloroform, 1,4-dioxane, or toluene.
  • the reaction is carried out in toluene.
  • the reaction may be carried out in the presence of a catalyst.
  • 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 the catalyst is used with respect to the starting material.
  • the reaction may be carried out at a temperature in the range of about 50°C to about 120°C. Preferably, the reaction is carried out in the range of about 100°C to about 120°C. The reaction may be carried out for a duration of about 3 mins to about 10 hours. Preferably, the reaction is carried out for a duration of about 6 hours.
  • the reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.
  • the organostannane intermediate may be reacted with compounds selected from 2-bromo-5- fluoro-pyrimidine, 2-iodo-5-fluoro-pyrimidine or 2-chloro-5-fluoro-pyrimidine, via Stille coupling to form a second intermediate.
  • compounds selected from 2-bromo-5-fluoro-pyrimidine, 2-iodo-5-fluoro- pyrimidine or 2-chloro-5-fluoro-pyrimidine may be reacted with 1-methyl-1H-imidazole-4- carboxylate derivatives that are suitable for Hiyama coupling, Suzuki coupling, Heck coupling, Kumada coupling or Negishi coupling.
  • Compounds selected from 2-bromo-5-fluoro-pyrimidine, 2-iodo-5-fluoro-pyrimidine or 2- chloro-5-fluoro-pyrimidine may be used in excess with respect to the organostannane intermediate.
  • a 1.1-times to 3-times excess of may be used with respect to the organostannane intermediate.
  • a 1.5-times excess of is used with respect to the the organostannane intermediate.
  • the reaction may be carried out in a non-polar solvent such as chloroform, 1,4-dioxane, xylene or toluene.
  • the reaction is carried out in xylene.
  • the reaction may be carried out in the presence of a catalyst.
  • the catalyst is a palladium compound.
  • 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.
  • Pd(PPh3)4 is used as the catalyst.
  • about 0.02 to about 0.5 equivalents of the catalyst is used with respect to the organostannane intermediate.
  • about 0.1 equivalents of the catalyst is used.
  • the reaction may be carried out at a temperature in the range of about 50°C to about 140°C.
  • the reaction is carried out at about 120°C.
  • the reaction may be carried out for a duration of about 10 hours to about 22 hours.
  • the reaction is carried out for a duration of 16 hours.
  • the reaction may be carried out under an inert atmosphere.
  • the reaction is carried out under a nitrogen atmosphere.
  • the second intermediate may be deprotected by reacting with an acid or a base.
  • acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid.
  • bases that may be used include but are not limited to lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • hydrochloric acid is used.
  • the deprotection may be carried out in neat acid or base.
  • the concentration of the acid or base may range from about 3 M to about 10 M. Preferably, a concentration of about 6 M is used.
  • the deprotection may be carried out at a temperature in the range of about 50°C to about 100°C. Preferably, the reaction is carried out at about 80°C.The deprotection may be carried out for a duration of about 6 hours to about 22 hours. Preferably, the reaction is carried out for a duration of about 16 hours.
  • the present invention also provides yet another alternative method for synthesizing carboxylic acid with general formula R-COOH as shown in the synthetic pathway below:
  • the R-COOH may be 5-(5-Methoxypyridin-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid.
  • the 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 may be reacted with tributyl-(5-methoxy-2-pyridyl)stannane or derivatives thereof (for example trimethyl-(5-methoxy-2-pyridyl)stannane), via Stille coupling to form an intermediate.
  • 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 may be reacted with 5-methoxy-2-pyridyl derivatives that are suitable for Hiyama coupling, Suzuki coupling, Heck coupling, Kumada coupling or Negishi coupling.
  • Tributyl-(5-methoxy-2-pyridyl)stannane or derivatives thereof may be used in excess with respect to the starting material.
  • a 1.1-times to 1.5-times excess of tributyl-(5-methoxy-2- pyridyl)stannane or derivatives thereof may be used with respect to the starting material.
  • a 1.2-times excess of tributyl-(5-methoxy-2-pyridyl)stannane or derivatives thereof is used with respect to the starting material.
  • the reaction may be carried out in a non-polar solvent such as chloroform, 1,4-dioxane, xylene or toluene.
  • the reaction is carried out in xylene.
  • the reaction may be carried out in the presence of a catalyst.
  • the catalyst is a palladium compound.
  • Examples of such palladium compounds include but are not limited to Pd(dtbpf)Cl 2 , Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd(dppf)Cl 2 , or Pd(dppp)Cl 2 . More preferably, Pd(PPh 3 ) 4 is used as the catalyst. Preferably about 0.02 to about 0.5 equivalents of the catalyst is used with respect to the starting material. Preferably, about 0.1 equivalents of the catalyst is used.
  • the reaction may be carried out at a temperature in the range of about 50°C to about 140°C. Preferably, the reaction is carried out at about 140°C.
  • the reaction may be carried out for a duration of about 10 hours to about 20 hours. Preferably, the reaction is carried out for a duration of about 16 hours.
  • the reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.
  • the intermediate may be deprotected by reacting with an acid or a base. Examples of acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid. Examples of bases that may be used include but are not limited to lithium hydroxide, sodium hydroxide or potassium hydroxide. Preferably, hydrochloric acid is used. The deprotection may be carried out in neat acid or base. The concentration of the acid or base may range from about 3 M to about 10 M.
  • a concentration of about 6 M is used.
  • the deprotection may be carried out at a temperature in the range of about 50°C to about 100°C.
  • the reaction is carried out at about 80°C.
  • the deprotection may be carried out for a duration of about 6 hours to about 22 hours.
  • the reaction is carried out for a duration of about 16 hours.
  • the present invention also provides yet another alternative method for synthesizing carboxylic acid with general formula R-COOH as shown in the synthetic pathway below:
  • the R-COOH may be 4-(5-Fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.
  • the 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 may be used. Examples of suitable protecting groups that may be used include Me, BOC or benzyl. Preferably, BOC is used as the protecting group. Examples of suitable reagents to form the first intermediate include but are not limited to, BOC- anhydride, MeOH, benzyl alcohol or 2-benzyloxy-1-methylpyridinium triflate.
  • BOC- anhydride is used.
  • the reagent may be used in excess with respect to the first intermediate.
  • a 1.5-times to 5- times excess of the reagent may be used with respect to the first intermediate.
  • the reaction may be carried out in the presence of a catalyst such as DMAP, imidazole or mixtures thereof.
  • a catalyst such as DMAP, imidazole or mixtures thereof.
  • imidazole is used as the catalyst.
  • the reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO, a polar protic solvent such as water, methanol, ethanol, isopropanol, tert-butyl alcohol, a non-polar solvent such as chloroform, 1,4-dioxane or any combinations thereof.
  • a polar aprotic solvent such as THF, DMF, DMSO
  • a polar protic solvent such as water, methanol, ethanol, isopropanol, tert-butyl alcohol, a non-polar solvent such as chloroform, 1,4-dioxane or any combinations thereof.
  • the reaction is carried out in a combination of THF and tert-butyl alcohol.
  • the reaction may be carried out at a temperature in the range of about 10°C to about 50°C.
  • the reaction is carried out at about 20°C.
  • the reaction may be carried out for a duration of about 6 to about 18 hours
  • the first intermediate may be converted into a boronic acid or derivatives thereof (for example boronic esters or organotrifluoroborate salts) to form a second intermediate.
  • the first intermediate may be reacted with a tri(alkyl)borate such as trimethylborate, tributylborate or triisopropylborate to form the second intermediate.
  • the tri(alkyl)borate may be used in excess with respect to the first intermediate.
  • a 1.2-times to 3-times excess of tri(alkyl)borate may be used with respect to the first intermediate.
  • a 1.5-times excess of tri(alkyl)borate is used with respect to the first intermediate.
  • the reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof.
  • a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof.
  • the reaction is carried out in THF.
  • the reaction is carried out in the presence of a Lewis base.
  • Lewis bases that may be used for the synthesis of the second intermediate include but are not limited to butyl lithium, lithium diisopropylamide (LDA), lithium diethylamide (LDEA), sodium amide (NaNH2), sodium hydride (NaH), lithium bis(trimethylsilyl)amide, or mixtures thereof.
  • the Lewis base used in the synthesis of the second intermediate is butyl lithium.
  • the Lewis base may be used in excess with respect to the first intermediate.
  • a 1.2-times to 3- times excess of the Lewis base may be used with respect to the first intermediate.
  • a 1.5-times excess of the Lewis base is used with respect to the first intermediate.
  • the reaction may be carried out at a temperature b in the range of about -78°C to about 60°C.
  • the reaction is carried out at about -78°C to about 20°C.
  • the reaction may be carried out for a duration of about 1 hour to about 8 hours.
  • the reaction is carried out for a duration of about 3 hours.
  • the second intermediate may be reacted with may be reacted with 2-bromo-5-fluoro- pyrimidine or 2-iodo-5-fluoro-pyrimidine or 2-chloro-5-fluoro-pyrimidine, via Suzuki coupling to form a third intermediate.
  • 2-bromo-5-fluoro-pyrimidine or 2-iodo-5-fluoro-pyrimidine or 2-chloro-5-fluoro- pyrimidine may be reacted with (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazol-4-yl) derivatives that are suitable for Hiyama coupling, Stille coupling, Heck coupling, Kumada coupling or Negishi coupling.
  • 2-bromo-5-fluoro-pyrimidine or 2-iodo-5-fluoro-pyrimidine or 2-chloro-5-fluoro-pyrimidine may be used in excess with respect to the second intermediate.
  • a 1.1-times to 3-times excess of may be used with respect to the second intermediate.
  • the reaction may be carried out in a polar aprotic solvent such as DMF, DMSO or mixtures thereof; in a polar protic solvent such as water, methanol, ethanol, isopropanol, tert-butyl alcohol, or any combination thereof.
  • the reaction is carried out in a combination of DMF and water.
  • the reaction may be carried out in the presence of a catalyst.
  • the catalyst is a palladium compound.
  • 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.
  • Pd(PPh3)4 is used as the catalyst.
  • about 0.02 to about 0.5 equivalents of the catalyst is used with respect to the second intermediate.
  • about 0.05 equivalents of the catalyst is used.
  • the reaction may be carried out in the presence of a base.
  • bases examples include but are not limited to K2CO3, KO t Bu, Cs2CO3, K3PO4, NaOH, or NEt3.
  • K2CO3 is used.
  • the base may be used in excess with respect to the second intermediate. A 1.1-times to 3-times excess of the base may be used with respect to the second intermediate. Preferably, a 1.5-times excess of the base is used with respect to the second intermediate.
  • the reaction may be carried out at a temperature in the range of about 50°C to about 153°C. Preferably, the reaction is carried out at about 80°C.The reaction may be carried out for a duration of about 8 hours to about 20 hours. Preferably, the reaction is carried out for a duration of about 12 hours.
  • the reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere.
  • the third intermediate formed may be deprotected by reacting with an acid. Examples of acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid. Preferably hydrochloric acid is used.
  • the deprotection may be carried out in a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1,4-dioxane or mixtures thereof. Preferably the reaction is carried out in 1,4-dioxane.
  • the deprotection may be carried out at a temperature in the range of about 20°C to about 80°C.
  • the reaction is carried out at about 20°C.
  • the deprotection may be carried out for a duration of about 8 hours to about 20 hours.
  • the reaction is carried out for a duration of about 12 hours.
  • the present invention also provides a method for preparing 3-(5-Fluoropyrimidin-2-yl)-5,6- dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid, as shown in the scheme below: Bromine may be added to a solution of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid in a solvent.
  • Examples of a solvent include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or a mixture thereof.
  • 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.
  • the reaction is carried out at about 0 °C.
  • the reaction may be carried out for a duration of about 30 minutes to about 4 hours.
  • the reaction may be carried out for a duration of about 2 hours.
  • the reaction mixture may be quenched by addition of saturated sodium thiosulfate aqueous solution to give 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid.
  • 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid may be reacted with 2-tert- butyl-3-isopropyl-1,1-dimethyl-isourea in a solvent.
  • a solvent include but are not limited to THF, DMF, DMSO or mixtures thereof.
  • the solvent is carried out in THF.
  • the reaction may be carried out at a temperature in the range of about -10°C to about 40°C. Preferably, the reaction is carried out in the range of at about 0 °C to about 20 °C.
  • the reaction may be carried out for a duration of about 10 hours to about 20 hours. Preferably, the reaction is carried out for a duration of about 16 hours.
  • the reaction mixture may be quenched by addition of saturated ammonium chloride aqueous solution to give tert-butyl 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate.
  • Tert-butyl 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate may be reacted with triisopropyl borate in a solvent.
  • a solvent include but are not limited to THF, DMF, DMSO or mixtures thereof.
  • 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.
  • the reaction is carried out in the range of at about 0 °C to about 20 °C.
  • n-BuLi may then be added.
  • the reaction may be carried out at a temperature in the range of about -100°C to about -50°C.
  • the reaction is carried out at about -78°C
  • the reaction may be carried out for a duration of about 30 minutes to about 4 hours.
  • the reaction is carried out for a duration of about 2 hours.
  • the reaction mixture may then be quenched by addition saturated ammonium chloride aqueous solution as described above to give (2-(tert-butoxycarbonyl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)boronic acid.
  • (2-(tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)boronic acid may be added to 2-bromo-5-fluoro-pyrimidine in the presence of a base.
  • Examples of a base that may be used include but are not limited to potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA or DIPEA, or mixtures thereof.
  • the base is potassium carbonate.
  • the reaction may be carried out in a solvent such as THF, DMF, DMSO, water or mixtures thereof.
  • the solvent is DMF and water.
  • the reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C.
  • Tetrakis(triphenylphosphine)palladium(0) may be added to give tert-butyl 3-(5- fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate.
  • the reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.
  • the reaction may be carried out at a temperature in the range of about 50°C to about 150°C. Preferably, the reaction is carried out at about 80°C.
  • the reaction may be carried out for a duration of about 10 hours to about 16 hours. Preferably, the reaction is carried out for a duration of about 12 hours.
  • Tert-butyl 3-(5-fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate may be treated with an acid to produce 3-(5-Fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazole-2-carboxylic acid.
  • acids that may be used include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid or mixtures thereof.
  • hydrochloric acid is used.
  • the reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof.
  • a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof.
  • the solvent is dioxane.
  • the reaction may be carried out at a temperature in the range of about 10°C to about 40°C.
  • the reaction is carried out at about 20 °C.
  • the reaction may be carried out for a duration of about 30 minutes to about 3 hours.
  • the reaction is carried out for a duration of about 1 hour.
  • 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.
  • Iodocopper and Tetrakis(triphenylphosphine)palladium(0) may 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 mixture may be purified to give methyl 3-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H- pyrazole-4-carboxylate. Preferably, it is purified by column chromatograph on silica gel.
  • Lithium hydroxide monohydrate may be added to methyl 3-(5-fluoropyridin-2-yl)-1,5-dimethyl- 1H-pyrazole-4-carboxylate in the presence of one or more solvents to give to give 3-(5- fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-4-carboxylic acid.
  • solvents include but are not limited to THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, dioxane or mixtures thereof.
  • 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 duration of about 1 hours to about 3 hours. Preferably, the reaction is carried out for a duration of about 2 hours.
  • 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 scheme below: 3,5-difluoropicolinonitrile may be added to 2H-triazole in the presence of a solvent and a base.
  • solvents include but are not limited to acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof.
  • the solvent is acetonitrile.
  • bases examples include but are not limited to potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA or DIPEA, or mixtures thereof.
  • 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 duration of about 10 hours to about 16 hours. Preferably, the reaction is carried out for a duration of about 12 hours.
  • the product may be purified to give 5-fluoro-3-(2H-1,2,3-triazol-2-yl)picolinonitrile. Preferably it is purified by flash silica gel chromatography.
  • 5-fluoro-3-(2H-1,2,3-triazol-2-yl)picolinonitrile may be stirred in an acid to give 5-Fluoro-3-(2H- 1,2,3-triazol-2-yl)picolinic acid.
  • acids include but are not limited to phosphoric acid, hydrochloric acid, trifluoroacetic acid or mixtures thereof.
  • 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.
  • the reaction is carried out at about 110 °C.
  • the reaction may be carried out for a duration of about 3 hours to about 7 hours.
  • the reaction is carried out for a duration of about 5 hours.
  • the present invention also provides a method for preparing 5-Fluoro-3-(5-fluoropyrimidin-2- yl)picolinic acid as shown in the scheme below:
  • (5-fluoropyrimidin-2-yl)-trimethyl-stannane may be added to methyl 3-bromo-5- fluoropicolinate and caesium fluoride in a solvent.
  • solvent include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or mixtures thereof.
  • the reaction is carried out in DMF.
  • Iodocopper and palladiumtriphenylphosphane may 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 duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.
  • the reaction mixture may be purified to give methyl 5-fluoro-3-(5-fluoropyrimidin-2- yl)picolinate. Preferably it is purified by column chromatograph on silica gel.
  • Lithium hydroxide monohydrate may be added to methyl 5-fluoro-3-(5-fluoropyrimidin-2- yl)picolinate in the presence of one or more solvents to give 5-fluoro-3-(5-fluoropyrimidin-2- yl)picolinic acid.
  • solvents include but are not limited to THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, dioxane or mixtures thereof.
  • 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 duration of about 1 hours to about 3 hours.
  • the reaction is carried out for a duration of about 2 hours.
  • the present invention also provides a method for preparing 5,6-Dimethyl-3-(pyrimidin-2- yl)picolinic acid, as shown in the scheme below:
  • 3-bromo-5,6-dimethylpyridin-2-amine may be added to tributyl(pyrimidin-2-yl)stannane in a solvent and caesium fluoride.
  • solvents include but are not limited to as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof.
  • the solvent is dioxane.
  • Iodocopper and palladiumtriphenylphosphane may be added to the mixture.
  • the reaction may be carried out at a temperature in the range of about 70°C to about 130°C. Preferably, the reaction is carried out at about 100 °C.
  • the reaction may be carried out for a duration of about 13 hours to about 19 hours.
  • the reaction is carried out for a duration of about 16 hours.
  • the residue may be purified to give 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-amine.
  • it is purified by column chromatography on silica gel.
  • 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-amine may be added to an acid or a combination of the acids.
  • Example of acids may be sulfuric acid, acetic acid, phosphoric acid, hydrochloric acid, trifluoroacetic acid, or a mixture thereof.
  • the acid is sulfuric acid and acetic acid.
  • a solution of sodium nitrite in water may be added to give 5,6-Dimethyl-3-(pyrimidin-2- yl)pyridin-2-ol.
  • the reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C.
  • the reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours.
  • 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-ol (1.4 g, 6.96 mmol, 1 eq) may be added to trifluoromethylsulfonyl trifluoromethanesulfonate in the presence of a solvent and a base to give residue 5,6-Dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl trifluoromethanesulfonate.
  • a solvent that may be used include but are not limited to THF, dichloromethane, ethyl acetate, DMF or DMSO or mixtures thereof.
  • the solvent is dichloromethane.
  • bases examples include but are not limited to potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA or DIPEA or mixtures thereof.
  • the base is DIPEA.
  • the reaction may be carried out at a temperature in the range of about 0°C to about 60°C. Preferably, the reaction is carried out at about 30°C.
  • the reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.
  • Bis(diphenylphosphino)ferrocene)palladium(II) dichloride may be added to 5,6- dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl trifluoromethanesulfonate in the presence of a solvent and a base to give methyl 5,6-dimethyl-3-(pyrimidin-2-yl)picolinate.
  • bases include but are not limited to potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA, DIPEA or mixtures thereof.
  • the base is TEA.
  • solvents include but are not limited to THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, dioxane or mixtures thereof.
  • solvent is methanol.
  • the reaction may be carried out at a temperature in the range of about 50°C to about 100°C. Preferably, the reaction is carried out at about 70°C.
  • the reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.
  • the reaction may be carried out in the presence of carbon monoxide at a pressure of 50 psi.
  • Lithium hydroxide monohydrate may be added to methyl 5,6-dimethyl-3-(pyrimidin-2- yl)picolinate in the presence of one or more solvents.
  • solvents include but are not limited to THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, dioxane or mixtures thereof.
  • 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.
  • the reaction is carried out at about 20°C.
  • the reaction may be carried out for a duration of about 1 hours to about 5 hours.
  • the reaction is carried out for a duration of about 3 hours.
  • the present invention also provides a method for preparing 4,6-Dimethyl-3-(pyrimidin-2- yl)picolinic acid, as shown in the scheme below:
  • 5-bromo-2,4-dimethylpyridine may be reacted with a mixture of tributyl(pyrimidin-2- yl)stannane, caesium fluoride, iodocopper and Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh 3 ) 4 ) in the presence of a solvent.
  • solvents include but are not limited to diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof.
  • 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.
  • the reaction is carried out at about 100°C.
  • the reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.
  • the crude product may be purified to give 2-(4,6-dimethylpyridin-3-yl)pyrimidine. Preferably, purification may be carried out by column chromatography on silica gel. Meta-chloroperoxybenzoic acid is added to a solution of 2-(4,6-dimethylpyridin-3-yl)pyrimidine in the presence of a solvent. Examples of solvent include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in dichloromethane.
  • the reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a duration of about 30 minutes hours to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours.
  • the reaction mixture may be quenched by addition of sodium sulfite to give 2,4-dimethyl-5- (pyrimidin-2-yl)pyridine 1-oxide. Trimethylsilyl cyanide may be added to 2,4-dimethyl-5-(pyrimidin-2-yl)pyridine 1-oxide in a solvent.
  • solvent may include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or mixtures thereof.
  • the solvent is dichloromethane.
  • the reaction may be carried out at a temperature in the range of about 0°C to about 40°C.
  • the reaction is carried out at about 20°C.
  • the reaction may be carried out for a duration of about 30 minutes to about 3 hours.
  • the reaction is carried out for a duration of about 1 hours.
  • N,N-dimethylcarbamoyl chloride may then be added.
  • the reaction may be carried out at a temperature in the range of about 0°C to about 40°C.
  • the reaction is carried out at about 20°C.
  • the reaction may be carried out for a duration of 14 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 17 hours.
  • Sodium hydroxide may be added to 4,6-dimethyl-3-(pyrimidin-2-yl)picolinonitrile in the presence of one or more solvents to give 4,6-Dimethyl-3-(pyrimidin-2-yl)picolinic acid.
  • solvents include but are not limited to THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, dioxane or mixtures thereof.
  • 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.
  • the reaction is carried out at about 60°C.
  • the reaction may be carried out for a duration of 36 hours to about 60 hours.
  • the reaction is carried out for a duration of about 48 hours.
  • the present invention also provides a method for preparing 6-Methyl-3-(pyrimidin-2- yl)pyrazine-2-carboxylic acid, as shown in the scheme below: 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane may be added to methyl 6-bromo-3- chloropyrazine-2-carboxylate in the presence of a solvent and a base.
  • solvents include but are not limited to as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof.
  • the solvent is dioxane.
  • bases include but are not limited to potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA or DIPEA, or mixtures thereof.
  • the base is potassium carbonate.
  • Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)Cl2) may then 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 duration of 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours.
  • Tributyl(pyrimidin-2-yl)stannane may be reacted with a mixture of methyl 3-chloro-6- methylpyrazine-2-carboxylate, caesium fluoride, iodocopper and Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh 3 ) 4 ) in the presence of a solvent.
  • solvent examples include but are not limited to THF, dichloromethane, ethyl acetate, DMF or DMSO.
  • the reaction is carried out in dichloromethane.
  • the reaction may be carried out in nitrogen.
  • the reaction may be carried out at a temperature in the range of about 100°C to about 140°C.
  • the reaction is carried out at about 120°C.
  • the reaction may be carried out for a duration of 3 hours to about 9 hours.
  • the reaction is carried out for a duration of about 6 hours.
  • Methyl 6-methyl-3-(pyrimidin-2-yl)pyrazine-2-carboxylate may be treated with an acid to produce 6-Methyl-3-(pyrimidin-2-yl)pyrazine-2-carboxylic acid.
  • acids include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid.
  • hydrochloric acid is used.
  • the reaction may be carried out at a temperature in the range of about 40°C to about 120°C.
  • the reaction is carried out at about 80°C.
  • the reaction may be carried out for a duration of 30 minutes to about 4 hours.
  • the reaction is carried out for a duration of about 2 hours.
  • the reaction may be carried out at a temperature in the range of about 40°C to about 100°C. Preferably, the reaction is carried out at about 70°C. The reaction may be carried out for a duration of 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.
  • Methyl 3-bromo-6-methylpicolinate may be added to tributyl(pyrimidin-2-yl)stannane, cesium fluoride, iodocopper, tetrakis(triphenylphosphine)palladium(0) in the presence of a solvent.
  • solvents include but are not limited to as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof.
  • the solvent is dioxane.
  • the reaction may be carried out at a temperature in the range of about 60°C to about 140°C. Preferably, the reaction is carried out at about 100°C.
  • the reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.
  • 3-chlorobenzenecarboperoxoic acid may be added to methyl 6-methyl-3-(pyrimidin-2- yl)picolinate in a solvent.
  • solvent examples include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or mixtures thereof.
  • 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.
  • the reaction is carried out at about 30°C.
  • the reaction may be carried out for a duration of about 13 hours to about 19 hours.
  • the reaction is carried out for a duration of about 16 hours.
  • the reaction mixture may be quenched by addition of a saturated sodium sulfite solution.
  • Phosphoryl chloride may be added to 2-(methoxycarbonyl)-6-methyl-3-(pyrimidin-2-yl)pyridine 1-oxide to form methyl 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinate.
  • the reaction may be carried out at a temperature in the range of about 90°C to about 150°C. Preferably, the reaction is carried out at about 120°C.
  • the reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours.
  • Lithium hydroxide monohydrate may be added to methyl 4-chloro-6-methyl-3-(pyrimidin-2- yl)picolinate in the presence of one or more solvents.
  • solvents include but are not limited to THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, 1,4- dioxane or mixtures thereof.
  • 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.
  • the reaction is carried out at about 20°C.
  • the reaction may be carried out for a duration of about 13 hours to about 19 hours.
  • the reaction is carried out for a duration of about 16 hours.
  • the present invention also provides a method for preparing 6-(Methyl-d3)-3-(pyrimidin-2- yl)picolinic acid, as shown in the scheme below:
  • Tributyl(pyrimidin-2-yl)stannane may be reacted with a mixture of methyl 6-amino-3- bromopicolinate, caesium fluoride, iodocopper and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh 3 ) 4 ) in the presence of a solvent.
  • solvent include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or combinations thereof.
  • the reaction is carried out in dichloromethane.
  • 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. Pyridine may be added into the mixture under an argon atmosphere. The reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a duration of about 15 minutes to about 1 hour. Preferably, the reaction is carried out for a duration of about 30 minutes.
  • the reaction is carried out at about 25°C.
  • the reaction may be carried out for a duration of about 30 minutes to about 4 hours.
  • the reaction is carried out for a duration of about 2 hours.
  • Methyl 6-(methyl-d3)-3-(pyrimidin-2-yl)picolinate may then be added to an acid and water.
  • acids include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid.
  • hydrochloric acid is used.
  • the reaction may be carried out at a temperature in the range of about 40°C to about 120°C.
  • the reaction is carried out at about 80°C.
  • the reaction may be carried out for a duration of about 9 hours to about 15 hours.
  • the reaction is carried out for a duration of about 12 hours.
  • the present invention also provides a method for preparing 6-(Methyl-d3)-3-(2H-1,2,3-triazol- 2-yl)picolinic acid hydrochloride.
  • 2H-triazole, caesium carbonate, N1,N2-dimethylcyclohexane-1,2-diamine, iodocopper may be added to a solution of 3-bromo-6-chloropicolinic acid in a solvent.
  • solvents include but are not limited to diethyl ether, benzene, toluene, chloroform, dioxane, methanol or mixtures thereof.
  • the solvents are dioxane and water.
  • the reaction may be carried out at a temperature in the range of about 80°C to about 120°C. Preferably, the reaction is carried out at about 100°C. The reaction may be carried out for a duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours.
  • 2-tert-butyl-1,3-diisopropyl-isourea may be added to 6-chloro-3-(2H-1,2,3-triazol-2-yl)picolinic acid in the presence of a solvent.
  • solvents include but are not limited to acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in THF.
  • the reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours.
  • Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)Cl2), tripotassium phosphate and tert-butyl 6-chloro-3-(2H-1,2,3-triazol-2-yl)picolinate may be added to (methyl- d3)boronic acid in the presence of a solvent to give methyl 5,6-dimethyl-3-(pyrimidin-2- yl)picolinate.
  • solvents include but are not limited to water, acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof.
  • the reaction is carried out in THF and water.
  • the reaction may be carried out at a temperature in the range of about 40°C to about 120°C. Preferably, the reaction is carried out at about 80°C. The reaction may be carried out for a duration of about 2 hours to about 6 hours. Preferably, the reaction is carried out for a duration of about 4 hours.
  • Tert-butyl 6-(methyl-d3)-3-(2H-1,2,3-triazol-2-yl)picolinate be treated with an acid to produce 6-(Methyl-d3)-3-(2H-1,2,3-triazol-2-yl)picolinic acid hydrochloride in the presence of a solvent.
  • acids include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid.
  • hydrochloric acid is used.
  • solvents include but are not limited to as diethyl ether, benzene, toluene, chloroform, dioxane, methanol or mixtures thereof.
  • 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.
  • the reaction is carried out at about 60 °C.
  • the reaction may be carried out for a duration of about 1 hours to about 4 hours.
  • the reaction is carried out for a duration of about 2 hours.
  • the present invention also provides a method for preparing 4-(5-Fluoropyrimidin-2-yl)-1- methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylic acid as shown in the scheme below: 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid may be added to Di-tert-butyl dicarbonate, tert-butyl alcohol and 4-Dimethylaminopyridine in the presence of a solvent.
  • solvents include but are not limited to water, acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof.
  • 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 duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours.
  • Tert-butyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate may be reacted with n-BuLi trideuterio(iodo)methane in a suitable solvent.
  • solvents include but are not limited to THF, DMF, DMSO or mixtures thereof.
  • the reaction is carried out in THF.
  • the reaction may be carried out at a temperature in the range of about -10°C to about 40°C. Preferably, the reaction is carried out in the range of at about 0 °C to about 20 °C. n-BuLi may then be added. The reaction may be carried out at a temperature in the range of about -100°C to about -50°C. Preferably, the reaction is carried out at about -78°C The reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours. The reaction mixture may be quenched by addition of saturated ammonium chloride solution.
  • N-Bromosuccinimide may added to a solution of tert-butyl 1-methyl-5-(methyl-d3)-1H- pyrazole-3-carboxylate in a solvent.
  • solvents include but are not limited to THF, DMF, DMSO or mixtures thereof.
  • 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.
  • the reaction is carried out at about 20 °C.
  • the reaction may be carried out for a duration of about 9 hours to about 15 hours.
  • the reaction is carried out for a duration of about 12 hours.
  • Isopropylmagnesium chloride lithium chloride may be added to tert-butyl 4-bromo-1-methyl-5- (methyl-d3)-1H-pyrazole-3-carboxylate in a solvent.
  • solvents include but are not limited to THF, DMF, DMSO or mixtures thereof.
  • 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.
  • the reaction is carried out at about -50 °C.
  • the reaction may be carried out for a duration of about 30 minutes to about 2 hours.
  • the reaction is carried out for a duration of about 1 hour.
  • Triisopropyl borate may then be added to the reaction mixture.
  • the reaction may be carried out at a temperature in the range of about -80°C to about -20°C. Preferably, the reaction is carried out at about -50 °C. The reaction may be carried out for a duration of about 1 hours to about 5 hours. Preferably, the reaction is carried out for a duration of about 3 hours.
  • 2-bromo-5-fluoro-pyrimidine and potassium carbonate may be added to (3-(tert- butoxycarbonyl)-1-methyl-5-(methyl-d3)-1H-pyrazol-4-yl)boronic acid in a solvent.
  • solvents include but are not limited to water, THF, DMF, DMSO or mixtures thereof.
  • the reaction is carried out in THF and water.
  • Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh 3 ) 4 ) may then be added.
  • the reaction may be carried out at a temperature in the range of about 60°C to about 120°C. Preferably, the reaction is carried out at about 90 °C.
  • the reaction may be carried out for a duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours.
  • 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.
  • the reaction is carried out at about 20 °C.
  • the reaction may be carried out for a duration of about 5 hours to about 11 hours.
  • the reaction is carried out for a duration of about 8 hours.
  • the present invention also provides a method for preparing 4-(5-Fluoropyridin-2-yl)-5-methyl- 1-(methyl-d3)-1H-pyrazole-3-carboxylic acid as shown in the scheme below: 2-bromo-5-fluoro-pyridine, potassium carbonate, and tetrakis(triphenylphosphine) palladium(0) (Pd(PPh 3 ) 4 ) may be added to (3-(tert-butoxycarbonyl)-5-methyl-1-(methyl-d3)- 1H-pyrazol-4-yl)boronic acid in the presence of one or more solvents.
  • solvents include but are not limited to water, acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof.
  • the reaction is carried out in DMF and water.
  • the reaction may be carried out under an inert atmosphere.
  • 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.
  • the reaction is carried out at about 80°C
  • the reaction may be carried out for a duration of about 10 hours to about 16 hours.
  • the reaction is carried out for a duration of about 12 hours.
  • the product may be purified to give tert-butyl 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)- 1H-pyrazole-3-carboxylate.
  • the product is purified by column chromatography on silica gel.
  • Tert-butyl 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate may be treated with an acid to produce 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3- carboxylic acid.
  • acids include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid or mixtures thereof.
  • hydrochloric acid is used.
  • the reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof.
  • 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.
  • the reaction is carried out at about 20 °C.
  • the reaction may be carried out for a duration of about 13 hours to about 19 hours.
  • the reaction is carried out for a duration of about 16 hours.
  • the present invention also provides a method for preparing 4-(5-Fluoropyrimidin-2-yl)-5- methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid as shown in the scheme below:
  • the reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 2 hours to about 4 hours. Preferably, the reaction is carried out for a duration of about 3 hours.
  • the mixture may be quenched with saturated ammonium chloride solution.
  • the product may be purified to give ethyl 4-bromo-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate. Preferably, it is purified by column chromatography on silica gel.
  • the reaction may be carried out at a temperature in the range of about 20°C to about 80°C. Preferably, the reaction is carried out at about 50°C. The reaction may be carried out for a duration of 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours.
  • Triisopropyl borate may be added to tert-butyl 4-bromo-5-methyl-1-(methyl-d3)-1H-pyrazole- 3-carboxylate in the presence of a solvent.
  • solvents include but are not limited to THF, DMF, DMSO or mixtures thereof.
  • the solvent is THF.
  • n-BuLi may then be added to give (3-(tert-Butoxycarbonyl)-5-methyl-1-(methyl-d3)-1H- pyrazol-4-yl)boronic acid.
  • the reaction may be carried out at a temperature in the range of about -100°C to about -50°C. Preferably, the reaction is carried out at about -78°C
  • the reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours.
  • the reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere.
  • the reaction mixture may be quenched by addition of saturated ammonium chloride solution to obtain (3-(tert-Butoxycarbonyl)-5-methyl-1-(methyl-d3)-1H-pyrazol-4-yl)boronic acid.
  • 2-bromo-5-fluoro-pyrimidine and potassium carbonate may be added to 3-(tert- butoxycarbonyl)-5-methyl-1-(methyl-d3)-1H-pyrazol-4-yl)boronic acid in the presence of one or more solvents.
  • solvents include but are not limited to water, THF, DMF, DMSO or mixtures thereof.
  • the solvents are DMF and water.
  • the reaction may be carried out under an inert atmosphere.
  • the reaction is carried out under an argon atmosphere.
  • Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) may then be added.
  • the reaction may be carried out at a temperature in the range of about 40°C to about 120°C.
  • the reaction is carried out at about 80 °C.
  • the reaction may be carried out for a duration of about 9 hours to about 15 hours.
  • the reaction is carried out for a duration of about 12 hours.
  • the mixture was stirred at 80°C for 12 hours.
  • the product may be purified to give tert-butyl 4-(5-fluoropyrimidin-2-yl)-5-methyl-1-(methyl- d3)-1H-pyrazole-3-carboxylate.
  • Tert-butyl 4-(5-fluoropyrimidin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate may be treated with an acid to produce 4-(5-fluoropyrimidin-2-yl)-5-methyl-1-(methyl-d3)-1H- pyrazole-3-carboxylic acid.
  • acids include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid or mixtures thereof.
  • hydrochloric acid is used.
  • the reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof.
  • a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof.
  • 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.
  • the reaction is carried out at about 20 °C.
  • the reaction may be carried out for a duration of about 13 hours to about 19 hours.
  • the reaction is carried out for a duration of about 16 hours.
  • Example 3 Synthesis of (R)-2-(((2S,3R)-3-(Benzylamino)-4-((tert- butyldiphenylsilyl)oxy)butan-2-yl)oxy)propanoic acid (d) To a solution of (2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (5 g, 11.53 mmol, 1 eq) in tetrahydrofuran (100 mL) was added (2S)-2-bromopropanoic acid (7.06 g, 46.12 mmol, 4 eq). The solution was cooled to 0°C.
  • MS mode was positive electrospray ionization. MS range was 50-2000.
  • Mobile phase A was 0.04% Trifluoroacetic acid in water
  • mobile phase B was 0.02% Trifluoroacetic acid in HPLC grade acetonitrile. The gradient was 5-95% B in1.50 min .5% B in 0.01 min, 5-95% B (0.01-0.70 min), 95% B (0.70-1.16min),95-5% B (1.16-1.17min) with a hold at 5% B for 0.33 min. The flow rate was 1.5 mL/min).
  • Example 6 Synthesis of ((2S,3R,6R)-4-Benzyl-2,6-dimethylmorpholin-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 eq) in tetrahydrofuran (25 mL) was added tetrabutylammonium fluoride trihydrate (1 M, 7.92 mL, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 2hrs. LCMS showed all the starting materials were consumed; desired MW was detected.
  • Example 8 Synthesis of tert-Butyl (2S,3R,6R)-3-((1,3-dioxoisoindolin-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 eq) in tetrahydrofuran (6.50 mL) was added isoindoline- 1,3-dione (566.78 mg, 3.85 mmol, 1.5 eq) and PPh 3 (1.01 g, 3.85 mmol, 1.5 eq) at 0°C.
  • MS range was 50-2000.
  • Mobile phase A was 0.04% Trifluoroacetic acid in water
  • mobile phase B was 0.02% Trifluoroacetic acid in HPLC grade acetonitrile.
  • the gradient was 5-95% B in1.50 min .5% B in 0.01 min, 5-95% B (0.01-0.70 min), 95% B (0.70-1.16min),95-5% B (1.16-1.17min) with a hold at 5% B for 0.33 min.
  • the flow rate was 1.5 mL/min).
  • 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 eq) in methanol (26 mL) was added NH2NH2.H2O (869.03 mg, 17.36 mmol, 842.08 ⁇ L, 10 eq). The mixture was stirred at 60°C for 2 hrs.
  • MS range was 50-2000.
  • Mobile phase A was 0.04% Trifluoroacetic acid in water
  • mobile phase B was 0.02% Trifluoroacetic acid in HPLC grade acetonitrile.
  • the gradient was 5-95% B in1.50 min .5% B in 0.01 min, 5-95% B (0.01-0.70 min), 95% B (0.70-1.16min),95-5% B (1.16-1.17min) with a hold at 5% B for 0.33 min.
  • the flow rate was 1.5 mL/min).
  • Example 10 Synthesis of tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5- (trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate (k-a), general procedure To a solution of tert-butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate (200 mg, 736.71 ⁇ mol, 1 eq) in dimethyl formamide (4 mL) was added K 2 CO 3 (203.63 mg, 1.47 mmol, 2 eq) and 2-chloro-5-(trifluoromethyl)pyrazine (201.71 mg, 1.11 mmol, 1.5 eq) at 25°C.
  • K 2 CO 3 203.63 mg, 1.47 mmol, 2 eq
  • 2-chloro-5-(trifluoromethyl)pyrazine 201.71 mg,
  • Example 11 Synthesis of tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylate (k-b), general procedure To a solution of tert-butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate (250 mg, 1.02 mmol, 1 eq) in DMSO (5 mL) was added 2-chloro-5-(trifluoromethyl)pyrimidine (280.15 mg, 1.53 mmol, 1.5 eq) and DIPEA (396.72 mg, 3.07 mmol, 534.66 ⁇ L, 3 eq) at 25°C.
  • 2-chloro-5-(trifluoromethyl)pyrimidine 280.15 mg, 1.53 mmol, 1.5 eq
  • DIPEA 396.72 mg
  • Mobile phase A was 0.04% Trifluoroacetic acid in water, and mobile phase B was 0.02% Trifluoroacetic acid in HPLC grade acetonitrile.
  • the gradient was 5-95% B in 1.50 min, 5% B in 0.01 min, 5-95% B (0.01-0.70 min), 95% B (0.70-1.16min), 95-5% B (1.16-1.17min) with a hold at 5% B for 0.33 min.
  • the flow rate was 1.5 mL/min.
  • the following intermediates were prepared.
  • Example 12 Synthesis of tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylate (k-c)
  • General procedure (see Example 10) used for making the compound (k-a) 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.
  • Example 13 Synthesis of tert-Butyl (2S,3R,6R)-3-(((5-chloropyridin-2-yl)amino)methyl)- 2,6-dimethylmorpholine-4-carboxylate (k-d)
  • General procedure (see Example 10) used for making the compound (k-a) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 5- chloro-2-fluoropyridine. Yield 43%, colourless oil.
  • Example 14 Synthesis of tert-Butyl (2S,3R,6R)-3-(((5-chloropyrimidin-2- yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (k-e)
  • General procedure (see Example 11) used for making the compound (k-b) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2,5- dichloropyrimidine. Yield 68%, white solid.
  • Example 15 Synthesis of tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((4- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylate (k-f)
  • General procedure (see Example 11) used for making the compound (k-b) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2- chloro-4-(trifluoromethyl)pyrimidine. Yield 59%, white solid.
  • LCMS (ESI+): m/z 391.2 (M+1), RT: 0.789 min.
  • Example 16 Synthesis of tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((6- (trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate (k-q)
  • General procedure (see Example 10) used for making tert-Butyl (2S,3R,6R)-2,6-dimethyl-3- (((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate (k) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2- chloro-6-(trifluoromethyl)pyrazine.
  • Example 19 Synthesis of tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5- (trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylate ( k-j)
  • General procedure (see Example 11) used for making the compound (k-b) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 3- bromo-2-fluoro-5-(trifluoromethyl)pyridine to give the title compound. Yield 75%, yellow solid.
  • Example 20 Synthesis of tert-butyl (2S,3R,6R)-3-(((3,5-bis(trifluoromethyl)pyridin-2- yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (k-k)
  • General procedure (see Example 11) used for making the compound (k-b) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2- chloro-3,5-bis(trifluoromethyl)pyridine. Yield 94%, yellow oil.
  • Example 21 Synthesis of tert-butyl (2S,3R,6R)-3-(((3-methoxy-5- (trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (k-l)
  • General procedure (see Example 11) used for making the compound (k-b) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2- chloro-3-methoxy-5-(trifluoromethyl)pyridine. Yield 34%, white solid.
  • Example 22 Synthesis of tert-Butyl (2S,3R,6R)-3-(((3-chloro-5-(trifluoromethyl)pyridin- 2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (k-m)
  • General procedure (see Example 10) used for making the compound (k-a) 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.
  • Example 24 Synthesis of tert-Butyl (2S,3R,6R)-3-(((3-cyano-5-(trifluoromethyl)pyridin- 2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (k-o)
  • General procedure (see Example 11) used for making the compound (k-b) 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.
  • Example 25 Synthesis of tert-Butyl (2S,3R,6R)-3-(((3-(difluoromethyl)-5- (trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (k- p)
  • General procedure (see Example 11) used for making the compound (k-b) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2- chloro-3-(difluoromethyl)-5-(trifluoromethyl)pyridine. Yield 80%, yellow solid.
  • Example 26 Synthesis of tert-Butyl (2S,3R,6R)-3-(((5-chloro-3-fluoropyridin-2- yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (k-q)
  • General procedure (see Example 11) used for making the compound (k-b) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 5- chloro-2,3-difluoropyridine. Yield 85%, white solid.
  • Example 27 Synthesis of tert-Butyl (2S,3R,6R)-3-(((3-fluoro-4-methyl-5- (trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (k-r)
  • General procedure (see Example 10) used for making the compound (k-a) 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.
  • Example 28 Synthesis of tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((4-methyl-5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylate (k-s)
  • General procedure (see Example 11) used for making the compound (k-b) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2,4- dichloro-5-(trifluoromethyl)pyrimidine to give tert-butyl (2S,3R,6R)-3-(((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate.
  • Example 29 Synthesis of N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyrazin-2-amine hydrochloride (l-a), general procedure To a solution of tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate (150 mg, 345.80 ⁇ mol, 1 eq) in dioxane (0.5 mL) was added HCl/dioxane (4 M, 2.60 mL, 30.11 eq) at 25°C.
  • MS range was 50-2000.
  • Mobile phase A was 0.04% Trifluoroacetic acid in water
  • mobile phase B was 0.02% Trifluoroacetic acid in HPLC grade acetonitrile.
  • the gradient was 5-95% B in 1.50 min, 5% B in 0.01 min, 5-95% B (0.01-0.70 min), 95% B (0.70-1.16min), 95-5% B (1.16-1.17min) with a hold at 5% B for 0.33 min.
  • the flow rate was 1.5 mL/min).
  • the following intermediates were prepared.
  • Example 30 Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyrimidin-2-amine hydrochloride (l-b) General procedure (see Example 29) used for making the compound (l-a) was repeated, using tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylate (l). Yield 99%, white solid.
  • Detection method was diode array (DAD).
  • MS mode was positive electrospray ionization. MS range was 50-2000.
  • Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC grade acetonitrile. The gradient was 10-100% B in 0.90 min, 10% B in 0.01 min, 10- 100% B (0.01-0.50 min) with a hold at 100% B for 0.40 min.
  • the flow rate was 2.0 mL/min).
  • Example 31 Synthesis of N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine hydrochloride (l-c)
  • General procedure (see Example 29) used for making the compound (l-a) was repeated, using tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl) morpholine-4-carboxylate (k-c). Yield 96%, yellow solid.
  • Example 32 Synthesis of 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3- yl)methyl)pyridin-2-amine hydrochloride (l-d)
  • General procedure (see Example 29) used for making the compound (l-a) was repeated, using tert-Butyl (2S,3R,6R)-3-(((5-chloropyridin-2-yl)amino)methyl)-2,6-dimethylmorpholine-4- carboxylate (k-d). Yield 99%, yellow solid.
  • LCMS (ESI+): m/z 256.3 (M+1), RT: 0.328 min (Column Halo C183.0*30mm, 5um.
  • Detection method was diode array (DAD). MS mode was positive electrospray ionization. MS range was 50-2000. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC grade acetonitrile. The gradient was 10-100% B in 0.90 min, 10% B in 0.01 min, 10- 100% B (0.01-0.50 min) with a hold at 100% B for 0.40 min. The flow rate was 2.0 mL/min).
  • Example 33 Synthesis of 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3- yl)methyl)pyrimidin-2-amine hydrochloride (l-e) General procedure (see Example 29) used for making the compound (l-a)was repeated, using tert-Butyl (2S,3R,6R)-3-(((5-chloropyrimidin-2-yl)amino)methyl)-2,6-dimethylmorpholine-4- carboxylate (k-e). Yield 85%, white solid.
  • Example 34 Synthesis of N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-4- (trifluoromethyl)pyrimidin-2-amine hydrochloride (l-f)
  • General procedure (see Example 29) used for making the compound (l-a)was repeated, using tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((4-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylate (k-f). Yield 97%, white solid.
  • LCMS (ESI+): m/z 291.3 (M+1), RT: 0.476 min.
  • Example 35 Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-6- (trifluoromethyl)pyrazin-2-amine hydrochloride (l-g)
  • General procedure (see Example 29) used for making the compound (l-a) was repeated, using tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((6-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate (k-g). Yield 81%, white solid.
  • Example 36 Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-4- (trifluoromethyl)pyridin-2-amine hydrochloride (l-h)
  • General procedure (see Example 29) used for making the compound (l-a was repeated, using tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((4-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylate (k-h). Yield 94%, colourless oil.
  • Example 37 Synthesis of N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-3-fluoro- 5-(trifluoromethyl)pyridin-2-amine hydrochloride (l-i)
  • General procedure (see Example 29) used for making the compound (l-a) was repeated, using tert-butyl (2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (k-i). Yield 99%, yellow solid.
  • Example 38 Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-methyl- 5-(trifluoromethyl)pyridin-2-amine (l-j), general procedure tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylate (1.1 g, 2.73 mmol, 1 eq) was dissolved in HCl/dioxane (4 M, 11 mL, 16.14 eq). The mixture was stirred at 25°C for 1 hr.
  • Example 39 N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-3,5-bis(trifluoro methyl)pyridin-2-amine hydrochloride (l-k)
  • General procedure (see Example 29) used for making the compound (l-a) was repeated, using tert-butyl (2S,3R,6R)-3-(((3,5-bis(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6-dimethyl morpholine-4-carboxylate (k-k). Yield 82%, yellow solid.
  • Example 40 N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-3-methoxy-5- (trifluoromethyl)pyridin-2-amine (l-l)
  • General procedure (see Example 38) used for making the compound (l-j) was repeated, using tert-butyl (2S,3R,6R)-3-(((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (k-l).Yield 95%, yellow solid.
  • Example 41 3-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine (l-m)
  • General procedure (see Example 38) used for making the compound (l-j) was repeated, using tert-butyl (2S,3R,6R)-3-(((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (k-m). Yield 99%, yellow solid.
  • Example 42 N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-methyl-5- (trifluoromethyl)pyrazin-2-amine (l-n)
  • General procedure (see Example 38) used for making the compound (l-j) was repeated, using tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate (k-n). Yield 96%, yellow oil.
  • Example 51 Synthesis of tert-butyl (2S,3R,6R)-3-((dibenzylamino)methyl)-2,6- dimethylmorpholine-4-carboxylate-5,5-d2 (d-f)
  • (2R,5R,6S)-5-((dibenzylamino)methyl)-2,6-dimethylmorpholin-3-one 8.5 g, 23.86 mmol, 1 eq
  • LiAlD 4 (3.01 g, 71.58 mmol, 4.09 mL, 3 eq) was added dropwise under N 2 at 0°C. Then the reaction was stirred at 40°C for 12 hours.
  • Example 52 Synthesis of tert-butyl (2S,3R,6R)-3-(aminomethyl)-2,6- dimethylmorpholine-4-carboxylate-5,5-d2 (d-g) 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 eq) in Trifluoroethanol (300 mL) Pd(OH)2 (1.56 g, 2.23 mmol, 20% purity, 0.1 eq) was added under argon.
  • Example 53 Synthesis of tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylate-5,5-d2 (d-h)
  • a solution of tert-butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate- 5,5-d2 (1 g, 3.65 mmol, 1 eq) in DMSO (20 mL) DIPEA (1.42 g, 10.96 mmol, 1.91 mL, 3 eq) and 2-fluoro-5-(trifluoromethyl)pyridine (723.77 mg, 4.38 mmol, 1.2 eq) was added.
  • Example 54 tert-Butyl (2S,3R,6R)-3-(((5-chloropyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate-5,5-d2 (d-i)
  • the titled compound (d-i) was prepared in analogy to the procedure described for compound (d-h) using 5-chloro-2-fluoropyridine. Yield 58%, colourless oil.
  • Example 55 Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl-5,5-d2)methyl)-5- (trifluoromethyl)pyridin-2-amine (d-j)
  • d-j A solution of tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylate-5,5-d2 (1.1 g, 2.81 mmol, 1 eq) in HCl/dioxane (4 M, 11 mL, 15.66 eq) was stirred at 20°C for 1 hr.
  • Example 56 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl-5,5- d2)methyl)pyridin-2-amine hydrochloride (d-k)
  • the titled compound was prepared in analogy to the procedure described for compound (d-j) using (2S,3R,6R)-3-(((5-chloropyridin-2-yl)amino)methyl)-2,6-dimethylmorpholine-4- carboxylate-5,5-d2. Yield 95%, yellow solid.
  • Example 57 Synthesis of (2S,3S,6R)-4-benzyl-2,6-dimethyl-5-oxomorpholine-3- carboxylic acid (d-m)
  • benzyl- L-allothreonine 40 g, 90.80 mmol, 1 eq
  • (2S)-2-bromopropanoic acid 41.67 g, 272.41 mmol, 3 eq
  • reaction was quenched by HCl/dioxane (4 N), adjust pH to 3 and concentrated.
  • the residue was dissolved in ethyl acetate (400 mL), and added DIPEA (35.21 g, 272.41 mmol, 47.45 mL, 3 eq), then T 4 P (130.85 g, 181.61 mmol, 50% purity, 2 eq) into the solution at 0°C.
  • the mixture was stirred at 25°C for 12 hrs. LCMS showed all the starting materials were consumed; desired mass was detected.
  • the reaction mixture was poured into aq. HCl (1 N), adjusted to pH 7, extracted with ethyl acetate (1000 mL x 3).
  • Example 58 Synthesis of (2R,5R,6S)-4-benzyl-5-(hydroxymethyl-d2)-2,6- dimethylmorpholin-3-one (d-n) To a solution of (2S,3S,6R)-4-benzyl-2,6-dimethyl-5-oxomorpholine-3-carboxylic acid (4 g, 15.19 mmol, 1 eq) in THF (80 mL) was added TEA (2.31 g, 22.79 mmol, 3.17 mL, 1.5 eq).
  • Example 59 Synthesis of ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholin-3-yl)methan-d2- ol (d-o)
  • the (2R,5R,6S)-4-benzyl-5-(hydroxymethyl-d2)-2,6-dimethylmorpholin-3-one (1.4 g, 5.57 mmol, 1 eq) in THF (2.8 mL) was added into the stirred solution of BH 3 .THF (1 M, 14.21 mL, 2.55 eq) at 0°C.
  • the reaction was warmed to 45°C and stirred for 2.5 hrs.
  • LCMS showed all the starting materials were consumed, desired mass was detected.
  • Example 60 Synthesis of tert-butyl (2S,3R,6R)-3-(hydroxymethyl-d2)-2,6- dimethylmorpholine-4-carboxylate (d-p) To a solution of ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholin-3-yl)methan-d2-ol (0.6 g, 2.53 mmol, 1 eq) in EtOAc (12 mL) was added Pd/C (134.52 mg, 126.40 ⁇ mol, 10% purity, 0.05 eq), (Boc)2O (827.61 mg, 3.79 mmol, 871.17 ⁇ L, 1.5 eq).
  • Example 61 Synthesis of tert-butyl (2S,3R,6R)-3-((1,3-dioxoisoindolin-2-yl)methyl)-2,6- dimethylmorpholine-4-carboxylate-5,5-d2 (d-q)
  • tert-butyl (2S,3R,6R)-3-(hydroxymethyl-d2)-2,6-dimethylmorpholine-4- carboxylate 0.6 g, 2.30 mmol, 1 eq
  • isoindoline-1,3-dione 508.63 mg, 3.46 mmol, 1.5 eq
  • PPh 3 PPh 3 (906.73 mg, 3.46 mmol, 1.5 eq) at 0°C
  • DIAD 699.03 mg, 3.46 mmol, 670.21 ⁇ L, 1.5 eq
  • Example 62 Synthesis of tert-butyl (2S,3R,6R)-3-(aminomethyl-d2)-2,6- dimethylmorpholine-4-carboxylate (d-r) 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 eq) in MeOH (18 mL) was added NH 2 NH 2 .H 2 O (801.88 mg, 16.02 mmol, 777.02 ⁇ L, 10 eq).
  • Example 63 tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl-d2)morpholine-4-carboxylate (d-s), general procedure To a solution of tert-butyl (2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4- carboxylate (140 mg, 454.65 ⁇ mol, 1 eq) in DMSO (3 mL) was added DIPEA (176.28 mg, 1.36 mmol, 237.57 ⁇ L, 3 eq) 2-fluoro-5-(trifluoromethyl)pyridine (90.07 mg, 545.58 ⁇ mol, 1.2 eq).
  • Example 64 tert-Butyl (2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridin-2- yl)amino)methyl-d2)-2,6-dimethylmorpholine-4-carboxylate (d-t)
  • the titled compound (d-t) was prepared in analogy to the procedure described for compound (d-t) using tert-butyl (2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4-carboxylate and 2,3-difluoro-5-(trifluoromethyl)pyridine Yield 86%, light yellow oil.
  • Example 65 tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridin- 2-yl)amino)methyl-d2)morpholine-4-carboxylate (d-u)
  • General procedure (see Example 19) used for making the compound (k-j) was repeated, using tert-butyl (2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4-carboxylate and 3- bromo-2-fluoro-5-(trifluoromethyl)pyridine to give the title compound.Yield 87%, colourless oil.
  • Example 66 N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl-d2)-5- (trifluoromethyl)pyridin-2-amine hydrochloride (d-v)
  • d-v A solution of tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl-d2)morpholine-4-carboxylate (140 mg, 357.67 ⁇ mol, 1 eq) in HCl/dioxane (4 M, 2.79 mL, 31.23 eq). The mixture was stirred at 25°C for 1hr.
  • Example 67 N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl-d2)-3-fluoro-5- (trifluoromethyl)pyridin-2-amine hydrochloride (d-w)
  • the titled compound (d-w) was prepared in analogy to the procedure described for compound (d-v) using tert-butyl (2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl- d2)-2,6-dimethylmorpholine-4-carboxylate Yield 83%, white solid.
  • Example 68 N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl-d2)-3-methyl-5- (trifluoromethyl)pyridin-2-amine hydrochloride (d-x)
  • the titled compound (d-x) was prepared in analogy to the procedure described for compound (d-v) using tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl-d2)morpholine-4-carboxylate Yield 90%, white solid.
  • Example 69 Synthesis of 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid To a solution of tert-butyl 4-iodo-1-methyl-1H-pyrazole-3-carboxylate (1.5 g, 4.87 mmol, 1 eq) in THF (60 mL) and H2O (15 mL) was added (4-cyanophenyl)boronic acid (929.95 mg, 6.33 mmol, 1.3 eq), K 3 PO 4 (3.10 g, 14.60 mmol, 3 eq) and Pd(dtbpf)Cl 2 (158.65 mg, 243.42 ⁇ mol, 0.05 eq).
  • Example 70 Synthesis of 4-(5-Cyanopyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid
  • Example 71 Synthesis of 5-(5-Fluoropyrimidin-2-yl)-1-methyl-1H-imidazole-4- carboxylic acid
  • Pd (PPh3)4 (1.06 g, 913.09 ⁇ mol, 0.1 eq)
  • trimethyl(trimethylstannyl)stannane 5.98 g, 18.26 mmol, 3.79 mL, 2 eq
  • Methyl 5-(5-fluoropyrimidin-2-yl)-1-methyl-1H-imidazole-4-carboxylate (600 mg, 1.78 mmol, 1 eq) was dissolved in 6N HCl (12 mL) at 20°C, then the mixture was stirred at 80°C for 2 hrs. LCMS showed all the starting materials were consumed, desired Ms was detected. The residue was quenched with water (10 mL), and extracted with ethyl acetate (3 ⁇ 30 mL). The aqueous phase were concentrated under reduced pressure to give the crude product. The crude product was directly used for the next step.
  • Example 73 Synthesis of 4-(5-Fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3- carboxylic acid
  • THF 50 mL
  • t-BuOH 50 mL
  • DMAP 557.75 mg, 4.57 mmol, 0.1 eq
  • tert-butoxycarbonyl tert-butyl carbonate 29.89 g, 136.96 mmol, 3 eq
  • the vessel was evacuated and backfilled with argon (this process was repeated three times), the palladiumtriphenylphosphane (601.70 mg, 520.70 ⁇ mol, 0.05 eq) was added into the mixture under argon, the vessel was evacuated and backfilled with argon (this process was repeated three times), then the mixture was stirred at 80°C for 12 hours. LCMS showed all the starting materials were consumed, desired mass was detected.
  • the reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product.
  • Example 74 Synthesis of 4-(5-Methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3- carboxylic acid
  • 3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazol-4-yl)boronic acid (1 g, 3.04 mmol, 1 eq) in DMF (7.2 mL)
  • 2-bromo-5-methoxy-pyridine 571.75 mg, 3.04 mmol, 1 eq
  • K2CO3 630.42 mg, 4.56 mmol, 1.5 eq
  • H2O 1.44 mL
  • Example 75 3-(5-Fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2- carboxylic acid
  • DCM 370 mL
  • Br 2 52.52 g, 328.62 mmol, 16.93 mL, 2 eq
  • reaction mixture was quenched by addition of saturated ammonium chloride aqueous solution (500 mL), extracted with ethyl acetate (2 x 300 mL), the combined organic layer was washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered, concentrated under reduced pressure to give a residue.
  • the residue was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 50%) to give tert-butyl 3-bromo-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazole-2-carboxylate (10 g, 77.21% yield) as a white solid.
  • Example 76 3-(5-Fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-4-carboxylic acid
  • methyl 3-iodo-1,5-dimethyl-1H-pyrazole-4-carboxylate 0.6 g, 2.08 mmol, 1 eq
  • (5-fluoro-2-pyridyl)-trimethyl-stannane 2.91 g, 7.27 mmol, 3.5 eq
  • dioxane (12 mL) was added CsF (631.33 mg, 4.16 mmol, 153.42 ⁇ L, 2 eq) at 20°C.
  • CsF 631.33 mg, 4.16 mmol, 153.42 ⁇ L, 2 eq
  • aqueous layer was adjusted the pH to 5 with 1N aq.HCl at 0°C, filtered, the filter cake was dried over under high reduced pressure to give 3-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-4- carboxylic acid (0.2 g, 68.90% yield, 99% purity) as a white solid.
  • Example 77 5-Fluoro-3-(2H-1,2,3-triazol-2-yl)picolinic acid
  • 2H-triazole (1.08 g, 15.70 mmol, 909.91 ⁇ L, 1 eq) in ACN (110 mL)
  • K 2 CO 3 5.43 g, 39.26 mmol, 2.5 eq.
  • the crude reaction mixture of 4 experiments was combined for workup. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • the crude product was purified by flash silica gel chromatography (Biotage®; 40 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 50% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to give a residue.
  • the residue was twice purified by prep-HPLC (TFA condition) to give 5-fluoro-3-(2H-1,2,3-triazol-2-yl)picolinonitrile (2.5 g, yield 21.04%) as a white solid.
  • Example 78 5-Fluoro-3-(5-fluoropyrimidin-2-yl)picolinic acid
  • DMF dimethyl sulfoxide
  • 5-fluoropyrimidin-2-yl)-trimethyl-stannane 3.19 g, 8.55 mmol, 4 eq
  • CsF 649.10 mg, 4.27 mmol, 157.74 ⁇ L, 2 eq
  • the mixture was degassed and purged with argon for 3 times, and then to the mixture was added palladiumtriphenylphosphane (246.89 mg, 213.65 ⁇ mol, 0.1 eq) and CuI (40.69 mg, 213.65 ⁇ mol, 0.1 eq) at 20°C.
  • the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (20 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 20%) to give residue.5,6-Dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl trifluoromethanesulfonate (1.9 g, 81.94% yield) was obtained as a yellow solid.
  • Example 81 6-Methyl-3-(pyrimidin-2-yl)pyrazine-2-carboxylic acid
  • methyl 6-bromo-3-chloropyrazine-2-carboxylate 1.5 g, 5.97 mmol, 1 eq
  • dioxane 15 mL
  • 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane 748.82 mg, 5.97 mmol, 833.87 ⁇ L, 1 eq
  • K 2 CO 3 (1.65 g, 11.93 mmol, 2 eq
  • Pd(dppf)Cl 2 .CH 2 Cl 2 (487.13 mg, 596.50 ⁇ mol, 0.1 eq) under N 2 .
  • the reaction mixture was concentrated under reduced pressure to give a residue.
  • the combined organic layers were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product.
  • the crude product was purified by column chromatograph on silica gel (eluted with methanol in ethyl acetate ether from 0% to 20%) to give methyl 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinate (430 mg, 79.98% yield) as yellow oil.
  • the mixture was degassed and purged with N2 for 3 times and stirred at 90°C for 12 hrs. LCMS showed all the starting materials were consumed, desired mass was detected.
  • the reaction mixture was poured into H 2 O (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organics were washed brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product.
  • Example 84 4-(5-Fluoropyrimidin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3- carboxylic acid
  • ethyl 4-bromo-5-methyl-1H-pyrazole-3-carboxylate 9.75 g, 41.83 mmol, 1 eq
  • THF 60 mL
  • NaH 3.35 g, 83.67 mmol, 60% purity, 2 eq
  • the reaction mixture was quenched by addition of saturated ammonium chloride solution (100 mL) at 0°C, and then diluted with water 50 mL and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (50 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • the crude product was stirred in a mixture of petroleum ether and ethyl acetate (10:1, 20 mL) for 30 minutes to form slurry, the solid was collected by filtration.
  • the mixture was degassed and purged with argon for 3 times again.
  • the mixture was stirred at 80°C for 12 hours.
  • LCMS showed the starting material was consumed and the desired mass was detected.
  • the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (3 x 50 mL). The combined organics were washed brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product.
  • Example 85 4-(5-Fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid
  • 2-bromo-5-fluoro-pyridine (796.38 mg, 4.53 mmol, 1.1 eq)
  • K2CO3 (852.83 mg, 6.17 mmol, 1.5 eq)
  • Pd(PPh3)4 (237.69 mg, 205.69 ⁇ mol, 0.05 eq) in DMF (15 mL) and H2O (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 12 hours under N2 atmosphere.
  • Example 86 6-(Methyl-d3)-3-(pyrimidin-2-yl)picolinic acid To a solution of methyl 6-amino-3-bromopicolinate (25 g, 108.20 mmol, 1 eq) in DMF (375 mL) was added tributyl(pyrimidin-2-yl)stannane (51.92 g, 140.66 mmol, 1.3 eq), CsF (32.87 g, 216.41 mmol, 2 eq), CuI (1.03 g, 5.41 mmol, 0.05 eq), Pd(PPh 3 ) 4 (6.25 g, 5.41 mmol, 0.05 eq).
  • Example 87 6-(Methyl-d3)-3-(2H-1,2,3-triazol-2-yl)picolinic acid hydrochloride
  • 3-bromo-6-chloropicolinic acid 5 g, 21.15 mmol, 1 eq
  • dioxane 100 mL
  • water 5 mL
  • 2H-triazole 1.75 g, 25.38 mmol, 1.47 mL, 1.2 eq
  • Cs2CO3 13.78 g, 42.29 mmol, 2 eq
  • N1,N2-dimethylcyclohexane-1,2-diamine (601.56 mg, 4.23 mmol, 0.2 eq)
  • CuI 201.36 mg, 1.06 mmol, 0.05 eq
  • Example 88 Synthesis of (4-(4-Chlorophenyl)-1-methyl-1H-pyrazol-3-yl)((2S,3R,6R)-2,6- dimethyl-3-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholino)methanone [1], general procedure To a solution of 4-(4-chlorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (56.42 mg, 206.58 ⁇ mol, 1.5 eq) in DCM (1 mL) was added DIPEA (71.20 mg, 550.89 ⁇ mol, 95.95 ⁇ L, 4 eq) and HATU (78.55 mg, 206.58 ⁇ mol, 1.5 eq) at 20°C.
  • DIPEA 71.20 mg, 550.89 ⁇ mol, 95.95 ⁇ L, 4 eq
  • HATU 78.55 mg, 206.58 ⁇
  • Example 90 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone [3]
  • General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 3-fluoro-2-(pyrimidin-2-yl)benzoic acid. Yield 17%, white solid.
  • Example 91 Synthesis of (4-(5-Chloropyridin-2-yl)-1-methyl-1H-pyrazol-3- yl)((2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)methanone [4] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 4-(5-chloropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid.
  • Example 92 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [5]
  • General procedure (see Example 88) used for the compound [1] was repeated, using N- (((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.Yield 35%, white solid.
  • Example 93 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [6]
  • General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.
  • Example 94 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone [7] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid.
  • Example 95 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(5-fluoro-2-(pyrimidin-2-yl)phenyl)methanone [8] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid. Yield 74%, light yellow solid.
  • Example 96 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(5-methyl-2-(2-methyl-2H-tetrazol-5-yl)phenyl)methanone [9] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 5-methyl-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid.
  • Example 97 Synthesis of (5-Chloro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((2S,3R,6R)-2,6- dimethyl-3-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)morpholino)methanone [10] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 5-chloro-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid.
  • Example 100 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazol-3- yl)methanone [13]
  • Example 105 Synthesis of ((2S,3R,6R)-3-(((5-Chloropyridin-2-yl)amino)methyl)-2,6- dimethylmorpholino)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [18] General procedure (see Example 88) used for making the compound [1] was repeated, using 5-chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)pyridin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.
  • Example 106 Synthesis of ((2S,3R,6R)-3-(((5-Chloropyrimidin-2-yl)amino)methyl)-2,6- dimethylmorpholino)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone [19] General procedure (see Example 88) used for making the compound [1] was repeated, using 5-chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)pyrimidin-2-amine hydrochloride and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid.
  • Example 107 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [20] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.
  • Example 108 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((4-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [21]
  • General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-4-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.
  • Example 110 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((4-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [23] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-4-(trifluoromethyl)pyridin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.
  • Example 111 Synthesis of 4-(3-((2S,3R,6R)-2,6-Dimethyl-3-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carbonyl)-1-methyl-1H- pyrazol-4-yl)benzonitrile [24] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid.
  • Example 112 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(4-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-3- yl)methanone [25] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 4-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid.
  • Example 113 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-3- yl)methanone [26]
  • General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid.
  • Example 114 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(5-(5-fluoropyrimidin-2-yl)-1-methyl-1H-imidazol-4- yl)methanone [27]
  • General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 5-(5-fluoropyrimidin-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid.
  • Example 115 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(5-(5-fluoropyrimidin-2-yl)-1-methyl-1H-imidazol-4- yl)methanone [28]
  • General procedure (see Example 88) used for the compound [1] was repeated, using N- (((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 5-(5-fluoropyrimidin-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid.
  • Example 116 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(5-(5-methoxypyridin-2-yl)-1-methyl-1H-imidazol-4- yl)methanone [29]
  • General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 5-(5-methoxypyrimidin-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid.
  • Example 117 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl)methanone [30] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(4-fluorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid.
  • Example 118 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [31]
  • General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.
  • Example 119 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [32]
  • General procedure (see Example 88) used for the compound [1] was repeated, using N- (((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.
  • Example 120 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [33]
  • General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.
  • Example 121 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone [34] General procedure (see Example 88) used for the compound [1] was repeated, using N- (((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid.
  • Example 122 Synthesis of ((2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone [35] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid.
  • Example 125 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone hydrochloride [38] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.
  • Example 126 Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [39]
  • Example 127 Synthesis of ((2S,3R,6S)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone [40] General procedure (see Example 88) used for making (the compound [1] was repeated, using N-(((2S,3R,6S)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid.
  • Example 128 Synthesis of (4-(5-Chloropyridin-2-yl)-1-methyl-1H-pyrazol-3- yl)((2S,3R,6S)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)methanone [41]
  • General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6S)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 4-(5-chloropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid.
  • Example 129 Synthesis of ((2S,3R,6S)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [42] General procedure (see Example 88) used for the compound [1] was repeated, using N- (((2S,3R,6S)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.
  • Example 130 Synthesis of ((2S,3R,6S)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(5-fluoro-2-(pyrimidin-2-yl)phenyl)methanone [43]
  • General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6S)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid. Yield 58%, white solid.
  • MS mode was positive electrospray ionization. MS range was 50-2000. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC grade acetonitrile. The gradient was 10-100% B in 0.90 min, 10% B in 0.01 min, 10-100% B (0.01-0.50 min) with a hold at 100% B for 0.40 min. The flow rate was 2.0 mL/min.) Example 145.
  • Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile.
  • IC 50 values of compounds 1-120 with respect to OX1R and OX2R receptors Antagonistic activity on both human orexin receptors OX1R and OX2R has been measured using the following procedure:
  • staining buffer HBSS/HEPES, probenecid and fluorescent calcium 6 assay dye
  • Antagonists test compounds were prepared as 10 mM stock solution in DMSO, then diluted with staining buffer. Then, the test compound solution (8 ⁇ L) was added to each respective well of the plate, followed by 30 min incubation at room temperature before measurement. For the IC50 compound determination (the concentration of compound needed to inhibit 50 % of the agonistic response), human Orexin-A was diluted in HBSS/HEPES buffer (5x working solution) and within FLIPR 10 ⁇ L/well was added and fluorescence measured. The test results are shown in Table 1 below.
  • Example 209 Metabolic Stability and Intrinsic Clearance in Human Liver Hepatocytes
  • Stock solutions of test compounds and the positive control were prepared at 10 mM and 30 mM, respectively, in dimethyl sulfoxide (DMSO).
  • the stock solutions of test compounds and positive control were diluted, respectively with Acetonitrile into a 100 ⁇ M and 300 ⁇ M (dosing solution), to get a final concentration of 1 ⁇ M and 3 ⁇ M in the incubation 96-well plates with 0.90% of Acetonitrile and 0.1% of DMSO.
  • cryopreserved hepatocyte cells were thawed in Williams’ Medium E containing 5% fetal bovine serum and 30% Percoll solution and other supplements, isolated and suspended in Incubation Medium (Williams’ Medium E (no phenol red) containing 2 mM L-Glutamine and 25 mM HEPES.). The cell suspension was then diluted with pre-warmed incubation Medium to 0.5 ⁇ 10 6 cells/mL and 198 ⁇ L pre-warmed suspension were added in 96-well plates. The dosing solution (2 ⁇ L) with test compounds were spiked in each well of the 96-well plates in duplicates.
  • samples to evaluate the metabolic clearance in presence of cryopreserved hepatocytes were incubated for 90 min (T90) with the incubation mixture (i.e. cells with incubation medium).
  • the incubation mixture i.e. cells with incubation medium.
  • samples, containing test compounds together with cell suspension diluted to 0.5 ⁇ 10 6 cells/mL were mixed to achieve a homogenous suspension for about 1 min, then 25 ⁇ L of each sample was immediately transferred into the well of the 96-well plates containing 125 ⁇ L of ice-cold stop solution (acetonitrile containing 200 ng/mL tolbutamide and 200 ng/mL labetalol as internal standards) followed by mixing.
  • the plates were incubated at 37°C in a 95% humidified incubator at 5% CO2 to start the reactions with constant shaking at about 650 rpm. At 15, 30, 60 and 90 min, samples were mixed and then 25 ⁇ L of each sample, at each time point, were transferred to the well containing 125 ⁇ L of ice-cold stop solution in a set of pre-labelled 96-well plates, followed by mixing.
  • Medium Control (MC) sample plates (labeled as T0-MC and T90-MC) were prepared by adding the incubation medium, except cell suspensions to each well. Samples were collected at time zero (T0) and after 90 min incubation (T90).
  • the reaction was stop by removing the plates from incubator and mixing with 125 ⁇ L of ice-cold stop solution. The plates were vortex immediately on a plate shaker at 600 rpm for 10 minutes. Then, all sample plates were centrifuged at 3220 x g for 20 min at 4°C. After centrifugation, 80 ⁇ L/well of supernatant in the sample plates were transferred to another set of pre-labeled 96-well plates which containing 240 ⁇ L of ultra-pure water according to the plate map. Analytical plates are sealed and store at 4°C until LC-MS/MS analysis.
  • the tested compounds 1-120 showed good binding efficiency for OX1 receptor; and showed excellent selectively for OX1 receptors over OX2 receptors. The majority of the tested compounds showed good metabolic stability in human liver hepatocytes.
  • the compounds provided by the present invention are more selective towards OX1 receptors and have better/similar metabolic stability in human liver hepatocytes.

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Abstract

The present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, solvates, adducts, polymorphs, isomers and derivatives thereof, that are useful as orexin antagonists, their preparation, their use in pharmaceutical compositions, and methods of using orexin antagonists to treat or prevent a disease or disorder mediated by orexin receptor activity.

Description

DESCRIPTION
TITLE OF THE INVENTION: MORPHOLINE OREXIN RECEPTOR ANTAGONISTS
FIELD OF THE INVENTION
The present invention relates to compounds, or pharmaceutically acceptable salts and derivatives thereof, that are useful as orexin antagonists; pharmaceutical compositions comprising such compounds, salts or derivatives thereof and, methods of using such compounds to treat or prevent a disease or disorder mediated by orexin receptor activity. Diseases or disorders mediated by orexin receptors include, but are not limited, to central nervous system (CNS) disorders, neurological diseases or eating disorders such as obesity, binge eating disorder (BED), schizophrenia (negative symptoms and CIAS), addiction to psychomotor stimulants such as cocaine, opiates, nicotine and alcohol, opioid use disorder, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, behaviour disorder and mood disorder depression.
BACKGROUND OF THE INVENTION
Orexins are a family of homologous peptides including species orexin A (OR-A) and orexin B (OX-B). Orexins, also known as hypocretin, are neuropeptides produced by a group of neurons located in the lateral hypothalamic area including the lateral hypothalamus and dorsomedial-perifornical area. Both orexin A (OR-A) and orexin B (OR-B) are synthesized from the precursor prepro-orexin. OR-A is a 33 amino acid-long peptide and has two intrachain disulfide bonds and OR-B is a linear 28 amino acid-long peptide. The orexin peptides bind to at least two distinct G-protein-coupled receptors, termed 0X1 and 0X2 receptors (0X1 R or 0X2R). The 0X1 receptor is selective for OR-A, with about 100-fold higher affinity than OR-B while the 0X2 receptor can bind both OR-A and OR-B with similar affinities.
Orexins have been found to stimulate food consumption, regulate states of sleep and wakefulness, and may be involved in neural mechanisms of drug abuse and addiction. The neuronal pathways and receptors via which orexins are involved in these processes seem to be partly overlapping and partly distinct. For example, findings have suggested that the arousal-promoting function of orexins is mainly promoted by 0X2 receptor whereas the role of orexin in regulating reward and feeding is predominantly mediated by 0X1 receptor.
Orexin receptors are suitable targets for the development of drug candidates for the treatment of a variety of orexin-related pathologies and symptoms, such as, but not limited to, central nervous system (CNS) disorders, sleep/wake disorders, anxiety, and obesity. Orexin receptor antagonists have been developed as potential treatments for sleep disorders such as insomnia and narcolepsy. These antagonists block the binding of orexins to their receptors, thereby reducing orexin signalling and promoting sleep. The development of orexin receptor antagonists has focused primarily on OX2 receptor antagonists, for the regulation of arousal and wakefulness. However, there is also interest in the development of OX1 receptor antagonists for the treatment of substance addiction, obesity and other metabolic disorders. Patent application WO2020247447A1 is directed towards substituted pyrazole and imidazole derivatives of compounds that are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved or implicated. It also relates to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved. Patent application WO2020247445A1 relates to substituted Imidazolo[2,1-b]oxazole, lmidazolo[2,1-b]thiazole, Imidazolo[2,1-b]oxadiazole, lmidazolo[2,1-b]oxadiathiazole derivatives as antagonists of orexin receptors, which may be used in the treatment or prevention of neurological and psychiatric disorders and disease. Patent application WO2017139603A1 relates to halo-substituted piperidine compounds, pharmaceutical compositions containing them, and methods of using them, including methods for treating substance addiction, panic disorder, anxiety, post-traumatic stress disorder, pain, depression, seasonal affective disorder, an eating disorder, or hypertension. Patent application WO2002090355A1 and granted patent EP1539747 relates to N-aroyl cyclic amine derivatives as orexin receptor antagonists and their potential use in the treatment of obesity, including obesity observed in Type 2 (non-insulin-dependent) diabetes patients, and/or sleep disorders, stroke, particularly ischemic or haemorrhagic stroke, and/or blocking the emetic response, i.e. useful in the treatment of nausea and vomiting. Patent application WO2013068935A1 relates to derivatives of 2-(1,2,3-triazol-2-yl)benzamide and 3-(1,2,3-triazol-2-yl)picolinamide and their use as orexin receptor antagonists in pharmaceutical compositions. Some of the compounds in this prior art document were found to have poor selectivity towards OX1R in comparison to OX2R, and also exhibit poor metabolic stability. However, there is still a need for developing a novel and potent selective OX1 receptor antagonists for the treatment of a disease or disorder mediated by orexin receptor activity such as central nervous system (CNS) disorders, neurological diseases or eating disorder, sleep disorder and substance addiction. There is also a need for developing an improved brain penetrant for the treatment of a disease or disorder mediated by orexin receptor activity such as central nervous system (CNS) disorders, neurological diseases or eating disorder, sleep disorder and substance addiction. SUMMARY OF THE INVENTION The present invention provides novel compounds, or pharmaceutically acceptable salts and derivatives thereof, compositions and use of the compounds in the treatment or prevention of diseases or disorders mediated by orexin receptor activity. The present invention provides novel OX1 receptor antagonists having good selectivity and binding properties, good potency, good brain penetration, improved pharmacokinetic properties, biological activities, improved solubility, improved residence time, good metabolic stability and chemical stability. The pharmaceutically acceptable salts and derivatives of the compounds of the present invention include, but not limited to hydrochlorides, chlorides, bromides, iodides, potassium salts, sodium salts, acetates such as trifluoroacetates, sulfates, sulfonates, oxalates, maleates, malonates, nitrates, tartrates, gluconates, succinates, mesylates, citrates, phosphates, diphosphate, aluminate, enantiomers, solvates, adducts, polymorphs, hydrates, tautomers, prodrugs, isotopically or radio-labelled derivatives and isomers. According to an aspect of the present invention, a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of general Formula I: wherein: Het represents a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof, wherein said heteroaromatic group is unsubstituted, mono-, di-substituted, or tri-substituted, wherein the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (C1-C4) straight chain alkyl, unsubstituted (C1-C4)-branched alkyl, unsubstituted (C3-C8) cycloalkyl, unsubstituted (C1-C4) alkoxy, substituted (C1-C4)-straight chain alkyl, substituted (C1-C4)-branched alkyl, substituted (C3-C8)cycloalkyl, a cyano group, substituted (C1-C4)alkoxy and halogen. Preferably, the substituent of the heteroaromatic group in Het is F, Cl, CHF2, CF3, methyl, ethyl, methoxy, nitrile or cyclopropyl. R is selected from the group consisting of a five or a six membered aromatic group or heteroaromatic group, wherein the aromatic group or heteroaromatic group is either unsubstituted or is substituted with one or more substituents. Preferably, R in the compound of Formula I comprises a five membered heteroaromatic group which is an unsubstituted pyrazole, an unsubstituted oxazole, an unsubstituted thiazole, an unsubstituted imidazole, a substituted pyrazole, a substituted oxazole, a substituted thiazole, a substituted imidazole or a derivative thereof; a six membered aromatic group which is an unsubstituted aryl, or substituted aryl, or a derivative thereof; or a six membered heteroaromatic group, which is an unsubstituted pyridine, an unsubstituted pyrimidine, an unsubstituted pyridazine, an unsubstituted pyrazine, a substituted pyridine, a substituted pyrimidine, a substituted pyridazine, a substituted pyrazine or any derivatives thereof. According to another aspect of the present invention, the compound of Formula I is a 2S,3R- stereoisomer: . According to another aspect of the present invention, the compound of Formula I is a 6R- stereoisomer, a 6S-stereoisomer or mixtures thereof: . Preferably, one or more of the hydrogen atom attached to the carbon atom in the morpholine ring of the compound of Formula I is replaced with one or more deuterium. Preferably, one or more of the hydrogen atom attached to the side chain in the morpholine of the compound of Formula I is replaced with one or more deuterium. According to another aspect of the present invention, the compound of Formula I is a deuterated compound, in which one or more hydrogen atoms is replaced or substituted by one or more 2H (deuterium).The deuterated compound of Formula I may have the following structure: ; wherein R and Het may be each independently as defined in Formula I. According to another aspect of the present invention, a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of Formula I(a) - (g):
wherein: R1 and R2 may be each independently selected from the group consisting of: hydrogen, unsubstituted (C1-C6)-straight chain alkyl; unsubstituted (C1-C6)-branched alkyl; substituted (C1-C6)-straight chain alkyl; substituted (C1-C6)-branched alkyl; deuterated (C1-C6)-straight chain alkyl; deuterated (C1-C6)-branched chain alkyl and halogen such as fluorine, chlorine or bromine; preferably R1 and R2 are each independently hydrogen, chlorine, fluorine, -CH3, or - CD3 (deuterium); R6 and R7 may be each independently hydrogen or deuterium; Het’ is selected from the group consisting of: a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, pyrazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof, wherein said heteroaromatic group is unsubstituted, mono-, or di- substituted, wherein the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (C1-C6)-straight chain or branched alkyl, substituted (C1-C6)-straight chain or branched alkyl, and halogen; preferably the halogen comprises fluorine, chlorine or bromine; and Het may be as defined herein with respect to Formula I. Preferably, the compound of Formula I(a)-(g) is a 6R,2S,3R-stereoisomer, 6S,2S,3R- stereoisomer or mixtures thereof. According to another aspect of the present invention, a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of Formula I(h) –I(i): wherein: R3 and R4 may be each independently selected from the group consisting of: hydrogen, (C1- C10)-straight chain alkyl; (C1-C10)-branched alkyl; (C1-C10)-substituted or unsubstituted alkyl, optionally (C1-C4)-straight chain alkyl; (C1-C4)-branched alkyl; and (C1-C4)-substituted or unsubstituted alkyl; R3 and R4 may form a substituted or unsubstituted ring; preferably R3 is hydrogen, -CH3 or -CD3; Y represents an aromatic group or a heteroaromatic group; a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, wherein the Y is independently selected from the group consisting of: aryl, pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, nicotinonitrile, benzonitrile, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof, preferably Y is mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of: unsubstituted (C1-C4)-alkyl or substituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy, a cyano group and halogen; preferably, the halogen is fluorine, chlorine or bromine; and Het may be as defined herein with respect to Formula I. Preferably, the aromatic heteroaromatic group in Y is substituted with CN, F, Br, Cl, -O-alkyl, preferably the alkyl group comprises 1-4 carbon atoms, preferably the alkoxy is -OCH3. According to another aspect of the present invention, a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of Formula I(k): 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). According to another aspect of the present invention, a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of Formula I(l) or I(m): 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); and R5 may be selected from hydrogen, (C1-C10)-straight chain alkyl; (C1-C10)-branched alkyl; (C1- C10)-substituted or unsubstituted alkyl, optionally (C1-C4)-straight chain alkyl; (C1-C4)-branched alkyl; (C1-C4)-substituted or unsubstituted alkyl; preferably R5 is hydrogen, -CH3 or -CD3. According to another aspect of the present invention, a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure of Formula I(n): wherein: R6 and R7 may be each independently hydrogen or deuterium; and R3, Het and Y may be each independently as defined in Formula I(h). Preferably, the compound of Formula I(h)-(n) is a 6R,2S,3R-stereoisomer, 6S,2S,3R- stereoisomer or mixtures thereof. According to another aspect of the present invention, there is provided a compound of Formula I or I(a-n) described herein or a pharmaceutical composition comprising the compound of Formula I or I(a-n) for use as a medicament. Preferably, the pharmaceutical composition is in a solid form such as a tablet or a capsule. According to another aspect of the present invention, there is provided a method of treating or preventing a disease or disorder mediated by orexin receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula I or I(a-n) described herein or pharmaceutically acceptable salts, and derivatives thereof, preferably in a dose, at a frequency, and for a duration to provide a beneficial effect a pharmaceutical composition described herein. According to another aspect of the present invention, there is provided use of a compound of Formula I or I(a-n) described herein, or a pharmaceutical composition described therein, in the preparation of a medicament for the treatment of diseases or disorders regulated by orexin receptor activity, and the use of such compounds for treatment or prevention of such diseases and disorders. According to yet another aspect of the present invention, there is provided a method of modulating the activity of orexin receptors OX1, OX2, or both, comprising contacting a cell comprising the orexin receptor with an effective amount of at least one compound of Formula I or I(a-n) described herein, or a pharmaceutical composition described herein. According to another aspect of the present invention, a method for the preparation of the compounds of the present invention is provided. DETAILED DESCRIPTION OF THE INVENTION According to one aspect of the present invention, a compound of Formula I or pharmaceutically acceptable salts and derivatives thereof is provided. ‘Het’ represents a heteroaromatic group and ‘R’ is a five 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, mono-, di-, or tri-substituted, wherein the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (C1-C4)-straight chain alkyl, unsubstituted (C1-C4)-branched alkyl, substituted (C1-C4)-straight chain alkyl, substituted (C1-C4)-branched alkyl, and halogen such as fluorine, chlorine or bromine. Preferably, the substituents of the heteroaromatic group comprises CF3. The five or six membered aromatic or heteroaromatic group ‘R’ may either be unsubstituted or substituted with one or more substituents. Preferably, the compound provided by Formula I is a 2S,3R-stereoisomer: The 2S,3R stereoisomer provided by the compound of Formula I or I(a-n) may bind stronger to the orexin receptors and may be more selective at binding to the OX1 receptor in comparison to other stereoisomers provided by compounds of Formula I or I(a-n). The 2S,3R,6R- stereoisomer are metabolically more stable in comparison to other stereoisomers provided by compounds of the present invention. More preferably, the compound of Formula I is a 2S,3R,6R-stereoisomer, a 6S,2S,3R- stereoisomer or mixtures thereof: . In another aspect, the compound of Formula I may be a deuterated compound. Preferably, one or more hydrogen atom is replaced or substituted by one or more deuterium, for example one or more hydrogen atom attached to the carbon atom of the morpholine ring, or one or more hydrogen atom in the side chain of the morpholine ring or one or more hydrogen atom in any of the substituents of the five or a six membered aromatic group or heteroaromatic group of ‘R’ group of Formula I may be replaced with one or more deuterium. The term “heteroaromatic” as used herein refers to an aromatic compound which contains heteroatoms such as oxygen, nitrogen or sulfur as part of the cyclic conjugated π system. The term “alkyl” as used herein refers to univalent groups derived from alkanes by removal of a hydrogen atom from any carbon atom –CnH2n+1. The term substituted alkyl refers to an alkyl wherein one or more hydrogen atoms of the alkyl group are replaced with one or more substituents selected from but not limited to halogen (such as fluorine, chlorine, or bromine), -OH, -CN. The term “fluoroalkyl” as used herein refers to an alkyl substituted by at least one fluorine atom. The term “alkoxy” as used herein refers to an alkyl bonded to oxygen (i.e. R-O). The term "aryl" as used herein refers to a monocyclic or bicyclic carbocyclic aromatic or aryl ring system. Phenyl is an example of a monocyclic aromatic or aryl ring system. “Halogen” can be F, Cl, Br or I, however, in preferred examples the halogen is F, Cl or Br. “Isotopically labelled compound” are chemical substances in which some atoms in their molecules are replaced by isotope atoms, typically different from naturally occurring isotopes. “Deuterated compounds” are compounds in which one or more hydrogen atom in the compound have been replaced by one or more deuterium atom. The term “deuterated alkyl” used herein refers to an alkyl group with one or more protons replaced with deuterium atoms. The term “substituted” as used herein refers to, for a particular group (e.g, alkyl, aryl, heteroaryl, aromatic), the replacement of one functional group by another (e.g., the substitution of an alkyl hydrogen by fluorine to provide fluoroalkyl). The term “solvate” is used herein to describe a compound in this invention that contains stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule such as ethanol. The term “hydrate” refers to when the said solvent is water. By “pharmaceutically acceptable” is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the subject to which it is administered. The term “therapeutically effective amount” (or more simply an “effective amount”) as used herein means the amount of active agent or active ingredient that is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which/whom it is administered. Preferably, where the “R” in the compound of Formula I is a five-membered heteroaromatic group, it may comprise an unsubstituted pyrazole, oxazole, thiazole, imidazole; a substituted pyrazole, oxazole, thiazole, imidazole; or a derivative thereof. The unsubstituted or substituted pyrazole may be a fused with a five or six membered ring. Preferably, where the “R” in the compound of Formula I is a six-membered aromatic group, it may comprise an unsubstituted aryl, or substituted aryl, or a derivative thereof. Preferably, where the “R” in the compound of Formula I is a six-membered heteroaromatic group, it may comprise an unsubstituted or substituted pyridine, pyrazine pyridazine, pyrimidine, triazine, triazole, tetrazole, imidazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole or any derivatives thereof, wherein said heteroaromatic group is unsubstituted, mono-, di-substituted or tri-substituted, wherein the substituents of the heteroaromatic group, if present, may be independently selected from the group consisting of: unsubstituted (C1-C4)- straight chain or branched alkyl, substituted straight chain or branched (C1-C4)-alkyl, deuterated (C1-C6)-straight chain alkyl, deuterated (C1-C6)-branched chain alkyl, and halogen. More preferably, where the “R” in the compound of Formula I is a six-membered aromatic group, the six-membered aromatic group has the structure of Formula II: wherein R1 may be selected from the group consisting of: hydrogen, unsubstituted (C1-C6)- straight chain alkyl; unsubstituted (C1-C6)-branched alkyl; substituted (C1-C6)-straight chain alkyl; substituted (C1-C6)-branched alkyl; deuterated (C1-C6)-straight chain alkyl; deuterated (C1-C6)-branched chain alkyl; and halogen such as chlorine, fluorine and bromine; preferably, R1 is Cl, F, CH3 or -CD3 (D=Deuterium); and Het’ may be selected from the group consisting of: a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, pyrazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof, wherein said heteroaromatic group is unsubstituted, mono-, or di- substituted, wherein the substituents of the heteroaromatic group, if present, may be independently selected from the group consisting of: (C1-C4)- straight chain or branched alkyl, substituted straight chain or branched (C1-C4)-alkyl, and halogen such fluorine, chlorine or bromine. Preferably, the substituent(s) of the heteroaromatic group of Het’ may be fluorine, chlorine or CH3. In some examples, Het’ of Formula II may be selected from: Preferably, where the “R” in the compound of Formula I is a six-membered heteroaromatic group, the six-membered heteroaromatic group has the structure of Formula III: wherein: R1 may be selected from the group consisting of hydrogen, unsubstituted (C1-C6)-straight chain alkyl; unsubstituted (C1-C6)-branched alkyl; substituted (C1-C6)-straight chain alkyl; substituted (C1-C6)-branched alkyl; deuterated (C1-C6)-straight chain alkyl; deuterated (C1-C6)- branched chain alkyl; and halogen such as fluorine, chlorine or bromine; preferably R1 is hydrogen, chlorine, fluorine, -CH3, or -CD3 (D=deuterium); and Het’ may be as defined herein with respect to Formula II. In some examples, Het’ of Formula III may be selected from: Preferably, where the “R” in the compound of Formula I is a six-membered heteroaromatic group, the six-membered heteroaromatic group has the structure of Formula III(a), III(b), III(c) and III(d): wherein: R1 may be as defined with respect to Formula III; R2 may be selected from the group consisting of: hydrogen, unsubstituted (C1-C6)-straight chain alkyl; unsubstituted (C1-C6)-branched alkyl; substituted (C1-C6)-straight chain alkyl; substituted (C1-C6)-branched alkyl; deuterated (C1-C6)-straight chain alkyl; deuterated (C1-C6)- branched chain alkyl; and halogen such as fluorine, chlorine or bromine, preferably R2 is hydrogen, chlorine, fluorine, -CH3 or -CD3 (D=Deuterium); and Het’ may be as defined herein with respect to Formula III. In some examples, Het’ of Formula III(a) –(b) may be selected from: . Where the “R” in Formula I is a five-membered heteroaromatic group, the five-membered heteroaromatic group may have the structure Formula IV: wherein: Y may represent an aromatic group; a substituted or unsubstituted aromatic group, a heteroaromatic group, a substituted or unsubstituted heteroaromatic group. Preferably, Y may be independently selected from the group consisting of: aryl, pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, nicotinonitrile, benzonitrile, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof; Y may be unsubstituted, mono-, or di-substituted, wherein the substituents may be independently selected from the group consisting of: unsubstituted or substituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy, a cyano group and halogen. Where Y is mono-, or di-substituted and the substituent(s) is a halogen, the halogen may preferably be fluorine, chlorine or bromine. Where Y is mono-, or di-substituted and the substituent(s) is a (C1-C4)-alkoxy, the alkoxy may preferably be -OCH3. Preferably, the substituent(s) of the aromatic or heteroaromatic group in Y is selected from CN, F, Br, Cl , or - OCH3. In some examples, Y of Formula IV may be selected from: Further, where the “R” in Formula I is a five-membered heteroaromatic group, the five- membered heteroaromatic group may have the structure Formula V or V(a) wherein: R3 and R4 may each be independently selected from the group consisting of: hydrogen, (C1- C10)-straight chain alkyl; (C1-C10)-branched alkyl; (C1-C10)-substituted or unsubstituted alkyl, optionally (C1-C4)-straight chain alkyl; (C1-C4)-branched alkyl; (C1-C4)-substituted or unsubstituted alkyl; deuterated (C1-C6)-straight chain alkyl and deuterated (C1-C6)-branched chain alkyl; R3 and R4 may form a substituted or unsubstituted ring; preferably R3 and R4 are each independently hydrogen, -CH3 or -CD3; and Y may be as defined herein with respect to Formula IV. In some examples, “Y” of Formula V may be: . Further, where the “R” in Formula I is a five-membered heteroaromatic group, the five- membered heteroaromatic group may have the structure Formula VI: Wherein Y is as defined with respect to Formula IV. In some examples, Y of Formula VI may be: . Further, where “R” in Formula I is a five-membered heteroaromatic group, the five-membered heteroaromatic group may have the structure of Formula VII: wherein: R5 may be selected from hydrogen, (C1-C10)-straight chain alkyl; (C1-C10)-branched alkyl; (C1- C10)-substituted or unsubstituted alkyl, optionally (C1-C4)-straight chain alkyl; (C1-C4)-branched alkyl; (C1-C4)-substituted or unsubstituted alkyl; deuterated (C1-C6)-straight chain alkyl, deuterated (C1-C6)-branched chain alkyl; preferably R5 is hydrogen, -CH3 or -CD3; and Y may be as defined herein with respect to Formula IV. In some examples, Y of Formula VII or VII(a) may be: In some examples, “R” of the compound of Formula I described herein may be selected from:
In further examples, “R” in the compound of Formula I described herein may be selected from: In further examples, “R” in the compound of Formula I described herein may be selected from:
Preferably, Het in 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 may be unsubstituted, mono-, or di-substituted, tri-substituted, wherein the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (C1-C4)-straight chain alkyl, unsubstituted (C1-C4)-branched alkyl, substituted (C1-C4)-straight chain alkyl, substituted (C1- C4)-branched alkyl, (C3-C8)-cycloalkyl, cyano, (C1-C4)-alkoxy and halogen such as fluorine, chlorine or bromine; preferably the substituent(s) of the heteroaromatic group in Het may be (C1-C4)-alkyl, (C1-C4)-fluoroalkyl, (C3-C8)-cycloalkyl, cyano, (C1-C4)-alkoxy or halogen; and more preferably, the substituent of the heteroaromatic group in Het is Cl, F, CHF2, CF3, methyl, ethyl , methoxy, nitrile or cyclopropyl. In some examples, “Het” in the compound of Formula I described herein may be selected from: In yet another example, the compound of Formula I has the following structure: wherein: R and Het may be each independently as defined herein with respect to Formula I to VIIa; and R6 and R7 are each independently H or deuterium (D). Preferably, the compound of Formula ID(a) and (ID(b) is a 6R,2S,3R-stereoisomer, 6S,2S,3R- stereoisomer or mixtures thereof. In yet another example, the compound of Formula I described herein has the structure of Formula I(a) – (n):
Formula I(g) Formula I(h)
Formula I(m) Formula I(n); wherein: Het, Het’, R1, R2, R3, R4, R5 and Y may be each independently as defined herein with respect to Formula I to VIIa; and R6 and R7 may be each independently H or deuterium (D). In further examples, a compound of the present invention may be selected from:
or pharmaceutically acceptable salts and derivatives thereof. According to another aspect of the present invention, a compound, or pharmaceutically acceptable salts and derivatives thereof is provided, wherein the compound has the structure Formula I-aa wherein: R8 is CF3 or a halogen, preferably the halogen is Cl; W1 is selected from the group consisting of: CH, N, -C-CH3, -C-CH2CH3, -C-F, -C-Cl, -C-CN, -C-CHF2, and -C-OMe; W2 is selected from the group consisting of: CH, N, -C-CH3 and -C-CH2CH3; and R may be as defined herein with respect to Formula I. In some examples, R in the compound of Formula I-aa may be selected from: ; wherein: R1 and R3 are each independently hydrogen, CH3 or -CD3; preferably R1 is CH3 or -CD3; preferably R3 is -CD3; Het’ and Y are each independently selected from . Preferably, the compound of Formula I-aa is a 6R,2S,3R-stereoisomer, 6S,2S,3R- stereoisomer or mixtures thereof. Preferably, the compound of Formula I-aa is selected from the group consisting of: ;
The compounds of the present invention may be in the form of pharmaceutically acceptable salts. A "pharmaceutically acceptable salt" is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Examples of “pharmaceutically acceptable salts” include, but not limited to, hydrochlorides, chlorides, bromides, iodides, potassium salts, sodium salts, acetates such as trifluoroacetate, sulfates, sulfonates, oxalates, maleates, malonates, nitrates, tartrates, gluconates, succinates, mesylates, citrates, phosphates or diphosphates and aluminates. In some examples, the pharmaceutically acceptable salt may be trifluoroacetate Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or tautomeric forms, prodrugs or a mixture thereof. The “pharmaceutically acceptable derivatives” of the compounds of the present invention disclosed herein includes, but is not limited to, enantiomers, solvates, adducts, polymorphs, hydrates, tautomers, prodrugs, isomers, isotopically or radio-labelled compounds or a mixture thereof. Isotopic Labelling in Described Compounds The present invention preferably further includes all pharmaceutically acceptable isotopically labelled compound [e.g., of Formula I or I(a-e)] An "isotopically" or "radio-labelled" compound is a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). For example, in certain examples, in compounds [e.g., of Formula I or I(a-e)], hydrogen atoms are replaced or substituted by one or more deuterium or tritium (e.g., hydrogen atoms on a (C1-C6)-alkyl or a (C1-C6)-alkoxy are replaced with deuterium, such as d3-methoxy or 1,1,2,2-d4-3-methylbutyl). Certain isotopically labelled compounds [e.g., compounds of Formula I or I(a-e)], for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies and in metabolic studies (preferably with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labelled compounds [e.g., 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 analogous to those described in the accompanying examples using an appropriate isotopically labelled reagent in place of the non-labelled reagent previously employed. Suitable isotopes that may be incorporated in compounds of the present application include but are not limited to isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H (also written as D for deuterium), 3H (also written as T for tritium),11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36Cl, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I, I31I, 31P, and 32P. Isotopically labelled compounds of this application and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent. Compounds provided by the present invention are non-peptide antagonists of human orexin receptors. The compounds provided by the present invention may be useful for the potential treatment or prevention of central nervous system (CNS) disorders, neurological diseases or eating disorders. The compounds of the present invention may be useful to treat diseases or disorders relating to dysfunctions of the orexin 1 receptor. The novel compounds provided by the present invention are non-peptide antagonists of human orexin receptors, especially the orexin-1 receptor. These compounds are particularly useful for the potential treatment or prevention of central nervous system (CNS) disorders, neurological diseases or eating disorders such as obesity, binge eating disorder (BED), schizophrenia (negative symptoms and CIAS), addiction to psychomotor stimulants such as cocaine, opiates, nicotine and alcohol, opioid use disorder, opioid dependence, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, behaviour disorder and mood disorder depression. The compounds of the present invention may be useful to treat diseases or disorders relating to dysfunctions of the orexin 1 receptor. Preferably, the novel compounds provided by the present invention are OX1 receptor selective antagonists. OX1 receptor antagonists are useful for treating diseases and disorders such as, but not limited to, substance abuse disorders, personality disorders, eating disorders, or anxiety-related disorders. However, antagonists targeting both OX1 and OX2 receptors are known to have sleep-inducing effects; therefore, identifying a highly OX1 selective antagonist with a sufficient window to OX2-mediated effects is very desirable, to prevent side-effects such as drowsiness or tiredness. Half-maximal inhibitory concentration (IC50) may be used in the present invention to demonstrate the efficiency of compounds provided by the present invention. The IC50 values provided in this disclosure indicates how much drug is needed to inhibit orexin receptors by half, thus providing a measure of compounds provided by the present invention. Compounds provided by the present invention may have an IC50 of at least 500 nM for OX1 receptors. Preferably, compounds provided by the present invention may have an IC50 value between 2 nM to 500 nM for OX1 receptors. Compounds provided by Formula I may have an IC50 value between 2 nM to 450 nM; between 2 nM to 400 nM; between 2 nM to 350 nM; between 2 nM to 300 nM; between 2 nM to 250 nM; between 2 nM to 200 nM between 2 nM to 150 nM; between 2 nM to 100 nM; between 2 nM to 50 nM; between 50 nM to 500 nM; between 50 nM to 450 nM; between 50 nM to 400 nM; between 50 nM to 350 nM; between 50 nM to 300 nM; between 50 nM to 250 nM; between 50 nM to 200 nM; between 50 nM to 150 nM; between 50 nM to 100 nM; between 100 nM to 500 nM; between 100 nM to 450 nM; between 100 nM to 400 nM; between 100 nM to 350 nM; between 100 nM to 300 nM; between 100 nM to 250 nM; between 100 nM to 200 nM; or between 100 nM to 150 nM for OX1 receptors. More preferably, compounds provided by the present invention may have an IC50 value between 2 nM to 100 nM for OX1 receptors. Compounds provided by the present invention may have an IC50 value between 2 nM to 90 nM; between 2 nM to 70 nM; between 2 nM to 50 nM; between 2 nM to 30 nM; between 2 nM to 10 nM; between 5 nM to 90 nM; between 5 nM to 80 nM; between 5 nM to 60 nM; between 5 nM to 50 nM; between 5 nM to 30 nM; between 5 nM to 20 nM; between 5 nM to 10 nM; between 10 nM to 80 nM; between 10 nM to 60 nM; between 10 nM to 70 nM; between 10 nM to 50 nM; between 10 nM to 30 nM; or between 10 nM to 20 nM for OX1 receptors. Most preferably, compounds provided by the present invention may have an IC50 value between 2 nM to 50 nM for OX1 receptors. Compounds provided by the present invention may have an IC50 value between 2 nM to 40 nM; between 2 nM to 30 nM; between 2 nM to 25 nM; between 2 nM to 20 nM; between 2 nM to 10 nM; between 2 nM to 5 nM; 3 nM to 40 nM; between 3 nM to 30 nM; between 3 nM to 25 nM; between 3 nM to 20 nM; between 3 nM to 10 nM; between 3 nM to 5 nM; 5 nM to 40 nM; between 5 nM to 30 nM; between 5 nM to 25 nM; between 5 nM to 20 nM; between 5 nM to 10 nM; 7 nM to 40 nM; between 7 nM to 30 nM; between 7 nM to 25 nM; between 7 nM to 20 nM; or between 7 nM to 10 nM for OX1 receptors. Most preferably, compounds provided by the present invention may have an IC50 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 for OX1 receptors. Compounds provided by the present invention may have an IC50 of at least 2000 nM for OX2 receptors. Preferably, compounds provided by the present invention have an IC50 of at least 5000 nM for OX2 receptors. Compounds provided by the present invention are at least 10 times more effective at binding to OX1 receptors compared to OX2 receptors. Preferably, compounds provided by the present invention are at least 100 times more effective at binding to OX1 receptors compared to OX2 receptors. Even more preferably, compounds provided by the present invention are at least 500 times more effective at binding to OX1 receptors compared to OX2 receptors. Most preferably, compounds provided by the present invention are at least 1000 times more effective at binding to OX1 receptors compared to OX2 receptors. It was found that the compounds of the present invention have improved residence time compared to known OX1 receptors. Orexin A was incubated with human OX1 receptor membranes for different incubation times in the presence or absence of 6 different concentrations of compounds. The non-specific binding was assessed in presence of unlabeled SB 334867 (1-(2-methylbenzo[d]oxazol-6-yl)-3-(1,5-naphthyridin-4-yl)urea, which is commercially available OX1R-ANT) for each incubation time. Kinetic parameters (kon, koff, residence time) were calculated by applying the Motulsky Mahan equation. Compounds of the present invention were found to show a higher residence time compared to reference compounds, suggesting a higher ligand-OX1R complex half-life which positively impacts the therapeutic dose in humans. For instance, compounds of present invention (such as compounds 51, 74, 120) showed higher ranking compared to known compounds such as those in WO2017129829, WO2017139603, JNJ-61393215 and ACT-539313. Improved drug residence time is advantageous, as longer drug-target residence time are generally more efficacious in vivo. As a result, lower therapeutic doses are needed. It is also generally known that drugs with longer residence times have increased efficacy and fewer side effects because they occupy a higher fraction of their target over a longer period of time, even after clearance from systemic circulation. Compounds provided by the present invention are metabolically stable, and may have improved pharmacokinetic properties such as improved drug oral bioavailability, improved permeability into cells, and improved brain exposure which are required for a CNS indication drugs. According to another aspect of the present invention, a pharmaceutical composition is provided, the pharmaceutical composition comprising a compound of present invention described herein and one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients may be added to streamline the manufacture of the pharmaceutical composition and ultimately facilitate physiological absorption of the drug. Further, pharmaceutically acceptable excipients used in the present invention may provide key benefits such as solubilisation, stabilisation, delivery enhancement, and formulation preservation. Non-limiting examples of types of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersing agents, disintegration agents, emulsifying agents, wetting agents, suspending agents, thickeners, solvents, isotonic agents, buffers, pH adjusters, absorption-delaying agents, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweetening agents, flavoring agents, coloring agents, encapsulating materials and coating materials. The use of such excipients in pharmaceutical formulations is known in the art. The compounds of the present invention may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein. The additional active ingredients may include other active agents that are effective in treating the diseases and disorders described herein. For example, additional active ingredients include those that are known to be useful for enhancing sleep quality and preventing and treating sleep disorders and sleep disturbances, anti-diabetic agents, cardiovascular therapies, anti-obesity agents, other orexin receptor antagonists, pain medications, anti-depressants, anti-anxiety agents, cognition-enhancing agents, anti- Alzheimer’s Disease therapies, and other active ingredients. The pharmaceutical composition or the compound provided by the present invention may be used as a medicament. The medicament may be used for preventing and/or treating a condition selected from, but are not limited to, central nervous system (CNS) disorders, neurological diseases or eating disorders such as obesity, binge eating disorder (BED), schizophrenia (negative symptoms and CIAS), addiction to psychomotor stimulants such as cocaine, opiates, nicotine and alcohol, opioid use disorder, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, behaviour disorder and mood disorder depression. The pharmaceutical composition provided by the present invention may be in the form of tablets, capsules, hard candies, powders, spansules, soft gels, liquid or aqueous suspensions. Preferably, the pharmaceutical composition provided by the present invention is in the form of tablets or capsules. The pharmaceutical composition provided by the present invention may be administered through oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intra-arterial, intraperitoneal, intracavitary and topical), topical (including transdermal, transmucosal, intranasal (e.g., by nasal spray or drop), ocular (e.g., by eye drop), pulmonary (e.g., by oral or nasal inhalation), and/or other suitable routes. Preferably, the pharmaceutical composition provided by the present invention is administered orally. According to yet another aspect of the present invention, a method of treating or preventing a disease or disorder mediated by orexin receptor activity is provided. The method comprising administering to a subject in need of such treatment an effective amount of at least one compound in accordance with the present invention (or any pharmaceutically acceptable salts, solvates, adducts, polymorphs, isotopically or radio-labelled derivatives and isomers thereof) or a pharmaceutical composition comprising of at least one compound in accordance with the present invention (or any pharmaceutically acceptable salts, solvates, adducts, polymorphs, isotopically or radio-labelled compounds and isomers thereof). The method provided by the present invention may be used for the treatment or for the prevention of diseases or disorders selected from but not limited to eating disorders, obesity, binge eating disorder (BED), schizophrenia (negative symptoms and CIAS), addiction to psychomotor stimulants such as cocaine, opiates, nicotine and alcohol, opioid use disorder, drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, behaviour disorder and mood disorder depression. Dosage regimens may be adjusted to provide the optimum desired response. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition. The amount of the compound of the present invention administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. As used herein, the term “subject” includes a human or non-human animal. An exemplary human subject includes a human subject having a disease (such as one described herein) (referred to as a patient), or a normal subject. The term “non-human animal” as used herein includes all vertebrates, such as non-mammals. According to another aspect of the present invention, the use of a compound in accordance with the present invention or a pharmaceutical composition comprising a compound in accordance with Formula I is provided. The compound in accordance with the present invention or the pharmaceutical composition comprising the compound in accordance with the present invention is used in the preparation of a medicament for the treatment of diseases or disorders regulated by orexin receptor activity and is used for treatment or prevention of such diseases and disorders. According to yet another aspect of the present invention, a method of modulating the activity of orexin receptors OX1, OX2, or both. The method comprising contacting a cell comprising the orexin receptor with an effective amount of at least one compound in accordance with the present invention or a pharmaceutical composition comprising a compound in accordance with the present invention. The method of contacting the cell comprising the orexin receptor with an effective amount of at least one compound in accordance with the present invention or a pharmaceutical composition comprising a compound in accordance with the present invention can either be carried out in vivo, in vitro or ex vivo. Preferably, the present invention provides a method of selectively modulating the activity of OX1 receptors. According to yet another aspect of the present invention, compounds of the present invention may be prepared by the synthetic pathway described in the examples below. The abbreviations used in the present disclosure are summarised: BOC tert-butyloxycarbonyl DMF dimethylformamide DMS dimethyl sulfide DMSO dimethylsulfoxide DMAP 4-dimethylaminopyridine DIAD diisopropyl azodicarboxylate DEAD diethyl azodicarboxylate DIPEA N, N-Diisopropylethylamine Fmoc Fluorenylmethyloxycarbonyl PG protecting group TBAF tetra-n-butylammonium fluoride TEA triethanolamine THF tetrahydrofuran Ts Tosyl eq Equivalents N Normality V Volume The term “hexaalkylditin” as used herein refers to general reagents used to prepare organostannes for Stille cross-coupling. Examples of “hexaalkylditin” include but are not limited to hexamethylditin or hexabutylditin. Compounds of Formula I may be prepared by starting with commercially available starting material N-benzyl-L-allothreonine (a). N-benzyl-L-allothreonine (a) may be reduced by reacting with a reducing agent to form intermediate b. The primary alcohol of intermediate b may be selectively protected by reacting with a suitable protecting group to form intermediate c. Intermediate c may undergo a nucleophilic substitution reaction with 2-bromopropanoic acid or 2-iodopropanoic acid to form intermediate d. Intermediate d may undergo intramolecular amide coupling in the presence of a coupling reagent to form intermediate e. Preferably, the coupling reagent used to make intermediate e is propylphosphonic anhydride (T3P). Intermediate e may be reduced to form intermediate f. The alcohol protecting protecting group is removed from intermediate f to form intermediate g. The benzyl protecting group from intermediate g may be removed through Pd/C-catalyzed hydrogenation. The deprotected amine may react with a suitable protecting group to form intermediate h. Intermediate h may be reacted with isoindoline-1,3-dione to form intermediate i. Intermediate i may be reacted with hydrazine or hydrazine hydrate to form intermediate j. Intermediate j may undergo a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of intermediate k-a to k-s. Preferably, intermediates k-a to k-s are deprotected to form corresponding intermediates l-a to l-s. Intermediates l-a to l-s may be reacted with a carboxylic acid having general formula R-COOH to form compounds 1-57, 61, 64-82, 85-95, 98-120. In another aspect of the present invention, compounds of Formula ID(a) may be prepared by starting with compound d-a. Compound d-a may be reduced by reacting with a reducing agent to form intermediate d-b. Intermediate d-b may undergo a nucleophilic substitution reaction with 2-bromopropanoic acid or 2-iodopropanoic acid to form intermediate d-c. Intermediate d- c is reacted with a base to form intermediate d-d. Compound d-d is deuterated to form intermediate d-e. The amino group from intermediate d-e is removed and the deprotected group may react with a suitable protecting group to form intermediate d-f. Intermediate d-f is hydrogenated to form compound d-g. Intermediate d-g may undergo a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of intermediate d-h and d-i. Preferably, intermediate d-h and d-i is deprotected to form corresponding intermediates d-j and dk. Intermediates d-j and dk may be reacted with a carboxylic acid having general formula R-COOH to form compounds 58, 59, 60, 62 and 63. Compounds of Formula ID(b) may be prepared by starting with compound a. N-benzyl-L- allothreonine (a) may undergo a nucleophilic substitution reaction with 2-bromopropanoic acid or 2-iodopropanoic acid to form intermediate d-l. Intermediate d-l may undergo intramolecular amide coupling in the presence of a coupling reagent to form intermediate d-m. Compound d- m is deuterated to form intermediate d-n. The carbonyl group of intermediate d-n is removed to form intermediate d-o. Intermediate d-o is selectively deprotected so that it may react with a suitable protecting group to form intermediate d-p. Intermediate d-p is protected to form intermediate d-q. Any suitable protecting group may be used. Intermediate d-q may be deprotected to form compound d-r. Intermediate d-r may undergo a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of intermediate d-s, d-t, and d-u. Preferably, intermediate d-s, d-t, and d-u are deprotected to form corresponding intermediates d-v, d-w, and d-x. Intermediates d-v, d-w, and d-x may be reacted with a carboxylic acid having general formula R-COOH to form compounds 83, 84, 96 and 97. The present invention provides a method for synthesizing intermediate b as shown in the synthetic pathway below: N-benzyl-L-allothreonine a is reduced by reacting with a reducing agent such as borane dimethyl sulfide to form intermediate b. Other suitable reducing agents may be used instead of borane dimethyl sulfide such as but not limited to lithium aluminum hydride, boron trifluoride diethyl etherate and diborane. The reducing agent may be used in excess with respect to starting material a. The excess is preferably 2-times to 10-times of the reducing agent with respect to starting material a. Preferably, a 5-times excess of the reducing agent is used with respect to starting material a. The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about 50°C to about 120°C. Preferably, the reaction is carried out in the range of about 60°C to about 100°C. More preferably, the reaction is carried out in the range of about 60°C to about 80°C. The reaction may be carried out for a duration of about 3 to about 10 hours. Preferably, for a duration of about 5 to about 8 hours. More preferably, the reaction is carried out for a duration of about 6 hours. The present invention provides a method for synthesizing intermediate c as shown in the synthetic pathway below, where PG refers to protecting group: The primary alcohol of intermediate b may be selectively protected using a suitable reagent such as tert-butyldiphenylsilyl to form intermediate c. Other suitable protecting groups may be used including but not limited to tert-butyldimethylsilyl, triisopropylsilyl or trimethylsilyl protecting group. Intermediate b may be reacted with tert-butyl(chloro)diphenylsilane to form intermediate c. Alternatively, intermediate b may be reacted with reagents such as tert-butyldimethylsilyl chloride, triisopropylsilyl chloride or trimethylsilyl chloride to form intermediate c.The reagent may be used in excess with respect to intermediate b. A 1.1-times to 1.5-times excess of the reagent may be used with respect to intermediate b. Preferably, a 1.2-times excess of the reagent is used with respect to intermediate b. The reaction may be carried out in the presence of a catalyst such as DMAP, imidazole or mixtures thereon. Preferably imidazole is used as the catalyst. The catalyst may be used in excess with respect to intermediate b. A 1.1-times to 2-times excess of the catalyst may be used with respect to intermediate b. Preferably, a 1.5-times excess of the catalyst is used with respect to intermediate b. The reaction may be carried out in polar solvents such as acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about 20°C to about 66°C. Preferably, the reaction is carried out at about 25°C.The reaction may be carried out for a duration of about 5 to about 18 hours. Preferably, the reaction is carried out for a duration of about 12 hours. The present invention provides a method for synthesizing intermediate d as shown in the synthetic pathway below, where PG refers to protecting group: Intermediate c may 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. 2-bromopropanoic acid or 2-iodopropanoic acid may be used in excess with respect to intermediate c. A 2-times to 7-times excess of 2-bromopropanoic acid or 2-iodopropanoic acid may be used with respect to intermediate c. Preferably, a 3-times excess of 2-bromopropanoic acid or 2-iodopropanoic acid is used with respect to intermediate c. The reaction is carried out in the presence of a Lewis base. Examples of Lewis bases that may be used for the synthesis of intermediate d include but are not limited to butyl lithium, lithium diisopropylamide (LDA), lithium diethylamide (LDEA), sodium amide (NaNH2), sodium hydride (NaH), lithium bis(trimethylsilyl)amide, or mixtures thereof. Preferably, the Lewis base used in the synthesis of intermediate d is sodium hydride.The Lewis base may be used in excess with respect to intermediate c. A 4-times to 10-times excess of the Lewis base may be used with respect to intermediate c. Preferably, an 8-times excess of the Lewis base is used with respect to intermediate c. The reaction may be carried out in polar solvents such as acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about -10°C to about 66°C. Preferably, the reaction may be carried out at a temperature in the range of about 0°C to about 60°C. The reaction may be carried out for a duration of about 2 to about 10 hours. Preferably, the reaction is carried out for a duration of about 6 hours. The present invention provides a method for synthesizing intermediate e as shown in the synthetic pathway below, where PG refers to protecting group: Intermediate d undergoes an intramolecular amide coupling reaction, optionally in the presence of a coupling reagent to form intermediate e. Suitable coupling reagents include, but are not limited to, DCC, 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. The reaction may be carried out in a polar aprotic solvent such as DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in DMF. The reaction may be carried out at a temperature in the range of about 15°C to about 153°C. Preferably, the reaction may be carried out at a temperature in the range of about 20°C to about 130°C or about 50°C to about 100°C. More preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a duration of about 1 hour to about 5 hours. Preferably, the reaction is carried out for a duration of about 2 hours. The present invention provides a method for synthesizing intermediate f as shown in the synthetic pathway below, where PG refers to protecting group: Intermediate e is reduced by reacting with a reducing agent such as borane dimethyl sulfide to form intermediate f. Other suitable reducing agents may be used instead of borane dimethyl sulfide such as but not limited to lithium aluminum hydride, boron trifluoride diethyl etherate and diborane. The reducing agent may be used in excess with respect to intermediate e. A 2-times to 10- times excess of the reducing agent may be used with respect to intermediate e. Preferably, a 4-times excess of the reducing agent is used with respect to intermediate e. The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about 20°C to about 66°C. Preferably, the reaction may be carried out at a temperature in the range of about 30°C to about 50°C. More preferably, the reaction is carried out at about 30°C. The reaction may be carried out for a duration of about 2 hours to about 8 hours. Preferably, the reaction is carried out for a duration of about 5 hours. The present invention provides a method for synthesizing intermediate g as shown in the synthetic pathway below, where PG’ refers to protecting group: The tert-butyl-diphenylsilane protecting group may be removed from intermediate f by reacting with a source of fluorine to form intermediate g. Suitable reagents as a source of fluorine include but are not limited to tetra-n-butylammonium fluoride (TBAF) or triethylamine trihydrofluoride. Preferably, TBAF is used to form intermediate g. The reagent may be used in excess with respect to intermediate f. A 1.1-times to 2-times excess of the reagent may be used with respect to intermediate f. Preferably, a 1.5-times excess of the reagent is used with respect to intermediate f. The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about 15°C to about 66°C. Preferably, the reaction is carried out at about 20°C to about 50°C. More preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a duration of about 30 mins to about 4 hours. Preferably, the reaction is carried out for a duration of about 1 hour. The present invention provides a method for synthesizing intermediate h as shown in the synthetic pathway below, where PG refers to protecting group: Intermediate g is reacted with hydrogen and palladium over carbon and is subsequently protected to form intermediate h. Preferably, the reaction is carried out under a hydrogen atmosphere at a pressure in the range of about 10 Psi to about 30 Psi. Preferably, the reaction is carried out at about 15 Psi. The conversion of intermediate g to intermediate h may be a one-pot process. Preferably, about 0.02 to about 0.5 equivalents of palladium over carbon is used. More preferably, about 0.05 equivalents of palladium over carbon is used. Any suitable protecting group may be used form intermediate h. Examples of suitable protecting groups that may be used include Fmoc, BOC or Ts. Preferably, BOC is used as the protecting group. Examples of suitable protecting group reagents to form intermediate h include but are not limited to fluorenylmethyloxycarbonyl chloride, 9-fluorenylmethylsuccinimidyl carbonate, 9- fluorenylmethyloxycarbonyl azide, BOC-anhydride, tosylchloride. Preferably, BOC-anhydride is used. The protecting group reagent may be used in excess with respect to intermediate g. A 1.1-times to 2-times excess of the reagent may be used with respect to intermediate g. Preferably, a 1.5-times excess of the reagent with respect to intermediate g. The reaction may be carried out in a polar aprotic solvent such as ethyl acetate, dichloromethane, THF, or mixtures thereof. Preferably, the reaction is carried out in ethyl acetate. The reaction may be carried out at a temperature in the range of about 15°C to about 77°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a duration of about 6 to about 18 hours. Preferably, the reaction is carried out for a duration of about 12 hours. The present invention provides a method for synthesizing intermediate i as shown in the synthetic pathway below, where PG’ refers to protecting group: Intermediate h is reacted with isoindoline-1,3-dione to form intermediate i. Isoindoline-1,3- dione may be used in excess with respect to intermediate h. A 1.1-times to 2-times excess of isoindoline-1,3-dione may be used with respect to intermediate h. Preferably, a 1.5-times excess of isoindoline-1,3-dione is used with respect to intermediate h. Preferably, the reaction is carried out in the presence of triphenylphosphine. Triphenylphosphine may be used in excess with respect to intermediate h. A 1.1-times to 2- times excess of triphenylphosphine may be used with respect to intermediate h. Preferably, a 1.5-times excess of triphenylphosphine is used with respect to intermediate h. The reaction is carried out in the presence of an oxidizer such as DIAD or DEAD. Preferably, the oxidizer DIAD is used. The oxidiser may be used in excess with respect to intermediate h. A 1.1-times to 2-times excess of the oxidiser may be used with respect to intermediate h. Preferably, a 1.5-times excess of the oxidiser is used with respect to intermediate h. The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about -10°C to about 66°C. Preferably, the reaction is carried out at about 0°C to about 20°C. The reaction may be carried out for a duration of about 5 to about 20 hours. Preferably, the reaction is carried out for a duration of about 16 hours. The present invention provides a method for synthesizing intermediate j as shown in the synthetic pathway below, where PG’ refers to protecting group: Intermediate i is reacted with hydrazine or hydrazine hydrate to form intermediate j. Preferably, intermediate i is reacted with hydrazine hydrate to form intermediate j. Hydrazine or hydrazine hydrate may be used in excess with respect to intermediate i. A 5- times to 20-times excess of hydrazine or hydrazine hydrate may be used with respect to intermediate i. Preferably, a 10-times excess of hydrazine or hydrazine hydrate is used with respect to intermediate i. The reaction may be carried out in a polar protic solvent such as alcohols including but not limited to methanol, ethanol, isopropanol or mixtures thereof. Preferably the reaction is carried out in methanol. The reaction may be carried out at a temperature in the range of about 40°C to about 65°C. Preferably, the reaction is carried out at about 60°C. The reaction may be carried out for a duration of about 1 to about 5 hours. Preferably, the reaction is carried out for a duration of about 2 hours. The present invention provides a method for synthesizing intermediate d-b shown in the synthetic pathway below: Compound d-a is reduced by reacting with a reducing agent such as borane tetrahydrofuran to form intermediate d-b. Other suitable reducing agents may be used instead of borane dimethyl sulfide such as but not limited to lithium aluminum hydride, boron trifluoride diethyl etherate and diborane. The reducing agent may be used in excess with respect to starting material d-a. The excess is preferably 2-times to 10-times of the reducing agent with respect to starting material d-a. Preferably, a 3-times excess of the reducing agent is used with respect to starting material aw. The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about -10°C to about 80°C. Preferably, the reaction is carried out in the range of about 0°C to about 70°C. More preferably, the reaction is carried out in the range of about 0°C to about 50°C. The reaction may be carried out for a duration of about 30 minutes to about 5 hours. Preferably, for a duration of about 1 hour to about 4 hours. More preferably, the reaction is carried out for a duration of about 2.5 hours. The present invention provides a method for synthesizing intermediate d-c as shown in the synthetic pathway below: Intermediate d-b may be reacted with 2-bromopropanoic acid or 2-iodopropanoic acid to form intermediate d-c.2-bromopropanoic acid or 2-iodopropanoic acid may be used in excess with respect to intermediate d-b or may be used in equal quantities. The reaction is carried out in the presence of a base, preferably a non-nucleophilic base. Examples that may be used for the synthesis of intermediate may include, but are not limited to N-N-Diisopropylethylamine (DIPEA), 1,8-Diazabicycloundec-7-ene (DBU), 1,5- Diazabicyclo(4.3.0)non-5-ene (DBN), or mixtures thereof. Preferably, the Lewis base used in the synthesis of intermediate ay is N-N-Diisopropylethylamine (DIPEA). The base may be used in excess with respect to intermediate d-b. A 2-times to 6-times excess of the base may be used with respect to intermediate d-b. Preferably, a 3-times excess of the base is used with respect to intermediate d-b. The reaction may be carried out in polar solvents such as acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in THF. 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 with respect to starting material aw. The excess is preferably 0.5-times to 4-times of the coupling agent with respect to starting material aw. Preferably, a 1-times excess of the coupling agent is used with respect to starting material aw. The reaction may be carried out at a temperature in the range of about -10°C to about 60°C. Preferably, the reaction may be carried out at a temperature in the range of about 0°C to about 25°C. The reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, for a duration of about 30 minutes to about 2 hours. More preferably, the reaction is carried out for a duration of about 1 hour. The present invention provides a method for synthesizing intermediate d-d as shown in the synthetic pathway below: Intermediate d-c is reacted with a base to form intermediate d-d. Examples of bases that may be used include but are not limited to lithium hydroxide, sodium hydroxide or potassium hydroxide. Preferably, potassium hydroxide is used. The base may be used in excess with respect to intermediate d-c. A 1-times to 4-times excess of the base may be used with respect to intermediate d-c. Preferably, a 2-times excess of the base is used with respect to intermediate d-c. The reaction may be carried out in a solvent such as THF, DMF, DMSO, a polar protic solvent such as water, methanol, ethanol, isopropanol, a non-polar solvent such as chloroform, 1,4- dioxane or any combination thereof. Preferably the reaction is carried out in a combination of isopropanol and water. The ratio of solvents 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 about 30:1. The ratio of isopropanol and water may be in the range of about 20:1 to about 40:1, more preferably about 30:1. The reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction may be carried out at a temperature of about 25°C. The reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, for a duration of about 30 minutes to about 2 hours. More preferably, the reaction is carried out for a duration of about 1 hour. The present invention provides a method for synthesizing intermediate d-e as shown in the synthetic pathway below: Intermediate d-d lactam is reduced with a deuterated reagent to form intermediate d-e. The deuterated reagent may be lithium aluminium deuteride or sodium borodeuteride. Preferably, the deuterated agent may be lithium aluminium deuteride. The deuterated reagent may be used in excess with respect to starting material d-d. The excess is preferably 1-times to 5-times of the deuterated reagent with respect to starting material d-d. Preferably, a 3-times excess of the deuterated reagent is used with respect to starting material d-d. The reaction may be carried out in polar solvents such as acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in THF. 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, more preferably the reaction may be carried out at a temperature of about 40°C. The reaction may be carried out for a duration of about 5 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 10 hours to about 14 hours. Preferably, for a duration of about 12 hours. The present invention provides a method for synthesizing intermediate d-f as shown in the synthetic pathway below: Intermediate d-e is protected to form intermediate d-f. Any suitable protecting group may be used. Examples of suitable protecting groups that may be used include Fmoc, BOC, or benzyl. Preferably, BoC is used as the protecting group. The protecting group reagent may be used in excess with respect to intermediate d-e. A 1.1- times to 2-times excess of the reagent may be used with respect to intermediate d-e. Preferably, a 1.5-times excess of the reagent with respect to intermediate d-e. The reaction may be carried out in a polar aprotic solvent such as ethyl acetate, dichloromethane, THF, or mixtures thereof. Preferably, the reaction is carried out in ethyl acetate. The reaction may be carried out at a temperature in the range of about 10°C to about 50°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a duration of about 30 minutes to about 3 hours. Preferably, the reaction is carried out for a duration of about 1 hour. The present invention provides a method for synthesizing intermediate d-g as shown in the synthetic pathway below: Intermediate d-f is reacted with hydrogen and palladium hydroxide over carbon and is subsequently protected to form intermediate d-g. 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. The reaction may be carried out in a solvent such as trifluoroethanol, ethyl acetate, dichloromethane, THF, or mixtures thereof. Preferably, the reaction is carried out in trifluoroethanol. Preferably, about 0.05 to about 0.5 equivalents of palladium over carbon is used. More preferably, about 0.1 equivalents of palladium over carbon is used. The reaction may be carried out at a temperature in the range of about 10°C to about 50°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a duration of about 1 hours to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours. The present invention provides a method for synthesizing intermediate d-l as shown in the synthetic pathway below: N-benzyl-L-allothreonine (a) may be reacted with 2-bromopropanoic acid or 2-iodopropanoic acid to form intermediate d-l. The reaction is carried out in the presence of a base, preferably a non-nucleophilic base. Examples that may be used for the synthesis of intermediate may include but are not limited to N-N-Diisopropylethylamine (DIPEA), 1,8-Diazabicycloundec-7-ene (DBU), 1,5- Diazabicyclo(4.3.0)non-5-ene (DBN), sodium tert-butoxide (t-BuONa) or mixtures thereof. Preferably, the base is sodium tert-butoxide (t-BuONa). The base may be used in excess with respect to compound a. A 3-times to 7-times excess of the base may be used with respect to compound a. Preferably, an 5-times excess of the base is used with respect to compound a. The reaction may be carried out in solvents such as solvent such as diethyl ether, benzene, toluene, chloroform, 1,4 dioxane or mixtures thereof. Preferably, the reaction is carried out in 1,4 dioxane. The reaction may be carried out at a temperature in the range of about -10°C to about 60°C. Preferably, the reaction may be carried out at a temperature in the range of about 0°C to about 20°C. The reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, for a duration of about 1 hours to about 3 hours. More preferably, the reaction is carried out for a duration of about 2 hours. The present invention provides a method for synthesizing intermediate d-m as shown in the synthetic pathway below: Intermediate d-l undergoes an intramolecular amide coupling reaction, optionally in the presence of a coupling reagent to form intermediate d-m. 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. The reaction may be carried out in a polar aprotic solvent such as ethyl acetate, dichloromethane, THF, or mixtures thereof. Preferably, the reaction is carried out in ethyl acetate. 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, caesium carbonate, sodium carbonate, sodium hydride, TEA or DIPEA. Preferably, the reaction is carried out in the presence of DIPEA. The reaction may be carried out at a temperature in the range of about -10°C to about 153°C. Preferably, the reaction may be carried out at a temperature in the range of about 20°C to about 130°C or about 50°C to about 100°C. More preferably, the reaction is carried out in the range of about 0°C to about 25°C. The reaction may be carried out for a duration of about 5 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours. The present invention provides a method for synthesizing intermediate d-n as shown in the synthetic pathway below: Intermediate d-m is reacted with isobutyl carbonochloridate d in the presence of a base, and a deuterated reagent or a mixture of deuterated reagents form intermediate d-n. The deuterated reagent may be deuterium oxide, lithium aluminium deuteride or sodium borodeuteride or any combination thereof. Preferably, the deuterated reagent may be sodium borodeuteride or sodium borodeuteride and deteurium oxide. The base may be triethylamine (TEA) or DIPEA. Preferably, the base is TEA. The deuterated reagent may be used in excess with respect to starting material d-m. The excess is preferably 0.5-times to 2-times of the deuterated reagent with respect to starting material d-m. Preferably, a 1.1-times excess of the deuterated reagent is used with respect to starting material d-m. The reaction may be carried out in polar solvents such as acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about -10°C to about 60°C. Preferably, the reaction may be carried out at a temperature in the range of about 0°C to about 25°C. The reaction may be carried out for a duration of about 1 hours to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours. The present invention provides a method for synthesizing intermediate d-o as shown in the synthetic pathway below: Intermediate d-n is reduced by reacting with a reducing agent to form intermediate d-o. The reducing agent may be borane, borane dimethyl sulfide such as but not limited to lithium aluminum hydride, boron trifluoride diethyl etherate and diborane. Preferably, the reducing agent is borane. The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about -10°C to about 80°C. Preferably, the reaction is carried out in the range of about 0°C to about 45°C. The reaction may be carried out for a duration of about 30 minutes to about 5 hours. Preferably, for a duration of about 1 hours to about 3 hours. More preferably, the reaction is carried out for a duration of about 2.5 hours. The present invention provides a method for synthesizing intermediate d-p as shown in the synthetic pathway below: Intermediate d-o is reacted with hydrogen and palladium over carbon and is subsequently protected to form intermediate d-p. 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. Preferably, about 0.02 to about 0.5 equivalents of palladium over carbon is used. More preferably, about 0.05 equivalents of palladium over carbon is used. Any suitable protecting group may be used form intermediate d-p. Examples of suitable protecting groups that may be used include Fmoc, BOC or Ts. Preferably, BOC is used as the protecting group. Examples of suitable protecting group reagents to form intermediate d-p include, but are not limited to, fluorenylmethyloxycarbonyl chloride, 9-fluorenylmethylsuccinimidyl carbonate, 9- fluorenylmethyloxycarbonyl azide, BOC-anhydride, tosyl chloride. Preferably, BOC-anhydride is used. The protecting group reagent may be used in excess with respect to intermediate d-o. A 1.1- times to 2-times excess of the reagent may be used with respect to intermediate bk. Preferably, a 1.5-times excess of the reagent with respect to intermediate d-o. The reaction may be carried out in a polar aprotic solvent such as ethyl acetate, dichloromethane, THF, or mixtures thereof. Preferably, the reaction is carried out in ethyl acetate. The reaction may be carried out at a temperature in the range of about 15°C to about 77°C. Preferably, the reaction is carried out at about 20°C.The reaction may be carried out for a duration of about 10 to about 20 hours. Preferably, the reaction is carried out for a duration of about 16 hours. The present invention provides a method for synthesizing intermediate d-q as shown in synthetic pathway below: Intermediate d-p is reacted with isoindoline-1,3-dione to form intermediate d-q. Isoindoline- 1,3-dione may be used in excess with respect to intermediate d-p. A 1.1-times to 2-times excess of isoindoline-1,3-dione may be used with respect to intermediate bl. Preferably, a 1.5- times excess of isoindoline-1,3-dione is used with respect to intermediate d-p. Preferably, the reaction is carried out in the presence of triphenylphosphine. Triphenylphosphine may be used in excess with respect to intermediate d-p. A 1.1-times to 2- times excess of triphenylphosphine may be used with respect to intermediate d-p. Preferably, a 1.5-times excess of triphenylphosphine is used with respect to intermediate d-p. The reaction is carried out in the presence of an oxidizer such as DIAD or DEAD. Preferably, the oxidizer DIAD is used. The oxidiser may be used in excess with respect to intermediate d- p. A 1.1-times to 2-times excess of the oxidiser may be used with respect to intermediate d-p. Preferably, a 1.5-times excess of the oxidiser is used with respect to intermediate d-p. The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about -10°C to about 66°C. Preferably, the reaction is carried out at about 0°C to about 20°C. The reaction may be carried out for a duration of about 5 to about 20 hours. Preferably, the reaction is carried out for a duration of about 16 hours. The present invention provides a method for synthesizing intermediate d-r as shown in the synthetic pathway below: Intermediate d-q is reacted with hydrazine or hydrazine hydrate to form intermediate bn. Preferably, intermediate bm is reacted with hydrazine hydrate to form intermediate d-r. Hydrazine or hydrazine hydrate may be used in excess with respect to intermediate d-q. A 5- times to 20-times excess of hydrazine or hydrazine hydrate may be used with respect to intermediate d-q. Preferably, a 10-times excess of hydrazine or hydrazine hydrate is used with respect to intermediate d-q. The reaction may be carried out in a polar protic solvent such as alcohols including but not limited to methanol, ethanol, isopropanol or mixtures thereof. Preferably the reaction is carried out in methanol. The reaction may be carried out at a temperature in the range of about 40°C to about 65°C. Preferably, the reaction is carried out at about 60°C.The reaction may be carried out for a duration of about 1 to about 5 hours. Preferably, the reaction is carried out for a duration of about 2 hours. 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-dimethylmorpholin-3-one or (2S,5R,6S)-4-Benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholin-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-dimethylmorpholin-3-yl)methanol or ((2S,3R,6S)-4-Benzyl-2,6- dimethylmorpholin-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-dioxoisoindolin-2-yl)methyl)-2,6-dimethylmorpholine-4- carboxylate or tert-Butyl(2S,3R,6S)-3-((1,3-dioxoisoindolin-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-dimethylmorpholin-3-one (intermediate d-n); ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholin-3-yl)methan-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-dioxoisoindolin-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). Preferably, intermediate j can be prepared starting from any of the intermediates (a) – (i). 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) is prepared by: - reducing N-benzyl-L-allothreonine (a) by reacting with a reducing agent to form 2R,3S)-2-(Benzylamino)butane-1,3-diol (intermediate b); - reacting intermediate (b) with tert-butyl(chloro)diphenylsilane to form (2S,3R)-3- (Benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (intermediate c); - reacting intermediate (c) with (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); - subjecting intermediate (d) to an intramolecular amide coupling reaction in the presence of a coupling reagent to form (2R,5R,6S)-4-Benzyl-5-(((tert- butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholin-3-one or (2S,5R,6S)-4- Benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholin-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 source of fluorine to form ((2S,3R,6R)-4-Benzyl- 2,6-dimethylmorpholin-3-yl)methanol (intermediate g) or ((2S,3R,6S)-4-Benzyl- 2,6-dimethylmorpholin-3-yl)methanol (intermediate g); - reacting intermediate (g) with hydrogen, palladium over 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-dioxoisoindolin-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate or tert- Butyl (2S,3R,6S)-3-((1,3-dioxoisoindolin-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). In one aspect of the present invention there is provided a method for synthesizing compounds 1-57, 61, 64-82, 85-95, 98-120 as shown in the synthetic pathway below: The structure of compounds 1-57, 61, 64-82, 85-95, 98-120 is as shown herein above. The present invention also provides a method for preparing a compound of Formula I: wherein R and Het are as herein defined above; said method comprising the steps of: (a) reacting tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate (intermediate j) with a halo-substituted heteroaromatic compound in the presence of a base to form a first intermediate compound (intermediates k-a to k-s); (b) reacting the first intemediate compound with an acid to form a second intermediate compound (intermediates I-a to I-s); and (c) reacting the second intemediate compound with a carboxylic acid having a general formula R-COOH to obtain a compound of Formula I. Preferably, intermediate j undergoes a nucleophilic aromatic substitution reaction with a halo- substituted heteroaromatic compound to form one of intermediates k-a to k-s. The intermediates k-a to k-s may be 6R,2S,3R-stereoisomer, 6S,2S,3R-stereoisomer or mixtures thereof. Preferably, intermediates k-a to k-s are: tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate or tert-Butyl (2S,3R,6S)-2,6-dimethyl-3-(((5- (trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate k-a); tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylate or tert-Butyl (2S,3R,6S)-2,6-dimethyl-3-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate k-b); tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylate or tert-Butyl (2S,3R,6S)-2,6-dimethyl-3-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate k-c); tert-Butyl (2S,3R,6R)-3-(((5-chloropyridin-2-yl)amino)methyl)-2,6-dimethylmorpholine-4- carboxylate or tert-Butyl (2S,3R,6S)-3-(((5-chloropyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (intermediate k-d); tert-Butyl (2S,3R,6R)-3-(((5-chloropyrimidin-2-yl)amino)methyl)-2,6-dimethylmorpholine-4- carboxylate or tert-Butyl (2S,3R,6S)-3-(((5-chloropyrimidin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (intermediate k-e); tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((4-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylate or tert-butyl (2S,3R,6S)-2,6-dimethyl-3-(((4- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate k-f); tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((6-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate or tert-Butyl (2S,3R,6S)-2,6-dimethyl-3-(((6- (trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate k-g); tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((4-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylate or tert-Butyl (2S,3R,6S)-2,6-dimethyl-3-(((4- (trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylate (intermediate k-h); tert-Butyl (2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (intermediate k-i); tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino) methyl)morpholine-4-carboxylate (intermediate k-j); tert-butyl (2S,3R,6R)-3-(((3,5-bis(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6-dimethyl morpholine-4-carboxylate (intermediate k-k); tert-butyl (2S,3R,6R)-3-(((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (intermediate k-l); tert-Butyl (2S,3R,6R)-3-(((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (intermediate k-m); tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate (intermediate k-n); tert-Butyl (2S,3R,6R)-3-(((3-cyano-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (intermediate k-o); tert-Butyl (2S,3R,6R)-3-(((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (intermediate k-p); tert-Butyl (2S,3R,6R)-3-(((5-chloro-3-fluoropyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (intermediate k-q); tert-Butyl (2S,3R,6R)-3-(((3-fluoro-4-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (intermediate k-r); or tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((4-methyl-5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylate (intermediate k-s). In some examples, 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 with a halo-substituted heteroaromatic compound in the presence of a base in step (a) to form the first intermediate compound. The first intemediate compound may be reacted with an acid to form the second intermediate compound; and the second intemediate compound may be reacted with a carboxylic acid having a general formula R-COOH to obtain a deuterated compound of Formula I. In one aspect of the present invention there is provided a method for synthesizing compounds 58, 59, 60, 62 and 63 as shown in the synthetic pathway below: The structure of compounds 58, 59, 60, 62 and 63 are as shown herein above. The present invention also provides a method for preparing compounds of Formula ID (a): wherein: R and Het are each as defined herein with respect to Formula I; and R6 is H or deuterium (D), the method comprising the steps of: (a) reacting tert-butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4- carboxylate-5,5-d2 (d-g) with a halo-substituted heteroaromatic compound in the presence of a base to form a first intermediate compound (d-h, d-i); (b) reacting the first intermediate compound with an acid to form a second intermediate compound (d-j, d-k); and (c) reacting the second intermediate compound with a carboxylic acid having a general formula R-COOH to obtain a compound of Formula ID(a). Preferably, intermediate d-g may be prepared starting from any of the intermediates d-a to d- f. Preferably, intermediate d-g may be prepared by: - reducing (2S,3S)-2-amino-N,N-dibenzyl-3-hydroxybutanamide by reacting with a reducing agent to form (2S,3R)-3-amino-4-(dibenzylamino)butan-2-ol (d-b); - reacting intermediate d-b with 2-bromopropanoic acid to form intermediate d-c in the presence of a Lewis base to form (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-dimethylmorpholin-3-one (intermediate d-d); - reducing intermediate d-d with a deuterated agent, and reacting with a protecting group to form tert-butyl (2S,3R,6R)-3-((dibenzylamino)methyl)-2,6- dimethylmorpholine-4-carboxylate-5,5-d2 (intermediate d-f); and - reacting intermediate d-f with hydrogen and palladium hydroxide over carbon and is subsequently protected to form intermediate d-g. Preferably, intermediate d-g undergoes a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of intermediates d-h and d-i. Preferably, intermediates d-h and d-i are: tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridin-2 yl)amino) methyl) morpholine-4-carboxylate-5,5-d2 (intermediate d-h); or tert-Butyl (2S,3R,6R)-3-(((5-chloropyridin-2-yl)amino)methyl)-2,6-dimethylmorpholine- 4-carboxylate-5,5-d2 (intermediate d-i). In one aspect of the present invention there is provided a method for synthesizing compounds 83, 84, 96 and 97 as shown in the synthetic pathway below:
The structure of compounds 83, 84, 96 and 97 are as shown herein above. The present invention also provides a method for preparing compounds of Formula ID(b): wherein: R and Het are each as defined herein with respect to Formula I; and R7 is H or deuterium (D); The method comprising the steps of: (a) reacting tert-butyl (2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4- carboxylate (d-r) with a halo-substituted heteroaromatic compound in the presence of a base to form a first intermediate (d-s to d-u); (b) reacting the first intermediates with an acid to form a second intermediate (d-r to d-t); and (c) reacting the second intermediates with a carboxylic acid having a general formula R- COOH to obtain a compound of Formula ID(b). Preferably, intermediate d-r can be prepared starting from any of the intermediates a, d-m to d-q. Preferably, intermediate d-r is prepared by: - reacting N-benzyl-L-allothreonine (a) with 2-bromopropanoic acid or 2- iodopropanoic, followed by an intramolecular amide coupling reaction with a coupling reaction to form (2S,3S,6R)-4-benzyl-2,6-dimethyl-5-oxomorpholine-3- carboxylic acid (intermediate d-m); - reducing intermediate d-m with a deuterated agent to form (2R,5R,6S)-4-benzyl- 5-(hydroxymethyl-d2)-2,6-dimethylmorpholin-3-one (intermediate d-n); - reducing intermediate d-n with a reducing agent to form ((2S,3R,6R)-4-benzyl-2,6- dimethylmorpholin-3-yl)methan-d2-ol (intermediate d-o); - reacting intermediate d-o with hydrogen and palladium over carbon and is subsequently protected 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-dioxoisoindolin-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (intermediate d-q); - reacting intermediate d-q with hydrazine or hydrazine hydrate to form intermediate d-r; Preferably, intermediate (d-r) undergoes a nucleophilic aromatic substitution reaction with a halo-substituted heteroaromatic compound to form one of intermediates d-s to d-u. Preferably, intermediates d-s to d-u are: tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl- d2)morpholine-4-carboxylate (intermediate d-s); tert-Butyl (2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl-d2)- 2,6-dimethylmorpholine-4-carboxylate (intermediate d-t); or tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl-d2)morpholine-4-carboxylate (intermediate d-u). The halo-substituted heteroaromatic compound may be selected from the group consisting of halo-substituted pyridine, halo-substituted pyridazine, halo-substituted pyrazine, halo- substituted pyrimidine, halo-substituted triazole, halo-substituted tetrazole, halo-substituted pyrazole, halo-substituted furan, halo-substituted thiophene, halo-substituted pyrrole, halo- substituted imidazole, halo-substituted isoxazole, halo-substituted oxazole, halo-substituted isothiazole, halo-substituted thiazole and any derivatives thereof, wherein said halo- substituted heteroaromatic group may be further substituted; wherein the further substituents of the halo-substituted heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (C1-C4)-straight chain alkyl, unsubstituted (C1-C4)-branched alkyl, substituted (C1-C4)-straight chain alkyl, substituted (C1-C4)-branched alkyl, (C3-C8)- cycloalky, (C1-C4) alkoxy, cyano, and halogen. Preferably, the further substituents of the heteroaromatic group is CHF2, CF3, cyclopropyl, methoxy, nitrile or a halogen such as chlorine, flourine. The halo-substituted heteroaromatic compound may be a fluoro-substituted heteroaromatic compound, chloro-substituted heteroaromatic compound, bromo-substituted heteroaromatic compound or iodo-substituted heteroaromatic compound. Preferably, the halo-substituted heteroaromatic compound may be a chloro-substituted heteroaromatic compound or a fluoro- substituted heteroaromatic compound. The halo-substituted heteroaromatic compound is preferably selected from 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, 2-chloro-6- (trifluoromethyl)pyrazine, 2-fluoro-4-(trifluoromethyl)pyridine, 2,3-difluoro-5- (trifluoromethyl)pyridine,3-bromo-2-fluoro-5-(trifluoromethyl)pyridine, 2-chloro-3,5- bis(trifluoromethyl)pyridine, 2-chloro-3-methoxy-5-(trifluoromethyl)pyridine, 3-chloro-2-fluoro- 5-(trifluoromethyl)pyridine, 3-methyl-5-(trifluoromethyl)pyrazin-2-ol (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. The nucleophilic aromatic substitution reaction is carried out in the presence of a base. Examples of bases that may be used include but are not limited to potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA or DIPEA. Preferably, the nucleophilic aromatic substitution reaction is carried out in the presence of potassium carbonate (K2CO3) or DIPEA. K2CO3 or DIPEA may be used as a base for preparing non- deuterated intermediates; and DIPEA may be used as a base for preparing deuterated intermediates. The base may be used in excess with respect to intermediate j, d-g or d-r. A 2-times to 6-times excess of the base may be used with respect to intermediate j, d-g or d-r. Preferably, a 3-times excess of the base is used with respect to intermediate j, d-g or d-r . The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in DMF or DMSO. The solvent may be DMF or DMSO for preparing non-deuterated intermediates. The solvent may be DMSO for preparing deuterated intermediates The nucleophilic aromatic substitution reaction may be carried out at a temperature in the range of about 50°C to about 189°C. Preferably, the reaction is carried out at about 60 °C to about 100°C. The reaction may be carried out at a temperature 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, more preferably the reaction is carried out at about 140°C. The reaction may be carried out for a duration of about 1 hour to about 5 hours. Preferably, the reaction is carried out for a duration of about 2 hours. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere. Preferably, intermediates k-a to k-s, d-h, d-i, d-s, dt, d-u are deprotected by treatment with an acid to form corresponding intermediates l-a to l-s, d-j, d-k, d-v, d-w, d-x. The intermediates l-a to l-s may be 6R,2S,3R-stereoisomer, 6S,2S,3R-stereoisomer or mixtures thereof. Preferably, intermediates l-a to l-s are: N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2- amine hydrochloride or N-(((2S,3R,6S)-2,6-Dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyrazin-2-amine hydrochloride (intermediate l-a); N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2- amine hydrochloride or N-(((2S,3R,6S)-2,6-dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyrimidin-2-amine hydrochloride (intermediate l-b); N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride or N-(((2S,3R,6S)-2,6-Dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine hydrochloride (intermediate l-c); 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)pyridin-2-amine hydrochloride or 5-Chloro-N-(((2S,3R,6S)-2,6-dimethylmorpholin-3-yl)methyl)pyridin- 2-amine hydrochloride (intermediate l-d); 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)pyrimidin-2-amine hydrochloride or 5-Chloro-N-(((2S,3R,6S)-2,6-dimethylmorpholin-3- yl)methyl)pyrimidin-2-amine hydrochloride (intermediate l-e); N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-4-(trifluoromethyl)pyrimidin-2- amine hydrochloride or N-(((2S,3R,6S)-2,6-Dimethylmorpholin-3-yl)methyl)-4- (trifluoromethyl)pyrimidin-2-amine hydrochloride (intermediate l-f); N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-6-(trifluoromethyl)pyrazin-2- amine hydrochloride or N-(((2S,3R,6S)-2,6-dimethylmorpholin-3-yl)methyl)-6- (trifluoromethyl)pyrazin-2-amine hydrochloride (intermediate l-g); N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-4-(trifluoromethyl)pyridin-2-amine hydrochloride or N-(((2S,3R,6S)-2,6-dimethylmorpholin-3-yl)methyl)-4- (trifluoromethyl)pyridin-2-amine hydrochloride (intermediate l-h); N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-3-fluoro-5- (trifluoromethyl)pyridin-2-amine hydrochloride (intermediate l-i); N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-methyl-5- (trifluoromethyl)pyridin-2-amine (intermediate l-j); N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-3,5-bis(trifluoromethyl)pyridin-2- amine hydrochloride (intermediate l-k) N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-3-methoxy-5- (trifluoromethyl)pyridin-2-amine (intermediate l-l); 3-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine (intermediate l-m); N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-methyl-5- (trifluoromethyl)pyrazin-2-amine (intermediate l-n); 2-((((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)amino)-5- (trifluoromethyl)nicotinonitrile hydrochloride (intermediate l-o); 3-(Difluoromethyl)-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine hydrochloride (intermediate l-p); 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-fluoropyridin-2-amine hydrochloride (intermediate l-q); N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-3-fluoro-4-methyl-5- (trifluoromethyl)pyridin-2-amine (intermediate l-r); or N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-4-methyl-5- (trifluoromethyl)pyrimidin-2-amine (intermediate l-s). Preferably, intermediates d-j and d-k are: N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyridin- 2-amine (intermediate d-j); 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl-5,5-d2)methyl)pyridin-2-amine hydrochloride (intermediate d-k). Preferably, intermediates d-v, d-w, and d-x are: N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl)pyridin-2- amine hydrochloride (intermediate d-v); N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl-d2)-3-fluoro-5-(trifluoromethyl) pyridin-2-amine hydrochloride (intermediate d-w); N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl-d2)-3-methyl-5-(trifluoromethyl) pyridin-2-amine hydrochloride (intermediate d-x). Examples of acids that may be used for the deprotection include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid. Preferably, hydrochloric acid is used for the deprotection of intermediates k-a to k-s, d-h, d-i, d-s, d-t, d-u. The deprotection may be carried out in a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1,4-dioxane or mixtures thereof. Preferably the reaction is carried out in 1,4-dioxane. Intermediates k-a to k-s, d-h, d-i, d-s, d-t, d-u is preferably reacted with 4M HCl in 1,4 dioxane. An excess of 4M HCl in 1,4-dioxane may be used with respect to intermediates k-a to k-s, d- h, d-i, d-s, d-t, d-u. A 15-times to 40-times excess of 4M HCl in 1,4-dioxane may be used with respect to intermediates k-a to k-s, d-h, d-i, d-s, d-t, d-u. Preferably, a 30-times excess of 4M HCl in 1,4-dioxane is used with respect to intermediates k-a to k-s, d-h, d-i, d-s, d-t, d- u. The deprotection may be carried out at a temperature in the range of about 12°C to about 40°C. Preferably, the reaction is carried out at about 25 °C. The deprotection 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 deprotection may be carried out for a duration of about 30 mins to about 5 hours. Preferably, the reaction is carried out for a duration of about 1 hour. The deprotection may be carried out for a duration of about 1 hours to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours. Preferably, intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x are reacted with carboxylic acid having the general formula R-COOH to form compounds 1-120 disclosed herein; wherein R is selected from the group consisting of a five or a six membered aromatic or heteroaromatic group, wherein the aromatic group or heteroaromatic group is either unsubstituted or is substituted with one or more substituents. Preferably, R in the compound of Formula I comprises a five membered heteroaromatic group which is an unsubstituted pyrazole, an unsubstituted oxazole, an unsubstituted thiazole, an unsubstituted imidazole, a substituted pyrazole, a substituted oxazole, a substituted thiazole, a substituted imidazole or a derivative thereof; or a six membered aromatic group which is unsubstituted aryl, or substituted aryl, or a derivative thereof. The carboxylic acid R-COOH preferably comprises 4-(4-chlorophenyl)-1-methyl-pyrazole-3- carboxylic acid (CAS 1534651-22-3), 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS 956317-36-5), 3-fluoro-2-(pyrimidin-2-yl)benzoic acid (CAS 1293285-04-7), 4-(5- chloropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (CAS 2125741-28-6), 4-(5- fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (CAS 2125741-56-0), 5- fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS 1186050-64-5), 5-fluoro-2-(pyrimidin-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-fluoropyrimidin-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-methoxypyridin-2-yl)-1-methyl- 1H-pyrazole-3-carboxylic acid (CAS 2024759-24-6), 5-(5-fluoropyrimidin-2-yl)-1-methyl-1H- imidazole-4-carboxylic acid, 5-(5-methoxypyridin-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid, 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid, 4-(5-fluoropyrimidin- 2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid, or 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H- pyrazole-3-carboxylic acid, 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3- carboxylic acid, 4-(5-fluoropyrimidin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid, 6-methyl-3-(pyrimidin-2-yl)picolinic acid (CAS 1228188-18-8), 6-methyl-3-(2H-1,2,3- triazol-2-yl)picolinic acid (CAS 1228188-37-1), 5-fluoro-3-(pyrimidin-2-yl)picolinic acid (CAS 1935682-37-3), 5-fluoro-2-(2H-1,2,3-triazol-2-yl)nicotinic acid (CAS 2138851-77-9), 5-fluoro- 2-(1H-pyrazol-1-yl)benzoic acid (CAS 1152964-04-9), 3-(pyrimidin-2-yl)picolinic acid (CAS 1228431-21-7), 3-(2H-1,2,3-triazol-2-yl)picolinic acid (CAS 1252907-86-0), 3-(5- fluoropyrimidin-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-(pyrazin-2-yl)picolinic acid (CAS 1228431-07-9), 6-methyl-3-(5- methylpyrimidin-2-yl)picolinic acid (CAS 1228431-09-1), 6-methyl-3-(4-methylpyrimidin-2- yl)picolinic acid (CAS 1228431-12-6), 3-(5-fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazole-2-carboxylic acid, 3-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-4-carboxylic acid, 5-fluoro-3-(2H-1,2,3-triazol-2-yl)picolinic acid, 5,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid, 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid, 6-methyl-3-(pyrimidin-2-yl)pyrazine-2- carboxylic acid, 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid, 4-(4-cyanophenyl)-1,5- dimethyl-1H-pyrazole-3-carboxylic, 6-(methyl-d3)-3-(pyrimidin-2-yl)picolinic acid, 6-(methyl- d3)-3-(2H-1,2,3-triazol-2-yl)picolinic acid, 4-(5-fluoropyrimidin-2-yl)-1-methyl-5-(methyl-d3)- 1H-pyrazole-3-carboxylic acid. The carboxylic acid may be used in excess with respect to intermediates l-a to l-s, d-j, d-k, d-v, d-w, d-x. A 1.2-times to 3-times excess of the carboxylic acid may be used with respect to intermediates l-a to l-s, d-j, d-k, d-v, d-w, d-x. Preferably, a 1.5-times excess of the carboxylic acid is used with respect to intermediates l-a to l-s, d-j, d-k, d-v, d-w, d-x. The reaction of intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x with carboxylic acid R-COOH may be carried out in the presence of a coupling reagent. Suitable coupling reagents include but are not limited to DCC, 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. The coupling reagent may be used in excess with respect to intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x. A 1.2-times to 3-times excess of the coupling reagent may be used with respect to intermediates I-a to I-s, d-j, d-k,d-v, d-w,d-x. Preferably, a 1.5-times excess of the coupling reagent is used with respect to intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x. The reaction of intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x with carboxylic acid R-COOH may be carried out in the presence of a base. Any suitable base may be used for this reaction. Examples of suitable bases include but are not limited DIPEA or TEA. Preferably, DIPEA is used as the base in the reaction. The base may be used in excess with respect to intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x. A 2-times to 6-times excess of the base may be used with respect to intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x. Preferably, a 4-times excess of the base is used with respect to intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x. The reaction of intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x with carboxylic acid R-COOH may be carried out in a polar aprotic solvent such as THF, dichloromethane, ethyl acetate, DMF or DMSO. Preferably the reaction is carried out in dichloromethane. The reaction of intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x with carboxylic acid R-COOH may be carried out at a temperature in the range of about -10°C to about 40°C. Preferably, the reaction is carried out from about 0°C to about 20°C. The reaction of intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x with carboxylic acid R-COOH may be carried out for a duration of about 1 hours to about 6 hours. Preferably, the reaction is carried out for a duration of about 2 hours. The present invention also provides a method for synthesizing carboxylic acid with general formula R-COOH as shown in the synthetic pathway below: The R-COOH group may be 4-(5-Methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. The starting material selected from tert-butyl 4-iodo-1-methyl-1H-pyrazole-3-carboxylate, tert- butyl 4-bromo-1-methyl-1H-pyrazole-3-carboxylate, or tert-butyl 4-chloro-1-methyl-1H- pyrazole-3-carboxylate may be reacted with (4-cyanophenyl)boronic acid or derivatives thereof (for example boronic esters or organotrifluoroborate salts), via Suzuki coupling to form an intermediate. Alternatively, the starting material selected from tert-butyl 4-iodo-1-methyl-1H-pyrazole-3- carboxylate, tert-butyl 4-bromo-1-methyl-1H-pyrazole-3-carboxylate, or tert-butyl 4-chloro-1- methyl-1H-pyrazole-3-carboxylate may be reacted with 4-cyanophenyl derivatives that are suitable for Hiyama coupling, Stille coupling, Heck coupling, Kumada coupling or Negishi coupling. (4-cyanophenyl)boronic acid or derivatives thereof may be used in excess with respect to the starting material. A 1.1-times to 1.5-times excess of (4-cyanophenyl)boronic acid or derivatives thereof may be used with respect to the starting material. Preferably, a 1.2-times excess of (4- cyanophenyl)boronic acid or derivatives thereof is used with respect to the starting material. The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO, a polar protic solvent such as water, methanol, ethanol, isopropanol, a non-polar solvent such as chloroform, 1,4-dioxane or any combination thereof. Preferably the reaction is carried out in a combination of THF and water. 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 the catalyst is used with respect to the starting material. More preferably, about 0.05 equivalents of the catalyst is used. The reaction may be carried out in the presence of a base. Examples of bases that may be used include but are not limited to K2CO3, KOtBu, Cs2CO3, K3PO4, NaOH, or NEt3. Preferably, K3PO4 is used. The base may be used in excess with respect to the starting material. A 2-times to 6-times excess of the base may be used with respect to the starting material. Preferably, a 3-times excess of the base is used with respect to the starting material. The reaction may be carried out at a temperature in the range of about 50 °C to about 100 °C. Preferably, the reaction is carried out at about 80 °C. The reaction may be carried out for a duration of about 30 mins to about 5 hours. Preferably, the reaction is carried out for a duration of about 2 hours. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere. The intermediate formed may be deprotected by reacting with an acid. Examples of acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid. Preferably, hydrochloric acid is used. The deprotection may be carried out in a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1,4-dioxane or mixtures thereof. Preferably the reaction is carried out in 1,4-dioxane. The deprotection may be carried out at a temperature in the range of about 20°C to about 80°C. Preferably, the reaction is carried out at about 50°C.More preferably, the reaction is carried out at about 20°C.The deprotection may be carried out for a duration of about 30 mins to about 5 hours. Preferably, the reaction is carried out for a duration of about 2 hours. The present invention also provides an alternative method for synthesizing carboxylic acid with general formula R-COOH as shown in the synthetic pathway below: The R-COOH group may be 4-(5-Cyanopyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid. The starting material (3-(tert-butoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)boronic acid, 3-(tert- butoxycarbonyl)-1-methyl-5-(methyl-d3)-1H-pyrazol-4-yl)boronic acid or derivatives thereof (for example boronic esters or organotrifluoroborate salts) may be reacted with compounds selected from 6-iodopyridine-3-carbonitrile, 6-bromopyridine-3-carbonitrile, 6-chloropyridine- 3-carbonitrile or 2-bromo-5-fluoro-pyrimidine, via Suzuki coupling to form an intermediate. Alternatively, the starting material may be reacted with (3-(tert-butoxycarbonyl)-1-methyl-1H- pyrazol-4-yl) derivatives that are suitable for Hiyama coupling, Stille coupling, Heck coupling, Kumada coupling or Negishi coupling. The compounds selected from 6-iodopyridine-3-carbonitrile, 6-bromopyridine-3-carbonitrile, 6-chloropyridine-3-carbonitrile or 2-bromo-5-fluoro-pyrimidine may be used in excess with respect to the starting material. A 1.1-times to 1.5-times excess of may be used with respect to the starting material. Preferably, a 1.2-times excess of is used with respect to the starting material. The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO, a polar protic solvent such as water, methanol, ethanol, isopropanol, a non-polar solvent such as chloroform, 1,4-dioxane or any combination thereof. Preferably the reaction is carried out in a combination of 1,4-dioxane and water.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 the catalyst is used with respect to the starting material. Preferably, about 0.05 equivalents of the catalyst is used.The reaction may be carried out in the presence of a base. Examples of bases that may be used include but are not limited to K2CO3, KOtBu, Cs2CO3, K3PO4, NaOH, or NEt3. Preferably, K3PO4 is used. The base may be used in excess with respect to the starting material. A 1.1-times to 5-times excess of the base may be used with respect to the starting material. Preferably, a 1.5-times excess of the base is used with respect to the starting material. The reaction may be carried out at a temperature in the range of about 50°C to about 100°C. Preferably, the reaction is carried out at about 80°C.The reaction may be carried out for a duration of about 30 mins to about 5 hours. Preferably, the reaction is carried out for a duration of about 2 hours. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere. The intermediate formed may be deprotected by reacting with an acid. Examples of acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid. Preferably. hydrochloric acid is used. The deprotection may be carried out in a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1,4-dioxane or mixtures thereof. Preferably the reaction is carried out in 1,4-dioxane. The deprotection may be carried out at a temperature in the range of about 10°C to about 50°C. Preferably, the reaction is carried out at about 20°C. The deprotection may be carried out for a duration of about 6 hours to about 18 hours. Preferably, the reaction is carried out for a duration of about 12 hours. Similarly, the method for synthesizing carboxylic acid with general formula R-COOH is shown in the synthetic pathway below: Preferably the R-COOH may be 4-(5-Methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3- carboxylic acid. The starting material (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazol-4-yl)boronic acid or derivatives thereof (for example boronic esters or organotrifluoroborate salts) may be reacted with compounds selected from 2-iodo-5-methoxy-pyridine, 2-bromo-5-methoxy-pyridine or 2- chloro-5-methoxy-pyridine, via Suzuki coupling to form an intermediate. Alternatively, the starting material may be reacted with (3-(tert-butoxycarbonyl)-1,5-dimethyl- 1H-pyrazol-4-yl) derivatives that are suitable for Hiyama coupling, Stille coupling, Heck coupling, Kumada coupling or Negishi coupling. The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO, a polar protic solvent such as water, methanol, ethanol, isopropanol, a non-polar solvent such as chloroform, 1,4-dioxane or any combination thereof. Preferably the reaction is carried out in a combination of DMF 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(PPh3)4 is used as the catalyst.Preferably, about 0.02 to about 0.5 equivalents of the catalyst is used with respect to the starting material. Preferably, about 0.05 equivalents of the catalyst is used. The reaction may be carried out in the presence of a base. Examples of bases that may be used include but are not limited to K2CO3, KOtBu, Cs2CO3, K3PO4, NaOH, or NEt3. Preferably, K3PO4 is used. The base may be used in excess with respect to the starting material. A 1.1- times to 5-times excess of the base may be used with respect to the starting material. Preferably, a 1.5-times excess of the base is used with respect to the starting material. The reaction may be carried out at a temperature in the range of about 50°C to about 100°C. Preferably, the reaction is carried out at about 80°C.The reaction may be carried out for a duration of 2 hours to about 16 hours. Preferably, the reaction is carried out for a duration of about 12 hours. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere. The intermediate formed may be deprotected by reacting with an acid. Examples of acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid. Preferably. hydrochloric acid is used. The deprotection may be carried out in a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1,4-dioxane or mixtures thereof. Preferably the reaction is carried out in 1,4-dioxane. The deprotection may be carried out at a temperature in the range of about 10°C to about 50°C. Preferably, the reaction is carried out at about 20°C. The deprotection may be carried out for a duration of about 6 hours to about 18 hours. Preferably, the reaction is carried out for a duration of about 12 hours. The present invention also provides another alternative method for synthesizing carboxylic acid with general formula R-COOH as shown in the synthetic pathway below: The R-COOH may be 5-(5-fluoropyrimidin-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid. The 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 may be converted to an organostannane intermediate by reacting with hexaalkylditin such as hexamethylditin or hexabutylditin. The hexaalkylditin may be used in excess with respect to the starting material. A 1.2-times to 5-times excess of may be used with respect to the starting material. Preferably, a 2-times excess of is used with respect to the starting material. The reaction may be carried out in a non-polar solvent such as chloroform, 1,4-dioxane, or toluene. Preferably the reaction is carried out in toluene. 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 the catalyst is used with respect to the starting material. More preferably, about 0.1 equivalents of the catalyst is used. The reaction may be carried out at a temperature in the range of about 50°C to about 120°C. Preferably, the reaction is carried out in the range of about 100°C to about 120°C. The reaction may be carried out for a duration of about 3 mins to about 10 hours. Preferably, the reaction is carried out for a duration of about 6 hours. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere. The organostannane intermediate may be reacted with compounds selected from 2-bromo-5- fluoro-pyrimidine, 2-iodo-5-fluoro-pyrimidine or 2-chloro-5-fluoro-pyrimidine, via Stille coupling to form a second intermediate. Alternatively, compounds selected from 2-bromo-5-fluoro-pyrimidine, 2-iodo-5-fluoro- pyrimidine or 2-chloro-5-fluoro-pyrimidine may be reacted with 1-methyl-1H-imidazole-4- carboxylate derivatives that are suitable for Hiyama coupling, Suzuki coupling, Heck coupling, Kumada coupling or Negishi coupling. Compounds selected from 2-bromo-5-fluoro-pyrimidine, 2-iodo-5-fluoro-pyrimidine or 2- chloro-5-fluoro-pyrimidine may be used in excess with respect to the organostannane intermediate. A 1.1-times to 3-times excess of may be used with respect to the organostannane intermediate. Preferably, a 1.5-times excess of is used with respect to the the organostannane intermediate. The reaction may be carried out in a non-polar solvent such as chloroform, 1,4-dioxane, xylene or toluene. Preferably, the reaction is carried out in xylene. 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 the catalyst is used with respect to the organostannane intermediate. Preferably, about 0.1 equivalents of the catalyst is used. The reaction may be carried out at a temperature in the range of about 50°C to about 140°C. Preferably, the reaction is carried out at about 120°C.The reaction may be carried out for a duration of about 10 hours to about 22 hours. Preferably, the reaction is carried out for a duration of 16 hours. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere. The second intermediate may be deprotected by reacting with an acid or a base. Examples of acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid. Examples of bases that may be used include but are not limited to lithium hydroxide, sodium hydroxide or potassium hydroxide. Preferably, hydrochloric acid is used. The deprotection may be carried out in neat acid or base. The concentration of the acid or base may range from about 3 M to about 10 M. Preferably, a concentration of about 6 M is used. The deprotection may be carried out at a temperature in the range of about 50°C to about 100°C. Preferably, the reaction is carried out at about 80°C.The deprotection may be carried out for a duration of about 6 hours to about 22 hours. Preferably, the reaction is carried out for a duration of about 16 hours. The present invention also provides yet another alternative method for synthesizing carboxylic acid with general formula R-COOH as shown in the synthetic pathway below: The R-COOH may be 5-(5-Methoxypyridin-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid. The 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 may be reacted with tributyl-(5-methoxy-2-pyridyl)stannane or derivatives thereof (for example trimethyl-(5-methoxy-2-pyridyl)stannane), via Stille coupling to form an intermediate. Alternatively, 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 may be reacted with 5-methoxy-2-pyridyl derivatives that are suitable for Hiyama coupling, Suzuki coupling, Heck coupling, Kumada coupling or Negishi coupling. Tributyl-(5-methoxy-2-pyridyl)stannane or derivatives thereof may be used in excess with respect to the starting material. A 1.1-times to 1.5-times excess of tributyl-(5-methoxy-2- pyridyl)stannane or derivatives thereof may be used with respect to the starting material. Preferably, a 1.2-times excess of tributyl-(5-methoxy-2-pyridyl)stannane or derivatives thereof is used with respect to the starting material. The reaction may be carried out in a non-polar solvent such as chloroform, 1,4-dioxane, xylene or toluene. Preferably the reaction is carried out in xylene. 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 the catalyst is used with respect to the starting material. Preferably, about 0.1 equivalents of the catalyst is used. The reaction may be carried out at a temperature in the range of about 50°C to about 140°C. Preferably, the reaction is carried out at about 140°C. The reaction may be carried out for a duration of about 10 hours to about 20 hours. Preferably, the reaction is carried out for a duration of about 16 hours. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere. The intermediate may be deprotected by reacting with an acid or a base. Examples of acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid. Examples of bases that may be used include but are not limited to lithium hydroxide, sodium hydroxide or potassium hydroxide. Preferably, hydrochloric acid is used. The deprotection may be carried out in neat acid or base. The concentration of the acid or base may range from about 3 M to about 10 M. Preferably, a concentration of about 6 M is used. The deprotection may be carried out at a temperature in the range of about 50°C to about 100°C. Preferably, the reaction is carried out at about 80°C. The deprotection may be carried out for a duration of about 6 hours to about 22 hours. Preferably, the reaction is carried out for a duration of about 16 hours. The present invention also provides yet another alternative method for synthesizing carboxylic acid with general formula R-COOH as shown in the synthetic pathway below: The R-COOH may be 4-(5-Fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. The 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 may be used. Examples of suitable protecting groups that may be used include Me, BOC or benzyl. Preferably, BOC is used as the protecting group. Examples of suitable reagents to form the first intermediate include but are not limited to, BOC- anhydride, MeOH, benzyl alcohol or 2-benzyloxy-1-methylpyridinium triflate. Preferably, BOC- anhydride is used. The reagent may be used in excess with respect to the first intermediate. A 1.5-times to 5- times excess of the reagent may be used with respect to the first intermediate. Preferably, a 3-times excess of the reagent with respect to the first intermediate. The reaction may be carried out in the presence of a catalyst such as DMAP, imidazole or mixtures thereof. Preferably imidazole is used as the catalyst. The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO, a polar protic solvent such as water, methanol, ethanol, isopropanol, tert-butyl alcohol, a non-polar solvent such as chloroform, 1,4-dioxane or any combinations thereof. Preferably the reaction is carried out in a combination of THF and tert-butyl alcohol. The reaction may be carried out at a temperature in the range of about 10°C to about 50°C. Preferably, the reaction is carried out at about 20°C.The reaction may be carried out for a duration of about 6 to about 18 hours. Preferably, the reaction is carried out for a duration of about 12 hours. The first intermediate may be converted into a boronic acid or derivatives thereof (for example boronic esters or organotrifluoroborate salts) to form a second intermediate. The first intermediate may be reacted with a tri(alkyl)borate such as trimethylborate, tributylborate or triisopropylborate to form the second intermediate. The tri(alkyl)borate may be used in excess with respect to the first intermediate. A 1.2-times to 3-times excess of tri(alkyl)borate may be used with respect to the first intermediate. Preferably, a 1.5-times excess of tri(alkyl)borate is used with respect to the first intermediate. The reaction may be carried out in a polar aprotic solvent such as THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF. The reaction is carried out in the presence of a Lewis base. Examples of Lewis bases that may be used for the synthesis of the second intermediate include but are not limited to butyl lithium, lithium diisopropylamide (LDA), lithium diethylamide (LDEA), sodium amide (NaNH2), sodium hydride (NaH), lithium bis(trimethylsilyl)amide, or mixtures thereof. Preferably, the Lewis base used in the synthesis of the second intermediate is butyl lithium. The Lewis base may be used in excess with respect to the first intermediate. A 1.2-times to 3- times excess of the Lewis base may be used with respect to the first intermediate. Preferably, a 1.5-times excess of the Lewis base is used with respect to the first intermediate. The reaction may be carried out at a temperature b in the range of about -78°C to about 60°C. Preferably, the reaction is carried out at about -78°C to about 20°C.The reaction may be carried out for a duration of about 1 hour to about 8 hours. Preferably, the reaction is carried out for a duration of about 3 hours. The second intermediate may be reacted with may be reacted with 2-bromo-5-fluoro- pyrimidine or 2-iodo-5-fluoro-pyrimidine or 2-chloro-5-fluoro-pyrimidine, via Suzuki coupling to form a third intermediate. Alternatively, 2-bromo-5-fluoro-pyrimidine or 2-iodo-5-fluoro-pyrimidine or 2-chloro-5-fluoro- pyrimidine may be reacted with (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazol-4-yl) derivatives that are suitable for Hiyama coupling, Stille coupling, Heck coupling, Kumada coupling or Negishi coupling. 2-bromo-5-fluoro-pyrimidine or 2-iodo-5-fluoro-pyrimidine or 2-chloro-5-fluoro-pyrimidine may be used in excess with respect to the second intermediate. A 1.1-times to 3-times excess of may be used with respect to the second intermediate. Preferably, a 1.5-tiFdeutmes excess of is used with respect to the second intermediate. The reaction may be carried out in a polar aprotic solvent such as DMF, DMSO or mixtures thereof; in a polar protic solvent such as water, methanol, ethanol, isopropanol, tert-butyl alcohol, or any combination thereof. Preferably the reaction is carried out in a combination of DMF and water. 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 the catalyst is used with respect to the second intermediate. Preferably, about 0.05 equivalents of the catalyst is used. The reaction may be carried out in the presence of a base. Examples of bases that may be used include but are not limited to K2CO3, KOtBu, Cs2CO3, K3PO4, NaOH, or NEt3. Preferably, K2CO3 is used. The base may be used in excess with respect to the second intermediate. A 1.1-times to 3-times excess of the base may be used with respect to the second intermediate. Preferably, a 1.5-times excess of the base is used with respect to the second intermediate. The reaction may be carried out at a temperature in the range of about 50°C to about 153°C. Preferably, the reaction is carried out at about 80°C.The reaction may be carried out for a duration of about 8 hours to about 20 hours. Preferably, the reaction is carried out for a duration of about 12 hours. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere. The third intermediate formed may be deprotected by reacting with an acid. Examples of acids that may be used include but are not limited to hydrochloric acid, trifluoroacetic acid or phosphoric acid. Preferably hydrochloric acid is used.The deprotection may be carried out in a non-polar solvent such as diethyl ether, benzene, toluene, chloroform, 1,4-dioxane or mixtures thereof. Preferably the reaction is carried out in 1,4-dioxane. The deprotection may be carried out at a temperature in the range of about 20°C to about 80°C. Preferably, the reaction is carried out at about 20°C.The deprotection may be carried out for a duration of about 8 hours to about 20 hours. Preferably, the reaction is carried out for a duration of about 12 hours. The present invention also provides a method for preparing 3-(5-Fluoropyrimidin-2-yl)-5,6- dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid, as shown in the scheme below: Bromine may be added to a solution of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid in a solvent. Examples of a solvent include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or a mixture thereof. Preferably the reaction is carried out in dichloromethane. The reaction may be carried out at a temperature in the range of about - 10°C to about 10°C. Preferably, the reaction is carried out at about 0 °C. The reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, the reaction may be carried out for a duration of about 2 hours. The reaction mixture may be quenched by addition of saturated sodium thiosulfate aqueous solution to give 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid. 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid may be reacted with 2-tert- butyl-3-isopropyl-1,1-dimethyl-isourea in a solvent. Examples of a solvent include but are not limited to THF, DMF, DMSO or mixtures thereof. Preferably the solvent is carried out in THF. The reaction may be carried out at a temperature in the range of about -10°C to about 40°C. Preferably, the reaction is carried out in the range of at about 0 °C to about 20 °C. The reaction may be carried out for a duration of about 10 hours to about 20 hours. Preferably, the reaction is carried out for a duration of about 16 hours. The reaction mixture may be quenched by addition of saturated ammonium chloride aqueous solution to give tert-butyl 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate. Tert-butyl 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate may be reacted with triisopropyl borate in a solvent. Examples of a solvent include but are not limited to THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about -10°C to about 40°C. Preferably, the reaction is carried out in the range of at about 0 °C to about 20 °C. n-BuLi may then be added. The reaction may be carried out at a temperature in the range of about -100°C to about -50°C. Preferably, the reaction is carried out at about -78°C The reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours. The reaction mixture may then be quenched by addition saturated ammonium chloride aqueous solution as described above to give (2-(tert-butoxycarbonyl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)boronic acid. (2-(tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)boronic acid may be added to 2-bromo-5-fluoro-pyrimidine in the presence of a base. Examples of a base that may be used include but are not limited to potassium carbonate, caesium 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 mixtures thereof. Preferably the solvent is DMF and water. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) may be added to give tert-butyl 3-(5- fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere. The reaction may be carried out at a temperature in the range of about 50°C to about 150°C. Preferably, the reaction is carried out at about 80°C. The reaction may be carried out for a duration of about 10 hours to about 16 hours. Preferably, the reaction is carried out for a duration of about 12 hours. Tert-butyl 3-(5-fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate may be treated with an acid to produce 3-(5-Fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazole-2-carboxylic acid. Examples of acids that may be used include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid or mixtures thereof. Preferably, hydrochloric acid is used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof. Preferably the solvent is dioxane. The reaction may be carried out at a temperature in the range of about 10°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 30 minutes to about 3 hours. Preferably, the reaction is carried out for a duration of about 1 hour. The present invention also provides a method for preparing 3-(5-Fluoropyridin-2-yl)-1,5- dimethyl-1H-pyrazole-4-carboxylic acid as shown in the scheme below: 5-fluoro-2-pyridyl)-trimethyl-stannane may be added to methyl 3-iodo-1,5-dimethyl-1H- pyrazole-4-carboxylate and caesium fluoride in a solvent. Examples of solvents include but are not limited to as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof. Preferably, the solvent is dioxane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. Iodocopper and Tetrakis(triphenylphosphine)palladium(0) may 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 mixture may be purified to give methyl 3-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H- pyrazole-4-carboxylate. Preferably, it is purified by column chromatograph on silica gel. Lithium hydroxide monohydrate may be added to methyl 3-(5-fluoropyridin-2-yl)-1,5-dimethyl- 1H-pyrazole-4-carboxylate in the presence of one or more solvents to give to give 3-(5- fluoropyridin-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 duration of about 1 hours to about 3 hours. Preferably, the reaction is carried out for a duration of about 2 hours. 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 scheme below: 3,5-difluoropicolinonitrile may 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 may be used include but are not limited to potassium carbonate, caesium 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 duration of about 10 hours to about 16 hours. Preferably, the reaction is carried out for a duration of about 12 hours. The product may be purified to give 5-fluoro-3-(2H-1,2,3-triazol-2-yl)picolinonitrile. Preferably it is purified by flash silica gel chromatography. 5-fluoro-3-(2H-1,2,3-triazol-2-yl)picolinonitrile may be stirred in an acid to give 5-Fluoro-3-(2H- 1,2,3-triazol-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 duration of about 3 hours to about 7 hours. Preferably, the reaction is carried out for a duration of about 5 hours. The present invention also provides a method for preparing 5-Fluoro-3-(5-fluoropyrimidin-2- yl)picolinic acid as shown in the scheme below: (5-fluoropyrimidin-2-yl)-trimethyl-stannane may be added to methyl 3-bromo-5- fluoropicolinate and caesium fluoride in a solvent. Examples of solvent include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in DMF. Iodocopper and palladiumtriphenylphosphane may 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 duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours. The reaction mixture may be purified to give methyl 5-fluoro-3-(5-fluoropyrimidin-2- yl)picolinate. Preferably it is purified by column chromatograph on silica gel. Lithium hydroxide monohydrate may be added to methyl 5-fluoro-3-(5-fluoropyrimidin-2- yl)picolinate in the presence of one or more solvents to give 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 duration of about 1 hours to about 3 hours. Preferably, the reaction is carried out for a duration of about 2 hours. The present invention also provides a method for preparing 5,6-Dimethyl-3-(pyrimidin-2- yl)picolinic acid, as shown in the scheme below:
3-bromo-5,6-dimethylpyridin-2-amine may be added to tributyl(pyrimidin-2-yl)stannane in a solvent and caesium fluoride. Examples of solvents include but are not limited to as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof. Preferably, the solvent is dioxane. Iodocopper and palladiumtriphenylphosphane may be added to the mixture. The reaction may be carried out at a temperature in the range of about 70°C to about 130°C. Preferably, the reaction is carried out at about 100 °C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours. The residue may be purified to give 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-amine. Preferably it is purified by column chromatography on silica gel. 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-amine may be added to an acid or a combination of the acids. Example of acids may be sulfuric acid, acetic acid, phosphoric acid, hydrochloric acid, trifluoroacetic acid, or a mixture thereof. Preferably, the acid is sulfuric acid and acetic acid. A solution of sodium nitrite in water may be added to give 5,6-Dimethyl-3-(pyrimidin-2- yl)pyridin-2-ol. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours. 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-ol (1.4 g, 6.96 mmol, 1 eq) may be added to trifluoromethylsulfonyl trifluoromethanesulfonate in the presence of a solvent and a base to give residue 5,6-Dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl trifluoromethanesulfonate. Examples of a solvent that may be used include but are not limited to THF, dichloromethane, ethyl acetate, DMF or DMSO or mixtures thereof. Preferably the solvent is dichloromethane. Examples of bases that may be used include but are not limited to potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA or DIPEA or mixtures thereof. Preferably the base is DIPEA. The reaction may be carried out at a temperature in the range of about 0°C to about 60°C. Preferably, the reaction is carried out at about 30°C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours. Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)Cl2) may be added to 5,6- dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl trifluoromethanesulfonate in the presence of a solvent and a base to give methyl 5,6-dimethyl-3-(pyrimidin-2-yl)picolinate. Examples of bases include but are not limited to potassium carbonate, caesium carbonate, sodium carbonate, sodium hydride, TEA, 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 duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours. The reaction may be carried out in the presence of carbon monoxide at a pressure of 50 psi. Lithium hydroxide monohydrate may be added to methyl 5,6-dimethyl-3-(pyrimidin-2- yl)picolinate in the presence of one or more solvents. Examples of solvents include but are not limited to THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, dioxane or mixtures thereof. Preferably, the solvents are methanol and THF. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a duration of about 1 hours to about 5 hours. Preferably, the reaction is carried out for a duration of about 3 hours. The present invention also provides a method for preparing 4,6-Dimethyl-3-(pyrimidin-2- yl)picolinic acid, as shown in the scheme below:
5-bromo-2,4-dimethylpyridine may be reacted with a mixture of tributyl(pyrimidin-2- yl)stannane, caesium fluoride, iodocopper and Tetrakis(triphenylphosphine)palladium(0) (Pd(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 duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours. The crude product may be purified to give 2-(4,6-dimethylpyridin-3-yl)pyrimidine. Preferably, purification may be carried out by column chromatography on silica gel. Meta-chloroperoxybenzoic acid is added to a solution of 2-(4,6-dimethylpyridin-3-yl)pyrimidine in the presence of a solvent. Examples of solvent include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in dichloromethane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a duration of about 30 minutes hours to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours. The reaction mixture may be quenched by addition of sodium sulfite to give 2,4-dimethyl-5- (pyrimidin-2-yl)pyridine 1-oxide. Trimethylsilyl cyanide may be added to 2,4-dimethyl-5-(pyrimidin-2-yl)pyridine 1-oxide in a solvent. Examples of solvent may include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or mixtures thereof. Preferably the solvent is dichloromethane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a duration of about 30 minutes to about 3 hours. Preferably, the reaction is carried out for a duration of about 1 hours. N,N-dimethylcarbamoyl chloride may then be added. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a duration of 14 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 17 hours. Sodium hydroxide may be added to 4,6-dimethyl-3-(pyrimidin-2-yl)picolinonitrile in the presence of one or more solvents to give 4,6-Dimethyl-3-(pyrimidin-2-yl)picolinic acid. Examples of solvents include but are not limited to THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, dioxane or mixtures thereof. Preferably, the solvents are methanol and water. The reaction may be carried out at a temperature in the range of about 30°C to about 90°C. Preferably, the reaction is carried out at about 60°C. The reaction may be carried out for a duration of 36 hours to about 60 hours. Preferably, the reaction is carried out for a duration of about 48 hours. The present invention also provides a method for preparing 6-Methyl-3-(pyrimidin-2- yl)pyrazine-2-carboxylic acid, as shown in the scheme below: 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane may 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 as 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, caesium carbonate, sodium carbonate, sodium hydride, TEA or DIPEA, or mixtures thereof. Preferably, the base is potassium carbonate. Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)Cl2) may then 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 duration of 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours. Tributyl(pyrimidin-2-yl)stannane may be reacted with a mixture of methyl 3-chloro-6- methylpyrazine-2-carboxylate, caesium fluoride, iodocopper and Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) in the presence of a solvent. Examples of solvent 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 in 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 duration of 3 hours to about 9 hours. Preferably, the reaction is carried out for a duration of about 6 hours. Methyl 6-methyl-3-(pyrimidin-2-yl)pyrazine-2-carboxylate may be treated with an acid to produce 6-Methyl-3-(pyrimidin-2-yl)pyrazine-2-carboxylic acid. Examples of acids include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid. Preferably, hydrochloric acid is used. The reaction may be carried out at a temperature in the range of about 40°C to about 120°C. Preferably, the reaction is carried out at about 80°C. The reaction may be carried out for a duration of 30 minutes to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours. The present invention also provides a method for preparing 4-Chloro-6-methyl-3-(pyrimidin-2- yl)picolinic acid, as shown in the scheme below: An acid and a solvent may be added to 3-bromo-6-methylpicolinic acid. Examples of acids include but are not limited to sulfuric acid, acetic acid, phosphoric acid, hydrochloric acid, trifluoroacetic acid, or mixtures thereof. Preferably, the acid is sulfuric acid. Examples of solvents include but are not limited to THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, 1,4-dioxane or mixtures thereof. Preferably, the solvent is methanol. The reaction may be carried out at a temperature in the range of about 40°C to about 100°C. Preferably, the reaction is carried out at about 70°C. The reaction may be carried out for a duration of 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours. Methyl 3-bromo-6-methylpicolinate may be added to tributyl(pyrimidin-2-yl)stannane, cesium fluoride, iodocopper, tetrakis(triphenylphosphine)palladium(0) in the presence of a solvent. Examples of solvents include but are not limited to as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof. Preferably, the solvent is dioxane. The reaction may be carried out at a temperature in the range of about 60°C to about 140°C. Preferably, the reaction is carried out at about 100°C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours. 3-chlorobenzenecarboperoxoic acid may be added to methyl 6-methyl-3-(pyrimidin-2- yl)picolinate in a solvent. Examples of solvent include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in dichloromethane. The reaction may be carried out at a temperature in the range of about 50°C to about 10°C. Preferably, the reaction is carried out at about 30°C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours. The reaction mixture may be quenched by addition of a saturated sodium sulfite solution. Phosphoryl chloride may be added to 2-(methoxycarbonyl)-6-methyl-3-(pyrimidin-2-yl)pyridine 1-oxide to form methyl 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinate. The reaction may be carried out at a temperature in the range of about 90°C to about 150°C. Preferably, the reaction is carried out at about 120°C. The reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours. Lithium hydroxide monohydrate may be added to methyl 4-chloro-6-methyl-3-(pyrimidin-2- yl)picolinate in the presence of one or more solvents. Examples of solvents include but are not limited to THF, DMF, DMSO, water, methanol, ethanol, isopropanol, chloroform, 1,4- dioxane or mixtures thereof. Preferably, the solvents are methanol and THF. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20°C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours. The present invention also provides a method for preparing 6-(Methyl-d3)-3-(pyrimidin-2- yl)picolinic acid, as shown in the scheme below: Tributyl(pyrimidin-2-yl)stannane may be reacted with a mixture of methyl 6-amino-3- bromopicolinate, caesium fluoride, iodocopper and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) in the presence of a solvent. Examples of solvent include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or combinations thereof. Preferably the reaction is carried out in dichloromethane. The reaction may be carried out in nitrogen. The reaction may be carried out at a temperature in the range of about 80°C to about 140°C. Preferably, the reaction is carried out at about 110°C. The reaction may be carried out for a duration of 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours. The residue may be quenched with a potassium fluoride aqueous solution to give methyl 6- amino-3-(pyrimidin-2-yl)picolinate. Tert-butyl nitrite and copper bromide may be added to methyl 6-amino-3-(pyrimidin-2- yl)picolinate in the presence of a solvent. Examples of solvents include but are not limited to acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in acetonitrile. The reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a duration of 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours. Trideuterio(deuteriooxy)methane was added to 5,7-ditert-butyl-3-phenyl-1,3-benzoxazol-3- ium tetrafluoroborate in methyl tert-butyl ether. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere. The reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction is carried out at about 25°C. Pyridine may be added into the mixture under an argon atmosphere. The reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a duration of about 15 minutes to about 1 hour. Preferably, the reaction is carried out for a duration of about 30 minutes. bis[2-(2-pyridyl)phenyl]iridium(1+)4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine hexafluorophosphate, 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine dibromonickel, quinuclidine may be added to the mixture. Methyl 6-bromo-3-(pyrimidin-2-yl)picolinate may then be added in dimethylacetamide to the mixture under an inert atmosphere. Preferably, the reaction is carried out under an argon atmosphere. The reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours. Methyl 6-(methyl-d3)-3-(pyrimidin-2-yl)picolinate may then be added to an acid and water. Examples of acids include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid. Preferably, hydrochloric acid is used. The reaction may be carried out at a temperature in the range of about 40°C to about 120°C. Preferably, the reaction is carried out at about 80°C. The reaction may be carried out for a duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours. The present invention also provides a method for preparing 6-(Methyl-d3)-3-(2H-1,2,3-triazol- 2-yl)picolinic acid hydrochloride. 2H-triazole, caesium carbonate, N1,N2-dimethylcyclohexane-1,2-diamine, iodocopper may be added to a solution of 3-bromo-6-chloropicolinic acid in a solvent. Examples of solvents include but are not limited to diethyl ether, benzene, toluene, chloroform, dioxane, methanol or mixtures thereof. Preferably the solvents are dioxane and water. The reaction may be carried out at a temperature in the range of about 80°C to about 120°C. Preferably, the reaction is carried out at about 100°C. The reaction may be carried out for a duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours. 2-tert-butyl-1,3-diisopropyl-isourea may be added to 6-chloro-3-(2H-1,2,3-triazol-2-yl)picolinic acid in the presence of a solvent. Examples of solvents include but are not limited to acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about 0°C to about 50°C. Preferably, the reaction is carried out at about 25°C. The reaction may be carried out for a duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours. Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)Cl2), tripotassium phosphate and tert-butyl 6-chloro-3-(2H-1,2,3-triazol-2-yl)picolinate may be added to (methyl- d3)boronic acid in the presence of a solvent to give methyl 5,6-dimethyl-3-(pyrimidin-2- yl)picolinate. Examples of solvents include but are not limited to water, acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in THF and water. The reaction may be carried out at a temperature in the range of about 40°C to about 120°C. Preferably, the reaction is carried out at about 80°C. The reaction may be carried out for a duration of about 2 hours to about 6 hours. Preferably, the reaction is carried out for a duration of about 4 hours. Tert-butyl 6-(methyl-d3)-3-(2H-1,2,3-triazol-2-yl)picolinate be treated with an acid to produce 6-(Methyl-d3)-3-(2H-1,2,3-triazol-2-yl)picolinic acid hydrochloride in the presence of a solvent. Examples of acids include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid. Preferably, hydrochloric acid is used. Example of solvents include but are not limited to as diethyl ether, benzene, toluene, chloroform, dioxane, methanol or mixtures thereof. Preferably the reaction is carried out in dioxane and methanol. The reaction may be carried out at a temperature in the range of about 30°C to about 90°C. Preferably, the reaction is carried out at about 60 °C. The reaction may be carried out for a duration of about 1 hours to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours. The present invention also provides a method for preparing 4-(5-Fluoropyrimidin-2-yl)-1- methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylic acid as shown in the scheme below: 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid may be added to Di-tert-butyl dicarbonate, tert-butyl alcohol and 4-Dimethylaminopyridine in the presence of a solvent. Examples of solvents include but are not limited to water, acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about 00°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours. Tert-butyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate may be reacted with n-BuLi trideuterio(iodo)methane in a suitable solvent. Examples of solvents include but are not limited to THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF. The reaction may be carried out at a temperature in the range of about -10°C to about 40°C. Preferably, the reaction is carried out in the range of at about 0 °C to about 20 °C. n-BuLi may then be added. The reaction may be carried out at a temperature in the range of about -100°C to about -50°C. Preferably, the reaction is carried out at about -78°C The reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours. The reaction mixture may be quenched by addition of saturated ammonium chloride solution. N-Bromosuccinimide may added to a solution of tert-butyl 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 DMF. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours. Isopropylmagnesium chloride lithium chloride may 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 duration of about 30 minutes to about 2 hours. Preferably, the reaction is carried out for a duration of about 1 hour. Triisopropyl borate may then be added to the reaction mixture. The reaction may be carried out at a temperature in the range of about -80°C to about -20°C. Preferably, the reaction is carried out at about -50 °C. The reaction may be carried out for a duration of about 1 hours to about 5 hours. Preferably, the reaction is carried out for a duration of about 3 hours. 2-bromo-5-fluoro-pyrimidine and potassium carbonate may be added to (3-(tert- butoxycarbonyl)-1-methyl-5-(methyl-d3)-1H-pyrazol-4-yl)boronic acid in a solvent. Examples of solvents include but are not limited to water, THF, DMF, DMSO or mixtures thereof. Preferably the reaction is carried out in THF and water. Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) may then be added. The reaction may be carried out at a temperature in the range of about 60°C to about 120°C. Preferably, the reaction is carried out at about 90 °C. The reaction may be carried out for a duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours. Tert-butyl 4-(5-fluoropyrimidin-2-yl)-1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylate be treated with an acid to 4-(5-fluoropyrimidin-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. Preferably, hydrochloric acid is used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof. Preferably the reaction is carried out in dioxane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 5 hours to about 11 hours. Preferably, the reaction is carried out for a duration of about 8 hours. The present invention also provides a method for preparing 4-(5-Fluoropyridin-2-yl)-5-methyl- 1-(methyl-d3)-1H-pyrazole-3-carboxylic acid as shown in the scheme below: 2-bromo-5-fluoro-pyridine, potassium carbonate, and tetrakis(triphenylphosphine) palladium(0) (Pd(PPh3)4) may be added to (3-(tert-butoxycarbonyl)-5-methyl-1-(methyl-d3)- 1H-pyrazol-4-yl)boronic acid in the presence of one or more solvents. Examples of solvents include but are not limited to water, acetonitrile, DMF, DMSO, pyridine, THF or mixtures thereof. Preferably the reaction is carried out in DMF and water. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere. The reaction may be carried out at a temperature in the range of about 50°C to about 150°C. Preferably, the reaction is carried out at about 80°C The reaction may be carried out for a duration of about 10 hours to about 16 hours. Preferably, the reaction is carried out for a duration of about 12 hours. The product may be purified to give tert-butyl 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)- 1H-pyrazole-3-carboxylate. Preferably the product is purified by column chromatography on silica gel. Tert-butyl 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate may be treated with an acid to produce 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3- carboxylic acid. Examples of acids include but are not limited to aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid or mixtures thereof. Preferably, hydrochloric acid is used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof. Preferably the reaction is carried out in dioxane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours. The present invention also provides a method for preparing 4-(5-Fluoropyrimidin-2-yl)-5- methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid as shown in the scheme below:
Sodium hydride may be added to ethyl 4-bromo-5-methyl-1H-pyrazole-3-carboxylate in a solvent to form a mixture. 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 duration of about 15 minutes to about 1 hour. Preferably, the reaction is carried out for a duration of about 30 minutes. Trideuterio(iodo)methane may be added into the mixture. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 2 hours to about 4 hours. Preferably, the reaction is carried out for a duration of about 3 hours. The mixture may be quenched with saturated ammonium chloride solution. The product may be purified to give ethyl 4-bromo-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate. Preferably, it is purified by column chromatography on silica gel. Lithium hydroxide monohydrate may be added to ethyl 4-bromo-5-methyl-1-(methyl-d3)-1H- pyrazole-3-carboxylate in the presence of one or more solvents to give 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. he reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 1 hours to about 3 hours. Preferably, the reaction is carried out for a duration of about 2 hours. 2-tert-butyl-1,3-diisopropyl-isourea may be added to 4-bromo-5-methyl-1-(methyl-d3)-1H- pyrazole-3-carboxylic acid in the presence of a solvent to give tert-butyl 4-bromo-5-methyl-1- (methyl-d3)-1H-pyrazole-3-carboxylate. Examples of solvent include but are not limited to THF, dichloromethane, ethyl acetate, DMF, DMSO or combinations thereof. Preferably the reaction is carried out in dichloromethane. The reaction may be carried out at a temperature in the range of about 20°C to about 80°C. Preferably, the reaction is carried out at about 50°C. The reaction may be carried out for a duration of 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours. Triisopropyl borate may 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. n-BuLi may then be added to give (3-(tert-Butoxycarbonyl)-5-methyl-1-(methyl-d3)-1H- pyrazol-4-yl)boronic acid. The reaction may be carried out at a temperature in the range of about -100°C to about -50°C. Preferably, the reaction is carried out at about -78°C The reaction may be carried out for a duration of about 30 minutes to about 4 hours. Preferably, the reaction is carried out for a duration of about 2 hours. The reaction may be carried out under an inert atmosphere. Preferably, the reaction is carried out under a nitrogen atmosphere. The reaction mixture may be quenched by addition of saturated ammonium chloride solution to obtain (3-(tert-Butoxycarbonyl)-5-methyl-1-(methyl-d3)-1H-pyrazol-4-yl)boronic acid. 2-bromo-5-fluoro-pyrimidine and potassium carbonate may be added to 3-(tert- butoxycarbonyl)-5-methyl-1-(methyl-d3)-1H-pyrazol-4-yl)boronic acid in the presence of one or more solvents. Examples of solvents include but are not limited to water, 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. Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) may then be added. The reaction may be carried out at a temperature in the range of about 40°C to about 120°C. Preferably, the reaction is carried out at about 80 °C. The reaction may be carried out for a duration of about 9 hours to about 15 hours. Preferably, the reaction is carried out for a duration of about 12 hours. The mixture was stirred at 80°C for 12 hours. The product may be purified to give tert-butyl 4-(5-fluoropyrimidin-2-yl)-5-methyl-1-(methyl- d3)-1H-pyrazole-3-carboxylate. Preferably it is purified by column chromatography on silica gel. Tert-butyl 4-(5-fluoropyrimidin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate may be treated with an acid to produce 4-(5-fluoropyrimidin-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. Preferably, hydrochloric acid is used. The reaction may be carried out in a solvent such as diethyl ether, benzene, toluene, chloroform, dioxane or mixtures thereof. Preferably the reaction is carried out in dioxane. The reaction may be carried out at a temperature in the range of about 0°C to about 40°C. Preferably, the reaction is carried out at about 20 °C. The reaction may be carried out for a duration of about 13 hours to about 19 hours. Preferably, the reaction is carried out for a duration of about 16 hours. EXAMPLES The present invention is further described with reference to the following examples, which are not provided to limit the scope of the present invention. I. General Synthetic Methods and Procedures Example 1: Synthesis of (2R,3S)-2-(Benzylamino)butane-1,3-diol (b) To a solution of N-benzyl-L-allothreonine (15 g, 68.10 mmol, 1 eq) in tetrahydrofuran (300 mL) was added BH3.DMS (10 M, 34.05 mL, 5 eq) at 0°C under N2. The mixture was stirred at 80°C for 6 hrs. LCMS showed all the starting materials were consumed, desired MW was detected. This reaction was cooled 0°C, then was quenched with methyl alcohol (100 mL). Then the solution was concentrated under reduced pressure to give crude product (14 g, 64.53 mmol, 94.75% yield) as a colorless oil, which was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.32 (br d, J=1.25 Hz, 5 H) 4.38 (br d, J=2.25 Hz, 1 H) 3.89 (br s, 2 H) 2.99 - 3.61 (m, 3 H) 1.73 - 2.47 (m, 2 H) 0.75 - 1.52 (m, 3 H). 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 eq) in dimethyl sulfoxide (300 mL) was added imidazole (7.85 g, 115.23 mmol, 1.5 eq) and TBDPSCl (25.34 g, 92.19 mmol, 23.59 mL, 1.2 eq). The mixture was stirred at 25°C for 12 hrs. LCMS showed all the starting materials were consumed; desired MW was detected. This reaction mixture was quenched by addition of water (1000 mL) at 0°C, then the mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (2 x 1000 mL), dried over Na2SO4, filtered, and concentrated to give crude product. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 4/1) to give (2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (6 g, 19.38 mmol, 25.23% yield) as colorless oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.57 - 7.68 (m, 4 H) 7.37 - 7.50 (m, 6 H) 7.15 - 7.31 (m, 5 H) 4.43 (d, J=4.88 Hz, 1 H) 3.60 - 3.85 (m, 5 H) 2.54 (m, 1 H) 1.05 (d, J=6.38 Hz, 3 H) 0.98 (s, 9 H). Example 3: Synthesis of (R)-2-(((2S,3R)-3-(Benzylamino)-4-((tert- butyldiphenylsilyl)oxy)butan-2-yl)oxy)propanoic acid (d) To a solution of (2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (5 g, 11.53 mmol, 1 eq) in tetrahydrofuran (100 mL) was added (2S)-2-bromopropanoic acid (7.06 g, 46.12 mmol, 4 eq). The solution was cooled to 0°C. The NaH (4.61 g, 115.30 mmol, 60% purity, 8 eq) was added into the solution at 0°C. The mixture was stirred at 60°C for 6 hrs. LCMS showed all the starting materials remained, 50% desired MW was detected. This reaction was poured into HCl (1 N), adjusted pH 7. This reaction was extracted with ethyl acetate (30 mL x 3), combined organic layer was concentrated under reduced pressure to give 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 light yellow oil. The product was used for the next step directly, without further purification. LCMS (ESI+): m/z = 506.4 (M+1), RT: 0.819 min (Column Agilent Poroshell SB-C18 3.0*30mm, 4um. Detection method was diode array (DAD). MS mode was positive electrospray ionization. MS range was 50-2000. Mobile phase A was 0.04% Trifluoroacetic acid in water, and mobile phase B was 0.02% Trifluoroacetic acid in HPLC grade acetonitrile. The gradient was 5-95% B in1.50 min .5% B in 0.01 min, 5-95% B (0.01-0.70 min), 95% B (0.70-1.16min),95-5% B (1.16-1.17min) with a hold at 5% B for 0.33 min. The flow rate was 1.5 mL/min). Example 4: Synthesis of (2R,5R,6S)-4-Benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)- 2,6-dimethylmorpholin-3-one (e) To a solution of (R)-2-(((2S,3R)-3-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2- yl)oxy)propanoic acid (5 g, 9.89 mmol, 1 eq) in dimethyl formamide (160 mL) was added T3P (12.58 g, 19.77 mmol, 11.77 mL, 50% purity, 2 eq) at 0°C. The mixture was stirred at 20°C for 2 hrs. LCMS showed all the starting materials were consumed; desired MW was detected. This reaction was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL x 3). Combined the organic layer, dried with Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 5/1) to give (2R,5R,6S)-4-benzyl-5-(((tert- butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholin-3-one (2.9 g, 5.65 mmol, 57.14% yield) as colorless oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.56 - 7.69 (m, 4 H) 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). Example 5: Synthesis of (2S,3R,6R)-4-Benzyl-3-(((tert-butyldiphenylsilyl)oxy)methyl)- 2,6-dimethylmorpholine (f) To a solution of (2R,5R,6S)-4-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6- dimethylmorpholin-3-one (2.9 g, 5.65 mmol, 1 eq) in THF (35 mL) was added BH3-Me2S (10 M, 2.26 mL, 4 eq) at 0°C. The mixture was stirred at 30°C for 5 hrs. LCMS showed all the starting materials were consumed; desired MW was detected. This reaction was cooled 0°C, then was quenched with methanol (30 mL). Then the solution was concentrated under reduced pressure to give crude product. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 5/1) to give (2S,3R,6R)-4-benzyl-3-(((tert- butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholine (2.1 g, 4.21 mmol, 74.55% yield) as colorless oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.62 - 7.74 (m, 4 H) 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, 9 H) 0.92 (d, J=6.13 Hz, 3 H). Example 6: Synthesis of ((2S,3R,6R)-4-Benzyl-2,6-dimethylmorpholin-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 eq) in tetrahydrofuran (25 mL) was added tetrabutylammonium fluoride trihydrate (1 M, 7.92 mL, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 2hrs. LCMS showed all the starting materials were consumed; desired MW was detected. This reaction was extracted with ethyl acetate (30 mL x 3), combined organic layer was concentrated under reduced pressure to give residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 4/1) to give ((2S,3R,6R)- 4-benzyl-2,6-dimethylmorpholin-3-yl)methanol (0.9 g, 3.44 mmol, 65.22% yield) as colorless oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.27 - 7.39 (m, 4 H) 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). 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-dimethylmorpholin-3-yl)methanol (900 mg, 3.44 mmol, 1 eq) in ethyl acetate (18 mL) was added Pd/C (183.15 mg, 172.11 μmol, 10% Pd over activated charcoal (w/w), 0.05 eq) and (Boc)2O (1.13 g, 5.16 mmol, 1.19 mL, 1.5 eq). The mixture was stirred at 25°C for 12 hrs under 15 Psi H2. LCMS showed all the starting material were consumed. This reaction was filtered and concentrated to give crude tert-butyl (2S,3R,6R)-3-(hydroxymethyl)-2,6-dimethylmorpholine-4-carboxylate (0.63 g, 2.31 mmol, 67.15% yield) as a colorless oil. The product was used for next step directly, without further purification. 1H NMR (400 MHz, DMSO-d6): δ ppm 4.40 - 4.51 (m, 1 H) 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). Example 8: Synthesis of tert-Butyl (2S,3R,6R)-3-((1,3-dioxoisoindolin-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 eq) in tetrahydrofuran (6.50 mL) was added isoindoline- 1,3-dione (566.78 mg, 3.85 mmol, 1.5 eq) and PPh3 (1.01 g, 3.85 mmol, 1.5 eq) at 0°C. Then DIAD (778.95 mg, 3.85 mmol, 746.84 μL, 1.5 eq) was added into the mixture at 0°C. The mixture was stirred at 20°C for 16 hrs. LCMS showed all the starting materials were consumed; desired MW was detected. This reaction was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL x 3). Combined the organic layer, dried with Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 4/1) to give 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 white solid. LCMS (ESI+): m/z = 375.2 (M+1), RT: 0.767 min (Column Agilent Poroshell SB-C18 3.0*30mm, 4um. Detection method was diode array (DAD). MS mode was positive electrospray ionization. MS range was 50-2000. Mobile phase A was 0.04% Trifluoroacetic acid in water, and mobile phase B was 0.02% Trifluoroacetic acid in HPLC grade acetonitrile. The gradient was 5-95% B in1.50 min .5% B in 0.01 min, 5-95% B (0.01-0.70 min), 95% B (0.70-1.16min),95-5% B (1.16-1.17min) with a hold at 5% B for 0.33 min. The flow rate was 1.5 mL/min). 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 eq) in methanol (26 mL) was added NH2NH2.H2O (869.03 mg, 17.36 mmol, 842.08 μL, 10 eq). The mixture was stirred at 60°C for 2 hrs. LCMS showed all the starting materials were consumed; desired MW was detected. This reaction was filtered to remove the insoluble. The filtrate was concentrated in vacuo to give crude tert-butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate (0.35 g, 1.43 mmol, 82.52% yield) as white solid. The product was used for next step directly, without further purification. LCMS (ESI+): m/z = 245.2 (M+1), RT: 0.510 min (Column Agilent Poroshell SB-C18 3.0*30mm, 4um. Detection method was diode array (DAD). MS mode was positive electrospray ionization. MS range was 50-2000. Mobile phase A was 0.04% Trifluoroacetic acid in water, and mobile phase B was 0.02% Trifluoroacetic acid in HPLC grade acetonitrile. The gradient was 5-95% B in1.50 min .5% B in 0.01 min, 5-95% B (0.01-0.70 min), 95% B (0.70-1.16min),95-5% B (1.16-1.17min) with a hold at 5% B for 0.33 min. The flow rate was 1.5 mL/min). Example 10: Synthesis of tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5- (trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate (k-a), general procedure To a solution of tert-butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate (200 mg, 736.71 μmol, 1 eq) in dimethyl formamide (4 mL) was added K2CO3 (203.63 mg, 1.47 mmol, 2 eq) and 2-chloro-5-(trifluoromethyl)pyrazine (201.71 mg, 1.11 mmol, 1.5 eq) at 25°C. Then the mixture was stirred at 100°C for 2 hrs. LCMS showed all the starting materials were consumed, desired MW was detected. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by prep-TLC (petroleum ether: ethyl acetate = 1:1) to give tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((5- (trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate (150 mg, 46.94% yield) as a white solid. 1H 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). Example 11: Synthesis of tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylate (k-b), general procedure To a solution of tert-butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate (250 mg, 1.02 mmol, 1 eq) in DMSO (5 mL) was added 2-chloro-5-(trifluoromethyl)pyrimidine (280.15 mg, 1.53 mmol, 1.5 eq) and DIPEA (396.72 mg, 3.07 mmol, 534.66 μL, 3 eq) at 25°C. Then the mixture was stirred at 80°C for 2 hrs under N2 atmosphere. LCMS showed the reaction was completed and desired MW was detected. The residue was quenched with ice water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate = 1:1). Compound tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrimidin-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-C183.0*30mm, 4um. Detection method was diode array (DAD). MS mode was positive electrospray ionization. MS range was 50-2000. Mobile phase A was 0.04% Trifluoroacetic acid in water, and mobile phase B was 0.02% Trifluoroacetic acid in HPLC grade acetonitrile. The gradient was 5-95% B in 1.50 min, 5% B in 0.01 min, 5-95% B (0.01-0.70 min), 95% B (0.70-1.16min), 95-5% B (1.16-1.17min) with a hold at 5% B for 0.33 min. The flow rate was 1.5 mL/min. Similarly, the following intermediates were prepared. Example 12: Synthesis of tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylate (k-c) General procedure (see Example 10) used for making the compound (k-a) 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. 1H 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, 2.75 Hz, 0.74 H) 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). Example 13: Synthesis of tert-Butyl (2S,3R,6R)-3-(((5-chloropyridin-2-yl)amino)methyl)- 2,6-dimethylmorpholine-4-carboxylate (k-d) General procedure (see Example 10) used for making the compound (k-a) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 5- chloro-2-fluoropyridine. Yield 43%, colourless oil. 1HNMR (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). Example 14: Synthesis of tert-Butyl (2S,3R,6R)-3-(((5-chloropyrimidin-2- yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (k-e) General procedure (see Example 11) used for making the compound (k-b) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2,5- dichloropyrimidine. Yield 68%, white solid. 1H 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 = 11.1 Hz, 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). Example 15: Synthesis of tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((4- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylate (k-f) General procedure (see Example 11) used for making the compound (k-b) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2- chloro-4-(trifluoromethyl)pyrimidine. Yield 59%, white solid. LCMS (ESI+): m/z =391.2 (M+1), RT: 0.789 min. Example 16: Synthesis of tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((6- (trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate (k-q) General procedure (see Example 10) used for making tert-Butyl (2S,3R,6R)-2,6-dimethyl-3- (((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate (k) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2- chloro-6-(trifluoromethyl)pyrazine. Yield 56%, colourless oil. LCMS (ESI+): m/z = 335.2 (M-55), RT=0.784 min. Example 17: Synthesis of tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((4- (trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylate (k-h) General procedure (see Example 10) used for making the compound (k-a) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2- fluoro-4-(trifluoromethyl)pyridine. Yield 63%, colourless oil. LCMS (ESI+): m/z = 390.2 (M+1), RT = 0.682 min. Example 18: Synthesis of tert-Butyl (2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridin- 2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (k-i) General procedure (see Example 11) used for making the compound (k-b) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2,3- difluoro-5-(trifluoromethyl)pyridine. Yield 36%, yellow solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.13 - 8.27 (m, 1 H), 7.76 (br d, J=11.38 Hz, 1 H), 7.54 (br s, 1 H), 7.15 (br d, J=1.00 Hz, 1 H), 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). Example 19: Synthesis of tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5- (trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylate ( k-j) General procedure (see Example 11) used for making the compound (k-b) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 3- bromo-2-fluoro-5-(trifluoromethyl)pyridine to give 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, 0.30 H), 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)pyridin-2- yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (1.55 g, 3.31 mmol, 1 eq) in THF (62 mL) and H2O (15.5 mL) was added K3PO4 (2.11 g, 9.93 mmol, 3 eq), MeB(OH)2 (297.19 mg, 4.96 mmol, 1.5 eq) and Pd(dtbpf)Cl2 (215.71 mg, 330.98 μmol, 0.1 eq). The mixture was stirred at 80°C for 2 hrs under N2. LCMS showed starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by adding water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 1/100). tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridin-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=5.44 Hz, 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, 3.00 H), 1.04 - 1.27 (m, 9.40 H), 0.98 (s, 6.00 H). Example 20: Synthesis of tert-butyl (2S,3R,6R)-3-(((3,5-bis(trifluoromethyl)pyridin-2- yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (k-k) General procedure (see Example 11) used for making the compound (k-b) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2- chloro-3,5-bis(trifluoromethyl)pyridine. Yield 94%, yellow oil. 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, 1.00 H), 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). Example 21: Synthesis of tert-butyl (2S,3R,6R)-3-(((3-methoxy-5- (trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (k-l) General procedure (see Example 11) used for making the compound (k-b) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2- chloro-3-methoxy-5-(trifluoromethyl)pyridine. Yield 34%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 7.90 - 7.98 (m, 1 H), 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, 1 H), 1.06 - 1.31 (m, 9 H), 1.01 (s, 6 H). Example 22: Synthesis of tert-Butyl (2S,3R,6R)-3-(((3-chloro-5-(trifluoromethyl)pyridin- 2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (k-m) General procedure (see Example 10) used for making the compound (k-a) 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. 1HNMR (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, 1.00 H), 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). Example 23: Synthesis of tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5- (trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholine-4-carboxylate (k-n) To a solution of 3-methyl-5-(trifluoromethyl)pyrazin-2-ol (218.69 mg, 1.23 mmol, 1.5 eq) in DMF (2 mL) was added DBU (373.85 mg, 2.46 mmol, 370.14 μL, 3 eq), then BOP (543.05 mg, 1.23 mmol, 1.5 eq) was added in portions at 0°C, the mixture was stirred at 0°C for 0.5 hours. Then tert-butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate (0.2 g, 818.57 μmol, 1 eq) was added at 0°C. The mixture was stirred at 20°C for 16 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition water (5 mL), extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether from 0% to 11% to afford tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate (0.18 g, 54.37% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.20 - 8.36 (m, 1 H), 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). Example 24: Synthesis of tert-Butyl (2S,3R,6R)-3-(((3-cyano-5-(trifluoromethyl)pyridin- 2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (k-o) General procedure (see Example 11) used for making the compound (k-b) 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. 1H 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, 1 H), 1.15 - 1.37 (m, 12 H). Example 25: Synthesis of tert-Butyl (2S,3R,6R)-3-(((3-(difluoromethyl)-5- (trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (k- p) General procedure (see Example 11) used for making the compound (k-b) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2- chloro-3-(difluoromethyl)-5-(trifluoromethyl)pyridine. Yield 80%, yellow solid. 1H NMR (400 MHz, DMSO-d6): δ = 7.79 - 8.56 (m, 2 H), 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). Example 26: Synthesis of tert-Butyl (2S,3R,6R)-3-(((5-chloro-3-fluoropyridin-2- yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (k-q) General procedure (see Example 11) used for making the compound (k-b) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 5- chloro-2,3-difluoropyridine. Yield 85%, white solid. 1H NMR (400 MHz, DMSO-d6): δ = 7.83 - 7.92 (m, 1 H), 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). Example 27: Synthesis of tert-Butyl (2S,3R,6R)-3-(((3-fluoro-4-methyl-5- (trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate (k-r) General procedure (see Example 10) used for making the compound (k-a) 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, 1 H), 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). Example 28: Synthesis of tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((4-methyl-5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carboxylate (k-s) General procedure (see Example 11) used for making the compound (k-b) was repeated, using tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate and 2,4- dichloro-5-(trifluoromethyl)pyrimidine to give tert-butyl (2S,3R,6R)-3-(((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate. Yield 38%, yellow solid. 1HNMR (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, 1.00 H), 1.04 - 1.28 (m, 15.00 H). tert-Butyl (2S,3R,6R)-3-(((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (600 mg, 1.41 mmol, 1 eq), 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane (1.06 g, 4.24 mmol, 1.18 mL, 3 eq), Cs2CO3 (1.38 g, 4.24 mmol, 3 eq) and Pd(dppf)Cl2 (103.34 mg, 141.23 μmol, 0.1 eq) were taken up into a microwave tube in dioxane (12 mL). Then the mixture was degassed and purged with N2 for 3 time. The sealed tube was heated at 140°C for 4 hrs under microwave. LCMS showed starting material was consumed completely and one main peak with desired mass was detected. After cooling to 25°C, the reaction mixture was quenched by adding water (15 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic was washed brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 1/100) to give (0.4 g, 70.03% yield) to give the title compound as a yellow oil. 1HNMR (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, 8.00 H), 1.20 (d, J=6.13 Hz, 3.35 H). Example 29: Synthesis of N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyrazin-2-amine hydrochloride (l-a), general procedure To a solution of tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate (150 mg, 345.80 μmol, 1 eq) in dioxane (0.5 mL) was added HCl/dioxane (4 M, 2.60 mL, 30.11 eq) at 25°C. Then the mixture was stirred at 25°C for 1 hr. LCMS showed all the starting materials were consumed, desired MW was detected. The reaction mixture was concentrated under reduced pressure to give the crude N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-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-C183.0*30mm, 4um. Detection method was diode array (DAD). MS mode was positive electrospray ionization. MS range was 50-2000. Mobile phase A was 0.04% Trifluoroacetic acid in water, and mobile phase B was 0.02% Trifluoroacetic acid in HPLC grade acetonitrile. The gradient was 5-95% B in 1.50 min, 5% B in 0.01 min, 5-95% B (0.01-0.70 min), 95% B (0.70-1.16min), 95-5% B (1.16-1.17min) with a hold at 5% B for 0.33 min. The flow rate was 1.5 mL/min). Similarly, the following intermediates were prepared. Example 30: Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyrimidin-2-amine hydrochloride (l-b) General procedure (see Example 29) used for making the compound (l-a) was repeated, using tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylate (l). Yield 99%, white solid. LCMS (ESI+): m/z =291.2 (M+1), RT: 0.351 min (Column Halo C183.0*30mm, 5um. Detection method was diode array (DAD). MS mode was positive electrospray ionization. MS range was 50-2000. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC grade acetonitrile. The gradient was 10-100% B in 0.90 min, 10% B in 0.01 min, 10- 100% B (0.01-0.50 min) with a hold at 100% B for 0.40 min. The flow rate was 2.0 mL/min). Example 31: Synthesis of N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine hydrochloride (l-c) General procedure (see Example 29) used for making the compound (l-a) was repeated, using tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridine-2-yl)amino)methyl) morpholine-4-carboxylate (k-c). Yield 96%, yellow solid. LCMS (ESI+): m/z =290.2 (M+1), RT: 0.368 min (Column Halo C183.0*30mm,5um. Detection method was diode array (DAD). MS mode was positive electrospray ionization. MS range was 50-2000. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC grade acetonitrile. The gradient was 10-100% B in 0.90 min, 10% B in 0.01 min, 10- 100% B (0.01-0.50 min) with a hold at 100% B for 0.40 min. The flow rate was 2.0 mL/min). Example 32: Synthesis of 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3- yl)methyl)pyridin-2-amine hydrochloride (l-d) General procedure (see Example 29) used for making the compound (l-a) was repeated, using tert-Butyl (2S,3R,6R)-3-(((5-chloropyridin-2-yl)amino)methyl)-2,6-dimethylmorpholine-4- carboxylate (k-d). Yield 99%, yellow solid. LCMS (ESI+): m/z =256.3 (M+1), RT: 0.328 min (Column Halo C183.0*30mm, 5um. Detection method was diode array (DAD). MS mode was positive electrospray ionization. MS range was 50-2000. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC grade acetonitrile. The gradient was 10-100% B in 0.90 min, 10% B in 0.01 min, 10- 100% B (0.01-0.50 min) with a hold at 100% B for 0.40 min. The flow rate was 2.0 mL/min). Example 33: Synthesis of 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3- yl)methyl)pyrimidin-2-amine hydrochloride (l-e) General procedure (see Example 29) used for making the compound (l-a)was repeated, using tert-Butyl (2S,3R,6R)-3-(((5-chloropyrimidin-2-yl)amino)methyl)-2,6-dimethylmorpholine-4- carboxylate (k-e). Yield 85%, white solid. 1H 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 = 6.6 Hz, 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). Example 34: Synthesis of N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-4- (trifluoromethyl)pyrimidin-2-amine hydrochloride (l-f) General procedure (see Example 29) used for making the compound (l-a)was repeated, using tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((4-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylate (k-f). Yield 97%, white solid. LCMS (ESI+): m/z =291.3 (M+1), RT: 0.476 min. Example 35: Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-6- (trifluoromethyl)pyrazin-2-amine hydrochloride (l-g) General procedure (see Example 29) used for making the compound (l-a) was repeated, using tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((6-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate (k-g). Yield 81%, white solid. LCMS (ESI+): m/z = 291.2 (M+1), RT=0.539 min. Example 36: Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-4- (trifluoromethyl)pyridin-2-amine hydrochloride (l-h) General procedure (see Example 29) used for making the compound (l-a was repeated, using tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((4-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylate (k-h). Yield 94%, colourless oil. LCMS (ESI+): m/z = 290.3 (M+1), RT = 0.541 min. Example 37: Synthesis of N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-3-fluoro- 5-(trifluoromethyl)pyridin-2-amine hydrochloride (l-i) General procedure (see Example 29) used for making the compound (l-a) was repeated, using tert-butyl (2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (k-i). 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, 2 H), 1.16 (dd, J=10.69, 6.44 Hz, 6 H). Example 38: Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-methyl- 5-(trifluoromethyl)pyridin-2-amine (l-j), general procedure tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylate (1.1 g, 2.73 mmol, 1 eq) was dissolved in HCl/dioxane (4 M, 11 mL, 16.14 eq). The mixture was stirred at 25°C for 1 hr. LCMS showed starting material was consumed completely and one main peak with desired mass was detected. The mixture was adjusted to pH 9 with NaHCO3 (aq) (20 mL), and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)methyl) morpholine-4-carboxylate (0.77 g, 82.86% yield) as a brown solid. The crude product was used for next step directly 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, 6.00 H). Example 39: N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-3,5-bis(trifluoro methyl)pyridin-2-amine hydrochloride (l-k) General procedure (see Example 29) used for making the compound (l-a) was repeated, using tert-butyl (2S,3R,6R)-3-(((3,5-bis(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6-dimethyl morpholine-4-carboxylate (k-k). Yield 82%, yellow solid. 1H 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). Example 40: N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-3-methoxy-5- (trifluoromethyl)pyridin-2-amine (l-l) General procedure (see Example 38) used for making the compound (l-j) was repeated, using tert-butyl (2S,3R,6R)-3-(((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (k-l).Yield 95%, yellow solid. 1HNMR (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). Example 41: 3-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine (l-m) General procedure (see Example 38) used for making the compound (l-j) was repeated, using tert-butyl (2S,3R,6R)-3-(((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (k-m). Yield 99%, yellow solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.35 (d, J=0.88 Hz, 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, 1 H), 0.96 - 1.11 (m, 6 H). Example 42: N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-methyl-5- (trifluoromethyl)pyrazin-2-amine (l-n) General procedure (see Example 38) used for making the compound (l-j) was repeated, using tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate (k-n). Yield 96%, yellow oil. LCMS (ESI+): m/z =305.3 (M+1), RT: 0.570 min Example 43: 2-((((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)amino)-5- (trifluoromethyl)nicotinonitrile hydrochloride (l-o) General procedure (see Example 29) used for making the compound (l-a) was repeated, using tert-butyl (2S,3R,6R)-3-(((3-cyano-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (k-o). Yield 94%, yellow solid. LCMS: (ESI+): m/z=315.2 (M+1), RT: 0.366 min. Example 44: 3-(Difluoromethyl)-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine hydrochloride (l-p) General procedure (see Example 29) used for making the compound (l-a) was repeated, using tert-butyl (2S,3R,6R)-3-(((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (k-p). Yield 96%, yellow solid. LCMS: (ESI+): m/z=340.2 (M+1), RT: 0.388 min Example 45: 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3- fluoropyridin-2-amine hydrochloride (l-q) General procedure (see Example 29) used for making the compound (l-a) was repeated, using tert-butyl (2S,3R,6R)-3-(((5-chloro-3-fluoropyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (k-q). Yield 99%, light brown solid. LCMS (ESI+): m/z = 274.1 (M+1), RT: 0.331 min. Example 46: N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-3-fluoro-4-methyl-5- (trifluoromethyl)pyridin-2-amine (l-r) General procedure (see Example 38) used for making the compound (l-j) was repeated, using tert-butyl (2S,3R,6R)-3-(((3-fluoro-4-methyl-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate (k-r). Yield 98%, yellow oil. LCMS (ESI+): m/z = 322.1 (M+1), RT: 0.377 min. Example 47: N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-4-methyl-5- (trifluoromethyl)pyrimidin-2-amine (l-s) General procedure (see Example 38) used for making the compound (l-j) was repeated, using tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((4-methyl-5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylate (k-s). Yield 73%, yellow oil. 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). Example 48: Synthesis of (2S,3R)-3-amino-4-(dibenzylamino)butan-2-ol (d-b). To a solution of (2S,3S)-2-amino-N,N-dibenzyl-3-hydroxybutanamide (32 g, 101.88 mmol, 1 eq) in THF (320 mL) was added BH3.THF (1 M, 305.65 mL, 3 eq) dropwise at 0°C under N2. The reaction was degassed with N2 for 3 times. The reaction was stirred at 25°C for 0.5 hr and then the reaction was warmed to 50°C and stirred for 2 hours. LCMS showed the starting material was consumed and the desired mass was detected. The reaction was quenched with by methanol (500 mL) slowly at 0°C and then the reaction was stirred at 50°C for 0.5 hr. The reaction was concentrated in vacuum to give (2S,3R)-3-amino-4-(dibenzylamino)butan- 2-ol (31 g, yield 85.59%) as a yellow oil. The product was used for next step without further purification. LCMS (ESI+): m/z =285.3 (M+1), RT: 0.568 min Example 49: Synthesis of (S)-2-bromo-N-((2R,3S)-1-(dibenzylamino)-3-hydroxybutan-2- yl)propanamide (d-c). To a solution of (2S,3R)-3-amino-4-(dibenzylamino)butan-2-ol (31 g, 87.20 mmol, 1 eq) in THF (310 mL) was added (2S)-2-bromopropanoic acid (13.33 g, 87.20 mmol, 1 eq) and DIPEA (33.79 g, 261.64 mmol, 45.5 mL, 3 eq). Then PyBrOP (44.72 g, 95.94 mmol, 1.1 eq) was added at 0°C and the reaction was stirred at 25°C for 1 hour. LCMS showed the starting material was consumed and the desired mass was detected. The combined solution was diluted with water (700 mL) and extracted with ethyl acetate (3 x 700 mL). The combined organic phase was washed with brine (500 mL), dried over Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 7/3 to 2/1) to give (S)-2-bromo-N-((2R,3S)-1- (dibenzylamino)-3-hydroxybutan-2-yl)propanamide (36 g, yield 88.60%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.31 (d, J=4.50 Hz, 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). Example 50: Synthesis of (2R,5R,6S)-5-((dibenzylamino)methyl)-2,6- dimethylmorpholin-3-one (d-d) To a solution of (S)-2-bromo-N-((2R,3S)-1-(dibenzylamino)-3-hydroxybutan-2-yl)propanamide (36 g, 77.26 mmol, 1 eq) in IPA (1100 mL) was added KOH (8.69 g, 154.52 mmol, 2 eq) in H2O (37 mL). The reaction was stirred at 25°C for 1 hour. LCMS showed most of the starting material was consumed and the desired mass was detected. The reaction was diluted with water (2 L) and extracted with ethyl acetate (3 x 1.5 L). The combined organic phase was washed with brine (3 x 700 mL), dried over Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm, 15 um); mobile phase: [H2O(0.04%HCl)-CAN]; gradient:15%-50% B over 20.0 min) to give (2R,5R,6S)-5-((dibenzylamino)methyl)-2,6-dimethylmorpholin-3-one (16 g, yield 58.16%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.86 (br d, J=4.38 Hz, 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). Example 51: Synthesis of tert-butyl (2S,3R,6R)-3-((dibenzylamino)methyl)-2,6- dimethylmorpholine-4-carboxylate-5,5-d2 (d-f) To a solution of (2R,5R,6S)-5-((dibenzylamino)methyl)-2,6-dimethylmorpholin-3-one (8.5 g, 23.86 mmol, 1 eq) in THF (85 mL) LiAlD4 (3.01 g, 71.58 mmol, 4.09 mL, 3 eq) was added dropwise under N2 at 0°C. Then the reaction was stirred at 40°C for 12 hours. LCMS showed the starting material was consumed and the desired mass was detected. The reaction was quenched with water (20 mL) under N2. To the remaining solution was added TEA (7.24 g, 71.58 mmol, 9.96 mL, 3 eq) and Boc2O (7.81 g, 35.79 mmol, 8.22 mL, 1.5 eq) at 0°C. The reaction was stirred at 25°C for 1 hour. LCMS showed the starting material was consumed and the desired mass was detected. The reaction was diluted with water (300 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic phase was washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=16/1 to 14/1) to give tert-butyl (2S,3R,6R)-3- ((dibenzylamino)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (10.3 g, yield 96.13%) 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, 1.95 H), 3.14 (d, J=13.01 Hz, 1.15 H), 2.65 - 2.77 (m, 1.05 H), 2.34 (dd, J=13.26, 4.38 Hz, 0.45 H), 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, 3.00 H). Example 52: Synthesis of tert-butyl (2S,3R,6R)-3-(aminomethyl)-2,6- dimethylmorpholine-4-carboxylate-5,5-d2 (d-g) 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 eq) in Trifluoroethanol (300 mL) Pd(OH)2 (1.56 g, 2.23 mmol, 20% purity, 0.1 eq) was added under argon. Then the mixture was degassed and purged with H2 for 3 times, and then the mixture was stirred at 25°C for 2 hours under H2 (15 psi) atmosphere. LCMS showed the starting material was consumed completely. The solution was filtered through a pad of Celite and the filter cake was washed with ethyl acetate (300 mL). The combined filtrates were concentrated to give tert-butyl (2S,3R,6R)-3-(aminomethyl)- 2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (5.9 g, yield 96.79%) 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). Example 53: Synthesis of tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)morpholine-4-carboxylate-5,5-d2 (d-h) To a solution of tert-butyl (2S,3R,6R)-3-(aminomethyl)-2,6-dimethylmorpholine-4-carboxylate- 5,5-d2 (1 g, 3.65 mmol, 1 eq) in DMSO (20 mL) DIPEA (1.42 g, 10.96 mmol, 1.91 mL, 3 eq) and 2-fluoro-5-(trifluoromethyl)pyridine (723.77 mg, 4.38 mmol, 1.2 eq) was added. The mixture was stirred at 140°C for 12 hrs. LCMS showed starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by added water (15mL), and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 1/100). Compound tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylate-5,5-d2 (1.1 g, 76.92% yield) was obtained as a yellow oil. 1HNMR (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, 1.80 H), 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 compound was prepared. Example 54: tert-Butyl (2S,3R,6R)-3-(((5-chloropyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate-5,5-d2 (d-i) The titled compound (d-i) was prepared in analogy to the procedure described for compound (d-h) using 5-chloro-2-fluoropyridine. Yield 58%, colourless 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). Example 55: Synthesis of N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl-5,5-d2)methyl)-5- (trifluoromethyl)pyridin-2-amine (d-j) A solution of tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylate-5,5-d2 (1.1 g, 2.81 mmol, 1 eq) in HCl/dioxane (4 M, 11 mL, 15.66 eq) was stirred at 20°C for 1 hr. LCMS showed starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was neutralized with NaHCO3 (aq) (15mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude N- (((2S,3R,6R)-2,6-dimethylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyridin-2-amine (0.75 g, 84.29% yield) as a yellow solid. 1HNMR (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 compound was prepared. Example 56: 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl-5,5- d2)methyl)pyridin-2-amine hydrochloride (d-k) The titled compound was prepared in analogy to the procedure described for compound (d-j) using (2S,3R,6R)-3-(((5-chloropyridin-2-yl)amino)methyl)-2,6-dimethylmorpholine-4- carboxylate-5,5-d2. Yield 95%, yellow solid. 1HNMR (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, 1.20 H), 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). Example 57: Synthesis of (2S,3S,6R)-4-benzyl-2,6-dimethyl-5-oxomorpholine-3- carboxylic acid (d-m) To a solution of t-BuONa (43.63 g, 454.02 mmol, 5 eq) in dioxane (400 mL) was added benzyl- L-allothreonine (20 g, 90.80 mmol, 1 eq) and (2S)-2-bromopropanoic acid (41.67 g, 272.41 mmol, 3 eq) at 0°C. The reaction was stirred at 20°C for 2 hrs. LCMS showed the starting materials were consumed. Then the reaction was quenched by HCl/dioxane (4 N), adjust pH to 3 and concentrated. The residue was dissolved in ethyl acetate (400 mL), and added DIPEA (35.21 g, 272.41 mmol, 47.45 mL, 3 eq), then T4P (130.85 g, 181.61 mmol, 50% purity, 2 eq) into the solution at 0°C. The mixture was stirred at 25°C for 12 hrs. LCMS showed all the starting materials were consumed; desired mass was detected. The reaction mixture was poured into aq. HCl (1 N), adjusted to pH 7, extracted with ethyl acetate (1000 mL x 3). The combined organic layers were washed with brine (500 mL x 2), dried over Na2SO4, filtered and concentrate to give crude product. This crude product was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 3/1) to give (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. Example 58: Synthesis of (2R,5R,6S)-4-benzyl-5-(hydroxymethyl-d2)-2,6- dimethylmorpholin-3-one (d-n) To a solution of (2S,3S,6R)-4-benzyl-2,6-dimethyl-5-oxomorpholine-3-carboxylic acid (4 g, 15.19 mmol, 1 eq) in THF (80 mL) was added TEA (2.31 g, 22.79 mmol, 3.17 mL, 1.5 eq). The solution was cooled to 0°C, isobutyl carbonochloridate (3.11 g, 22.79 mmol, 2.98 mL, 1.5 eq) was added into the solution at 0°C. The mixture was stirred at 25°C for 30 mins, then filtered, sodium borodeuteride (632.25 mg, 16.71 mmol, 1.1 eq) was dissolved in D2O (2 mL) and added it to the filtrate at 0°C. Then the reaction was stirred at 25°C for 1.5 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. This reaction was poured into aq. HCl (1 N,), adjusted to pH 7, extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrate to give crude product, which was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 3/1) to give (2R,5R,6S)-4- benzyl-5-(hydroxymethyl-d2)-2,6-dimethylmorpholin-3-one (1.5 g, 39.29% yield) as colorless oil. LCMS (ESI+): m/z =252.4 (M+1), RT: 0.559 min. Example 59: Synthesis of ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholin-3-yl)methan-d2- ol (d-o) The (2R,5R,6S)-4-benzyl-5-(hydroxymethyl-d2)-2,6-dimethylmorpholin-3-one (1.4 g, 5.57 mmol, 1 eq) in THF (2.8 mL) was added into the stirred solution of BH3.THF (1 M, 14.21 mL, 2.55 eq) at 0°C. The reaction was warmed to 45°C and stirred for 2.5 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. This reaction was quenched with MeOH (10 mL) and concentrated under reduced pressure to give crude product. The residue was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrate to give crude product. The crude product was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 3/1) to give ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholin-3- yl)methan-d2-ol (0.6 g, 43.11% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.28 - 7.39 (m, 4 H), 7.19 - 7.26 (m, 1 H), 4.22 (s, 1 H), 3.89 (d, J=13.88 Hz, 1 H), 3.79 (m, 1 H), 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=6.13 Hz, 3 H). Example 60: Synthesis of tert-butyl (2S,3R,6R)-3-(hydroxymethyl-d2)-2,6- dimethylmorpholine-4-carboxylate (d-p) To a solution of ((2S,3R,6R)-4-benzyl-2,6-dimethylmorpholin-3-yl)methan-d2-ol (0.6 g, 2.53 mmol, 1 eq) in EtOAc (12 mL) was added Pd/C (134.52 mg, 126.40 μmol, 10% purity, 0.05 eq), (Boc)2O (827.61 mg, 3.79 mmol, 871.17 μL, 1.5 eq). The mixture was stirred at 20°C for 16 hrs under 15 Psi H2. TLC showed all the starting material were consumed. This reaction was filtered, the filtrate was concentrated to give crude product, which was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 4/1) to give tert-butyl (2S,3R,6R)- 3-(hydroxymethyl-d2)-2,6-dimethylmorpholine-4-carboxylate (0.6 g, 91.16% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 4.42 (d, J=4.50 Hz, 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). Example 61: Synthesis of tert-butyl (2S,3R,6R)-3-((1,3-dioxoisoindolin-2-yl)methyl)-2,6- dimethylmorpholine-4-carboxylate-5,5-d2 (d-q) To a solution of tert-butyl (2S,3R,6R)-3-(hydroxymethyl-d2)-2,6-dimethylmorpholine-4- carboxylate (0.6 g, 2.30 mmol, 1 eq) in THF (6 mL) was added isoindoline-1,3-dione (508.63 mg, 3.46 mmol, 1.5 eq) and PPh3 (906.73 mg, 3.46 mmol, 1.5 eq) at 0°C, then DIAD (699.03 mg, 3.46 mmol, 670.21 μL, 1.5 eq) was added into the mixture at 0°C. The mixture was stirred at 20°C for 16 hrs. LCMS showed all the starting material was consumed, desired mass was detected. This reaction was poured into ice water (50 mL), and extracted with ethyl acetate (50 mL x 3), the combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 4/1) to give 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, 69.50% yield, 67% purity) as white solid 1H NMR (400 MHz, DMSO-d6): δ ppm 4.01 - 4.21 (m, 1 H), 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). Example 62: Synthesis of tert-butyl (2S,3R,6R)-3-(aminomethyl-d2)-2,6- dimethylmorpholine-4-carboxylate (d-r) 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 eq) in MeOH (18 mL) was added NH2NH2.H2O (801.88 mg, 16.02 mmol, 777.02 μL, 10 eq). The mixture was stirred at 60°C for 2 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. This reaction was filtered to remove the insoluble material. The filtrate was concentrated in vacuo, diluted with ethyl acetate (50 mL), washed with saturated aq. NaHCO3 (10 mL), water (10 mL), then brine (10 mL), dried over Na2SO4, filtered and concentrated under high vacuum to give tert-butyl (2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4- carboxylate (400 mg, 81.09% yield) as colorless oil. 1H 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). Example 63: tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl-d2)morpholine-4-carboxylate (d-s), general procedure To a solution of tert-butyl (2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4- carboxylate (140 mg, 454.65 μmol, 1 eq) in DMSO (3 mL) was added DIPEA (176.28 mg, 1.36 mmol, 237.57 μL, 3 eq) 2-fluoro-5-(trifluoromethyl)pyridine (90.07 mg, 545.58 μmol, 1.2 eq). The mixture was stirred at 140°C for 2 hrs. LCMS showed all the starting material were consumed. This reaction was filtered and concentrated to give crude product. The residue was purified by prep-TLC (SiO2, petroleum ether: ethyl acetate = 1:1). tert-Butyl (2S,3R,6R)-2,6- dimethyl-3-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl-d2)morpholine-4-carboxylate (140 mg, 78.67% yield) was obtained as a light yellow oil. 1HNMR (400 MHz, DMSO-d6) : δ ppm 8.19 - 8.40 (m, 1 H), 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. Example 64: tert-Butyl (2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridin-2- yl)amino)methyl-d2)-2,6-dimethylmorpholine-4-carboxylate (d-t) The titled compound (d-t) was prepared in analogy to the procedure described for compound (d-t) using tert-butyl (2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4-carboxylate and 2,3-difluoro-5-(trifluoromethyl)pyridine Yield 86%, light yellow oil. 1HNMR (400 MHz, DMSO-d6) : δ ppm 8.13 - 8.34 (m, 1 H), 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, 1 H), 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). Example 65: tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridin- 2-yl)amino)methyl-d2)morpholine-4-carboxylate (d-u) General procedure (see Example 19) used for making the compound (k-j) was repeated, using tert-butyl (2S,3R,6R)-3-(aminomethyl-d2)-2,6-dimethylmorpholine-4-carboxylate and 3- bromo-2-fluoro-5-(trifluoromethyl)pyridine to give the title compound.Yield 87%, colourless 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, 0.90 H), 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). Example 66: N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl-d2)-5- (trifluoromethyl)pyridin-2-amine hydrochloride (d-v) A solution of tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl-d2)morpholine-4-carboxylate (140 mg, 357.67 μmol, 1 eq) in HCl/dioxane (4 M, 2.79 mL, 31.23 eq). The mixture was stirred at 25°C for 1hr. LCMS showed all the starting material was consumed. This reaction was filtered and concentrated to give crude N- (((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl)pyridin-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, 2 H), 1.06 (d, J=6.63 Hz, 3 H), 1.01 (d, J=6.13 Hz, 3 H). Similarly, the following compounds were prepared. Example 67: N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl-d2)-3-fluoro-5- (trifluoromethyl)pyridin-2-amine hydrochloride (d-w) The titled compound (d-w) was prepared in analogy to the procedure described for compound (d-v) using tert-butyl (2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl- d2)-2,6-dimethylmorpholine-4-carboxylate Yield 83%, white solid. 1HNMR (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, 1 H), 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). Example 68: N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl-d2)-3-methyl-5- (trifluoromethyl)pyridin-2-amine hydrochloride (d-x) The titled compound (d-x) was prepared in analogy to the procedure described for compound (d-v) using tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl-d2)morpholine-4-carboxylate Yield 90%, white solid. 1HNMR (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, 2.81 Hz, 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). Example 69: Synthesis of 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid To a solution of tert-butyl 4-iodo-1-methyl-1H-pyrazole-3-carboxylate (1.5 g, 4.87 mmol, 1 eq) in THF (60 mL) and H2O (15 mL) was added (4-cyanophenyl)boronic acid (929.95 mg, 6.33 mmol, 1.3 eq), K3PO4 (3.10 g, 14.60 mmol, 3 eq) and Pd(dtbpf)Cl2 (158.65 mg, 243.42 μmol, 0.05 eq). The mixture was stirred at 80 °C for 2hr under N2. LC-MS showed the starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and the filter was concentrated to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=0/1 to 30/1) to give tert-butyl 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylate (1.4 g, 4.94 mmol, 72.50% yield) as a brown solid. LCMS (ESI+): m/z =284.5 (M+1), RT: 0.718 min. 1H 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 eq) in HCl/dioxane (15 mL) was stirred at 50 °C for 2hr. LC-MS showed the starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and the filter cake was dried to give 4-(4-cyanophenyl)-1-methyl- 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). Example 70: Synthesis of 4-(5-Cyanopyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid To a solution of (3-(tert-butoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)boronic acid (500 mg, 2.21 mmol, 1 eq) in H2O (0.1 mL) and dioxane (0.5 mL) was added 6-bromopyridine-3-carbonitrile (485.78 mg, 2.65 mmol, 1.2 eq) and K3PO4 (1.41 g, 6.64 mmol, 3 eq) at 25°C. The mixture degassed and purged with N2 for 3 times. Then ditert-butyl(cyclopentyl)phosphane dichloropalladium iron (72.08 mg, 110.60 μmol, 0.05 eq) was added into the reaction mixture at 25°C. The mixture was degassed and purged with N2 for 3 times and stirred at 80°C for 2 hrs. LCMS showed all the starting materials were consumed, desired MS was detected. The reaction mixture was pour into H2O (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organics were washed brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 1/2) to give tert-butyl 4-(5-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylate (520 mg, 82.68% yield) as a yellow solid. 1H NMR: (400 MHz, CHLOROFORM-d): δ ppm 8.82 (d, J=1.75 Hz, 1 H), 8.14 (d, J=8.38 Hz, 1 H), 7.89 - 8.06 (m, 2 H), 4.02 (s, 3 H), 1.61 (s, 9 H). A solution of tert-butyl 4-(5-cyanopyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylate (520 mg, 1.83 mmol, 1 eq) in 4N/HCl dioxane (10 mL) was stirred at 20°C for 12 hrs. LCMS showed all the starting materials were consumed, desired MS was detected. The reaction mixture was filtered to afford filter cake and filter cake dried in vacuum to give 4-(5-cyanopyridin-2-yl)-1- methyl-1H-pyrazole-3-carboxylic acid (470 mg, 97.09% yield, HCl) as a white solid. 1H 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). Example 71: Synthesis of 5-(5-Fluoropyrimidin-2-yl)-1-methyl-1H-imidazole-4- carboxylic acid A suspension of methyl 5-bromo-1-methyl-1H-imidazole-4-carboxylate (2 g, 9.13 mmol, 1 eq) in toluene (20 mL) at 20°C was degassed and purged with N2 for 3 times. Pd (PPh3)4 (1.06 g, 913.09 μmol, 0.1 eq) and trimethyl(trimethylstannyl)stannane (5.98 g, 18.26 mmol, 3.79 mL, 2 eq) was added into the reaction mixture at 20°C. The suspension was degassed and purged with N2 for 3 times, then the mixture was stirred at 120°C for 6 hrs under N2. LCMS showed all the starting materials were consumed, desired Ms was detected. The reaction mixture was concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (Al2O3, petroleum ether/ethyl acetate=1/0 to 0/1) to give methyl 1- methyl-5-(trimethylstannyl)-1H-imidazole-4-carboxylate (1.7 g, yield 49.17%) as a yellow oil. 1H 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-(trimethylstannyl)-1H-imidazole-4-carboxylate (1 g, 2.64 mmol, 1 eq) in xylene (20 mL) was added 2-bromo-5-fluoro-pyrimidine (701.02 mg, 3.96 mmol, 1.5 eq) at 20°C. The suspension was degassed and purged with N2 for 3 times. Pd (PPh3)4 (305.15 mg, 264.07 μmol, 0.1 eq) was added into the reaction mixture at 20°C. The suspension was degassed and purged with N2 for 3 times. Then the mixture was stirred at 140°C for 16 hrs under N2. LCMS showed all the starting materials were consumed, desired Ms was detected. The residue was quenched with water (20 mL), and extracted with dichloromethane (5×30 mL). The combined organics were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/1 to 0/1). The crude methyl 5-(5-fluoropyrimidin-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-fluoropyrimidin-2-yl)-1-methyl-1H-imidazole-4-carboxylate (600 mg, 1.78 mmol, 1 eq) was dissolved in 6N HCl (12 mL) at 20°C, then the mixture was stirred at 80°C for 2 hrs. LCMS showed all the starting materials were consumed, desired Ms was detected. The residue was quenched with water (10 mL), and extracted with ethyl acetate (3×30 mL). The aqueous phase were concentrated under reduced pressure to give the crude product. The crude product was directly used for the next step. The crude 5-(5-fluoropyrimidin-2-yl)-1- methyl-1H-imidazole-4-carboxylic acid (400 mg, yield 69.58%) was obtained as a yellow solid, was used without further purification. LCMS (ESI+): m/z =223.2 (M+1), RT: 0.255 min Example 72: Synthesis of 5-(5-Methoxypyridin-2-yl)-1-methyl-1H-imidazole-4- carboxylic acid To a solution of methyl 5-bromo-1-methyl-1H-imidazole-4-carboxylate (500 mg, 2.28 mmol, 1 eq) in xylene (10 mL) was added Pd (PPh3)4 (263.78 mg, 228.27 μmol, 0.1 eq) at 20°C. The suspension was degassed and purged with N2 for 3 times. Tributyl-(5-methoxy-2- pyridyl)stannane (1.09 g, 2.74 mmol, 1.2 eq) was added into the reaction mixture at 20°C. The suspension was degassed and purged with N2 for 3 times. Then the mixture was stirred at 140°C for 16 hrs under N2. LCMS showed all the starting materials were consumed, desired Ms was detected. The residue was quenched with water (20 mL), and extracted with ethyl acetate (4×20 mL). The combined organics were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/4 to 0/1). Compound methyl methyl 5-(5-methoxypyridin-2-yl)-1-methyl-1H- imidazole-4-carboxylate (400 mg, yield 67.33%) was obtained as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.40 (d, J=2.63 Hz, 0.95 H) 7.81 (s, 1.00 H) 7.63 (d, J=8.25 Hz, 1.05 H) 7.49 (dd, J=8.76, 3.10 Hz, 1.00 H) 3.90 (s, 3.00 H) 3.63 (s, 3 H) 3.56 (s, 3.00 H). A solution of methyl 5-(5-methoxypyridin-2-yl)-1-methyl-1H-imidazole-4-carboxylate (200 mg, 768.45 μmol, 1 eq) in 6N HCl (4 mL) was stirred at 80°C for 24 hrs. LCMS showed all the starting materials were consumed, desired Ms was detected. The reaction mixture was concentrated under reduced pressure to give the crude 5-(5-methoxypyridin-2-yl)-1-methyl- 1H-imidazole-4-carboxylic acid (220 mg, yield 95.54%) as a yellow solid. The crude product was directly used for the next step. 1H 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, 3.00 Hz, 1.15 H) 3.93 (s, 3.05 H) 3.74 (s, 3.00 H). Example 73: Synthesis of 4-(5-Fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3- carboxylic acid To a solution of 4-bromo-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (10 g, 46.65 mmol, 1 eq) in THF (50 mL) and t-BuOH (50 mL) was added DMAP (557.75 mg, 4.57 mmol, 0.1 eq) and tert-butoxycarbonyl tert-butyl carbonate (29.89 g, 136.96 mmol, 3 eq) at 20°C, then the mixture was stirred at 20°C for 12 hours. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. Then the residue was diluted with water (300 mL) and extracted with dichloromethane (300 mL x 3). The combined organic layer was washed brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 20%) to give tert-butyl 4- bromo-1,5-dimethyl-1H-pyrazole-3-carboxylate (3.5 g, yield 27.86%) as a white solid. 1H 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 eq) and triisopropyl borate (3.59 g, 19.08 mmol, 4.39 mL, 1.5 eq) in THF (70 mL) was added n-BuLi (1.22 g, 19.08 mmol, 1.5 eq) dropwise at -78°C, then the mixture was stirred at -78°C for 1 hour. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was quenched by addition saturated ammonium chloride solution (50 mL) at 0°C, and then diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was triturated with petroleum ether: ethyl acetate (50 mL, 10:1) at 20°C for 30 minutes, the mixture was filtered and the filter cake was dried in high vacuum to give (3- (tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazol-4-yl)boronic acid (2.52 g, yield 82.52%) as a white solid. 1H NMR: (400 MHz, DMSO-d6): δ ppm 8.49 (s, 2.00 H) 3.79 (s, 3.00 H) 2.41 (s, 3.00 H) 1.53 (s, 9.00 H). To a mixture of (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazol-4-yl)boronic acid (2.5 g, 10.41 mmol, 1 eq) in DMF (37.5 mL) was added 2-bromo-5-fluoro-pyridine (2.75 g, 15.62 mmol, 1.5 eq) and then a solution of K2CO3 (2.16 g, 15.62 mmol, 1.5 eq) in H2O (7.5 mL) was added at 20°C. The vessel was evacuated and backfilled with argon (this process was repeated three times), the palladiumtriphenylphosphane (601.70 mg, 520.70 μmol, 0.05 eq) was added into the mixture under argon, the vessel was evacuated and backfilled with argon (this process was repeated three times), then the mixture was stirred at 80°C for 12 hours. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 20%) to give tert-butyl 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H- pyrazole-3-carboxylate (2.51 g, yield 82.73%) as a light-yellow solid. LCMS (ESI+): m/z =292.0 (M+1), RT: 0.417 min. A solution of tert-butyl 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (2.5 g, 8.58 mmol, 1 eq) in HCl/dioxane (4 M, 50 mL) was stirred at 20°C for 12 hours. LCMS showed all the starting materials were consumed; desired mass was detected. The reaction mixture was concentrated under reduced pressure to give 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H- pyrazole-3-carboxylic acid (2.3 g, yield 98.65%, HCl) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.62 (d, J=2.88 Hz, 1.00 H) 7.79 (td, J=8.76, 3.00 Hz, 1.00 H) 7.58 (dd, J=8.82, 4.57 Hz, 1.00 H) 3.85 (s, 3.00 H) 2.27 (s, 3.00 H). Example 74: Synthesis of 4-(5-Methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3- carboxylic acid To a solution of (3-(tert-butoxycarbonyl)-1,5-dimethyl-1H-pyrazol-4-yl)boronic acid (1 g, 3.04 mmol, 1 eq) in DMF (7.2 mL) was added 2-bromo-5-methoxy-pyridine (571.75 mg, 3.04 mmol, 1 eq) and a solution of K2CO3 (630.42 mg, 4.56 mmol, 1.5 eq) in H2O (1.44 mL) at 20°C, the vessel was evacuated and backfilled with N2 (this process was repeated three times), then Pd(PPh3)4 (175.70 mg, 152.04 μmol, 0.05 eq) was added into the mixture under N2, the vessel was evacuated and backfilled with N2 (this process was repeated three times). Then the mixture was stirred at 80°C for 12 hours. LCMS showed the starting material was consumed and product with desired mass was detected. The reaction solution was poured into ice water (20 mL), extracted with ethyl acetate (3 x 30 mL), the combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give a residue. The residue was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 50%) to give tert-butyl 4-(5- methoxypyridin-2-yl)-1,5-dimethyl-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-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (0.5 g, 1.55 mmol, 1 eq) in dioxane/HCl (4N) (10 mL) was stirred at 20°C for 12 hours. LCMS showed the starting material was consumed and product with desired mass was detected. The reaction mixture was filtered, and the filter cake was dried in high vacuum to give 4-(5- methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (0.37 g, 76.79% yield) as a white solid. 1H 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. Example 75: 3-(5-Fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2- carboxylic acid To a solution of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (25 g, 164.31 mmol, 1 eq) in DCM (370 mL) was added Br2 (52.52 g, 328.62 mmol, 16.93 mL, 2 eq) dropwise at 0°C. Then the reaction mixture was stirred at 0°C for 2 hours. LCMS showed the starting material was consumed and product with desired mass was detected. The reaction mixture was quenched by addition saturated sodium thiosulfate aqueous solution (100 mL), the reaction solution was filtered, and the filter cake was dried over under high reduced pressure to give 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (36.5 g, 95.18% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ = 4.13 - 4.24 (m, 2 H), 2.82 (t, J=7.32 Hz, 2 H), 2.55 (dt, J=14.85, 7.52 Hz, 2 H). To a solution of 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (10 g, 42.85 mmol, 1 eq) in THF (200 mL) was added 2-tert-butyl-3-isopropyl-1,1-dimethyl-isourea (23.95 g, 128.55 mmol, 3 eq) at 0°C. The mixture was stirred at 20°C for 16 hours. TLC showed the starting material was consumed completely and new spot was observed. The reaction mixture was quenched by addition of saturated ammonium chloride aqueous solution (500 mL), extracted with ethyl acetate (2 x 300 mL), the combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give a residue. The residue was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 50%) to give tert-butyl 3-bromo-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazole-2-carboxylate (10 g, 77.21% yield) as a white solid. 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 eq) in THF (40 mL) was added triisopropyl borate (2.33 g, 12.41 mmol, 2.85 mL, 1.5 eq) at 20°C. Then n-BuLi (2.5 M, 4.96 mL, 1.5 eq) was added into the mixture dropwise at -78°C and the mixture was stirred at -78°C for 2 hours. LCMS showed product with desired mass was detected. The reaction mixture was quenched by addition saturated ammonium chloride aqueous solution (100 mL) and then extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatograph on silica gel (eluted with methanol in ethyl acetate from 0% to 50%) to give (2- (tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)boronic acid (0.9 g, 35.40% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ = 4.08 - 4.15 (m, 2 H), 3.57 (s, 2 H), 2.82 - 2.96 (m, 2 H), 2.50 - 2.56 (m, 2 H), 1.54 (s, 9 H). To a solution of (2-(tert-butoxycarbonyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)boronic acid (0.9 g, 2.93 mmol, 1 eq) in DMF (13.5 mL) was added 2-bromo-5-fluoro-pyrimidine (518.13 mg, 2.93 mmol, 1 eq) and a solution of K2CO3 (606.94 mg, 4.39 mmol, 1.5 eq) in H2O (3 mL) at 20°C, the vessel was evacuated and backfilled with N2 (this process was repeated three times), then Pd(PPh3)4 (53.97 mg, 146.39 μmol, 0.05 eq) was added into the mixture under N2, the vessel was evacuated and backfilled with N2 (this process was repeated three times). Then the mixture was stirred at 80°C for 12 hours. LCMS showed the starting material was consumed and product with desired mass was detected. The reaction solution was poured into ice water (50 mL), extracted with ethyl acetate (3 x 30 mL), the combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give a residue. The residue was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 30%) to give tert-butyl 3- (5-fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (0.78 g, 73.54% yield) as a yellow solid. 1H 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 (quin, J=7.33 Hz, 2 H), 1.45 (s, 9 H). A solution of tert-butyl 3-(5-fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2- carboxylate (0.78 g, 2.15 mmol, 1 eq) in 4N HCl/dioxane (16 mL) was stirred at 20°C for 1 hour. LCMS showed the starting material was consumed and product with desired mass was detected. The reaction solution was concentrated under reduced pressure to give 3-(5- fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (0.45 g, 82.52% yield, 98% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ = 14.44 - 15.49 (m, 1 H), 9.03 (s, 2 H), 4.22 (t, J=7.38 Hz, 2 H), 3.15 (br t, J=7.38 Hz, 2 H), 2.62 (br t, J=7.38 Hz, 2 H). LCMS (ESI+): m/z =249.1 (M+1), RT: 0.322 min. Example 76: 3-(5-Fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-4-carboxylic acid To a solution of methyl 3-iodo-1,5-dimethyl-1H-pyrazole-4-carboxylate (0.6 g, 2.08 mmol, 1 eq) and (5-fluoro-2-pyridyl)-trimethyl-stannane (2.91 g, 7.27 mmol, 3.5 eq) in dioxane (12 mL) was added CsF (631.33 mg, 4.16 mmol, 153.42 μL, 2 eq) at 20°C. The mixture was degassed and purged with N2 for 3 times. Then Pd(PPh3)4 (240.14 mg, 207.81 μmol, 0.1 eq) and CuI (39.58 mg, 207.81 μmol, 0.1 eq) was added into the mixture at 20°C. The mixture was degassed and purged with N2 for 3 times and stirred at 120°C for 12 hours. LCMS showed the starting material was consumed and product with desired mass was detected. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (20 mL x 3). The filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 30%) to give methyl 3-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-4-carboxylate (0.35 g, 58.79% yield) as a yellow solid. 1H 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-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-4-carboxylate (0.35 g, 1.22 mmol, 1 eq) in THF (3.5 mL) and H2O (1.75 mL) was added LiOH.H2O (76.90 mg, 1.83 mmol, 1.5 eq) at 20°C. The mixture was stirred at 20°C for 2 hours. LCMS showed the starting material was consumed and product with desired mass was detected. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (10 x 3 mL). The aqueous layer was adjusted the pH to 5 with 1N aq.HCl at 0°C, filtered, the filter cake was dried over under high reduced pressure to give 3-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-4- carboxylic acid (0.2 g, 68.90% yield, 99% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ = 16.00 (br d, J=1.75 Hz, 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). Example 77: 5-Fluoro-3-(2H-1,2,3-triazol-2-yl)picolinic acid To a solution of 3,5-difluoropicolinonitrile (2.2 g, 15.70 mmol, 1 eq), 2H-triazole (1.08 g, 15.70 mmol, 909.91 μL, 1 eq) in ACN (110 mL) was added K2CO3 (5.43 g, 39.26 mmol, 2.5 eq). The mixture was stirred at 25 °C for 12 hrs. TLC indicated starting material was consumed completely and many new spots formed. The crude reaction mixture of 4 experiments was combined for workup. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by flash silica gel chromatography (Biotage®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to give a residue. The residue was twice purified by prep-HPLC (TFA condition) to give 5-fluoro-3-(2H-1,2,3-triazol-2-yl)picolinonitrile (2.5 g, yield 21.04%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.90 (d, J=2.50 Hz, 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-triazol-2-yl)picolinonitrile (0.9 g, 4.76 mmol, 1 eq) in HCl (12 M, 81 mL) was stirred at 110°C for 5 hrs. LC-MS showed starting material was consumed completely and one main peak with desired mass was detected. The crude reaction mixture from 4 parallel reactions was combined for workup. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HCl condition) to give 5-fluoro-3-(2H-1,2,3-triazol-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). Example 78: 5-Fluoro-3-(5-fluoropyrimidin-2-yl)picolinic acid To a solution of methyl 3-bromo-5-fluoropicolinate (500 mg, 2.14 mmol, 1 eq) in DMF (10 mL) was added (5-fluoropyrimidin-2-yl)-trimethyl-stannane (3.19 g, 8.55 mmol, 4 eq) and CsF (649.10 mg, 4.27 mmol, 157.74 μL, 2 eq), the mixture was degassed and purged with argon for 3 times, and then to the mixture was added palladiumtriphenylphosphane (246.89 mg, 213.65 μmol, 0.1 eq) and CuI (40.69 mg, 213.65 μmol, 0.1 eq) at 20°C. The mixture was stirred at 110°C for 16 hours under argon. LCMS showed all the starting materials were consumed; desired mass was detected. The mixture was filtered, and then the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 15%) to give methyl 5-fluoro-3-(5-fluoropyrimidin-2-yl)picolinate (199 mg, 37.08% yield) as an yellow oil. 1H NMR (400 MHz, DMSO-d6): δ = ppm 9.09 (d, J=0.88 Hz, 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, 3 H). To a solution of methyl 5-fluoro-3-(5-fluoropyrimidin-2-yl)picolinate (199 mg, 792.23 μmol, 1 eq) in THF (1 mL) and H2O (1 mL) was added LiOH·H2O (66.49 mg, 1.58 mmol, 2 eq) at 20°C. The mixture was stirred at 20°C for 2 hours. LCMS showed all the starting materials were consumed, desired MS was detected. The reaction was diluted with water (10 mL) and extracted with ethyl acetate 10 mL (10 mL x 3). The phase layer was adjusted to pH=2 with 1 N HCl at 0°C, the reaction was diluted with water (5 mL) and extracted with (dichloromethane: MeOH) = (5:1, 10 mL x 5). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-fluoro-3-(5- fluoropyrimidin-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. Example 79: 5,6-Dimethyl-3-(pyrimidin-2-yl)picolinic acid
To a solution of 3-bromo-5,6-dimethylpyridin-2-amine (4.2 g, 20.89 mmol, 1 eq) in dioxane (85 mL) was added tributyl(pyrimidin-2-yl)stannane (9.25 g, 25.07 mmol, 1.2 eq) and CsF (6.35 g, 41.78 mmol, 2 eq), the mixture was degassed and purged with argon for 3 times, and then CuI (397.83 mg, 2.09 mmol, 0.1 eq) and palladiumtriphenylphosphane (770.17 mg, 2.09 mmol, 0.1 eq) was added to the mixture at 20°C, the mixture was degassed and purged with argon for 3 times. The mixture was stirred at 100°C for 16 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. The mixture was filtered, and then the filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 40%) to give 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-amine (3.6 g, 86.07% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.86 (d, J=4.88 Hz, 2 H), 8.37 (s, 1 H), 7.33 (t, J=4.88 Hz, 1 H), 2.30 (s, 3 H), 2.16 (s, 3 H). To a solution of 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-amine (2 g, 9.99 mmol, 1 eq) in AcOH (20 mL) was added H2SO4 (3.2 mL) dropwise at 0°C. Then a solution of NaNO2 (1.38 g, 19.98 mmol, 2 eq) in H2O (10 mL) was added dropwise at 0°C. The mixture was stirred at 20°C for 2 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. 5,6-Dimethyl-3-(pyrimidin-2-yl)pyridin-2-ol (1.62 g, 80.60% yield) was obtained as a yellow solid. 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 solution of 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-ol (1.4 g, 6.96 mmol, 1 eq) in DCM (28 mL) was added DIPEA (3.60 g, 27.83 mmol, 4.85 mL, 4 eq) at 20°C, then trifluoromethylsulfonyl trifluoromethanesulfonate (2.94 g, 10.44 mmol, 1.72 mL, 1.5 eq) was added dropwise at 0°C. The mixture was stirred at 30°C for 16 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (20 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 20%) to give residue.5,6-Dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl trifluoromethanesulfonate (1.9 g, 81.94% yield) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.98 (d, J=4.88 Hz, 2 H), 8.48 (s, 1 H), 7.58 (t, J=4.88 Hz, 1 H), 2.50 (s, 3 H), 2.40 (s, 3 H). To a solution of 5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl trifluoromethanesulfonate in methanol (40 mL) was added Pd(dppf)Cl2 (417.13 mg, 570.08 μmol, 0.1 eq) and TEA (1.73 g, 17.10 mmol, 2.38 mL, 3 eq) at 20°C. The mixture was stirred at 70°C for 16 hrs under CO (50 psi). LCMS showed all the starting materials were consumed; desired mass was detected. The mixture reaction was filtered and then the filtrate was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 20%) to give methyl 5,6-dimethyl-3- (pyrimidin-2-yl)picolinate (500 mg, 36.05% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.90 (d, J=4.88 Hz, 2 H), 8.29 (s, 1 H), 7.49 (t, J=4.94 Hz, 1 H), 3.72 (s, 3 H), 2.50 (s, 3 H), 2.37 (s, 3 H). To a solution of methyl 5,6-dimethyl-3-(pyrimidin-2-yl)picolinate (100 mg, 411.08 μmol, 1 eq) in methanol (0.5 mL) and THF (0.5 mL) and H2O (0.5 mL) was added LiOH.H2O (34.50 mg, 822.16 μmol, 2 eq) at 20°C. The mixture was stirred at 20°C for 3 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The phase layer was adjusted to pH=3 with 1 N 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), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid (90 mg, 95.51% yield) as a yellow solid. 1H 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). Example 80: 4,6-Dimethyl-3-(pyrimidin-2-yl)picolinic acid
A mixture of 5-bromo-2,4-dimethylpyridine (1.00 g, 5.37 mmol, 1 eq), tributyl(pyrimidin-2- yl)stannane (2.38 g, 6.45 mmol, 1.2 eq), CsF (1.63 g, 10.75 mmol, 2 eq), Pd(PPh3)4 (621.11 mg, 537.49 μmol, 0.1 eq) and CuI (102.37 mg, 537.49 μmol, 0.1 eq) in dioxane (20 mL) was degassed and purged with argon for 3 times, and then the mixture was stirred at 100°C for 16 hours under argon atmosphere. LCMS showed the reaction was completed. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether from 0% to 60% to afford 2-(4,6-dimethylpyridin-3-yl)pyrimidine (0.5 g, 50.22% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.95 (d, J=4.88 Hz, 2 H), 8.84 (s, 1 H), 7.49 (t, J=4.88 Hz, 1 H), 7.23 (s, 1 H), 2.52 (s, 3 H), 2.49 (s, 3 H). To a solution of 2-(4,6-dimethylpyridin-3-yl)pyrimidine (0.5 g, 2.70 mmol, 1 eq) in DCM (10 mL) was added m-CPBA (822.05 mg, 4.05 mmol, 85% purity, 1.5 eq) in portions at 0°C. The mixture was stirred at 20°C for 2 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition Na2SO3 (20 mL) at 0°C, and then adjusted to pH=8 with NaHCO3 at 0°C, then diluted with DCM (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2,4-dimethyl-5-(pyrimidin-2-yl)pyridine 1-oxide (0.5 g, 92.05% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.97 (d, J=5.02 Hz, 2 H), 8.61 (s, 1 H), 7.55 (t, J=4.89 Hz, 1 H), 7.44 - 7.51 (m, 1 H), 2.50 (s, 3 H), 2.39 (s, 3 H). To a solution of 2,4-dimethyl-5-(pyrimidin-2-yl)pyridine 1-oxide (0.5 g, 2.48 mmol, 1 eq) in DCM (10 mL) was added TMSCN (739.55 mg, 7.45 mmol, 932.60 μL, 3 eq), the mixture was stirred at 20°C for 1 hour, then N,N-dimethylcarbamoyl chloride (400.82 mg, 3.73 mmol, 341.99 μL, 1.5 eq) was added to the mixture, the mixture was stirred at 20°C for 16 hours. LCMS showed the reaction was completed. The reaction mixture was diluted with water (20 mL) and adjusted to pH=8 with aq. NaHCO3 at 0°C, extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether from 0% to 30% to afford 4,6-dimethyl-3-(pyrimidin-2-yl)picolinonitrile (0.4 g, 76.57% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.06 (d, J=4.88 Hz, 2 H), 7.61 - 7.73 (m, 2 H), 2.56 (s, 3 H), 2.28 (s, 3 H). To a solution of 4,6-dimethyl-3-(pyrimidin-2-yl)picolinonitrile (0.3 g, 1.43 mmol, 1 eq) in methanol (3 mL) and H2O (3 mL) was added NaOH (171.23 mg, 4.28 mmol, 3 eq), the mixture was stirred at 60°C for 48 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved with water (10 mL) and adjusted to pH=5 with 1 N HCl at 0°C, then the mixture was lyophilized to give 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid (0.8 g, 85.60% yield, 35% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.89 (d, J=5.00 Hz, 2 H), 7.49 (t, J=4.88 Hz, 1 H), 7.45 (s, 1 H), 2.54 (s, 3 H), 2.20 (s, 3 H). Example 81: 6-Methyl-3-(pyrimidin-2-yl)pyrazine-2-carboxylic acid To a solution of methyl 6-bromo-3-chloropyrazine-2-carboxylate (1.5 g, 5.97 mmol, 1 eq) in dioxane (15 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (748.82 mg, 5.97 mmol, 833.87 μL, 1 eq), K2CO3 (1.65 g, 11.93 mmol, 2 eq) and Pd(dppf)Cl2.CH2Cl2 (487.13 mg, 596.50 μmol, 0.1 eq) under N2. The reaction was stirred at 100°C for 12 hours. LCMS showed all the starting materials were consumed; the desired mass was detected. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=8/1 to 6/1) to give methyl 3-chloro-6-methylpyrazine-2- carboxylate (600 mg, yield 53.91%) as a yellow solid. 1H 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 eq) in DMF (9 mL) was added tributyl(pyrimidin-2-yl)stannane (1.78 g, 4.82 mmol, 1.5 eq), CsF (976.87 mg, 6.43 mmol, 2 eq), CuI (61.24 mg, 321.55 μmol, 0.1 eq) and Pd(PPh3)4 (371.57 mg, 321.55 μmol, 0.1 eq) under N2. The reaction was stirred at 120°C for 6 hrs. LCMS showed the reaction was completed. The reaction was diluted with water (10 mL) and aqueous KF (20 mL) was added. The remaining mixture was stirred at 25°C for 30 min 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), dried over Na2SO4, filtered, and concentrated in vacuum to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/8 to 0/1) to give methyl 6-methyl-3- (pyrimidin-2-yl)pyrazine-2-carboxylate (700 mg, yield 70.92%, 75% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.98 (d, J=4.88 Hz, 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-(pyrimidin-2-yl)pyrazine-2-carboxylate (700 mg, 2.28 mmol, 1 eq) in hydrochloric acid (10 mol/L, 10 V) was stirred at 80°C for 2 hours. LCMS showed all the starting material was consumed; the desired mass was detected. The reaction was concentrated in vacuum to give 6-methyl-3-(pyrimidin-2-yl)pyrazine-2-carboxylic acid (200 mg, yield 40.57%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.95 (d, J=4.88 Hz, 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). Example 82: 4-Chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid
To a solution of 3-bromo-6-methylpicolinic acid (5 g, 23.14 mmol, 1 eq) in MeOH (50 mL) was added H2SO4 (2.27 g, 23.14 mmol, 1.23 mL, 1 eq) at 20°C and stirred at 70°C for 16 hours. LCMS showed all the starting material was consumed and product with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layer was washed with saturated sodium chloride aqueous solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 3-bromo-6-methylpicolinate (5 g, 93.90% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 7.84 (d, J=8.25 Hz, 1 H), 7.14 (d, J=8.25 Hz, 1 H), 3.99 (s, 3 H), 2.56 (s, 3 H). To a solution of methyl 3-bromo-6-methylpicolinate (4 g, 17.39 mmol, 1 eq), tributyl(pyrimidin- 2-yl)stannane (7.70 g, 20.86 mmol, 1.2 eq) and cesium fluoride (5.28 g, 34.77 mmol, 2 eq) in dioxane (80 mL) was added iodocopper (331.13 mg, 1.74 mmol, 0.1 eq) and palladiumtriphenylphosphane (2.01 g, 1.74 mmol, 0.1 eq) at 20°C under N2. The mixture was stirred at 100°C for 16 hours. LCMS showed all the starting materials were consumed and product with desired mass was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude product which was purified by column chromatograph on silica gel (eluted with ethyl acetate in petroleum ether from 0% to 50%) to give methyl 6-methyl-3-(pyrimidin-2-yl)picolinate (4.1 g, 51.43% yield, 50% purity) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ = ppm 8.91 (d, J=4.75 Hz, 2 H), 8.49 (d, J=8.13 Hz, 1 H), 7.53 - 7.55 (m, 1 H), 7.50 (br t, J=4.82 Hz, 1 H), 3.75 (s, 3 H), 2.57 (s, 3 H). To a solution of methyl 6-methyl-3-(pyrimidin-2-yl)picolinate (4.1 g, 8.94 mmol, 50% purity 1 eq) in DCM (40 mL) was added 3-chlorobenzenecarboperoxoic acid (3.63 g, 17.89 mmol, 85% purity, 2 eq) in portions at 0°C and stirred at 30°C for 16 hours. LCMS showed all the starting materials were consumed and product with desired mass was detected. The reaction mixture was quenched by addition saturated with sodium sulfite solution (50 mL) at 0°C and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatograph on silica gel (eluted with methanol in ethyl acetate ether from 0% to 10%) to give 2-(methoxycarbonyl)-6-methyl-3-(pyrimidin-2-yl)pyridine 1-oxide (1.77 g, 80.71% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ = ppm 8.94 (d, J=4.88 Hz, 2 H), 8.23 (d, J=8.26 Hz, 1 H), 7.75 (d, J=8.38 Hz, 1 H), 7.56 (t, J=4.88 Hz, 1 H), 3.88 (s, 3 H), 2.44 (s, 3 H). A solution of 2-(methoxycarbonyl)-6-methyl-3-(pyrimidin-2-yl)pyridine 1-oxide (500 mg, 2.04 mmol, 1 eq) in POCl3 (5 mL) was stirred at 120°C for 2 hours. LCMS showed all the starting materials were consumed and product with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (10 mL) and adjusted to pH=8 at 0°C, then the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatograph on silica gel (eluted with methanol in ethyl acetate ether from 0% to 20%) to give methyl 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinate (430 mg, 79.98% yield) as yellow oil. 1H NMR (400 MHz, DMSO-d6): δ = ppm 8.94 (d, J=4.88 Hz, 2 H), 7.85 (s, 1 H), 7.57 (t, J=4.94 Hz, 1 H), 3.58 (s, 3 H), 2.59 (s, 3 H). To a solution of methyl 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinate (400 mg, 758.50 μmol, 1 eq) in MeOH (4 mL) and THF (4 mL) was added a solution of LiOH.H2O (63.65 mg, 1.52 mmol, 2 eq) in H2O (4 mL) at 20°C and stirred at 20°C for 16 hours. LCMS showed all the starting materials were consumed and product desired mass was detected. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane and methanol (10 mL x 3, 5: 1). The combined organic layers were washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid (154 mg, 81.33% yield) as a yellow solid. LCMS (ESI+): m/z =250.1 (M+1), RT: 0.207 min. Example 83: 4-(5-Fluoropyrimidin-2-yl)-1-methyl-5-(methyl-d3)-1H-pyrazole-3- carboxylic acid
To a solution of 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (5 g, 24.39 mmol, 1 eq) in THF (25 mL) and t-BuOH (25 mL) was added Boc2O (15.97 g, 73.17 mmol, 16.81 mL, 3 eq) and DMAP (297.96 mg, 2.44 mmol, 0.1 eq) at 20°C. The reaction mixture was stirred at 20°C for 12 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was filtered to afford filtrate and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 1/1) to give tert-butyl 5-bromo-1- methyl-1H-pyrazole-3-carboxylate (6 g, 21.83 mmol, 89.50% yield, 95% purity) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 6.75 (s, 1 H), 3.95 (s, 3 H), 1.59 (s, 9 H). To a solution of tert-butyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate (9.5 g, 34.56 mmol, 1 eq) in THF (180 mL) was added n-BuLi (2.5 M, 20.74 mL, 1.5 eq) drop-wise at -78°C under N2. The reaction mixture was stirred at -78°C for 1 hrs, then trideuterio(iodo)methane (5.89 g, 41.48 mmol, 2.53 mL, 1.2 eq) was added to the mixture drop-wise at -78°C. The reaction mixture was stirred -78°C for 2 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was quenched by addition of saturated NH4Cl solution (600 mL) at 0°C, and then extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 2/1) to give tert-butyl 1- methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylate (5 g, 23.34 mmol, 67.52% yield, 93% purity) as a colorless oil. 1H NMR: (400 MHz, CHLOROFORM-d): δ ppm 6.50 (s, 1 H), 3.84 (s, 3 H), 1.60 (s, 9 H). To a solution of tert-butyl 1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylate (5.9 g, 27.54 mmol, 1 eq) in DMF (120 mL) was added NBS (6.37 g, 35.80 mmol, 1.3 eq) at 20°C. The reaction mixture was stirred 20°C for 12 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was quenched by addition water (360 mL) at 0°C, and then extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 1/1) to give tert-butyl 4-bromo-1- methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylate (7.8 g, 26.92 mmol, 97.76% yield, 96% purity) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 3.87 (s, 3 H), 1.62 (s, 9 H). To a solution of tert-butyl 4-bromo-1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylate (7.8 g, 26.92 mmol, 1 eq) in THF (160 mL) was added i-PrMgCl-LiCl (1.3 M, 37.27 mL, 1.8 eq) drop- wise at -50°C. The mixture was stirred at -50°C for 1 hr. Triisopropyl borate (10.13 g, 53.84 mmol, 12.38 mL, 2 eq) was added into the reaction mixture drop-wise at -50°C. Then the mixture was stirred at -50°C for 3 hrs. TLC showed starting material was consumed completely. The reaction mixture was quenched with water (500 mL) and adjusted pH 5 with aq. HCl (1 N). The mixture was extracted with ethyl acetate (3 x 500 mL). The combined organics were washed brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was triturated in methyl tert-butyl ether (10 mL) at 25°C for 30 minutes and filtered to afford filter cake. The filter cake was dried on vacuum to give (3-(tert-butoxycarbonyl)-1-methyl-5- (methyl-d3)-1H-pyrazol-4-yl)boronic acid (4.3 g, 15.92 mmol, 59.14% yield, 90% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.50 (br s, 2 H), 3.79 (s, 3 H), 1.44 - 1.65 (m, 9 H). To a solution of (3-(tert-butoxycarbonyl)-1-methyl-5-(methyl-d3)-1H-pyrazol-4-yl)boronic acid (4.3 g, 15.92 mmol, 1 eq) in H2O (20 mL) and DMF (82 mL) was added 2-bromo-5-fluoro- pyrimidine (5.64 g, 31.84 mmol, 2 eq) and K2CO3 (6.60 g, 47.76 mmol, 3 eq) at 25°C. The mixture degassed and purged with N2 for 3 times. Pd(PPh3)4 (1.84 g, 1.59 mmol, 0.1 eq) was added into the reaction mixture at 25°C. The mixture was degassed and purged with N2 for 3 times and stirred at 90°C for 12 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was poured into H2O (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organics were washed brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 1/2) to give tert-butyl 4-(5-fluoropyrimidin-2-yl)-1-methyl-5-(methyl- d3)-1H-pyrazole-3-carboxylate (3.2 g, 10.19 mmol, 63.98% yield, 94% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.91 (s, 2 H), 3.82 (s, 3 H), 1.37 (s, 9 H). To a solution of tert-butyl 4-(5-fluoropyrimidin-2-yl)-1-methyl-5-(methyl-d3)-1H-pyrazole-3- carboxylate (3.1 g, 9.87 mmol, 1 eq) in 4N/HCl dioxane (30 mL) was stirred at 20°C for 8 hrs. LCMS showed all the starting materials were consumed, desired mass was detected. The reaction mixture was filtered to afford filter cake and filter cake dried in vacuum to give 4-(5- fluoropyrimidin-2-yl)-1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylic acid (2.7 g, 9.60 mmol, 97.27% yield, 98% purity, HCl) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.95 (d, J=0.88 Hz, 2 H), 3.85 (s, 3 H). Example 84: 4-(5-Fluoropyrimidin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3- carboxylic acid To a solution of ethyl 4-bromo-5-methyl-1H-pyrazole-3-carboxylate (9.75 g, 41.83 mmol, 1 eq) in THF (60 mL) was added NaH (3.35 g, 83.67 mmol, 60% purity, 2 eq) in portions at 0°C. The mixture was stirred at 0°C for 0.5 hours. Then trideuterio(iodo)methane (7.13 g, 50.20 mmol, 3.06 mL, 1.2 eq) was added into the mixture at 0°C. The mixture was stirred at 20°C for 3 hours. LCMS showed the starting material was consumed and the desired mass was detected. The mixture was quenched with saturated ammonium chloride solution (200 mL) at 0°C. The mixture was extracted with ethyl acetate (3 x 200 mL). The combined organics were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. It was purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether from 0% to 20% to afford ethyl 4- bromo-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate (7.84 g, 74.93% yield) as a yellow oil. LCMS (ESI+): m/z =250.0 (M+1), RT: 0.468 min 1H NMR (400 MHz, DMSO-d6): δ ppm 4.26 (q, J = 7.0 Hz, 2H), 2.27 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H). To a solution of ethyl 4-bromo-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate (7.82 g, 31.27 mmol, 1 eq) in MeOH (39.1 mL) and H2O (39.1 mL) was added LiOH.H2O (2.62 g, 62.53 mmol, 2 eq). The mixture was stirred at 20°C for 2 hours. LCMS showed the starting material was consumed and the desired mass was detected. The mixture was concentrated under reduced pressure to remove methyl alcohol. Then the mixture was adjusted to pH=2 with 1 N HCl at 0°C, filtered and filter cake was washed with water (5 mL x 3) and dried in high vacuum to give 4-bromo-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid (6.97 g, 95.37% yield) as a white solid. LCMS (ESI+): m/z =222.1 (M+1), RT: 0.303 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.80 (br d, J = 2.9 Hz, 1H), 2.26 (s, 3H). To a solution of 4-bromo-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid (7.67 g, 34.54 mmol, 1 eq) in DCM (230 mL) was added 2-tert-butyl-1,3-diisopropyl-isourea (20.76 g, 103.62 mmol, 3 eq) dropwise at 0°C. The mixture was stirred at 50°C for 16 hours. LCMS showed the starting material was consumed and the desired mass was detected. The reaction mixture was diluted with water (150 mL) and extracted with dichloromethane (3 x 150 mL). The combined organic layer was washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether from 0% to 21% to give tert-butyl 4-bromo-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate (7.43 g, 77.31% yield) as a white solid. LCMS (ESI+): m/z =222.1 (M-56+1), RT: 0.487 min 1H NMR (400 MHz, DMSO-d6): δ ppm 2.75 (td, J = 1.7, 3.5 Hz, 3H), 1.76 (s, 9H). To a solution of give tert-butyl 4-bromo-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate (7.4 g, 26.60 mmol, 1 eq) and triisopropyl borate (7.50 g, 39.91 mmol, 9.17 mL, 1.5 eq) in THF (150 mL) was added n-BuLi (2.5 M, 15.96 mL, 1.5 eq) dropwise at -78°C under N2. The mixture was stirred at -78°C for 2 hours. LCMS showed the reaction was completed. The reaction mixture was quenched by addition of saturated ammonium chloride solution (100 mL) at 0°C, and then diluted with water 50 mL and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (50 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was stirred in a mixture of petroleum ether and ethyl acetate (10:1, 20 mL) for 30 minutes to form slurry, the solid was collected by filtration. (3-(tert- Butoxycarbonyl)-5-methyl-1-(methyl-d3)-1H-pyrazol-4-yl)boronic acid (5.38 g, 83.19% yield) was obtained as a white solid. LCMS (ESI+): m/z =188.2 (M-56+1), RT: 0.364 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.50 (s, 2 H), 2.41 (s, 3 H), 1.53 (s, 9 H). To a solution of 3-(tert-butoxycarbonyl)-5-methyl-1-(methyl-d3)-1H-pyrazol-4-yl)boronic acid (1 g, 4.11 mmol, 1 eq) and 2-bromo-5-fluoro-pyrimidine (1.09 g, 6.17 mmol, 1.5 eq) in DMF (15 mL) and H2O (3 mL) was added K2CO3 (852.83 mg, 6.17 mmol, 1.5 eq). The mixture was degassed and purged with argon for 3 times. Then Pd(PPh3)4 (237.69 mg, 205.69 μmol, 0.05 eq) was added into the mixture. The mixture was degassed and purged with argon for 3 times again. The mixture was stirred at 80°C for 12 hours. LCMS showed the starting material was consumed and the desired mass was detected. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (3 x 50 mL). The combined organics were washed brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether from 0% to 15% to give tert-butyl 4-(5-fluoropyrimidin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylate (1.01 g, 75.80% yield) as a yellow oil. LCMS (ESI+): m/z =296.2 (M+1), RT: 0.408 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.99 (s, 2H), 2.61 - 2.53 (m, 3H), 1.44 (s, 9H). The compound tert-butyl 4-(5-fluoropyrimidin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3- carboxylate (1.01 g, 3.42 mmol, 1 eq) was dissolved into HCl / dioxane (4 N, 20 mL). The mixture was stirred at 20°C for 16 hours. LCMS showed the starting material was consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give 4-(5-fluoropyrimidin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid (0.9 g, 95.46% yield) as a white solid. LCMS (ESI+): m/z =240.2 (M+1), RT: 0.292 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.95 (s, 2H), 2.47 (s, 3H). Example 85: 4-(5-Fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid A mixture of (3-(tert-butoxycarbonyl)-5-methyl-1-(methyl-d3)-1H-pyrazol-4-yl)boronic acid (1 g, 4.11 mmol, 1 eq), 2-bromo-5-fluoro-pyridine (796.38 mg, 4.53 mmol, 1.1 eq), K2CO3 (852.83 mg, 6.17 mmol, 1.5 eq), Pd(PPh3)4 (237.69 mg, 205.69 μmol, 0.05 eq) in DMF (15 mL) and H2O (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 12 hours under N2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was filtered and the filtrate was diluted with water 50 mL and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (50 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel eluted with ethyl acetate in petroleum ether from 0% to 15% to afford the product. Compound tert-butyl 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1H- pyrazole-3-carboxylate (1 g, 82.59% yield) was obtained as a light yellow solid. LCMS (ESI+): m/z =295.3 (M+1), RT: 0.417 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.59 (d, J=3.00 Hz, 1 H), 7.76 (td, J=8.76, 3.00 Hz, 1 H), 7.46 (dd, J=8.63, 4.50 Hz, 1 H), 2.23 (s, 3 H), 1.32 (s, 9 H). A mixture of tert-butyl 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3- carboxylate (1 g, 3.40 mmol, 1 eq) in HCl/dioxane, 4 N (5 mL) was stirred at 20°C for 16 hours under N2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)- 1H-pyrazole-3-carboxylic acid (0.9 g, 96.44% yield) as a white solid. LCMS (ESI+): m/z =239.2 (M+1), RT: 0.280 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.68 (d, J=2.88 Hz, 1 H), 7.87 (td, J=8.76, 3.00 Hz, 1 H), 7.63 (dd, J=8.76, 4.50 Hz, 1 H), 2.27 (s, 3 H). Example 86: 6-(Methyl-d3)-3-(pyrimidin-2-yl)picolinic acid To a solution of methyl 6-amino-3-bromopicolinate (25 g, 108.20 mmol, 1 eq) in DMF (375 mL) was added tributyl(pyrimidin-2-yl)stannane (51.92 g, 140.66 mmol, 1.3 eq), CsF (32.87 g, 216.41 mmol, 2 eq), CuI (1.03 g, 5.41 mmol, 0.05 eq), Pd(PPh3)4 (6.25 g, 5.41 mmol, 0.05 eq). Then the mixture was degassed and purged with N2 for 3 times. The mixture was stirred at 110°C for 12 hrs. LCMS showed all the starting materials were consumed; desired mass was detected. The residue was quenched with KF aqueous solution (100 mL) and the mixture was filtered to afford filtrate. The filtrate was extracted with ethyl acetate (5 × 200 mL). The combined organics were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was dissolved in ethyl acetate and adjusted pH 3 with HCl (4 N). The mixture was filtered to afford filter cake. The filter cake was extracted with ethyl acetate (5 × 100 mL) while adjusting pH 10 with Na2CO3. The combined organic layers were washed brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 6-amino-3-(pyrimidin-2-yl)picolinate (11 g, 44.16% yield) as light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.77 (d, J=4.88 Hz, 2 H), 8.26 (d, J=8.88 Hz, 1 H), 7.31 (t, J=4.82 Hz, 1 H), 6.77 (br s, 2 H), 6.63 (d, J=8.76 Hz, 1 H), 3.73 (s, 3 H). To a solution of methyl 6-amino-3-(pyrimidin-2-yl)picolinate (11 g, 47.78 mmol, 1 eq) in acetonitrile (110 mL) was added CuBr (10.28 g, 71.67 mmol, 1.5 eq) and tert-butyl nitrite (14.78 g, 143.34 mmol, 17.05 mL, 3 eq). The mixture was stirred at 25°C for 12 hrs. LCMS showed all the starting material were consumed; desired mass was detected. The residue was adjusted to pH 7 with N2CO3 and extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 4/1) to give methyl 6- bromo-3-(pyrimidin-2-yl)picolinate (3.3 g, 23.48% yield) as light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.96 (d, J=4.88 Hz, 2 H), 8.53 (d, J=8.38 Hz, 1 H), 7.99 (d, J=8.38 Hz, 1 H), 7.58 (t, J=4.88 Hz, 1 H), 3.79 (s, 3 H). To a solution of trideuterio(deuteriooxy)methane (122.63 mg, 3.40 mmol, 138.10 μL, 2 eq) in MTBE (10 mL) was added 5,7-ditert-butyl-3-phenyl-1,3-benzoxazol-3-ium tetrafluoroborate (1.08 g, 2.72 mmol, 1.6 eq) at 25°C under Ar. Then the reaction was stirred 25°C for 5 mins under Ar. Pyridine (147.92 mg, 1.87 mmol, 150.94 μL, 1.1 eq) was added into the mixture under Ar. Then the reaction was stirred 25°C for 30 mins. The reaction was filtered to give clear solution under Ar. To the above solution was added bis[2-(2-pyridyl)phenyl]iridium(1+) 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine hexafluorophosphate (23.31 mg, 25.50 μmol, 0.015 eq), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine dibromonickel (41.39 mg, 85.00 μmol, 0.05 eq), quinuclidine (330.78 mg, 2.98 mmol, 1.75 eq); then methyl 6-bromo-3-(pyrimidin-2- yl)picolinate (0.5 g, 1.70 mmol, 1 eq) in DMA (10 mL) was added into the mixture under Ar. The mixture was stirred at 2 hrs for 25°C under Argon blue LEDs (450 nm). LCMS showed the reaction was finished; desired mass was detected. This reaction was concentrated under reduced pressure, the residue was poured into ice water (300 mL), and extracted with ethyl acetate (3 × 300 mL). Combined the organic layer, dried with Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 2/1) to give methyl 6-(methyl- d3)-3-(pyrimidin-2-yl)picolinate (0.8 g, 30.70% yield) as light yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.72 (d, J=4.88 Hz, 2 H), 8.414 (d, J=7.98 Hz, 1 H), 7.31 (d, J=8.38 Hz, 1 H), 7.17 (m, 1 H). A solution of methyl 6-(methyl-d3)-3-(pyrimidin-2-yl)picolinate (800 mg, 3.44 mmol, 1 eq) in HCl (8 mL) and Water (8 mL) was stirred at 80°C for 12 hrs. LCMS showed the starting materials were consumed; desired mass was detected. This reaction was concentrated under reduced pressure to give 6-(methyl-d3)-3-(pyrimidin-2-yl)picolinic acid (800 mg, 91.19% yield) as light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.91 (d, J=4.88 Hz, 2 H), 8.40 (d, J=8.13 Hz, 1 H), 7.48 - 7.55 (m, 2 H). Example 87: 6-(Methyl-d3)-3-(2H-1,2,3-triazol-2-yl)picolinic acid hydrochloride To a solution of 3-bromo-6-chloropicolinic acid (5 g, 21.15 mmol, 1 eq) in dioxane (100 mL) and water (5 mL) was added 2H-triazole (1.75 g, 25.38 mmol, 1.47 mL, 1.2 eq), Cs2CO3 (13.78 g, 42.29 mmol, 2 eq), N1,N2-dimethylcyclohexane-1,2-diamine (601.56 mg, 4.23 mmol, 0.2 eq), CuI (201.36 mg, 1.06 mmol, 0.05 eq) at 0°C. The mixture was stirred at 100°C for 12 hrs. LCMS showed all the starting materials were consumed; desired mass was detected. This reaction was poured into ice water (100 mL), filtered to remove insoluble. This filter liquor was extracted with ethyl acetate (3 × 100 mL). Then the aqueous phase was adjusted to pH 5 with HCl (1 N), extracted with ethyl acetate (3 × 100 mL). Combined organic layer was dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give the crude 6-chloro-3-(2H-1,2,3-triazol-2-yl)picolinic acid (4 g, 84.22% yield) as white solid. This reaction was used for next step directly without further purification. LCMS (ESI+): m/z =225.1 (M+1-56), RT:0.167 min. To a solution of 6-chloro-3-(2H-1,2,3-triazol-2-yl)picolinic acid (5 g, 22.26 mmol, 1 eq) in THF (50 mL) was added 2-tert-butyl-1,3-diisopropyl-isourea (8.92 g, 44.52 mmol, 2 eq) at 0°C. The mixture was stirred at 25°C for 12 hrs. LCMS showed desired product was detected. The reaction solution was poured into ice water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined the organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 4/1) to give tert-butyl 6-chloro-3-(2H-1,2,3-triazol- 2-yl)picolinate (1.2 g, 19.20% yield) as white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.43 (d, J=8.63 Hz, 1 H), 8.26 (s, 2 H), 7.90 (d, J=8.63 Hz, 1 H), 1.44 (s, 9 H). To a solution of (methyl-d3)boronic acid (2.5 g, yield 79.45%) in water (10 mL) and THF (40 mL) was added Pd(dppf)Cl2 (23.22 mg, 35.62 μmol, 0.01 eq), K3PO4 (2.27 g, 10.69 mmol, 3 eq) and tert-butyl 6-chloro-3-(2H-1,2,3-triazol-2-yl)picolinate (1 g, 3.56 mmol, 1 eq) at 20°C. The mixture was stirred at 80°C for 4 hrs. LCMS showed all the starting materials were consumed; desired mass was detected. This reaction was poured into water (50 mL). This reaction was extracted with ethyl acetate (3 × 50 mL), combined organic layer was concentrated under reduced pressure to give residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 1/2) to give tert-butyl 6-(methyl- d3)-3-(2H-1,2,3-triazol-2-yl)picolinate (800 mg, 85.29% yield) as dark brown solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.20 (d, J=8.51 Hz, 1 H), 8.18 (s, 2 H), 7.60 (d, J=8.38 Hz, 1 H), 1.40 (s, 9 H). A solution of tert-butyl 6-(methyl-d3)-3-(2H-1,2,3-triazol-2-yl)picolinate (800 mg, 3.04 mmol, 1 eq) in HCl/dioxane (6 N, 8 mL) and MeOH (0.8 mL) was stirred at 60°C for 2 hrs. LCMS showed the starting materials were consumed; desired mass was detected. This reaction was concentrated under reduced pressure to give crude 6-(methyl-d3)-3-(2H-1,2,3-triazol-2- yl)picolinic acid hydrochloride (700 mg, 94.55% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.18 - 12.45 (m, 2 H), 8.21 (d, J=8.38 Hz, 1 H), 8.15 (s, 2 H), 7.59 (d, J=8.38 Hz, 1 H). Example 88: Synthesis of (4-(4-Chlorophenyl)-1-methyl-1H-pyrazol-3-yl)((2S,3R,6R)-2,6- dimethyl-3-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholino)methanone [1], general procedure To a solution of 4-(4-chlorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (56.42 mg, 206.58 μmol, 1.5 eq) in DCM (1 mL) was added DIPEA (71.20 mg, 550.89 μmol, 95.95 μL, 4 eq) and HATU (78.55 mg, 206.58 μmol, 1.5 eq) at 20°C. Then the mixture was stirred at 0°C for 1 hr. N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride (50 mg, 137.72 μmol, 1 eq) was added into reaction mixture at 0°C. Then the mixture was stirred at 20°C for 2 hrs. LCMS showed all the starting materials were consumed; desired MW was detected. The reaction mixture was concentrated under reduced pressure to give the crude product, which was directly purified by Prep-HPLC and lyophilized to give (4- (4-chlorophenyl)-1-methyl-1H-pyrazol-3-yl)((2S,3R,6R)-2,6-dimethyl-3-(((5- (trifluoromethyl)pyrazin-2-yl)amino)methyl)morpholino)methanone (41.7 mg, 58.66% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.37 (s, 0.21H), 8.17 (s, 0.68H), 8.10 (s, 0.25H), 8.04 - 7.88 (m, 1.20H), 7.80 - 7.69 (m, 1.39H), 7.39 (br d, J = 8.4 Hz, 1.45H), 7.33 (s, 1.03H), 7.27 (br d, J = 8.4 Hz, 1.45H), 4.77 (br dd, J = 3.3, 5.7 Hz, 0.23H), 4.32 (br d, J = 11.8 Hz, 0.72H), 3.99 (br d, J = 9.4 Hz, 0.73H), 3.82 (s, 0.80H), 3.78 - 3.63 (m, 0.80H), 3.57 (s, 2.11H), 3.53 - 3.36 (m, 2.66H), 3.28 - 3.20 (m, 0.33H), 3.16 - 2.98 (m, 1H), 2.80 - 2.70 (m, 0.71H), 1.27 - 1.06 (m, 3H), 1.02 - 0.87 (m, 3H). LCMS (ESI+): m/z =509.2 (M+1), RT: 2.972 min (The gradient was 5%B in 0.40 min and 5- 95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5%B in 0.01 min, the flow rate was 0.8 ml/min. Mobile phase A was H2O+10mM NH4HCO3, mobile phase B was Acetonitrile. Column Xbridge-C182.1*50mm 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Using intermediates I-a to I-s, d-j, d-k, d-v, d-w, d-x and known carboxylic acids the following compounds were prepared similarly. Example 89: Synthesis of (4-(4-Chlorophenyl)-1-methyl-1H-pyrazol-3-yl)((5R,6S)-2,2- difluoro-6-methyl-5-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)methanone [2] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid. Yield 22%, white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.36 (s, 0.32H), 8.06 (s, 1.24H), 8.02 - 7.85 (m, 2.32H), 7.67 (d, J = 8.3 Hz, 0.31H), 7.41 (d, J = 8.3 Hz, 0.68H), 7.36 (dd, J = 1.2, 8.1 Hz, 0.33H), 7.07 (dd, J = 1.3, 8.2 Hz, 0.63H), 6.82 (s, 0.63H), 6.44 (br s, 0.25H), 4.66 - 4.57 (m, 0.31H), 4.23 (dd, J = 2.4, 13.9 Hz, 0.68H), 3.69 (br dd, J = 2.9, 6.7 Hz, 0.42H), 3.53 (br dd, J = 3.7, 14.1 Hz, 0.38H), 3.47 - 3.38 (m, 0.69H), 3.37 - 3.30 (m, 0.51H), 3.30 - 3.22 (m, 1.52H), 3.22 - 3.07 (m, 0.75H), 2.97 (br d, J = 12.0 Hz, 0.33H), 2.74 - 2.67 (m, 0.7H), 2.30 - 2.24 (m, 0.97H), 1.93 (s, 2H), 1.19 (br d, J = 6.6 Hz, 1.26H), 1.09 (d, J = 6.1 Hz, 2.1H), 0.92 - 0.81 (m, 3H). LCMS (ESI+): m/z =476.27 (M+1), RT: 10.670 min (The gradient was 10-80% B in 16.00 min , 80%-100%B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile . Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80deg. Example 90: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone [3] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 3-fluoro-2-(pyrimidin-2-yl)benzoic acid. Yield 17%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.95 (d, J=4.88 Hz, 0.90 H) 8.89 (d, J=4.75 Hz, 0.88 H) 8.39 (s, 0.41 H) 7.94 - 8.11 (m, 2.14 H) 7.59 (t, J=4.88 Hz, 0.48 H) 7.48 (br t, J=4.88 Hz, 0.86 H) 7.35 - 7.42 (m, 0.54 H) 7.07 - 7.17 (m, 0.51 H) 6.85 (br s, 1.25 H) 4.57 (br d, J=2.00 Hz, 0.43 H) 4.16 (m, 0.48 H) 3.60 - 3.82 (m, 1.30 H) 3.55 (m, 0.97 H) 3.42 (br d, J=2.88 Hz, 0.86 H) 3.17 - 3.26 (m, 0.63 H) 2.95 - 3.15 (m, 0.96 H) 2.67 (m, 0.53 H) 1.07 - 1.21 (m, 3.00 H) 0.89 - 1.05 (m, 3.05 H). LCMS (ESI+): m/z =491.1 (M+1), RT: 2.289 min (The gradient was 5%B in 0.40min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD) and evaporative light scattering detection (ELSD) . MS mode was positive electrospray ionization. MS range was 100-1000.) Example 91: Synthesis of (4-(5-Chloropyridin-2-yl)-1-methyl-1H-pyrazol-3- yl)((2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)methanone [4] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 4-(5-chloropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid. Yield 40%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.50 (s, 0.85 H) 8.39 (s, 0.25 H) 8.29 - 8.35 (m, 0.27 H) 8.15 (s, 0.62 H) 8.04 (s, 0.65 H) 7.99 (br s, 0.24 H) 7.92 (br s, 0.92 H) 7.82 (m, 0.89 H) 7.71 (s, 0.64 H) 7.40 - 7.53 (m, 0.95 H) 4.72 - 4.83 (m, 0.25 H) 4.38 (br d, J=11.51 Hz, 0.66 H) 3.97 (br s, 0.70 H) 3.80 - 3.87 (m, 1.00 H) 3.75 (br d, J=5.75 Hz, 0.59 H) 3.58 - 3.68 (m, 3.01 H) 3.41 - 3.55 (m, 1.67 H) 3.30 (br s, 0.69 H) 2.96 - 3.08 (m, 0.27 H) 2.79 (br t, J=12.32 Hz, 0.66 H) 1.46 (br d, J=6.63 Hz, 0.26 H) 1.13 - 1.28 (m, 2.85 H) 0.92 - 1.06 (m, 3.00 H). LCMS (ESI+): m/z = 510.2 (M+1), RT: 7.687 min (The gradient was 30-90% B in 16.00 min, 90%-100%B in 4.00 min, 100-30% B in 0.01min, and then held at 30% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80 deg.) Example 92: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [5] General procedure (see Example 88) used for the compound [1] was repeated, using N- (((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.Yield 35%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.85 (d, J=2.50 Hz, 1.76 H) 8.68 (br s, 0.33 H) 8.60 (br s, 0.35 H) 8.55 (br s, 0.56 H) 8.49 (br s, 0.53 H) 7.87 (br t, J=5.19 Hz, 0.57 H) 7.59 (br t, J=5.13 Hz, 0.35 H) 4.74 - 4.82 (m, 0.37 H) 4.36 (br d, J=12.51 Hz, 0.64 H) 3.84 (br d, J=7.25 Hz, 1.15 H) 3.75 (s, 1.52 H) 3.60 - 3.70 (m, 1.63 H) 3.54 - 3.59 (m, 0.44 H) 3.41 - 3.54 (m, 3.61 H) 3.19 (br d, J=12.63 Hz, 0.48 H) 2.99 - 3.08 (m, 0.43 H) 2.77 (br t, J=12.32 Hz, 0.73 H) 2.60 (s, 1.14 H) 2.50 (s, 1.87 H) 1.14 - 1.25 (m, 3.06 H) 0.90 - 1.01 (m, 3.00 H). LCMS (ESI+): m/z =509.1 (M+1), RT: 2.441 min (The gradient was 5%B in 0.40min and 5- 95% B in 2.60 min , hold on 95% B in 1.00min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 93: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [6] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 36%, white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.77 - 8.90 (m, 1.85 H) 8.31 (s, 0.30 H) 8.13 (br s, 0.56 H) 7.47 - 7.69 (m, 0.95 H) 7.15 (br t, J=5.07 Hz, 0.94 H) 6.62 (br d, J=9.13 Hz, 0.30 H) 6.44 (d, J=8.88 Hz, 0.63 H) 4.63 - 4.75 (m, 0.33 H) 4.36 (dd, J=12.94, 1.56 Hz, 0.64 H) 3.79 - 3.88 (m, 1.08 H) 3.77 (s, 1.16 H) 3.53 - 3.72 (m, 2.08 H) 3.42 - 3.52 (m, 3.50 H) 3.19 (br dd, J=13.20, 2.44 Hz,0.47 H) 2.87 - 2.96 (m, 0.37 H) 2.65 - 2.75 (m,0.81 H) 2.61 (s, 1.06 H) 2.46 (s, 1.94 H) 1.14 - 1.25 (m, 3.12 H) 0.90 - 1.02 (m, 3.00 H). LCMS (ESI+): m/z =508.1 (M+1), RT: 2.258 min (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 94: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone [7] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. Yield 37%, white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.30 (s, 0.30 H) 8.16 (s, 1.14 H) 8.10 (s, 0.55 H) 7.97 (br s, 0.59 H) 7.87 (dd, J=8.94, 4.94 Hz, 0.29 H) 7.54 - 7.73 (m, 1.58 H) 7.39 - 7.51 (m, 1.30 H) 7.12 (td, J=8.47, 2.81 Hz, 0.58 H) 6.74 (dd, J=8.19, 2.69 Hz, 0.58 H) 6.54 - 6.65 (m, 1.07 H) 4.60 (br d, J=10.63 Hz, 0.30 H) 4.25 (dd, J=13.57, 2.31 Hz, 0.62 H) 3.82 - 3.92 (m, 0.34 H) 3.73 - 3.81 (m, 0.35 H) 3.50 - 3.66 (m, 1.02 H) 3.40 - 3.50 (m, 0.67 H) 3.29 (br s,1.88 H) 3.07 - 3.15 (m, 0.29 H) 2.66 - 2.78 (m, 0.70 H) 2.46 (br s, 0.32 H) 1.19 - 1.27 (m, 1.35 H) 1.07 - 1.16 (m, 2.21 H) 0.81 - 1.03 (m, 3.00 H). LCMS (ESI+): m/z =479.2 (M+1), RT: 12.188 min (The gradient was 10-80% B in 16.00 min, 80%-100%B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile . Xbridge C18 4.6*150mm column (5 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80 deg.) Example 95: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(5-fluoro-2-(pyrimidin-2-yl)phenyl)methanone [8] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid. Yield 74%, light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (m, 1.85 H) 8.41 (s, 0.38 H) 8.18 (m, 0.41 H) 8.12 (br s, 0.42 H) 7.92 - 8.09 (m, 2.29 H) 7.52 (t, J=4.82 Hz, 0.45 H) 7.44 (t, J=4.82 Hz, 0.53 H) 7.37 (m, 0.51 H) 7.08 (m, 0.47 H) 6.68 - 6.81 (m, 0.82 H) 4.67 - 4.79 (m, 0.45 H) 4.38 (m, 0.47 H) 3.90 (m, 0.48 H) 3.75 - 3.86 (m, 0.43 H) 3.66 - 3.75 (m, 0.52 H) 3.53 - 3.61 (m, 0.89 H) 3.45 (m, 0.82 H) 3.37 - 3.42 (m, 0.76 H) 3.12 - 3.18 (m, 0.82 H) 2.71 - 2.85 (m, 0.98 H) 1.26 (d, J=6.63 Hz, 1.22 H) 1.16 (d, J=6.00 Hz, 2.05 H) 0.81 - 1.03 (m, 3.00 H). LCMS (ESI+): m/z =491.2 (M+1), RT: 11.193 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C18 4.6*150 mm column (5 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80 deg.) Example 96: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(5-methyl-2-(2-methyl-2H-tetrazol-5-yl)phenyl)methanone [9] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 5-methyl-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid. Yield 38%, white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.30 - 8.37 (m, 0.46 H) 8.06 (br s, 0.38 H) 7.82 (d, J=8.13 Hz, 0.39 H) 7.63 - 7.70 (m, 1.38 H) 7.44 (dt, J=7.25, 5.32 Hz, 0.99 H) 7.26 - 7.35 (m, 0.54 H) 7.11 - 7.16 (m, 0.45 H) 6.76 (s, 0.52 H) 6.64 (br d, J=8.38 Hz, 0.77 H) 6.36 (br s, 0.30 H) 4.65 - 4.73 (m, 0.47 H) 4.32 - 4.47 (m, 3.63 H) 4.00 - 4.23 (m, 0.64 H) 3.86 (br dd, J=6.63, 2.75 Hz, 0.62 H) 3.59 - 3.70 (m, 0.73 H) 3.49 - 3.58 (m, 0.97 H) 3.38 - 3.49 (m, 2.02 H) 3.20 - 3.29 (m, 0.36 H) 2.96 (br d, J=11.88 Hz, 0.90 H) 2.80 (br t, J=12.26 Hz, 0.65 H) 2.41 (s, 0.30 H) 2.21 (s, 1.21 H) 1.92 (s, 1.42 H) 1.24 (br d, J=6.63 Hz, 1.21 H) 1.17 (br d, J=6.00 Hz, 2.12 H) 0.86 - 0.98 (m, 3.03 H). LCMS (ESI+): m/z = 490.2 (M+1), RT:2.422 min (The gradient was 5% B in 0.40min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50 mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 97: Synthesis of (5-Chloro-2-(2-methyl-2H-tetrazol-5-yl)phenyl)((2S,3R,6R)-2,6- dimethyl-3-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)morpholino)methanone [10] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 5-chloro-2-(2-methyl-2H-tetrazol-5-yl)benzoic acid. Yield 22%, white solid 1H NMR (400 MHz, DMSO-d6): δ 8.31 (s, 0.47 H) 8.04 (br d, J=1.13 Hz, 0.53 H) 7.97 (d, J=8.38 Hz, 0.41 H) 7.77 (d, J=8.38 Hz, 0.48 H) 7.57 - 7.71 (m, 1.57 H) 7.41 - 7.51 (m, 0.92 H) 7.36 - 7.40 (m, 0.44 H) 7.01 (s, 0.52 H) 6.79 (br s, 0.31 H) 6.62 (br d, J=8.88 Hz, 0.81 H) 4.67 (br d, J=10.63 Hz, 0.43 H) 4.31 - 4.48 (m, 3.65 H) 3.81 - 4.02 (m, 1.00 H) 3.44 - 3.71 (m, 2.43 H) 3.16 - 3.30 (m, 0.80 H) 3.03 (br d, J=11.88 Hz, 0.48 H) 2.72 - 2.91 (m, 1.11 H) 1.15 - 1.28 (m, 3.21 H) 0.94 (br dd, J=11.88, 6.38 Hz, 3.00 H). LCMS (ESI+): m/z = 510.1 (M+1), RT: 2.496 min (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min , hold on 95% B in 1.00 min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 98: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazol-3- yl)methanone [11] General procedure (see Example 88) used for the compound [1] was repeated, using N- (((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid. Yield 60%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.85 (d, J=0.75 Hz, 0.73 H) 8.80 (s, 1.07 H) 8.69 (br s, 0.37 H) 8.60 (br d, J=2.88 Hz, 0.38 H) 8.52 (d, J=2.88 Hz, 0.53 H) 8.46 (d, J=2.75 Hz, 0.54 H) 8.38 (s, 0.35 H) 8.20 (s, 0.50 H) 7.86 (br t, J=5.75 Hz, 0.55 H) 7.58 - 7.64 (m, 0.52 H) 4.76 - 4.85 (m, 0.41 H) 4.40 (dd, J=13.51, 2.63 Hz, 0.58 H) 3.87 (s, 1.08 H) 3.80 - 3.86 (m, 0.82 H) 3.66 - 3.79 (m, 2.36 H) 3.60 (s, 1.85 H) 3.41 - 3.56 (m, 2.18 H) 2.99 - 3.17 (m, 1.07 H) 2.81 (dd, J=13.57, 11.19 Hz, 0.65 H) 1.21 (dd, J=15.57, 6.44 Hz, 3.16 H) 0.95 (dd, J=14.13, 6.38 Hz, 3.00 H). LCMS (ESI+): m/z =495.1 (M+1), RT: 2.268 min (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min , hold on 95% B in 1.00 min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000. Example 99: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazol-3- yl)methanone [12]
General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid. Yield 34%, white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.78 - 8.83 (m, 1.84 H) 8.40 (s, 0.33 H) 8.32 (s, 0.32 H) 8.18 (s, 0.54 H) 8.10 (br s, 0.56 H) 7.49 - 7.67 (m, 0.98 H) 7.08 - 7.23 (m, 0.96 H) 6.57 - 6.67 (m, 0.36 H) 6.44 (br d, J=8.76 Hz, 0.61 H) 4.71 (br dd, J=4.50, 2.13 Hz, 0.36 H) 4.40 (dd, J=13.45, 2.56 Hz, 0.64 H) 3.82 - 3.90 (m, 1.78 H) 3.65 - 3.74 (m, 1.95 H) 3.57 (s, 2.79 H) 3.42 - 3.50 (m, 1.17 H) 3.11 - 3.16 (m, 0.37 H) 2.89 - 2.97 (m, 0.40 H) 2.75 (br dd, J=13.20, 11.32 Hz, 0.68 H) 1.14 - 1.26 (m, 3.26 H) 0.95 (dd, J=18.57, 6.32 Hz, 3.15 H). LCMS (ESI+): m/z = 494.1 (M+1), RT: 2.136 min. (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min , hold on 95% B in 1.00 min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000. Example 100: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazol-3- yl)methanone [13]
General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid. Yield 28%, white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.81 (s, 1.81 H) 8.38 (d, J=12.38 Hz, 0.51 H) 8.14 - 8.18 (m, 1.26 H) 7.80 - 8.01 (m, 1.94 H) 7.53 - 7.65 (m, 0.51 H) 4.70 - 4.78 (m, 0.28 H) 4.42 (dd, J=13.51, 2.38 Hz, 0.71 H) 3.81 - 3.91 (m, 1.11 H) 3.64 - 3.80 (m, 2.80 H) 3.55 (br s, 1.04 H) 3.52 (s, 2.23 H) 3.38 - 3.49 (m, 0.64 H) 3.17 (d, J=5.25 Hz, 0.20 H) 3.06 - 3.14 (m, 0.35 H) 2.93 - 3.03 (m, 0.33 H) 2.80 (dd, J=13.38, 11.26 Hz, 0.75 H) 1.17 - 1.26 (m, 3.02 H) 0.89 - 1.00 (m, 3.00 H). LCMS (ESI+): m/z =495.2 (M+1), RT:10.211 min (The gradient was 10-80% B in 16.00 min, 80%-100%B in 4.00 min, 100-10% B in 0.01 min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150 mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range wa 100-1000. The column temperature is 80 deg. Example 101: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl)methanone [14]
General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 4-(4-fluorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid. Yield 37%, white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.36 (s, 0.19 H) 8.18 (s, 0.64 H) 8.02 - 8.07 (m, 0.25 H) 7.85 - 8.01 (m, 1.12 H) 7.72 (d, J=4.88 Hz, 1.33 H) 7.39 - 7.47 (m, 0.1 H) 7.23 - 7.38 (m, 1.79 H) 7.07 - 7.23 (m, 1.90 H) 4.77 (dt, J=9.44, 3.72 Hz, 0.21 H) 4.31 (dd, J=13.63, 2.50 Hz, 0.69 H) 3.94 (br d, J=10.01 Hz, 0.69 H) 3.79 - 3.87 (m, 0.78 H) 3.61 - 3.78 (m, 0.76 H) 3.55 (s, 2.02 H) 3.34 - 3.52 (m, 2.51 H) 3.09 - 3.22 (m, 0.26 H) 2.91 - 3.07 (m, 0.92 H) 2.73 (dd, J=13.51, 11.13 Hz, 0.68 H) 1.10 - 1.48 (m, 3.16 H) 0.85 - 1.00 (m, 3.00 H). LCMS (ESI+): m/z =493.2 (M+1), RT:2.518 min (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min , hold on 95% B in 1.00 min, and then 95-5%B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 102: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-3- yl)methanone [15]
General procedure (see Example 88) used for making (the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 4-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid. Yield 39%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.46 (d, J=2.76 Hz, 0.917 H), 8.38 (s, 0.246 H), 8.27 (s, 0.259 H), 8.15 (s, 0.633 H), 7.99 (s, 0.966 H), 7.93 (br s, 0.861 H), 7.71 (s, 0.731 H), 7.60 - 7.68 (m, 0.905 H), 7.43 - 7.57 (m, 0.922 H), 4.71 - 4.83 (m, 0.277 H), 4.38 (dd, J=13.61, 2.57 Hz, 0.760 H), 3.91 - 4.03 (m, 0.768 H), 3.83 (s, 1.103 H), 3.75 (br t, J=5.96 Hz, 0.551 H), 3.37 - 3.68 (m, 5.572 H), 2.71 - 3.09 (m, 1.109 H), 1.10 - 1.35 (m, 3.276 H), 0.86 - 1.08 (m, 3.000 H). LCMS (ESI+): m/z =494.1 (M+1), RT:2.338 min (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min , hold on 95% B in 1.00 min, and then 95-5%B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 103: Synthesis of ((2S,3R,6R)-3-(((5-Chloropyridin-2-yl)amino)methyl)-2,6- dimethylmorpholino)(4-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazol-3-yl)methanone [16]
General procedure (see Example 88) used for making the compound [1] was repeated, using 5-chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)pyridin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid. Yield 11%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.81 (d, J=4.38 Hz, 1.63 H) 8.40 (s, 0.29 H) 8.22 (s, 0.48 H) 8.00 (d, J=2.38 Hz, 0.28 H) 7.76 (d, J=2.50 Hz, 0.48 H) 7.52 - 7.67 (m, 0.48 H) 7.44 (dd, J=9.01, 2.63 Hz, 0.36 H) 7.33 (dd, J=9.01, 2.63 Hz, 0.52 H) 6.46 - 6.59 (m, 1.24 H) 6.35 (d, J=8.88 Hz, 0.50 H) 4.64 - 4.73 (m, 0.35 H) 4.38 (dd, J=13.51, 2.13 Hz, 0.57 H) 3.90 (s, 1.17 H) 3.76 - 3.86 (m, 0.91 H) 3.63 - 3.71 (m, 3.13 H) 3.40 - 3.48 (m, 2.14 H) 3.13 (br d, J=11.13 Hz, 0.54 H) 2.84 - 2.94 (m, 0.64 H) 2.66 - 2.75 (m, 1.38 H) 1.20 (br dd, J=14.63, 6.38 Hz, 3.19 H) 0.94 (dd, J=14.82, 6.32 Hz, 3.00 H). LCMS (ESI+): m/z =460.1 (M+1), RT: 1.870 min (The gradient was 5%B in 0.40min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5%B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 104: Synthesis of (4-(5-Chloropyridin-2-yl)-1-methyl-1H-pyrazol-3- yl)((2S,3R,6R)-3-(((5-chloropyrimidin-2-yl)amino)methyl)-2,6- dimethylmorpholino)methanone [17]
General procedure (see Example 88) used for making the compound [1] was repeated, using 5-chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)pyrimidin-2-amine hydrochloride and 4-(5-chloropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid. Yield 47%, white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.56 - 8.48 (m, 0.84H), 8.35 (s, 0.88H), 8.13 (s, 0.60H), 8.10 - 7.94 (m, 1.05H), 7.89 - 7.76 (m, 0.95H), 7.56 - 7.41 (m, 0.96H), 7.35 - 7.10 (m, 1.01H), 4.86 - 4.75 (m, 0.35H), 4.33 (dd, J = 2.3, 13.5 Hz, 0.65H), 4.19 - 4.07 (m, 0.66H), 3.87 (s, 1.01H), 3.83 - 3.75 (m, 0.45H), 3.73 (s, 1.93H), 3.71 - 3.54 (m, 1.89H), 3.51 - 3.39 (m, 1.09H), 3.28 (br s, 1.07H), 3.01 (dd, J = 11.3, 13.5 Hz, 0.35H), 2.80 (dd, J = 11.3, 13.3 Hz, 0.64H), 1.26 - 1.13 (m, 3.07H), 1.06 - 0.92 (m, 3.00H). LCMS (ESI+): m/z =476.1 (M+1), RT: 2.333 min (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min , hold on 95% B in 1.00 min, and then 95-5%B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 105: Synthesis of ((2S,3R,6R)-3-(((5-Chloropyridin-2-yl)amino)methyl)-2,6- dimethylmorpholino)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [18] General procedure (see Example 88) used for making the compound [1] was repeated, using 5-chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)pyridin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 29%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.87 (s, 1.12 H) 8.82 (s, 0.65 H) 7.99 (d, J=2.50 Hz, 0.26 H) 7.80 (d, J=2.38 Hz, 0.50 H) 7.44 (dd, J=8.88, 2.63 Hz, 0.31 H) 7.34 (dd, J=9.01, 2.50 Hz, 0.57 H) 6.51 - 6.57 (m, 0.93 H) 6.43 - 6.50 (m, 0.34 H) 6.34 (d, J=9.01 Hz, 0.61 H) 4.61 - 4.69 (m, 0.35 H) 4.30 - 4.38 (m, 0.61 H) 3.68 - 3.88 (m, 2.71 H) 3.53 - 3.67 (m, 3.20 H) 3.37 - 3.52 (m, 2.36 H) 3.16 - 3.23 (m, 0.39 H) 2.85 (br d, J=12.51 Hz, 0.43 H) 2.62 (s, 1.42 H) 2.43 - 2.49 (m, 1.60 H) 1.14 - 1.23 (m, 2.96 H) 0.90 - 1.00 (m, 3.00 H). LCMS (ESI+): m/z =474.1 (M+1), RT: 1.990 min (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min , hold on 95% B in 1.00 min, and then 95-5%B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 106: Synthesis of ((2S,3R,6R)-3-(((5-Chloropyrimidin-2-yl)amino)methyl)-2,6- dimethylmorpholino)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone [19] General procedure (see Example 88) used for making the compound [1] was repeated, using 5-chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)pyrimidin-2-amine hydrochloride and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. Yield 30%, white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.43 - 8.28 (m, 0.92H), 8.16 (s, 0.99H), 8.13 (s, 0.09H), 8.09 (s, 0.50H), 8.02 (br d, J = 4.5 Hz, 0.43H), 7.88 (dd, J = 4.9, 9.0 Hz, 0.27H), 7.69 (dd, J = 4.8, 8.9 Hz, 0.54H), 7.59 (br t, J = 5.4 Hz, 0.81H), 7.50 (br dd, J = 3.2, 5.1 Hz, 0.08H), 7.45 (dt, J = 2.9, 8.5 Hz, 0.30H), 7.26 (dt, J = 2.9, 8.5 Hz, 0.55H), 7.01 (dd, J = 2.8, 8.5 Hz, 0.25H), 6.66 (dd, J = 2.8, 8.4 Hz, 0.57H), 5.35 - 5.30 (m, 0.01H), 4.67 (td, J = 3.5, 6.7 Hz, 0.31H), 4.20 (dd, J = 2.4, 13.6 Hz, 0.59H), 4.00 - 3.70 (m, 0.46H), 3.69 - 3.42 (m, 0.95H), 3.41 - 3.32 (m, 1.18H), 3.31 - 3.07 (m, 1.89H), 2.87 - 2.70 (m, 0.63H), 1.25 - 1.08 (m, 3.25H), 1.03 - 0.81 (m, 3.00H). LCMS (ESI+): m/z =446.2 (M+1), RT: 10.501 min (The gradient was 10-80% B in 16.00 min, 80%-100%B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C18 4.6*150 mm column (5 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80 deg.) Example 107: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [20] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 42%, white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.79 - 8.89 (m, 1.89 H) 8.38 (s, 0.26 H) 8.18 (s, 0.66 H) 7.99 (br s, 0.25 H) 7.81 - 7.93 (m, 1.61 H) 4.71 (td, J=6.97, 2.69 Hz, 0.27 H) 4.38 (dd, J=13.51, 2.50 Hz, 0.74 H) 3.85 (br dd, J=6.69, 2.81 Hz, 0.26 H) 3.75 - 3.82 (m, 0.88 H) 3.71 - 3.75 (m, 1.09 H) 3.63 - 3.70 (m, 0.76 H) 3.47 - 3.62 (m, 2.20 H) 3.42 (s, 2.60 H) 3.16 (br dd, J=13.38, 2.25 Hz, 0.33 H) 2.98 (br dd, J=12.82, 10.44 Hz, 0.35 H) 2.76 (dd, J=13.51, 11.13 Hz, 0.76 H) 2.59 (s, 0.84 H) 2.43 (s, 2.07 H) 1.16 - 1.25 (m, 3.00 H) 0.91 - 1.01 (m, 3.31 H). LCMS (ESI+): m/z = 509.1 (M+1), RT: 2.398 min (The gradient was 5%B in 0.40min and 5- 95% B in 2.60 min , hold on 95% B in 1.00 min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 108: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((4-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [21] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-4-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 38%, white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.94 - 8.79 (m, 1.78H), 8.72 - 8.52 (m, 0.34H), 8.47 (br dd, J = 4.5, 14.9 Hz, 0.60H), 7.76 - 7.56 (m, 0.62H), 7.44 - 7.20 (m, 0.35H), 7.00 (br s, 0.33H), 6.91 (br t, J = 5.4 Hz, 0.61H), 4.77 (br s, 0.34H), 4.36 (br d, J = 12.0 Hz, 0.62H), 3.89 (br d, J = 8.8 Hz, 0.68H), 3.84 - 3.69 (m, 1.66H), 3.69 - 3.55 (m, 1.63H), 3.48 (br d, J = 13.4 Hz, 2.96H), 3.37 (br s, 0.26H), 3.27 - 2.94 (m, 0.81H), 2.82 - 2.70 (m, 0.64H), 2.61 (br s, 1.01H), 2.43 (s, 1.89H), 1.28 - 1.11 (m, 3.01H), 1.03 - 0.87 (m, 3.00H). LCMS (ESI+): m/z =509.2 (M+1), RT: 2.420 min (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50 mm, 5 um Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization.MS range was 100-1000.) Example 109: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((6-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [22] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-6-(trifluoromethyl)pyrazin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 39%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.79 - 8.90 (m, 1.81 H) 8.07 - 8.22 (m, 0.45 H) 7.99 (s, 1.34 H) 7.68 (br s, 0.96 H) 4.64 - 4.73 (m, 0.24 H) 4.35 (dd, J=13.57, 2.56 Hz, 0.73 H) 3.77 - 3.92 (m, 1.31 H) 3.71 (s, 0.76 H) 3.60 - 3.69 (m, 0.92 H) 3.52 - 3.60 (m, 1.02 H) 3.43 - 3.50 (m, 1.18 H) 3.37 - 3.43 (m, 2.76 H) 3.00 - 3.14 (m, 0.52 H) 2.77 (dd, J=13.45, 11.19 Hz, 0.73 H) 2.59 (s, 0.77 H) 2.39 (s, 2.14 H) 1.13 - 1.28 (m, 3.07 H) 0.88 - 1.03 (m, 3.00 H). LCMS (ESI+): m/z =509.1 (M+1), RT: 2.391 min (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50 mm, 5 um Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization.MS range was 100-1000.) Example 110: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((4-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [23] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-4-(trifluoromethyl)pyridin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 37%, white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.81 - 8.87 (m, 1.78 H) 8.22 (d, J=5.38 Hz, 0.31 H) 7.99 (d, J=5.25 Hz, 0.58 H) 6.91 (t, J=5.69 Hz, 0.62 H) 6.83 - 6.88 (m, 0.32 H) 6.81 (s, 0.33 H) 6.74 (d, J=5.25 Hz, 0.34 H) 6.61 (d, J=5.00 Hz, 0.62 H) 6.53 (s, 0.61 H) 4.63 - 4.70 (m, 0.33 H) 4.36 (dd, J=13.51, 2.50 Hz, 0.63 H) 3.86 - 3.95 (m, 0.68 H) 3.79 - 3.86 (m, 0.70 H) 3.77 (s, 0.98 H) 3.59 - 3.69 (m, 1.52 H) 3.50 - 3.58 (m, 1.04 H) 3.48 (s, 2.04 H) 3.40 - 3.47 (m, 0.78 H) 3.19 (dd, J=13.45, 2.44 Hz, 0.33 H) 2.89 (dd, J=13.45, 10.82 Hz, 0.33 H) 2.71 (dd, J=13.57, 11.19 Hz, 0.74 H) 2.61 (s, 1.07 H) 2.45 (s, 1.80 H) 1.13 - 1.28 (m, 3.23 H) 0.91 - 1.04 (m, 3.00 H). LCMS (ESI+): m/z = 508.2 (M+1), RT: 2.155 min. (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50 mm, 5 um Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization.MS range was 100-1000.) Example 111: Synthesis of 4-(3-((2S,3R,6R)-2,6-Dimethyl-3-(((5- (trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholine-4-carbonyl)-1-methyl-1H- pyrazol-4-yl)benzonitrile [24] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(4-cyanophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid. Yield 21%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.64 (br d, J=7.13 Hz, 0.55 H) 8.02 - 8.43 (m, 2.25 H) 7.84 - 7.99 (m, 1.05 H) 7.69 - 7.79 (m, 1.90 H) 7.41 - 7.56 (m, 1.97 H) 4.81 - 4.88 (m, 0.28 H) 4.27 - 4.35 (m, 1.29 H) 3.61 - 3.90 (m, 3.91 H) 3.39 - 3.58 (m, 3.88 H) 3.08 - 3.18 (m, 0.57 H) 2.82 (dd, J=13.63, 11.26 Hz, 0.73 H) 1.15 - 1.25 (m, 3.10 H) 0.97 - 1.06 (m, 3.00 H). LCMS (ESI+): m/z = 500.1 (M+1), Rt=2.410 min. (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50 mm, 5 um Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization.MS range was 100-1000.) Example 112: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(4-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-3- yl)methanone [25] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 4-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid. Yield 30%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.40 (s, 0.24 H) 8.14 - 8.23 (m, 1.75 H) 7.85 - 7.99 (m, 1.78 H) 7.75 (d, J=1.00 Hz, 0.62 H) 7.29 - 7.44 (m, 1.85 H) 4.70 - 4.80 (m, 0.27 H) 4.37 (dd, J=13.63, 2.75 Hz, 0.66 H) 3.88 (dt, J=6.66, 3.36 Hz, 0.74 H) 3.67 - 3.85 (m, 4.49 H) 3.56 - 3.67 (m, 0.93 H) 3.54 (s, 1.98 H) 3.43 - 3.52 (m, 2.12 H) 3.39 (td, J=3.63, 2.25 Hz, 0.57 H) 3.23 - 3.31 (m, 0.60 H) 2.96 (dd, J=13.51, 11.01 Hz, 0.31 H) 2.77 (dd, J=13.45, 11.19 Hz, 0.68 H) 1.27 - 1.32 (m, 0.16 H) 1.17 - 1.25 (m, 2.76 H) 0.91 - 1.05 (m, 3.00 H). LCMS (ESI+): m/z = 506.2 (M+1), Rt=2.187 min (the gradient was 5%B in 0.40min and 5- 95% B in 2.60 min , hold on 95% B in 1.00min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Luna C18 2*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000). Example 113: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-3- yl)methanone [26] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid. Yield 10%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.58 - 8.72 (m, 0.74 H) 8.41 (dd, J=19.82, 2.81 Hz, 1.13 H) 8.17 - 8.25 (m, 1.32 H) 7.95 (s, 0.60 H) 7.76 - 7.94 (m, 1.01 H) 7.27 - 7.47 (m, 2.02 H) 4.77 - 4.86 (m, 0.39 H) 4.34 (dd, J=13.57, 2.56 Hz, 0.60 H) 4.08 (dt, J=10.07, 3.41 Hz, 0.61 H) 3.84 (s, 1.30 H) 3.81 - 3.83 (m, 3.03 H) 3.74 - 3.80 (m, 0.63 H) 3.66 - 3.72 (m, 0.41 H) 3.64 (s, 1.80 H) 3.35 - 3.63 (m, 3.67 H) 3.28 (br d, J=2.38 Hz, 0.32 H) 2.75 - 3.06 (m, 1.10 H) 1.16 - 1.25 (m, 3.10 H) 0.97 (dd, J=14.57, 6.44 Hz, 3.00 H). LCMS (ESI+): m/z = 506.2 (M+1), Rt=2.064 min. (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50 mm, 5 um Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization.MS range was 100-1000.) Example 114: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(5-(5-fluoropyrimidin-2-yl)-1-methyl-1H-imidazol-4- yl)methanone [27] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 5-(5-fluoropyrimidin-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid. Yield 32%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.90 (s, 1.60 H) 8.34 - 8.55 (m, 0.35 H) 7.97 - 8.14 (m, 0.90 H) 7.75 - 7.95 (m, 1.70 H) 7.49 (s, 0.60 H) 4.77 - 4.87 (m, 0.10 H) 4.66 - 4.75 (m, 0.20 H) 4.30 (m, 0.70 H) 4.12 - 4.22 (m, 0.75 H) 3.89 (s, 0.80 H) 3.78 - 3.85 (m, 0.65 H) 3.68 - 3.76 (m, 2.60 H) 3.57 - 3.66 (m, 1.10 H) 3.42 - 3.54 (m, 2.15 H) 2.95 (m, 0.35 H) 2.70 (m, 1.00 H) 1.17 - 1.25 (m, 3.00 H) 0.88 - 1.10 (m, 2.80 H). LCMS (ESI+): m/z =495.1 (M+1), RT: 2.177 min (the gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. The column Kinetex C182.1*50 mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000). Example 115: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(5-(5-fluoropyrimidin-2-yl)-1-methyl-1H-imidazol-4- yl)methanone [28] General procedure (see Example 88) used for the compound [1] was repeated, using N- (((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 5-(5-fluoropyrimidin-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid. Yield 27%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.84 - 9.00 (m, 1.80 H) 8.07 - 8.33 (m, 0.90 H) 7.42 - 7.92 (m, 2.15 H) 6.95 - 7.29 (m, 1.00 H) 6.31 - 6.68 (m, 1.00 H) 4.62 - 4.72 (m, 0.30 H) 4.29 (m, 0.70 H) 4.02 - 4.13 (m, 0.70 H) 3.70 - 3.94 (m, 4.25 H) 3.53 - 3.68 (m, 1.75 H) 3.37 - 3.52 (m, 1.85 H) 2.89 (m, 0.35 H) 2.63 (m, 0.85 H) 1.13 - 1.27 (m, 3.15 H) 0.91 - 1.10 (m, 3.00 H). LCMS (ESI+): m/z =494.1 (M+1), RT: 2.045 min (the gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. The column Kinetex C182.1*50 mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000). Example 116: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(5-(5-methoxypyridin-2-yl)-1-methyl-1H-imidazol-4- yl)methanone [29] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 5-(5-methoxypyrimidin-2-yl)-1-methyl-1H-imidazole-4-carboxylic acid. Yield 34%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.53 (s, 0.10 H) 8.28 - 8.40 (m, 1.05 H) 8.03 - 8.20 (m, 1.45 H) 7.79 - 7.95 (m, 0.45 H) 7.64 - 7.75 (m, 0.95 H) 7.43 (d, J=8.63 Hz, 1.35 H) 7.35 - 7.40 (m, 0.90 H) 7.26 - 7.32 (m, 0.25 H) 4.65 (br dd, J=10.69, 2.94 Hz, 0.90 H) 4.20 (dd, J=13.51, 2.50 Hz, 0.70 H) 3.95 - 4.04 (m, 0.25 H) 3.82 - 3.91 (m, 2.80 H) 3.65 - 3.75 (m, 1.40 H) 3.53 (s, 2.85 H) 3.38 - 3.51 (m, 2.05 H) 2.98 (br dd, J=13.45, 10.94 Hz, 0.30 H) 2.66 (dd, J=13.57, 11.07 Hz, 0.80 H) 1.13 - 1.26 (m, 3.30 H) 0.97 - 1.13 (m, 3.00 H). LCMS (ESI+): m/z =506.2 (M+1), RT: 2.060 min (the gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. The column Kinetex C182.1*50 mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000). Example 117: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(4-fluorophenyl)-1-methyl-1H-pyrazol-3-yl)methanone [30] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(4-fluorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid. Yield 42%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.38 - 8.66 (m, 1.80 H) 8.05 (s, 0.35 H) 7.82 - 7.99 (m, 1.15 H) 7.81 (s, 0.70 H) 7.23 - 7.39 (m, 2.05 H) 7.10 - 7.19 (m, 1.95 H) 4.77 - 4.86 (m, 0.35 H) 4.28 (dd, J=13.63, 2.50 Hz, 0.65 H) 4.10 - 4.19 (m, 0.70 H) 3.83 (s, 0.90 H) 3.61 - 3.73 (m, 3.05 H) 3.35 - 3.50 (m, 2.65 H) 3.13 - 3.21 (m, 1.00 H) 3.04 - 3.12 (m, 0.35 H) 2.78 (dd, J=13.70, 11.19 Hz, 0.70 H) 1.12 - 1.21 (m, 3.00 H) 0.96 (d, J=6.63 Hz, 3.00 H). LCMS (ESI+): m/z = 493.1 (M+1), Rt=2.498 min (the gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. The column Kinetex C182.1*50 mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000). Example 118: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [31] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 61%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.41 - 8.67 (m, 3.00 H) 7.99 (t, J=5.63 Hz, 0.70 H) 7.75 (t, J=5.88 Hz, 0.30 H) 7.63 - 7.71 (m, 1.00 H) 7.29 - 7.39 (m, 1.00 H) 4.71 - 4.81 (m, 0.30 H) 4.21 - 4.32 (m, 1.30 H) 3.75 (s, 1.00 H) 3.62 - 3.72 (m, 1.00 H) 3.56 (s, 2.00 H) 3.36 - 3.52 (m, 2.40 H) 3.26 (qd, J=6.46, 2.63 Hz, 1.00 H) 3.05 (dd, J=13.45, 10.94 Hz, 0.30 H) 2.73 (dd, J=13.70, 11.19 Hz, 0.70 H) 2.41 (s, 1.00 H) 2.28 (s, 2.00 H) 1.11 - 1.24 (m, 3.00 H) 0.93 - 1.05 (m, 3.00 H). LCMS (ESI+): m/z =508.2 (M+1), RT: 2.510 min (the gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. The column Kinetex C182.1*50 mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000). Example 119: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [32] General procedure (see Example 88) used for the compound [1] was repeated, using N- (((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 25%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.50 - 8.59 (m, 1.00 H) 8.08 - 8.32 (m, 1.00 H) 7.42 - 7.72 (m, 2.00 H) 7.11 - 7.39 (m, 2.00 H) 6.26 - 6.62 (m, 1.00 H) 4.67 (br d, J=3.88 Hz, 0.20 H) 4.20 - 4.34 (m, 1.40 H) 3.77 (s, 1.00 H) 3.56 - 3.73 (m, 1.00 H) 3.52 (s, 2.00 H) 3.35 - 3.50 (m, 2.40 H) 3.24 (br d, J=3.63 Hz, 1.00 H) 2.95 (dd, J=13.57, 10.82 Hz, 0.30 H) 2.67 - 2.74 (m, 0.70 H) 2.41 (s, 1.00 H) 2.22 (s, 2.00 H) 1.11 - 1.23 (m, 3.00 H) 0.94 - 1.07 (m, 3.00 H). LCMS (ESI+): m/z =507.2 (M+1), RT: 2.392 min (the gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. The column Kinetex C182.1*50 mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000). Example 120: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [33] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 38%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.50 - 8.59 (m, 1.00 H) 8.19 - 8.38 (m, 1.00 H) 7.83 - 8.01 (m, 1.00 H) 7.60 - 7.79 (m, 2.00 H) 7.30 - 7.39 (m, 1.00 H) 4.66 - 4.75 (m, 0.20 H) 4.28 (dd, J=13.57, 2.31 Hz, 0.70 H) 4.08 (br d, J=9.76 Hz, 0.70 H) 3.61 - 3.79 (m, 1.30 H) 3.32 - 3.53 (m, 5.00 H) 2.93 - 3.26 (m, 1.30 H) 2.70 (dd, J=13.38, 11.51 Hz, 0.80 H) 2.39 (s, 0.80 H) 2.20 (s, 2.20 H) 1.11 - 1.23 (m, 3.00 H) 0.97 (d, J=6.63 Hz, 3.00 H). LCMS (ESI+): m/z =508.2 (M+1), RT: 2.505 min (the gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. The column Kinetex C182.1*50 mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000). Example 121: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone [34] General procedure (see Example 88) used for the compound [1] was repeated, using N- (((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. Yield 29%, white solid. 1H NMR (400 MHz, DMSO-d6): δ = 8.71 - 8.58 (m, 1.30H), 8.34 (br d, J = 1.0 Hz, 0.60H), 8.23 - 8.14 (m, 2.10H), 8.13 - 8.05 (m, 0.70H), 7.94 - 7.84 (m, 0.35H), 7.69 (dd, J = 4.8, 8.6 Hz, 0.65H), 7.53 - 7.39 (m, 0.40H), 7.18 (br t, J = 8.6 Hz, 0.65H), 6.92 (br d, J = 7.7 Hz, 0.30H), 6.66 (br d, J = 8.0 Hz, 0.60H), 4.77 - 4.60 (m, 0.40H), 4.23 (br d, J = 12.9 Hz, 0.70H), 3.83 - 3.62 (m, 1.10H), 3.53 - 3.40 (m, 1.20H), 3.40 - 3.33 (m, 1.00H), 3.27 (br d, J = 2.7 Hz, 1.30H), 3.19 (br s, 0.60H), 2.76 (br t, J = 12.2 Hz, 0.70H), 1.22 (br d, J = 6.8 Hz, 1.10H), 1.12 (br d, J = 6.2 Hz, 1.90H), 1.01 - 0.84 (m, 3.00H). LCMS (ESI+): m/z =480.1 (M+1), RT: 2.937 min, 3.113 min (double peak, rotamers) (the gradient was 5%B in 0.40 min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in 0.01min, the flow rate was 0.8 ml/min. Mobile phase A was H2O+10mM NH4HCO3, mobile phase B was Acetonitrile. Column Xbridge-C182.1*50mm 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 122: Synthesis of ((2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone [35] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. Yield 37%, white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.48 - 8.35 (m, 0.40H), 8.17 (d, J = 1.2 Hz, 1.20H), 8.09 (s, 3.10H), 7.93 - 7.83 (m, 0.40H), 7.67 (br dd, J = 4.6, 8.8 Hz, 0.60H), 7.52 - 7.39 (m, 0.50H), 7.15 (br t, J = 8.1 Hz, 0.60H), 6.95 - 6.78 (m, 0.90H), 4.73 - 4.57 (m, 0.40H), 4.28 (br d, J = 13.7 Hz, 0.60H), 3.81 - 3.69 (m, 1.10H), 3.58 - 3.35 (m, 2.10H), 3.25 (br d, J = 9.5 Hz, 1.10H), 3.15 (br d, J = 6.7 Hz, 0.60H), 2.74 (br t, J = 12.4 Hz, 0.70H), 1.23 (br d, J = 6.2 Hz, 1.00H), 1.19 - 1.10 (m, 2.00H), 1.02 - 0.86 (m, 3.00H). LCMS (ESI+): m/z =480.2 (M+1), RT: 2.918 min, 3.084 min (double peak, rotamers) (the gradient was 5%B in 0.40 min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5%B in 0.01 min, the flow rate was 0.8 ml/min. Mobile phase A was H2O+10mM NH4HCO3, mobile phase B was Acetonitrile. Column Xbridge-C182.1*50mm 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization.MS range was 100-1000.) Example 123: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(3-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazol-4- yl)methanone [36] General procedure (see Example 88) used for the compound [1] was repeated, using N- (((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 3-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazole-4-carboxylic acid. Yield 8.8%, white solid. 1H NMR (400 MHz, DMSO-d6): δ = 9.01 - 8.82 (m, 1.65H), 8.39 - 8.09 (m, 0.55H), 7.65 (dd, J = 2.2, 8.9 Hz, 0.80H), 7.57 - 7.35 (m, 0.70H), 7.25 - 6.93 (m, 0.95H), 6.70 - 6.52 (m, 0.80H), 4.74 - 4.63 (m, 0.20H), 4.36 (dd, J = 2.4, 13.7 Hz, 0.70H), 3.89 (s, 1.30H), 3.60 (br d, J = 2.4 Hz, 2H), 3.57 (s, 2.20H), 3.47 - 3.34 (m, 2.70H), 3.28 - 3.21 (m, 0.55H), 2.91 (br s, 0.40H), 2.73 (dd, J = 11.4, 13.1 Hz, 0.70H), 1.18 (d, J = 6.2 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H). LCMS (ESI+): m/z =494.1 (M+1), RT: 2.058 min (the gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. The column Kinetex C182.1*50 mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000). Example 124: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [37] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 21%, white solid. 1H NMR (400 MHz, DMSO-d6): δ = 0.98 (d, J=6.63 Hz, 3.00 H), 1.10 - 1.22 (m, 3.00 H), 2.21 (s, 2.10 H), 2.40 (s, 0.90 H), 2.66 (dd, J=13.51, 11.01 Hz, 0.80 H), 2.88 (dd, J=13.38, 11.01 Hz, 0.30 H), 3.04 - 3.22 (m, 1.10 H), 3.34 - 3.46 (m, 3.00 H), 3.49 (s, 2.30 H), 3.54 - 3.73 (m, 0.90 H), 3.76 (s, 0.90 H), 3.78 - 3.88 (m, 3.00 H), 4.11 (dt, J=10.10, 3.08 Hz, 0.70 H), 4.26 (dd, J=13.51, 2.50 Hz, 0.70 H), 4.64 - 4.70 (m, 0.30 H), 6.29 - 6.61 (m, 1.00 H), 7.10 - 7.40 (m, 3.00 H), 7.50 (dd, J=8.88, 2.25 Hz, 1.00 H), 8.13 (s, 0.70 H), 8.23 - 8.33 (m, 1.20 H). LCMS (ESI+): m/z =519.2 (M+1), RT: 2.084 min (the gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. The column Kinetex C182.1*50 mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000). Example 125: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone hydrochloride [38] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 58%, brown solid. 1H NMR: (400 MHz, DMSO-d6): δ ppm 8.51 - 8.69 (m, 1.20 H) 8.37 - 8.50 (m, 1.60 H) 8.04 (br t, J=5.69 Hz, 0.70 H) 7.67 - 7.92 (m, 1.20 H) 7.39 - 7.61 (m, 1 H) 4.55 - 4.73 (m, 1 H) 4.19 (br dd, J=13.76, 2.50 Hz, 1 H) 3.92 (s, 2 H) 3.79 (s, 1 H) 3.66 - 3.74 (m, 2 H) 3.59 (s, 2 H) 3.47 (br dd, J=9.51, 6.00 Hz, 3 H) 3.09 - 3.16 (m, 0.35 H) 2.73 (dd, J=13.70, 11.32 Hz, 0.65 H) 2.17 - 2.41 (m, 3 H) 1.12 - 1.25 (m, 3 H) 0.99 - 1.11 (m, 3 H). LCMS (ESI+): m/z =520.2 (M+1), RT: 2.308 min (the gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Luna C18 50*2.0 mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection. MS mode was positive electrospray ionization. MS range was 100-1000.) Example 126: Synthesis of ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [39] General procedure (see Example 88) used for making (the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 4-(5-methoxypyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 47%, brown solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.44 - 8.38 (m, 1H), 8.33 (s, 0.30H), 8.23 (s, 0.70H), 7.88 (s, 0.30H), 7.84 - 7.71 (m, 1H), 7.69 (s, 0.70H), 7.57 (d, J = 8.8 Hz, 0.30H), 7.39 (br d, J = 8.9 Hz, 0.70H), 4.65 - 4.37 (m, 1H), 4.22 - 4.14 (m, 0.70H), 3.97 - 3.84 (m, 3.30H), 3.77 (s, 1H), 3.72 - 3.68 (m, 1H), 3.55 - 3.35 (m, 4.40H), 3.24 (br dd, J = 2.1, 4.9 Hz, 0.60H), 3.07 (br dd, J = 11.0, 13.4 Hz, 0.30H), 2.71 (br dd, J = 11.4, 13.6 Hz, 0.70H), 2.31 (s, 1H), 2.13 (s, 2H), 1.22 - 0.99 (m, 6H). LCMS (ESI+): m/z =520.2 (M+1), RT: 2.148 min (the gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. The column Kinetex C182.1*50 mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000). Using (2R)-2-bromopropanoic acid for preparing of intermediate (d) and following the same synthetic route the following compounds were prepared. Example 127: Synthesis of ((2S,3R,6S)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone [40] General procedure (see Example 88) used for making (the compound [1] was repeated, using N-(((2S,3R,6S)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid. Yield 22%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.31 - 8.38 (m, 0.29 H) 8.11 (s, 1.20 H) 8.03 (s, 1.27 H) 7.82 (d, J=8.25 Hz, 0.10 H) 7.75 (d, J=8.25 Hz, 0.24 H) 7.58 - 7.67 (m, 0.98 H) 7.46 (d, J=8.25 Hz, 0.70 H) 7.31 - 7.39 (m, 1.10 H) 7.11 (dd, J=8.25, 1.50 Hz, 0.66 H) 7.02 (br d, J=5.75 Hz, 1.31 H) 6.87 (d, J=1.38 Hz, 0.64 H) 6.50 - 6.65 (m, 1.12 H) 4.59 - 4.66 (m, 0.21 H) 4.48 - 4.55 (m, 0.10 H) 4.02 - 4.18 (m, 2.03 H) 3.86 - 4.01 (m, 0.43 H) 3.76 (br dd, J=13.45, 4.44 Hz, 0.24 H) 3.59 (br d, J=2.63 Hz, 0.62 H) 3.39 - 3.54 (m, 1.74 H) 3.29 (br d, J=4.75 Hz, 0.56 H) 3.19 - 3.27 (m, 1.17 H) 3.14 (br dd, J=13.63, 4.00 Hz, 0.20 H) 2.86 - 2.95 (m, 0.33 H) 2.40 (s, 0.40 H) 2.19 (s, 0.66 H) 1.95 (s, 2.02 H) 1.15 - 1.22 (m, 2.92 H) 1.11 (br d, J=6.50 Hz, 0.33 H) 1.05 (d, J=6.75 Hz, 0.73 H) 0.87 (d, J=6.63 Hz, 2.00 H). LCMS (ESI+): m/z =475.2 (M+1), RT: 2.409 min (The gradient was 5%B in 0.40min and 5- 95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in 0.01min, the flow rate was 0.8 ml/min. Mobile phase A was H2O+10mM NH4HCO3, mobile phase B was Acetonitrile. Column Xbridge-C182.1*50mm 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 128: Synthesis of (4-(5-Chloropyridin-2-yl)-1-methyl-1H-pyrazol-3- yl)((2S,3R,6S)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)methanone [41] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6S)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 4-(5-chloropyridin-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid. Yield 48%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.49 (d, J=2.13 Hz, 0.19 H) 8.41 (d, J=2.25 Hz, 0.73 H) 8.28 - 8.33 (m, 0.21 H) 8.14 (s, 0.57 H) 8.11 (s, 0.60 H) 7.98 (br s, 0.16 H) 7.92 (br s, 0.78 H) 7.78 - 7.86 (m, 0.84 H) 7.76 (s, 0.63 H) 7.42 - 7.55 (m, 0.91 H) 4.78 (br s, 0.18 H) 4.18 (br d, J=13.38 Hz, 1.30 H) 4.10 (br dd, J=6.38, 2.75 Hz, 0.17 H) 4.03 (br dd, J=6.50, 2.63 Hz, 0.68 H) 3.93 (br dd, J=6.57, 2.69 Hz, 0.83 H) 3.87 (s, 0.19 H) 3.82 (s, 0.62 H) 3.66 - 3.79 (m, 0.34 H) 3.59 (s, 2.32 H) 3.50 - 3.57 (m, 1.05 H) 3.29 (br d, J=4.13 Hz, 0.39 H) 3.18 (br d, J=13.76 Hz, 0.19 H) 1.46 (d, J=6.75 Hz, 0.31 H) 1.35 (br d, J=6.63 Hz, 2.00 H) 1.16 (br d, J=6.38 Hz, 0.54 H) 1.06 (br d, J=6.63 Hz, 0.59 H) 0.92 - 1.00 (m, 2.26 H). LCMS (ESI+): m/z =510.1 (M+1), RT: 2.435 min (The gradient was 5%B in 0.40 min and 5- 95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5%B in 0.01min, the flow rate was 0.8 ml/min. Mobile phase A was H2O+10mM NH4HCO3, mobile phase B was Acetonitrile. Column Xbridge-C182.1*50mm 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 129: Synthesis of ((2S,3R,6S)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [42] General procedure (see Example 88) used for the compound [1] was repeated, using N- (((2S,3R,6S)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 69%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.85 - 8.85 (m, 0.48 H) 8.87 (s, 1.25 H) 8.80 (s, 0.22 H) 8.70 (br s, 0.24 H) 8.60 (br d, J=2.25 Hz, 0.63 H) 8.57 (d, J=2.88 Hz, 0.63 H) 8.51 (d, J=2.63 Hz, 0.68 H) 7.88 (br t, J=5.38 Hz, 0.24 H) 7.45 (br t, J=5.50 Hz, 0.24 H) 4.72 - 4.80 (m, 1.60 H) 4.10 - 4.25 (m, 0.89 H) 4.06 (br dd, J=6.63, 2.88 Hz, 1.54 H) 3.84 - 3.97 (m, 0.89 H) 3.81 (br d, J=5.75 Hz, 1.54 H) 3.76 (s, 0.89 H) 3.64 - 3.74 (m, 1.04 H) 3.55 (s, 2.26 H) 3.42 - 3.52 (m, 1.13 H) 3.24 (dd, J=13.63, 4.25 Hz, 0.71 H) 3.06 (br d, J=13.76 Hz, 0.26 H) 2.60 (s, 0.72 H) 2.52 (s, 2.03 H) 1.38 (d, J=6.63 Hz, 2.02 H) 1.15 (d, J=6.50 Hz, 0.75 H) 1.10 (d, J=6.63 Hz, 0.70 H) 0.94 (d, J=6.63 Hz, 2.00 H). LCMS (ESI+): m/z =509.1 (M+1), RT: 2.427 min (The gradient was 5%B in 0.40 min and 5- 95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5%B in 0.01 min, the flow rate was 0.8 ml/min. Mobile phase A was H2O+10mM NH4HCO3, mobile phase B was Acetonitrile. Column Xbridge-C182.1*50mm 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 130: Synthesis of ((2S,3R,6S)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(5-fluoro-2-(pyrimidin-2-yl)phenyl)methanone [43] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6S)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid. Yield 58%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.91 (d, J=4.88 Hz, 1.30 H) 8.84 (br d, J=4.75 Hz, 1.04 H) 8.36 - 8.49 (m, 0.45 H) 8.20 (br dd, J=8.50, 5.75 Hz, 0.33 H) 8.04 - 8.16 (m, 1.11 H) 7.91 - 8.02 (m, 2.35 H) 7.52 (t, J=4.94 Hz, 0.76 H) 7.31 - 7.45 (m, 1.37 H) 7.05 (td, J=8.47, 2.69 Hz, 0.71 H) 6.95 - 7.00 (m, 0.25 H) 6.85 (dd, J=8.94, 2.44 Hz, 0.63 H) 4.73 (br dd, J=6.07, 2.19 Hz, 0.29 H) 4.49 (br d, J=2.50 Hz, 0.13 H) 4.07 - 4.29 (m, 2.10 H) 3.90 - 4.05 (m, 0.62 H) 3.75 (br s, 0.68 H) 3.54 - 3.71 (m, 1.72 H) 3.43 - 3.53 (m, 1.85 H) 3.02 (br d, J=13.38 Hz, 0.57 H) 2.04 - 2.14 (m, 0.34 H) 1.27 (d, J=6.63 Hz, 2.00 H) 1.20 (br d, J=6.63 Hz, 1.07 H) 1.11 (br d, J=6.50 Hz, 1.20 H) 0.86 (br d, J=6.38 Hz, 1.98 H). LCMS (ESI+): m/z =491.1 (M+1), RT: 2.376 min (The gradient was 5%B in 0.40 min and 5- 95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5%B in 0.01 min, the flow rate was 0.8 ml/min. Mobile phase A was H2O+10mM NH4HCO3, mobile phase B was Acetonitrile. Column Xbridge-C182.1*50mm 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 131. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-5-methyl-1-(methyl-d3)-1H- pyrazol-3-yl)methanone [44] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid. Yield 34%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.82 - 8.87 (m, 2 H), 8.44 - 8.71 (m, 2 H), 7.54 - 7.91 (m, 1 H), 4.78 (br dd, J=8.69, 3.69 Hz, 0.35 H), 4.36 (dd, J=13.63, 2.25 Hz, 0.60 H), 3.84 (br dd, J=9.69, 2.56 Hz, 1 H), 3.59 - 3.77 (m, 2 H), 3.47 - 3.55 (m, 1 H), 3.42 - 3.45 (m, 0.55 H), 3.18 (br dd, J=13.63, 2.75 Hz, 0.50 H), 3.00 - 3.07 (m, 0.40 H), 2.76 (dd, J=13.32, 11.19 Hz, 0.60 H), 2.52 - 2.61 (m, 3 H), 1.16 - 1.24 (m, 3 H), 0.95 (dd, J=13.26, 6.38 Hz, 3 H). LCMS (ESI+): m/z =512.2 (M+1), RT: 2.417 min (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min , hold on 95% B in 1.00 min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 132. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1H- pyrazol-3-yl)methanone [45] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid. Yield 28%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.41 - 8.68 (m, 3 H), 7.99 (t, J=5.82 Hz, 0.70 H), 7.76 (t, J=5.82 Hz, 0.30 H), 7.62 - 7.72 (m, 1 H), 7.29 - 7.40 (m, 1 H), 4.72 - 4.81 (m, 0.25 H), 4.21 - 4.32 (m, 1.35 H), 3.68 (br dd, J=9.82, 6.32 Hz, 1 H), 3.42 - 3.53 (m, 2.40 H), 3.26 (br dd, J=6.82, 2.56 Hz, 1 H), 3.06 (dd, J=13.95, 11.07 Hz, 0.30 H), 2.74 (dd, J=13.76, 11.01 Hz, 0.70 H), 2.42 (s, 1 H), 2.28 (s, 2 H), 1.09 - 1.23 (m, 3 H), 0.92 - 1.04 (m, 3 H). LCMS (ESI+): m/z =511.2 (M+1), RT: 2.358 min (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min , hold on 95% B in 1.00 min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 133. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1H- pyrazol-3-yl)methanone [46] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 4-(5-fluoropyridin-2-yl)-5-methyl-1-(methyl-d3)-1H-pyrazole-3-carboxylic acid. Yield 40%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.59 - 8.51 (m, 1H), 8.36 (s, 0.20H), 8.20 (s, 0.80H), 7.99 - 7.90 (m, 1H), 7.76 (d, J = 1 Hz, 1H), 7.74 - 7.61 (m, 1H), 7.38 - 7.30 (m, 1H), 4.74 - 4.66 (m, 0.20H), 4.28 (dd, J = 2.7, 13.6 Hz, 0.80H), 4.08 (br d, J = 10.6 Hz, 0.80H), 3.75 - 3.62 (m, 0.60H), 3.52 - 3.36 (m, 2.60H), 3.25 - 3.19 (m, 0.30H), 3.13 - 2.96 (m, 1H), 2.70 (dd, J = 11.1, 13.6 Hz, 0.80H), 2.39 (s, 0.70H), 2.20 (s, 2.20H), 1.22 - 1.12 (m, 3H), 0.97 (d, J = 6.6 Hz, 3H). LCMS (ESI+): m/z =511.2 (M+1), RT: 2.357 min (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min , hold on 95% B in 1.00 min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 134. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(3-(5-fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-2-yl)methanone [47] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 3-(5-fluoropyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2- carboxylic acid. Yield 34%, white solid. 1H NMR (400 MHz, DMSO-d6): δ = 8.84 (s, 1 H), 8.79 (s, 1 H), 8.57 - 8.73 (m, 1 H), 8.48 (br d, J=4.27 Hz, 1 H), 7.82 (br t, J=5.65 Hz, 0.60 H), 7.59 (br t, J=5.65 Hz, 0.35 H), 4.75 - 4.85 (m, 0.35 H), 4.34 - 4.45 (m, 0.65 H), 4.11 (br t, J=6.90 Hz, 1 H), 3.79 - 4.02 (m, 2 H), 3.63 - 3.78 (m, 2 H), 3.41 - 3.58 (m, 2 H), 3.08 - 3.17 (m, 1 H), 2.88 - 3.07 (m, 2 H), 2.79 (br dd, J=13.30, 11.17 Hz, 1 H), 2.55 - 2.64 (m, 1 H), 1.15 - 1.27 (m, 3 H), 0.96 (dd, J=14.93, 6.40 Hz, 3 H). LCMS (ESI+): m/z = 521.48 (M+1), RT: 11.622 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01 min, and then held at 10% for 3 mins, the flow rate was 1.0 ml/min. Mobile phase A was 10 mM ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6 x 150 mm column (3.5 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80ºC.) Example 135. ((2S,3R,6R)-3-(((5-(Difluoromethyl)pyrimidin-2-yl)amino)methyl)-2,6- dimethylmorpholino)(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)methanone [48] General procedure (see Example 88) used for making the compound [1] was repeated, using 5-(difluoromethyl)-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)pyrimidin-2-amine hydrochloride and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 33%, white solid. 1H NMR (400 MHz, DMSO-d6): δ = 8.60 - 8.52 (m, 1H), 8.47 (br d, J = 9.8 Hz, 0.60H), 8.31 (s, 1.35H), 7.66 (s, 1.70H), 7.44 - 7.27 (m, 1.30H), 7.10 - 6.73 (m, 1H), 4.81 - 4.72 (m, 0.30H), 4.32 - 4.20 (m, 1.40H), 3.76 (s, 0.90H), 3.73 - 3.59 (m, 1H), 3.55 (s, 2.10H), 3.51 - 3.35 (m, 2.60H), 3.29 - 3.20 (m, 1H), 3.03 (dd, J = 11.1, 13.5 Hz, 0.30H), 2.72 (dd, J = 11.1, 13.5 Hz, 0.70H), 2.42 (s, 1H), 2.27 (s, 2H), 1.14 (d, J = 6.1 Hz, 3H), 0.99 (br d, J = 6.8 Hz, 3H). LCMS (ESI+): m/z =490.1 (M+1), RT: 2.167 min (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min , hold on 95% B in 1.00 min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 136. ((2S,3R,6R)-3-(((5-(Difluoromethyl)pyrazin-2-yl)amino)methyl)-2,6- dimethylmorpholino)(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)methanone [49] General procedure (see Example 88) used for making the compound [1] was repeated, using 5-(difluoromethyl)-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)pyrazin-2-amine hydrochloride and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 40%, white solid. 1H NMR (400 MHz, DMSO-d6):δ = 8.61 - 8.51 (m, 1H), 8.19 (d, J = 1.1 Hz, 0.20H), 8.01 (d, J = 0.9 Hz, 0.75H), 7.92 (d, J = 1.0 Hz, 0.20H), 7.74 - 7.68 (m, 1.50H), 7.67 - 7.60 (m, 1H), 7.53 (br s, 0.20H), 7.37 - 7.29 (m, 1H), 6.99 - 6.66 (m, 1H), 4.75 - 4.64 (m, 0.20H), 4.27 (dd, J = 2.6, 13.6 Hz, 0.80H), 4.15 - 4.05 (m, 0.80H), 3.75 (s, 0.65H), 3.71 - 3.62 (m, 0.65H), 3.47 (br s, 0.50H), 3.45 (s, 2.55H), 3.44 - 3.33 (m, 1.90H), 3.29 - 3.20 (m, 0.30H), 3.06 (br dd, J = 2.5, 6.6 Hz, 0.80H), 3.02 - 2.93 (m, 0.20H), 2.69 (dd, J = 11.1, 13.6 Hz, 0.80H), 2.40 (s, 0.60H), 2.19 (s, 2.30H), 1.15 (d, J = 6.3 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H). LCMS (ESI+): m/z =490.2 (M+1), RT: 2.171 min (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min , hold on 95% B in 1.00 min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 137. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(3-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-4- yl)methanone [50] General procedure (see Example 88) used for making (4-(4-Chlorophenyl)-1-methyl-1H- pyrazol-3-yl)((2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)methanone [1] was repeated, using N-(((2S,3R,6R)-2,6- dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 3-(5- fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-4-carboxylic acid. Yield 39%, white solid. 1H NMR (400 MHz, DMSO-d6): δ = 8.62 (d, J=2.64 Hz, 0.50 H), 8.34 - 8.59 (m, 1 H), 8.22 (s, 0.50 H), 7.65 - 8.11 (m, 4 H), 4.64 - 4.92 (m, 0.40 H), 4.34 (br d, J=11.04 Hz, 0.60 H), 3.69 - 3.91 (m, 2.50 H), 3.41 - 3.61 (m, 2.50 H), 3.08 - 3.27 (m, 2 H), 2.82 - 3.03 (m, 1 H), 2.58 - 2.73 (m, 1 H), 2.12 - 2.30 (m, 0.60 H), 1.80 - 2.01 (m, 2.40 H), 1.04 - 1.29 (m, 3 H), 0.61 - 1.01 (m, 3 H). LCMS (ESI+): m/z = 508.45 (M+1), RT: 11.045 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01 min, and then held at 10% for 3 mins, the flow rate was 1.0 ml/min. Mobile phase A was 10 mM ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6 x 150 mm column (3.5 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80ºC.) Example 138. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [51], general procedure A solution of 6-methyl-3-(pyrimidin-2-yl)picolinic acid (44.63 mg, 207.40 μmol, 2 eq) and N- (((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride (30 mg, 103.70 μmol, 1 eq) in ethyl acetate (1 mL) was heated to 60°C. Then 2,4,6-tributyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (149.44 mg, 207.40 μmol, 50% purity, 2 eq) was added dropwise at 60°C. The mixture was stirred at 60°C for 3 hours. LCMS showed the starting material was consumed completely. The mixture was poured into ice- water (w/w = 1/1) (2 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (3 mL x 3). The combined organic phase was washed with brine (2 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was further purified by prep-HPLC to give ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone (11.5 mg, 22.76% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ= 8.94 (d, J = 4.9 Hz, 2H), 8.48 - 8.18 (m, 2H), 7.64 (br d, J = 3.6 Hz, 1H), 7.55 (br s, 0.60H), 7.52 - 7.38 (m, 2H), 7.07 (br s, 0.30H), 6.59 (br d, J = 9.0 Hz, 1H), 4.61 (br s, 0.30H), 4.32 (dd, J = 2.4, 13.4 Hz, 0.70H), 3.95 - 3.63 (m, 4.10H), 3.39 (br d, J = 9.5 Hz, 0.80H), 3.12 - 3.00 (m, 0.60H), 2.65 (dd, J = 11.1, 13.3 Hz, 0.80H), 2.48 (br s, 3H), 1.18 (d, J = 6.3 Hz, 3H), 1.01 (br d, J = 6.6 Hz, 3H). LCMS (ESI+): m/z =487.4 (M+1), RT: 11.856 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01 min, and then held at 10% for 3 mins, the flow rate was 1.0 ml/min. Mobile phase A was 10 mM ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6 x 150 mm column (3.5 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80ºC.) Example 139. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone [52] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Yield 31%, white solid. 1H NMR (400 MHz, DMSO-d6): δ = 8.31 (s, 0.35H), 8.23 - 8.16 (m, 1.60H), 8.15 - 8.06 (m, 1.90H), 7.66 - 7.56 (m, 1H), 7.49 (d, J = 8.5 Hz, 0.35H), 7.41 - 7.30 (m, 1.25H), 7.13 - 7.02 (m, 0.30H), 6.63 - 6.49 (m, 1H), 4.66 - 4.54 (m,0.30H), 4.28 (dd, J = 2.5, 13.6 Hz, 0.70H), 3.88 - 3.81 (m, 0.40H), 3.79 - 3.52 (m, 3.25H), 3.48 - 3.36 (m, 1.15H), 3.15 - 3.04 (m, 0.65H), 2.74 - 2.63 (m, 0.85H), 2.47 (s, 1H), 2.41 - 2.30 (m, 2H), 1.21 (d, J = 6.6 Hz, 1H), 1.16 (d, J = 6.3 Hz, 2H), 1.01 - 0.95 (m, 3H). LCMS (ESI+): m/z =476.3 (M+1), RT: 11.950 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01 min, and then held at 10% for 3 mins, the flow rate was 1.0 ml/min. Mobile phase A was 10 mM ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6 x 150 mm column (3.5 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80ºC.) Example 140. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(5-fluoro-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone [53] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 5-fluoro-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Yield 41%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.64 (d, J=2.13 Hz, 0.25 H), 8.29 - 8.41 (m, 0.80 H), 8.10 - 8.28 (m, 3.00 H), 8.00 (br s, 0.50 H), 7.53 - 7.65 (m, 0.90 H), 7.25 (br s, 0.55 H), 7.11 (br s, 0.30 H), 6.61 (br d, J=8.63 Hz, 0.30 H), 6.49 (br d, J=8.38 Hz, 0.55 H), 4.64 (br s, 0.35 H), 4.31 (br dd, J=13.32, 2.31 Hz, 0.60 H), 3.77 - 3.93 (m, 0.85 H), 3.46 - 3.58 (m, 3.60 H), 3.16 - 3.23 (m, 0.65 H), 2.98 - 3.07 (m, 0.40 H), 2.75 (br dd, J=13.32, 11.19 Hz, 0.65 H), 1.15 - 1.25 (m, 3.00 H), 0.98 (br dd, J=6.13, 4.25 Hz, 2.80 H). LCMS (ESI+): m/z =480.47 (M+1), RT: 11.863 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01 min, and then held at 10% for 3 mins, the flow rate was 1.0 ml/min. Mobile phase A was 10 mM ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6 x 150 mm column (3.5 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80ºC.) Example 141. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(5-fluoro-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [54] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 5-fluoro-3-(pyrimidin-2-yl)picolinic acid. Yield 19%, white solid. 1H NMR (400 MHz, DMSO-d6): δ = 8.92 - 9.01 (m, 1.85 H), 8.66 (d, J=2.75 Hz, 0.3 H), 8.37 (dd, J=9.63, 2.75 Hz, 1 H), 8.32 (s, 1 H), 8.20 - 8.27 (m, 1 H), 8.06 (br s, 1 H), 7.51 - 7.65 (m, 2 H), 7.31 (br t, J=5.07 Hz, 1 H), 7.13 (br s, 1 H), 6.47 - 6.65 (m, 1 H), 4.60 - 4.67 (m, 1 H), 4.33 (dd, J=13.45, 2.44 Hz, 1 H), 3.83 - 3.96 (m, 1 H), 3.49 - 3.75 (m, 4 H), 3.12 - 3.20 (m, 1 H), 3.00 - 3.09 (m, 1 H), 2.73 (dd, J=13.20, 11.19 Hz, 1 H), 1.16 - 1.26 (m, 3 H), 0.93 - 1.05 (m, 3 H). LCMS (ESI+): 491.2 (M+H)+, RT: 2.882 min (The gradient was 5% B in 0.40 min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5% B in 0.01 min, the flow rate was 0.8 ml/min. Mobile phase A was H2O+10mM NH4HCO3, mobile phase B was Acetonitrile. Xbridge-C18 2.1*50mm 5um column. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 142. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(5-fluoro-3-(5-fluoropyrimidin-2-yl)pyridin-2- yl)methanone [55] General procedure (see Example 88) used for making (4-(4-Chlorophenyl)-1-methyl-1H- pyrazol-3-yl)((2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)methanone [1] was repeated, using N-(((2S,3R,6R)-2,6- dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 5-fluoro- 3-(5-fluoropyrimidin-2-yl)picolinic acid. Yield 57%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.11 - 8.99 (m, 2H), 8.65 (d, J = 2.8 Hz, 0.40H), 8.33 (d, J = 2.8 Hz, 0.20H), 8.32 - 8.24 (m, 1H), 8.21 (dd, J = 2.8, 9.5 Hz, 0.70H), 8.06 (br s, 0.70H), 7.65 - 7.52 (m, 1H), 7.28 (br t, J = 5.3 Hz, 0.65H), 7.11 (br s, 0.35H), 6.65 - 6.45 (m, 1H), 4.68 - 4.59 (m, 0.30H), 4.33 (dd, J = 2.6, 13.6 Hz, 0.60H), 3.93 (br dd, J = 2.9, 6.6 Hz, 0.40H), 3.88 - 3.78 (m, 0.40H), 3.76 - 3.46 (m, 4H), 3.20 - 3.02 (m, 0.70H), 2.74 (dd, J = 11.3, 13.4 Hz, 0.60H), 1.27 - 1.15 (m, 3H), 1.00 (dd, J = 6.4, 9.1 Hz, 3H). LCMS (ESI+): m/z =509.2 (M+1), RT: 3.002 min (The gradient was 5% B in 0.40 min and 5- 95% B at 0.40-3.40 min, hold on 95% B for 0.45 min, and then 95-5% B in 0.01 min, the flow rate was 0.8 ml/min. Mobile phase A was H2O+10mM NH4HCO3, mobile phase B was Acetonitrile. Xbridge-C182.1*50mm 5um column. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 143. ((2S,3R,6R)-3-(((5-Chloropyridin-2-yl)amino)methyl)-2,6- dimethylmorpholino)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone [56] General procedure (see Example 88) used for making the compound [1] was repeated, using 5-chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)pyridin-2-amine hydrochloride and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. Yield 26%, light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.18 - 8.05 (m, 2H), 8.05 - 7.85 (m, 1H), 7.68 - 7.61 (m, 1H), 7.51 - 7.34 (m, 1.40H), 7.21 (dt, J = 3.1, 8.4 Hz, 0.60H), 6.92 - 6.83 (m, 1H), 6.80 - 6.72 (m, 1H), 6.56 - 6.45 (m, 1H), 4.62 - 4.46 (m, 0.40H), 4.23 (dd, J = 2.5, 13.3 Hz, 0.60H), 3.92 - 3.61 (m, 1H), 3.60 - 3.41 (m, 1.50H), 3.28 - 3.24 (m, 1H), 3.23 - 3.07 (m, 0.80H), 2.71 (dd, J = 11.0, 13.4 Hz, 0.70H), 2.53 (br d, J = 6.9 Hz, 1H), 1.25 - 1.08 (m, 3H), 1.01 - 0.85 (m, 3H). LCMS (ESI+): m/z =445.36 (M+1), RT: 11.457 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01 min, and then held at 10% for 3 mins, the flow rate was 1.0 ml/min. Mobile phase A was 10 mM ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6 x 150 mm column (3.5 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80ºC.) Example 144. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)methanone [57] General procedure (see Example 88) used for making (4-(4-Chlorophenyl)-1-methyl-1H- pyrazol-3-yl)((2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)methanone [1] was repeated, using N-(((2S,3R,6R)-2,6- dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 5-fluoro- 2-(2H-1,2,3-triazol-2-yl)nicotinic acid. Yield 58%, light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ = 8.21 - 8.41 (m, 1 H), 7.50 - 7.70 (m, 1 H), 6.44 - 6.65 (m, 1 H), 3.98 - 4.25 (m, 1 H), 3.42 - 3.83 (m, 4 H), 2.79 - 2.93 (m, 1 H), 2.68 (dd, J=13.07, 11.44 Hz, 1 H), 1.27 (s, 2 H), 1.14 - 1.20(m, 3 H), 1.09 - 1.13 (m, 3 H), 1.06 (s, 7 H). LCMS (ESI+): m/z = 390.2 (M+1), RT: 0.498 min (Halo C183.0 x 30 mm column, 5 um. Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 50-2000. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC grade acetonitrile. The gradient was 10-100% B in 0.90 min, 10% B in 0.01 min, 10-100% B (0.01-0.50 min) with a hold at 100% B for 0.40 min. The flow rate was 2.0 mL/min.) Example 145. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino-5,5-d2)(5-fluoro-2-(2H-1,2,3-triazol-2- yl)phenyl)methanone [58] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. Yield 65%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.30 (s, 0.35 H), 8.16 (s, 1.10 H), 8.04 - 8.12 (m, 0.75 H), 7.97 (br s, 0.60 H), 7.87 (dd, J=8.94, 4.94 Hz, 0.35 H), 7.55 - 7.72 (m, 1.60 H), 7.36 - 7.52 (m, 1.45 H), 7.13 (td, J=8.47, 2.94 Hz, 0.60 H), 6.75 (dd, J=8.32, 2.81 Hz, 0.60 H), 6.49 - 6.66 (m, 1.30 H), 4.47 - 4.66 (m, 0.40 H), 3.82 - 3.93 (m, 0.40 H), 3.73 - 3.81 (m, 0.40 H), 3.51 - 3.65 (m, 1.00 H), 3.45 (q, J=6.25 Hz, 0.50 H), 3.30 (br d, J=6.00 Hz, 2.45 H), 1.23 (d, J=6.75 Hz, 1.05 H), 1.13 (d, J=6.13 Hz, 1.95 H), 0.83 - 0.99 (m, 3.00 H). LCMS (ESI+): m/z =481.47 (M+1), RT: 12.285 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01 min, and then held at 10% for 3 mins, the flow rate was 1.0 ml/min. Mobile phase A was 10 mM ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6 x 150 mm column (3.5 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80ºC.) Example 146. ((2S,3R,6R)-3-(((5-Chloropyridin-2-yl)amino)methyl)-2,6- dimethylmorpholino-5,5-d2)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [59] General procedure (see Example 88) used for making compound [1] was repeated, using 5- chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl-5,5-d2)methyl)pyridin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 16%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.77 - 8.91 (m, 1.80 H), 7.75 - 8.03 (m, 0.80 H), 7.31 - 7.47 (m, 0.90 H), 6.49 - 6.58 (m, 0.95 H), 6.45 (br t, J=5.25 Hz, 0.30 H), 6.34 (d, J=9.01 Hz, 0.60 H), 4.65 (ddd, J=7.97, 5.60, 2.69 Hz, 0.35 H), 3.70 - 3.87 (m, 2.40 H), 3.55 - 3.67 (m, 3.00 H), 3.36 - 3.52 (m, 2.00 H), 2.62 (s, 1.05 H), 2.51 (br s, 2.10 H), 1.12 - 1.27 (m, 3.10 H), 0.95 (dd, J=18.51, 6.50 Hz, 3.00 H). LCMS (ESI+): m/z =476.1 (M+1), RT: 1.978 min (The gradient was 5%B in 0.40 min and 5- 95% B in 2.60 min , hold on 95% B in 1.00 min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 147. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino-5,5-d2)(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [60] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 71%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.50 - 8.57 (m, 0.80 H), 8.07 - 8.39 (m, 0.90 H), 7.75 (br dd, J=8.82, 2.31 Hz, 0.10 H), 7.57 - 7.71 (m, 1.15 H), 7.46 (br dd, J=8.94, 2.06 Hz, 0.65 H), 7.25 - 7.39 (m, 1.60 H), 7.16 (br s, 0.20 H), 6.57 (br d, J=8.88 Hz, 0.30 H), 6.32 (d, J=8.88 Hz, 0.60 H), 4.64 - 4.71 (m, 0.20 H), 4.23 (dt, J=10.13, 3.31 Hz, 0.60 H), 3.58 - 3.99 (m, 1.80 H), 3.52 (s, 2.00 H), 3.38 - 3.48 (m, 2.20 H), 3.17 - 3.26 (m, 1.20 H), 2.41 (s, 0.70 H), 2.22 (s,1.70 H), 1.11 - 1.22 (m, 0.90 H), 0.91 - 1.07 (m, 3.00 H). LCMS: m/z = 509.2 (M+1), RT: 2.206 min (The gradient was 5%B in 0.40 min and 5-95% B in 2.60 min , hold on 95% B in 1.00 min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Column Kinetex C182.1*50mm, 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 148. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)methanone [61] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 5-fluoro-2-(1H-pyrazol-1-yl)benzoic acid. Yield 45%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.38 (s, 0.20 H), 7.90 - 8.18 (m, 3.50 H), 7.67 - 7.80 (m, 1 H), 7.62 (dd, J=9.01, 4.88 Hz, 0.30 H), 7.34 - 7.48 (m, 1 H), 7.08 (td, J=8.38, 3.00 Hz, 1 H), 6.69 - 6.82 (m, 1 H), 6.41 - 6.61 (m, 1 H), 4.48 - 4.67 (m, 0.20 H), 4.27 (dd, J=13.20, 2.19 Hz, 0.70 H), 3.60 - 3.79 (m, 0.50 H), 3.44 - 3.59 (m, 1 H), 3.34 - 3.41 (m, 1 H), 3.13 - 3.25 (m, 1.50 H), 2.93 - 3.07 (m,0.60 H), 2.70 (br dd, J=13.45, 11.32 Hz, 0.80 H), 2.21 - 2.31 (m, 0.70 H), 1.05 - 1.23 (m, 3 H), 0.83 - 1.02 (m, 3 H). LCMS (ESI+): m/z =479.42 (M+1), RT: 11.238 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01 min, and then held at 10% for 3 mins, the flow rate was 1.0 ml/min. Mobile phase A was 10 mM ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6 x 150 mm column (3.5 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80ºC.) Example 149. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino-5,5-d2)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [62] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyridin-2- amine hydrochloride and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 58%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.94 (d, J=4.88 Hz, 1.30 H), 8.88 (d, J=4.88 Hz, 0.60 H), 8.35 - 8.46 (m, 1.00 H), 8.18 - 8.34 (m, 1.00 H), 7.64 (br d, J=6.00 Hz, 1.00 H), 7.55 (br s, 0.55 H), 7.37 - 7.52 (m, 2.00 H), 7.10 (br s, 0.30 H), 6.55 - 6.66 (m, 1.00 H), 4.57 - 4.64 (m, 0.30 H), 3.89 - 3.96 (m, 0.40 H), 3.79 - 3.88 (m, 0.90 H), 3.62 - 3.78 (m, 2.75 H), 2.48 (s, 3.00 H) 1.13 - 1.27 (m, 3.00 H), 0.94 - 1.05 (m, 3.00 H). LCMS (ESI+): m/z =489.47 (M+1), RT: 11.859 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80℃.) Example 150. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino-5,5-d2)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2- yl)methanone [63] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Yield 50%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.31 (s, 0.30 H), 8.20 (d, J=8.51 Hz, 0.45 H), 8.17 (s, 1.20 H), 8.12 (s, 0.65 H), 8.10 (br d, J=8.13 Hz, 1.15 H), 7.57 - 7.65 (m, 1.00 H), 7.49 (d, J=8.50 Hz, 0.30 H), 7.37 (br d, J=8.38 Hz, 0.75 H), 7.30 - 7.35 (m, 0.55 H), 7.08 (br s, 0.30 H), 6.50 - 6.64 (m, 1.00 H), 4.56 - 4.63 (m, 0.30 H), 3.85 (br dd, J=6.69, 2.81 Hz, 0.45 H), 3.75 (br s, 0.70 H), 3.61 - 3.70 (m, 1.30 H), 3.52 - 3.60 (m, 2.00 H), 2.47 (s, 0.85 H), 2.37 (s, 2.00 H), 1.21 (d, J=6.63 Hz, 1.00 H), 1.15 (d, J=6.25 Hz, 2.00 H), 0.98 (dd, J=6.44, 2.56 Hz, 3.00 H). LCMS (ESI+): m/z = 478.49 (M+1), RT:11.970 min (The gradient was 10-80% B in 16.00 min , 80%-100% B in 4.00 min, 100-10% B in 0.01 min, and then held at10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80℃.) Example 151. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [64] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 26%, white solid. 1H NMR (400 MHz, DMSO-d6): δ = ppm 8.82 - 9.02 (m, 2 H), 8.38 - 8.48 (m, 0.60 H), 8.32 (br d, J=8.00 Hz, 0.50 H), 8.22 (br s, 0.50 H), 7.96 - 8.14 (m, 1.50 H), 7.81 (br s, 0.30 H), 7.44 - 7.54 (m, 1 H), 7.27 - 7.43 (m, 1 H), 4.60 - 4.73 (m, 0.30 H), 4.35 (dd, J=13.57, 2.56 Hz, 0.60 H), 3.86 - 4.17 (m, 1 H), 3.39 - 3.83 (m, 4 H), 2.92 - 3.23 (m, 1 H), 2.62 - 2.81 (m, 1 H), 2.23 - 2.45 (m, 3 H), 1.14 - 1.33 (m, 3 H), 0.89 - 1.08 (m, 3 H). LCMS (ESI+): m/z =488.53 (M+1), RT: 11.064 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01 min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10 mM ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6 x 150 mm column (3.5 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80℃.) Example 152. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone [65] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine hydrochloride and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Yield 38%, white powder. 1H NMR (400 MHz, DMSO-d6): δ = ppm 8.39 (s, 0.30 H), 8.09 - 8.23 (m, 2.60 H), 7.87 - 8.09 (m, 2.30 H), 7.80 (br s, 0.30 H), 7.47 (d, J=8.38 Hz, 0.30 H), 7.34 (br d, J=8.38 Hz, 0.70 H), 4.58 - 4.70 (m, 0.30 H), 4.30 (dd, J=13.57, 2.69 Hz, 0.70 H), 3.91 - 4.03 (m, 0.30 H), 3.82 - 3.90 (m, 0.40 H), 3.42 - 3.71 (m, 3.50 H), 2.95 - 3.26 (m, 1.30 H), 2.76 (dd, J=13.38, 11.13 Hz, 0.70 H), 2.41 (s, 1 H), 2.28 (s, 2 H), 1.12 - 1.28 (m, 3 H), 0.89 - 1.07 (m, 3 H). LCMS (ESI+): m/z = 477.51 (M+1), RT: 11.153 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01 min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10 mM ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6 x 150 mm column (3.5 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80℃.) Example 153. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(3-(pyrimidin-2-yl)pyridin-2-yl)methanone [66] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 3-(pyrimidin-2-yl)picolinic acid. Yield 31%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.82 - 8.96 (m, 2 H), 8.41 - 8.77 (m, 2 H), 7.99 - 8.32 (m, 1 H), 7.37 - 7.72 (m, 3 H), 6.47 - 6.68 (m, 1 H), 4.76 - 4.82 (m, 1 H), 4.46 (dd, J=13.63, 2.50 Hz, 0.60 H), 4.02 - 4.21 (m, 0.70 H), 3.68 - 4.00 (m, 3 H), 3.57 (br dd, J=12.95, 3.19 Hz, 0.60 H), 3.12 - 3.25 (m, 0.60 H), 2.83 (dd, J=13.51, 11.13 Hz, 0.50 H), 1.23 - 1.42 (m, 3 H), 1.00 - 1.19 (m, 3 H). LCMS (ESI+): m/z =473.48 (M+1), RT: 11.006 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01 min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10 mM ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6 x 150 mm column (3.5 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80℃.) Example 154. (3-(2H-1,2,3-Triazol-2-yl)pyridin-2-yl)((2S,3R,6R)-2,6-dimethyl-3-(((5- (trifluoromethyl)pyridin-2-yl)amino)methyl)morpholino)methanone [67] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 3-(2H-1,2,3-triazol-2-yl)picolinic acid. Yield 42%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.60 (d, J = 4.3 Hz, 0.30H), 8.39 - 8.29 (m, 0.70H), 8.27 - 8.13 (m, 3H), 8.01 (br s, 0.60H), 7.67 (dd, J = 4.7, 8.3 Hz, 0.40H), 7.65 - 7.53 (m, 1H), 7.48 (dd, J = 4.9, 7.9 Hz, 0.70H), 7.31 (br s, 0.70H), 7.10 (br s, 0.30H), 6.64 - 6.47 (m, 1H), 4.64 (br t, J = 5.4 Hz, 0.40H), 4.30 (dd, J = 2.4, 13.4 Hz, 0.70H), 3.92 - 3.76 (m, 0.70H), 3.71 - 3.49 (m, 3.5H), 3.44 (br d, J = 2.9 Hz, 1H), 3.20 - 3.00 (m, 1H), 2.73 (dd, J = 11.1, 13.4 Hz, 0.70H), 1.28 - 1.13 (m, 3H), 1.05 - 0.93 (m, 3H). LCMS (ESI+): m/z =462.2 (M+1), RT: 2.858 min (The gradient was 5% B in 0.40 min and 5- 95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in 0.01min, the flow rate was 0.8 ml/min. Mobile phase A was H2O+10mM NH4HCO3, mobile phase B was Acetonitrile. Xbridge C182.1*50mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection. MS mode was positive electrospray ionization. MS range was 100-1000.) Example 155. ((2S,3R,6R)-2,6-Dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [68] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyridin- 2-amine and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 25%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.79 - 8.95 (m, 1.90 H), 8.29 - 8.45 (m, 1.00 H), 8.00 - 8.25 (m, 1.00 H), 7.28 - 7.54 (m, 3.00 H), 6.68 (br dd, J=5.82, 3.31 Hz, 0.50 H), 6.19 (br t, J=5.00 Hz, 0.50 H), 4.69 - 4.79 (m, 0.50 H), 4.26 (dd, J=13.32, 2.44 Hz, 0.50 H), 3.91 - 4.03 (m, 1.00 H), 3.81 - 3.90 (m, 1.00 H), 3.73 - 3.80 (m, 0.50 H), 3.59 - 3.70 (m, 1.00 H), 3.51 - 3.58 (m, 0.60 H), 3.39 - 3.45 (m, 0.60 H), 3.01 - 3.18 (m, 1.30 H), 2.54 - 2.69 (m, 0.70 H), 2.37 - 2.49 (m, 3.10 H), 2.03 - 2.20 (m, 3.00 H), 1.13 - 1.30 (m, 3.10 H), 0.93 - 1.00 (m, 3.00 H). LCMS: m/z = 501.48 (M+1), RT: 12.649 min (The gradient was 10-80% B in 16.00 min, 80%- 100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80℃.) Example 156. ((2S,3R,6R)-2,6-Dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone [69] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyridin-2- amine and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Yield 17%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.14 - 8.22 (m, 1.80 H), 8.02 - 8.09 (m, 1.00 H), 7.89 - 8.02 (m, 0.85 H), 7.48 (br d, J=8.00 Hz, 1.30 H), 7.29 (d, J=8.38 Hz, 0.60 H), 6.57 (br t, J=4.88 Hz, 0.60 H), 6.22 (br t, J=5.50 Hz, 0.40 H), 4.64 - 4.78 (m, 0.40 H), 4.23 (dd, J=13.38, 2.25 Hz, 0.60 H), 3.61 - 3.95 (m, 2.50 H), 3.39 - 3.59 (m, 1.80 H), 2.97 - 3.18 (m, 1.50 H), 2.61 - 2.83 (m, 0.70 H), 2.47 (s, 1.20 H), 2.29 (s, 1.90 H), 2.05 - 2.18 (m, 3.00 H), 1.08 - 1.29 (m, 3.10 H), 0.97 (dd, J=6.32, 3.19 Hz, 3.00 H). LCMS: m/z = 490.48 (M+1), RT: 12.785 min (The gradient was 10-80% B in 16.00 min, 80%- 100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80℃.) Example 157. ((2S,3R,6R)-3-(((5-Cyclopropylpyrimidin-2-yl)amino)methyl)-2,6- dimethylmorpholino)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [70] General procedure (see Example 88) used for making the compound [1] was repeated, using 5-cyclopropyl-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)pyrimidin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 29%, white solid. 1H NMR (400 MHz, DMSO-d6): δ = 8.89 (d, J=10.01 Hz, 2 H), 8.13 (s, 1 H), 7.98 (s, 1 H), 6.19 - 6.78 (m, 1 H), 4.73 (dt, J=9.63, 3.63 Hz, 0.40 H), 4.34 (dd, J=13.45, 2.44 Hz, 0.50 H), 3.76 - 3.87 (m, 2.60 H), 3.65 (ddt, J=10.15, 6.77, 3.36, 3.36 Hz, 1 H), 3.60 (s, 1.50 H), 3.41 - 3.58 (m, 1.50 H), 3.35 - 3.40 (m, 0.50 H), 3.23 (dd, J=13.57, 2.44 Hz, 0.50 H), 2.93 (dd, J=13.51, 10.88 Hz, 0.50 H), 2.59 - 2.76 (m, 2 H), 2.53 (s, 2 H), 1.64 - 1.83 (m, 1 H), 1.10 - 1.28 (m, 3 H), 0.96 (dd, J=13.88, 6.38 Hz, 3 H), 0.80 - 0.90 (m, 2 H), 0.53 - 0.70 (m, 2 H). LCMS (ESI+): m/z = 481.51 (M+1), RT: 10.550 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80℃.) Example 158. ((2S,3R,6R)-3-(((5-Cyclopropylpyrimidin-2-yl)amino)methyl)-2,6- dimethylmorpholino)(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3-yl)methanone [71] General procedure (see Example 88) used for making the compound [1] was repeated, using 5-cyclopropyl-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)pyrimidin-2-amine hydrochloride and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 22%, white solid. 1H NMR (400 MHz, DMSO-d6): δ = 8.51 - 8.62 (m, 1 H), 7.82 - 8.15 (m, 2 H), 7.60 - 7.70 (m, 1 H), 7.27 - 7.43 (m, 1 H), 6.43 - 6.92 (m, 1 H), 4.18 - 4.79 (m, 1.50 H), 3.79 (s, 1 H), 3.65 - 3.73 (m, 0.50 H), 3.63 (s, 2 H), 3.41 - 3.59 (m, 2 H), 3.37 (br dd, J=6.69, 2.56 Hz, 1 H), 3.29 (br s, 1 H), 2.96 (dd, J=13.45, 10.94 Hz, 0.30 H), 2.70 (dd, J=13.45, 11.19 Hz, 0.70 H), 2.44 (s, 1 H), 2.33 (s, 2 H), 1.62 - 1.78 (m, 1 H), 1.08 - 1.26 (m, 3 H), 0.90 - 1.07 (m, 3 H), 0.78 - 0.89 (m, 2 H), 0.45 - 0.65 (m, 2 H). LCMS (ESI+): m/z = 480.2 (M+1), RT: 2.581 min (The gradient was 5% B in 0.40 min and 5- 95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in 0.01min, the flow rate was 0.8 ml/min. Mobile phase A was H2O+10mM NH4HCO3, mobile phase B was Acetonitrile. Xbridge C182.1*50mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection. MS mode was positive electrospray ionization. MS range was 100-1000.) Example 159. ((2S,3R,6R)-3-(((5-Chloropyridin-2-yl)amino)methyl)-2,6- dimethylmorpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [72] General procedure (see Example 138) used for making the compound [51] was repeated, using 5-chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)pyridin-2-amine hydrochloride and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 36%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.84 - 8.99 (m, 1.90 H), 8.37 - 8.48 (m, 0.95 H), 7.88 - 8.02 (m, 0.85 H), 7.39 - 7.53 (m, 2.90 H), 7.06 (br s, 0.70 H), 6.48 - 6.57 (m, 0.95 H), 6.45 (br t, J=5.19 Hz, 0.30 H), 4.54 - 4.61 (m, 0.30 H), 4.30 (dd, J=13.38, 2.50 Hz, 0.70 H), 3.86 - 3.96 (m, 1.00 H), 3.52 - 3.83 (m, 3.10 H), 3.28 (br d, J=3.13 Hz, 0.40 H), 2.96 - 3.14 (m, 0.60 H), 2.61 (dd, J=13.32, 11.07 Hz, 0.75 H), 2.51 - 2.56 (m, 2.95 H), 1.15 - 1.25 (m, 3.15 H), 0.94 - 1.05 (m, 3.00 H). LCMS (ESI+): m/z =453.4 (M+1), RT: 10.976 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80℃.) Example 160. ((2S,3R,6R)-3-(((5-Chloropyridin-2-yl)amino)methyl)-2,6- dimethylmorpholino)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone [73] General procedure (see Example 88) used for making the compound [1] was repeated, using 5-chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)pyridin-2-amine hydrochloride and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Yield 19%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.09 - 8.25 (m, 2.65 H), 7.99 (d, J=2.50 Hz, 0.30 H), 7.80 (d, J=2.38 Hz, 0.55 H), 7.37 - 7.54 (m, 1.90 H), 6.81 (br s, 0.65 H), 6.44 - 6.55 (m, 0.95 H), 6.42 (br t, J=5.38 Hz, 0.30 H), 4.50 - 4.62 (m, 0.30 H), 4.26 (dd, J=13.32, 2.31 Hz, 0.65 H), 3.79 - 3.88 (m, 0.30 H), 3.41 - 3.77 (m, 3.90 H), 2.96 - 3.16 (m, 0.60 H), 2.65 (dd, J=13.26, 11.26 Hz, 0.75 H), 2.52 (br s, 1.00 H), 2.43 (s, 2.00 H), 1.13 - 1.23 (m, 3.05 H), 0.93 - 1.03 (m, 2.95 H). LCMS (ESI+): m/z =442.4 (M+1), RT: 11.092 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80℃.) Example 161. ((2S,3R,6R)-3-(((3-Fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)- 2,6-dimethylmorpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [74] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-fluoro-5-(trifluoromethyl)pyridin- 2-amine hydrochloride and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 29%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.79 - 9.00 (m, 1.80 H), 8.30 - 8.45 (m, 0.90 H), 8.02 - 8.27 (m, 0.95 H), 7.60 - 7.84 (m, 1.70 H), 7.32 - 7.55 (m, 1.90 H), 7.03 (br s, 0.25 H), 4.74 (br dd, J=6.07, 3.44 Hz, 0.25 H), 4.30 (br d, J=12.38 Hz, 0.70 H), 3.62 - 4.10 (m, 4.00 H), 3.39 (br d, J=13.38 Hz, 0.70.00 H), 3.16 - 3.26 (m, 0.30 H), 3.04 (br d, J=12.51 Hz, 0.20 H), 2.65 (br t, J=12.13 Hz, 0.80 H), 2.24 - 2.47 (m, 3.00 H), 1.12 - 1.37 (m, 3.00 H), 0.75 - 1.08 (m, 3.00 H). LCMS (ESI+): m/z =505.61 (M+1), RT:12.353 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80℃.) Example 162. ((2S,3R,6R)-3-(((3-Fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)- 2,6-dimethylmorpholino)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone [75] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-fluoro-5-(trifluoromethyl)pyridin-2- amine hydrochloride and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Yield 68%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.13 - 8.22 (m, 2.00 H), 8.05 - 8.11 (m, 1.30 H), 7.97 (s, 0.70 H), 7.74 (br dd, J=11.44, 2.19 Hz, 1.00 H), 7.41 - 7.51 (m, 1.00 H), 7.36 (d, J=8.50 Hz, 0.70 H), 7.06 (br s, 0.30 H), 4.70 (dt, J=10.01, 3.69 Hz, 0.30 H), 4.25 (dd, J=13.51, 2.63 Hz, 0.70 H), 3.92 - 4.06 (m, 0.35 H), 3.66 - 3.90 (m, 2.00 H), 3.49 - 3.62 (m, 1.30 H), 3.41 (br d, J=3.38 Hz, 0.70 H), 3.13 - 3.27 (m, 0.60 H), 3.04 (dd, J=13.63, 2.63 Hz, 0.40 H), 2.74 (dd, J=13.38, 11.26 Hz, 0.70 H), 2.41 (s, 1.00 H), 2.35 (s, 2.00 H), 1.23 (d, J=6.63 Hz, 1.00 H), 1.15 (d, J=6.25 Hz, 2.00 H), 0.95 - 1.00 (m, 3.00 H). LCMS (ESI+): m/z =494.2 (M+1), RT:3.059 min (The gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% trifluoroacetic acid in water, mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 2.1*50mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 163. ((2S,3R,6R)-3-(((3,5-Bis(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [76] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3,5-bis(trifluoromethyl)pyridin-2- amine hydrochloride and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 33%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.78 - 8.91 (m, 2.00 H), 8.65 (s, 0.50 H), 8.27 - 8.41 (m, 1.50 H), 8.01 (s, 1.00 H), 7.48 (t, J=4.94 Hz, 0.50 H), 7.29 - 7.42 (m, 2.00 H), 6.96 (br t, J=4.82 Hz, 0.50 H), 4.79 (dt, J=9.97, 3.14 Hz, 0.50 H), 4.28 (dd, J=13.45, 2.56 Hz, 0.50 H), 4.00 - 4.15 (m, 1.00 H), 3.96 (dt, J=6.69, 3.41 Hz, 0.50 H), 3.84 - 3.91 (m, 0.50 H), 3.76 (dt, J=13.70, 4.16 Hz, 0.50 H), 3.69 (ddd, J=10.57, 6.44, 3.13 Hz, 1.00 H), 3.52 (br dd, J=6.63, 2.50 Hz, 0.45 H), 3.43 - 3.49 (m, 0.60 H), 3.22 - 3.27 (m, 0.50 H), 3.06 (dd, J=13.57, 2.69 Hz, 0.50 H), 2.67 (dd, J=13.38, 11.26 Hz, 0.50 H), 2.28 - 2.42 (m, 3.00 H), 1.27 (d, J=6.63 Hz, 1.60 H), 1.15 (d, J=6.13 Hz, 1.40 H), 0.97 (t, J=5.75 Hz, 3.00 H). LCMS (ESI+): m/z =555.2 (M+1), RT:3.262 min (The gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% trifluoroacetic acid in water, mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. Kinetex C18 column 2.1*50mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 164. ((2S,3R,6R)-3-(((3,5-Bis(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholino)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone [77] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3,5-bis(trifluoromethyl)pyridin-2-amine hydrochloride and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Yield 62%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.64 (s, 0.40 H), 8.28 (s, 0.45 H), 8.03 - 8.18 (m, 2.75 H), 8.01 (br d, J=2.13 Hz, 1.00 H), 7.30 - 7.48 (m, 1.00 H), 7.19 - 7.26 (m, 0.50 H), 6.96 (br t, J=5.13 Hz, 0.50 H), 4.77 (dt, J=10.32, 3.16 Hz, 0.50 H), 4.24 (dd, J=13.38, 2.63 Hz, 0.50 H), 4.03 - 4.16 (m, 0.50 H), 3.65 - 3.92 (m, 2.00 H), 3.54 - 3.63 (m, 0.50 H), 3.42 - 3.53 (m, 1.00 H), 3.25 (br d, J=11.01 Hz, 0.50 H), 3.01 - 3.13 (m, 1.00 H), 2.82 (dd, J=13.57, 11.19 Hz, 0.50 H), 2.39 (s, 1.50 H), 2.23 (s, 1.50 H), 1.10 - 1.27 (m, 3.00 H), 0.97 (dd, J=9.51, 6.50 Hz, 3.00 H). LCMS (ESI+): m/z =544.37 (M+1), RT:14.167 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80℃.) Example 165. ((2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(3-(5-fluoropyrimidin-2-yl)-6-methylpyridin-2- yl)methanone [78] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 3-(5-fluoropyrimidin-2-yl)-6-methylpicolinic acid. Yield 31%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.93 - 9.11 (m, 1.80 H), 8.33 - 8.40 (m, 0.90 H), 8.19 - 8.32 (m, 0.85 H), 7.63 (br d, J=8.75 Hz, 0.95 H), 7.55 (br s, 0.60 H), 7.42 (d, J=8.13 Hz, 0.95 H), 7.06 (br s, 0.30 H), 6.55 - 6.67 (m, 0.95 H), 4.62 (td, J=6.85, 2.69 Hz, 0.30 H), 4.31 (dd, J=13.45, 2.44 Hz, 0.70 H), 3.84 - 3.98 (m, 0.95 H), 3.63 - 3.81 (m, 2.95 H), 3.40 (br s, 0.55 H), 3.09 (br d, J=6.88 Hz, 0.55 H), 2.64 (dd, J=13.26, 11.26 Hz, 0.90 H), 2.47 (s, 2.80 H), 1.15 - 1.27 (m, 3.00 H), 0.94 - 1.07 (m, 2.95 H). LCMS (ESI+): m/z =505.3 (M+1), RT: 12.534 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80℃.) Example 166. ((2S,3R,6R)-3-(((3-Methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)- 2,6-dimethylmorpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [79] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-methoxy-5- (trifluoromethyl)pyridin-2-amine and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 14%, pink solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.75 - 8.98 (m, 2.00 H), 8.33 - 8.46 (m, 1.00 H), 7.84 - 8.03 (m, 1.00 H), 7.32 - 7.55 (m, 2.80 H), 7.09 - 7.19 (m, 1.00 H), 6.46 (br t, J=5.07 Hz, 0.20 H), 4.64 - 4.74 (m, 0.25 H), 4.28 (dd, J=13.32, 2.31 Hz, 0.70 H), 3.99 - 4.09 (m, 1.00 H), 3.92 - 3.98 (m, 1.00 H), 3.86 (s, 3.50 H), 3.64 - 3.80 (m, 2.00 H), 3.05 - 3.24 (m, 0.65 H), 2.59 (dd, J=13.20, 11.19 Hz, 0.85 H), 2.50 (s, 3.00 H), 1.15 - 1.30 (m, 3.05 H), 0.97 - 1.05 (m, 3.00 H). LCMS (ESI+): m/z =517.52 (M+1), RT:12.106 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80℃.) Example 167. ((2S,3R,6R)-3-(((3-Methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)- 2,6-dimethylmorpholino)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone [80] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-methoxy-5-(trifluoromethyl)pyridin-2- amine and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Yield 56%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 7.99 - 8.23 (m, 3.00 H), 7.73 - 7.98 (m, 1.00 H), 7.36 - 7.51 (m, 1.00 H), 7.06 - 7.17 (m, 1.65 H), 6.42 (br t, J=5.44 Hz, 0.25 H), 4.67 (br dd, J=8.57, 4.06 Hz, 0.25 H), 4.23 (dd, J=13.38, 2.50 Hz, 0.70 H), 3.75 - 3.94 (m, 5.50 H), 3.47 - 3.66 (m, 2.00 H), 3.07 - 3.22 (m, 0.50 H), 2.68 (br dd, J=13.26, 11.26 Hz, 1.00 H), 2.35 - 2.48 (m, 3.00 H), 1.10 - 1.27 (m, 3.00 H), 0.92 - 1.07 (m, 3.00 H). LCMS (ESI+): m/z =506.51 (M+1), RT:12.211 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature is 80℃.) Example 168. ((2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(6-(methyl-d3)-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [81] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 6-(methyl-d3)-3-(pyrimidin-2-yl)picolinic acid. Yield 22%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.84 - 9.00 (m, 1.80 H), 8.35 - 8.47 (m, 0.95 H), 8.18 - 8.34 (m, 0.90 H), 7.60 - 7.68 (m, 0.95 H), 7.56 (br s, 0.55 H), 7.44 - 7.52 (m, 0.90 H), 7.37 - 7.44 (m, 0.90 H), 7.09 (br s, 0.30 H), 6.54 - 6.67 (m, 1.00 H), 4.56 - 4.66 (m, 0.30 H), 4.32 (dd, J=13.45, 2.56 Hz, 0.70 H), 3.62 - 3.99 (m, 4.00 H), 3.40 (br s, 0.75 H), 3.00 - 3.16 (m, 0.60 H), 2.65 (dd, J=13.38, 11.13 Hz, 0.75 H), 1.14 - 1.27 (m, 3.00 H), 0.91 - 1.08 (m, 3.00 H). LCMS (ESI+): m/z =490.4 (M+1), RT: 11.554 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 169. ((2S,3R,6R)-3-(((3-Fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)- 2,6-dimethylmorpholino)(6-(methyl-d3)-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [82] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-fluoro-5-(trifluoromethyl)pyridin- 2-amine hydrochloride and 6-(methyl-d3)-3-(pyrimidin-2-yl)picolinic acid. Yield 16%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.82 - 8.97 (m, 1.85 H), 8.31 - 8.43 (m, 0.95 H), 8.04 - 8.25 (m, 0.95 H), 7.69 - 7.78 (m, 0.95 H), 7.67 (br s, 0.70 H), 7.42 - 7.51 (m, 0.85 H), 7.35 - 7.41 (m, 0.90 H), 7.02 (br s, 0.25 H), 4.74 (dt, J=9.51, 3.75 Hz, 0.25 H), 4.30 (dd, J=13.45, 2.44 Hz, 0.75 H), 3.89 - 4.05 (m, 1.30 H), 3.62 - 3.88 (m, 2.75 H), 3.39 (dt, J=13.29, 3.36 Hz, 0.70 H), 3.21 (dd, J=13.51, 11.01 Hz, 0.25 H), 3.04 (dd, J=13.51, 2.63 Hz, 0.25 H), 2.65 (dd, J=13.32, 11.19 Hz, 0.75 H), 1.12 - 1.30 (m, 3.05 H), 0.93 - 1.06 (m, 3.00 H). LCMS (ESI+): m/z =508.1 (M+1), RT: 2.295 min (The gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% trifluoroacetic acid in water, mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. Kinetex C18 column 2.1*50mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 170. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl-d2)morpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [83] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl)pyridin-2- amine hydrochloride and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 72%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.87 - 8.97 (m, 1.95 H), 8.36 - 8.48 (m, 0.95 H), 8.20 - 8.34 (m, 0.95 H), 7.64 (br s, 0.90 H), 7.55 (br s, 0.50 H), 7.46 - 7.52 (m, 1.05 H), 7.38 - 7.45 (m, 1 H), 7.10 (br s, 0.25 H), 6.56 - 6.66 (m, 0.95 H), 4.61 (d, J=2.75 Hz, 0.35 H), 4.32 (m, 0.70 H), 3.93 (m, 0.35 H), 3.83 (br d, J=9.26 Hz, 0.55 H), 3.62 - 3.77 (m, 1.75 H), 3.01 - 3.14 (m, 0.65 H), 2.65 (m, 0.80 H), 2.48 (s, 2.85 H), 1.15 - 1.26 (m, 3.05 H), 0.96 - 1.05 (m, 3.00 H). LCMS (ESI+): m/z =489.6 (M+1), RT: 11.516 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 171. ((2S,3R,6R)-3-(((3-Fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl- d2)-2,6-dimethylmorpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [84] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl-d2)-3-fluoro-5- (trifluoromethyl)pyridin-2-amine hydrochloride and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 70%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.85 - 8.96 (m, 1.90 H), 8.31 - 8.44 (m, 0.95 H), 8.06 - 8.25 (m, 0.95 H), 7.63 - 7.80 (m, 1.70 H), 7.43 - 7.53 (m, 1.05 H), 7.35 - 7.42 (m, 0.95 H), 7.03 (s, 0.25 H), 4.73 (d, J=2.88 Hz, 0.25 H), 4.30 (m, 0.70 H), 3.90 - 3.99 (m, 0.30 H), 3.83 (br s, 0.70 H), 3.74 - 3.81 (m, 0.75 H), 3.64 - 3.74 (m, 1.00 H), 3.22 (m, 0.30 H), 3.04 (m, 0.30 H), 2.66 (m, 0.75 H), 2.38 - 2.47 (m, 2.95 H), 1.14 - 1.30 (m, 3.10 H), 0.95 - 1.05 (m, 3.00 H). LCMS (ESI+): m/z =507.2 (M+1), RT: 2.592 min (The gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% trifluoroacetic acid in water, mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. Kinetex C18 column 2.1*50mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 172. ((2S,3R,6R)-3-(((3-Chloro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)- 2,6-dimethylmorpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [85] General procedure (see Example 138) used for making the compound [51] was repeated, using 3-chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin- 2-amine and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 70%, pink solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.76 - 8.97 (m, 2.00 H), 8.40 (d, J=8.13 Hz, 0.40 H), 8.37 (s, 0.30 H), 8.31 (d, J=8.13 Hz, 0.60 H), 8.18 (s, 0.60 H), 7.94 (s, 0.90 H), 7.46 - 7.56 (m, 1.25 H), 7.37 - 7.45 (m, 0.75 H), 7.33 (d, J=8.13 Hz, 0.65 H), 6.88 (br t, J=5.13 Hz, 0.40 H), 4.76 (dt, J=10.04, 3.30 Hz, 0.40 H), 4.29 (dd, J=13.45, 2.44 Hz, 0.65 H), 3.83 - 4.05 (m, 2.10 H), 3.60 - 3.82 (m, 2.15 H), 3.39 (dt, J=13.41, 3.67 Hz, 0.65 H), 3.22 (dd, J=13.38, 11.01 Hz, 0.40 H), 3.03 - 3.11 (m, 0.40 H), 2.65 (dd, J=13.32, 11.19 Hz, 0.75 H), 2.39 - 2.46 (m, 3.00 H), 1.13 - 1.31 (m, 3.20 H), 0.98 (dd, J=6.32, 3.69 Hz, 3.10 H). LCMS (ESI+): m/z =521.1 (M+1), RT: 2.621 min (The gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% trifluoroacetic acid in water, mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. Kinetex C18 column 2.1*50mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 173. ((2S,3R,6R)-3-(((3-Chloro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)- 2,6-dimethylmorpholino)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone [86] General procedure (see Example 88) used for making the compound [1] was repeated, using 3-chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2- amine and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Yield 38%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.35 (d, J=0.75 Hz, 0.30 H), 8.12 - 8.20 (m, 1.50 H), 8.01 - 8.10 (m, 1.80 H), 7.94 (dd, J=7.50, 1.63 Hz, 0.95 H), 7.46 (d, J=8.38 Hz, 0.30 H), 7.27 - 7.37 (m, 1.30 H), 6.90 (t, J=5.50 Hz, 0.35 H), 4.73 (dt, J=10.26, 3.31 Hz, 0.35 H), 4.25 (dd, J=13.45, 2.56 Hz, 0.65 H), 3.93 - 4.08 (m, 0.35 H), 3.66 - 3.93 (m, 2.05 H), 3.47 - 3.64 (m, 1.05 H), 3.35 - 3.43 (m, 0.80 H), 3.13 - 3.27 (m, 1.05 H), 3.06 (dd, J=13.63, 2.63 Hz, 0.35 H), 2.77 (dd, J=13.38, 11.26 Hz, 0.70 H), 2.26 - 2.47 (m, 3.00 H), 1.10 - 1.28 (m, 3.05 H), 0.92 - 1.02 (m, 3.00 H). LCMS (ESI+): m/z =511.1 (M+1), RT: 13.297 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 174. ((2S,3R,6R)-2,6-Dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [87] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyrazin- 2-amine and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 62%, purple solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.89 (dd, J=16.51, 4.88 Hz, 2 H), 7.97 - 8.42 (m, 2 H), 7.41 - 7.55 (m, 1 H), 6.94 - 7.41 (m, 2 H), 4.24 - 4.88 (m, 1 H), 3.89 - 4.08 (m, 1 H), 3.40 - 3.83 (m, 3 H), 3.10 - 3.28 (m, 1 H), 2.99 (dd, J=13.38, 2.63 Hz, 0.50 H), 2.72 (dd, J=13.51, 11.26 Hz, 0.50 H), 2.40 (d, J=5.50 Hz, 3 H), 2.23 - 2.38 (m, 3 H), 1.11 - 1.30 (m, 3 H), 0.95 (dd, J=11.94, 6.44 Hz, 3 H). LCMS (ESI+): m/z =502.2 (M+1), RT: 11.383 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 175. ((2S,3R,6R)-2,6-Dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholino)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone [88] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyrazin-2- amine and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Yield 51%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.05 - 8.32 (m, 3 H), 7.88 - 8.01 (m, 1 H), 6.98 - 7.51 (m, 2 H), 4.21 - 4.83 (m, 1 H), 3.79 - 4.09 (m, 1 H), 3.38 - 3.71 (m, 3 H), 2.95 - 3.23 (m, 1 H), 2.77 - 2.92 (m, 1 H), 2.14 - 2.47 (m, 6 H), 1.09 - 1.32 (m, 3 H), 0.96 (dd, J=12.07, 6.44 Hz, 3 H). LCMS (ESI+): m/z =491.2 (M+1), RT: 11.528 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 176. 2-((((2S,3R,6R)-2,6-Dimethyl-4-(6-methyl-3-(pyrimidin-2- yl)picolinoyl)morpholin-3-yl)methyl)amino)-5-(trifluoromethyl)nicotinonitrile [89]
General procedure (see Example 138) used for making the compound [51] was repeated, using 2-((((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)amino)-5- (trifluoromethyl)nicotinonitrile hydrochloride and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 42%, white solid. 1H NMR (400 MHz, METHANOL-d4): δ = 8.77 - 8.89 (m, 2 H), 8.51 - 8.60 (m, 1 H), 8.25 - 8.40 (m, 1 H), 7.97 - 8.10 (m, 1 H), 7.28 - 7.48 (m, 2 H), 4.43 (dd, J=13.70, 2.56 Hz, 1 H), 3.92 - 4.19 (m, 3 H), 3.73 - 3.87 (m, 1 H), 3.59 (dd, J=13.88, 3.75 Hz, 1 H), 3.34 - 3.39 (m, 1 H), 3.18 (dd, J=13.63, 2.75 Hz, 1 H), 2.87 (dd, J=13.51, 11.13 Hz, 1 H), 2.56 (d, J=12.01 Hz, 3 H), 1.40 (d, J=6.63 Hz, 2 H), 1.27 (d, J=6.13 Hz, 2 H), 1.02 - 1.17 (m, 3 H). LCMS (ESI+): 512.3 (M+H)+, RT: 11.986 min (The gradient was 10-80% B in 16.00 min, 80%- 100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 177. ((2S,3R,6R)-3-(((3-(Difluoromethyl)-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)-2,6-dimethylmorpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2- yl)methanone [90] General procedure (see Example 138) used for making the compound [51] was repeated, using 3-(difluoromethyl)-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine hydrochloride and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 27%, white solid. 1H NMR (400 MHz, METHANOL-d4): δ = 8.41 - 8.89 (m, 3 H), 7.74 - 8.25 (m, 1 H), 7.31 - 7.49 (m, 2 H), 6.71 - 7.06 (m, 1 H), 4.80 - 4.84 (m, 1 H), 4.41 (dd, J=13.57, 2.56 Hz, 1 H), 3.89 - 4.20 (m, 3 H), 3.55 - 3.81 (m, 2 H), 3.12 - 3.29 (m, 1 H), 2.78 (dd, J=13.32, 11.32 Hz, 1 H), 2.41 - 2.61 (m, 3 H), 1.40 (d, J=6.63 Hz, 2 H), 1.25 (d, J=6.13 Hz, 1 H), 1.01 - 1.10 (m, 3 H). LCMS (ESI+): 537.4 (M+H)+, RT: 12.895 min (The gradient was 10-80% B in 16.00 min, 80%- 100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 178. ((2S,3R,6R)-3-(((3-(Difluoromethyl)-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)-2,6-dimethylmorpholino)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2- yl)methanone [91] General procedure (see Example 88) used for making the compound [1] was repeated, using 3-(difluoromethyl)-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl) pyridin-2-amine hydrochloride and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Yield 27%, white solid. 1H NMR (400 MHz, METHANOL-d4): δ = 8.08 - 8.49 (m, 2 H), 7.73 - 8.01 (m, 3 H), 7.41 (dd, J=62.41, 8.38 Hz, 1 H), 6.87 (td, J=54.69, 10.44 Hz, 1 H), 4.78 - 4.84 (m, 1 H), 4.38 (dd, J=13.57, 2.69 Hz, 1 H), 3.86 - 4.09 (m, 3 H), 3.56 - 3.73 (m, 1 H), 3.10 - 3.28 (m, 1 H), 2.85 (dd, J=13.51, 11.13 Hz, 1 H), 2.32 - 2.61 (m, 3 H), 1.37 (d, J=6.63 Hz, 2 H), 1.23 (d, J=6.25 Hz, 1 H), 1.05 (dd, J=13.01, 6.50 Hz, 3 H). LCMS (ESI+): 526.3 (M+H)+, RT: 12.988 min (The gradient was 10-80% B in 16.00 min, 80%- 100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 179. ((2S,3R,6R)-3-(((5-Chloro-3-fluoropyridin-2-yl)amino)methyl)-2,6- dimethylmorpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [92] General procedure (see Example 138) used for making the compound [51] was repeated, using 5-chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-fluoropyridin-2-amine hydrochloride and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 12%, white solid. 1H NMR (400 MHz, DMSO-d6): δ = 8.81 - 8.99 (m, 2 H), 8.33 - 8.46 (m, 1 H), 7.76 - 7.95 (m, 1 H), 7.57 - 7.69 (m, 1 H), 7.36 - 7.53 (m, 2 H), 6.31 - 7.20 (m, 1 H), 4.18 - 4.77 (m, 1 H), 3.60 - 3.99 (m, 4 H), 3.01 - 3.30 (m, 1 H), 2.56 - 2.69 (m, 1 H), 2.47 (s, 3 H), 1.12 - 1.30 (m, 3 H), 0.90 - 1.09 (m, 3 H). LCMS (ESI+): m/z = 471.15 (M+1), RT: 11.226 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 180. ((2S,3R,6R)-3-(((5-Chloro-3-fluoropyridin-2-yl)amino)methyl)-2,6- dimethylmorpholino)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone [93] General procedure (see Example 88) used for making the compound [1] was repeated, using 5-chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-fluoropyridin-2-amine hydrochloride and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Yield 55%, white solid. 1H NMR (400 MHz, DMSO-d6): δ = 8.01 - 8.27 (m, 3 H), 7.66 - 7.90 (m, 1 H), 7.57 - 7.66 (m, 1 H), 7.39 - 7.51 (m, 1 H), 6.31 - 7.04 (m, 1 H), 4.17 - 4.74 (m, 1 H), 3.64 - 3.90 (m, 2.4 H), 3.55 (ddd, J=10.72, 6.35, 2.94 Hz, 1 H), 3.39 (br d, J=5.50 Hz, 1 H), 3.01 - 3.22 (m, 0.5 H), 2.69 (br dd, J=13.38, 11.13 Hz, 1 H), 2.37 - 2.48 (m, 3 H), 1.09 - 1.26 (m, 3 H), 0.89 - 1.05 (m, 3 H). LCMS (ESI+): m/z = 460.1 (M+1), RT: 3.299 min (The gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% trifluoroacetic acid in water, mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. Kinetex C18 column 2.1*50mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 181. ((2S,3R,6R)-3-(((3-Fluoro-4-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)-2,6-dimethylmorpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2- yl)methanone [94] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-fluoro-4-methyl-5- (trifluoromethyl)pyridin-2-amine and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 13%, white solid. 1H NMR (400 MHz, DMSO-d6): δ = 8.77 - 9.01 (m, 2 H), 8.27 - 8.46 (m, 1 H), 7.90 - 8.16 (m, 1 H), 7.56 (br s, 0.70 H), 7.42 - 7.52 (m, 1 H), 7.34 - 7.41 (m, 1 H), 6.92 (br s, 0.3 H), 4.23 - 4.78 (m, 1 H), 3.61 - 4.05 (m, 4 H), 3.34 - 3.42 (m, 1 H), 3.17 - 3.25 (m, 0.30 H), 3.00 - 3.07 (m, 0.25 H), 2.62 (br d, J=11.26 Hz, 0.50 H), 2.35 - 2.46 (m, 3 H), 2.23 (br s, 3 H), 1.10 - 1.30 (m, 3 H), 0.89 - 1.08 (m, 3 H). LCMS (ESI+): m/z = 519.61 (M+1), RT: 12.479 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 182. ((2S,3R,6R)-3-(((4-Ethyl-3-fluoro-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)-2,6-dimethylmorpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2- yl)methanone [95] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-4-ethyl-3-fluoro-5- (trifluoromethyl)pyridin-2-amine hydrochloride and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 7%, white solid. 1H NMR (400 MHz, DMSO-d6): δ = 88.78 - 8.99 (m, 2 H), 8.30 - 8.45 (m, 1 H), 7.94 - 8.19 (m, 1 H), 7.57 (br s, 0.75 H), 7.42 - 7.51 (m, 1 H), 7.40 (d, J=8.13 Hz, 1 H), 6.92 (br s, 0.25 H), 4.22 - 4.78 (m, 1 H), 3.60 - 4.05 (m, 4 H), 3.37 (br d, J=12.88 Hz, 1 H), 3.17 - 3.25 (m, 0.3 H), 3.05 (br dd, J=13.26, 2.13 Hz, 0.25 H), 2.64 (br d, J=9.13 Hz, 2.5 H), 2.35 - 2.47 (m, 3 H), 1.08 - 1.29 (m, 6 H), 0.93 - 1.07 (m, 3 H). LCMS (ESI+): m/z = 533.61 (M+1), RT: 13.393 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 183. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl-d2)morpholino)(4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [96] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 4-(5-fluoropyridin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Yield 42%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.54 - 8.71 (m, 0.90 H), 8.12 - 8.38 (m, 0.95 H), 7.64 - 7.77 (m, 1.20 H), 7.51 (br d, J=7.25 Hz, 0.70 H), 7.36 - 7.45 (m, 0.95 H), 7.34 (s, 0.65 H), 7.21 (br s, 0.25 H), 6.27 - 6.73 (m, 1.00 H), 4.23 - 4.78 (m, 1.75 H), 3.83 (s, 0.75 H), 3.74 (m, 0.30 H), 3.47 - 3.64 (m,3.25 H), 3.22 - 3.34 (m, 1.00 H), 2.67 - 3.09 (m, 1.05 H), 2.21 - 2.50 (m, 3.00 H), 1.17 - 1.29 (m, 3.00 H), 0.98 - 1.13 (m, 3.00 H). LCMS (ESI+): m/z =509.2 (M+1), RT: 2.283 min (The gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% trifluoroacetic acid in water, mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. Kinetex C18 column 2.1*50mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 184. ((2S,3R,6R)-2,6-Dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl-d2)morpholino)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2- yl)methanone [97] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl-d2)-3-methyl-5-(trifluoromethyl)pyridin-2- amine and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Yield 46%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.14 - 8.22 (m, 1.70 H), 8.00 - 8.09 (m, 1.20 H), 7.91 (s, 0.50 H), 7.48 (br d, J=8.00 Hz, 1.30 H), 7.28 (d, J=8.38 Hz, 0.55 H), 6.05 - 6.64 (m, 1.00 H), 4.71 (d, J=2.75 Hz, 0.40 H), 4.23 (dd, J=13.45, 2.31 Hz, 0.60 H), 3.79 - 3.91 (m, 0.40 H), 3.63 (br s, 0.50 H), 3.41 - 3.60 (m, 1.00 H), 2.97 - 3.18 (m, 1.30 H), 2.72 (dd, J=13.38, 11.26 Hz, 0.60 H), 2.47 (s, 1.10 H), 2.29 (s, 1.70 H), 2.05 - 2.18 (m, 2.90 H), 1.08 - 1.27 (m, 3.00 H), 0.90 - 1.01 (m, 2.90 H). LCMS (ESI+): m/z =492.54 (M+1), RT:12.207 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 185. ((2S,3R,6R)-2,6-Dimethyl-3-(((4-methyl-5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [98] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-4-methyl-5-(trifluoromethyl) pyrimidin-2-amine and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 50%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.85 - 9.01 (m, 1.90 H), 8.30 - 8.55 (m, 1.90 H), 8.06 - 8.29 (m, 0.75 H), 7.32 - 7.55 (m, 2.20 H), 4.26 - 4.74 (m, 1.00 H), 3.57 - 4.02 (m, 4.00 H), 3.35 - 3.42 (m, 0.50 H), 3.05 - 3.27 (m, 0.50 H), 2.62 - 2.74 (m, 0.80 H), 2.55 (s, 1.70H), 2.29 - 2.46 (m, 3.80H), 1.14 - 1.27 (m, 3.00 H), 0.92 - 1.06 (m, 3.00 H). LCMS: m/z = 502.40 (M+1), RT:12.249 min (The gradient was 10-80% B in 16.00 min, 80%- 100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 186. ((2S,3R,6R)-2,6-Dimethyl-3-(((4-methyl-5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazol-3- yl)methanone [99] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-4-methyl-5-(trifluoromethyl)pyrimidin-2- amine and 4-(5-fluoropyrimidin-2-yl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid.Yield 42%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.80 - 8.93 (m, 1.80 H), 8.26 - 8.56 (m, 0.90 H), 7.31 - 7.76 (m, 1.00 H), 4.76 (br d, J=3.00 Hz, 0.35 H), 4.35 (br d, J=13.01 Hz, 0.60 H), 3.91 - 3.99 (m, 0.30 H), 3.79 - 3.90 (m, 0.80 H), 3.59 - 3.79 (m, 2.80 H), 3.37 - 3.58 (m, 3.70 H), 2.97 - 3.24 (m, 0.80 H), 2.75 (dd, J=13.32, 11.32 Hz, 0.60 H), 2.60 (d, J=2.50 Hz, 1.10 H), 2.18 - 2.49 (m, 4.70 H), 1.14 - 1.27 (m, 3.00 H), 0.91 - 1.02 (m, 2.90 H). LCMS: m/z = 523.2 (M+1), RT: 2.518 min (The gradient was 5% B in 0.40 min and 5-95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% trifluoroacetic acid in water, mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. Kinetex C18 column 2.1*50mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 187. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(5,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [100] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2- amine hydrochloride and 5,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid. Yield 28%, pink solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.84 - 8.98 (m, 2 H), 8.57 - 8.71 (m, 2 H), 8.43 (br s, 1 H), 8.21 - 8.28 (m, 1 H), 7.42 - 7.64 (m, 1 H), 4.26 - 4.77 (m, 1 H), 3.60 - 3.98 (m, 4 H), 3.30 - 3.36 (m, 0.70 H), 3.02 - 3.21 (m, 0.50 H), 2.65 (dd, J=13.32, 11.07 Hz, 0.80 H), 2.31 - 2.49 (m, 6 H), 1.14 - 1.28 (m, 3 H), 0.91 - 1.05 (m, 3 H). LCMS (ESI+): m/z =502.22 (M+1), RT: 12.264 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 188. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [101] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2- amine hydrochloride and 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid. Yield 6%, pink solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.82 - 8.98 (m, 2 H), 8.53 - 8.73 (m, 2.70 H), 7.40 - 7.59 (m, 1.20 H), 7.20 - 7.34 (m, 1 H), 4.44 - 4.58 (m, 0.20 H), 4.12 (dd, J=13.45, 2.44 Hz, 0.70 H), 3.66 - 4.05 (m, 3 H), 3.34 - 3.64 (m, 2 H), 3.14 - 3.25 (m, 0.40 H), 2.53 - 2.59 (m, 0.70 H), 2.49 (br s, 2.40 H), 2.31 - 2.39 (m, 3 H), 2.29 (s, 0.60 H), 0.98 - 1.20 (m, 6 H). LCMS (ESI+): m/z =502.37 (M+1), RT: 11.827 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C18 4.6*150 mm column (3.5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 189. ((2S,3R,6R)-3-(((3-(Difluoromethyl)-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)-2,6-dimethylmorpholino)(6-(methyl-d3)-3-(pyrimidin-2-yl)pyridin-2- yl)methanone [102] General procedure (see Example 138) used for making the compound [51] was repeated, using 3-(difluoromethyl)-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine hydrochloride and 6-(methyl-d3)-3-(pyrimidin-2-yl)picolinic acid. Yield 4%, white solid. 1H NMR (400 MHz, METHANOL-d4): δ = 8.76 - 8.87 (m, 2 H), 8.58 (d, J=8.13 Hz, 1 H), 8.40 - 8.49 (m, 1 H), 8.21 (s, 1 H), 7.79 (br s, 1 H), 7.30 - 7.51 (m, 2 H), 6.72 - 7.05 (m, 1 H), 4.80 - 4.85 (m, 1 H), 4.41 (dd, J=13.63, 2.63 Hz, 1 H), 3.90 - 4.18 (m, 3 H), 3.70 - 3.80 (m, 1 H), 3.47 - 3.67 (m, 1 H), 3.11 - 3.29 (m, 2 H), 2.74 - 2.84 (m, 1 H), 1.40 (d, J=6.75 Hz, 2 H), 1.25 (d, J=6.25 Hz, 1 H), 1.01 - 1.09 (m, 3 H). LCMS (ESI+): 540.5 (M+H)+, RT: 13.051 min (The gradient was 10-80% B in 16.00 min, 80%- 100% B in 4.00 min, 100-10% B in 0.01min, and then held at10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150 mm column (3.5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 190. ((2S,3R,6R)-2,6-Dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(6-(methyl-d3)-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [103] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyridin- 2-amine and 6-(methyl-d3)-3-(pyrimidin-2-yl)picolinic acid. Yield 27%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.77 - 8.97 (m, 1.80 H), 8.28 - 8.45 (m, 0.90 H), 7.98 - 8.24 (m, 0.90 H), 7.27 - 7.54 (m, 2.70 H), 6.69 (br dd, J=5.88, 3.25 Hz, 0.50 H), 6.20 (br t, J=5.00 Hz, 0.40 H), 4.75 (td, J=7.25, 2.63 Hz, 0.40 H), 4.27 (dd, J=13.32, 2.31 Hz, 0.50 H), 3.91 - 4.03 (m, 0.95H), 3.85 (br t, J=6.25 Hz, 0.90 H), 3.70 - 3.80 (m, 0.50 H), 3.64 (ddt, J=13.90, 10.83, 3.14, 3.14 Hz, 1.00 H), 3.50 - 3.57 (m, 0.50 H), 3.37 - 3.42 (m, 0.60 H), 3.00 - 3.19 (m,0.90 H), 2.59 (dd, J=13.26, 11.26 Hz, 0.50 H), 2.01 - 2.24 (m, 2.80 H), 1.08 - 1.35 (m, 3.00 H), 0.97 (d, J=6.38 Hz,2.80 H). LCMS: m/z = 504.36 (M+1), RT:12.574 min (The gradient was 10-80% B in 16.00 min, 80%- 100% B in 4.00 min, 100-10% B in 0.01min, and then held at10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150 mm column (3.5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 191. ((2S,3R,6R)-3-(((3-Chloro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)- 2,6-dimethylmorpholino)(6-(methyl-d3)-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [104] General procedure (see Example 138) used for making the compound [51] was repeated, using 3-chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin- 2-amine and 6-(methyl-d3)-3-(pyrimidin-2-yl)picolinic acid. Yield 39%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.73 - 8.98 (m, 1.85 H), 8.34 - 8.44 (m, 0.70 H), 8.31 (d, J=8.00 Hz, 0.55 H), 8.17 (s, 0.55 H), 7.94 (s, 0.85 H), 7.45 - 7.56 (m, 1.20 H), 7.37 - 7.44 (m, 0.70 H), 7.33 (d, J=8.13 Hz, 0.60 H), 6.88 (br t, J=4.94 Hz, 0.40 H), 4.69 - 4.81 (m, 0.40 H), 4.29 (br d, J=11.26 Hz, 0.60 H), 3.82 - 4.06 (m, 2.00 H), 3.59 - 3.81 (m, 2.00 H), 3.35 - 3.45 (m, 0.70 H), 3.16 - 3.28 (m, 0.45 H), 3.06 (dd, J=13.20, 2.06 Hz, 0.40 H), 2.65 (br dd, J=12.88, 11.63 Hz, 0.70 H), 1.12 - 1.32 (m, 3.00 H), 0.98 (dd, J=6.07, 3.44 Hz, 3.00 H). LCMS (ESI+): m/z =524.2 (M+1), RT: 2.668 min (The gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% trifluoroacetic acid in water, mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. Kinetex C18 column 2.1*50mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 192. ((2S,3R,6R)-3-(((3-Ethyl-5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)- 2,6-dimethylmorpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [105] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-ethyl-5-(trifluoromethyl)pyrazin-2- amine hydrochloride and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 42%, pink solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.91 (d, J=4.88 Hz, 0.90 H), 8.86 (d, J=4.88 Hz, 1.00 H), 8.38 (d, J=8.00 Hz, 0.50 H), 8.24 - 8.28 (m, 0.95 H), 8.03 (s, 0.45 H), 7.50 (t, J=4.94 Hz, 0.45 H), 7.43 (t, J=4.94 Hz, 0.50 H), 7.38 (d, J=8.13 Hz, 0.50 H), 7.28 (d, J=8.13 Hz, 0.90 H), 7.01 (br t, J=5.88 Hz, 0.50 H), 4.80 (dt, J=10.76, 3.56 Hz, 0.50 H), 4.30 (dd, J=13.57, 2.44 Hz, 0.45 H), 3.91 - 4.07 (m, 1.00 H), 3.62 - 3.82 (m, 2.00 H), 3.52 - 3.61 (m, 0.50 H), 3.42 (dt, J=12.95, 3.47 Hz, 0.45 H), 3.26 - 3.31 (m, 0.50 H), 3.20 (dd, J=13.51, 11.01 Hz, 0.50 H), 2.96 - 3.03 (m, 0.50 H), 2.66 - 2.77 (m, 2.10 H), 2.54 (s, 0.50 H), 2.39 (s, 1.50 H), 2.25 (s, 1.40 H), 1.14 - 1.28 (m, 6.00 H), 0.95 (dd, J=11.32, 6.44 Hz, 3.00 H). LCMS (ESI+): m/z =516.3 (M+1), RT: 12.889 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C18 4.6*150 mm column (3.5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 193. ((2S,3R,6R)-3-(((3-Fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)- 2,6-dimethylmorpholino)(6'-methyl-[2,3'-bipyridin]-2'-yl)methanone [106] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-fluoro-5-(trifluoromethyl)pyridin- 2-amine hydrochloride and 6'-methyl-[2,3'-bipyridine]-2'-carboxylic acid. Yield 40%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.54 - 8.75 (m, 0.95 H), 8.20 (s, 0.20 H), 7.81 - 8.07 (m, 2.80H), 7.59 - 7.78 (m, 2.80 H), 7.31 - 7.47 (m, 1.20 H), 7.24 (d, J=8.13 Hz, 0.80 H), 6.99 - 7.07 (m, 0.20 H), 4.70 (m, 0.20 H), 4.26 (m, 0.80 H), 3.93 (m, 0.25 H), 3.62 - 3.84 (m, 2.00 H), 3.35 - 3.48 (m, 1.60 H), 3.17 (m, 0.25 H), 2.92 - 3.08 (m, 0.95 H), 2.66 (m, 0.85 H), 2.28 - 2.44 (m, 33.00 H), 1.08 - 1.27 (m, 3.20 H), 0.89 - 1.00 (m, 3.00 H). LCMS (ESI+): m/z =504.1 (M+1), RT: 3.357 min (The gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% trifluoroacetic acid in water, mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. Kinetex C18 column 2.1*50mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 194. ((2S,3R,6R)-2,6-Dimethyl-3-(((4-methyl-5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(6-methyl-[3,3'-bipyridin]-2-yl)methanone [107] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-4-methyl-5- (trifluoromethyl)pyrimidin-2-amine and 6-methyl-[3,3'-bipyridine]-2-carboxylic acid. Yield 4%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.55 - 8.72 (m, 1.85 H), 8.44 (br d, J=13.76 Hz, 0.15 H), 8.40 (s, 0.40 H), 8.19 (s, 0.30 H), 7.88 - 8.03 (m, 0.75 H), 7.74 - 7.86 (m, 1.90 H), 7.37 - 7.66 (m, 1.50 H), 7.09 - 7.29 (m, 0.75 H), 4.56 - 4.67 (m, 0.20 H), 4.28 (m, 0.80 H), 3.50 - 3.66 (m, 1.05 H), 3.35 - 3.45 (m, 0.90 H), 3.17 - 3.32 (m, 1.80 H), 3.00 - 3.12 (m, 0.95 H), 2.84 - 2.93 (m, 0.25 H), 2.62 - 2.71 (m, 1.20 H), 2.35 - 2.46 (m, 2.20 H), 2.16 - 2.30 (m, 3.75 H), 1.02 - 1.17 (m, 3.00 H), 0.77 - 0.95 (m, 3.00 H). LCMS (ESI+): m/z =501.2 (M+1), RT: 2.912 min (The gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% trifluoroacetic acid in water, mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. Kinetex C18 column 2.1*50mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 195. ((2S,3R,6R)-3-(((3-Fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)- 2,6-dimethylmorpholino)(6-methyl-3-(pyrazin-2-yl)pyridin-2-yl)methanone [108] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-fluoro-5-(trifluoromethyl)pyridin-2- amine hydrochloride and 6-methyl-3-(pyrazin-2-yl)picolinic acid. Yield 7%, yellow solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.91 - 8.96 (m, 0.90 H), 8.74 (s, 0.70 H), 8.63 - 8.69 (m, 0.90 H), 8.60 (d, J=2.38 Hz, 0.20 H), 7.97 - 8.21 (m, 1.90 H), 7.58 - 7.83 (m, 1.80 H), 7.31 - 7.44 (m, 1.00 H), 7.03 (br s, 0.30 H), 4.60 - 4.75 (m, 0.20 H), 4.24 (dd, J=13.51, 2.25 Hz, 0.75 H), 3.96 (ddd, J=13.48, 10.29, 6.38 Hz, 0.30 H), 3.61 - 3.88 (m, 2.15 H), 3.35 - 3.53 (m, 2.00 H), 3.17 - 3.29 (m, 1.20 H), 3.00 - 3.10 (m, 0.30 H), 2.61 - 2.73 (m, 0.90 H), 2.35 - 2.45 (m, 3.00 H), 1.09 - 1.25 (m, 3.40 H), 0.95 - 1.03 (m, 3.00H). LCMS: m/z = 505.3 (M+1), RT: 2.514 min (The gradient was 5% B in 0.40 min and 5-95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% trifluoroacetic acid in water, mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. Kinetex C18 column 2.1*50mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 196. ((2S,3R,6R)-3-(((3-Fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)- 2,6-dimethylmorpholino)(6-methyl-3-(pyrimidin-2-yl)pyrazin-2-yl)methanone [109] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-fluoro-5-(trifluoromethyl)pyridin- 2-amine hydrochloride and 6-methyl-3-(pyrimidin-2-yl)pyrazine-2-carboxylic acid. Yield 10%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.91 - 9.02 (m, 1.85 H), 8.57 - 8.67 (m, 0.90 H), 8.20 (s, 0.25 H), 8.02 (s, 0.60 H), 7.69 - 7.80 (m, 0.95 H), 7.52 - 7.63 (m, 0.95 H), 7.40 (br s, 0.65 H), 7.06 - 7.12 (m, 0.30 H), 4.66 - 4.73 (m, 0.30 H), 4.20 - 4.28 (m, 0.70 H), 4.00 - 4.08 (m, 0.30 H), 3.63 - 3.93 (m, 2.40 H), 3.34 - 3.58 (m, 2.40 H), 3.12 - 3.29 (m, 0.65 H), 2.76 (dd, J=13.13, 11.63 Hz, 0.70 H), 2.37 - 2.46 (m, 2.90 H), 1.25 (br d, J=6.88 Hz, 1.25 H), 1.16 (d, J=6.13 Hz, 1.95 H), 0.96 - 1.06 (m, 3.00 H). LCMS (ESI+): m/z =506.2 (M+1), RT: 2.371 min (The gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% trifluoroacetic acid in water, mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. Kinetex C18 column 2.1*50mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 197. ((2S,3R,6R)-2,6-Dimethyl-3-(((4-methyl-5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(6-methyl-3-(5-methylpyrimidin-2-yl)pyridin-2- yl)methanone [110] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-4-methyl-5- (trifluoromethyl)pyrimidin-2-amine and 6-methyl-3-(5-methylpyrimidin-2-yl)picolinic acid. Yield 15%, yellow solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.70 - 8.83 (m, 1.90 H), 8.53 (s, 0.15 H), 8.43 (br d, J=4.50 Hz, 0.80 H), 8.31 - 8.41 (m, 0.80 H), 8.12 - 8.31 (m, 0.70 H), 7.33 - 7.52 (m, 1.20 H), 4.63 - 4.73 (m, 0.25 H), 4.32 (dd, J=13.51, 2.63 Hz, 0.70 H), 3.99 - 4.08 (m, 0.45 H), 3.90 - 3.99 (m, 0.4 H), 3.64 - 3.89 (m, 3.00 H), 3.34 - 3.44 (m, 0.65 H), 3.03 - 3.29 (m, 0.55 H), 2.61 - 2.75 (m, 1.00 H), 2.52 - 2.59 (m, 2.00 H), 2.43 (s, 0.80 H), 2.36 - 2.41 (m, 2.00 H), 2.33 (s, 3.15 H), 2.29 (s, 0.80 H), 1.14 - 1.28 (m, 3.40 H), 0.94 - 1.06 (m, 3.00 H). LCMS (ESI+): m/z =516.5 (M+1), RT: 13.100 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C18 4.6*150 mm column (3.5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 198. ((2S,3R,6R)-2,6-Dimethyl-3-(((4-methyl-5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(6-methyl-3-(4-methylpyrimidin-2-yl)pyridin-2- yl)methanone [111] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-4-methyl-5- (trifluoromethyl)pyrimidin-2-amine and 6-methyl-3-(4-methylpyrimidin-2-yl)picolinic acid. Yield 5%, yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.71 - 8.80 (m, 0.90 H), 8.52 (s, 0.10 H), 8.34 - 8.43 (m, 1.40 H), 8.24 - 8.33 (m, 0.70 H), 8.16 (br d, J=1.25 Hz, 0.30 H), 7.31 - 7.51 (m, 2.20 H), 4.67 (br dd, J=6.44, 3.06 Hz, 0.20 H), 4.33 (dd, J=13.51, 2.38 Hz, 0.70 H), 3.61 - 3.97 (m, 3.90 H), 3.03 - 3.18 (m, 0.65 H), 2.63 - 2.71 (m, 1.05 H), 2.51 - 2.56 (m, 5.05 H), 2.30 - 2.44 (m, 4.05 H), 1.16 - 1.27 (m, 3.10 H), 0.95 - 1.05 (m, 3.00 H). LCMS (ESI+): m/z =516.2 (M+1), RT: 2.633 min (The gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold at 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% trifluoroacetic acid in water, mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. Kinetex C18 column 2.1*50mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 199. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [112] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2- amine hydrochloride and 6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 64%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.86 - 8.99 (m, 1.90 H), 8.55 - 8.71 (m, 1.85 H), 8.31 - 8.44 (m, 1.65 H), 7.63 (br s, 0.30 H), 7.35 - 7.56 (m, 2.00 H), 4.64 - 4.76 (m, 0.30 H), 4.32 (br d, J=13.26 Hz, 0.75 H), 3.87 - 3.99 (m, 1.40 H), 3.64 - 3.85 (m, 3.00 H), 3.04 - 3.25 (m, 0.65 H), 2.61 - 2.73 (m, 1.00 H), 2.53 (s, 2.00 H), 2.43 (s, 0.75 H), 1.14 - 1.29 (m, 3.00 H), 0.91 - 1.07 (m, 3.00 H). LCMS (ESI+): m/z =488.37 (M+1), RT:11.423 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C18 4.6*150 mm column (3.5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 200. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(4,6-dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone [113] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride and 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid. Yield 46%, pink solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.78 - 8.98 (m, 2 H), 8.24 - 8.35 (m, 1 H), 7.55 - 7.88 (m, 1.70 H), 7.39 - 7.54 (m, 1 H), 7.21 - 7.30 (m, 1 H), 6.98 (br s, 0.30 H), 6.50 - 6.66 (m, 1 H), 4.37 - 4.48 (m, 0.20 H), 4.10 (dd, J=13.38, 2.25 Hz, 0.80 H), 3.64 - 4.01 (m, 3 H), 3.41 - 3.63 (m, 1.50 H), 3.03 - 3.24 (m, 0.50 H), 2.52 - 2.57 (m, 1 H), 2.39 - 2.47 (m, 3 H), 2.27 - 2.36 (m, 3 H), 0.96 - 1.22 (m, 6 H). LCMS (ESI+): m/z =501.53 (M+1), RT: 12.234 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C18 4.6*150 mm column (3.5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 201. (4,6-Dimethyl-3-(pyrimidin-2-yl)pyridin-2-yl)((2S,3R,6R)-3-(((3-fluoro-5- (trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6-dimethylmorpholino)methanone [114] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-fluoro-5-(trifluoromethyl)pyridin- 2-amine hydrochloride and 4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid. Yield 48%, pink solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.81 - 8.96 (m, 2 H), 8.11 - 8.22 (m, 1 H), 7.96 (br s, 0.80 H), 7.66 - 7.79 (m, 1 H), 7.38 - 7.53 (m, 1 H), 7.21 - 7.29 (m, 1 H), 6.88 - 6.97 (m, 0.20 H), 4.50 - 4.59 (m, 0.20 H), 4.08 (dd, J=13.57, 2.56 Hz, 0.80 H), 3.82 - 4.03 (m, 2.50 H), 3.58 - 3.78 (m, 0.60 H), 3.38 - 3.48 (m, 1.50 H), 3.09 - 3.26 (m, 0.40 H), 2.54 (br s, 1 H), 2.26 - 2.44 (m, 6 H), 0.97 - 1.24 (m, 6 H). LCMS (ESI+): m/z =519.46 (M+1), RT: 13.070 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C18 4.6*150 mm column (3.5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 202. ((2S,3R,6R)-3-(((3-(Difluoromethyl)-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)-2,6-dimethyltetrahydro-2H-pyran-4-yl)(6-(methyl-d3)-3-(2H-1,2,3- triazol-2-yl)pyridin-2-yl)methanone [115] General procedure (see Example 88) used for making the compound [1] was repeated, using 3-(difluoromethyl)-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine hydrochloride and 6-(methyl-d3)-3-(2H-1,2,3-triazol-2- yl)picolinic acid.Yield 47%, white solid. 1H NMR (400 MHz, DMSO-d6): δ = 8.52 (s, 1 H), 8.01 - 8.24 (m, 3 H), 7.85 (br s, 1 H), 7.40 (dd, J=60.10, 8.44 Hz, 1 H), 6.85 - 7.24 (m, 2 H), 4.73 (dt, J=8.38, 4.19 Hz, 1 H), 4.24 (dd, J=13.51, 2.63 Hz, 1 H), 3.66 - 3.96 (m, 2 H), 3.44 - 3.58 (m, 2 H), 2.98 - 3.25 (m, 1 H), 2.78 (dd, J=13.38, 11.26 Hz, 1 H), 1.11 - 1.27 (m, 3 H), 0.97 (dd, J=6.44, 2.44 Hz, 3 H). LCMS (ESI+): 529.5 (M+H)+, RT: 13.234 min (The gradient was 10-80% B in 16.00 min, 80%- 100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150 mm column (3.5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 203. ((2S,3R,6R)-2,6-Dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholino)(6-(methyl-d3)-3-(2H-1,2,3-triazol-2-yl)pyridin-2- yl)methanone [116] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-methyl-5-(trifluoromethyl)pyridin-2- amine and 6-(methyl-d3)-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Yield 53%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.14 - 8.22 (m, 1.90 H), 8.07 (s, 0.70 H), 8.02 (d, J=8.50 Hz, 0.60 H), 7.91 (s, 0.60 H), 7.48 (br d, J=8.25 Hz, 1.40 H), 7.28 (d, J=8.38 Hz, 0.60 H), 6.58 (br t, J=5.07 Hz, 0.60 H), 6.23 (t, J=5.32 Hz, 0.40 H), 4.64 - 4.80 (m, 0.40 H), 4.23 (dd, J=13.51, 2.50 Hz, 0.60 H), 3.80 - 3.90 (m, 1.20 H), 3.69 - 3.79 (m, 0.70 H), 3.61 - 3.68 (m, 0.60 H), 3.51 - 3.59 (m, 0.50 H), 3.39 - 3.51 (m, 1.40 H), 3.09 - 3.19 (m, 0.50 H), 3.00 - 3.08 (m, 1.00 H), 2.72 (dd, J=13.32, 11.19 Hz, 0.60H), 2.12 (d, J=14.88 Hz, 3.00 H), 1.10 - 1.28 (m, 3.20 H), 0.96 (dd, J=6.38, 3.50 Hz, 3.10 H). LCMS: m/z = 493.67 (M+1), RT:12.720 min (The gradient was 10-80% B in 16.00 min, 80%- 100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C184.6*150 mm column (3.5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 204. ((2S,3R,6R)-3-(((3-Fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)- 2,6-dimethylmorpholino)(6-(methyl-d3)-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone [117] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-fluoro-5-(trifluoromethyl)pyridin-2- amine hydrochloride and 6-(methyl-d3)-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Yield 27%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.14 - 8.22 (m, 1.85 H), 8.05 - 8.13 (m, 1.20 H), 7.98 (s, 0.65 H), 7.69 - 7.80 (m, 1.00 H), 7.42 - 7.52 (m, 1.00 H), 7.36 (d, J=8.38 Hz, 0.70 H), 7.08 (br s, 0.30 H), 4.65 - 4.76 (m, 0.30 H), 4.26 (dd, J=13.45, 2.44 Hz, 0.70 H), 3.93 - 4.07 (m, 0.30 H), 3.63 - 3.91 (m, 2.00 H), 3.49 - 3.62 (m, 1.00 H), 3.36 - 3.45 (m, 0.80 H), 3.16 - 3.31 (m, 0.90 H), 2.99 - 3.08 (m, 0.30 H), 2.74 (dd, J=13.32, 11.44 Hz, 0.75 H), 1.10 - 1.27 (m, 3.00 H), 0.98 (d, J=6.63 Hz, 3.00 H). LCMS (ESI+): m/z =497.2 (M+1), RT: 3.333 min (The gradient was 5% B in 0.40 min and 5- 95% B at 0.40-3.40 min, hold at 95% B for 0.45 min, and then 95-5% B in 0.01min, the flow rate was 0.8 ml/min. Mobile phase A was H2O+10mM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was an Xbridge-C18 2.1*50mm 5um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) Example 205. ((2S,3R,6R)-3-(((3-Chloro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)- 2,6-dimethylmorpholino)(6-(methyl-d3)-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone [118] General procedure (see Example 88) used for making the compound [1] was repeated, using 3-chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2- amine and 6-(methyl-d3)-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Yield 20%, white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.35 (s, 0.25 H), 7.89 - 8.21 (m, 4.00 H), 7.28 - 7.50 (m, 1.55 H), 6.90 (br t, J=5.32 Hz, 0.30 H), 4.69 - 4.78 (m, 0.30 H), 4.25 (br dd, J=13.45, 2.31 Hz, 0.60 H), 3.95 - 4.07 (m, 0.35 H), 3.83 - 3.90 (m, 0.50 H), 3.66 - 3.82 (m, 1.55 H), 3.46 - 3.62 (m, 1.35 H), 3.37 (br s, 1.20 H), 3.21 (br d, J=11.13 Hz, 1.00 H), 3.06 (br dd, J=13.38, 2.00 Hz, 0.35 H), 2.77 (br dd, J=13.20, 11.44 Hz, 0.70 H), 1.11 - 1.29 (m, 3.00 H), 0.92 - 1.04 (m, 3.00 H). LCMS (ESI+): m/z =513.50 (M+1), RT:13.465 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C18 4.6*150 mm column (3.5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 206. (4-Chloro-6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((2S,3R,6R)-2,6- dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)morpholino)methanone [119] General procedure (see Example 138) used for making the compound [51] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2- amine hydrochloride and 4-chloro-6-methyl-3-(pyrimidin-2-yl)picolinic acid. Yield 80%, yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.89 - 9.01 (m, 2 H), 8.54 - 8.67 (m, 2 H), 8.29 (br t, J=4.50 Hz, 1 H), 7.59 - 7.65 (m, 1 H), 7.47 - 7.58 (m, 1 H), 4.48 (dt, J=9.85, 3.46 Hz, 0.25 H), 4.03 - 4.13 (m, 0.70 H), 3.91 (br d, J=10.38 Hz, 0.70 H), 3.69 - 3.86 (m, 2 H), 3.60 - 3.68 (m, 0.30 H), 3.54 (dt, J=13.98, 4.96 Hz, 0.30 H), 3.41 - 3.49 (m, 1 H), 3.13 - 3.26 (m, 0.70 H), 2.60 (br dd, J=13.45, 11.19 Hz, 1 H), 2.39 - 2.48 (m, 3 H), 0.99 - 1.25 (m, 6 H). LCMS (ESI+): m/z =522.23 (M+1), RT: 12.122 min (The gradient was 10-80% B in 16.00 min, 80%-100% B in 4.00 min, 100-10% B in 0.01min, and then held at 10% for 3 min, the flow rate was 1.0 ml/min. Mobile phase A was 10mM Ammonium bicarbonate, mobile phase B was HPLC grade acetonitrile. Xbridge C18 4.6*150 mm column (3.5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. The column temperature was 80℃.) Example 207. ((2S,3R,6R)-2,6-Dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholino)(4-(5-fluoropyrimidin-2-yl)-1-methyl-5-(methyl-d3)-1H- pyrazol-3-yl)methanone [120] General procedure (see Example 88) used for making the compound [1] was repeated, using N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride and 4-(5-fluoropyrimidin-2-yl)-1-methyl-5-(methyl-d3)-1H-pyrazole-3-carboxylic acid. Yield 51%, white solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 8.80 - 8.90 (m, 1.85 H), 8.43 - 8.75 (m, 1.90 H), 7.53 - 7.93 (m, 1.05 H), 4.73 - 4.83 (m, 0.35 H), 4.36 (m, 0.65 H), 3.80 - 3.89 (m, 1.05 H), 3.73 - 3.78 (m, 1.40 H), 3.59 - 3.72 (m, 1.65 H), 3.38 - 3.59 (m, 3.70 H), 3.15 - 3.22 (m, 0.40 H), 2.97 - 3.08 (m, 0.35 H), 2.76 (m, 0.65 H), 1.15 - 1.26 (m, 3.05 H), 0.95 (m, 3.00 H). LCMS (ESI+): m/z = 512.2 (M+1), Rt=2.429 min (The gradient was 5% B in 0.40 min and 5- 95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. Kinetex C182.1*50 mm, 5um column. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.) II. IC50 values of compounds 1-120 with respect to OX1R and OX2R receptors Antagonistic activity on both human orexin receptors OX1R and OX2R has been measured using the following procedure: Example 208: In vitro assay: Intracellular calcium measurement HEK cells expressing the human orexin-1 receptor (OX1R) and the human orexin-2 receptor (OX2R), were seeded at 20000 cells / well into 384-well plates. On the day of the assay, after removal of the medium, 40 and 32µL of staining buffer (HBSS/HEPES, probenecid and fluorescent calcium 6 assay dye) was added to IC50 wells, respectively, and the cells were incubated for 90 min at room temperature. Antagonists test compounds were prepared as 10 mM stock solution in DMSO, then diluted with staining buffer. Then, the test compound solution (8 µL) was added to each respective well of the plate, followed by 30 min incubation at room temperature before measurement. For the IC50 compound determination (the concentration of compound needed to inhibit 50 % of the agonistic response), human Orexin-A was diluted in HBSS/HEPES buffer (5x working solution) and within FLIPR 10 µL/well was added and fluorescence measured. The test results are shown in Table 1 below. Example 209: Metabolic Stability and Intrinsic Clearance in Human Liver Hepatocytes Stock solutions of test compounds and the positive control were prepared at 10 mM and 30 mM, respectively, in dimethyl sulfoxide (DMSO). The stock solutions of test compounds and positive control, were diluted, respectively with Acetonitrile into a 100 µM and 300 µM (dosing solution), to get a final concentration of 1 µM and 3 µM in the incubation 96-well plates with 0.90% of Acetonitrile and 0.1% of DMSO. The cryopreserved hepatocyte cells were thawed in Williams’ Medium E containing 5% fetal bovine serum and 30% Percoll solution and other supplements, isolated and suspended in Incubation Medium (Williams’ Medium E (no phenol red) containing 2 mM L-Glutamine and 25 mM HEPES.). The cell suspension was then diluted with pre-warmed incubation Medium to 0.5 × 106 cells/mL and 198 μL pre-warmed suspension were added in 96-well plates. The dosing solution (2 μL) with test compounds were spiked in each well of the 96-well plates in duplicates. The samples to evaluate the metabolic clearance in presence of cryopreserved hepatocytes were incubated for 90 min (T90) with the incubation mixture (i.e. cells with incubation medium). At time zero (T0), samples, containing test compounds together with cell suspension diluted to 0.5 × 106 cells/mL were mixed to achieve a homogenous suspension for about 1 min, then 25 μL of each sample was immediately transferred into the well of the 96-well plates containing 125 μL of ice-cold stop solution (acetonitrile containing 200 ng/mL tolbutamide and 200 ng/mL labetalol as internal standards) followed by mixing. The plates were incubated at 37°C in a 95% humidified incubator at 5% CO2 to start the reactions with constant shaking at about 650 rpm. At 15, 30, 60 and 90 min, samples were mixed and then 25 μL of each sample, at each time point, were transferred to the well containing 125 μL of ice-cold stop solution in a set of pre-labelled 96-well plates, followed by mixing. Medium Control (MC) sample plates (labeled as T0-MC and T90-MC) were prepared by adding the incubation medium, except cell suspensions to each well. Samples were collected at time zero (T0) and after 90 min incubation (T90). At each corresponding time point, the reaction was stop by removing the plates from incubator and mixing with 125 μL of ice-cold stop solution. The plates were vortex immediately on a plate shaker at 600 rpm for 10 minutes. Then, all sample plates were centrifuged at 3220 x g for 20 min at 4°C. After centrifugation, 80 μL/well of supernatant in the sample plates were transferred to another set of pre-labeled 96-well plates which containing 240 μL of ultra-pure water according to the plate map. Analytical plates are sealed and store at 4°C until LC-MS/MS analysis. Peak areas were determined from the extracted chromatograms and in vitro half-life of parent compound was determined by regression analysis in the Ln percent parent disappearance vs. time curve. The in vitro Intrinsic Clearance (in vitro Clint, in µL/min/106 cells) was determined from the slope value using the following equation: in vitro CLint=KV/N (V=incubation volume (0.2 mL); N= number of hepatocytes per well. Compounds with hCLint LV.hep values ranging from 20 to 35 indicate moderate metabolic stability, while compounds with hCLint LV.hep values below 20, indicate good metabolic stability. The limit of quantification in the assay is 6.4. The test results are shown in Table 1 below. Table 1. Bioactivity of exemplary compounds with respect to OX1R and OX2R receptors, and Metabolic Stability and Intrinsic Clearance of exemplary compounds in Human Liver Hepatocytes
The tested compounds 1-120 showed good binding efficiency for OX1 receptor; and showed excellent selectively for OX1 receptors over OX2 receptors. The majority of the tested compounds showed good metabolic stability in human liver hepatocytes. The compounds provided by the present invention are more selective towards OX1 receptors and have better/similar metabolic stability in human liver hepatocytes. Various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

Claims

CLAIMS:
1 . A compound of Formula I or pharmaceutically acceptable salts, and derivatives thereof, wherein:
Het represents a heteroaromatic group selected from the group consisting of: pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, furan, thiophene, pyrrole, imidazole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof, wherein said heteroaromatic group is unsubstituted, mono-, di-, or tri-substituted, wherein the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (C1-C4)-straight chain alkyl, unsubstituted (C1-C4)-branched alkyl, unsubstituted (C3-C8)-cycloalkyl, unsubstituted (C1-C4)-alkoxy, substituted (C1-C4)-straight chain alkyl, substituted (C1-C4)-branched alkyl, substituted (C3-C8)-cycloalkyl, a cyano group, substituted (C1-C4)-alkoxy and halogen; and
R is selected from the group consisting of a five or a six membered aromatic or heteroaromatic group, wherein the aromatic or heteroaromatic group is either unsubstituted, or is substituted with one or more substituents.
2. A compound according to claim 1 wherein the compound of Formula I is a 2S,3R- stereoisomer: preferably, the compound of Formula I is a 6R-stereoisomer, a 6S-stereoisomer or a mixture thereof.
3. A compound according to claim 1 or 2 wherein the compound of Formula I is a deuterated compound, in which one or more hydrogen atom is replaced with one or more deuterium, preferably the deuterated compound of Formula I has the following structure: wherein: Het and R are each independently as defined in claims 1 to 3; and R6 and R7 are each independently H or deuterium (D).
4. A compound according to claims 1 to 3 wherein the substituent of the heteroaromatic group in Het is (C1-C4)- alkyl, (C1-C4)-fluoroalkyl, (C3-C8)-cycloalkyl, cyano, (C1-C4)-alkoxy or halogen, preferably the substituent of the heteroaromatic group in Het is Cl, F, -CHF2, -CF3, - CH3, -C2H5, methoxy, nitrile or cyclopropyl.
5. A compound according to any one of the claims 1 to 4 wherein R comprises a five membered heteroaromatic group which is an unsubstituted pyrazole, an unsubstituted oxazole, an unsubstituted thiazole, an unsubstituted imidazole, a substituted pyrazole, a substituted oxazole, a substituted thiazole, a substituted imidazole, or a derivative thereof; a six membered heteroaromatic group which is an unsubstituted pyridine, an unsubstituted pyrimidine, an unsubstituted pyridazine, an unsubstituted pyrazine, a substituted pyridine, a substituted pyrimidine, a substituted pyridazine, a substituted pyrazine or any derivatives thereof; or a six membered aromatic group which is an unsubstituted aryl, or substituted aryl, or a derivative thereof.
6. A compound according to any one of the claims 1 to 5 wherein R is selected from:
wherein:
R3, R4 and R5 are each independently selected from hydrogen, (C1-C10)-straight chain alkyl; (C1-C10)-branched alkyl; (C1-C10)-substituted or unsubstituted alkyl, optionally (C1-C4)-straight chain alkyl; (C1-C4)-branched alkyl; (C1-C4)-substituted or unsubstituted alkyl; deuterated (C1-C6)-straight chain alkyl, deuterated (C1-C6)-branched chain alkyl; R3 and R4 may form a substituted or unsubstituted ring; preferably R3, R4 and R5 are each independently selected from hydrogen, -CH3 or -CD3 (deuterated form);
Y represents an aromatic group or a heteraromatic group; a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, wherein the Y is independently selected from the group consisting of: aryl, pyridine, pyridazine, pyrazine, pyrimidine, triazole, tetrazole, pyrazole, nicotinonitrile, benzonitrile, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof, wherein the substituents are independently selected from the group consisting of: unsubstituted or substituted (C1-C4)- alkyl, unsubstituted or substituted (C1-C4)-alkoxy, a cyano group and halogen such as fluorine, bromine or chlorine.
7. A compound according to claim 6 wherein the substituent of the aromatic or heteroaromatic group in Y is selected from CN, F, Br, Cl or -O-alkyl, wherein the alkyl group comprises 1-4 carbon atoms, preferably the alkoxy is -OCH3.
8. A compound according to claim 6 or 7 wherein Y is selected from the group consisting of:
9. A compound according to any one of the claims 1 to 8 wherein R is selected from the group consisting of:
10. A compound according to any one of the claims 1 to 5 wherein R is wherein:
R1 and R2 are each independently selected from the group consisting of: hydrogen, unsubstituted (C1-C6)-straight chain alkyl, unsubstituted (C1-C6)-branched alkyl, substituted (C1-C6)-straight chain alkyl, substituted (C1-C6)-branched alkyl, deuterated (C1-C6)-straight chain alkyl, deuterated (C1-C6)-branched chain alkyl, and halogen; and
Het’ is selected from the group consisting of: a heteroaromatic group selected from the group consisting of pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, tetrazole, imidazole, pyrazole, furan, thiophene, pyrrole, isoxazole, oxazole, isothiazole, thiazole and any derivatives thereof, wherein said heteroaromatic group is unsubstituted, mono-, or disubstituted, wherein the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: (C1-C4)-straight chain or branched alkyl, substituted straight chain or branched (CrC4)-alkyl, and halogen, preferably the substituents of the heteroaromatic group, if present, are independently selected from the group consisting of: fluorine, chlorine, and -CH3.
11. A compound according to claim 10 wherein R1 and R2 are each independently selected from the group consisting of: hydrogen, chlorine, fluorine, -CH3, and -CD3.
12. A compound according to any one of the claims 1 to 5, 10 and 11, wherein the Het’ is selected from the group consisting of:
13. A compound according to any one of the claims 1 to 5 and 10 to 12 wherein R is selected from the group consisting of:
14. A compound according to any preceding claim 1 to 13 wherein Het is selected from
15. A compound according to any one of claims 1 to 14, wherein the compound has the structure of Formula l(a), l(b), l(c), l(d), l(e), l(f), l(g), l(h), l(i), l(j), l(k), l(l), l(m), l(n):
wherein: R1, R2, R3, R4, R5, Het, Het’ and Y are each independently as defined in any preceding claim; and R6 and R7, if present, are each independently hydrogen or deuterium.
16. A compound according to any one of the claims 1 to 9, 14 and 15 wherein the compound is selected from the group consisting of:
or pharmaceutically acceptable salts and derivatives thereof.
17. A compound according to any one of the claims 1 to 5 and 10 to 15 wherein the compound is selected from the group consisting of: or pharmaceutically acceptable salts and derivatives thereof.
18. A compound of formula l-aa, or pharmaceuticals acceptable salts and derivatives therefore:
(Formula l-aa) wherein:
R8 is CF3 or a halogen, preferably the halogen is Cl;
W1 is selected from the group consisting of: -CH, N, -C-CH3, -C-CH2CH3, -C-F, -C-CI, -C-CN, -C-CHF2, and -C-OMe;
W2 is selected from the group consisting of: -CH, N, -C-CH3 and -C-CH2CH3; and
R is a five membered heteroaromatic group which is an unsubstituted pyrazole, an unsubstituted oxazole, an unsubstituted thiazole, an unsubstituted imidazole, a substituted pyrazole, a substituted oxazole, a substituted thiazole, a substituted imidazole or a derivative thereof; or a six membered heteroaromatic group, which is an unsubstituted pyridine, an unsubstituted pyrimidine, an unsubstituted pyridazine, an unsubstituted pyrazine, a substituted pyridine, a substituted pyrimidine, a substituted pyridazine, a substituted pyrazine or any derivatives thereof.
19. A compound according to claim 18, wherein R is selected from: wherein:
R1 and R3 are each independently hydrogen, -CH3 or -CD3; preferably 1 is -CH3or -CD3; preferably R3 is -CD3; and
Het’ and Y are each independently selected from or
20. A compound according to claim 18 or 19, wherein the compound is selected from the group consisting of:
21. A compound according to any preceding claim, wherein the pharmaceutically acceptable salt and derivative is selected from the group consisting of: hydrochlorides, chlorides, bromides, iodides, potassium salts, sodium salts, acetates, trifluoroacetate, sulfates, sulfonates, oxalates, maleates, malonates, nitrates, tartrates, gluconates, succinates, mesylates, citrates, phosphates or diphosphates, aluminates, enantiomers, solvates, adducts, polymorphs, hydrates, tautomers, isomers, prodrugs, isotopically or radio- labelled compounds, and mixtures thereof; preferably the pharmaceutically acceptable salt and derivative is trifluoroacetates.
22. A pharmaceutical composition comprising (a) a compound according to any of claims 1 to 21 ; and (b) one or more pharmaceutically acceptable excipients; preferably the pharmaceutical composition is in the form of a tablet or a capsule.
23. A compound according to claims 1 to 21 or a pharmaceutical composition according to claim 22 for use as a medicament.
24. A method of treating or preventing a disease or disorder mediated by orexin receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound of any one of claims 1 to 21 or a pharmaceutical composition according to claim 22.
25. The method according to claim 24, wherein the disease or disorder is selected from the group consisting of: an eating disorder, obesity, binge eating disorder (BED), schizophrenia (negative symptoms and CIAS), addiction to psychomotor stimulants such as cocaine, opiates, nicotine and alcohol, opioid use disorder, drug abuse or addiction, opioid dependence, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, behavior disorder and mood disorder depression.
26. Use of a compound according to any of claims 1 to 21 or a pharmaceutical composition according to claim 22, in the preparation of a medicament for the treatment of diseases or disorders regulated by orexin receptor activity, and the use of such compounds for treatment or prevention of such diseases and disorders.
27. A method of modulating the activity of an orexin receptor 0X1 , 0X2, or both, comprising contacting a cell comprising the orexin receptor with an effective amount of at least one compound according to any one of claims 1 to 21 , or a pharmaceutical composition according to claim 22.
28. A method according to claim 27 wherein the step of contacting the cell is in vivo, in vitro or ex vivo.
29. A method for preparing a compound of Formula I according to claim 1 , wherein R and Het are each independently as defined in any preceding claim 1 to 20, said method comprising the steps of:
(a) 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) reacting the first intemediate compound with an acid to form a second intermediate compound; and
(c) reacting the second intemediate compound with a carboxylic acid having a general formula R-COOH to obtain a compound of Formula I.
30. The method according to claim 29 wherein tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6- dimethylmorpholine-4-carboxylate is a deuterated compound, 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 method according to any preceding claim 29 or 301 wherein the compound of
Formula I is a deuterated compound having the following structures:
wherein R and Het are each independently as defined in any preceding claim 1 to 20; and R6 and R7 are each independently H or Deuterium; said method comprising the steps of:
(a) 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) reacting the first intemediate compound with an acid to form a second intermediate compound; and
(c) reacting the second intemediate compound with a carboxylic acid having a general formula R-COOH to obtain a deuterated compound of Formula I.
32. The method according to claim 29, 30 or 31 wherein the halo-substituted heteroaromatic compound is selected from the group consisting of: halo-substituted pyridine, halo-substituted pyridazine, halo-substituted pyrazine, halo-substituted pyrimidine, halo- substituted triazole, halo-substituted tetrazole, halo-substituted pyrazole, halo-substituted furan, halo-substituted thiophene, halo-substituted pyrrole, halo-substituted imidazole, halo- substituted isoxazole, halo-substituted oxazole, halo-substituted isothiazole, halo- substituted thiazole and any derivatives thereof, wherein said halo-substituted heteroaromatic group may be further substituted; wherein the further substituents of the halo- substituted heteroaromatic group, if present, are independently selected from the group consisting of: unsubstituted (C1-C4)-straight chain alkyl, unsubstituted (C1-C4)-branched alkyl, substituted (C1-C4)-straight chain alkyl, substituted (C1-C4)-branched alkyl, substituted or unsubstituted (C3-C8)-cycloalkyl, a cyano group, substituted or un substituted (C1-C4)- alkoxy and halogen.
33. The method according to claim 31 wherein the further substituent of the heteroaromatic group is selected from the group consisting of: (C1-C4)-alkyl, (C1-C4)-fluoroalkyl, (C3-C8)- cycloalkyl, a cyano group, (C1-C4)-alkoxy and halogen; preferably the further substituents of the heteroaromatic group is selected from the group consisting of: Cl, F, -CHF2, -CF3, -CH3, - C2H5, methoxy, nitrile and cyclopropyl.
34. The method according to any preceding claim 29 to 33 wherein the halo-substituted heteroaromatic compound is selected from the group consisting of: a fluoro-substituted heteroaromatic compound, chloro-substituted heteroaromatic compound, bromo-substituted heteroaromatic compound and iodo-substituted heteroaromatic compound.
35. The method according to any preceding claim 29 to 34 wherein the halo-substituted heteroaromatic compound is selected from the group consisting of: 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, 3-methyl-5- (trifluoromethyl)pyrazin-2-ol (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, and 2,4-dichloro-5-(trifluoromethyl)pyrimidine.
36. The method according to any preceding claim 29 to 35 wherein the base is potassium carbonate or DI PEA.
37. The method according to any preceding claim 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, preferably the solvent is DMF or DMSO.
38. The method according to any preceding claim 29 to 37 wherein the method comprises at least one of the following features:
(i) wherein step (a) is carried out at a temperature in the range of about 50°C to about 189°C, preferably at a temperature about 80°C; (ii) wherein step (b) is carried out at a temperature in the range of about 12°C to about 40°C, preferably at about 20°C.
39. The method according to any preceding claim 29 to 38 wherein the method comprises at least one of the following features:
(i) wherein step (a) is carried out for a duration of about 6 to about 18 hours, preferably for a duration of about 12 hours;
(ii) wherein step (b) is carried out for a duration of about 30 mins to about 5 hours, preferably for a duration of about 2 hours.
40. The method according to any preceding claim 29 to 39 wherein the acid is selected from the group consisting of: aqueous phosphoric acid, hydrochloric acid, trifluoroacetic acid and mixture thereof; preferably the acid is hydrochloric acid.
41 . The method according to any preceding claim 29 to 40 wherein step (b) is carried out in the presence of a non-polar solvent selected from the group consisting of: diethyl ether, benzene, toluene, chloroform, 1 ,4-dioxane or mixtures thereof, preferably the non-polar solvent is 1,4-dioxane.
42. The method according to any preceding claim 29 to 41 wherein R in R-COOH group is selected from the group consisting of: a five or a six membered aromatic or heteroaromatic group, wherein the aromatic group or heteroaromatic group is either unsubstituted or is substituted with one or more substituents; preferably, R comprises a five membered heteroaromatic group which is an unsubstituted pyrazole, oxazole, thiazole, imidazole, a substituted pyrazole, oxazole, thiazole, imidazole or a derivative thereof; or a six membered heteroaromatic group which is an unsubstituted pyridine, an unsubstituted pyrimidine, an unsubstituted pyridazine, an unsubstituted pyrazine, a substituted pyridine, a substituted pyrimidine, a substituted pyridazine, a substituted pyrazine or any derivatives thereof; or a six membered aromatic group which is unsubstituted aryl, or substituted aryl, or a derivative thereof.
43. The method according to any preceding claim 29 to 42 wherein the carboxylic acid R- COOH comprises 4-(4-chlorophenyl)-1-methyl-pyrazole-3-carboxylic acid (CAS 1534651-22- 3), 5-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (CAS 956317-36-5), 3-fluoro-2-(pyrimidin-2- yl)benzoic acid (CAS 1293285-04-7), 4-(5-chloropyridin-2-yl)-1-methyl-1H-pyrazole-3- carboxylic acid (CAS 2125741-28-6), 4-(5-fluoropyrimidin-2-yl)-1 ,5-dimethyl-1 H-pyrazole-3- carboxylic acid (CAS 2125741-56-0), 5-fluoro-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (CAS 1186050-64-5), 5-fluoro-2-(pyrimidin-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-fluoropyrimidin-2-yl)-1-methyl-1H-pyrazole-3- carboxylic acid (CAS 2044704-99-4), 4-(4-fluorophenyl)-1-methyl-1 H-pyrazole-3-carboxylic acid (CAS 127919-87-3), 4-(4-cyanophenyl)-1-methyl-1 H-pyrazole-3-carboxylic acid, 4-(5- methoxypyridin-2-yl)-1-methyl-1 H-pyrazole-3-carboxylic acid (CAS 2024759-24-6), 5-(5- fluoropyrimidin-2-yl)- 1 -methyl- 1 H-imidazole-4-carboxylic acid, 5-(5-methoxypyridin-2-yl)-1- methyl-1 H-imidazole-4-carboxylic acid, 4-(5-fluoropyridin-2-yl)-1 ,5-dimethyl-1 H-pyrazole-3- carboxylic acid, 4-(5-fluoropyrimidin-2-yl)-1-methyl-1 H-pyrazole-3-carboxylic acid, 4-(5- methoxypyridin-2-yl)-1 ,5-dimethyl-1 H-pyrazole-3-carboxylic acid, 6-methyl-3-(pyrimidin-2- yl)picolinic acid (CAS 1228188-18-8); 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (CAS 1228188-37-1); 5-fluoro-3-(pyrimidin-2-yl)picolinic acid (CAS 1935682-37-3); 5-fluoro-2-(2H- 1 ,2,3-triazol-2-yl)nicotinic acid (CAS 2138851-77-9); 5-fluoro-2-(1 H-pyrazol-1-yl)benzoic acid (CAS 1152964-04-9); 3-(pyrimidin-2-yl)picolinic acid (CAS 1228431-21-7); 3-(2H-1 ,2,3-triazol- 2-yl)picolinic acid (CAS 1252907-86-0); 3-(5-fluoropyrimidin-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-(pyrazin-2-yl)picolinic acid (CAS 1228431-07-9), 6-methyl-3-(5-methylpyrimidin-2-yl)picolinic acid (CAS 1228431-09-1),
6-methyl-3-(4-methylpyrimidin-2-yl)picolinic acid (CAS 1228431-12-6), 3-(5-fluoropyrimidin-2- yl)-5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazole-2-carboxylic acid, 3-(5-fluoropyridin-2-yl)-1 ,5- dimethyl-1 H-pyrazole-4-carboxylic acid, 5-fluoro-3-(2H-1 ,2,3-triazol-2-yl)picolinic acid, 5,6- dimethyl-3-(pyrimidin-2-yl)picolinic acid,4,6-dimethyl-3-(pyrimidin-2-yl)picolinic acid, 6- methyl-3-(pyrimidin-2-yl)pyrazine-2-carboxylic acid, 4-(5-fluoropyridin-2-yl)-5-methyl-1- (methyl-d3)-1 H-pyrazole-3-carboxylic acid, 4-(5-fluoropyrimidin-2-yl)-5-methyl-1-(methyl-d3)- 1 H-pyrazole-3-carboxylic acid, 6-(methyl-d3)-3-( pyrimidin-2-yl)picolinic acid, 6-(methyl-d3)-3- (2H-1 ,2,3-triazol-2-yl)picolinic acid, or 4-(5-fluoropyrimidin-2-yl)-1-methyl-5-(methyl-d3)-1H- pyrazole-3-carboxylic acid.
44. The method according to any preceding claim 29 to 43, wherein the method comprises at least one of the following features: wherein step (c) is carried out in the presence of a coupling reagent, preferably the coupling reagent is HATU or T4P; wherein step (c) is carried out in the presence of a base, preferably the base is DI PEA; wherein step (c) is carried out in the presence of a polar aprotic solvent selected from the group consisting of THF, dichloromethane, ethyl acetate, DMF, DMSO and combinations thereof, preferably polar aprotic solvent is dichloromethane. wherein 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 wherein step (c) is carried out for a duration of about 1 hour to about 6 hours, preferably for a duration of about 2.5 hours.
45. The method according to any preceding claim 29, 32 to 44 wherein the first intermediate compound is: tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate; tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylate; tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylate; tert-Butyl (2S,3R,6R)-3-(((5-chloropyridin-2-yl)amino)methyl)-2,6-dimethylmorpholine- 4-carboxylate; tert-Butyl (2S,3R,6R)-3-(((5-chloropyrimidin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate; tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((4-(trifluoromethyl)pynmidin-2- yl)amino)methyl)morpholine-4-carboxylate; tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((6-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate; tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((4-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylate; tert-Butyl (2S,3R,6R)-3-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate; tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)morpholine-4-carboxylate; tert-butyl (2S,3R,6R)-3-(((3,5-bis(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate; tert-butyl (2S,3R,6R)-3-(((3-methoxy-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-
2,6-dimethylmorpholine-4-carboxylate; tert-Butyl (2S,3R,6R)-3-(((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate; tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyrazin-2- yl)amino)methyl)morpholine-4-carboxylate; tert-Butyl (2S,3R,6R)-3-(((3-cyano-5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate; tert-Butyl (2S,3R,6R)-3-(((3-(difluoromethyl)-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate; tert-Butyl (2S,3R,6R)-3-(((5-chloro-3-fluoropyridin-2-yl)amino)methyl)-2,6- dimethylmorpholine-4-carboxylate; tert-Butyl (2S,3R,6R)-3-(((3-fluoro-4-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl)-2,6-dimethylmorpholine-4-carboxylate; or tert-butyl (2S,3R,6R)-2,6-dimethyl-3-(((4-methyl-5-(trifluoromethyl)pyrimidin-2- yl)amino)methyl)morpholine-4-carboxylate.
46. The method according to any preceding claim 30 to 44, wherein the first intermediate compound is: tert-butyl(2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl) morpholine-4-carboxylate-5,5-d2 ; tert-Butyl (2S,3R,6R)-3-(((5-chloropyridin-2-yl)amino)methyl)-2,6-dimethylmorpholine- 4-carboxylate-5,5-d2 ; tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl- d2) morpholine-4-carboxylate ; tert-Butyl (2S,3 ,6 )-3-(((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)methyl-d2)-
2,6-dimethylmorpholine-4-carboxylate ; or tert-Butyl (2S,3R,6R)-2,6-dimethyl-3-(((3-methyl-5-(trifluoromethyl)pyridin-2- yl)amino)methyl-d2)morpholine-4-carboxylate .
47. The method according to any preceding claim 29, 32 to 45 wherein the second intermediate compound is:
/V-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrazin-2- amine hydrochloride;
/V-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyrimidin-2- amine hydrochloride; /V-(((2S.3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine hydrochloride;
5-Chloro-/V-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)pyridin-2-amine hydrochloride;
5-Chloro-/V-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)pyrimidin-2-amine hydrochloride;
N-(((2S,3R,6R) -2,6-Dimethylmorpholin-3-yl)methyl)-4-(trifluoromethyl)pyrimidin-2- amine hydrochloride ;
N-(((2S,3R,6/?)-2,6-dimethylmorpholin-3-yl)methyl)-6-(trifluoromethyl)pyrazin-2- amine hydrochloride; or
N-(((2S,3R,6/?)-2,6-dimethylrnorpholin-3-yl)methyl)-4-(trifluoromethyl)pyridin-2-amine hydrochloride;
N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-3-fluoro-5-
(trifluoromethyl)pyridin-2-amine hydrochloride;
N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-methyl-5-
(trifluoromethyl)pyridin-2-amine;
N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-3,5-bis(trifluoromethyl)pyridin-2- amine hydrochloride;
N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-3-methoxy-5-
(trifluoromethyl)pyridin-2-amine;
3-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-5-
(trifluoromethyl)pyridin-2-amine;
N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-methyl-5-
(trifluoromethyl)pyrazin-2-amine;
2-((((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)amino)-5- (trifluoromethyl)nicotinonitrile hydrochloride;
3-(Difluoromethyl)-N-(((2S,3R,6R)-2,6-dirnethylmorpholin-3-yl)methyl)-5-
(trifluoromethyl)pyridin-2-amine hydrochloride;
5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl)methyl)-3-fluoropyridin-2-amine hydrochloride;
N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-3-fluoro-4-methyl-5-
(trifluoromethyl)pyridin-2-amine; or
N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl)-4-methyl-5-
(trifluoromethyl)pyrimidin-2-amine.
48. The method according to any preceding claim 30 to 44 or 46 wherein the second intermediate compound is:
N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl-5,5-d2)methyl)-5-(trifluoromethyl)pyridin- 2-amine ; 5-Chloro-N-(((2S,3R,6R)-2,6-dimethylmorpholin-3-yl-5,5-d2)methyl)pyridin-2-amine hydrochloride ;
N-(((2S.3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl-d2)-5-(trifluoromethyl)pyridin-2- amine hydrochloride ;
N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl-d2)-3-fluoro-5- (trifluoromethyl)pyridin-2-amine hydrochloride ; or N-(((2S,3R,6R)-2,6-Dimethylmorpholin-3-yl)methyl-d2)-3-methyl-5-(trifluoromethyl) pyridin-2-amine hydrochloride .
49. The method according to claim 29, wherein tert-Butyl (2S,3R,6R)-3-(aminomethyl)-2,6- dimethylmorpholine-4-carboxylate or (2S,3R, 6S)-3-(hydroxymethyl)-2,6-dimethyl morpholine- 4-carboxylate (intermediate j) is prepared by: reducing N-benzyl-L-allothreonine a by reacting with a reducing agent to form (2R,3S)-2-(Benzylamino)butane-1 ,3-diol (intermediate b); reacting intermediate b with tert-butyl(chloro)diphenylsilane to form (2S,3R)-3- (Benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (intermediate c); reacting intermediate c with (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); subjecting intermediate d to an intramolecular amide coupling reaction in the presence of a coupling reagent to form (2R,5R,6S)-4-Benzyl-5-(((tert- butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholin-3-one or (2S,5R,6S)-4- Benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholin-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 source of fluorine to form ((2S,3R,6R)-4-Benzyl-2,6- dimethylmorpholin-3-yl)methanol (intermediate g) or ((2S, 3R, 6S)-4-Benzy I-2, 6- dimethylmorpholin-3-yl)methanol (intermediate g); reacting intermediate g with hydrogen, palladium over 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-dioxoisoindolin-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate or tert- Butyl (2S,3R,6S)-3-((1 ,3-dioxoisoindolin-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).
50. The method according to claim 30 or 31 , wherein tert-butyl (2S,3R,6R)-3- (aminomethyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 is prepared by: reducing (2S, 3S)-2-amino-N,N-dibenzyl-3-hydroxybutanamide by reacting with a reducing agent to form (2S, 3R)-3-amino-4-(dibenzylamino)butan-2-ol (d-b); reacting intermediate d-b with 2-bromopropanoic acid to form intermediate d-c in the presence of a Lewis base to form (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-dimethylmorpholin-3-one (intermediate d-d); reducing intermediate d-d with a deuterated agent, and reacting 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 reacting intermediate d-f with hydrogen and palladium hydroxide over carbon and is subsequently protected to form intermediate d-g.
51 . The method according to claim 43, wherein tert-butyl (2S,3R,6R)-3-(aminomethyl-d2)- 2,6-dimethylmorpholine-4-carboxylate (intermediate d-r) is prepared by: reacting N-benzyl-L-allothreonine (a) with 2-bromopropanoic acid or 2- iodopropanoic, followed by an intramolecular amide coupling reaction with a coupling reaction to form (2S,3S, 6R)-4-benzyl-2,6-dimethyl-5-oxomorpholine-3- carboxylic acid (intermediate d-m); reducing intermediate d-m with a deuterated agent to form (2R,5R, 6S)-4-benzyl- 5-(hydroxymethyl-d2)-2,6-dimethylmorpholin-3-one (intermediate d-n); reducing intermediate d-n with a reducing agent to form ((2S,3R,6R)-4-benzyl-2,6- dimethylmorpholin-3-yl)methan-d2-ol (intermediate d-o); reacting intermediate d-o with hydrogen and palladium over carbon and is subsequently protected 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-dioxoisoindolin-2-yl)methyl)-2,6-dimethylmorpholine-4-carboxylate-5,5-d2 (intermediate d-q); reacting intermediate d-q with hydrazine or hydrazine hydrate to form intermediate d-r;
52. A compound which is:
(2R,3S)-2-(Benzylamino)butane-1 ,3-diol (intermediate b);
(2S,3R)-3-(Benzylamino)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (intermediate c);
(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-dimethylmorpholin-3-one or (2S,5R,6S)-4-Benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,6-dimethylmorpholin-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-dimethylmorpholin-3-yl)methanol or ((2S,3R,6S)-4-Benzyl-2,6- dimethylmorpholin-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-dioxoisoindolin-2-yl)methyl)-2,6-dimethylmorpholine-4- carboxylate or tert-Butyl(2S,3R,6S)-3-((1 ,3-dioxoisoindolin-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-dimethylmorpholin-3-one (intermediate d-n);
((2S,3R, 6R)-4-benzyl-2,6-dimethylmorpholin-3-yl)methan-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-dioxoisoindolin-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).
EP24754433.1A 2023-07-21 2024-07-22 Morpholine orexin receptor antagonists Pending EP4688155A1 (en)

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GBGB2311281.6A GB202311281D0 (en) 2023-07-21 2023-07-21 Orexin receptor antagonists
PCT/PT2024/050029 WO2025023852A1 (en) 2023-07-21 2024-07-22 Morpholine orexin receptor antagonists

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WO2002044172A1 (en) * 2000-11-28 2002-06-06 Smithkline Beecham P.L.C. Morpholine derivatives as antagonists of orexin receptors
WO2002090355A1 (en) 2001-05-05 2002-11-14 Smithkline Beecham P.L.C. N-aroyl cyclic amines
CZ20033437A3 (en) * 2001-06-28 2004-09-15 Smithkline Beecham P.L.C. N-aroyl cyclic amine derivatives functioning as orexin receptor antagonists
DE60309481T2 (en) 2002-09-18 2007-06-21 Glaxo Group Ltd., Greenford CYCLIC N-AROYLAMINES AS OREXINE RECEPTOR ANTAGONISTS
ES2572703T3 (en) 2011-11-08 2016-06-01 Actelion Pharmaceuticals Ltd. 2- (1,2,3-Triazol-2-yl) benzamide and 3- (1,2,3-triazol-2-yl) picolinamide derivatives as orexin receptor antagonists
US9834526B2 (en) * 2013-12-19 2017-12-05 Merck Sharp & Dohme Corp. HIV protease inhibitors
GB201601703D0 (en) 2016-01-29 2016-03-16 C4X Discovery Ltd Therapeutic compounds
AU2017217931B2 (en) 2016-02-12 2020-10-22 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators
AU2020286381C1 (en) 2019-06-04 2025-07-10 Hager Biosciences, Llc Imidazolo derivatives, compositions and methods as orexin antagonists
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