Isoxazolidine as a RIPK1 inhibitor and its use

Abstract

This disclosure relates to compounds of formula (I): [Formula 1] JPEG2026516096000052.jpg35170 (wherein X1, X2, and X3 are independently selected from CR6 or N; R1 represents a 5-membered or 6-membered heteroaryl group, where the heteroaryl is optionally substituted; R2 is a 4, 5, or 6-membered heteroaryl group in which 1 to 3 ring atoms are independently selected from nitrogen, oxygen, or sulfur; a 5 or 6-membered heterocycle in which 1 to 3 ring atoms are independently selected from nitrogen and oxygen; or a spiro(C7-C 10 ) represents a heterobicyclic compound; R3 represents H- or a (C1-C4) alkyl group; R4 represents H- or a (C1-C4) alkyl group; or R3 and R4, together with the carbon atoms to which they are bonded, form a cyclopropyl ring or a cyclobutyl ring; R5 and R6 independently represent H, a (C1-C6) alkyl group or a halogen); and / or relating to pharmaceutically acceptable salts, solvates or stereoisomers thereof. The disclosure further relates to pharmaceutical compositions containing the novel compounds.

Description

[Technical Field]

[0001] This disclosure relates to novel isoxazolidine derivatives useful as pharmaceuticals. The novel compounds are particularly useful as kinase inhibitors, and even more so as RIPK1 inhibitors. They are efficient in treating and / or preventing acute and chronic neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS).

[0002] This disclosure further relates to a pharmaceutical composition containing the novel compound. [Background technology]

[0003] Inflammation can be a protective mechanism in response to harmful stimuli such as pathogen invasion and tissue damage, but chronic inflammation is a crucial underlying factor in many human diseases, including neurodegeneration, rheumatoid arthritis, autoimmune and inflammatory diseases, and cancer. Similarly, activation of cell death pathways such as necrosis and apoptosis, which are useful in eliminating infected or damaged cells, is also a crucial underlying mechanism in human diseases, including acute and chronic neurodegenerative diseases. Receptor-interacting protein kinase 1 (UniProtKB Q13546) is a key regulator of inflammation, apoptosis, and necroptosis. Receptor-interacting protein kinase 1 plays a vital role in regulating the inflammatory response mediated by the nuclear factor-κ light chain enhancer (NF-κB) of activated B cells. More recent studies have shown that its kinase activity controls necroptosis, a form of necrotizing cell death that was traditionally considered passive and unregulated, and that it is characterized by a unique morphology. Furthermore, receptor-interacting protein kinase 1 is part of a pro-apoptotic complex that exhibits its activity in regulating apoptosis.

[0004] Receptor-interacting protein kinase 1 undergoes complex and intricate regulatory mechanisms, including ubiquitination, deubiquitination, and phosphorylation. These regulatory events collectively determine whether cells survive and activate an inflammatory response, or die by apoptosis or necrotosis. Dysregulation of receptor-interacting protein kinase 1 signaling can lead to excessive inflammation or cell death, while studies have shown that inhibition of receptor-interacting protein kinase 1 may be an effective treatment for diseases involving inflammation or cell death.

[0005] RIPK1 inhibition has been identified as a promising mechanism for addressing a variety of diseases, including rheumatoid arthritis (RA), psoriasis, multiple sclerosis, Alzheimer's disease, and inflammatory bowel diseases such as Crohn's disease, amyotrophic lateral sclerosis (ALS), or ulcerative colitis (UC). While access to the central nervous system (CNS) is necessary to treat some of these diseases, such as multiple sclerosis (MS) and Alzheimer's disease, access to the CNS is not inherently necessary for other diseases such as rheumatoid arthritis, psoriasis, Crohn's disease, or inflammatory bowel diseases (IBD) such as UC.

[0006] Different RIPK1 inhibitors have already been described in patent applications such as International Publication No. 2014 / 125444, International Publication No. 2016 / 185423, or International Publication No. 2016 / 027253 (GSK).

[0007] The RIPK1 inhibitor GSK2982772 (an oxazepinone derivative disclosed in International Publication No. 2014 / 125444) was evaluated in a Phase II clinical trial for rheumatoid arthritis (RA), psoriasis, and ulcerative colitis (UC).

[0008] Dihydropyrazole compounds having phenyl substituents and pyrimidine-piperidine elements on the dihydropyrazole are disclosed by GSK in International Publication No. 2018 / 092089 as RIPK1 inhibitors. Other dihydropyrazole compounds as RIPK1 inhibitors are disclosed in International Publication No. 2020224656.

[0009] Isoxazolidine compounds having a phenyl substituent and a pyrimidine-piperidine element on an isoxazolidine are disclosed by GSK in International Publication No. 2019 / 130230 as RIPK1 inhibitors. Similar isoxazolidine compounds are disclosed in Specification KR2020-087922 (Voronoi) and International Publication No. 2020 / 043173.

[0010] Isoxazolidine compounds with reduced ability to cross the blood-brain barrier as RIPK1 inhibitors are disclosed in International Publication No. 2021 / 245070.

[0011] Compounds containing a cycloalkyl element as RIPK1 inhibitors are disclosed in International Publication No. 2022194259. [Overview of the project] [Means for solving the problem]

[0012] According to one of its purposes, this disclosure relates to compounds of formula (I): [ka] (In the formula, X1, X2, and X3 are selected independently from CR6 or N; R1 represents a five-membered or six-membered heteroaryl group, where the heteroaryl is optionally substituted with one or two groups independently selected from halogens, (C1-C6) alkyl groups, and -CN groups; R2 is - A 4, 5, or 6-membered heteroaryl (where 1 to 3 ring atoms are independently selected from nitrogen, oxygen, or sulfur, and the heteroaryl is optionally substituted with one or two R7 atoms); - A 5- or 6-membered heterocycle in which 1 to 3 ring atoms are independently selected from nitrogen and oxygen (the heterocycle is optionally substituted with 1, 2, or 3 R8 atoms); or - Spiro(C7-C) is a ring atom in which one or two ring atoms are selected from nitrogen or oxygen. 10 ) Heterobicyclic compounds (the heterocycle is optionally substituted by one or two R9 groups) It represents; R3 represents an H- or (C1-C4) alkyl group; R4 represents an H- or (C1-C4) alkyl group; Alternatively, R3 and R4, together with the carbon atoms to which they are bonded, form a cyclopropyl ring or a cyclobutyl ring; R5 and R6 independently represent H, (C1-C6) alkyl groups, or halogens; Each R7 independently represents a (C1-C6) alkyl group, a halogen, -NH2, or -OH; Each R9 independently represents a (C1-C6) alkyl group, halogen, or oxo; Each R8 independently represents OH, oxo, halogen, (C1-C6)alkyl, O-(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2, or (C1-C6)fluoroalkyl. Or relating to pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

[0013] In a related embodiment, pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient are provided herein.

[0014] In another embodiment, a process for producing compounds of formula (I) and intermediates thereof is provided herein.

[0015] In another embodiment, compounds of formula (I) or pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided herein for use as pharmaceuticals.

[0016] In another embodiment, compounds of formula (I) or pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided herein for use in the treatment and / or prevention of diseases, disorders, or conditions at least partially mediated by receptor-interacting protein kinase 1.

[0017] In another embodiment, compounds of formula (I) or pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided herein for use in the treatment and / or prevention of a disease selected from Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS).

[0018] In another embodiment, methods for inhibiting receptor-interacting protein kinase 1 are provided herein. Further provided are methods for treating a disease, disorder or condition at least partially mediated by receptor-interacting protein kinase 1, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition of formula (I) described herein to a subject in need thereof. The disclosure also provides the use of a compound or composition of formula (I) in the manufacture of a pharmaceutical for treating a disease, disorder or condition at least partially mediated by receptor-interacting protein kinase 1.

[0019] Furthermore, the compounds of formula (I) in this disclosure have been observed to exhibit very interesting development potential. In particular, the solubility of the compounds of formula (I) according to this disclosure has been evaluated according to pharmacopoeia standards and is considered convenient. [Modes for carrying out the invention]

[0020] definition In this specification, the term "alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group having the number of atoms indicated. More specifically, (C x -C y) An alkyl group (where x and y are integers and x < y) is a straight-chain or branched-chain saturated aliphatic group containing x to y carbon atoms. For example, (C1-C4) alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl groups.

[0021] "Cycloalkyl" refers to a saturated or partially unsaturated, optionally substituted cyclic hydrocarbon group having the indicated number of atoms. More specifically, a (C3-C z )-cycloalkyl group (z is an integer of 4 or more) contains 3 to z carbon atoms. For example, a (C3-C8)-cycloalkyl group contains 3 to 8 carbon atoms and is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0022] The term "halogen" refers to a chlorine, fluorine, bromine, or iodine atom, and particularly refers to a chlorine or fluorine atom.

[0023] "Fluoroalkyl" refers to an alkyl group as defined above substituted with at least one fluorine atom. In other words, at least one hydrogen atom of the alkyl group is replaced by a fluorine atom. Examples that may be mentioned include CH₂F, CHF₂, CH₂CHF₂, -CH₂CH₂F, etc. When all hydrogen atoms belonging to the alkyl group are replaced by fluorine atoms, the fluoroalkyl group can be called a perfluoroalkyl group. Examples that may be mentioned include a trifluoromethyl group or a trifluoroethyl group, etc.

[0024] The term "heterocycloalkyl" refers to saturated or partially unsaturated 4- to 7-membered cycloalkyl groups, particularly 4- to 6-membered cycloalkyl groups, that contain one or two heteroatoms, independently selected from oxygen, nitrogen, and sulfur, and especially oxygen or nitrogen. Examples include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, azilidinyl, oxanyl, oxetanyl, tetrahydropyranyl, morpholinyl, tetrahydrofuranyl, oxepanyl, diazepanyl, dioxanyl, dihydropyranyl, tetrahydropyranyl, and tetrahydrothiopyranyl. Heterocycloalkyl groups are favorably tetrahydrofuranyl or tetrahydropyranyl.

[0025] The term "heteroaryl" refers to a cyclic 5-6 membered aromatic group containing 2-5 carbon atoms and 1-3 heteroatoms such as nitrogen, oxygen, or sulfur. Such nitrogen atoms may be substituted with oxygen atoms to form an -NO bond. Such -NO bonds may be in the form of N-oxide (-N+-O-). The heteroaryl group is monocyclic in the configuration of this disclosure. Examples of heteroaryl groups include, but are not limited to, thiophenyl, furanyl, thiadiazolyl, thiazolyl, imidazolyl, pyridadinyl, triazinyl, pyrazinyl, oxadiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and pyridonyl groups. The heteroaryl groups are advantageously pyridinyl, pyrazinyl, pyrimidinyl, and thiazolyl.

[0026] The term "heterocycloalkyl" refers to saturated or partially unsaturated, 4-6 membered cycloalkyl groups containing one or two heteroatoms independently selected from oxygen, nitrogen, and sulfur, particularly oxygen or nitrogen. Examples include, but are not limited to, morpholinyl, piperadinyl, piperidinyl, pyrrolidinyl, oxazolidinyl, isoxazolidinyl, azilidinyl, oxanyl, oxetanyl, tetrahydropyranyl, morpholinyl, tetrahydrofuranyl, oxepanyl, diazepanyl, dioxanyl, dihydropyranyl, tetrahydropyranyl, and tetrahydrothiopyranyl. Heterocycloalkyl groups are advantageously pyrrolidinyl, oxazolidinyl, etc.

[0027] "Spiro (C7-C 10 The term "heterobicyclic ring" refers to two rings linked by a defining single common atom, each containing 7 to 10 carbon atoms, where 1 to 3 carbon atoms are replaced by heteroatoms such as oxygen, nitrogen, or sulfur, more specifically nitrogen and oxygen atoms. Examples include, but are not limited to, 7-azaspiro[3.5]nonanyl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, and 2-oxa-7-azaspiro[3.5]nonan-7-yl, 2-oxa-6-azaspiro[3.3]heptaneyl; 1-oxa-6-azaspiro[3.3]heptaneyl; 6,6-difluoro-2-azaspiro[3.3]heptanyl; 1-oxa-6-azaspiro[3.3]heptaneyl; 7,7-difluoro-2-azaspiro[3.3]heptanyl ;6,6-difluoro-2-azaspiro[3.3]heptane-3-onyl;7,7-difluoro-2-azaspiro[3.3]heptane-3-onyl;2-oxa-6-azaspiro[3.3]heptane-7-onyl;5-oxa-2-azaspiro[3.4]octanyl, 5-oxa-2-azaspiro[3.4]octane-3-onyl;6-oxa-2-azaspiro[3.4]octanyl, 5-azaspiro[2.5]octane-4-onyl and 5-azaspiro[2.4]heptane-4-onyl group. Spiro(C7-C 10The complex bicyclic ring is advantageously 7-oxa-2-azaspiro[3.5]nonan-2-yl or 2-oxa-7-azaspiro[3.5]nonan-7-yl.

[0028] This specification may also use multiple compound terms to describe groups containing two or more functionalities. Such terms will be understood by those skilled in the art. For example, heterocyclyl C1-C4 alkyl includes C1-C4 alkyls substituted with heterocyclyl.

[0029] The term "voluntarily substituted" refers to either the substituted group, structure, or molecule, or the unsubstituted one.

[0030] When optional substituents are selected from "one or more" groups, it should be understood that this definition includes all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups. If there are multiple substituents, it should be understood that the selected substituents may be the same or different.

[0031] When a numerical range is given, the range is understood to include the endpoints.

[0032] The phrase "compounds disclosed herein" means, both generally and specifically, the compounds disclosed herein.

[0033] The term "pharmaceutically acceptable" is used herein to mean a compound, material, composition and / or dosage form suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, in proportion to a reasonable benefit / risk ratio, within the bounds of sound medical judgment.

[0034] In this regard, the term “pharmaceutically acceptable salt” refers to relatively non-toxic inorganic and organic acid addition salts of the compounds of the present disclosure. These salts can be prepared in situ during the manufacturing process of the administration excipient or dosage form, or by separately reacting the purified compounds of the present disclosure in free base form with a suitable organic or inorganic acid and then isolating the salts thus formed during subsequent purification.

[0035] As used herein, the term “pharmaceutically acceptable excipient” refers to a substance that helps administer an activator to a subject. “pharmaceutically acceptable” means that the excipient is compatible with the other components of the formulation and is not harmful to its recipient. Useful pharmaceutical excipients in this disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, flow enhancers, coatings, sweeteners, flavors, and colorants.

[0036] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulant, that is involved in transporting or carrying the compound of interest from one organ or part of the body to another organ or part of the body.

[0037] References to “treating” or “treatment” should be understood to include the prevention and mitigation of established symptoms of a condition. Therefore, “treating” or “treating” a condition, disorder, or pathology includes (1) preventing or delaying the onset of clinical symptoms of a condition, disorder, or pathology in a person who has or is susceptible to the condition, disorder, or pathology but has not yet experienced or shown any clinical or asymptomatic symptoms of the condition, disorder, or pathology; (2) inhibiting the condition, disorder, or pathology, i.e., stopping, reducing, or delaying the onset or recurrence of the disease (in the case of maintenance therapy) or at least one clinical or asymptomatic symptom thereof; or (3) reducing or attenuating the disease, i.e., causing the regression of at least one of the condition, disorder, or clinical or asymptomatic symptoms thereof.

[0038] "Prevention" or "prevention" means any treatment of a disease or condition that prevents the development of the clinical symptoms of the disease or condition. In some embodiments, the compound may be administered to subjects (including humans) who are at risk of developing the disease or condition or who have a family history of the disease or condition.

[0039] "Subject" refers to a human being who has been or will be the subject of treatment, observation, or experimentation. The methods described herein may be useful for human treatment.

[0040] The "therapeutic dose" refers to the amount of a compound sufficient to have such an effect on treating a disease when administered to a mammal. The "therapeutic dose" varies depending on the compound, the disease and its severity, as well as the age, weight, etc., of the mammal being treated, and this can be easily determined by those skilled in the art.

[0041] As used herein, chemical nomenclature, unless otherwise defined, has the meanings used in the Art of this invention.

[0042] compound In this specification, formula (I): [ka] (In the formula, X1, X2, and X3 are selected independently from CR6 or N; R1 represents a five-membered or six-membered heteroaryl group, where the heteroaryl is optionally substituted with one or two groups independently selected from halogens, (C1-C6) alkyl groups, and -CN groups; R2 is - A 5- or 6-membered heteroaryl (where 1 to 3 ring atoms are independently selected from nitrogen, oxygen, or sulfur, and the heteroaryl is optionally substituted by one or two R7 atoms); - A 5- or 6-membered heterocycle in which 1 to 3 ring atoms are independently selected from nitrogen and oxygen (the heterocycle is optionally substituted with 1 or 2 R8 atoms); or - Spiro(C7-C) is a ring atom in which one or two ring atoms are selected from nitrogen or oxygen. 10 ) Heterobicyclic compounds (the heterocycle is optionally substituted by one or two R9 groups) It represents; R3 represents an H- or (C1-C4) alkyl group; R4 represents an H- or (C1-C4) alkyl group; Alternatively, R3 and R4, together with the carbon atoms to which they are bonded, form a cyclopropyl ring or a cyclobutyl ring; R5 and R6 independently represent H, (C1-C6) alkyl groups, or halogens; Each of R7 and R9 independently represents a (C1-C6) alkyl group or halogen; Each R8 independently represents a compound of OH, oxo, halogen, (C1-C6)alkyl, O-(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2 or (C1-C6)fluoroalkyl; Alternatively, pharmaceutically acceptable salts, solvates, or stereoisomers thereof are disclosed.

[0043] In this specification, formula (I): [ka] (In the formula, X1, X2, and X3 are selected independently from CR6 or N; R1 represents a five-membered or six-membered heteroaryl group, where the heteroaryl is optionally substituted with one or two groups independently selected from halogens, (C1-C6) alkyl groups, and -CN groups; R2 is - A 4, 5, or 6-membered heteroaryl (where 1 to 3 ring atoms are independently selected from nitrogen, oxygen, or sulfur, and the heteroaryl is optionally substituted with one or two R7 atoms); - A 5- or 6-membered heterocycle in which 1 to 3 ring atoms are independently selected from nitrogen and oxygen (the heterocycle is optionally substituted with 1, 2, or 3 R8 atoms); or - Spiro(C7-C) is a ring atom in which one or two ring atoms are selected from nitrogen or oxygen. 10 ) Heterobicyclic compounds (the heterocycle is optionally substituted by one or two R9 groups) It represents; R3 represents an H- or (C1-C4) alkyl group; R4 represents an H- or (C1-C4) alkyl group; Alternatively, R3 and R4, together with the carbon atoms to which they are bonded, form a cyclopropyl ring or a cyclobutyl ring; R5 and R6 independently represent H, (C1-C6) alkyl groups, or halogens; Each R7 independently represents a (C1-C6) alkyl group, a halogen, -NH2, or -OH; Each R9 independently represents a (C1-C6) alkyl group, halogen, or oxo; Each R8 independently represents a compound of OH, oxo, halogen, (C1-C6)alkyl, O-(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N[(C1-C6)alkyl]2 or (C1-C6)fluoroalkyl; Alternatively, pharmaceutically acceptable salts, solvates, or stereoisomers thereof are disclosed.

[0044] One embodiment disclosed herein is represented by formula (I): (In the formula, X1, X2, and X3 are selected independently from CR6 or N; R1 represents a 5- or 6-membered heteroaryl group, wherein said heteroaryl is optionally substituted by one or two groups independently selected from halogen, (C1-C6) alkyl group, and -CN group; R2 is - a 5- or 6-membered heteroaryl in which 1 to 3 ring atoms are independently selected from nitrogen, oxygen or sulfur (said heteroaryl is optionally substituted by one or two R7s); - a 5- or 6-membered heterocycle in which 1 to 3 ring atoms are independently selected from nitrogen and oxygen (said heterocycle is optionally substituted by one, two or three R8s); or - a spiro(C7-C 10 ) bicyclic heterocyclic compound in which one or two ring atoms are selected from nitrogen or oxygen (the heterocycle is optionally substituted by one or two R9s) represents; R3 represents H- or (C1-C4) alkyl group; R4 represents H- or (C1-C4) alkyl group; Alternatively, R3 and R4 together with the carbon atom to which they are attached form a cyclopropyl ring or a cyclobutyl ring; R5 and R6 independently represent H, (C1-C6) alkyl group or halogen; Each R7 and R9 independently represents (C1-C6) alkyl group or halogen; Each R8 independently represents OH, oxo, halogen, (C1-C6) alkyl, O-(C1-C6) alkyl, -NH2, -NH(C1-C6) alkyl, -N[(C1-C6) alkyl]2 or (C1-C6) fluoroalkyl) compound; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0045] According to one embodiment of the compound of formula (I), X1, X2 and X3 are N; or X1 and X2 are N and X3 is CR6; or X2 and X3 are N, and X1 is CR6; or X1 and X3 are N, and X2 is CR6.

[0046] According to one embodiment of the compound of formula (I), X1, X2, and X3 are N.

[0047] According to another embodiment of the compound of formula (I), X1 and X2 are N, X3 is CR6, and R6 is H or fluorine.

[0048] According to another embodiment of the compound of formula (I), X2 and X3 are N, X1 is CR6, and R6 is H or fluorine.

[0049] According to another embodiment of the compound of formula (I), X1 and X3 are N, X2 is CR6, and R6 is H or fluorine.

[0050] According to one embodiment, R1 in formula (I) is a pyridinyl, pyrazinyl, pyrimidinyl, oxazolyl, or thiazolyl group (optionally substituted with one or two groups independently selected from halogens, (C1-C2) alkyl groups, and -CN groups) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0051] In another embodiment, R2 in formula (I) is an imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, or pyrimidinyl group (optionally substituted by one or two R7 groups, wherein R7 is independently selected from a CH3 group and a halogen, and in particular is a CH3 group); or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0052] According to one embodiment, R2 in formula (I) is piperidinyl, morpholinyl, pyrrolidinyl, oxazolidinyl group, azetidinyl, or oxetanyl (optionally substituted by 1, 2, or 3 R8 groups, wherein R8 is independently selected from OH, oxo, halogen, (C1-C2)alkyl group, O-(C1-C2)alkyl group, and CF3, and in particular optionally substituted by oxo), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0053] According to one embodiment, R2 in formula (I) is piperidinyl, morpholinyl, pyrrolidinyl, oxazolidinyl group, azetidinyl, or oxetanyl (optionally substituted by one or two R8 groups, wherein R8 is independently selected from OH, oxo, halogen, (C1-C2) alkyl group, and CF3, and in particular optionally substituted by oxo), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0054] According to one embodiment, R2 in formula (I) is a 5-azaspiro[2.5]octane-4-onyl group, a 5-azaspiro[2.4]heptane-4-onyl group, a 7-azaspiro[3.5]nonanyl, a 7-oxa-2-azaspiro[3.5]nonan-2yl and a 2-oxa-7-azaspiro[3.5]nonan-7yl, a 2-oxa-6-azaspiro[3.3]heptanyl; a 1-oxa-6-azaspiro[3.3]heptanyl; a 6,6-difluoro-2-azaspiro[3.3]heptanyl; a 1-oxa-6-azaspiro[3.3]heptanyl; a 7,7-difluoro-2-azaspiro Spiro[3.3]heptanyl; 6,6-difluoro-2-azaspiro[3.3]heptan-3-onyl; 7,7-difluoro-2-azaspiro[3.3]heptan-3-onyl; 2-oxa-6-azaspiro[3.3]heptan-7-onyl; 5-oxa-2-azaspiro[3.4]octanyl and 5-oxa-2-azaspiro[3.4]octanyl; or 6-oxa-2-azaspiro[3.4]octanyl, optionally substituted with one or two R9 groups; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0055] According to one embodiment, R2 in formula (I) is a 7-oxa-2-azaspiro[3.5]nonane-2-yl group, a 5-azaspiro[2.5]octane-4-on-yl group, a 5-azaspiro[2.4]heptane-4-on-yl group, or a 2-oxa-7-azaspiro[3.5]nonane-7-yl group, particularly a 5-azaspiro[2.5]octane-4-on-yl group or a 5-azaspiro[2.4]heptane-4-on-yl group, and is optionally substituted by one or two R9 selected from methyl or fluorine.

[0056] In another embodiment, R3 represents H or a (C1-C2) alkyl group, and R4 represents H or a (C1-C2) alkyl group; or R3 and R4 together form a cyclopropyl ring with the carbon atoms to which they are bonded.

[0057] According to another embodiment of the compound of formula (I), R3 is H and R4 is H.

[0058] According to another embodiment of the compound of formula (I), R3 is a methyl group and R4 is a methyl group.

[0059] According to another embodiment of the compound of formula (I), R3 and R4 together form a cyclopropyl ring with the carbon atoms to which they are bonded.

[0060] According to another embodiment of the compound of formula (I), R5 is H, methyl, or fluorine.

[0061] According to another embodiment of the compound of formula (I), R5 is H.

[0062] According to another embodiment of the compound of formula (I), R5 is fluorine.

[0063] According to another embodiment of the compound of formula (I), each R7 and R9 independently represents a methyl group, fluorine, or chlorine.

[0064] According to another embodiment of the compound of formula (I), each R8 independently represents OH, oxo, halogen, methyl group, O-CH3, -NH2, -NH-CH3, -N[-CH3]2, or CF3.

[0065] This specification further describes compounds of formula (I): [ka] (In the formula, X1 represents N; X2 and X3 are as described above; R1 represents a pyridinyl, pyrazinyl, oxazolyl, or thiazolyl group, which is optionally substituted with one or two groups independently selected from a fluorine atom and a methyl group; R2 is - A five-membered heteroaryl molecule in which two or three ring atoms are independently selected from nitrogen, oxygen, or sulfur (the heteroaryl molecule is optionally substituted by one R7); - A five-membered heterocycle in which one or two ring atoms are independently selected from nitrogen and oxygen (the heterocycle is optionally substituted with one or two R8 atoms); or - A spiro(C7-C8) heterobicyclic compound in which one atom is nitrogen (the heterocycle is optionally substituted by one R9 atom). It represents; R3 and R4 represent H; Alternatively, R3 and R4, together with the carbon atoms to which they are bonded, form a cyclopropyl group; R5 represents H; R7 represents methyl; R9 represents oxo; Each R8 independently represents either oxo or methyl. Alternatively, pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided.

[0066] This specification further describes compounds of formula (I): [ka] (In the formula, X1 represents N; X2 and X3 are as described above; R1 represents a pyridinyl, pyrazinyl, or thiazolyl group, which is optionally substituted with one or two groups independently selected from a fluorine atom and a methyl group; R2 is - A five-membered heteroaryl (where the heteroaryl is optionally substituted by one R7) in which two or three ring atoms are independently selected from nitrogen, oxygen, or sulfur; or - A five-membered heterocycle with one ring atom being nitrogen (the heterocycle is optionally substituted by one R8 atom). It represents; R3 and R4 represent H; Alternatively, R3 and R4, together with the carbon atoms to which they are bonded, form a cyclopropyl group; R5 represents H; R7 represents methyl; R9 represents oxo; R8 represents oxo; Alternatively, pharmaceutically acceptable salts, solvates, or stereoisomers thereof are provided.

[0067] The nomenclature for the following compounds (1) to (116) was established in accordance with the principles of the International Union of Pure and Applied Chemistry. The prefixes "cis" and "trans" were also used to assign the relative stereochemistry of two adjacent chiral centers.

[0068] According to a preferred embodiment, the compound of formula (I) is (1)(S)-(3-(5-fluoropyridine-3-yl)isoxazolidine-2-yl)(1-(6-(pyridine-3-yl)pyrimidine-4-yl)piperidine-4-yl)methanone, (2)(S)-3-(2-(4-(3-(pyrazine-2-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-yl)oxazolidine-2-one, (3)(S)-1-(4-(4-(3-(pyrazine-2-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-2-yl)pyrrolidine-2-one, (4)(S)-1-(2-(4-(3-(pyrazine-2-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-yl)pyrrolidine-2-one, (5)3-[5-fluoro-2-[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-yl]oxazolidine-2-one, (6) 1-[5-fluoro-2-[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-yl]pyrrolidine-2-one, (7) 1-[6-(2-methylimidazole-1-yl)pyrimidine-4-yl]-4-piperidyl]-[(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-yl]methanone, (8) 1-[4-(2-methylpyrazole-3-yl)-1,3,5-triazine-2-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone, (9)[1-[4-(4-methylpyrazole-1-yl)pyrimidine-2-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone, (10)[1-(5-fluoro-4-pyrazole-1-ylpyrimidine-2-yl)-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone, (11)[1-(4-oxazole-2-ylpyrimidine-2-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone, (12)[1-(5-fluoro-4-oxazol-2-ylpyrimidine-2-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone, (13)[1-(5-fluoro-2-oxazole-2-ylpyrimidine-4-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone, (14)[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]-[1-(4-thiazole-2-yl-1,3,5-triazine-2-yl)-4-piperidyl]methanone, (15)[1-[4-(2-methylpyrazole-3-yl)pyrimidine-2-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone, (16)[1-[2-(4-methylpyrazole-1-yl)pyrimidine-4-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone, (17)[1-[6-(4-methylpyrazole-1-yl)pyrimidine-4-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone, (18)[1-[6-(2-methylpyrazole-3-yl)pyrimidine-4-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone, (19)[1-[5-fluoro-4-(2-methylpyrazole-3-yl)pyrimidine-2-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone, (20)[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-yl]-[1-[4-(2-methylimidazole-1-yl)pyrimidine-2-yl]-4-piperidyl]methanone, (21)[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-yl]-[1-[4-(2-methylimidazole-1-yl)pyrimidine-2-yl]-4-piperidyl]methanone, (22)[1-[4-(2,4-dimethylimidazole-1-yl)-5-fluoropyrimidine-2-yl]-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone, (23)[1-[4-(2-methylimidazole-1-yl)-1,3,5-triazine-2-yl]-4-piperidyl]-[(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-yl]methanone, (24)[1-[2-(2-methylpyrazole-3-yl)pyrimidine-4-yl]-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone, (25)[1-(5-fluoro-2-pyrimidine-5-ylpyrimidine-4-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone, (26)(S)-(1-(4-(2-methyl-1H-imidazole-1-yl)-1,3,5-triazine-2-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone, (27)(S)-(1-(5-fluoro-4-(thiazole-5-yl)pyrimidine-2-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone, (28)(S)-(1-(6-(1-methyl-1H-pyrazole-5-yl)pyrimidine-4-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone, (29)(S)-(1-(2-(2-methyl-1H-imidazole-1-yl)pyrimidine-4-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone, (30)(S)-(1-(4-(2-methyl-1H-imidazole-1-yl)pyrimidine-2-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone, (31)(S)-(1-(6-(2-methyl-1H-imidazole-1-yl)pyrimidine-4-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone, (32)(S)-(1-(5-fluoro-4-(1H-pyrazole-1-yl)pyrimidine-2-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone, (33)[5-[6-(2-methylimidazole-1-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (34)[5-[6-(2-methylpyrazole-3-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (35)[1-[4-(2-methylimidazole-1-yl)-1,3,5-triazine-2-yl]piperidine-4-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (36)3-[2-[4-[(3S)-3-(5-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-yl]oxazolidine-2-one, (37)[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[4-(1,3-oxazole-2-yl)pyrimidine-2-yl]piperidine-4-yl]methanone, (38)[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[4-(1,3-thiazole-2-yl)-1,3,5-triazine-2-yl]piperidine-4-yl]methanone, (39)[(8R)-5-[6-(2-methylpyrazole-3-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-pyrazine-2-yl-1,2-oxazolidine-2-yl]methanone, (40)[(3S)-3-(2-methyl-1,3-thiazole-4-yl)-1,2-oxazolidine-2-yl]-[1-[6-(2-methyl-1,2,4-triazole-3-yl)pyrimidine-4-yl]piperidine-4-yl]methanone, (41)[(3S)-3-(2-methyl-1,3-thiazole-4-yl)-1,2-oxazolidine-2-yl]-[(8R)-5-[6-(2-methyl-1,2,4-triazole-3-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]methanone, (42)[(3S)-3-(2-methyl-1,3-thiazole-4-yl)-1,2-oxazolidine-2-yl]-[(8R)-5-[6-(3-methyltriazole-4-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]methanone, (43)[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[(8R)-5-[6-(2-methyl-1,2,4-triazole-3-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]methanone, (44) 1-[2-[(8R)-8-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]-5-azaspiro[2.5]octan-5-yl]pyrimidine-4-yl]pyrrolidine-2-one, (45)[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[4-(2-methylpyrazole-(3-yl)-1,3,5-triazine-2-yl]piperidine-4-yl]methanone, (46) 1-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (47) 1-[2-[4-[(3S)-3-pyrazine-2-yl-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]piperidine-2-one, (48)[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[(8R)-5-[4-(2-methylpyrazole-3-yl)-1,3,5-triazine-2-yl]-5-azaspiro[2.5]octan-8-yl]methanone, (49)[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[6-(2-methyl-1,2,4-triazole-3-yl)pyrimidine-4-yl]piperidine-4-yl]methanone, (50)1-[2-[4-[(3S)-3-(5-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (51) 5-[2-[4-[(3S)-3-(5-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one, (52) 5-[2-[4-[(3S)-3-(2-methyl-1,3-thiazole-4-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one, (53) 5-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one, (54) 5-[2-[4-[(3S)-3-(2-methyl-1,3-oxazol-4-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one, (55) 1-[2-[4-[(3S)-3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (56) 1-[2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (57) 5-[2-[4-[(3S)-3-pyrazine-2-yl-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2.5]octane-4-one, (58) 3,3-difluoro-1-[2-[4-[(3S)-3-pyrazine-2-yl-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (59) 3,3-difluoro-1-[2-[4-[(3S)-3-(2-methyl-1,3-thiazole-4-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (60)1-[2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-3,3-dimethylpyrrolidine-2-one, (61) 5-[2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one, (62) 1-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-3-methylimidazolidined-2-one, (63)4-[2-[(8R)-8-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]-5-azaspiro[2.5]octan-5-yl]pyrimidine-4-yl]morpholin-3-one, (64)[1-[5-fluoro-4-(2-methylimidazole-1-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (65)3-[2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-1,3-oxazolidine-2-one, (66) 3,3-difluoro-1-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]piperidine-2-one, (67)[1-[5-fluoro-2-(1,3-oxazol-2-yl)pyrimidine-4-yl]piperidine-4-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (68) 5-[5-fluoro-2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one, (69)[(8R)-5-[4-(2-methylpyrazole-3-yl)-1,3,5-triazine-2-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (70)5-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one, (71) 1-[4-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-2-yl]pyrrolidine-2-one, (72) 5-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2.5]octan-4-one, (73) 3,3-difluoro-1-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (74) 3,3-difluoro-1-[2-[4-[(3S)-3-(5-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (75) 3,3-difluoro-1-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (76) 3,3-difluoro-1-[2-[4-[(3S)-3-(5-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]piperidine-2-one, (77)[1-[5-fluoro-4-(2-methylimidazole-1-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (78)[5-[6-(2-methylimidazole-1-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (79)[5-[6-(2-methylimidazole-1-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (80)[5-[6-(2-methylpyrazole-3-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (81) 1-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (82)1-[6-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (83)[(8R)-5-[4-(4-methylpyrazole-1-yl)pyrimidine-2-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-pyrazine-2-yl-1,2-oxazolidine-2-yl]methanone, (84) 3,3-dimethyl-1-[4-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-2-yl]pyrrolidine-2-one, (85)1-[4-[(8R)-8-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]-5-azaspiro[2.5]octan-5-yl]pyrimidine-2-yl]pyrrolidine-2-one, (86)1-[6-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (87)1-[4-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-2-yl]pyrrolidine-2-one, (88) 5,5-dimethyl-1-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (89) 1-[2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5,5-dimethylpyrrolidine-2-one, (90)5-[4-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-2-yl]-5-azaspiro[2.5]octan-4-one, (91)3-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-1,3-oxazolidine-2-one, (92)1-[2-[4-[(3S)-3-(2-methyl-1,3-thiazole-4-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (93)(3R)-3-Methoxy-1-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]piperidine-2-one, (94)(3S)-3-methoxy-1-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]piperidine-2-one, (95) 1-[2-[4-[(3S)-3-(2-methyl-1,3-oxazol-4-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (96)(3R)-1-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-3-methoxypiperidine-2-one, (97)(3S)-1-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-3-methoxypiperidine-2-one, (98)[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[4-(oxetan-2-yl)pyrimidine-2-yl]piperidine-4-yl]methanone, (99)[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[4-(oxetan-2-yl)pyrimidine-2-yl]piperidine-4-yl]methanone, (100)1-[2-[(8R)-8-[(3S)-3-pyrazine-2-yl-1,2-oxazolidine-2-carbonyl]-5-azaspiro[2.5]octan-5-yl]pyrimidine-4-yl]pyrrolidine-2-one, (101)[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[4-(oxetan-3-yl)pyrimidine-2-yl]piperidine-4-yl]methanone, (102)[1-[4-(5-amino-2-methylpyrazole-3-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (103)5-[5-fluoro-2-[4-[(3S)-3-(5-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one, (104)5-[5-fluoro-2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one, (105)5-[5-fluoro-2-[4-[(3S)-3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one, (106)[1-[4-[(3S)-3-fluoropyrrolidine-1-yl]pyrimidine-2-yl]piperidine-4-yl]-[(3S3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-yl]methanone, (107)[1-[4-[(3R)-3-methoxypyrrolidine-1-yl]pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-yl]methanone (108)[1-[4-[(3S)-3-methoxypyrrolidine-1-yl]pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-yl]methanone, (109)5-[5-fluoro-2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one, (110)1-[5-fluoro-2-[4-[(3S)-3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (111)[1-[4-(4-amino-5-methylpyrazole-1-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (112)[1-[4-(4-amino-5-methylpyrazole-1-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (113)[1-[4-(3-methoxyazetidine-1-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-yl]methanone, (114)3-[5-fluoro-2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-1,3-oxazolidine-2-one, (115)3-[5-fluoro-2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-1,3-oxazolidine-2-one, and (116)3-[5-fluoro-2-[4-[(3S)-3-(5-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-1,3-oxazolidine-2-one, Alternatively, a pharmaceutically acceptable salt, solvate, or stereoisomer thereof may be selected.

[0069] According to a more preferred embodiment of the present disclosure, the compound of formula (I) is selected from the group consisting of compounds (1) to (3), (5) to (33) and (35), or is a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0070] According to a more preferred embodiment of the present disclosure, the compound of formula (I) is selected from the group consisting of compounds (5) to (8), (10) to (12), (14), (15), (19), (20), (22), (23), (25) to (27), (29), (30), (32), and (35), or is a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0071] According to a more preferred embodiment of the present disclosure, the compound of formula (I) is selected from the group consisting of compounds (3), (11), (14), (15), (38), (39), (40), (42), (43), (45), (48), (49), (52), (53), (54), (55), (57), (62), (65), (69), and (91), or is a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0072] According to a more preferred embodiment of the present disclosure, the compound of formula (I) is selected from the group consisting of compounds (3), (11), (14), (15), (38), (39) to (40), (42), (43), (45), and (48), or is a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0073] Some of the compounds of this disclosure are listed in Table 1 along with their structures, but these are merely examples and do not limit the scope of this disclosure.

[0074] The NMR and LC / MS data in Table 1 were obtained according to the methods detailed in the experimental section provided for the detailed synthesis example.

[0075] [Table 1]

[0076] [Table 2]

[0077] [Table 3]

[0078] [Table 4]

[0079] [Table 5]

[0080] [Table 6]

[0081] [Table 7]

[0082] Table 8

[0083] Table 9

[0084] Table 10

[0085] Table 11

[0086] Table 12

[0087] Table 13

[0088] Table 14

[0089] Table 15

[0090] Table 16

[0091] Table 17

[0092] Table 18

[0093] Table 19

[0094] Table 20

[0095] Table 21

[0096] Table 22

[0097] Table 23

[0098] Table 24

[0099] Table 25

[0100] Table 26

[0101] Table 27

[0102] Table 28

[0103]

Table 29

[0104]

Table 30

[0105] Production process The compounds of formula I can be prepared using the methods disclosed herein and their routine modifications, which will be apparent in view of the disclosure herein and methods well known in the art.

[0106] Scheme 1: General synthesis of the compounds of formula (I)

Chemical formula

[0107] Step 2 consists of hydrolyzing the alkyl ester of formula (IV) to form the compound of formula (IIa), which can be achieved under well-known conditions using, for example, lithium hydroxide or sodium hydroxide in water or in a solvent mixture such as THF / water or THF / water / MeOH.

[0108] Step 1 is an amide coupling between a suitable substituted isoxazolidine compound of formula (III), in the form of a free base or a salt thereof, such as a halide salt thereof, and the compound of formula (IIa). This can be achieved by a standard acid activation method using, for example, ethyl cyanohydroxyiminoethyl (Oxyma), acid chlorides, HOBt, HATU, HBTU, PyBOP, or 1-propanephosphonic anhydride (T3P) in an aprotic solvent such as DMF, DMSO, or acetonitrile under basic conditions, for example, in the presence of diisopropylethylamine (DIEA) or triethylamine (TEA), to form the compound of formula (I). The reactants may be stirred for 2 to 12 hours until complete conversion to the product is observed by LC / MS.

[0109] Substituted isoxazolidines of formula (III) can be synthesized by known procedures from the literature, for example, International Publication No. 2017096301, International Publication No. 2019130230, and International Publication No. 2021245070.

[0110] According to the fourth synthesis method (SM2) shown in Scheme 1, the compound of formula (I) can be obtained by reacting the isoxazolidine derivative of formula (IIb) with the compound of formula (V). This step may also involve nucleophilic substitution under well known conditions, particularly aromatic nucleophilic substitution, where X is a leaving group, particularly a halogen, such as a chlorine atom, a fluorine atom, a bromine atom, or an iodine atom, and the compound of formula (I) is formed in a protic solvent such as THF, acetonitrile, dioxane, NMP, DMSO, or DMF at a temperature in the range of 60°C to 120°C, for example, under microwave conditions, in the presence of a base, such as diisopropylethylamine, K2CO3, Et3N, or tBuOK.

[0111] Scheme 2: Synthesis of the compound of formula (IIb) [ka] The compound of general formula (IIb) can be synthesized in step 1, starting from compound (VI) in a deprotection step, where the PG of formula (VI) is a protecting group, such as tert-butoxycarbonyl. Step 1 can be carried out under the following two acidic conditions: - Compound (VI) can be dissolved in dioxane, and by adding HCl while stirring, the HCl salt of the corresponding compound of formula (IIb) can be obtained, or - Compound (VI) can be dissolved in DCM, and TFA can be added while stirring to obtain the TFA salt of the corresponding compound of formula (IIb).

[0112] Alternatively, step 1 may be carried out using a compound of formula (VI) in which PG is a benzyloxycarbonyl group, under metal-catalyzed hydrogenation conditions, for example, together with Pd / C.

[0113] The compound of general formula (VI) can be obtained in step 2 by reacting the compound of formula (VII) with the isoxazolidine of formula (III) under the same amide coupling conditions as described for step 1 of SM1 in scheme 1.

[0114] The compounds of formulas (VII) and (III) can be synthesized by procedures known from the literature.

[0115] Scheme 3: Synthesis of the compound of formula (IV) [ka] According to the third synthetic method (SM3), the compound of general formula (IV) can be obtained by reacting the compound of general formula (IX) with compound R2-H or compound R2-Y, where R2 is as defined in formula (I). Depending on the nature of the bond between R2 of compound (IV) and the other parts of the molecule, the reaction may proceed as follows: If the bond is a CC bond, - This is carried out by reacting a compound of formula (IX) with R2-Y (where Y is a boronic acid or boronic acid ester) in the presence of a catalyst, typically a palladium catalyst, a base, such as K2CO3, such as dioxane and / or water, under Suzuki coupling conditions; or - This is carried out by reacting R2-Y (where Y is a stannane derivative, boronic acid or ester or other organometallic reagent) in the presence of a catalyst, typically a palladium catalyst, a base, such as K2CO3, or in dioxane, under coupling conditions; or If the bond is a CN bond, the synthesis is carried out under the same conditions as described in synthesis method (SM2), where X in compound (IX) is a leaving group, in particular a halogen, such as a chlorine atom.

[0116] According to the fourth synthesis method (SM4), the compound of general formula (IV) can be obtained by reacting the compound of general formula (XI) with the compound of general formula (VIII) under the same conditions as described in the synthesis method (SM2), where X is a leaving group, particularly a halogen, such as a chlorine atom, a fluorine atom, a bromine atom, or an iodine atom.

[0117] Compounds of formulas (IX) and (XI) can be synthesized by procedures known from the literature. The synthesis of intermediates I-AA1 to I-AA6, which are representative examples of compounds of such formulas, is described in particular in the following examples herein.

[0118] Further compounds of formula (I) can be obtained by converting functional groups such as acids, esters, amides, nitriles, and halogens in a compound to other functional groups (interconversion of functional groups) using standard methods such as esterification, saponification, halogenation, and the Suzuki reaction.

[0119] The synthesis of typical compounds described herein can be achieved as described in the following examples. When available, reagents can be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers. It will be understood that other process conditions can be used when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, unless otherwise specified. The optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures.

[0120] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent specific functional groups from undergoing unwanted reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, numerous protecting groups are described in Wuts, P.G.M., Greene, T.W., & Greene, T.W. (2006), Greene’s protective groups in organic synthesis, Hoboken, N.J., Wiley-Interscience, and the references cited therein.

[0121] Furthermore, the compounds of the present disclosure may contain one or more chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0122] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof. The terms “solvent,” “inert organic solvent,” or “inert solvent” refer to solvents that are inert under the reaction conditions described herein (e.g., including benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane, "DCM"), diethyl ether, methanol, pyridine, etc.). Unless otherwise specified, the solvents used in the reactions of this disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably argon.

[0123] Pharmaceutical composition The compounds described herein are typically administered in the form of pharmaceutical compositions. Accordingly, pharmaceutical compositions are also provided herein that contain one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog, and one or more pharmaceutically acceptable media selected from carriers, adjuvants, and excipients.

[0124] In another embodiment, pharmaceutical compositions comprising the compounds described herein as active ingredients are disclosed. The compounds of this disclosure are typically, but not necessarily, formulated into pharmaceutical compositions before administration to a patient. These pharmaceutical compositions comprise an effective amount of at least one compound of this disclosure as defined herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0125] The excipient is selected from conventional excipients known to those skilled in the art, according to the desired pharmaceutical form and method of administration.

[0126] These pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal, or rectal administration contain an active ingredient which is a compound of formula (I), or, where appropriate, a salt or solvate thereof, which may be administered to subjects such as humans in unit doses in mixtures with conventional pharmaceutical excipients for the prevention or treatment of diseases, disorders, or conditions mediated at least partially by receptor-interacting protein kinase 1, particularly acute and chronic neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS).

[0127] Unit dose Appropriate unit dosage forms include oral forms such as tablets, soft or hard gel capsules, powders, granules, and oral solutions or suspensions; sublingual, buccal, tracheal, intraocular, and intranasal administration forms; intramuscular or intravenous administration forms; rectal administration forms; and implants.

[0128] When prepared in unit dosage forms, the pharmaceutical compositions of this disclosure typically contain 1 mg to 1000 mg of the active ingredient. The amount of the active ingredient combined with one or more excipients to produce a single unit dosage form will inevitably vary depending on the host being treated and the specific route of administration. For example, formulations intended for oral administration to humans generally contain, for example, 0.5 mg to 0.5 g of the active ingredient, combined with an appropriate and convenient amount of excipients, which may vary in weight from about 5 to about 98 percent of the total composition.

[0129] As an example, a unit dose form of a compound described herein in tablet form may include the following components: Compound 50.0mg Mannitol 223.75 mg Croscarmellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg

[0130] When using the compounds of this disclosure for therapeutic or preventive purposes, they are generally administered in a daily dose that is acceptable, for example, in the range of 0.1 mg / kg to 75 mg / kg body weight, and are given in divided doses as needed.

[0131] Generally, lower doses are administered when parenteral routes are used. Therefore, for example, for intravenous or intraperitoneal administration, doses in the range of 0.1 mg / kg to 30 mg / kg body weight are commonly used. Oral administration may also be particularly preferred in tablet form. Typically, a single dosage form contains approximately 0.5 mg to 0.5 g of the compound of this disclosure.

[0132] There may be specific cases where a higher or lower dose is appropriate. Such doses do not exceed the scope of this disclosure. According to common practice, the appropriate dose for each patient is determined by a physician in accordance with the mode of administration and the patient's weight and response.

[0133] Treatment method In other embodiments, methods for treating receptor-interacting protein kinase 1-mediated diseases or disorders are provided herein. These methods involve administering a therapeutically effective amount of a compound or pharmaceutical composition described herein to a subject in need thereof. In some embodiments, the receptor-interacting protein kinase 1-mediated disease or disorder is Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS).

[0134] Therefore, the receptor-interacting protein kinase 1 inhibitors of this disclosure are useful for treating receptor-interacting protein kinase 1-mediated diseases and conditions, including, but not limited to, neurodegenerative diseases and central nervous system (CNS) diseases.

[0135] Neurodegenerative diseases and CNS diseases The receptor-interacting protein kinase 1 inhibitors described herein may also be used to treat neurodegenerative diseases. Neurodegenerative diseases can affect many bodily activities, including balance, movement, speech, breathing, and cardiac function. Neurodegenerative diseases may be hereditary or may be caused by medical conditions such as alcoholism, tumors, stroke, toxins, chemicals, and viruses. Non-exclusive examples of neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease.

[0136] In certain embodiments, the compounds and compositions of the Disclosure are useful for treating Alzheimer's disease. In certain embodiments, the compounds and compositions of the Disclosure are useful for treating Parkinson's disease. In certain embodiments, the compounds and compositions of the Disclosure are useful for treating amyotrophic lateral sclerosis (ALS).

[0137] More generally, the receptor-interacting protein kinase 1 inhibitors described herein can be used to preserve neuronal viability and promote axonal growth and neuronal function within the central nervous system (CNS). Therefore, the compounds may be used to reduce or even restore the loss of cognitive, motor, and sensory functions associated with disease or impairment of the CNS by maintaining neuronal viability and / or promoting axonal regeneration and / or neuronal function.

[0138] If desired, the effective daily dose of the active compound may be administered in unit dosage form as 2, 3, 4, 5, 6 or more subdoses, administered separately at appropriate intervals throughout the day. In certain embodiments, the disclosure relates to a compound for inhibiting cell death, wherein the compound is represented by formula (I). In certain embodiments, the compound of the disclosure is an inhibitor of cell death. In any case, the compound of the disclosure exerts its effect on inhibiting cell death more strongly at concentrations of less than about 50 micromoles in one embodiment, less than about 10 micromoles in another embodiment, and most strongly at concentrations of less than 1 micromoles in another embodiment. The compound of the disclosure can be tested in standard animal models of stroke and in standard protocols such as those described by Hara, H., et al. Proc. Natl. Acad. Sci. USA, 1997. 94(5):2007-12.

[0139] When the compounds of this disclosure are administered to humans and animals as pharmaceuticals, they can be given either on their own or as pharmaceutical compositions containing, for example, 0.1% to 99.5% (or, in another embodiment, 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0140] The compounds or compositions thereof of this disclosure may be administered once, twice, three times, or four times daily. Administration or treatment with the compounds may also be continued for several days; for example, treatment will generally last for at least 7, 14, or 28 days during one treatment cycle. Treatment cycles are well known, frequently alternating with rest periods of approximately 1 to 28 days, generally about 7 or 14 days, between cycles. In certain embodiments, treatment cycles may be continuous.

[0141] When administered orally, the total daily dose for human subjects may be 1 mg to 1,000 mg, approximately 1,000 to 2,000 mg / day, approximately 10 to 500 mg / day, approximately 50 to 300 mg / day, approximately 75 to 200 mg / day, or approximately 100 to 150 mg / day.

[0142] The daily dose may also be described as the total amount of the compound described herein administered per dose or per day. The daily dose of the compound may be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day. In certain embodiments, the method involves administering an initial daily dose of about 1 to 800 mg of the compound described herein and increasing the dose incrementally until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose may be increased daily, every other day, twice a week, or once a week.

[0143] In certain embodiments, the compound or pharmaceutical formulation is administered orally. In certain embodiments, the compound or pharmaceutical formulation is administered intravenously. Other routes of administration include sublingual, intramuscular, and transdermal administration.

[0144] The formulations of this disclosure may be administered orally, parenterally, topically, or rectally. They are, of course, provided in a form suitable for each route of administration. For example, they may be administered by injection, infusion, or inhalation in the form of tablets or capsules, by injection, inhalation, eye drops, ointment, suppository, etc.; topically by lotion or ointment; and rectally by suppository. In certain embodiments, administration is orally. [Examples]

[0145] The following examples describe the preparation of specific compounds. These examples are illustrative and not limiting.

[0146] Numerous variations and alternative compositions, methods, and systems can be envisioned by those skilled in the art without departing from the spirit and scope of this disclosure.

[0147] Abbreviation: ACN Acetonitrile Argon aq. Water-based n-BuOH (n-butanol) DCM Dichloromethane DEA (Diethylamine) DIBAL-H Diisobutylaluminum Hydrogenate DIPEA N,N-diisopropylethylamine DIAD Diisopropylazodicarboxylate DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) EA or HCl (ethyl acetate) EE ethyl ether eq. equivalent weight ESI Electrospray Ionization EtOH Ethanol FA Formic Acid H, hr, or hrs hours HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-R thiazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate nHept n-heptane HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HOBt 1-hydroxybenzotriazole (RP)HPLC (Reverse Phase) High-Pressure Liquid Chromatography IBX 2-Iodoxybenzoic acid IPA Isopropylamine RP LC (Reverse-Phase Liquid Chromatography) LC / MS Liquid Chromatography / Mass Spectrometry M molar concentration MW microwave m / z mass-to-charge ratio MeOH methanol min N Normal NMR nuclear magnetic resonance PE (Petroleum Ether) prep. PyBOP Benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate rt room temperature sat. saturation SFC Supercritical Fluid Chromatography TEA (Triethylamine) TFA (Trifluoroacetic Acid) TFAA Trifluoroacetic anhydride THF (Tetrahydrofuran) TLC (Thin-Layer Chromatography) RT retention time UV ultraviolet light

[0148] Silica gel chromatography Silica gel chromatography was performed using either CombiFlash® Rf (Teledyne ISCO), a Biotage Isolera One automated flash purification system, or two Buch systems equipped with pre-filled cartridges (combinations of C-660, C-605, C-620, C-635 and C-660, C-605, C-615, C-630).

[0149] Preparative reverse-phase HPLC For preparative reverse-phase HPLC, we used an Agilent 1200 preparative HPLC instrument, a Gilson instrument (GX-271 liquid handler, 331 / 332 pump, UV / VIS-155), a Waters automated purification LC preparative system, or a Biotage instrument with a C18 column and a water (0.1% FA) / ACN gradient.

[0150] NMR 400MHz:NMR spectra were recorded using a Bruker AVANCE II 400 spectrometer operating at a proton frequency of 400.23MHz. The instrument was equipped with a 5mm BBI room-temperature probe head. Alternatively, a Bruker AVANCE III HD 400MHz or Bruker AVANCE NEO 400MHz was used.

[0151] 600 MHz: NMR spectra were recorded using a Bruker AVANCE III 600 spectrometer operating at a proton frequency of 600.05 MHz. The instrument was equipped with a 5 mm BBI room-temperature probe head.

[0152] LC / MS instrument for analysis for Method A Retention time and mass detection were performed using a Waters Acquity UHPLC system combined with a Waters SQD mass detector. The injection volume was 1.0 μl. Molecular weight is given in grams / moles [g / mol], and detected mass is given in mass / charge [m / z].

[0153] Analytical LC / MS instrument for methods B, D, E, and chiral method H For retention time and mass detection, Agilent LC / MS systems (LC1200 series / MS6120 quadrupole LC / MS, LC1260 infinity / MS6120 quadrupole LC / MS, or LC1260 Infinity II / MSD Infinity Lab) were used. Molecular weight is given in grams / moles [g / mol], and detected mass is given in mass / charge [m / z].

[0154] LC / MS instrument for analysis of methods C, Q, R, and S Retention time and mass detection were performed using the SHIMADZU LC-30AD system combined with a PDA or DAD mass detector.

[0155] For retention time and mass detection, Agilent LC / MS systems (LC1200 series / MS6120 quadrupole LC / MS, LC1260 infinity / MS6120 quadrupole LC / MS, or LC1260 Infinity II / MSD Infinity Lab) were used. Molecular weight is given in grams / moles [g / mol], and detected mass is given in mass / charge [m / z].

[0156] Chiral analyzer for methods F, G, I, J, K, L, M, T, U, Y, AA, AB, AD, AE, AF, AG, AI, AJ, AK, AM, AN and AP The SHIMADZU LC-30AD sf system was used for SFC retention time.

[0157] Methods for analytical LC / MS for H, N, O, P, W, X, Z, AC and AH For the retention period, we used Agilent's LC system (Agilent-1260 series system).

[0158] LC / MS-Method A Gradient: 98% H2O (0.05% FA / 2% ACN (0.035% FA)) for 0.2 minutes; then 98% H2O (0.05% FA) to 98% ACN (0.035% FA) for 3.6 minutes; then 98% ACN (0.035% FA) for 0.5 minutes; flow rate: 1.0 ml / min; column: 2.1 × 50 mm Waters ACQUITY UPLC BEH C18, 1.7 μm, 55°C. UV data: Retention time adλ = 220 nm (given in minutes) MS data: ES+ ionization, given as [M+H]+ unless otherwise specified, m / z

[0159] LC / MS-Method B Gradient: 1.0 min from 93% H2O (0.05% TFA) / 7% acetonitrile to 95% acetonitrile, followed by 0.45 min of 95% acetonitrile. Flow rate: 1.1 ml / min. Column: 2.0 × 10 mm Luna C18, 3 μm, 30°C. Injection volume: 0.2 μl. UV data: retention time given in minutes at λ220nm MS data: ES + ionization, unless otherwise specified [M + H] + The given m / z

[0160] LC / MS-Method C Gradient: 0.8 min from 95% H2O (0.0375% TFA) / 5% ACN (0.01875% TFA) to 5% H2O (0.0375% TFA) / 95% ACN (0.01875% TFA); Flow rate: 1.5 ml / min, Column: Kinetex EVO C18 2.1 × 30 mm, 5 μm, 50°C UV data: retention time given in minutes at λ220nm MS data: ES + ionization, [M + H] unless otherwise specified. + The given m / z

[0161] LC / MS-Method D Gradient: 0.8 min from 100% H2O (0.0375% TFA) / 0% ACN (0.01875% TFA) to 40% H2O (0.0375% TFA) / 60% ACN (0.01875% TFA); then 0.4 min for 40% H2O (0.0375% TFA) / 60% ACN (0.01875% TFA); flow rate: 1.5 ml / min, column: Kinetex EVO C18 2.1 × 30 mm, 5 μm, 50℃ UV data: retention time given in minutes at λ220nm MS data: ES + ionization, [M + H] unless otherwise specified. + The given m / z

[0162] LC / MS-Method E Gradient: 99% H2O (0.05% TFA) / 1% ACN to 7% ACN over 0.3 min; then 7% ACN to 95% ACN over 1.3 min; flow rate: 1.1 ml / min; column: 2.0 × 10 mm Luna C18, 3 μm, 30°C; injection volume: 0.2 μl UV data: retention time given in minutes at λ220nm MS data: ES+ ionization, given as [M+H]+ unless otherwise specified, m / z

[0163] LC / MS method Q Gradient: 1.05 min from 95% H2O (0.0375% TFA) / 5% ACN (0.01875% TFA) to 5% H2O (0.0375% TFA) / 95% ACN (0.01875% TFA); Flow rate: 2 ml / min, Column: HALO C 18 3.0 x 30 mm, 5.0 μm, 50℃ UV data: Retention time given in minutes, adλ 220nm. Detector: PDA MS data: ES+ ionization, given as [M+H]+ unless otherwise specified, m / z

[0164] LC / MS method R Gradient: 1.05 min from 95%H2O(0.025%NH3·H2O) / 5%ACN to 5%H2O(0.025%NH3·H2O) / 5%ACN; maintain 5%A:95%B for 0.4 min, then return to 95%A:5%B for 0.3 min. Flow rate: 2 ml / min, Column: Kinetex EVO C18 2.1×30 mm, 5 μm, 50℃ UV data: Retention time given in minutes, adλ 220nm. Detector: PDA MS data: ES+ ionization, given as [M+H]+ unless otherwise specified, m / z

[0165] LC / MS method S Gradient: 1.05 min from 95%H2O(0.025%NH3·H2O) / 5%ACN to 5%H2O(0.025%NH3·H2O) / 5%ACN; maintain 5%A:95%B for 0.4 min, then return to 95%A:5%B for 0.3 min. Flow rate: 2 ml / min, Column: Kinetex EVO C18 2.1×30 mm, 5 μm, 40℃ UV data: Retention time given in minutes, adλ 220nm. Detector: PDA MS data: ES+ ionization, given as [M+H]+ unless otherwise specified, m / z

[0166] Chiral analysis methods: Method F Mobile phase: Phase A is CO2, Phase B is MeOH (0.05% DEA); Gradient: 5%~40% MeOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Column: Chiralcel OJ-3 50×4.6 mm ID, 3 μm, 35℃; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0167] Method G Mobile phase: Phase A is CO2, Phase B is EtOH (0.05% DEA); Gradient: 5%~40% EtOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Column: Chiralpak IF-3 50×4.6 mm, 3 μm, 35℃; Back pressure: 100 Bar; Detector: DAD UV data: retention time given in minutes at λ220nm

[0168] Method H Mobile phase: Phase A is CO2, Phase B is MeOH (0.05% DEA); Gradient: 5%~40% MeOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Column: Chiralcel OJ-3 50×4.6 mm ID, 3 μm, 35℃; Back pressure: 100 Bar; Detector: DAD UV data: retention time given in minutes at λ220nm

[0169] Method I Mobile phase: Phase A is CO2, Phase B is MeOH (0.05% DEA); Gradient: 5%~40% MeOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Column: Chiralpak AD-3 50×4.6 mm ID, 3 μm, 35℃; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0170] Method J Mobile phase: Phase A is CO2, Phase B is iPrOH (0.05% DEA); Gradient: 5%~40% iPrOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Column: Chiralpak IC-3 50×4.6 mm ID, 3 μm, 35°C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0171] Method K Mobile phase: Phase A is CO2, Phase B is MeOH (0.05% DEA); Gradient: 5%~40% MeOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Column: Chiralpak IC-3 50×4.6 mm ID, 3 μm, 35℃; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0172] Method L Mobile phase: Phase A is CO2, Phase B is MeOH (0.05% DEA); Gradient: 5%~40% MeOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Column: Chiralpak IG-3 50×4.6 mm ID, 3 μm, 35°C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0173] Method M Mobile phase: Phase A is CO2, Phase B is EtOH (0.05% DEA); Gradient: 5%~40% EtOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Column: Chiralpak AD-3 50×4.6 mm ID, 3 μm, 35℃; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0174] Method N Mobile phase: Phase A is CO2, Phase B is MeOH (0.05% DEA); Gradient: EtOH (0.05% DEA) 5%~40% in CO2; Flow rate: 3 mL / min; Column: Chiralpak AD-3 50×4.6 mm ID, 3 μm, 35℃; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0175] Method O Mobile phase: Phase A is CO2, Phase B is MeOH (0.05% DEA); Gradient: EtOH (0.05% DEA) 5%~40% in CO2; Flow rate: 3 mL / min; Column: Chiralpak AD-3 50×4.6 mm ID, 3 μm, 35℃; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0176] Method P Mobile phase: Phase A is CO2, Phase B is MeOH (0.05% DEA); Gradient: 5%~40% EtOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Column: Chiralcel OD-3 50×4.6 mm, 3 μm, 35℃; Back pressure: 100 Bar; Detector: DAD UV data: retention time given in minutes at λ220nm

[0177] Method T Mobile phase: Phase A is CO2, Phase B is EOH (0.05% DEA); Gradient: EtOH (0.05% DEA) 5%~40% in CO2; Flow rate: 3 mL / min; Column: Cellulose-2 50 × 4.6 mm ID, 3 μm 35°C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0178] Method U Mobile phase: Phase A is CO2, Phase B is iPrOH + ACN (0.05% DEA); Gradient: iPrOH + CAN (0.05% DEA) 5%~40% in CO2; Flow rate: 3 mL / min; Column: Chiralpak IK-3 50×4.6 mm ID, 3 μm, 35°C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0179] Method W Mobile phase: Phase A is CO2, Phase B is MeOH (0.05% DEA); Gradient: MeOH (0.05% DEA) in CO2, 5%~40%; Flow rate: 3 mL / min; Column: Chiralcel OJ-3 50×4.6 mm ID, 3 μm, 35°C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0180] Method X Mobile phase: Phase A is CO2, Phase B is EtOH (0.05% DEA); Gradient: EtOH (0.05% DEA) in CO2, 5%~40%; Flow rate: 3 mL / min; Column: Chiralcel OJ-3 50×4.6 mm ID, 3 μm, 35°C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0181] Method Y Mobile phase: Phase A is CO2, Phase B is iPrOH (0.05% DEA); Gradient: 5%~40% iPrOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Column: Chiralcel OJ-3 50×4.6 mm ID, 3 μm, 35°C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0182] Method Z Mobile phase: Phase A is CO2, Phase B is EtOH (0.05% DEA); Gradient: EtOH (0.05% DEA) in CO2, 5%~40%; Flow rate: 3 mL / min; Column: Chiralcel OD-3 50 × 4.6 mm, 3 μm, 35°C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0183] Method AA Mobile phase: Phase A is CO2, Phase B is iPrOH + ACN (0.05% DEA); Gradient: iPrOH + ACN (0.05% DEA); CO2 (0.05% DEA) 5%~40%; Flow rate: 3 mL / min; Column: Chiralcel OD-3 50 × 4.6 mm, 3 μm, 35°C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0184] Method AB Mobile phase: Phase A is CO2, Phase B is iPrOH + ACN (0.05% DEA); Gradient: iPrOH + ACN (0.05% DEA); CO2 (0.05% DEA) 5%~40%; Flow rate: 3 mL / min; Column: Chiralpak AY-3 50×4.6 mm ID, 3 μm, 35°C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0185] method ac Mobile phase: Phase A is CO2, Phase B is iPrOH (0.05% DEA); Gradient: 5%~40% iPrOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Column: Chiralpak AD-3 50×4.6 mm ID, 3 μm, 35°C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0186] Method AD Mobile phase: Phase A is CO2, Phase B is iPrOH (0.05% DEA); Gradient: 5%~40% iPrOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Column: Chiralpak AS-3 50×4.6 mm ID, 3 μm, 35°C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0187] Method AE Mobile phase: Phase A is CO2, Phase B is EtOH (0.05% DEA); Gradient: EtOH (0.05% DEA) in CO2, 5%~40%; Flow rate: 3 mL / min; Column: Chiralcel OJ-3 50×4.6 mm, 3 μm, 35°C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0188] Method AF Mobile phase: Phase A is CO2, Phase B is iPrOH + ACN (0.05% DEA); Gradient: iPrOH + ACN (0.05% DEA); CO2 (0.05% DEA) 5%~40%; Flow rate: 3 mL / min; Column: Kromasil (S,S)Whelk-O1 50×4.6 mm ID, 3 μm, 35°C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0189] Method AG Mobile phase: Phase A is CO2, Phase B is EtOH (0.05% DEA); Gradient: 5% to 40% EtOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Column: Chiralpak AS-3 50 x 4.6 mm ID, 3 μm, 35 °C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0190] Method AH Mobile phase: Phase A is CO2, Phase B is EtOH (0.05% DEA); Gradient: 5% to 40% EtOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Column: Chiralpak AD-3 50 x 4.6 mm ID, 3 μm, 35 °C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0191] Method AI Mobile phase: Phase A is CO2, Phase B is EtOH (0.05% DEA); Gradient: 5% to 40% EtOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Column: Chiralpak IC-3 50 x 4.6 mm ID, 3 μm, 35 °C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0192] Method AJ Mobile phase: Phase A is CO2, Phase B is iPrOH + ACN (0.05% DEA); Gradient: iPrOH + ACN (0.05% DEA) 5%~50% in CO2; Flow rate: 3 mL / min; Column: Chiralpak AS-3 50×4.6 mm ID, 3 μm, 35℃; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0193] Method AK Mobile phase: Phase A is CO2, Phase B is EtOH + ACN (0.05% DEA); Gradient: EtOH+ACN (0.05% DEA) 5% to 40% in CO2; Flow rate: 3 mL / min; Column: Chiralpak IG-3 50 x 4.6 mm ID, 3 μm, 35 °C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0194] Method AL Mobile phase: Phase A is CO2, Phase B is iPrOH + ACN (0.05% DEA); Gradient: iPrOH + ACN (0.05% DEA) 5%~40% in CO2; Flow rate: 3 mL / min; Column: Kromasil (S,S)Whelk-O1 50×4.6 mm ID, 3 μm, 35°C; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0195] How AM Mobile phase: Phase A is CO2, Phase B is EtOH + ACN (0.05% DEA); Gradient: EtOH+ACN (0.05%DEA) 5% to 50% in CO2; Flow rate: 3mL / min; Column: Chiralpak AD-3 50 x 4.6mm ID, 3μm, 35℃; Backpressure: 100Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0196] method an Mobile phase: Phase A is CO2, Phase B is iPrOH + ACN (0.05% DEA); Gradient: iPrOH + ACN (0.05% DEA) 5%~40% in CO2; Flow rate: 3 mL / min; Column: Chiralpak AD-3 50×4.6 mm ID, 3 μm, 35℃; Back pressure: 100 Bar; Detector: PDA UV data: retention time given in minutes at λ220nm

[0197] Method AP Mobile phase: Phase A is CO2, Phase B is EtOH (0.05% DEA); Gradient: EtOH (0.05% DEA) in CO2, 5%~40%; Flow rate: 3 mL / min; Column: Chiralcel OD-3 50×4.6 mm ID, 3 μm, 35°C; Back pressure: 100 Bar; Detector: DAD UV data: retention time given in minutes at λ220nm

[0198] salt For compounds listed as HCl-, TFA-, or other salts, the exact amount of each salt is usually not determined. Therefore, the amount of salt can range from as low as 0.01 equivalents to a maximum of 5.0 equivalents, depending on the chemical structure (e.g., the number of basic centers).

[0199] Chiral purity If the enantiomer ratio exceeds 90:10, isolate the compound and name it as a single enantiomer. If the enantiomer ratio is less than 90:10, use the racemic mixture.

[0200] Synthesis method: General procedure General Procedure 1: Amide Coupling with HATU One equivalent of carboxylic acid and 1.5 equivalents of HATU were dissolved in dry DMF (2 ml / mmol carboxylic acid). The corresponding base (6-10 equivalents) was then added with stirring. After 15 minutes, the corresponding amine (1 equivalent as free base or HX salt) dissolved in dry DMF was added with stirring. The reaction was stirred for 2-12 hours until complete conversion to the product was observed by LC / MS. Diluted sodium bicarbonate solution was then added, and the aqueous phase was extracted with EA (3x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography and / or RP preparative HPLC to obtain the corresponding product. Common bases used in amide coupling are DIPEA or TEA.

[0201] General procedure 2: Deprotection of the Boc group to obtain the HCl salt 205 mg of tert-butyl(3S)-3-pyrazine-2-ylisoxazolidine-2-carboxylate was dissolved in 6 ml of dioxane, and 9.42 ml of HCl (4 M in dioxane) was added while stirring at room temperature. After standing overnight, the solvent was removed under vacuum, the residue was dissolved in ACN / water, and the mixture was freeze-dried overnight to obtain the corresponding HCl salt.

[0202] General procedure 3: Deprotection of the Boc group to obtain the TFA salt The corresponding component (155 mg) was dissolved in DCM (8 ml), and TFA (442 μL) was added. After stirring at room temperature for 3 hours, the solvent was removed, and the residue was freeze-dried from water / ACN to obtain the corresponding crude substance as the TFA salt.

[0203] General procedure 4: Hydrolysis of Me or ethyl ester to carboxylic acid To a THF (50 ml) solution of the corresponding ethyl or methyl ester (14.80 mmol), LiOH·H2O (1 M, 29.60 ml, 2 equivalents) was added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was adjusted to pH 3 with 4N aqueous HCl, concentrated under vacuum, and purified by reverse-phase HPLC.

[0204] Intermediate: Intermediate I-01: (3S)-3-pyrazine-2-ylisoxazolidine hydrochloride (corresponding to formula (III)) Step 1: I-01a: tert-butyldimethyl-[(E)-3-pyrazine-2-ylaryloxy]silane 2-Bromopyrazine (2.5 g), (E)-3-(tert-butyldimethylsilyloxy)propene-1-ylboronic acid pinacol ester (5.3 ml), and cesium carbonate (9.73 g) were dissolved in a mixture of dioxane (42 ml) and water (10.5 ml). Ar was then bubbling into the solution for 5 minutes, and chloro(2-dicyclohexylphosphino-2',4',6'-RTi-isopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (590 mg) was added. Ar was again bubbling into the solution for 5 minutes, and the mixture was refluxed under Ar with stirring for 1 hour. After cooling, water and EA were added. The aqueous phase was extracted with EA (2x). The combined organic phase was dried over sodium sulfate, filtered, and concentrated under vacuum to obtain 6.36 g of the title compound, which was used directly in the next step.

[0205] Step 2: I-01: (E)-3-pyrazine-2-ilpropa-2-en-1-ol 6.36 g of tert-butyldimethyl-[(E)-3-pyrazine-2-ylallyloxy]silane was dissolved in 100 ml of THF, the mixture was cooled to 0°C, and 31.75 ml of tetrabutylammonium fluoride (1 M in THF) was added. After 2 hours, solid NaHCO3 was added with stirring. After 1.5 hours, the suspension was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (200 g of SiO2, 100% DCM for 5 minutes; 10% ethanol from 100% DCM for 45 minutes; then 10% EtOH for 15 minutes). The fractions containing the pure product were combined, and the solvent was removed under vacuum to obtain 1.82 g of the title compound. LC / MS: m / z=137.2[M+H]+; RT: 0.64 min (LC / MS-Method A)

[0206] Step 3: I-01c: (E)-3-pyrazine-2-ilpropa-2-enal (E)-3-pyrazine-2-ylpropa-2-en-1-ol (1.82 mg) was dissolved in DCM (90 ml), and MnO2 (23.24 g) was added while stirring. After 30 minutes, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain 1.12 g of the title compound, which was used directly in the next step. LC / MS: m / z=135.1[M+H]+; RT: 0.73 min (LC / MS-Method A).

[0207] Step 4: I-01d: tert-butyl(3S)-5-hydroxy-3-pyrazine-2-ylisoxazolidine-2-carboxylate [Diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]trimethylsilane (700 mg) was dissolved in DCM (40 ml), and the mixture was cooled to 0°C. (E)-3-pyrazine-2-ylpropa-2-enal (1.12 g) was dissolved in DCM (10 ml), and tert-butyl N-hydroxycarbamate (1.36 g) was added while stirring. After standing overnight in a refrigerator (4°C), silyl ether (0.1 equivalent) and carbamate (0.5 equivalent) were added, and the mixture was stored in a refrigerator for 24 hours. Then, saturated NH4Cl solution was added. The aqueous phase was extracted with DCM (2x), and the combined organic phase was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC six times (flow rate 75 ml / min, 17.5 min, from 90% H2O / 10% ACN to 10% H2O / 90% ACN; Agilent Prep C18-10 μm, 30 × 250 mm). The fractions containing the pure product were combined, ACN was removed under vacuum, and the aqueous phase was freeze-dried to obtain 358 mg of the title compound. LC / MS: m / z=268.3[M+H]+; RT: 1.19 min (LC / MS-Method A).

[0208] Step 5: I-01e: tert-butyl N-hydroxy-N-[(1S)-3-hydroxy-1-pyrazine-2-ylpropyl]carbamate 360 mg of tert-butyl(3S)-5-hydroxy-3-pyrazine-2-yl-isoxazolidine-2-carboxylate was dissolved in 20 ml of methanol, cooled to 0°C, and 50 mg of NaBH4 was added while stirring. After 1 hour, saturated NH4Cl solution was added. The aqueous phase was extracted with DCM (5x), and the combined organic phase was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (flow rate 75 ml / min, 17.5 min to 10% H2O / 90% ACN; Agilent Prep C18-10 μm, 30 × 250 mm). The fractions containing the pure product were combined, ACN was removed under vacuum, and the aqueous phase was freeze-dried to obtain 209 mg of the title compound. LC / MS: m / z=270.3[M+H]+; RT: 1.06 min (LC / MS-Method A)

[0209] Step 6: I-01f: tert-butyl(3S)-3-pyrazine-2-ylisoxazolidine-2-carboxylate 205 mg of tert-butyl N-hydroxy-N-[(1S)-3-hydroxy-1-pyrazine-2-ylpropyl]carbamate was dissolved in 5 ml of THF, and triphenylphosphine (290 mg) and DIAD (210 μl) were added while stirring. After stirring for 1 hour, the solvent was removed by vacuum, and the residue was purified by preparative HPLC (flow rate 75 ml / min, 15 min from 90% H2O / 10% ACN to 10% H2O / 90% ACN, Agilent Prep C18-10 μm, 30 × 250 mm). The fractions containing the product were combined, ACN was removed under vacuum, and the aqueous phase was freeze-dried to obtain 275 mg of the title compound still containing approximately 50 mol% reduced DIAD. LC / MS: m / z=252.3[M+H]+; RT: 1.38 min (LC / MS-Method A).

[0210] Step 7: I-01: (3S)-3-pyrazine-2-ylisoxazolidine hydrochloride 205 mg of tert-butyl(3S)-3-pyrazine-2-ylisoxazolidine-2-carboxylate was dissolved in 6 ml of dioxane, and HCl (9.42 ml, 4 M in dioxane) was added while stirring at room temperature. After standing overnight, the solvent was removed by vacuum, the residue was dissolved in ACN / water, and lyophilized overnight to obtain 256 mg of the title compound, which contained approximately 50 mol% of reduced DIAD from step 6, but this did not affect the next step. LC / MS: m / z=152.2[M+H]+; RT: 0.46 min (LC / MS-Method A).

[0211] Intermediate I-02: (3S)-3-(2-methylthiazole-4-yl)isoxazolidine thifluoroacetate (corresponding to compound (III)) Step 1: I-02a: Ethyl 2-methylthiazole-4-carboxylate To a solution of thioacetamide (7.86 g, 104.61 mmol) in EtOH (60 ml), ethyl 3-bromo-2-oxopropanoate (20 g, 102.56 mmol) was added dropwise over 10 minutes, and the mixture was stirred at 25°C for 12 hours. The mixture was added to 300 ml of 1N HCl, stirred for 0.5 hours, then the pH was adjusted to 8, the solution was extracted with EA (200 ml x 3), dried over Na2SO4, and concentrated. The crude product was triturated with PE. Purification with EA=5:1 (30 ml) yielded the title compound (10.6 g, yield 58%) as a brown solid. 1 H NMR (CDCl3,400MHz): δ ppm 8.04(1H),4.43(2H),2.78(3H),1.41(3H).

[0212] Step 2: I-02b: 2-Methylthiazole-4-carbaldehyde To a solution of ethyl 2-methylthiazole-4-carboxylate (9.6 g, 56.07 mmol, 1 equivalent) in DCM (96 ml), DIBAL-H (1 M, 84.10 ml) was added. The mixture was stirred at -78 °C for 3 hours. The reaction mixture was quenched with methanol (5 ml), heated to 25 °C, filtered, and concentrated under reduced pressure. The mixture was purified by flash silica gel chromatography (PE:EA = 1:0 to 5:1) to obtain the title compound (5.5 g, yield 76%) as a yellow oil. 1 H NMR (CDCl3,400MHz): δ ppm 9.99(1H),8.05(1H),2.79(3H).

[0213] Step 3: I-02c: (E)-3-(2-methylthiazole-4-yl)propane-2-enal A mixture of 2-methylthiazole-4-carbaldehyde (5.5 g, 34.60 mmol) and (formylmethylene)triphenylphosphorane (10.53 g, 34.60 mmol) in THF (55 ml) was degassed, purged three times with N2, and then stirred at 70°C for 3 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (PE:EA=4:1) to obtain the title compound (4.5 g, yield 80%) as a yellow oil. 1 H NMR (CDCl3,400MHz): δ ppm 9.70(1H),7.45(1H),7.39(1H),6.93(1H),2.76(3H).

[0214] Step 4: I-02d: tert-butyl(3S)-5-hydroxy-3-(2-methylthiazole-4-yl)isoxazolidine-2-carboxylate To a solution of [diphenyl-[(2R)-pyrrolidine-2-yl]methoxy]trimethylsilane (1.78 g, 5.48 mmol) in CHCl3 (42 ml), (E)-3-(2-methylthiazole-4-yl)prop-2-enal (4.2 g, 27.41 mmol) and tert-butyl N-hydroxycarbamate (4.02 g, 30.16 mmol) were added at 0°C. The mixture was smoothly heated to 25°C and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative RP-LC (column: Agela C18, 20 μm, 120 Å; mobile phase: water / 0.1% saturated NH3 aqueous solution-ACN; B%: 5%~30%, 10 min; flow rate: 25 ml / min) to obtain the title compound (3.9 g, yield 50%) as a yellow oil.

[0215] Step 5: I-02e: tert-butyl N-hydroxy-N-[(1S)-3-hydroxy-1-(2-methylthiazole-4-yl)propyl]carbamate To a methanol (34 ml) solution of tert-butyl(3S)-5-hydroxy-3-(2-methylthiazole-4-yl)isoxazolidine-2-carboxylate (3.4 g, 11.87 mmol), NaBH4 (494.10 mg, 13.06 mmol) was added at 0°C. The mixture was stirred for 2 hours. The reaction mixture was quenched at 0°C with saturated NH4Cl solution (2 ml), diluted with water (200 ml), and extracted with EA (150 ml x 3). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (PE:EA = 2:1 to 1:1) to obtain the title compound (2.44 g, yield 70%) as a yellow oil. 1 H NMR (CDCl3,400MHz): δ ppm 7.02(1H),5.46(1H),3.78(2H),2.71(3H),2.39-2.28(1H),2.17-2.09(1H),1.49(9H).

[0216] Step 6: I-02f: tert-butyl(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-carboxylate To a solution of tert-butyl N-hydroxy-N-[(1S)-3-hydroxy-1-(2-methylthiazole-4-yl)propyl]carbamate (2.4 g, 8.32 mmol) in THF (24 ml), tributylphosphan (2.69 g, 13.32 mmol) and DIAD (2.19 g, 10.82 mmol) were added at 0°C and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative RP LC (flow rate: 100 ml / min; gradient: 95% H2O (0.1% FA) / 5% ACN to 40% H2O (0.1% FA) / 60% ACN in 15 min; 40% H2O (0.1% FA) / 60% ACN in 3 min; column: Welch Ultimate XB_C18, 20-40 μm, 120 Å, ID 72 mm × H 300 mm) and flash silica gel column chromatography (PE:EA = 1:0~4:1) to obtain the title compound, which was further purified by SFC (column: Daicel Chiralpak The compound was purified using an AD (250 mm × 30 mm, 10 μm); mobile phase A: CO2, B: 0.1% NH3 aqueous solution in methanol; B%: 15%~15%, 5.6; 60 minutes; flow rate: 50 ml / min; back pressure: 100 bar) to obtain the title compound (483 mg, 99.6% ee) as a grayish-white solid. LC / MS: m / z 171.2[M+H-100]; RT 0.822 min (Method C) 1 H NMR (CDCl3,400MHz): δ ppm 7.07(1H),5.37(1H),4.18-4.11(1H),3.92(1H),2.71-2.69(4H),2.56-2.47(1H),1.50(9H). Analysis SFC: RT 0.93 min (99.8%, Method I); R-enantiomer RT: 0.54 min (Method I)

[0217] Step 7: I-02: (3S)-3-(2-methylthiazole-4-yl)isoxazolidinetrifluoroacetate 155 mg of tert-butyl(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-carboxylate was dissolved in 8 ml of DCM, and 442 μL of TFA was added. After stirring at room temperature for 3 hours, the solvent was removed, and the residue was freeze-dried in water / ACN to obtain 179 mg of crude substance. LC / MS: m / z = 171.1[M+H] + ;RT: 0.46 min (LC / MS-Method B)

[0218] Intermediate I-03: (3S)-3-(6-methyl-3-pyridyl)isoxazolidine (TFA salt) (corresponding to compound (III)) Step 1: I-03a.5-[(E)-3,3-diethoxypropa-1-enyl]-2-methylpyridine A mixture of 5-bromo-2-methylpyridine (20 g, 116.26 mmol, 1 equivalent), 3,3-diethoxypropene (60.54 g, 465.06 mmol, 70.89 ml, 4 equivalents), Pd(OAc)2 (1.31 g, 5.81 mmol, 0.05 equivalents), K2CO3 (32.14 g, 232.53 mmol, 2 equivalents), KCl (8.67 g, 116.26 mmol, 1 equivalent), and tetrabutylammonium acetate (70.11 g, 232.53 mmol, 70.82 ml, 2 equivalents) in 400 ml of DMF was degassed, purged three times with N2, and then stirred at 80°C for 16 hours under an N2 atmosphere. The reaction mixture was concentrated, diluted with water (1000 mL), and extracted with EA (300 mL x 3). The combined organic layer was washed with brine (300 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 5-[(E)-3,3-diethoxypropa-1-enyl]-2-methylpyridine (27 g, crude) as a red liquid, which was used directly in the next step.

[0219] Step 2: I-03b.(E)-3-(6-methyl-3-pyridyl)prop-2-enal A solution of 5-[(E)-3,3-diethoxypropa-1-enyl]-2-methylpyridine (27 g, 122.01 mmol, 1 equivalent) in HCl (1 M, 244 mL, 2 equivalents) was stirred at 25°C for 0.5 hours. The mixture was adjusted to pH 6-7 with saturated NaHCO3 solution (230 ml) and extracted with EA (200 ml x 3). The combined organic layers were washed with brine (500 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (PE:EA = 10:1-2:3) to obtain (E)-3-(6-methyl-3-pyridyl)propa-2-enal (14.2 g, yield 79.06%) as a yellow solid. LC / MS: m / z 148.1[M+1]+:RT: 0.21 min (Method D). 1 H NMR(CHCl3,400MHz)δ ppm 9.65(d,J=7.6Hz,1H),8.59(d,J=2.2Hz,1H),7.72(dd,J=2.4,8.1Hz,1H),7.40(d ,J=16.0Hz,1H),7.17(d,J=8.1Hz,1H),6.67(dd,J=7.6,16.1Hz,1H),2.55(s,3H).

[0220] Step 3: I-03c.tert-butyl(3S)-5-hydroxy-3-(6-methyl-3-pyridyl)isoxazolidine-2-carboxylate To a solution of [diphenyl-[(2R)-pyrrolidine-2-yl]methoxy]trimethylsilane (6.95 g, 21.34 mmol, 0.2 equivalents) in CHCl3 (160 ml), (E)-3-(6-methyl-3-pyridyl)prop-2-enal (15.7 g, 106.68 mmol, 1 equivalent) was added all at once at 0°C, and the mixture was stirred at 0°C for 30 minutes. Then, tert-butyl N-hydroxycarbamate (15.62 g, 117.34 mmol, 1.1 equivalents) was added. The mixture was smoothly warmed to 25°C and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was separated by preparative RP LC (flow rate: 400 mL / min; gradient: 95% H2O (0.1% FA) / 5% ACN to 85% H2O (0.1% FA) / 15% ACN at 20 min; 85% H2O (0.1% FA) / 15% ACN at 20 min; 79% H2O (0.1% FA) / 21% ACN at 10 min; 79% H2O (0.1% FA) / 21% ACN at 15 min; column: Phenomenex Luna The sample was purified using a C18 filter (10 μm, 100 Å, ID 150 mm × H 400 mm) to obtain tert-butyl(3S)-5-hydroxy-3-(6-methyl-3-pyridyl)isoxazolidine-2-carboxylate (15.2 g, yield 50.84%) as a yellow oily substance. LC / MS: m / z 281.2[M+1] + ;RT 0.677 min (Method D). 1 H NMR(DMSO-d6,400MHz)δ ppm 8.36(d,J=2.2Hz,1H),7.57(dd,J=2.3,8.1Hz,1H),7.22(d,J=7.9Hz,1H),6.95(br d,J=1.5Hz,1H),5.63(t,J=3.9Hz,1H),5.19(t,J=8.3Hz,1H),2.58(dd,J=8. 4,12.4Hz,1H),2.44(s,3H),2.13(ddd,J=4.3,8.2,12.1Hz,1H),1.37(s,9H).

[0221] Step 4: I-03d.N-hydroxy-N-[(1S)-3-hydroxy-1-(6-methyl-3-pyridyl)propyl]carbamate To a methanol (155 ml) solution of tert-butyl(3S)-5-hydroxy-3-(6-methyl-3-pyridyl)isoxazolidine-2-carboxylate (15.2 g, 54.22 mmol, 1 equivalent), NaBH4 (2.26 g, 59.65 mmol, 1.1 equivalents) was gradually added at 0°C. The mixture was stirred at 0°C for 2 hours under an N2 atmosphere. The mixture was quenched with saturated NH4Cl solution (100 mL), diluted with water (100 mL), extracted with EA (200 mL x 2), dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by preparative RP LC (flow rate: 100 mL / min; gradient: 10 min from 100% H2O (0.1% FA) / 0% ACN to 78% H2O (0.1% FA) / 22% ACN; 20 min from 78% H2O (0.1% FA) / 22% ACN to 78% H2O (0.1% FA) / 22% ACN; column: Welch Ultimate XB_C18, 20-40 μm, 120 Å, ID 32 mm × H 210 mm) to obtain tert-butyl N-hydroxy-N-[(1S)-3-hydroxy-1-(6-methyl-3-pyridyl)propyl]carbamate (7.45 g, yield 46.23%, ee 83.492%) as a yellow gum-like substance. LC / MS: m / z 283.1[M+1] + ;RT=0.485 min (Method D). 1 H NMR(DMSO-d6 400MHz)δ ppm 9.15(s,1H),8.37(d,J=1.8Hz,1H),7.62(dd,J=2.2,7.9Hz,1H),7.21(d,J=8.1Hz,1H),5.15(dd,J=6.8,8.3Hz,1H), 4.51(t,J=4.8Hz,1H),3.45(qd,J=5.6,11.0Hz,1H),2.44(s,3H),2.23-2.05(m,1H),1.93-1.81(m,1H),1.37(s,9H). s Enantiomer Chiral SFC RT: 1.648 minutes (Method J).

[0222] Step 5: I-03e.tert-butyl(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carboxylate To a solution of N-hydroxy-N-[(1S)-3-hydroxy-1-(6-methyl-3-pyridyl)propyl]carbamate (7.45 g, 26.39 mmol, 1 equivalent) in THF (75 ml), tributylphosphan (8.54 g, 42.22 mmol, 10.42 ml, 1.6 equivalents) and DIAD (6.94 g, 34.30 mmol, 6.67 ml, 1.3 equivalents) were added at 0°C. The mixture was smoothly heated to 25°C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative RP LC (flow rate: 200 mL / min; gradient: 80% H2O (0.1% FA) / 20% ACN to 60% H2O (0.1% FA) / 40% ACN in 12 minutes; 60% H2O (0.1% FA) / 40% ACN in 15 minutes; column: Welch Ultimate XB_C18, 20 μm, 100 Å, ID 75 mm × H 348 mm) to obtain I-03e (5.2 g, yield 74.61%) as a yellow oily substance.

[0223] 5.2 g of I-03e was further purified by SFC (column: Chiralpak IC-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A is CO2, phase B is MeOH (0.05% DEA); gradient elution: 5-40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 Bar) to obtain tert-butyl(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carboxylate (peak 1, 4.7 g, >99.9% ee) as a yellow oily substance and (3R)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carboxylate (peak 2, 313 mg, 99.13% ee) as a yellow oily substance. LC / MS: m / z 265.1[M+1] + ;RT: 0.755 minutes (Method D). 1HNMR(DMSO-d6 400MHz,)δ=8.38(d,J=2.3Hz,1H),7.59(dd,J=2.4,8.0Hz,1H),7.23(d,J=8.0Hz,1H),5.16(dd,J=6.0,8.5Hz,1H),4.15(dt,J=3.0,7.8Hz,1H), 3.74(ddd,J=7.0,8.2,9.1Hz,1H),2.79(dddd,J=3.1,6.8,8.8,12.1Hz,1H),2.44(s,3H),2.16(dddd,J=6.0,7.6,9.3,12.2Hz,1H),1.38(s,9H). Chiral SFC:s Enantiomer RT: 1.463 min (Method K, 100%) Chiral SFC:s Enantiomer RT: 2.042 min (Method K, 100%)

[0224] I-03: (3S)-3-(6-methyl-3-pyridyl)isoxazolidine (corresponding to compound (III) of formula) 500 mg, 1.89 mmol of tert-butyl(S)-3-(6-methylpyridine-3-yl)isoxazolidine-2-carboxylate was dissolved in 15 ml of DCM, and 1.5 ml, 19.47 mmol of TFA was added at room temperature with stirring. After standing overnight, the solvent was removed under vacuum. The residue was freeze-dried to obtain 693 mg of the title compound. LC / MS: m / z = 165.4 [M + H] + ;RT: 0.22 min (LC / MS-Method A).

[0225] Intermediate I-04: 3-(5-fluoro-3-pyridyl)isoxazolidine HCl / TFA salt (corresponding to compound (III)) Step 1: I 04-1a: (E)-3-(5-fluoro-3-pyridyl)prop-2-enal A mixture of 3-bromo-5-fluoropyridine (48 g), propa-2-enal (45.87 g), Pd(OAc)2 (3.06 g), benzyltriethylammonium chloride (62.12 g), and TEA (82.80 g) in DMF (400 ml) was stirred at 70°C for 12 hours under an N2 atmosphere. The mixture was concentrated, diluted with water (800 ml), extracted with ethyl acetate (500 ml x 3), washed with saturated saline (1 l), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel column chromatography (PE:EA = 1:1) to obtain 26.7 g of the title compound. 1 1H NMR (CDCl 3400MHz): δ ppm 9.77(1H),8.62(1H),8.55(1H),7.60(1H),7.50(1H),6.78(1H).

[0226] Step 2: I-04-1b: tert-butyl(S)-3-(5-fluoro-3-pyridyl)-5-hydroxyisoxazolidine-2-carboxylate To a solution of diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]-trimethylsilane (21.54 g, 66.16 mmol, 0.2 equivalents) in CHCl3 (500 ml), (E)-3-(5-fluoropyridine-3-yl)acrylaldehyde (50 g, 330.82 mmol, 1 equivalent) was added and the mixture was stirred at 0°C for 30 minutes. Then, tert-butyl N-hydroxycarbamate (48.45 g, 363.91 mmol, 1.1 equivalents) was added at 0°C. The mixture was smoothly heated to 25°C and stirred for 12 hours. LC-MS showed that the desired mass was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative RP LC (flow rate: 400 mL / min; gradient: 85% H2O (0.1% FA) / 15% ACN to 65% H2O (0.1% FA) / 35% ACN at 60 min; 65% H2O (0.1% FA) / 35% ACN to 65% H2O (0.1% FA) / 35% ACN at 20 min; column: Phenomenex luna C18, 15 μm, 100 Å, ID 150 mm × H 400 mm) to obtain tert-butyl(S)-3-(5-fluoro-3-pyridyl)-5-hydroxy-isoxazolidine-2-carboxylate (45 g, 158.29 mmol, yield 47.85%) as a yellow solid. LC / MS: m / z = 285.2[M+H] + RT: 0.775 minutes (LC / MS - Method C) was obtained.

[0227] Step 3: I-04-1c: tert-butyl N-[(1S)-(5-fluoro-3-pyridyl)-3-hydroxypropyl]-N-hydroxycarbamate To a solution of tert-butyl 3-(5-fluoro-3-pyridyl)-5-hydroxy-isoxazolidine-2-carboxylate (45 g, 158.29 mmol, 1 equivalent) in MeOH (450 ml), NaBH4 (5.99 g, 158.29 mmol, 1 equivalent) was added at 0°C, and the mixture was stirred at 0°C for 15 minutes. LC-MS confirmed the detection of the desired mass. The reaction mixture was quenched with saturated NH4Cl solution (40 ml), diluted with water (100 ml), and extracted with ELISA (600 ml x 3). The combined organic layers were washed with brine (1200 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative RP LC (flow rate: 400 mL / min; gradient: 51 min from 90% H2O (0.1% FA) / 10% ACN to 64% H2O (0.1% FA) / 36% ACN; 11 min from 64% H2O (0.1% FA) / 36% ACN to 64% H2O (0.1% FA) / 36% ACN; column: Phenomenex luna C18 (15 μm, 100 Å, ID 150 mm × H 400 mm) to obtain tert-butyl 3-(5-fluoro-3-pyridyl)isoxazolidine-2-carboxylate (35 g, yield 77.23%) as a yellow oily substance. LC / MS: m / z = 287.2[M+H] + RT: 0.685 minutes (LC / MS - Method C) was obtained.

[0228] Step 4: I-04-1d: tert-butyl(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-carboxylate To a solution of tert-butyl 3-(5-fluoro-3-pyridyl)isoxazolidine-2-carboxylate (33 g, 115.26 mmol, 1 equivalent) in THF (400 ml), tributylphosphan (37.31 g, 184.42 mmol, 45.50 ml, 1.6 equivalents) and DIAD (30.30 g, 149.84 mmol, 29.13 ml, 1.3 equivalents) were added at 0°C. The mixture was smoothly warmed to 25°C and stirred for 12 hours. LC-MS showed that the desired mass was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was combined with the previous batch on a 2g scale and purified by preparative RP LC (flow rate: 400 mL / min; gradient: 75% H2O (0.1% FA) / 25% ACN to 52% H2O (0.1% FA) / 48% ACN at 50 min; 52% H2O (0.1% FA) / 48% ACN to 52% H2O (0.1% FA) / 48% ACN at 11 min; column: Phenomenex luna C18, 15 μm, 100 Å, ID 150 mm × H 400 mm) and silica gel column chromatography (PE:EA = 4:1 to 2:1) to obtain intermediate I-04 (23.5 g, yield 75.99%, 71.3% ee) as a yellow oily substance, which is a mixture of the two isomers.

[0229] The product was further purified by SFC (column: DAIEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3H2O ​​MEOH]; B%: 35%~35%, 5.4; 400 min) to obtain I-04-1d-peak 1 (2.5 g, yield 10.48%, >99.9% ee) as a yellow oily substance and I-04-peak 2 (18 g, yield 75.91%, >99.9% ee) as a yellow oily substance. LC / MS: m / z = 269.2[M+H] + RT: 0.741 minutes (LC / MS - Method C) was obtained. 1H NMR(CDCl3,400MHz):δ ppm 8.47-8.33(m,2H),7.45(td,J=2.0,9.3Hz,1H),5.28(dd,J=5.6,8.8Hz,1H),4.20(dt,J=3.5,7.9Hz,1H),3.89(dt, J=7.1,8.6Hz,1H),2.84(dddd,J=3.4,7.1,8.8,12.3Hz,1H),2.28(dddd,J=5.6,7.8,9.1,12.3Hz,1H),1.47(s,9H). Chiral SFC:S isomer RT 1.297 min (100%, Method I) Chiral SFC:RT of R isomer 0.691 min (100%, Method I)

[0230] Step 5: I-04-1: 3-(5-fluoro-3-pyridyl) isoxazolidine TFA salt 174.4 mg of tert-butyl 3-(5-fluoro-3-pyridyl)isoxazolidine-2-carboxylate was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (0.5 ml) and stirred overnight. The mixture was evaporated under reduced pressure and freeze-dried twice to obtain 158 mg of the title compound. LC / MS: m / z=169.2[M+H]+; RT: 0.69 min (LC / MS-Method A)

[0231] I-04-2: (3S)-3-(5-fluoro-3-pyridyl)isoxazolidine HCl salt (corresponding to compound (III) of formula) Step 1: I-04-2a: tert-butyl 3-(5-fluoro-3-pyridyl)-5-hydroxyisoxazolidine-2-carboxylate To a solution of [diphenyl-[(2S)-pyrrolidine-2-yl]methoxy]trimethylsilane (11.50 g) in chloroform (260 ml), (E)-3-(5-fluoro-3-pyridyl)prop-2-enal (26.7 g) and tert-butyl N-hydroxycarbamate (28.23 g) were added at 0°C. The mixture was smoothly heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated. The residue was purified using preparative RP-LC (flow rate: 400 ml / min; gradient: 90% H2O (0.1% FA) / 10% ACN to 60% H2O (0.1% FA) / 40% ACN over 50 minutes; 60% H2O (0.1% FA) / 40% ACN to 60% H2O (0.1% FA) / 40% ACN over 25 minutes; column: Phenomenex luna C18, 15 μm, 100 Å, ID 150 mm × H 400 mm) to obtain 25 g of the title compound. 1 H NMR (CDCl3400MHz): δ ppm 8.45-8.37(2),7.44(1H),5.94-5.84(1H),5.39(1H),2.84(1H),2.33-2.20(1H),1.47(9H).

[0232] I-04-2b:tert-butylN-[(1S)-1-(5-fluoro-3-pyridyl)-3-hydroxypropyl]-N-hydroxycarbamate To a methanol (250 ml) solution of tert-butyl 3-(5-fluoro-3-pyridyl)-5-hydroxyisoxazolidine-2-carboxylate (25 g), NaBH4 (3.99 g) was added at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution (50 ml), then diluted with water (800 ml), and extracted with ethyl acetate (1 l x 3). The combined organic layers were washed with brine (1 l), dried over Na2SO4, filtered, and concentrated. The crude product was purified by RP-LC (flow rate: 200 ml / min; gradient: 90% H2O (0.1% FA) / 10% ACN to 60% H2O (0.1% FA) / 40% ACN in 15 min; 60% H2O (0.1% FA) / 40% ACN to 60% H2O (0.1% FA) / 40% ACN in 8 min; column: Welch Ultimate XB_C18, 20-40 μm, 120 Å, ID 95 mm × H 365 mm) to obtain 23.5 g of the title compound (enantiomer ratio: 94.7 (S): 5.3 (R)). 1 H NMR (CDCl3400MHz): δ ppm 8.49-8.30(2H),7.66-7.51(1H),5.33(1H),3.89-3.71(2H),2.41(1H),2.05(1H),1.47(9H). Chiral SFC:S isomer:tert-butyl N-[(1S)-1-(5-fluoro-3-pyridyl)-3-hydroxypropyl]-N-hydroxycarbamate:RT 0.90 min, 94.7% (Method I) Chiral SFC:R isomer:tert-butyl N-[(1R)-1-(5-fluoro-3-pyridyl)-3-hydroxypropyl]-N-hydroxycarbamate:RT 0.97 min, 5.3% (Method I)

[0233] Step 3. I-04-2c:tert-butyl(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-carboxylate To a solution of tert-butyl N-[1-(5-fluoro-3-pyridyl)-3-hydroxypropyl]-N-hydroxycarbamate (23.5 g) in THF (235 ml), tributyl phosphate (26.57 g) and DIAD (21.58 g) were added at 0°C. The mixture was smoothly heated to 25°C and stirred under an N2 atmosphere for 12 hours. The reaction mixture was then concentrated. The residue was purified by preparative RP HPLC (flow rate: 400 ml / min; gradient: 80% H2O (0.1% FA) / 20% ACN to 56% H2O (0.1% FA) / 44% ACN in 44 minutes; 56% H2O (0.1% FA) / 44% ACN to 56% H2O (0.1% FA) / 44% ACN in 19 minutes; column: Phenomenex luna C18, 15 μm, 100 Å, ID 150 mm × H 400 mm), and then purified by silica gel column chromatography (PE:EA = 10:1 to 0:1) to obtain 14.3 g of the title compound. 1 H NMR (CDCl3400MHz): δ ppm 8.42(1H),8.38(1H),7.46(1H),5.28(1H),4.21(1H),3.90(1H),2.85(1H),2.29(1H),1.48(9H). Chiral HPLC: (Chiralcel AD-H, 4.6 mm x 250 mm, 5 μm; EtOH + 0.1% IPA; flow rate 0.75 ml / min; T30°C). tert-butyl(3R)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-carboxylate; RT 5.47 min (5.3%). tert-butyl(3S)-3-(5-fluoro-3-pyridyl)isoxazolidine-2-carboxylate:RT 10.18 min, 94.7%.

[0234] I-04-2: (3S)-3-(5-fluoro-3-pyridyl)isoxazolidine HCl salt (corresponding to compound (III) of formula) Following general procedure 2, 129 mg of the title compound was obtained. LC / MS: m / z=169.2[M+H]+; RT: 0.68 min (LC / MS-Method A).

[0235] Intermediate I-05: (3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine (corresponding to compound (III)) Step 1: I-05a: (E)-3-(6-chloro-5-fluoro-3-pyridyl)propa-2-enal A mixture of 5-bromo-2-chloro-3-fluoropyridine (35 g, 166.32 mmol, 1 equivalent), acrolein (37.30 g, 665.30 mmol, 44.51 ml, 4 equivalents), Pd(OAc)2 (3.73 g, 16.63 mmol, 0.1 equivalent), benzyl(triethyl)ammonium chloride (37.88 g, 166.32 mmol, 1 equivalent), and TEA (50.49 g, 498.97 mmol, 69.45 ml, 3 equivalents) in 360 ml of DMF was stirred at 80°C for 8 hours under an N2 atmosphere. The reaction mixture was concentrated, diluted with water (2000 mL), and extracted with EA (1500 mL x 3). The combined organic layers were washed with brine (2000 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 5:1) to obtain compound (E)-3-(6-chloro-5-fluoro-3-pyridyl)propa-2-enal (14 g, yield 45.36%) as a yellow solid. 1 H NMR(CDCl3,400MHz):δ ppm 9.76(d,J=7.4Hz,1H),8.40(d,J=2.0Hz,1H),7.67(dd,J=2.0,8.4Hz,1H),7.46(d,J=16.1Hz,1H),6.75(dd,J=7.3,16.1Hz,1H).

[0236] Step 2: I-05b: (E)-3-(5-fluoro-6-methyl-3-pyridyl)propa-2-enal A mixture of compound (E)-3-(6-chloro-5-fluoro-3-pyridyl)propa-2-enal (8 g, 43.11 mmol, 1 equivalent), methylboronic acid (7.74 g, 129.32 mmol, 3 equivalents), Pd(PPh3)4 (9.96 g, 8.62 mmol, 0.2 equivalents), and K2CO3 (17.87 g, 129.32 mmol, 3 equivalents) in dioxane (80 ml) was stirred at 100 °C for 12 hours. The reaction mixture was diluted with water (200 mL) and extracted with EA (150 mL x 3). The combined organic layers were washed with brine (300 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 4:1) to obtain (E)-3-(5-fluoro-6-methyl-3-pyridyl)propa-2-enal (3.6 g, yield 50.56%) as a yellow solid. LC / MS; m / z 166.2[M+1] + :RT: 0.586 minutes (Method C). 1 H NMR (CDCl3 400MHz): δ ppm 9.74(d,J=7.5Hz,1H),8.48(s,1H),7.57-7.43(m,2H),6.73(dd,J=7.5,16.1Hz,1H),2.59(d,J=2.9Hz,3H).

[0237] Step 3: I-05 c;tert-butyl(3S)-3-(5-fluoro-6-methyl-3-pyridyl)-5-hydroxy-isoxazolidine-2-carboxylate To a solution of [diphenyl-[(2R)-pyrrolidine-2-yl]methoxy]trimethylsilane (2.56 g, 7.87 mmol, 0.2 equivalents) in CHCl3 (60 ml), (E)-3-(5-fluoro-6-methyl-3-pyridyl)prop-2-enal (6.5 g, 39.35 mmol, 1 equivalent) was added at 0°C, and the mixture was stirred at 0°C for 0.5 hours. Then, tert-butyl N-hydroxycarbamate (5.76 g, 43.29 mmol, 1.1 equivalents) was added at 0°C, and the mixture was smoothly heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative RP LC (flow rate: 200 mL / min; gradient: 85% H2O (0.1% FA) / 15% ACN to 50% H2O (0.1% FA) / 50% ACN in 28 mins; 50% H2O (0.1% FA) / 50% ACN to 50% H2O (0.1% FA) / 50% ACN in 10 mins; column: Welch Ultimate XB_C18 20~40 μm, 120 Å, ID 75 mm × H 348 mm) to obtain tert-butyl(3S)-3-(5-fluoro-6-methyl-3-pyridyl)-5-hydroxyisoxazolidine-2-carboxylate (6.3 g, yield 53.66%) as a brown oily substance. LC / MS: m / z 299.2 [M+1] + ;RT: 0.692 minutes (Method C). 1 H NMR(CDCl3400MHz):δ ppm 8.27(s,1H),7.34(dd,J=1.8,10.0Hz,1H),5.90(d,J=4.2Hz,1H),5.60(br s,1H),5.33(t,J=8.3Hz,1H),2.80(dd,J=8.4,12.5Hz,1H),2.52(d,J=2.8Hz,3H),2.30-2.19(m,1H),1.45(s,9H).

[0238] Step 4. I-05d: tert-butyl N-[(1S)-1-(5-fluoro-6-methyl-3-pyridyl)-3-hydroxypropyl]-N-hydroxycarbamate To a methanol solution (50 ml) of tert-butyl(3S)-3-(5-fluoro-6-methyl-3-pyridyl)-5-hydroxyisoxazolidine-2-carboxylate (5 g, 16.76 mmol, 1 equivalent), NaBH4 (507.26 mg, 13.41 mmol, 0.8 equivalents) was added at 0°C, and the mixture was stirred at 0°C for 15 minutes. The reaction mixture was quenched with saturated NH4Cl solution (20 ml), diluted with water (100 ml), and extracted with EA (100 ml x 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was combined with the previous batch on a 2g scale and purified by preparative RP LC (flow rate: 400 mL / min; gradient: 95% H2O (0.1% FA) / 5% ACN to 65% H2O (0.1% FA) / 35% ACN at 28 min; 65% H2O (0.1% FA) / 35% ACN to 65% H2O (0.1% FA) / 35% ACN at 10 min; Welch Ultimate XB_C18 20-40 μm, 120 Å ID75 mm × H348 mm) to obtain tert-butyl N-[(1S)-1-(5-fluoro-6-methyl-3-pyridyl)-3-hydroxypropyl]-N-hydroxycarbamate (6.5 g, crude, 94.5% ee) as a pale yellow oil. LC / MS: m / z 301.2[M+1] + ;RT: 0.705 min (Method C). 1 H NMR(CDCl3,400MHz):δ ppm 8.20(s,1H),7.99(br d,J=4.6Hz,1H),7.45(dd,J=1.7,10.1Hz,1H),5.33(dd,J=4.6,10.9Hz,1H),3.86- 3.71(m,2H),2.76-2.44(m,1H),2.44-2.35(m,4H),2.04-1.95(m,1H),1.49(s,9H) Chiral SFC:s Enantiomer RT: 1.41 min (97.3%, Method L) Chiral SFC:R Enantiomer RT: 1.34 min (2.7%, Method L).

[0239] Step 5: I-05e:3.5.tert-butyl(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-carboxylate To a solution of tert-butyl N-[(1S)-1-(5-fluoro-6-methyl-3-pyridyl)-3-hydroxypropyl]-N-hydroxycarbamate (6 g, 19.98 mmol, 1 equivalent) in THF (60 ml), tributyl phosphate (6.47 g, 31.97 mmol, 7.89 ml, 1.6 equivalents) and DIAD (5.25 g, 25.97 mmol, 5.05 ml, 1.3 equivalents) were added at 0°C. The mixture was smoothly warmed to 20°C and stirred for 12 hours. The mixture was combined with the previous batch on a 500 mg scale and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative RP LC (flow rate: 400 mL / min; gradient: 90% H2O (0.1% FA) / 10% ACN to 60% H2O (0.1% FA) / 40% ACN in 20 mins; 60% H2O (0.1% FA) / 40% ACN to 60% H2O (0.1% FA) / 40% ACN in 8 mins; column: Welch Ultimate XB_C18 20-40 μm, 120 Å, ID 75 mm × H 348 mm) and silica gel column chromatography (PE:EA = 1:0 to 1:2) to obtain tert-butyl(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-carboxylate (4.6 g, yield 80.01%, purity 98.1%, 91.2% ee) as a colorless oil. The product was further purified by SFC (column: DAIEL CHIRALPAK IC (250 mm × 30 mm, 5 μm); mobile phase: [0.1% NH3H2O ​​MEOH]; B%: 30%~30%, 4.0 min; 70 min) to obtain I-05e (3.5 g, yield 74.66%, >99.9% ee) as a yellow oily substance. LC / MS: m / z 283.2[M+1] + ;RT: 0.814 minutes (Method C). 1H NMR(CDCl3,400MHz):δ ppm 8.28(s,1H),7.40(dd,J=1.8,10.0Hz,1H),5.24(dd,J=5.6,8.7Hz,1H),4.20(dt,J=3.4,8.0Hz,1H),3.89(dt,J=7.1,8.6Hz, 1H),2.82(dddd,J=3.5,7.1,8.8,12.3Hz,1H),2.52(d,J=2.9Hz,3H),2.27(dddd,J=5.6,7.8,9.0,12.3Hz,1H),1.48(s,9H). Chiral SFC:RT 1.13 minutes (100%, Method K)

[0240] Intermediate I-05: (3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine TFA salt (corresponding to compound (III)) Following general procedure 3, 656 mg of the title compound was obtained. LC / MS: m / z = 183.1 [M + H] + ;RT: 0.79 minutes (Method A).

[0241] Intermediate I-28: (3S)-3-(2-methyloxazol-4-yl)isoxazolidine HCl salt Step 1: I-28a. 2-Methyloxazole-4-carbaldehyde Similar to step 5 of I-05, starting with methyl 2-methyloxazole-4-carboxylate (10.0 g, 0.0709 mol, 1.00 equivalent), 2-methyloxazole-4-carbaldehyde (crude, containing a large amount of solvent toluene) was obtained and used in the next step without purification.

[0242] Step 2: I-28b.(E)-3-(2-methyloxazol-4-yl)propa-2-enal Similar to step 5 of I-05b, starting with 2-methyloxazole-4-carbaldehyde (84.9 g, 0.279 mol), (E)-3-(2-methyloxazole-4-yl)propa-2-enal (12.1 g, 0.0829 mol, 29.7% yield in 2 steps) was obtained. 1H NMR(400MHz, CDCl3)δ=9.66(d,J=8.0Hz,1H),7.80(s,1H),7.28(d,J=15.6Hz,1H),6.82(dd,J=15.6,8.0Hz,1H),2.51(s,3H).

[0243] Step 3. I-28c. tert-butylrac-(3S)-5-hydroxy-3-(2-methyloxazol-4-yl)isoxazolidine-2-carboxylate Similar to step 5 of I-05c, starting with (E)-3-(2-methyloxazol-4-yl)propa-2-enal (6.40 g, 0.0467 mol), tert-butylrac-(3S)-5-hydroxy-3-(2-methyloxazol-4-yl)isoxazolidine-2-carboxylate (8.50 g, purity 67.0%, yield 45.1%) was obtained as a brown gum-like substance. 1 H NMR(400MHz,DMSO-d6)δ=7.80(s,1H),6.88-6.80(m,1H),5.58(s,1H),5.13(t,J=7.6Hz,1H),2.38-2.34(m,5H),1.40(s,9H).

[0244] Step 4. I-28d. tert-butyl N-hydroxy-N-[(1S)-3-hydroxy-1-(2-methyloxazol-4-yl)propyl]carbamate Similar to step 5 of I.05d, tert-butylrac-(3S)-5-hydroxy-3-(2-methyloxazol-4-yl)isoxazolidine-2-carboxylate (14.5 g, purity 67.0%, 0.0354 mol) was used to obtain tert-butylN-hydroxy-N-[(1S)-3-hydroxy-1-(2-methyloxazol-4-yl)propyl]carbamate (8.10 g, purity 80.0%, 0.0238 mol, yield 67.2%) as a yellow gum-like substance. 1H NMR(400MHz,DMSO-d6)δ=8.87(s,1H),7.72(d,J=1.2Hz,1H),5.08(dd,J=8.4,5.6Hz,1H) ,4.44(t,J=4.8Hz,1H),3.47-3.38(m,2H),2.35(s,3H),1.97-1.85(m,2H),1.41(s,9H).

[0245] Step 5. I-28 e.tert-butyl(3S)-3-(2-methyloxazol-4-yl)isoxazolidine-2-carboxylate Similar to step 5 of I.05e, starting with tert-butyl N-hydroxy-N-[(1S)-3-hydroxy-1-(2-methyloxazol-4-yl)propyl]carbamate (8.10 g, purity 80.0%, 0.0238 mol, 1.00 equivalent), the crude product (3S)-3-(2-methyloxazol-4-yl)isoxazolidine-2-carboxylate (5.80 g, 48.4% ee) was obtained as a white solid. The above product was recrystallized in cosolvent PE / siRNA (v / v 20 / 1) to obtain pure tert-butyl (3S)-3-(2-methyloxazol-4-yl)isoxazolidine-2-carboxylate (2.30 g, 98.8% ee, 39.7% yield). 1 H NMR(400MHz,CDCl3)δ=7.47(d,J=0.8Hz,1H),5.20(dd,J=8.8,4.4Hz,1H),4.15(td,J=7.6,4.8 Hz, 1H), 3.89 (q, J=7.6Hz, 1H), 2.66-2.56 (m, 1H), 2.52-2.45 (m, 1H), 2.43 (s, 3H), 1.50 (s, 9H). LCMS(ESI)m / z=277.2[M+Na] + and 531.3[2M+Na] + ;RT 0.50 min (Method Q). Chiral SFC:RT 0.773 minutes (100%, Method G)

[0246] Step 6. I-28. (3S)-3-(2-methyloxazol-4-yl)isoxazolidine HCl salt. Following general procedure 2, a 1.50g white solid with a purity of approximately 66.7% was obtained and used as is.

[0247] Intermediate I-29; (3S)-3-(5-methylpyrazine-2-yl)isoxazolidine As stated in the international publication pamphlet No. 2021245070A1.

[0248] Intermediate I-30: (3S)-3-(6-methylpyrazine-2-yl)isoxazolidine As stated in the international publication pamphlet No. 2021245070A1.

[0249] Intermediate I-31: (3S)-3-(5-methyl-3-pyridyl)isoxazolidine As stated in the international publication pamphlet No. 2021245070A1.

[0250] General synthesis of intermediates I-06 to I-13 and I-32 to I-36. Intermediate I-06: 4-Piperidyl-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanonetrifluoroacetate (corresponding to compound (IIb)) (following scheme 2) Step 1: I-06a: tert-butyl 4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]piperidine-1-carboxylate Following general procedure 1, 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (1.3 g) was dissolved in dry DMF (25 ml), and DIPEA (2.99 ml) and HATU (3.8 g) were added with stirring. After 15 minutes, (3S)-3-pyrazine-2-ylisoxazolidine TFA salt (1.3 g) dissolved in dry DMF (10 ml) was added with stirring. After 2 hours, saturated sodium bicarbonate solution was added, and the aqueous phase was extracted with EA (3x). The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (80 g SiO2, 100% n-heptane to 100% EA in 20 minutes). The fractions containing the product were combined, and the solvent was removed under vacuum. The residue was further purified by preparative HPLC (flow rate 50 ml / min; 90% H2O / 10% ACN to 10% H2O / 90% ACN in 15 minutes; Agilent Prep C18-10 μm, 30 × 250 mm). The fractions containing the product were combined, ACN was removed under vacuum, and the aqueous phase was freeze-dried overnight to obtain 1.07 g of the title compound. LC / MS: m / z = 363.3[M+H] + ;RT: 1.76 min (LC / MS-Method A).

[0251] Step 2: I-06: 4-Piperidyl-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanotrifluoroacetate Following general procedure 3, 1.75 g of the title compound was obtained. LC / MS: m / z = 263.2[M+H] + ;RT: 0.39 minutes (Method A).

[0252] Similarly, the following intermediates were synthesized.

[0253] Intermediate I-07: (3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-yl]-(4-piperidyl)methanone; 2,2,2-trifluoroacetic acid (corresponding to the compound of formula (IIb)) (following scheme 2) Step 1: Intermediate I-07 Following general procedure 1, starting with 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (162.1 g, 0.697 mmol) and (3S)-3-(2-methylthiazole-4-yl)isoxazolidine, we obtained 2,2,2-trifluoroacetic acid (179 mg, 0.63 mmol)tert-butyltert-butyl4-[(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-carbonyl]piperidine-1-carboxylate (240 mg, 72%). LC / MS: m / z = 382.2[M+H] + ;RT: 0.736 minutes (Method B).

[0254] Step 2: Intermediate I-09 - (3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-yl)-(4-piperidyl)methanone; 2,2,2-trifluoroacetic acid Following general procedure 3, the title compound was obtained in 99% yield, starting with tert-butyl(S)-4-(3-(5-fluoropyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-carboxylate (600 mg, 1.58 mmol). LC / MS: m / z = 282.1[M+H] + ;RT: 0.668 min (Method E).

[0255] Intermediate I-08 Step 1: Benzyl 4-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]piperidine-1-carboxylate (corresponding to compound (IIb)) (follow scheme 2) Following general procedure 1, intermediate I-03 (5 g, 18.28 mmol, 1 equivalent, 3HCl) and 1-benzyloxycarbonylpiperidine-4-carboxylic acid (5.05 g, 19.19 mmol, 1.05 equivalents) were stirred at 20°C for 2 hours to obtain the title compound (7.4 g, 93.94% yield) as a red oil. LC / MS m / z 410.3[M+1] + ;RT 0.776 (Method C) 1H NMR(CDCl3,400MHz)δ ppm 8.46(d,J=2.0Hz,1H),7.56(dd,J=2.3,8.1Hz,1H),7.40-7.29(m,5H),7. 17(d,J=8.1Hz,1H),5.40(dd,J=6.1,8.7Hz,1H),5.13(s,2H),4.30(dt,J =3.4,7.8Hz,1H),4.26-4.08(m,2H),3.98-3.87(m,1H),3.03-2.81(m,4H ),2.57(s,3H),2.43-2.31(m,2H),2.01-1.81(m,1H),1.79-1.62(m,3H).

[0256] [(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]-(4-piperidyl)methanone To a solution of benzyl 4-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]piperidine-1-carboxylate (6.4 g, 15.63 mmol, 1 equivalent) in ACN (64 ml), Pd / C (640 mg, 10% purity) was added under an N2 atmosphere. This suspension was degassed and purged three times under an H2 atmosphere. The mixture was stirred under H2 (15 Psi) at 20°C for 3 hours. LC / MS showed that the desired mass was detected. The mixture was filtered and concentrated. The residue was purified by preparative HPLC (column: Kromasil Eternity XT 250×80mm×10um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 10%~40%, 18 min) to obtain I-08 (2.2g, yield 44.26%, ee 95.3%) as a white solid. LC / MS, m / z 276.0[M+1] + ;RT 1.377 minutes (Method D) 1H NMR(CDCl3,400MHz)δ ppm 8.46(d,J=2.1Hz,1H),7.51(dd,J=2.3,8.1Hz,1H),7.12(d,J=7.9Hz,1H),5.40(dd,J=6.2,8.6Hz,1H),4.28(dt,J=3.4,7.8Hz,1H ),3.95-3.86(m,1H),3.14(dt,J=4.1,8.4Hz,2H),2.96-2.80(m,2H),2.76-2.63(m,2H),2.54(s,3H),2.40-2.29(m,1H),1.88(br dd,J=2.5,13.0Hz,1H),1.73(br s, 1H), 1.68 (td, J=4.2, 8.3Hz, 2H), 1.65-1.58 (m, 1H). Chiral SFC RT of S-enantiomers 1.361 min (97.6%, Method P).

[0257] Intermediate I-09: (S)-(3-(5-fluoropyridine-3-yl)isoxazolidine-2-yl)(piperidine-4-yl)methanone, 2,2,2-trifluoroacetic acid (corresponding to the compound of formula (IIb)) (following scheme 2) Step 1: (S)-4-(3-(5-fluoropyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-carboxylate Following general procedure 1, tert-butyl(S)-4-(3-(5-fluoropyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-carboxylate (3.2 g, 55%) was obtained starting from 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.43 g, 6.22 mmol) and (S)-3-(5-fluoropyridine-3-yl)isoxazolidine-2-carbonyl)piperidine-1-carboxylate, which corresponds to intermediate I-04-1. LC / MS: m / z = 280.1[M+1-Boc] + ;RT: 0.79 minutes (Method B).

[0258] Step 2: (S)-(3-(5-fluoropyridine-3-yl)isoxazolidine-2-yl)(piperidine-4-yl)methanone, 2,2,2-trifluoroacetic acid The title compound was obtained in 99% yield following general procedure 3. LC / MS: m / z = 280.2[M+H] + ;RT: 0.39 minutes (Method B).

[0259] Intermediate I-10[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-yl]-(4-piperidyl)methanone (corresponding to compound (IIb)) Step 1: To a 15 ml solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.71 g, 7.46 mmol, 1.2 equivalents) in DMF (15 ml), HBTU (4.72 g, 12.44 mmol, 2 equivalents) and DIEA (4.82 g, 37.32 mmol, 6.50 ml, 6 equivalents) were added, and the mixture was stirred at 25°C for 15 minutes. Intermediate I-05 (1.36 g, 6.22 mmol, 1 equivalent, HCl) was added, and the mixture was stirred at 25°C for 12 hours under an N2 atmosphere. LC-MS showed that the desired mass was detected. The mixture was filtered and purified by preparative RP LC (flow rate: 200 ml / min; gradient: 85% H2O (0.1% FA) / 15% ACN to 50% H2O (0.1% FA) / 50% ACN in 20 mins; 50% H2O (0.1% FA) / 50% ACN in 10 mins; column: Welch Ultimate XB_C18 20~40 μm; 120 Å, ID 75 mm × H 348 mm) and silica gel column chromatography (PE:EA = 2:1~0:1) to obtain I-10 (1.5 g, yield 61.30%, >99.9% ee) as a yellow solid. LC / MS: m / z = 394.3[M+1-Boc] + ;RT: 0.800 min (Method C). 1 1H NMR (CDCl 3,400MHz):δ ppm 8.26(s,1H),7.24(dd,J=1.8,9.9Hz,1H),5.40(dd,J=6.2,8.7Hz,1H),4.28(dt,J=3.4,7.7Hz,1H),4.18-4.04(m,2H),3.90(ddd,J=6.7,8.2,9. 2Hz,1H),2.96-2.76(m,4H),2.49(d,J=2.9Hz,3H),2.34(dddd,J=6.1,7 .5,9.3,12.4Hz,1H),1.93-1.83(m,1H),1.72-1.59(m,3H),1.45(s,9H). Chiral SFC:RT 1.999 minutes (100%, Method M).

[0260] Intermediate I-11: 5-azaspiro[2.5]octan-8-yl-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone, 2,2,2-trifluoroacetic acid (corresponding to compound (IIb)) Step 1: tert-butyl 8-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-5-azaspiro[2.5]octane-5-carboxylate A mixture of 5-tert-butoxycarbonyl-5-azaspiro[2.5]octane-8-carboxylic acid (800 mg, 3.13 mmol), (3S)-3-(6-methyl-3-pyridyl)isoxazolidine (943 mg, 3.45 mmol, 3HCl), HATU (2.38 g, 6.27 mmol), and DIEA (2.73 ml, 15.67 mmol) in DMF (8 ml) was stirred at 25°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenexluna C18 150×40mm×15um; mobile phase: [water (0.225% FA)-ACN]; B%: 20%~50%, 10 min) to obtain the title compound as a yellow solid (936 mg, 74%) as a mixture of the two isomers. 1H NMR(400MHz,CDCl3)δ=3.92-3.66(m,1H),3.40(d,J=13.6Hz,1H),3.31(t,J=10.8Hz,1H),3.13(d,J=13.6Hz,1H),2.1 5(t,J=4.8Hz,1H),2.06-1.96(m,1H),1.96-1.84(m,1H),0.68(d,J=9.2Hz,1H),0.64-0.53(m,2H),0.47-0.35(m,1H). LC / MS: m / z 402.1[M+1] + ;RT: 0.683 minutes (Method C). Chiral SFC:RT 1.216 (isomer 1, 44.76%, method O) 1.697 (isomer 2, 55.2%, method O) Step 2: 5-azaspiro[2.5]octan-8-yl-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone, TFA salt.

[0261] To a solution of tert-butyl 8-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-5-azaspiro[2.5]octane-5-carboxylate (300 mg, 747 μmol) in DCM (1.5 mL), TFA (332 μL, 4.48 mmol) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound as a yellow solid (240 mg). LC / MS: m / z 301.9 [M+1] + RT: 0.128 mins (broad peak) (Method D).

[0262] Intermediate 11-(R)-(8R)-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone and Intermediate 11-(S)-(8S)-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone A similar method was used, involving the coupling of two isomers of 5-tert-butoxycarbonyl-5-azaspiro[2.5]octane-8-carboxylic acid, (8R) and (8S). These were obtained by chiral separation of racemic 5-tert-butoxycarbonyl-5-azaspiro[2.5]octane-8-carboxylic acid (12.0 g, 0.0470 mol), and separated by SFC (column: DAIEL CHIRALPAK IG 250 mm × 30 mm × 5 μm; conditions: CO2-MeOH, B%: 15%, isocomposition elution mode) to obtain tert-butyl((8R)-5-tert-butoxycarbonyl-5-azaspiro[2.5]octane-8-carboxylic acid (5.90 g, 0.0231 mol, yield 49.2%) as a yellow oil, and (8S)-tert-butoxycarbonyl-5-azaspiro[2.5]octane-8-carboxylic acid (4.20 g, 0.0165 mol, yield 35.0%) as a yellow oil. RT 0.808 Isomer 1 (R,S); RT 0.855 (Isomer 2 (S,S) (Method K). Chiral SFC: 1.53 min (100% ee, (S,S) isomer); 1.788 min (99.3% ee, (R,S) isomer) (Method H)

[0263] The stereochemistry of the (S,S)-isomer was clearly determined by its X-ray structure.

[0264] Intermediate I-32.(8R)-5-azaspiro[2.5]octan-8-yl-[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone (HCl salt) The synthesis was carried out using general procedures 1 and 2, starting with (8R)-5-tert-butoxycarbonyl-5-azaspiro[2.5]octane-8-carboxylic acid (250 mg, 0.979 mmol, 1.00 equivalent) and I-05 (800 mg, crude, purity approximately 24%, 0.00106 mol, 1.10 equivalent), to obtain (8R)-5-azaspiro[2.5]octane-8-yl-[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone (HCl salt) I-32 (390 mg, crude, purity approximately 77.9%) as a white solid. LCMS: m / z = 320.2[M+H] + . RT 0.455 (Method C)

[0265] Intermediate I-33.(8R)-5-azaspiro[2.5]octan-8-yl-[(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-yl]methanone (HCl salt) The compound was synthesized using general procedures 1 and 2, starting with (8R)-5-tert-butoxycarbonyl-5-azaspiro[2.5]octane-8-carboxylic acid (600 mg, 0.00235 mol) and I-02 762 mg (crude product, purity approximately 63.0%) to obtain 5-azaspiro[2.5]octane-8-yl-[(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-yl]methanone. LCMS: m / z = 308.2[M+H] + . RT 0.463 (Method Q) (1H NMR(400MHz,CDCl3)δ=8.53(d,J=1.2Hz,1H),8.40(s,1H),7.90(d,J=6.0Hz,1H),5.56(d,J=6.0 Hz,1H),5.51(dd,J=8.8,6.0Hz,1H),4.75(t,J=13.2Hz,2H),4.38-4.28(m,2H),4.22-4.13(m,2 H),4.02-3.94(m,1H),3.89(dd,J=9.2,3.6Hz,2H),3.33(s,3H),3.07-2.98(m,1H),2.97-2.86( m,2H),2.85-2.77(m,1H),2.75-2.65(m,1H),2.56(s,3H),1.99-1.87(m,1H),1.82-1.67(m,3H).

[0266] Intermediate I-34.[(3S)-3-(5-methyl-3-pyridyl)isoxazolidine-2-yl]-(4-piperidyl)methanone (HCl salt) Synthesized using general procedures 1 and 2, 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (2.16 g, 0.00945 mol, 1.00 equivalent) and I-31 (7.50 g, crude, purity approximately 20.6%, 0.00945 mol, 1.00 equivalent) yielded I-34:HCl salt [(3S)-3-(5-methyl-3-pyridyl)isoxazolidine-2-yl]-(4-piperidyl)methanone (4.26 g, crude, purity approximately 56.6%), which was then used directly in the following reaction.

[0267] Intermediate I-35.(8R)-5-azaspiro[2.5]octan-8-yl-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone (HCl salt) The synthesis was carried out using general procedures 1 and 2, starting with (8R)-5-tert-butoxycarbonyl-5-azaspiro[2.5]octane-8-carboxylic acid (2.00 g, 0.00783 mol) and I-01 (2.15 g, crude, purity approximately 66.0%, 0.00947 mol, 1.20 equivalents), to obtain (8R)-5-azaspiro[2.5]octane-8-yl-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone (HCl salt) I-35 (1.47 g, 0.00510 mol, yield 66.0%) as a white solid. 1 H NMR(400MHz,CD3OD)δ=8.66(d,J=1.2Hz,1H),8.61-8.57(m,1H),8.53(d,J=2.8 Hz,1H),5.49(dd,J=8.8,5.6Hz,1H),4.41-4.33(m,1H),4.11-4.04(m,1H),3.7 1(d,J=12.4Hz,1H),3.30-3.25(m,1H),3.22-3.06(m,1H),2.98-2.84(m,1H),2 .74(t,J=4.2Hz,1H),2.67-2.51(m,2H),2.28-2.11(m,2H),0.79-0.56(m,4H). LCMS: m / z = 289.2[M+H] + . RT 0.348 min (Method C) Chiral SFC:RT 1.234, 100% ee (Method T)

[0268] Intermediate I-36.[(3S)-3-(5-methylpyrazine-2-yl)isoxazolidine-2-yl]-(4-piperidyl)methanone (HCl salt) The compound was synthesized using general procedures 1 and 2. Starting with 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (3.14 g, 0.0137 mol) and I-29 (3.14 g, 0.0137 mol, 1.20 equivalents), [(3S)-3-(5-methylpyrazine-2-yl)isoxazolidine-2-yl]-(4-piperidyl)methanone (HCl salt) I-36 (2.5 g, purity 65%) was obtained as a white solid. This compound was used in the next step without further purification.

[0269] Intermediate AA-1: Methyl 1-(6-chloropyrimidine-4-yl)piperidine-4-carboxylate (corresponding to compound (IX)) A mixture of 4,6-dichloropyrimidine (80 g, 536.99 mmol, 1 equivalent), methylpiperidine-4-carboxylate (96.47 g, 536.99 mmol, 1 equivalent, HCl), and DIEA (208.21 g, 1.61 mol, 280.60 ml, 3 equivalents) in n-BuOH (700 ml) was degassed, purged with N2, and then stirred at 80°C for 2 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove n-BuOH. Then, it was diluted with H2O (100 ml) and EA (200 ml), adjusted to pH 6 with 1N HCl solution, and extracted with ethyl acetate (200 ml x 3). The combined organic layers were washed with 500 ml of NaHCO3 aqueous solution and 500 ml of brine, dried over Na2SO4, filtered, and concentrated to obtain the title compound (crude product 135.4 g, 529.53 mmol, yield 97%) as a yellow solid. LC / MS: m / z = 256.1[M+H] + ;RT: 0.737 min (LC / MS method C). 1H NMR(400MHz,DMSO-d6):δ ppm 8.32(s,1H),6.97(s,1H),4.38-4.19(m,2H),3.62(s,3H),3.16-3.02(m, 2H), 2.71 (tt, J=4.0, 10.8Hz, 1H), 1.96-1.84 (m, 2H), 1.60-1.44 (m, 2H).

[0270] Intermediate AA-2: Methyl 1-(4-bromo-5-fluoropyrimidine-2-yl)piperidine-4-carboxylate (corresponding to compound (IX)) Step 1: 2-Chloro-5-fluoropyrimidine-4-amine A mixture of 2,4-dichloro-5-fluoropyrimidine (100 g, 600 mmol) in NH3·H2O (200 ml) was stirred at 60°C for 1 hour. The reaction mixture was filtered to obtain 2-chloro-5-fluoropyrimidine-4-amine (78 g, 68%). 1 H NMR (400MHz, DMSO-d6): δ ppm 8.09 (1H), 7.81 (2H).

[0271] Step 2: Methyl 1-(4-amino-5-fluoropyrimidine-2-yl)piperidine-4-carboxylate A mixture of 2-chloro-5-fluoropyrimidine-4-amine (67 g, 456 mmol), methylpiperidine-4-carboxylate hydrochloride (122.37 g, 720 mmol), and DIPEA (205.42 g) in n-BuOH (670 ml) was stirred at 100°C for 12 hours under an N2 atmosphere. The reaction mixture was then concentrated under reduced pressure to remove the solvent. The residue was diluted with water (500 ml) and extracted with EA (300 ml x 3). The combined organic layer was washed with brine (500 ml), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 10:1 to 4:1) to obtain ethyl 1-(4-amino-5-fluoropyrimidine-2-yl)piperidine-4-carboxylate (73 g, 63%). 1H NMR (400MHz, CDCl3): δ ppm 7.81(1H),4.82(2H),4.49(2H),3.69(3H),3.00-2.87(2H),2.52(1H),1.92(2H),1.76-1.57(2H).

[0272] Step 3: Methyl 1-(4-bromo-5-fluoropyrimidine-2-yl)piperidine-4-carboxylate A mixture of methyl 1-(4-amino-5-fluoropyrimidine-2-yl)piperidine-4-carboxylate (68.8 g, 270 mmol) and CuBr2 (120.87 g) in DCM (688 ml) was mixed with isopentyl nitrite (63.40 g) at 0°C. The mixture was smoothly heated to 25°C and stirred for 12 hours. The reaction mixture was then filtered, the filtrate was diluted with water (500 ml), and extracted with DCM (500 ml x 3). The combined organic layers were washed with brine (1000 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (PE:EA = 20:1 to 10:1) to obtain intermediate AA-2 (26 g, 32%). 1 H NMR (400MHz, CDCl3): δ ppm 8.06(1H),4.53(2H),3.71(3H),3.14-2.98(2H),2.58(1H),2.03-1.93(2H),1.80-1.62(2H).

[0273] Intermediate AA-3: Methyl 1-(2-chloro-5-fluoropyrimidine-4-yl)piperidine-4-carboxylate (corresponding to compound (IX)) To a solution of compound 2,4-dichloro-5-fluoropyrimidine (10 g, 59.89 mmol, 1 equivalent) and methylpiperidine-4-carboxylate (11.30 g, 62.89 mmol, 1.05 equivalents, HCl) in DCM (100 ml), TEA (9.09 g, 89.84 mmol, 12.50 ml, 1.5 equivalents) was added. The mixture was stirred at 25°C for 12 hours. TLC showed that the starting material was completely consumed and many new spots were formed. According to TLC, the reaction was cumbersome. The reaction mixture was diluted with 100 mL of water and extracted with DCM (100 mL x 3). The combined organic layer was washed with 100 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 0 to 10 / 1). Intermediate AA3 (13.55 g, 83% yield) was obtained as a yellow oily substance. 1 H NMR(CDCl3,400MHz,)δ=7.85(d,J=6.3Hz,1H),4.35(td,J=3.7,13.7Hz,2H),3.64(s,3H),3.14(d dd,J=2.9,11.2,13.7Hz,2H),2.57(tt,J=4.2,10.6Hz,1H),1.98-1.89(m,2H),1.81-1.65(m,2H).

[0274] Intermediate AA-4: Methyl 1-(4-chloro-1,3,5-triazine-2-yl)piperidine-4-carboxylate (corresponding to compound (IX)) To a solution of 2,4-dichloro-1,3,5-triazine (25 g, 166.70 mmol, 1 equivalent) in dioxane (300 ml), DIEA (60.98 ml, 350.08 mmol, 2.1 equivalents) and methylpiperidine-4-carboxylate (29.95 g, 166.70 mmol, 1 equivalent, HCl) were added. The mixture was stirred at 25°C for 1 hour. TLC showed that the starting material was completely consumed and two new spots had formed. The reaction mixture was concentrated, diluted with water (300 mL), extracted with EA (200 mL x 2), washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated. Intermediate AA-4 (44.5 g, crude) was obtained as a white solid and used in the next step without further purification. 1 H NMR(400MHz,CDCl3)δ=8.34(s,1H),4.68-4.47(m,2H),3.71(s,3H),3.19(dddd,J=3.1,7. 8,10.9,13.7Hz,2H),2.64(tt,J=4.1,10.6Hz,1H),2.04-1.97(m,2H),1.80-1.67(m,2H).

[0275] Intermediate AA-5: Methyl 1-(2-chloropyrimidine-4-yl)piperidine-4-carboxylate (corresponding to compound (IX)) A mixture of 2,4-dichloropyrimidine (2 g, 13.42 mmol, 1 equivalent), methylpiperidine-4-carboxylate (1.92 g, 13.42 mmol, 1 equivalent), and DIEA (5.21 g, 40.27 mmol, 7.02 ml, 3 equivalents) in n-BuOH (20 ml) was degassed, purged with N2, and then stirred under an N2 atmosphere at 80°C for 2 hours. LC / MS showed that no starting material remained. Several new peaks were observed on LC / MS, and approximately 74% of the desired mass was detected. The mixture was diluted with H2O (30 mL) and extracted with SiO2 (30 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 25g SepaFlash® silica flash column, eluate in petroleum ether with a 0-50% ethyl acetate gradient @ 50 ml / min) to obtain intermediate AA-5 (985 mg, yield 7%) as a white solid. LC / MS: m / z 256.1[M+1] + , RT 0.759 min (Method C). 1 H NMR:(CDCl3,400MHz)δ ppm 8.03(d,J=6.2Hz,1H),6.41(d,J=6.1Hz,1H),4.25(br s,2H),3.71(s,3H),3.12(ddd,J=3.0,11.0,13.7Hz,2H),2.63(tt,J=4.1,10.6Hz,1H),2.06-1.96(m,2H),1.81-1.68(m,2H).

[0276] Intermediate AA-6.tert-butyl1-(4-oxazole-2-ylpyrimidine-2-yl)piperidine-4-carboxylate (corresponding to compound (IX)) Step 1a: A mixture of methyl 2-chloropyrimidine-4-carboxylate (860 mg, 4.9 mmol), tert-butylpiperidine-4-carboxylate hydrochloride (1 g, 4.5 mmol), and DIPEA (2.75 mL, 3.5 equivalents) in ACN (15 ml) was stirred in MW at 100°C for 1 hour. LC / MS demonstrated conversion to the desired product. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-Hep / EA gradient) to obtain methyl 2-(4-tert-butoxycarbonyl-1-piperidyl)pyrimidine-4-carboxylate (1.1 g, 76%). LC / MS: m / z 322.2[M+1] + , RT 2.39 min (Method A).

[0277] Step 1b: Following the general procedure for ester hydrolysis, the desired product, 2-(4-tert-butoxycarbonyl-1-piperidyl)pyrimidine-4-carboxylic acid hydrochloride (950 mg, 80%), was obtained starting from methyl 2-(4-tert-butoxycarbonyl-1-piperidyl)pyrimidine-4-carboxylate (1.1 g, 3.43 mmol). LC / MS: m / z 308.2[M+1] + , RT 1.99 min (Method A).

[0278] Step 2a: Following the general procedure for amide coupling, the desired product, tert-butyl 1-[4-(2,2-dimethoxyethylcarbamoyl)pyrimidine-4-carboxylate (61.7 mg, 28%), was obtained using 2-(4-tert-butoxycarbonyl-1-piperidyl)pyrimidine-4-carboxylate (195 mg, 0.64 mmol), aminoacetaldehyde dimethyl acetal (0.274 ml, 2.5 mmol), and 3 equivalents of DIPEA. LC / MS: m / z 395.2[M+1] + , RT 2.3 min (Method A).

[0279] Step 2b: To a solution of tert-butyl 1-[4-(2,2-dimethoxyethylcarbamoyl)pyrimidine-2-yl]piperidine-4-carboxylate (40 mg, 0.10 mmol) in dioxane (3 ml), HCl (4N in dioxane, 1 ml) was added, and the mixture was stirred overnight at room temperature. The mixture was neutralized with saturated aqueous NaHCO3 solution and extracted with DCM (3×). The combined organic layer was dried over MgSO4, filtered, and the residue evaporated. The crude product tert-butyl 1-[4-(2-oxoethylcarbamoyl)pyrimidine-2-yl]piperidine-4-carboxylate (30 mg; 85%) was used in the next step without further purification. LC / MS: m / z 395.2[M+1] + , RT 2.3 min (Method A).

[0280] Step 3: To a solution of t1-[4-(2-oxoethylcarbamoyl)pyrimidine-2-yl]piperidine-4-carboxylate (150 mg, 0.43 mmol) in THF (12 ml), Burgess reagent (307 mg, 1,292 mmol) was added. The mixture was stirred in MW at 80°C for 20 minutes, and complete conversion to the product was shown by LC / MS. The mixture was neutralized with saturated aqueous NaHCO3 and extracted by DCM (3×). The combined organic layers were dried over MgSO4, filtered, and the residue was evaporated. The residue was purified by silica gel chromatography (nHept / EE gradient - (nHep_100%~80%EE=30 min)) to obtain intermediate AA-6 (71 mg, 50%). LC / MS: m / z 331.2[M+1] + , RT 2.35 min (Method A). 1 H NMR(400MHz,DMSO-d6)δ ppm 8.53(d,J=5.01Hz,1H),8.35(s,1H),7.50(s,1H),7.20(d,J=4.89Hz,1H),4.58(m,2H),3.11(m,2H),2.57(m,1H),2.50(u),1.88(br dd,J=13.45,3.18Hz,2H),1.48(m,2H),1.41(s,9H),1.24(br d,J=3.79Hz,1H).

[0281] Intermediate I-12: 1-[6-(2-methylimidazole-1-yl)pyrimidine-4-yl]piperidine-4-carboxylic acid (corresponding to compound (IIa)) (following step 2 of SM3 in Scheme 3 and SM1 in Scheme 1) I-12-a: Methyl 1-[6-(2-methylimidazole-1-yl)pyrimidine-4-yl]piperidine-4-carboxylate A mixture of intermediate-AA-1 (3.97 g, 15.53 mmol, 1 equivalent), 2-methyl-1H-imidazole (2.55 g, 31.05 mmol, 2 equivalents), K2CO3 (8.58 g, 62.10 mmol, 4 equivalents), and CuI (1.48 g, 7.76 mmol, 0.5 equivalents) in DMSO (40 ml) was degassed and purged three times with N2. The mixture was stirred at 120°C for 12 hours under an N2 atmosphere. The reaction mixture was filtered, diluted with water (400 ml), and extracted with ethyl acetate (200 ml x 3). The combined organic layers were washed with brine (300 ml), dried over Na2SO4, filtered, concentrated, and purified by flash silica gel chromatography (eluate: petroleum ether and ethyl acetate, gradient: 35%-70% ethyl acetate and eluate: MeOH and DCM, gradient: 5%-15% MeOH) to obtain the title compound I-12a (2.3 g, 7.63 mmol, yield 49%) as a yellow oil. LC / MS: m / z = 302.1[M+H] + ;RT: 0.615 min (LC / MS method C). 1 H NMR(400MHz,CDCl3):δ ppm 8.54(s,1H),7.30(s,1H),7.04(s,1H),6.41(s,1H),4.32(br d,J=13.1Hz,2H),3.73(s,3H),3.18(ddd,J=3.0,11.0,13.7Hz,2H),2.67(s,3H),2.08-2.03(m,2H),1.84-1.74(m,3H).

[0282] Intermediate I-12: 1-[6-(2-methylimidazole-1-yl)pyrimidine-4-yl]piperidine-4-carboxylic acid A solution of methyl 1-[6-(2-methylimidazol-1-yl)pyrimidin-4-yl]piperidine-4-carboxylate (4.46 g, 14.80 mmol, 1 eq) in THF (50 ml) was added with LiOH·H2O (1 M, 29.60 ml, 2 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was adjusted to pH 3 with 4 N aqueous HCl, and the mixture was concentrated in vacuo and purified by reverse phase HPLC (column: Welch Ultimate XB_C18, 20 - 40 μm, 120 Å; eluent: water (0.1% formic acid) and acetonitrile, gradient: 100% - 10% acetonitrile in 20 min, 10% acetonitrile in 20 min, flow rate: 100 ml / min) to afford the title compound (3.5 g, 10.81 mmol, 73% yield, HCl) as a yellow solid. LC / MS: m / z = 288.2 [M+H] + ; RT: 0.700 min (LC / MS method D). 1 1H NMR (400 MHz, D2O): δ ppm 8.50 (s, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.08 (s, 1H), 4.34 - 4.17 (m, 2H), 3.34 - 3.26 (m, 2H), 2.83 - 2.76 (m, 1H), 2.73 (s, 3H), 2.06 (br dd, J = 3.4, 13.5 Hz, 2H), 1.75 - 1.65 (m, 2H).

[0283] Intermediate I-13: 1-[6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]piperidine-4-carboxylic acid (corresponding to the compound of formula (IIa)) (according to step 2 of SM3 in Scheme 3 and SM1 in Scheme 1) I-13a: Methyl 1-[6-(2-methylpyrazol-3-yl)pyrimidin-4-yl]piperidine-4-carboxylate To a solution of intermediate-AA-1 (25 g, 97.77 mmol, 1 equivalent) in dioxane (200 ml) and H2O (40 ml), K2CO3 (27.03 g, 195.54 mmol, 2 equivalents), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (20.34 g, 97.77 mmol, 1 equivalent) and Pd(dppf)Cl2 (7.15 g, 9.78 mmol, 0.1 equivalent) were added. The mixture was stirred at 120°C for 2 hours under an N2 atmosphere. The residue was diluted with H2O (200 ml) and extracted with ethyl acetate (300 ml x 2). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash silica gel chromatography (column: 220g SepaFlash® Silica Flash, eluate: petroleum ether and ethyl acetate, gradient: 0%~20% ethyl acetate, flow rate: 100 ml / min) to obtain the title compound (29.3 g, yield 88%) as a yellow oily substance. LC / MS: m / z = 302.1[M+H] + ;RT: 0.644 min (LC / MS method C).

[0284] Intermediate I-13: 1-[6-(2-methylpyrazole-3-yl)pyrimidine-4-yl]piperidine-4-carboxylic acid To a solution of methyl 1-[6-(2-methylpyrazole-3-yl)pyrimidine-4-yl]piperidine-4-carboxylate (29.3 g, 97.23 mmol, 1 equivalent) in THF (250 ml) and H2O (50 ml), LiOH·H2O (12.24 g, 291.69 mmol, 3 equivalents) was added. The mixture was stirred at 25°C for 12 hours, the pH was adjusted to 5 with 1N HCl solution, concentrated under reduced pressure, and filtered. The filtered cake was washed with H2O (50 ml) and polished with ethyl acetate at 20°C for 1 hour to obtain intermediate I-13 (19.4 g, 64.89 mmol, yield 67%) as a gray solid. LC / MS: m / z = 288.4[M+H] + ; RT: 0.295 min (LC / MS method C). 1H NMR(400MHz,DMSO-d6):δ ppm 12.30(s,1H),8.57(d,J=0.9Hz,1H),7.48(d,J=2.0Hz,1H),7.13(d,J=0.9Hz,1H),6.95(d,J=2.0Hz,1H),4.3 7(d,J=12.6Hz,2H),4.14(s,3H),3.17-3.02(m,2H),2.64-2.54(m,1H),1.97-1.83(m,2H),1.58-1.41(m,2H).

[0285] Intermediate I-14: 1-(5-fluoro-4-pyrazole-1-ylpyrimidine-2-yl)piperidine-4-carboxylic acid (corresponding to compound (IIa)) (following step 2 of SM3 in Scheme 3 and SM1 in Scheme 1) Step 1; I-18a: To a DMSO (50 mL) solution of intermediate AA-2 (5 g, 15.72 mmol, 1.2 equivalents) and imidazole (891.60 mg, 13.10 mmol, 1 equivalent), CuI (498.86 mg, 2.62 mmol, 0.2 equivalents), proline (603.14 mg, 5.24 mmol, 0.4 equivalents), and K2CO3 (5.43 g, 39.29 mmol, 3 equivalents) were added. The mixture was stirred under N2 at 90°C for 72 hours. LC / MS showed that the desired mass was obtained. The reaction mixture was diluted with 200 mL of H2O and extracted with 20 mL of EA (100 mL x 3). The combined organic layers were washed with 200 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 4 / 1) to obtain the intermediate I-14-methyl ester (2.2 g, 7.21 mmol, yield 55.02%) as a white solid. LC / MS: m / z 306.8 [M+1] + ;RT: 0.872 minutes (Method C). 11H NMR (CDCl3, 400 MHz) δ = 8.46 (d, J = 2.7 Hz, 1H), 8.35 (d, J = 4.0 Hz, 1H), 7.89 (d, J = 1.2 Hz, 1H), 6.56 - 6.45 (m, 1H), 4.61 (dt, J = 13.5, 3.6 Hz, 2H), 3.72 (s, 3H), 3.20 - 3.02 (m, 2H), 2.61 (tt, J = 11.0, 3.9 Hz, 1H), 2.02 (br dd, J = 13.5, 3.4 Hz, 2H), 1.85 - 1.58 (m, 3H) .

[0286] Step 2 - Intermediate I-14: A mixture of Intermediate 14 - methyl ester (2.2 g, 7.21 mmol, 1 equivalent), LiOH·H2O (1 M, 14.41 mL, 2 equivalents) in THF (4 mL) and H2O (12 mL) was stirred at 25 °C for 2 h. LC / MS indicated that the desired mass was obtained. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with EA for 20 min to give Intermediate I-14 (2 g, 6.87 mmol, 95.29% yield) as a white solid. LC / MS: m / z 292.1 [M+1] + ; RT: 0.541 min (Method C). 1 1H NMR (CDCl3, 400 MHz) δ 8.36 (d, J = 2.8 Hz, 1H), 8.27 (d, J = 4.0 Hz, 1H), 7.82 (d, J = 1.1 Hz, 1H), 6.44 (dd, J = 2.6, 1.8 Hz, 1H), 4.53 (dt, J = 13.6, 3.7 Hz, 2H), 3.13?3.00 (m, 2H), 2.57 (tt, J = 1 ? 9, 3.9 Hz, 1H), 1.97 (br dd, J = 13.6, 3.4 Hz, 2H), 1.77?1.62 (m, 2H).

[0287] Intermediate I-15: 1 1-[5-Fluoro-4-(2-methylpyrazol-3-yl)pyrimidin-2-yl]piperidine-4-carboxylic acid (corresponding to the compound of formula (IIa)) (according to Step 2 of SM3 in Scheme 3 and SM1 in Scheme 1) Step 1: The intermediate AA-2 (3 g, 9.43 mmol, 1 equivalent), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (2.94 g, 14.14 mmol, 1.5 equivalents), K2CO3 (1.95 g, 14.14 mmol, 1.5 equivalents), and Pd(PPh3)4 (344.99 mg, 471.49 μmol, 0.05 equivalents) were degassed in a solution of dioxane (36 mL) and H2O (6 mL), purged three times with N2, and then stirred under an N2 atmosphere at 80°C for 15 hours. LC / MS showed detection of the desired mass, and TLC showed the formation of new spots. The residue was diluted with H2O (100 mL) and extracted with CH2Cl2 (100 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 45g SepaFlash® silica flash column, eluate in petroleum ether with a 0-50% ethyl acetate gradient @ 60 ml / min) to obtain the intermediate I-15-methyl ester (2.9 g, 9.08 mmol, yield 96.31%) as a yellow solid. LC / MS: m / z 320.4 [M+1] + ;RT: 0.922 minutes (Method C). 1 H NMR:(CDCl3,400MHz)δ ppm 8.29(d,J=2.9Hz,1H),7.58(d,J=2.1Hz,1H),6.91(dd,J=2.1,4.2Hz,1H),4.59(td,J=3.6,13 .4Hz,2H),4.30(s,3H),3.73(s,3H),3.22-3.05(m,2H),2.63(tt,J=4.0,11.0Hz,1H),2.02(br dd,J=3.4,13.5Hz,2H),1.83-1.67(m,2H).

[0288] Step 2: 1-[5-fluoro-4-(2-methylpyrazole-3-yl)pyrimidine-2-yl]piperidine-4-carboxylic acid A solution of intermediate I-15-methyl ester (2.8 g, 8.77 mmol, 1 equivalent) and LiOH·H2O (735.90 mg, 17.54 mmol, 2 equivalents) in THF (14 ml) and H2O (14 ml) was stirred at 25°C for 3 hours. LC / MS confirmed the detection of the desired mass. The reaction mixture was concentrated under reduced pressure to remove the solvent, the pH was adjusted to 4-5 with 1 M HCl, diluted with H2O (30 ml), stirred for 5 minutes, filtered, and washed with H2O to obtain a crude solid. The residue was triturated with petroleum ether:ethyl acetate (1:1) at 25°C for 30 minutes to obtain intermediate I-15 (2.2 g, 7.21 mmol, yield 82.18%) as a yellow solid. LC / MS: m / z 305.9 [M+1] + ;RT:0.647 minutes (Method C) 1 H NMR:(DMSO-d6,400MHz)δ ppm 12.26(br s,1H),8.55(d,J=2.9Hz,1H),7.60(d,J=2.0Hz,1H),6.85(dd,J=2.1,4.1Hz,1H ),4.45(td,J=3.5,13.3Hz,2H),3.20-3.01(m,2H),2.77-2.61(m,1H),1.90(br dd,J=3.2,13.3Hz,2H),1.64-1.40(m,2H)

[0289] Intermediate I-16: 1-(5-fluoro-4-oxazole-2-ylpyrimidine-2-yl)piperidine-4-carboxylic acid (corresponding to compound (IIa)) (following step 2 of SM3 in Scheme 3 and SM1 in Scheme 1) Step 1. 1-(5-fluoro-4-oxazol-2-ylpyrimidine-2-yl)piperidine-4-carboxylate methyl ester The degassed mixture of intermediate AA-2 (4 g, 12.57 mmol, 1 equivalent) and tributyl(oxazole-2-yl) stannan (9.00 g, 25.15 mmol, 2 equivalents) in dioxane (30 mL) was stirred at room temperature (25 °C). This yellow solution was degassed with N2 flux for 10 minutes, and Pd(PPh3)4 (1.45 g, 1.26 mmol, 0.1 equivalent) was added. The solution was stirred at 100 °C for 12 hours. LC / MS showed that the reaction was successful. The solvent was removed, the solution was dissolved in H2O (50 mL), extracted with EA (50 mL x 2), washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The residue was purified by flash silica gel chromatography (eluate with a 10-30% EA / PE gradient) to obtain the intermediate I-16-methyl ester (2.88 g, 72%) as a yellow solid. LC / MS: m / z 306.9 [M+H] + ;RT: 0.682 minutes (Method C). 1 H NMR(400MHz,DMSO-d6)δ=8.64(d,J=2.9Hz,1H),8.42(s,1H),7.57(s,1H),4.53-4.47(m,2H),3.62(s, 3H),3.13-3.05(m,2H),2.66(tt,J=3.8,11.1Hz,1H),1.92(dd,J=3.0,13.1Hz,2H),1.58-1.47(m,2H).

[0290] Step 2-1-(5-fluoro-4-oxazol-2-ylpyrimidine-2-yl)piperidine-4-carboxylic acid A solution of intermediate AA2-methyl ester (50 mg, 0.16 mmol), LiOH (5.8 mg, 1.5 equivalents), THF (3 ml), and H2O (0.75 ml) was stirred at 25°C for 4.5 hours. LC / MS confirmed the detection of the desired mass. The reaction mixture was concentrated under reduced pressure to remove the solvent, the pH was adjusted to 4-5 with 1 M HCl, extracted with EA (2×), dried, filtered, and evaporated to obtain intermediate I-16 (55 mg, 100%). LC / MS: m / z 293.1[M+H] + ;RT: 1.47 minutes (Method A). 1 H NMR(DMSO-d6,400MHz)δ ppm 12.24(br s,1H),8.64(d,J=2.93Hz,1H),8.42(s,1H),7.57(s,1H),4.50(m,2H),3.10(m,2H),1.92(br dd,J=9.84,3.48Hz,2H),1.89(br s,1H),1.52(m,2H),1.18(t,J=7.09,7.09Hz,1H).

[0291] Intermediate I-17: 1-(5-fluoro-4-oxazole-2-ylpyrimidine-2-yl)piperidine-4-carboxylic acid (corresponding to compound (IIa)) (following step 2 of SM3 in Scheme 3 and SM1 in Scheme 1) Step 1: A degassed mixture of tributyl(oxazole-2-yl) stannan (3 g, 10.96 mmol, 1 equivalent) and intermediate AA-3 (7.85 g, 21.92 mmol, 2 equivalents) in dioxane (30 ml) was stirred at room temperature (25 °C). This yellow solution was degassed with N2 flux for 10 minutes, and Pd(PPh3)4 (1.27 g, 1.10 mmol, 0.1 equivalent) was added. The solution was stirred at 100 °C for 12 hours. LC / MS confirmed the reaction was successful. The solvent was removed, the solution was dissolved in H2O (50 ml), extracted with EA (50 ml x 2), washed with brine (40 ml), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The residue was purified by flash silica gel chromatography (eluent on a 20-60% ethyl acetate / petroleum ether gradient). Next, the product was purified by reverse-phase HPLC (under 0.1% FA conditions). The intermediate I-17-methyl ester (2.38 g, 79% yield) was obtained as a yellow solid. 1 H NMR(DMSO- δ6;400MHz):δ=8.37(br d,J=6.6Hz,1H),8.27(s,1H),7.43(s,1H),4.40(br d,J=13.2Hz,2H),3.62(s,3H),3.24(br t,J=12.5Hz,2H),2.78-2.69(m,1H),1.97(br d,J=13.3Hz,2H),1.64(q,J=11.5Hz,2H).

[0292] Step 2: 1-(5-fluoro-4-oxazol-2-ylpyrimidine-2-yl)piperidine-4-carboxylic acid To a solution of intermediate I-17-methyl ester (2.28 g, 7.44 mmol, 1 equivalent) in THF (23 ml), LiOH·H2O (1 M, 14.89 ml, 2 equivalents) was added. The mixture was stirred at 25°C for 3 hours. LC / MS showed that reactant 1 was completely consumed and a single major peak with the desired mass was detected. The reaction mixture was adjusted to pH=3 with 1N HCl aqueous solution, the precipitate was collected by filtration and dried under vacuum. Intermediate I-17 (2 g, 92%) was obtained as a white solid. LC / MS: m / z 292.1[M+H] + ;0.710 min (Method C). 1 H NMR(DMSO 400MHz):δ=12.31(s,1H),8.37(d,J=6.8Hz,1H),8.27(s,1H),7.43(s,1H), 4.43-4.35(m,2H),3.29-3.19(m,2H),2.61(tt,J=4.0,10.9Hz,1H),1.95(br dd,J=3.2,13.5Hz,2H),1.67-1.56(m,2H).

[0293] Intermediate I-18: 1-(4-thiazole-2-yl-1,3,5-triazine-2-yl)piperidine-4-carboxylic acid (corresponding to compound (IIa)) (following step 2 of SM3 in Scheme 3 and SM1 in Scheme 1) Step 1: 1-(4-thiazole-2-yl-1,3,5-triazine-2-yl)piperidine-4-carboxylate methyl ester Under N2 conditions at -78°C, n-BuLi (2.5M, 31.15mL, 1.02 equivalents) was added dropwise to a solution of thiazole (6.5g, 76.36 mmol, 549.45 μL, 1 equivalent) in THF (200 mL), and the mixture was stirred at -78°C for 0.5 hours. Then, tributyl(chloro)stannane (24.85g, 76.36 mmol, 20.54 mL, 1 equivalent) was added, and the mixture was heated to 20°C for 1 hour. The mixture was concentrated, the residue was dissolved in hexane (120 mL), the resulting precipitate was removed by filtration, and the filtrate was concentrated to obtain tributyl(thiazole-2-yl)stannane (29 g), which was used in the next step without further purification.

[0294] A mixture of tributyl(thiazole-2-yl) stannan (5.83 g, 15.58 mmol, 2 equivalents), intermediate AA-4 (2 g, 7.79 mmol, 1 equivalent), and Pd(PPh3)4 (900.36 mg, 779.16 μmol, 0.1 equivalent) in dioxane (20 ml) was degassed, purged three times with N2, and then stirred at 100°C for 4 hours under an N2 atmosphere. LC / MS showed no residual sm and the desired m / z was detected. TLC showed the formation of several spots. The mixture was concentrated and purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluate @ 80 ml / min on a 30-55% ethyl acetate / petroleum ether gradient) to obtain intermediate I-18-methyl ester (520 mg, yield 22%) as a yellow solid. LC / MS: m / z 306.2[M+H] + ;0.798 min (Method C).

[0295] Step 2: 1-(4-thiazole-2-yl-1,3,5-triazine-2-yl)piperidine-4-carboxylic acid To a solution of intermediate I-18-methyl ester (2.1 g, 6.88 mmol, 1 equivalent) in THF (5 ml), LiOH (1 M, 13.75 ml, 2 equivalents) was added. The mixture was stirred at 20°C for 2 hours. LC / MS showed that one major peak was at the desired m / z. The reaction mixture was concentrated, washed with EA (8 mL x 2), pH adjusted to 3 with 1 N HCl, extracted with EA (10 mL x 3), dried over Na2SO4, filtered, and concentrated. Intermediate I-18 (1.2 g, 63%) was obtained as a yellow solid. LC / MS: m / z 292.1[M+H] + ;0.731 min (Method C). 1 H NMR(DMSO,400MHz)δ=12.27(br s,1H),8.67(s,1H),8.10(br s,1H),8.04(br s,1H),4.68-4.48(m,2H),3.21(q,J=11.0Hz,2H),2.61(br t,J=10.6Hz,1H),2.04-1.92(m,2H),1.54(q,J=11.5Hz,2H).

[0296] Intermediate I-19: 1-[4-(2-methylimidazole-1-yl)-1,3,5-triazine-2-yl]piperidine-4-carboxylic acid (corresponding to compound (IIa)) (following step 2 of SM3 in Scheme 3 and SM1 in Scheme 1) Step 1: To a 40 ml ACN (ACN) solution of 2-methylimidazole (1.44 g, 17.53 mmol, 48.56 μL, 1.5 equivalents), K2CO3 (3.23 g, 23.37 mmol, 2 equivalents) and intermediate AA-4 (3 g, 11.69 mmol, 1 equivalent) were added. The mixture was stirred at 60°C for 12 hours. LC / MS showed that no intermediate AA-3 remained. Several new peaks were observed on LC / MS, and approximately 56% of the desired compound was detected. The residue was diluted with 50 mL of H2O and extracted with 50 mL (50 mL x 2) of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 4g SepaFlash® silica flash column, eluate @ 80 mL / min with a 0-100% ethyl acetate / petroleum ether gradient) to obtain the intermediate I-19-methyl ester (2.8 g, 8.98 mmol, yield 76.87%, purity 97%) as a yellow oily substance. LC / MS m / z 303.2[M+1] + ;RT.0.634 minutes (Method C). 1 H NMR(CDCl3d,400MHz)8.55-8.49(m,1H),7.84(d,J=1.6Hz,1H),6.97-6.92(m,1H),4.68(br d,J=13.8Hz,1H),4.62-4.49(m,1H),3.73(s,3H),3.28-3.19(m,2H),2.84-2.81(m,3H),2.72-2.62(m,1H),2.03(br s,1H),1.83-1.72(m,3H).

[0297] Step 2: 1-[4-(2-methylimidazole-1-yl)-1,3,5-triazine-2-yl]piperidine-4-carboxylic acid A mixture of intermediate I-19-methyl ester (2.8 g, 9.26 mmol, 1 equivalent), THF (24 ml), and LiOH·H2O (1.55 g, 37.05 mmol, 4 equivalents) in H2O (6 mL) was degassed, and the mixture was stirred at 25°C for 2 hours. LC / MS showed that no intermediate I-19-methyl ester remained. Several new peaks were shown on LC / MS, and approximately 99% of the desired compound was detected. The pH was adjusted to 3-4 with 1N HCl, and intermediate I-19 (2.24 g, 7.61 mmol, yield 82.21%, purity 98%) was obtained as a white solid. LC / MS: m / z 289.1[M+1] + ;RT.0.675 minutes (Method D). 1 H NMR(CDCl3,400MHz)13.37(s,1H),12.61(d,J=1.1Hz,1H),11.70-11.62(m,1H),9.34-9.19(m,3H),7.95(br d,J=2.4Hz,3H),7.46(s,2H),7.37(br t,J=3.8Hz,1H),6.75-6.68(m,2H),6.36-6.26(m,2H).

[0298] Intermediate I-20: 1-[4-(2-methylpyrazole-3-yl)pyrimidine-2-yl]piperidine-4-carboxylic acid (corresponding to compound (IIa)) (following step 2 of SM4 in Scheme 3 and SM1 in Scheme 1) Step 1: To a mixture of 2,4-dichloropyrimidine (5 g, 33.56 mmol, 1 equivalent) in dioxane (40 mL), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (6.98 g, 33.56 mmol, 1 equivalent), K2CO3 (9.28 g, 67.12 mmol, 2 equivalents), Pd(dppf)Cl2 (2.74 g, 3.36 mmol, 0.1 equivalent), and H2O (10 mL) were added. The mixture was degassed, purged with N2, and then stirred at 80°C for 12 hours under an N2 atmosphere. LC / MS showed that no starting material remained, and several new peaks were shown on the LC / MS, with approximately 40% of the desired mass detected. The residue was diluted with H2O (60 mL) and extracted with EA (60 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (0.1% FA conditions) to obtain 2-chloro-4-(2-methylpyrazole-3-yl)pyrimidine (4.43 g, 20.50 mmol, yield 61.08%, purity 90%) as a yellow solid. LC / MS: m / z 195.1 [M+1] + ;RT: 0.723 minutes (Method D). 1 H NMR:(CDCl3,400MHz)δ ppm 8.64(d,J=5.3Hz,1H),7.56(d,J=2.1Hz,1H),7.49(d,J=5.3Hz,1H),6.82(d,J=2.1Hz,1H),4.47-4.30(m,3H).

[0299] Step 2: A mixture of 2-chloro-4-(2-methylpyrazole-3-yl)pyrimidine (5.43 g, 27.92 mmol, 1 equivalent), methylpiperidine-4-carboxylate (4.00 g, 27.92 mmol, 1 equivalent), and DIEA (10.82 g, 83.75 mmol, 14.59 mL, 3 equivalents) in n-BuOH (60 mL) was degassed, and the mixture was stirred at 80°C for 2 hours under an N2 atmosphere. LC / MS showed that approximately 8% of the starting material remained. Several new peaks were shown on LC / MS, and approximately 84% of the desired compound was detected. The residue was diluted with H2O (60 mL) and extracted with EA (60 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®, 80g SepaFlash® silica flash column, eluate @ 50 ml / min with a 0-70% ethyl acetate / petroleum ether gradient) to obtain the intermediate I-20-methyl ester (6.4 g, 20.81 mmol, yield 74.56%, purity 98%) as a yellow oily substance. LC / MS: m / z 302.2[M+1] + ;RT: 0.823 minutes (Method C). 1 H NMR:(CDCl3,400MHz)δ ppm 8.35(d,J=5.3Hz,1H),7.50(d,J=2.0Hz,1H),6.76(d,J=5.1Hz,1H),6.69(d,J=1.9Hz,1H),4.67(td,J=3.7,13.4Hz, 2H),4.28(s,3H),3.71(s,3H),3.20-3.09(m,2H),2.64(tt,J=4.0,10.9Hz,1H),2.06-1.98(m,2H),1.82-1.69(m,2H)

[0300] Step 3: 1-[4-(2-methylpyrazole-3-yl)pyrimidine-2-yl]piperidine-4-carboxylic acid A mixture of intermediate I-20-methyl ester (2 g, 6.64 mmol, 1 equivalent), LiOH·H2O (557.02 mg, 13.27 mmol, 2 equivalents), and H2O (0.8 mL) in THF (3.2 mL) was stirred at 25°C for 2 hours under an N2 atmosphere. LC / MS showed that no starting material remained. Several new peaks were observed on LC / MS, and approximately 99% of the desired compound was detected. The residue was diluted with H2O (30 mL) and extracted with EA (30 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was adjusted to pH 3-4 with 1N HCl, filtered, and intermediate I-20 (1.8 g, 5.95 mmol, yield 89.67%, purity 95%) was obtained as a white solid. LC / MS: m / z 288.4[M+1] + ;RT: 0.890 min (Method D). 1 H NMR:(D2O,400MHz)δ ppm 8.13(d,J=5.0Hz,1H),7.48-7.44(m,1H),6.72(br d,J=5.1Hz,1H),6.69(d,J=0.9Hz,1H),4.35(br d,J=13.2Hz,2H),4.00(s,3H),2.91(br t,J=12.0Hz,2H),2.44-2.34(m,1H),1.86(br t,J=5.4Hz,2H),1.48(dq,J=3.9,12.2Hz,2H).

[0301] Intermediate I-21: 1-(4-oxazole-2-ylpyrimidine-2-yl)piperidine-4-carboxylic acid TFA salt (corresponding to compound (IIa)) (following step 2 of SM1 or scheme 1) 0.2 ml of TFA was added to a mixture of tert-butyl 1-(4-oxazole-2-ylpyrimidine-2-yl)piperidine-4-carboxylate (150 mg) in 50 ml of DCM, and the mixture was stirred overnight at room temperature. An additional 0.2 ml of TFA was then added, and the mixture was stirred at 40°C, but no further transformation was observed by LC / MS. The mixture was then evaporated, the residue was dissolved in toluene and evaporated (2×), dissolved in ACN / H2O, and lyophilized to obtain intermediate I-21 as a white solid (73.8 mg / 71%). LC / MS: m / z 275.1 [M+1] + ;RT: 1.38 minutes (Method A). 1 H NMR(DMSO-d6,400MHz,)δ ppm 8.53(d,J=4.89Hz,1H),8.35(s,1H),7.50(s,1H),7.20(d,J=4.89Hz,1H),4.59(m,2H),3.12(m,2H),2.57(m,1H),1.92(br dd,J=13.39,3.12Hz,2H),1.51(m,2H).

[0302] Intermediate I-22: 1-[4-(2-methylimidazole-1-yl)pyrimidine-2-yl]piperidine-4-carboxylic acid (corresponding to compound (IIa)) (following step 2 of SM4 in Scheme 3 and SM1 in Scheme 1) Step 1: Ethyl 1-[4-(2-methylimidazole-1-yl)pyrimidine-2-yl]piperidine-4-carboxylate) To a mixture of 2-chloro-4-(2-methylimidazole-1-yl)pyrimidine (340.44 mg, 1.75 mmol) in ACN (5 ml), ethylpiperidine-4-carboxylate (0.245 ml, 1.6 mmol) was added, followed by DIPEA (0.692 ml, 3.97 mmol). The mixture was stirred in MW at 120°C for 1 hour. Complete conversion to the product was shown by LC / MS. The reaction mixture was evaporated, and the residue was purified by silica gel chromatography (A: DCM, B: DCM / MeOH 9 / 1; gradient 0% B → 50% B) to obtain the remaining DIPEA and the desired product, intermediate I-22-ethyl ester, which was used directly in the next step.

[0303] Step 2: 1-[4-(2-methylimidazole-1-yl)pyrimidine-2-yl]piperidine-4-carboxylic acid A solution of intermediate I-22-ethyl ester (ethyl 1-[4-(2-methylimidazole-1-yl)pyrimidine-2-yl]piperidine-4-carboxylate) (501.5 mg, 1.59 mmol) in NaOH (2N in THF / MeOH 1:1:1) (10 ml) was stirred overnight at room temperature. The solvent was evaporated, and the residue was acidified with 1 M H2SO4. The resulting solution was concentrated to 6 mL, and the residue was purified by HPLC to obtain intermediate I-22 (284 mg, 62%). LC / MS: m / z 288.2[M+1] + ;RT: 0.88 min (method A). 1 1H NMR: 1 H NMR(DMSO-d6,400MHz)δ ppm 8.49(d,J=5.38Hz,1H),7.78(d,J=1.59Hz,1H),7.08(m,1H),6.87(d,J=5.38Hz,1H),4.50(br d,J=13.08Hz,2H),3.13(m,2H),2.67(s,3H),2.59(m,1H),2.50(u),1.91(m,2H),1.52(m,2H).

[0304] Intermediate I-23: 1-[4-(4-methylpyrazole-1-yl)pyrimidine-2-yl]piperidine-4-carboxylic acid (corresponding to compound (IIa)) (following SM4 and SM1 of Scheme 3 or step 2 of Scheme 1) Step 1: Ethyl 1-[4-(4-methylpyrazole-1-yl)pyrimidine-2-yl]piperidine-4-carboxylate To a mixture of 2-chloro-4-(4-methyl-1h-pyrazole-1-yl)pyrimidine (687.98 mg, 3.39 mmol) in ACN (18 ml), ethylpiperidine-4-carboxylate (500 mg, 2.74 mmol) was added, followed by DIPEA (2.15 ml, 12.3 mmol). The mixture was stirred in MW at 120°C for 30 minutes. Complete conversion to the product was shown by LC / MS, and the reaction mixture was evaporated. The residue was purified by silica gel chromatography (heptane: EA gradient) to obtain the desired product, intermediate I-23-ethyl ester (865 mg, 89%). LC / MS: m / z 316.3 [M+1] + ;RT: 0.844 minutes (Method B).

[0305] Step 2: 1-[4-(4-methylpyrazole-1-yl)pyrimidine-2-yl]piperidine-4-carboxylic acid A solution of intermediate I-23-ethyl ester (ethyl 1-[4-(2-methylimidazole-1-yl)pyrimidine-2-yl]piperidine-4-carboxylate) (865 mg, 2.74 mmol) in NaOH (2N in THF / MeOH 1:1:1) (42 ml) was stirred overnight at room temperature. The solvent was evaporated, and the residue was acidified with 1 M H2SO4. The resulting solution was concentrated to 6 mL, and the residue was purified by HPLC to obtain intermediate I-23 (753 mg, 96%). LC / MS: m / z 288.3 [M+1] + ;RT: 0.644 minutes (Method B). 1H NMR(DMSO-d6,400MHz)δ ppm 12.23(br s,1H),8.46(s,1H),8.39(d,J=5.38Hz,1H),7.68(s,1H),6.98(d,J=5.26Hz,1H),4.58(br d,J =13.20Hz,2H),3.10(br t,J=11.06,11.06Hz,2H),2.57(m,1H),2.11(s,3H),1.92(m,1H),1.89(br s,1H),1.51(m,2H).

[0306] Intermediate I-24: 1-[2-(2-methylpyrazole-3-yl)pyrimidine-4-yl]piperidine-4-carboxylic acid (corresponding to compound (IIa)) (following SM3 and SM1 of Scheme 3 or step 2 of Scheme 1) Step 1: 1-[2-(2-methylpyrazole-3-yl)pyrimidine-4-yl]piperidine-4-carboxylate methyl ester To a solution of intermediate AA-5 (2.85 g, 13.69 mmol, 1 equivalent) in dioxane (28 ml), K2CO3 (3.78 g, 27.38 mmol, 2 equivalents), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (3.5 g, 13.69 mmol, 1 equivalent) H2O (7 mL) and Pd(dppf)Cl2 (1.12 g, 1.37 mmol, 0.1 equivalent) were added, and the mixture was stirred at 120°C for 12 hours under an N2 atmosphere. LC / MS showed that no starting material remained. Several new peaks were shown by LC / MS, and approximately 27% of the desired compound was detected. The residue was diluted with H2O (100 mL) and extracted with EA (30 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®, 40g SepaFlash® silica flash column, eluate at 30 mL / min with a 30-70% EA / PE gradient) to obtain the intermediate I-24 methyl ester (3.72 g, 70% yield, 80% purity) as a yellow oil. LC / MS: m / z 302.1[M+1] + ;RT 0.399 min (Method C).

[0307] Step 2: 1-[2-(2-methylpyrazole-3-yl)pyrimidine-4-yl]piperidine-4-carboxylic acid Intermediate I-24 methyl ester (3.52 g, 11.68 mmol, 1 equivalent), LiOH·H2O (980.27 mg, 23.36 mmol, 2 equivalents), and H2O (8 ml) were mixed in THF (32 ml), and the mixture was stirred at 25°C for 12 hours under an N2 atmosphere. LC / MS showed that no starting material remained. Several new peaks were shown by LC / MS, and approximately 65% ​​of the desired compound was detected. The residue was diluted with H2O (40 mL) and extracted with SiO (40 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (0.1% FA conditions) to obtain intermediate I-24 (1.3 g, 38%) as a white solid. LC / MS: m / z 288.1[M+1] + ;RT 0.348 min (Method C). 1 H NMR:(DMSO-d6,400MHz)δ ppm 8.27(d,J=6.2Hz,1H),7.45(d,J=1.8Hz,1H),6.88(d,J=1.8Hz,1H),6.79(d ,J=6.4Hz,1H),4.38-4.26(m,2H),4.21(s,3H),3.18-3.06(m,2H),2.68(br s,1H),2.64-2.55(m,1H),1.92(br dd,J=2.9,13.2Hz,2H),1.62-1.45(m,2H).

[0308] Intermediate I-25.1-[2-(4-methylpyrazole-1-yl)pyrimidine-4-yl]piperidine-4-carboxylic acid (corresponding to compound (IIa)) (following step 2 of SM4 in Scheme 3 and SM1 in Scheme 1) Step 1: A mixture of 4-chloro-2-(4-methylpyrazole-1-yl)pyrimidine (680 mg, 3.39 mmol) and ethylpiperidine carboxylate (500 mg, 3.08 mmol) in ACN (18 ml) was mixed with DIPEA (2.5 ml; 2.8 mmol). The mixture was stirred in MW at 120°C for 30 minutes. LC-MS showed complete conversion to the desired product. The mixture was diluted with ELISA and extracted with saturated NH4Cl. The aqueous phase was extracted with EE (2×), and the combined organic phase was dried over MgSO4, concentrated, and purified by silica gel column chromatography (heptane:EE gradient) to obtain intermediate I-25 ethyl ester as a white solid (517 mg, 52%). LC / MS: m / z 316.4 [M+1] + ;RT 0.836 min (Method B).

[0309] Step 2: 1-[2-(4-methylpyrazole-1-yl)pyrimidine-4-yl]piperidine-4-carboxylic acid A solution of intermediate I-25 ethyl ester (517 mg, 1.64 mmol) in 2N NaOH / THF / MeOH (1:1:1) was stirred overnight at room temperature. The organic solvent was then evaporated, and the resulting aqueous phase was acidified with 1N H2SO4. The precipitate was filtered and dried in an oven to obtain intermediate I-25 as a white solid (381 mg, 81%). LC / MS: m / z 288.2[M+1] + ;RT 1.66 min (Method A). 1 H NMR(DMSO-d6,600MHz)δ ppm 12.25(br s,1H),8.46(s,1H),8.39(d,J=5.32Hz,1H),7.68(s,1H),6.98(d,J=5.32Hz,1H),4. 58(dt,J=13.34,3.51,3.51Hz,2H),3.10(m,2H),2.57(m,1H),2.11(s,3H),1.90(br dd,J=13.48,3.39Hz,2H),1.51(m,2H).

[0310] Intermediate I-26.1-[6-(4-methylpyrazole-1-yl)pyrimidine-4-yl]piperidine-4-carboxylic acid (corresponding to compound (IIa)) (following step 2 of SM4 in Scheme 3 and SM1 in Scheme 1) Step 1: A mixture of 4-chloro-6-(4-methylpyrazole-1-yl)pyrimidine (695 mg, 3.39 mmol) and ethylpiperidine carboxylate (500 mg, 3.08 mmol) in CAN (18 ml) was mixed with DIPEA (2.5 ml; 2.8 mmol). The mixture was stirred in MW at 120°C for 30 minutes. LC-MS showed complete conversion to the desired product. The mixture was diluted with EA and extracted with saturated NH4Cl. The aqueous phase was extracted with EA (2×), the combined organic phase was dried over MgSO4, concentrated, and purified by silica gel column chromatography (heptane: SiO gradient) to obtain intermediate I-26 ethyl ester as a white solid (883 mg, 90%). LC / MS: m / z 316.3 [M+1] + ;RT 0.869 min (Method B).

[0311] Step 2: 1-[6-(4-methylpyrazole-1-yl)pyrimidine-4-yl]piperidine-4-carboxylic acid A solution of intermediate I-26 ethyl ester (883 mg, 2.8 mmol) in 2N NaOH / THF / MeOH (1:1:1) was stirred overnight at room temperature. The organic solvent was then evaporated, and the resulting aqueous phase was acidified with 1N H2SO4. The precipitate was filtered and dried in an oven to obtain intermediate I-26 as a white solid (679.9 mg, 84%). LC / MS: m / z 288.1[M+1] + ;RT 1.63 min (Method A). 1H NMR(DMSO-d6,400MHz)δ ppm 12.27(br s,1H),8.41(s,1H),8.34(s,1H),7.67(s,1H),7.06(s,1H),4.29(br d,J=10.76Hz,2H),3.13(m,2H),2.58(m,1H),2.10(s,3H),1.91(br dd,J=13.45,3.30Hz,2H),1.53(m,2H).

[0312] Intermediate I-27.1-[4-(2-methylpyrazole-3-yl)-1,3,5-triazine-2-yl]piperidine-4-carboxylic acid (corresponding to compound (IIa)) (following step 2 of SM3 in Scheme 3 and SM1 in Scheme 1) Step 1 To a solution of I-AA 4 (10 g, 38.96 mmol, 1 equivalent) in dioxane (80 ml), K2CO3 (10.77 g, 77.92 mmol, 2 equivalents), Pd(dppf)Cl2 (2.85 g, 3.90 mmol, 0.1 equivalent), H2O (20 ml), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (8.11 g, 38.96 mmol, 1 equivalent) were added. The mixture was stirred at 80°C for 12 hours. LC-MS showed that no starting material remained. Several new peaks were observed by LC-MS, and approximately 41% of the desired compound was detected. The residue was diluted with 100 mL of H2O and extracted with 100 mL (100 mL x 2) of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®, 20g SepaFlash® silica flash column, eluate @ 80 mL / min on a 0-80% ethyl acetate / petroleum ether gradient) to obtain the intermediate I-27-methyl ester (11.3 g, 33.26 mmol, yield 85.39%, purity 89%) as a white solid. LCMS: m / z 303.2[M+1] + ;RT 0.836 min (Method C). 1H NMR(CDCl3,400MHz)8.59(s,1H),7.50(d,J=1.7Hz,1H),7.09(d,J=1.7Hz,1H),4.66(br d,J=10.6Hz,2H),4.34-4.30(s,3H),3.72(s,3H),3.20(br t,J=12.3Hz,2H),2.66(tt,J=4.0,10.6Hz,1H),2.04-1.98(m,2H),1.83-1.71(m,2H).

[0313] Step 2: 1-[4-(2-methylpyrazole-3-yl)-1,3,5-triazine-2-yl]piperidine-4-carboxylic acid A mixture of intermediate I-27-methyl ester (11.3 g, 37.38 mmol, 1 equivalent), H2O (20 mL), and LiOH·H2O (6.27 g, 149.51 mmol, 4 equivalents) in THF (90 mL) was degassed, and the mixture was then stirred at 25°C for 2 hours. LC-MS showed that no starting material remained. Several new peaks were observed on LC-MS, and approximately 14% of the desired compound (low ionization of COOH) was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The crude product was purified by reverse-phase HPLC (flow rate: 200 mL / min; gradient: 5% ACN / 95% H2O (0.1% FA) to 40% ACN / 60% H2O (0.1% FA) in 25 minutes; 40% ACN / 60% H2O (0.1% FA) in 20 minutes; column: Welch Ultimate XB_C18, 20-40 μm, 120 Å) to obtain intermediate I-27 (8.5 g, yield 78%) as a white solid. LCMS: m / z 289.4[M+1] + ;RT 0.842 (Method D) 1 H NMR (DMSO-d6,400MHz)12.80-12.01(m,1H),8.65(s,1H),7.53(d,J=2.0Hz,1H),7.05(d,J=1.9Hz,1H),4. 59-4.50(m,2H),4.24(s,3H),3.26-3.17(m,2H),2.65-2.58(m,1H),2.00-1.89(m,2H),1.63-1.46(m,2H).

[0314] Intermediate I-37: 1-[4-(2-oxo-1-piperidyl)pyrimidine-2-yl]piperidine-4-carboxylic acid To a mixture of Ar-Cl 19 (5.19 g, 0.0245 mol, 1.00 equivalent) and piperidine-4-carboxylic acid (3.48 g, 0.0270 mol, 1.10 equivalent) in the cosolvent dioxane / H2O (v / v=2 / 1, 110 ml), TEA (6.82 ml, 0.0490 mol, 2.00 equivalent) was added. The resulting mixture was heated at 90°C for 16 hours. The mixture was concentrated directly to remove most of the dioxane solvent, and then washed once with ethyl acetate (5 mL) to remove organic solvent-soluble impurities. The remaining aqueous phase was adjusted to pH approximately 5 with citric acid (saturated aqueous solution), and the formed precipitate was collected by filtration and washed with a small amount of water to obtain intermediate I-37 (6.12 g, 0.0201 mol, yield 82.0%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=8.20(d,J=5.6Hz,1H),7.23(d,J=5.6Hz,1H),4.48(d,J=13.2Hz,2H),3. 88(t,J=6.0Hz,2H),3.09-2.95(m,2H),2.58-2.50(m,3H),1.92-1.73(m,6H),1.56-1.39(m,2H). LCMS m / z = 305.2[M+H] + ;RT 0.478(Method Q)

[0315] Intermediate I-38: 1-[4-(4-oxo-5-azaspiro[2,4]heptan-5-yl)pyrimidine-2-yl]piperidine-4-carboxylic acid I-38 was synthesized in the same manner as intermediate I-37, but crude intermediate I-38 (610 mg, purity 60.0%, 0.00116 mol, 86.3% yield, contaminated with TEA) was obtained as a yellow solid using Ar-Cl3 (300 mg, 0.001 mol, 1.00 equivalent) and piperidine-4-carboxylic acid (191 mg, 0.001 mol, 1.10 equivalent). 1H NMR(400MHz,DMSO-d6)δ=8.21(d,J=5.6Hz,1H),7.42(d,J=5.6Hz,1H),4.49(d,J=13.2Hz,2H),4.04-3.99(m,2H),3.05-2.98(m,2) H),2.53-2.51(m,1H),2.17-2.12(m,2H),1.86(dd,J=13.2,2.8Hz,2H),1.55-1.39(m,2H),1.04-1.01(m,2H),0.96-0.91(m,2H). MS(ESI)m / z=317.2[M+H] + . (Compound 13, Method Q)

[0316] Intermediate I-39: 1-[4-(4-oxo-5-azaspiro[2,5]octan-5-yl)pyrimidine-2-yl]piperidine-4-carboxylic acid I-39 was synthesized in the same manner as intermediate I-37, but using Ar-Cl 19 (190 mg, 0.000799 mol, 1.00 equivalent) and piperidine-4-carboxylic acid (124 mg, 0.000959 mol, 1.20 equivalent), I-39 (210 mg, 0.000636 mol, yield 79.5%) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=8.17(d,J=5.6Hz,1H),7.19(d,J=5.6Hz,1H),4.47(d,J=13.2Hz,2H),3.98(t,J=6.0Hz,2H),3.07-2.95(m,2H),2.56-2 .53(m,1H),2.02-1.92(m,2H),1.86(dd,J=13.2,2.8Hz,2H),1.77-1.71 (m,2H),1.53-1.39(m,2H),1.19(q,J=3.2Hz,2H),0.73(q,J=3.2Hz,2H). LCMS: m / z = 331.2[M+H] + . RT 0.497 (Method Q)

[0317] Intermediate I-40: 1-[4-(2-oxoxazolidine-3-yl)pyrimidine-2-yl]piperidine-4-carboxylic acid I-40 was synthesized in the same manner as intermediate I-37, but crude I-40 was obtained using Ar-Cl2 (350 mg, 0.00167 mol, 1.00 equivalent) and piperidine-4-carboxylic acid (258 mg, 0.00200 mol, 1.20), and this was used directly in the synthesis of Example 65.

[0318] Intermediate I-41: 1-[5-fluoro-4-(2-methylimidazole-1-yl)pyrimidine-2-yl]piperidine-4-carboxylic acid I-40 was synthesized in the same manner as intermediate I-37, but using Ar-Cl 30 (2.00 g, 0.00941 mol, 1.00 equivalent) and piperidine-4-carboxylic acid (1.34 g, 0.0103 mol, 1.10 equivalent), 1-[5-fluoro-4-(2-methylimidazole-1-yl)pyrimidine-2-yl]piperidine-4-carboxylic acid (2.20 g, 0.00721 ​​mol, yield 76.6%) was obtained as a white solid. 1 H NMR(400MHz,CD3OD)δ=8.58(d,J=2.8Hz,1H),7.55(dd,J=3.2,1.6Hz,1H),7.11(d,J=1.6Hz,1H),4.65(dt,J =13.6,3.6Hz,2H),3.29-3.20(m,2H),2.75-2.70(m,1H),2.67(s,3H),2.12-2.03(m,2H),1.80-1.68(m,2H). LCMS(ESI)m / z=306.2[M+H] + . RT 0.454 (Method Q)

[0319] Intermediate I-42.1-[4-(2-oxopyrrolidine-1-yl)pyrimidine-2-yl]piperidine-4-carboxylic acid I-42 was synthesized in the same manner as intermediate I-37, but using Ar-Cl3 (5.47 g, 0.0277 mol, 1.00 equivalent) and piperidine-4-carboxylic acid (3.93 g, 0.0304 mol, 1.10 equivalent), 1-[4-(2-oxopyrrolidine-1-yl)pyrimidine-2-yl]piperidine-4-carboxylic acid (3.85 g, 0.0133 mol, 47.9% yield) was obtained as a white solid. 1H NMR(400MHz,DMSO-d6)δ=12.63-11.90(br s,1H),8.21(d,J=6.0Hz,1H),7.50(d,J= 6.0Hz,1H),4.50-4.42(m,2H),3.93(t,J=7.2Hz,2H),3.13-3.01(m,2H),2 .61-2.51(m,3H),2.07-1.97(m,2H),1.92-1.83(m,2H),1.55-1.43(m,2H). LC / MS m / z = 291.0[M+H] + ;RT 0.664(Method Q)

[0320] Intermediate I-43.1-[6-(2-oxopyrrolidine-1-yl)pyrimidine-4-yl]piperidine-4-carboxylic acid I-43 was synthesized in the same manner as intermediate I-37, but using Ar-Cl 31 (2.80 g, 0.0142 mol, 1.00 equivalent) and piperidine-4-carboxylic acid (3.66 g, 0.0283 mol, 2.00 equivalent), I-43 (3.40 g, 0.0117 mol, yield 82.7%) was obtained as a white solid. 1 H NMR(400MHz,CD3OD)δ=8.30(s,1H),7.64(s,1H),4.29(d,J=13.2Hz,2H),4.06-3.97(m,2H),3.10(ddd,J=1 3.6,11.2,2.8Hz,2H),2.68-2.58(m,3H),2.11(quin,J=7.6Hz,2H),2.03-1.93(m,2H),1.71-1.56(m,2H).

[0321] Intermediate I-44: 1-[4-(3-methoxy-2-oxo-1-piperidyl)pyrimidine-2-yl]piperidine-4-carboxylic acid I-44 was synthesized starting from Ar-Cl 28 (2.0 g, 78% purity, 0.82 mmol) and piperidine-4-carboxylic acid (1.25 g, 1.5 equivalents), similar to intermediate 42, and this compound was used as the crude starting material in the next step.

[0322] Intermediate I-45: 1-[4-(2-methyl-5-nitropyrazole-3-yl)pyrimidine-2-yl]piperidine-4-carboxylic acid Intermediate I-45 was synthesized starting from Ar-Cl32 (416 mg, 1.74 mmol) and piperidine-4-carboxylic acid (235 mg, 1.05 equivalents), similar to intermediate 42, to obtain intermediate I-45, which was then used as the crude product (61% purity) in the next step.

[0323] Intermediate I-46.1-[5-fluoro-4-(2-oxoxazolidine-3-yl)pyrimidine-2-yl]piperidine-4-carboxylic acid This was synthesized starting from Ar-Cl5 (1.0 g, 84% purity, 3.86 mmol) and piperidine-4-carboxylic acid (584 mg, 1.10 equivalents), as in intermediate 42, to obtain intermediate I-46 as a white solid (1.10 g, 46%). 1 H NMR(400MHz,DMSO-d6)δ=12.61-11.92(br s,1H),8.39(d,J=3.2Hz,1H),4.50(t,J=7.6Hz,2H),4.39(d,J=13.2Hz,2H),4.12(t,J= 7.6Hz,2H),3.10-2.95(m,2H),2.49-2.46(m,1H),1.93-1.79(m,2H),1.56-1.39(m,2H). LC / MS m / z = 311.2[M+H] + ;RT 0.494 (Method Q).

[0324] Intermediate I-47.1-[5-fluoro-4-(4-oxo-5-azaspiro[2,4]heptan-5-yl)pyrimidine-2-yl]piperidine-4-carboxylic acid This was synthesized starting from Ar-Cl34 (400 mg, 1.66 mmol) and piperidine-4-carboxylic acid (235 mg, 1.05 equivalents), as in intermediate 42, to obtain intermediate I-47 as a white solid (386 mg, 69%). 1H NMR(400MHz,DMSO-d6)δ=12.24(br s,1H),8.37(d,J=3.2Hz,1H),4.50-4.30(m,2H),3.95(t,J=7.2Hz,2H),3.10-2.96(m,2H),2.53-2.51(m,1H) ),2.26-2.17(m,2H),1.86(dd,J=13.2,2.8Hz,2H),1.56-1.40(m,2H),1.02-0.97(m,2H),0.97-0.92(m,2H). LC / MS m / z = 335.2[M+H] + ;RT 0.534(Method Q)

[0325] General scheme for the synthesis of Examples 1, 2, 3, 4, 5, 6, 22, 23, 29, 30, 31, 32, 33, and 34 (corresponding to compounds of formula (I)) (following SM2 of Scheme 1) Preparation of aryl chlorides (1-37) These structures are summarized in Table 2 below.

[0326] [Table 31]

[0327] [Table 32]

[0328] Aryl chloride 1:(4-chloro-6(pyridine-3-yl)pyrimidine - commercially available) Aryl chloride 2: To a solution of 2-oxazolidinone (292.3 mg, 3.29 mmol) in DMF (10 ml), NaH (60% in mineral oil, 3.62 mmol) was added. After stirring for 15 minutes, 2,4-dichloropyrimidine (0.5 g, 3.29 mmol) was added in two portions. The mixture was stirred at room temperature for 1 hour, and LC / MS showed complete conversion to the desired product. The reaction mixture was quenched with water and extracted with EA (3×). The organic layer was then washed with water and saturated aqueous NaCl solution, dried over Na₂SO₄, filtered, and the solvent evaporated. The product was purified by silica gel chromatography to obtain the desired product Ar-Cl₂ (394 mg, 60%). LCMS: m / z 200.4[M+1] + ;RT 0.435 (Method B)

[0329] Aryl chloride 3 and aryl chloride 4: To a solution of 2-oxazolidinone (285.6 mg, 3.29 mmol) in DMF (10 ml), NaH (60% in mineral oil, 3.62 mmol) was added. After stirring for 15 minutes, 2,4-dichloropyrimidine (0.5 g, 3.29 mmol) was added in two portions. The mixture was stirred at room temperature for 1 hour, and LC / MS showed complete conversion to the desired product. The reaction mixture was quenched with water and extracted with EA (3×). The organic layer was then washed with water and saturated aqueous NaCl solution, dried over Na₂SO₄, filtered, and the solvent evaporated. The product was purified by silica gel chromatography to obtain the desired products Ar-Cl₃ (105 mg, 16%) and Ar-Cl₄ (82 mg, 13%). LCMS Ar-Cl-3: m / z 200.1[M+1] + ;RT 0.428 (Method B) LCMS Ar-Cl 4: m / z 200.1 [M+1] + ;RT 0.527 (Method B)

[0330] Aryl chloride 5:3-(2-chloro-5-fluoropyrimidine-4-yl)oxazolidine-2-one To a solution of 2-oxazolidinone (52 mg, 0.59 mmol) in DMF (10 ml), NaH (60% in mineral oil, 26 mg, 0.65 mmol) was added. After stirring for 15 minutes, 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.59 mmol) was added in two portions. The mixture was stirred at room temperature for 1 hour, and LC / MS showed complete conversion to the desired product. The reaction mixture was quenched with water and extracted with EA (3×). The organic layer was then washed with water and saturated aqueous NaCl solution, dried over Na₂SO₄, filtered, and the solvent evaporated. The product was purified by silica gel chromatography to obtain the desired product Ar-Cl₅ (105 mg, 81%). LCMS: m / z 217.0[M+1] + ;RT 0.94 min (Method A).

[0331] Aryl chloride 6:1-(2-chloro-5-fluoropyrimidine-4-yl)pyrrolidine-2-one To a solution of 2-pyrrolidone (50 mg, 0.59 mmol) in DMF (10 ml), NaH (60% in mineral oil, 26 mg, 0.59 mmol) was added. After stirring for 15 minutes, 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.59 mmol) was added in two portions. The mixture was stirred at room temperature for 1 hour, and LC / MS showed complete conversion to the desired product. The reaction mixture was quenched with water and extracted with EA (3×). The organic layer was then washed with water and saturated aqueous NaCl solution, dried over Na₂SO₄, filtered, and the solvent evaporated. The product was purified by silica gel chromatography to obtain the desired product Ar-Cl₂ (38 mg, 19%). LCMS: m / z 216.1[M+1] + ;RT 0.477 min (Method B).

[0332] Aryl chloride 7:2-chloro-4-(2,4-dimethylimidazole-1-yl)-5-fluoropyrimidine 2,4-dimethyl-1H-imidazole (25 mg, 0.26 mmol) and 2,4-dichloro-5-fluoropyrimidine (47.7 mg, 0.28 mmol) were dissolved in dry ACN (10 mL), to which Cs₂CO₃ (127 mg) was added. The mixture was stirred at room temperature for 15 minutes, and complete conversion to the desired product was shown by LC / MS. The reaction mixture was quenched with water and extracted with EA (3 ×). The organic layer was then washed with water and saturated aqueous NaCl solution, dried over Na₂SO₄, filtered, and the solvent evaporated. The product was purified by silica gel chromatography to obtain the desired product Ar-Cl₂ (22 mg, 37%). LCMS: m / z 227.1[M+1] + ;RT 0.584 min (Method E).

[0333] Aryl chloride 8-1-(2-chloro-5-fluoropyrimidine-4-yl)pyrrolidine-2-one To a solution of 2-pyrrolidone (50.9 mg, 0.59 mmol) in DMF (3 ml), NaH (60% in mineral oil, 26 mg, 0.65 mmol) was added. After stirring for 15 minutes, 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.59 mmol) was added in two portions. The mixture was stirred at room temperature for 1 hour, and LC / MS showed complete conversion to the desired product. The reaction mixture was quenched with water and extracted with EA (3 ×). The organic layer was then washed with water and saturated aqueous NaCl solution, dried over Na₂SO₄, filtered, and the solvent evaporated. The product was purified by silica gel chromatography to obtain the desired product Ar-Cl₂ (38 mg, 29%). LCMS: m / z 216.1[M+1] + ;RT 0.477 min (Method B).

[0334] Aryl chloride 9 and aryl chloride 10: To a solution of 2-methylimidazole (200 mg, 2.41 mmol) and 2,4-dichloropyrimidine (0.4 g, 2.65 mmol) in ACN (8 ml), Cs2CO3 (1.18 g, 3.62 mmol) was added. After stirring overnight at room temperature, complete conversion to the desired product was shown by LC / MS. The reaction mixture was quenched with water and extracted with EA (3 ×). The organic layer was then washed with water and saturated aqueous NaCl solution, dried over Na2SO4, filtered, and the solvent evaporated. The product was purified by silica gel chromatography and then by preparative HPLC to obtain the desired products Ar-Cl9 (101 mg, 22%) and Ar-Cl10 (151 mg, 32%). LCMS Ar-Cl 9: m / z 200.1 [M+1] + ;RT 0.470 (Method E) LCMS Ar-Cl 10: m / z 200.1 [M+1] + ;RT 0.581 (Method E)

[0335] Aryl chloride 11-4-chloro-6-(2-methyl-1H-imidazole-yl)pyrimidine, commercially available. Aryl chloride 12: To a solution of pyrazole (43.48 mg, 0.63 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.57 mmol) in dry ACN (10 mL), Cs2CO3 (0.41 g, 1.25 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and complete conversion to the desired product was shown by LC / MS. The reaction mixture was quenched with water and extracted with EA (3 ×). The organic layer was then washed with water and saturated aqueous NaCl solution, dried over Na2SO4, filtered, and the solvent evaporated. The product was purified by preparative HPLC chromatography to obtain the desired product Ar-Cl 12 (92 mg, 81%). LCMS: m / z 199.0[M+1] + ;RT 0.601 (Method B)

[0336] Aryl Chloride 13:4-Chloro-6-(2-methylpyrazole-3-yl)pyrimidine To a mixture of 4,6-dichloropyrimidine (5 g, 33.56 mmol, 1 equivalent) in dioxane (40 mL), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (6.98 g, 33.56 mmol, 1 equivalent), K2CO3 (9.28 g, 67.12 mmol, 2 equivalents), Pd(dppf)Cl2 (2.74 g, 3.36 mmol, 0.1 equivalent), and H2O (10 mL) were added. The mixture was degassed, purged with N2, and then stirred at 80°C for 12 hours under an N2 atmosphere. LC / MS showed that no starting material remained, and several new peaks were shown on the LC / MS, with approximately 40% of the desired mass detected. The residue was diluted with H2O (60 mL) and extracted with EA (60 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (0.1% FA conditions) to obtain Ar-Cl13 (4.43 g, 20.50 mmol, yield 61.08%, purity 90%) as a yellow solid.

[0337] Aryl chloride 14:4-chloro-6-(2-methyl-1,2,4-triazol-3-yl)pyrimidine To a solution of 5-bromo-1-methyl-1,2,4-triazole (6.00 g, 0.0370 mol, 1.00 equivalent) in THF (180 ml), n-BuLi (2.5 M in THF, 17.8 ml, 0.0444 mol, 1.20 equivalent) was added dropwise at -78°C. After stirring at the same temperature for 30 minutes, ZnCl2 (1 M THF solution, 111 ml, 0.111 mol, 3.00 equivalent) was slowly added. After stirring at -78°C for 30 minutes, the resulting mixture was raised to 25°C and stirred for 1 hour. Then, a mixture of 4-6-dichloropyrimidine (11.0 g, 0.0741 mol, 2.00 equivalent) and Pd(PPh3)4 (2.14 g, 0.00185 mol, 5%) in THF (60 mL) was added at 25°C. The resulting mixture was stirred at 70°C for 16 hours. The reaction was quenched with NH4Cl (saturated aqueous solution, 100 ml), diluted with water (100 ml), and then extracted with HCl (3 × 150 ml). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4 solid, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE / HCl = 10 / 1 to 2 / 1) to obtain Ar-Cl 14 (448 mg, purity 94.0%, 0.00215 mol, yield 5.81%) as a white solid. 1 H NMR(400MHz, CDCl3)δ=9.09(s,1H),8.27(s,1H),8.00(s,1H),4.43(s,3H). LCMS: m / z = 196.1[M+H] + . RT 0.518 min (Method C)

[0338] Aryl chloride 15:4-chloro-6-(3-methyltriazol-4-yl)pyrimidine A mixture of tributyl-(3-methyltriazole-4-yl) stannan (4.00 g, 50.0% purity, 0.00537 mol, 1.00 equivalent), 4,6-dichloropyrimidine (1.04 g, 0.00699 mol, 1.30 equivalent), LiCl (0.0456 g, 0.00107 mol, 20%), and Pd(PPh3)2Cl2 (0.377 g, 0.000537 mol, 10%) in DMF (75 ml) was degassed with N2 flux for 10 minutes. The solution was stirred at 70°C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to remove most of the solvent. The residue was diluted with water (100 mL) and extracted with siRNA (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na2SO4 solids, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE / Â=5 / 1~2 / 1) to obtain Ar-Cl 15 (456 mg, purity 77.0%, 0.00180 mol, yield 33.4%) as a yellow solid. 1 H NMR(400MHz, CDCl3)δ=9.09(d,J=0.8Hz,1H),8.19(s,1H),7.67(d,J=0.8Hz,1H),4.49(s,3H). LCMS(ESI)m / z=196.1[M+H] + . RT 0.434 (Method C)

[0339] Aryl chloride 16:5-(2-chloropyrimidine-4-yl)-5-azaspiro[2.4]heptan-4-one A mixture of 2,4-dichloropyrimidine (2.01 g, 0.013 mol, 1.50 equivalents), Pd(OAc)2 (0.203 g, 0.001 mol, 10%), XantPhos (1.04 g, 0.002 mol, 20%), Cs2CO3 (4.40 g, 0.0135 mol, 1.50 equivalents), and 5-azaspiro[2.4]heptan-4-one (1.00 g, 0.009 mol, 1.00 equivalent) in THF (30 mL) was degassed, purged three times with N2 at 0°C, and the resulting mixture was stirred at 70°C for 2 hours. After filtration through Celite and washing with DCM, the filtrate was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / siRNA = 1 / 0 to 10 / 1) to obtain Ar-Cl 16 (1.70 g, yield 84.5%) as a yellow oily substance. 1 H NMR(400MHz,CDCl3)δ=8.43(d,J=5.6Hz,1H),8.32(d,J=5.6Hz,1H),4.18(t,J=7.2Hz,2H),2.27(t,J=7.2Hz,2H),1.34-1.28(m,2H),1.01-0.95(m,2H). LCMS(ESI)m / z=224.1[M+H] + . RT 0.575 (Method C)

[0340] Aryl chloride 17:1-(2-chloropyrimidine-4-yl)-3,3-difluoropyrrolidine-2-one Ar-Cl 17 (640 mg, 55%) was synthesized as a white solid using the same method as for Ar-Cl 16, with 3,3-difluoropyrrolinidine-2-one (1.47 g, 0.00991 mol, 2.00 equivalents) and 2,4-dichloropyrimidine (739 mg, 0.00496 mol, 1.00 equivalent). 1 H NMR(400MHz, CDCl3)δ=8.60(d,J=5.6Hz,1H),8.36(d,J=5.6Hz,1H),4.15(t,J=6.8Hz,2H),2.76-2.60(m,2H).

[0341] Aryl chloride 18:1-(2-chloropyrimidine-4-yl)-3,3-dimethylpyrrolidine-2-one Ar-Cl 18 (5.10 g, 85%) was synthesized as a white solid using the same method as for Ar-Cl 16, with 3,3-dimethylpyrrolidine-2-one (3 g, 0.0265 mol, 1.00 equivalent) and 2,4-dichloropyrimidine (6.3 g, 1.5 equivalent).

[0342] Aryl chloride 19:1 5-(2-chloropyrimidine-4-yl)-5-azaspiro[2.5]octan-4-one Ar-Cl 19 (456 mg, 79%) was synthesized as a white solid using the same method as for Ar-Cl 16, with 5-azaspiro[2,5]octan-4-one (300 mg, 2.4 mmol, 1.00 equivalent) and 2,4-dichloropyrimidine (536 mg, 1.5 equivalent). 1 H NMR(400MHz,CDCl3)δ=8.40(d,J=6.0Hz,1H),8.17(d,J=6.0Hz,1H),4.17-4.08(m,2H ),2.13-2.03(m,2H),1.85-1.76(m,2H),1.46(q,J=3.6Hz,2H),0.79(q,J=3.6Hz,2H).

[0343] Aryl chloride 20:1-(2-chloropyrimidine-4-yl)-3,3-difluoropiperidine-2-one Ar-Cl 20 (220 mg, 5%) was synthesized as a white solid using the same method as for Ar-Cl 16, with 3,3-difluoropiperidine-2-one (2.5 g, 0.0185 mol, 1.00 equivalent) and 2,4-dichloropyrimidine (3.3 g, 1.2 equivalents). 1 H NMR(400MHz,DMSO-d6)δ=8.72(d,J=5.6Hz,1H),8.07(d,J=5.6Hz,1H),3.99(t,J=6.0Hz,2H),2.48-2.38(m,2H),2.12-2.00(m,2H).

[0344] Aryl chloride 21:4-(2-chloropyrimidine-4-yl)morpholin-3-one Ar-Cl 21 (7.70 g, 71%) was synthesized as a white solid using the same method as for Ar-Cl 16, with morpholine-3-one (5 g, 0.0495 mol, 1.00 equivalent) and 2,4-dichloropyrimidine (8.84 g, 1.2 equivalents). 1 H NMR (400MHz, DMSO-d6) δ=8.65(d,J=5.6Hz,1H),8.30(d,J=5.6Hz,1H),4.33(s,2H),4.02-3.93(m,4H).

[0345] Aryl chloride 22:1-(2-chloropyrimidine-4-yl)-3-methylimidazolidined-2-one Ar-Cl₂₂ (3.90 g, 92%) was synthesized using the same method as for Ar-Cl₂₆, with 3-methylimidazolin-2-one (2 g, 0.0470 mol, 1.00 equivalent) and 2,4-dichloropyrimidine (4.46 g, 1.5 equivalent) to obtain Ar-Cl₂₂ as a yellowish solid. 1 H NMR(400MHz,CDCl3)δ=8.45(d,J=6.0Hz,1H),8.34(d,J=6.0Hz,1H),4.13-4.05(m,2H),3.42-3.51(m,2H),2.85-2.76(s,3H).

[0346] Aryl Chloride 23: 2-Methylsulfonyl-4-(oxetan-3-yl)pyrimidine Step 1: 4-Chloro-2-methylsulfanylpyrimidine (4.00 g, 0.0249 mol, 1.00 equivalent), 3-bromooxetane (4.43 g, 0.0324 mol, 1.30 equivalent), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (0.279 g, 0.000249 mol, 1 mol%, CAS: 870987-63-6), NiCl2.dtbbpy(0.0496 A mixture of (g, 0.000125 mol, 5 mol‰, CAS: 1034901-50-2), TTMSS (6.19 g, 0.0249 mol, 1.00 equivalent, CAS: 1873-77-4), and Na2CO3 (5.28 g, 0.0498 mol, 2.00 equivalent) in DME (150 ml) was degassed, purged with N2, and then stirred at 25°C for 16 hours and irradiated with a 455 nm blue LED. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE / siRNA = 2 / 1 to 0 / 1) to obtain methylsulfanyl-4-(oxetan-3-yl)pyrimidine (3.58 g, 0.0197 mol, yield 78.9%) as a brown solid. 1 H NMR(400MHz,CDCl3)δ=8.48(d,J=5.2Hz,1H),6.93(d,J=5.2Hz,1H),5.05-4.98(m,2H),4.97-4.89(m,2H),4.32-4.22(m,1H),2.61(s,3H).

[0347] Step 2: A mixture of methylsulfanyl-4-(oxetan-3-yl)pyrimidine (1.76 g, 0.00966 mol, 1.00 equivalent) in THF (50 mL) was added to a solution of oxon (4.88 g, 0.0290 mol, 3.00 equivalent) in water (10 mL) at 0°C. After stirring at 25°C for 18 hours, another oxon (12.2 g, 0.0725 mol, 7.50 equivalent) was added at 0°C. The resulting mixture was stirred further at 25°C for 18 hours. The mixture was then diluted with water (100 mL) and extracted with DCM (4 × 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na₂SO₄ solids, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE / Â=3 / 1~0 / 1) to obtain Ar-Cl23 (573 mg, 0.00267 mol, yield 27.7%) as a white solid. 1 H NMR(400MHz,CDCl3)δ=8.91(d,J=5.2Hz,1H),7.60(d,J=5.2Hz,1H),5.11(dd,J=8.4,6.0Hz,2H),4.91(t,J=6.0Hz,2H),4.55-4.42(m,1H),3.41(s,3H).

[0348] Aryl chloride 24:2-chloro-4-(4-methylpyrazole-1-yl)pyrimidine To a solution of 4-methylpyrazole (1.00 g, 0.00671 mol, 1.33 equivalents) in ACN (10 ml), 2,4-dichloropyrimidine (0.413 g, 0.00503 mol, 1.00 equivalent) and Cs2CO3 (1.75 g, 0.00537 mol, 1.07 equivalents) were added at 0°C. The mixture was stirred at 25°C for 2 hours. The mixture was filtered, washed with HCl (50 ml), and then concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE / HCl = 10 / 1 to 3 / 1) to obtain Ar-Cl24 (0.790 g, purity 60%, 44.0%) as a yellow solid. 1H NMR (400MHz, CDCl3) δ=8.56(d,J=5.6Hz,1H),8.31(s,1H),7.78(d,J=5.6Hz,1H),7.62(s,1H),2.15(s,3H). LCMS(ESI)m / z=238.2[M+H] + . RT 0.539 minutes (Method C)

[0349] Aryl chloride 25:1-(4-chloropyrimidine-2-yl)-3,3-dimethylpyrrolidine-2-one Step 1: Using 3,3-dimethylpyrrolidine-2-one (946 mg, 0.00836 mol, 1.50 equivalents) and 2-chloro-4-methylsulfanylpyrimidine (895 mg, 0.00557 mol, 1.00 equivalent), the same method as for Ar-Cl 16 was used to synthesize 3,3-dimethyl-1-(4-methylsulfanylpyrimidine-2-yl)pyrrolidine-2-one (1.40 g, purity 84.0%, 88.9%) as a yellow oily substance. 1 H NMR(400MHz, CDCl3)δ=8.28(d,J=5.2Hz,1H),6.89(d,J=5.2Hz,1H),3.99(t,J=7.2Hz,2H),2.61(s,3H),1.97(t,J=7.2Hz,2H),1.28(s,6H). LCMS(ESI)m / z=238.2[M+H] + . RT 0.522 minutes (Method C)

[0350] Step 2: To a 20 ml ACN solution of 3,3-dimethyl-1-(4-methylsulfanylpyrimidine-2-yl)pyrrolidine-2-one (1.40 g, 84.0% purity, 0.00496 mol, 1.00 equivalent), concentrated HCl (0.661 ml, 0.00793 mol, 1.60 equivalent) and SO2Cl2 (1.64 ml, 0.0198 mol, 4.00 equivalent) were sequentially added at 0°C. After stirring at 25°C for 30 minutes, the mixture was poured into an ice-cooled NaHCO3 solution (saturated aqueous solution, 30 mL) and then extracted with RINKAN (3 × 30 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 solid, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE / Ã=15 / 1~2 / 1) to obtain Ar-Cl 25 (282 mg, purity 78.0%, 0.000975 mol, yield 19.7%) as a yellow oily substance. 1 H NMR(400MHz,CDCl3)δ=8.57(d,J=5.2Hz,1H),7.06(d,J=5.2Hz,1H),3.98(t,J=7.2Hz,2H),2.00(d,J=7.2Hz,2H),1.28(s,6H). LCMS(ESI)m / z=226.2[M+H] + . RT 0.546 min (Method C).

[0351] Aryl chloride 26:1-(2-chloropyrimidine-2-yl)-5,5-dimethylpyrrolidine-2-one Ar-Cl 26 (2.70 g, 96% purity, 52%) was synthesized using the same method as for Ar-Cl 16, with 5,5-dimethylpyrrolidone-2-one (2 g, 0.0470 mol, 1.00 equivalent) and 2,4-dichloropyrimidine (4.94 g, 1.5 equivalent) to obtain Ar-Cl 26 as a green solid. 1 H NMR(400MHz,CDCl3)δ=8.45(d,J=5.6Hz,1H),8.09(d,J=5.6Hz,1H),2.63(t,J=8.4Hz,2H),2.05-1.98(m,2H),1.68(s,6H). MS(ESI)m / z=226.1[M+H] +. RT 0.582 (Method C).

[0352] Aryl chloride 27:5-(4-chloropyrimidine-2-yl)-5-azaspiro[2.5]octan-4-one To a solution of 5-azaspiro[2.5]octan-4-one (770 mg, 0.00615 mol, 1.00 equivalent) in DMF (15 ml), NaH (60%, 0.271 g, 0.00677 mol, 1.10 equivalent) was added at 0°C under an N2 atmosphere. After stirring at 25°C for 30 minutes, 4-chloro-2-methylsulfonylpyrimidine (1.78 g, 0.00923 mol, 1.50 equivalent) was added at 0°C, and the mixture was stirred at 25°C for 12 hours. The mixture was quenched with pre-cooled NH4Cl (saturated aqueous solution, 20 ml) and extracted with siRNA (3 × 25 ml). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous Na2SO4 solid, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE / SiO7 = 10 / 1 to 1 / 1) to obtain Ar-Cl27 (341 mg, purity 79.0%, 18.4%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ=8.59(d,J=5.2Hz,1H),7.13(d,J=5.2Hz,1H),4.08-4.02(m,2H ),2.14-2.07(m,2H),1.88-1.81(m,2H),1.49(q,J=3.6Hz,2H),0.72(q,J=3.6Hz,2H). LCMS(ESI)m / z=238.2[M+H] + . RT 0.540 (Method C).

[0353] Aryl chloride 28:3-(2-chloropyrimidine-4-yl)oxazolidine-2-one Ar-Cl 28 (4.40 g, 36%) was synthesized using the same method as for Ar-Cl 16, with oxazolidine-2-one (5.0 g, 57.4 mmol, 1.00 equivalent) and 2,3-dichloropyrimidine (1.28 g, 86.1 mmol, 1.00 equivalent).

[0354] Aryl chloride 29: 2-methylsulfonyl-4-(oxetan-2-yl)pyrimidine Step 1: 4-Chloro-2-methylsulfamylpyrimidine (1.50g, 0.00934mol, 1.00 equivalent), oxetane-2-carboxylic acid (1.43g, 0.0140mol, 1.50 equivalent), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (0.210g, 0.000187mol, 2%, CAS:870987-63-6), NiCl2·dtbbpy (0.186g, 0.00 A mixture of 0.467 mol, 5%, CAS: 1034901-50-2), phthalimide (1.37 g, 0.00934 mol, 1.00 equivalent, CAS: 85-41-6), and BTMG (2.40 g, 0.0140 mol, 1.50 equivalent, CAS: 29166-72-1) in DMSO (100 ml) was degassed, purged with N2, and then stirred at 25°C for 16 hours and irradiated with a 455 nm blue LED. The reaction mixture was diluted with brine (100 mL) and then extracted with siRNA (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4 solids, filtered, and concentrated to obtain a residue (4.23 g). The residue was purified by column chromatography (SiO2, PE / siRNA = 8 / 1 to 2 / 1) to obtain 2-methylsulfamyl-4-(oxetan-2-yl)pyrimidine (1.42 g, purity 78.0%, 0.00609 mol, yield 65.2%, phthalimide contamination) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ=8.58(d,J=4.8Hz,1H),7.30(d,J=4.8Hz,1H),5.71-5.61(m,1H),4.92-4.79 (m,1H),4.75-4.66(m,1H),3.24-3.09(m,1H),2.74-2.61(m,1H),2.60-2.59(m,1H),2.57(s,3H). LCMS:m / z=183.2[M+H]+. RT=0.496 minutes (Method C)

[0355] Step 2: To a 40 ml solution of 2-methylsulfamyl-4-(oxetan-2-yl)pyrimidine (2.07 g, 0.0114 mol, 1.00 equivalent) in MeOH, a 10 ml solution of Oxon (5.73 g, 0.0341 mol, 3.00 equivalent) in water was added all at once at 0°C. After stirring at 25°C for 22 hours, another Oxon (2.87 g, 0.0170 mol, 1.50 equivalent) was added at 0°C. The resulting mixture was stirred further at 25°C for 5 hours. The mixture was quenched by adding Na2SO3 (saturated aqueous solution, 30 mL) dropwise at 0°C. After stirring at 25°C for 1 hour, the mixture was concentrated directly under reduced pressure to remove most of the MeOH, and then extracted with SiO2SO3 (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 solids, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / Ã=3 / 1~1 / 1) to obtain Ar-Cl29 (0.374 g, 0.00175 mol, yield 15.4%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ=8.98(d,J=4.8Hz,1H),7.94(d,J=4.8Hz,1H),5.87(dd,J=8.8,6.4Hz,1 H),5.00-4.87(m,1H),4.76-4.66(m,1H),3.37(s,3H),3.34-3.22(m,1H),2.75-2.64(m,1H).

[0356] Aryl Chloride 30: 2-Chloro-5-fluoro-4-(2-methylimidazole-1-yl)pyrimidine To a solution of 2-methyl-1H-imidazole (2.00 g, 0.0244 mol, 1.00 equivalent) and 2,4-dichloro-5-fluoropyrimidine (8.13 g, 0.0487 mol, 2.00 equivalent) in ACN (25 ml), Cs2CO3 (9.13 g, 0.0280 mol, 1.15 equivalent) was added all at once at 0°C. After stirring at 25°C for 2 hours, the resulting mixture was stirred at 80°C for 3 hours. The reaction mixture was diluted with ice-cold water (100 ml), concentrated under reduced pressure to remove most of the ACN, and then extracted with SiO2 (2 × 80 ml) and n-BuOH (80 ml). The combined organic layers were dried over anhydrous Na2SO4 solids, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE / siRNA = 3 / 1 to 0 / 1) to obtain Ar-Cl 30 (4.00 g, 0.0188 mol, yield 77.2%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ=8.63(d,J=2.8Hz,1H),7.40(dd,J=3.6,1.6Hz,1H),7.08(d,J=1.6Hz,1H),2.70(s,3H).

[0357] Aryl chloride 31:1-(6-chloropyrimidine-4-yl)pyrrolidine-2-one Ar-Cl31 (4.7 g, 88%) was synthesized using the same method as for Ar-Cl16, with pyrrolidine-2-one (2.14 ml, 1.05 equivalents) and 4,6-dichloropyrimidine (4 g, 1.5 equivalents), and was obtained as a yellowish solid. 1 H NMR(400MHz, CDCl3)δ=8.71(s,1H),8.47(s,1H),4.08(t,J=7.6Hz,2H),2.69(t,J=7.6Hz,2H),2.18(quin,J=7.6Hz,2H). LCMS:m / z=198.1[M+H]+. RT, 0.462 min (Method Q)

[0358] Aryl Chloride 32:4-Chloro-6-(2-methyl-5-nitropyrazole-3-yl)pyrimidine A solution of 4-chloro-6-(2-methylpyrazole-3-yl)pyrimidine (530 mg, 0.00272 mol, 1.00 equivalent) in TFAA (6 mL) from pump 1 and HNO3 (98% purity, 0.290 mL, 0.00408 mol, 1.50 equivalent) from pump 2 were simultaneously pumped into a flow reactor (25°C). After 25 minutes, the reaction mixture was collected in a bottle (containing 20 ml of ice-cold water). The resulting reaction mixture was filtered, and the filtered cake was dried under vacuum to obtain Ar-Cl32 (416 mg, 0.00174 mol, yield 63.8%). 1H NMR(400MHz,CD3OD)δ=8.81(d,J=5.2Hz,1H),7.92(d,J=5.2Hz,1H),7.74(s,1H),4.37(s,3H).

[0359] Aryl Chloride 33: 2-Chloro-4-(3-methoxyazetidine-1-yl)pyrimidine To a 15 ml ACN (ACN) solution of 3-methoxyacetylidine (300 mg, 0.00243 mol, 1.00 equivalent), TEA (0.841 ml, 0.00607 mol, 2.50 equivalent) and 2,4-dichloropyrimidine (434 mg, 0.00291 mol, 1.20 equivalent) were added at 0°C. The mixture was stirred at 25°C for 16 hours. The mixture was diluted with a pre-cooled NH4Cl solution (saturated aqueous solution, 100 ml) and then extracted with HCl (3 × 100 ml). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 solid, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE / Â5 = 4 / 1 to 1 / 1) to obtain Ar-Cl33 (387 mg, 0.00194 mol, yield 79.9%) as a white solid. 1 H NMR(400MHz,CDCl3)δ=8.01(d,J=6.0Hz,1H),6.08(d,J=6.0Hz,1H),4.40-4.34(m,1H),4.33-4.21(m,2H),4.00(d,J=6.8Hz,2H),3.35(s,3H). LCMS:m / z=200.2[M+H]+. RT, 0.435 min (Method Q)

[0360] Aryl chloride 34:5-(2-chloro-5-fluoropyrimidine-4-yl)-5-azaspiro[2.4]heptan-4-one Ar-Cl34 (1.8 g, 83%) was synthesized as a white solid using the same method as for Ar-Cl16, with 5-azaspiro[2,4]heptan-4-one (1 g, 9.0 mmol, 1.00 equivalent) and 2,4-dichloro-5-fluoropyrimidine (2.25 g, 1.5 equivalent). 1 H NMR(400MHz,CDCl3)δ=8.42(d,J=2.4Hz,1H),4.12-4.06(m,2H),2.30(t,J=7.2Hz,2H),1.34-1.29(m,2H),1.01-0.95(m,2H). LCMS:m / z=242.2[M+H]+. RT, 0.544 min (Method Q)

[0361] Aryl Chloride 35:2-Chloro-4-[(3R or 3S)-3-methoxypyrrolidine-1-yl]pyrimidine Isomer R was synthesized using the same method as for Ar-Cl 33, with (3R)-3-methoxypyrrolidine hydrochloride (300 mg, 2.2 mmol) and 2,4-dichloropyrimidine (487 mg, 3.2 mmol), yielding Ar-Cl 35 (R-isomer) (398 mg, 85%) as a white solid. 1 H NMR(400MHz, CDCl3)δ=8.00(d,J=6.0Hz,1H),6.20(s,1H),4.12-3.98(m,1H),3.96-3.39(m,4H),3.36(s,3H),2.39-2.04(m,2H).

[0362] Isomer S was synthesized using a similar method, but (3S)-3-methoxypyrrolidine (120 mg, 0.56 mmol) was used.

[0363] Aryl chloride 36:2-chloro-4-[(3S)-3-fluoropyrrolidine-1-yl]pyrimidine Ar-Cl36 (447 mg, 93%) was obtained as a white solid by synthesis using 300 mg (2.39 mmol) of (3S)-3-fluoropyrrolidine and 534 mg (3.58 mmol) of 2,4-dichloropyrimidine, in the same manner as for Ar-Cl33. 1H NMR(400MHz,CDCl3)δ=8.05(d,J=6.0Hz,1H),6.24(s,1H),5.49-5.26(m,1H) ,4.15-3.89(m,1H),3.83-3.42(m,3H),2.55-2.35(m,1H),2.32-2.05(m,1H).

[0364] Aryl chloride 37: Ethyl 1-(2-chloropyrimidine-4-yl)-5-methylpyrazole-4-carboxylate To a solution of (2-chloropyrimidine-4-yl)hydrazine (1.60 g, the crude product described above) in EtOH (16 ml), HCl (1 M aqueous solution, 1.6 ml) and ethyl(2E)-2-(dimethylaminomethylene)-3-oxobutanoic acid (3.07 g, 0.0166 mol) were sequentially added at 0°C. The resulting mixture was stirred at 0°C for 1 hour. NaHCO3 (saturated aqueous solution, 2 ml) and water (30 ml) were added to the mixture, and then extracted with SiO2 (2 × 50 ml). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 solid, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to obtain Ar-Cl37 (570 mg, 0.00214 mol, 11.5%) as a white solid. 1H NMR (400MHz, CDCl3) δ=8.67(d,J=5.6Hz,1H),8.07(s,1H),7.93(d,J=5.6Hz,1H),4.35(q,J=7.2Hz,2H),3.09(s,3H),1.39(t,J=7.2Hz,3H).

[0365] General procedure for coupling intermediate (XX) with aryl chloride Solutions of intermediates I-06 to I-11 or I-32 to I-35 (1.05 equivalents) and the corresponding Ar-Cl (1 equivalent) and base (3 to 10 equivalents) were prepared in the corresponding solvents. The mixtures were heated to the corresponding temperature for 2 to 16 hours until complete conversion was shown by LC / MS. The mixtures were filtered and purified directly by preparative HPLC, or quenched with a pre-cooled NH4Cl solution (saturated aqueous solution) and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 solid, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography, NPLC, or preparative HPLC to obtain the desired product.

[0366] In the following embodiments, the following method was used.

[0367] [Table 33]

[0368] Example 1: (S)-(3-(5-fluoropyridine-3-yl)isoxazolidine-2-yl)(1-(6-(pyridine-3-yl)pyrimidine-4-yl)piperidine-4-yl)methanone (Method I) Intermediate I-09 (50 mg, 80.47 μmol), Ar-Cl1 (24.35 mg, 120.70 μmol), and potassium carbonate (24.47 mg, 177.02 μmol) were introduced into the reaction vessel. Acetonitrile (1.5 ml) was then added, and the mixture was heated in MW at 120°C for 2 hours. After this time, LC / MS showed complete conversion, and the reaction product was filtered and purified by preparative HPLC. The corresponding fraction was lyophilized to obtain Example 1 as a white solid (35 mg, 60%).

[0369] The following examples were synthesized in the same manner using the starting materials, intermediates, and coupling methods shown above and in Table 3: 1, 2, 3, 4, 5, 6, 22, 23, 29, 30, 31, 32, 33, 34, 36, 39, 40, 41, 42, 43, 44, 49, 51, 52, 53, 58, 59, 60, 61, 62, 63, 66, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 83, 85, 87, 88, 89, 90, 91, 92, 98, 99, 100, 101.

[0370] [Table 34]

[0371] [Table 35]

[0372] [Table 36]

[0373] Example 2: (S)-3-(2-(4-(3-(pyrazine-2-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-yl)oxazolidine-2-one Starting with a solution of intermediate I-06 TFA salt (40 mg, 60.0 μmol), Ar-Cl2 (12.4 mg, 60.0 μmol), and DIPEA (90 μL, 0.51 mmol) in acetonitrile (0.5 ml), Example 2 was obtained as a white solid (7.9 mg, 33%) after preparative HPLC purification at MW, 100°C, 1 hour.

[0374] Example 3: (S)-1-(4-(4-(3-(pyrazine-2-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-2-yl)pyrrolidine-2-one Starting with a solution of intermediate I-06 TFA salt (33 mg, 50.0 μmol), Ar-Cl3 (9.9 mg, 50.0 μmol), and DIPEA (60 μL, 0.37 mmol) in acetonitrile (0.5 ml): MW, 100°C, 1 hour (twice). Example 3 was purified by silica gel chromatography to obtain a white solid (8.5 mg, 44%) (4 g silica gel, gradient: 5 min 100% DCM / 30 min 100% DCM to 5% EtOH, then 10 min 5% EtOH).

[0375] Example 4: (S)-1-(2-(4-(3-(pyrazine-2-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-yl)pyrrolidine-2-one Starting with a solution of intermediate I-06 TFA salt (37 mg, 56.0 μmol), Ar-Cl4 (56.0 μmol), and DIPEA (60 μL, 0.37 mmol) in acetonitrile (0.5 ml): after preparative HPLC purification without TFA by MW, 100°C, 1 hour, Example 4 was obtained as a white solid (8.0 mg, 30%).

[0376] Example 5: 3-[5-fluoro-2-[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-yl]oxazolidine-2-one Starting with a solution of intermediate I-06 TFA salt (46 mg, 69.0 μmol / l) and Ar-Cl5 (69.0 μmol) and DIPEA (90 μL, 0.51 mmol) in acetonitrile (0.5 ml): after preparative HPLC purification without TFA by MW, 100°C, 1 hour, Example 5 was obtained as a white solid (8.0 mg, 30%).

[0377] Example 6: 1-[5-fluoro-2-[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-yl]pyrrolidine-2-one Starting with a solution of intermediate I-06 TFA salt (40 mg, 60.0 μmol / l) and Ar-Cl6 (60.0 μmol) and DIPEA (90 μL, 0.51 mmol) in acetonitrile (0.5 ml): after preparative HPLC purification without TFA by MW, 100°C, 1 hour, Example 6 was obtained as a white solid (10.3 mg, 34%).

[0378] Example 22: [1-[4-(2,4-dimethylimidazole-1-yl)-5-fluoropyrimidine-2-yl]-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone Starting with a solution of intermediate I-06 TFA salt (36 mg, 54.0 μmol) and Ar-Cl 7 (54.0 μmol) and DIPEA (90 μL, 0.51 mmol) in acetonitrile (0.5 ml): combift 12 g silica gel over MW, 100°C, 1 hour; gradient: 5 min 100% DCM / 30 min 100% DCM to 5% EtOH, then 10 min 5% EtOH for silica gel purification. Example 22 was obtained as a white solid (14.8 mg, 61%).

[0379] Example 23: [1-[4-(2-methylimidazole-1-yl)-1,3,5-triazine-2-yl]-4-piperidyl]-[(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-yl]methanone Starting with a solution of intermediate I-07 TFA salt (30 mg, 80.0 μmol / l), Ar-Cl 8 (29.7 mg, 150.0 μmol), and DIPEA (70 μL, 0.38 mmol) in acetonitrile (1.5 ml): under MW, 100°C, 1 hour, silica gel purification and subsequent preparative HPLC without TFA yielded Example 23 as a white solid (6.5 mg, 19%).

[0380] Example 29: (S)-(1-(2-(2-methyl-1H-imidazole-1-yl)pyrimidine-4-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone Starting with a solution of intermediate I-06 TFA salt (40 mg, 60.0 μmol / l), Ar-Cl9 (13.2 mg, 70.0 μmol), and DIPEA (50 μL, 0.28 mmol) in acetonitrile (0.5 ml): after silica gel purification and subsequent preparative HPLC without TFA under MW, 100°C, for 1 hour, Example 29 was obtained as a white solid (21.6 mg, 91%).

[0381] Example 30: (S)-(1-(4-(2-methyl-1H-imidazole-1-yl)pyrimidine-2-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone Starting with a solution of intermediate I-06 TFA salt (40 mg, 60.0 μmol), Ar-Cl 10 (13.2 mg, 70.0 μmol), and DIPEA (50 μL, 0.28 mmol) in acetonitrile (0.5 ml): under MW, 100°C, 1 hour, silica gel purification and subsequent preparative HPLC without TFA yielded Example 30 as a white solid (19.9 mg, 84%).

[0382] Example 31: (S)-(1-(6-(2-methyl-1H-imidazole-1-yl)pyrimidine-4-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone Starting with a solution of intermediate I-06 TFA salt (30 mg, 50.0 μmol), Ar-Cl 11 (11 mg, 50.0 μmol), and DIPEA (30 μL, 0.18 mmol) in acetonitrile (1.5 ml): preparative HPLC (once without TFA, once with TFA) was performed under MW, 100°C, for 1.5 hours to obtain Example 31 as a white solid (12 mg, 63%).

[0383] Example 32: (S)-(1-(5-fluoro-4-(1H-pyrazole-1-yl)pyrimidine-2-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone- Starting with a solution of intermediate I-06 TFA salt (80 mg, 110.0 μmol), Ar-Cl 12 (12.1 mg, 60.0 μmol), and DIPEA (80 μL, 0.45 mmol) in acetonitrile (3.5 ml): purified with silica gel under MW, 100°C, 1.5 hours, followed by preparative HPLC (without TFA), Example 32 was obtained as a white solid (17.9 mg, 38%).

[0384] Example 33 - [5-[6-(2-methylimidazole-1-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone The title compound was prepared in the same manner as in Example 1, using 5-azaspiro[2.5]octan-8-yl-[3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone I-11 (80 mg, 265 μmol), Ar-Cl 11 4-chloro-6-(2-methylimidazole-1-yl)pyrimidine (56.8 mg, 292 μmol), and DIEA (370 μL, 2.12 mmol) in DMSO (1 mL). The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150 × 25 mm × 10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 0%~25%, 10 min) to obtain the title compound as a white solid (40 mg, 32%), as a 1:1 mixture of the two diastereomers.

[0385] Example 34 - [5-[6-(2-methylpyrazole-3-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone The title compound was prepared in the same manner as in Example 1, using 5-azaspiro[2.5]octan-8-yl-[3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone I-11 (80 mg, 265 μmol), Ar-Cl 13 4-chloro-6-(2-methylpyrazole-3-yl)pyrimidine (56.8 mg, 292 μmol), and DIEA (370 μL, 2.12 mmol) in DMSO (1 mL). The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150 × 25 mm × 10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 0%~30%, 10 min) to obtain Example 34 as a white solid (40 mg, 32%), as a 1:1 mixture of the two diastereomers.

[0386] Example 36: 3-[2-[4-[(3S)-3-(5-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-yl]oxazolidine-2-one The title compound was prepared in the same manner as in Example 1, using I-34 (512 mg, 56% purity, 0.105 mmol), Ar-Cl2 (150 mg, 0.752 mmol), and TEA (10 equivalents) in MeCN (5 mL) at 60°C. The residue was purified by preparative HPLC to obtain Example 36 as a white solid (195 mg, 59%). Chiral SFC:RT 0.875 min (100% ee) (Method AH)

[0387] Example 39: [(8R)-5-[6-(2-methylpyrazole-3-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-pyrazine-2-yl-1,2-oxazolidine-2-yl]methanone The title compound was prepared at 60°C using the same method as in Example 1, with a solution of I-35 (200 mg, 0.69 mmol), Ar-Cl 13 4-chloro-6-(2-methylpyrazole-3-yl)pyrimidine (148 mg, 0.76 mmol), and DIPEA (0.361 ml, 3 equivalents) in DMSO (1 ml). The residue was purified by preparative HPLC to obtain Example 39 as a white solid (206 mg, 66%). Chiral SFC:RT 1.973 minutes (100% ee) (Method AP)

[0388] Example 40: [(3S)-3-(2-methyl-1,3-thiazole-4-yl)-1,2-oxazolidine-2-yl]-[1-[6-(2-methyl-1,2,4-triazole-3-yl)pyrimidine-4-yl]piperidine-4-yl]methanone The title compound was prepared at room temperature using the same method as in Example 1, with I-07 (390 mg, 62% purity, 102 μmol), Ar-Cl 14 (200 mg, 102 μmol), and TEA (1.42 mL, 10 equivalents) in DMF (4 mL). The residue was purified by preparative HPLC to obtain Example 40 as a white solid (234 mg, 52%). Chiral SFC:RT 1.751 min (100% ee) (Method Z)

[0389] Example 41: [(3S)-3-(2-methyl-1,3-thiazole-4-yl)-1,2-oxazolidine-2-yl]-[(8R)-5-[6-(2-methyl-1,2,4-triazole-3-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]methanone The title compound was prepared in the same manner as in Example 1, using I-33 (264 mg, 767 μmol), Ar-Cl 14 (150 mg, 767 μmol), and TEA (1.07 mL, 10 equivalents) in DMSO (1 mL). The residue was purified by preparative HPLC to obtain Example 41 as a white solid (271 mg, 76%). Chiral SFC:RT 1.162 minutes (100% ee) (Method: AI)

[0390] Example 42: [(3S)-3-(2-methyl-1,3-thiazole-4-yl)-1,2-oxazolidine-2-yl]-[(8R)-5-[6-(3-methyltriazole-4-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]methanone The title compound was prepared at 25°C using the same method as in Example 1, with a solution of I-33 (311 mg, 89% purity, 901 μmol), Ar-Cl 15 (218 mg, 77% purity, 858 μmol), and TEA (1.19 ml, 10 equivalents) in DMF (2 ml). The residue was purified by preparative HPLC to obtain Example 42 as a white solid (107 mg, 27%). Chiral SFC:RT 1.703 minutes (100% ee) (Method AC)

[0391] Example 43: [(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[(8R)-5-[6-(2-methyl-1,2,4-triazole-3-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]methanone The title compound was prepared at room temperature using the same method as in Example 1, with I-32 (203 mg, 636 μmol), Ar-Cl 14 (124 mg, 636 μmol), and TEA (883 μL, 10 equivalents) in DMF (2 mL). The residue was purified by preparative HPLC to obtain Example 43 as a white solid (162 mg, 53%). Chiral SFC:RT 1.595 min (100% ee) (Method AH)

[0392] Example 44: 1-[2-[(8R)-8-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]-5-azaspiro[2.5]octan-5-yl]pyrimidine-4-yl]pyrrolidine-2-one The title compound was prepared in the same manner as in Example 1, using I-11(R) (480 mg, 50% purity, 860 μmol), Ar-Cl3 (187 mg, 940 μmol), and DIPEA (1.5 mL, 10 equivalents) in DMSO (3 mL). The residue was purified by preparative HPLC to obtain Example 44 as a white solid. Chiral SFC:RT 1.256 min (100% ee) (Method X)

[0393] Example 49: [(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[6-(2-methyl-1,2,4-triazole-3-yl)pyrimidine-4-yl]piperidine-4-yl]methanone The title compound was prepared at 25°C using the same method as in Example 1, with a solution of I-10 (246 mg, 839 μmol), Ar-Cl 14 (164 mg, 839 μmol), and TEA (1.17 ml, 10 equivalents) in DMF (6 ml). The residue was purified by preparative HPLC to obtain Example 49 as a white solid (159 mg, 42%). Chiral SFC:RT 1.239 min (100% ee) (Method X)

[0394] Example 51: 5-[2-[4-[(3S)-3-(5-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one The title compound was prepared at 60°C using a MeCN solution of I-34 (686 mg, 54% purity, 134 μmol), Ar-Cl 16 (250 mg, 112 μmol), and DIPEA (10 equivalents) in the same manner as in Example 1. The residue was purified by preparative HPLC to obtain Example 51 as a white solid (313 mg, 60%). Chiral SFC:RT 1.515 min (100% ee) (Method AG)

[0395] Example 52: 5-[2-[4-[(3S)-3-(2-methyl-1,3-thiazole-4-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one The title compound was prepared in the same manner as in Example 1, using I-07 (629 mg, 60% purity, 134 μmol), Ar-Cl 16 (250 mg, 112 μmol), and DIPEA (10 equivalents) in MeCN at 60°C. The residue was purified by preparative HPLC to obtain Example 52 as a white solid (129 mg, 25%). Chiral SFC:RT 1.831 min (100% ee) (Method AJ)

[0396] Example 53: 5-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one The title compound was prepared at 60°C using a MeCN solution of I-09 (681 mg, 55% purity, 134 μmol), Ar-Cl 16 (250 mg, 112 μmol), and DIPEA (10 equivalents) in the same manner as in Example 1. The residue was purified by preparative NPLC to obtain Example 53 as a white solid (167 mg, 32%). Chiral SFC:RT 2.054 min (100% ee) (Method AJ)

[0397] Example 58: 3,3-difluoro-1-[2-[4-[(3S)-3-pyrazine-2-yl-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one The title compound was prepared at 60°C using a MeCN solution of I-06 (210 mg, 62% purity, 496 μmol), Ar-Cl 17 (120 mg, 514 μmol), and DIPEA (10 equivalents) in the same manner as in Example 1. The residue was purified by preparative HPLC to obtain Example 58 as a white solid (126 mg, 55%). Chiral SFC:RT 1,850 minutes (100% ee) (Method X)

[0398] Example 59: 3,3-difluoro-1-[2-[4-[(3S)-3-(2-methyl-1,3-thiazole-4-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one The title compound was prepared at 60°C using a MeCN solution of I-07 (471 mg, 38%, 642 μmol), Ar-Cl 17 (150 mg, 642 μmol), and DIPEA (10 equivalents) in the same manner as in Example 1. The residue was purified by preparative HPLC to obtain Example 59 as a white solid (225 mg, 72%). Chiral SFC:RT 0.910 min (100% ee) (Method AH)

[0399] Example 60: 1-[2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-3,3-dimethylpyrrolidine-2-one The title compound was prepared at 60°C using a MeCN solution of I-10 (858 mg, 77% purity, 143 μmol), Ar-Cl 18 (540 mg, 227 μmol), and DIPEA (10 equivalents) in the same manner as in Example 1. The residue was purified by preparative HPLC to obtain Example 60 as a white solid (300 mg, 27%). Chiral SFC: RT minutes (100% ee) (Method X)

[0400] Example 61: 5-[2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one The title compound was prepared at 60°C using a MeCN solution of I-10 (404 mg, 65% purity, 8.94 mmol), Ar-Cl 16 (200 mg, 8.94 mmol), and DIPEA (10 equivalents) in the same manner as in Example 1. The residue was purified by preparative HPLC to obtain Example 61 as a white solid (245 mg, 56%). Chiral SFC: RT minutes (100% ee) (Method X)

[0401] Example 62: 1-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-3-methylimidazolidined-2-one The title compound was prepared at 60°C using a MeCN solution of I-09 (350 mg, 877 μmol), Ar-Cl22 (205 mg, 965 μmol), and DIPEA (10 equivalents) in the same manner as in Example 1. The residue was purified by preparative HPLC to obtain Example 62 as a white solid (257 mg, 64%). Chiral SFC: RT minutes (100% ee) (Method X)

[0402] Example 63: 4-[2-[(8R)-8-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]-5-azaspiro[2.5]octan-5-yl]pyrimidine-4-yl]morpholin-3-one The title compound was prepared at 60°C using a MeCN solution of I-11(R) (665 mg, 24% purity, 530 μmol), Ar-Cl21 (113 mg, 530 μmol), and DIPEA (10 equivalents) in the same manner as in Example 1. The residue was purified by preparative HPLC to obtain the compound of Example 63 as a white solid (98 mg, 39%). Chiral SFC: RT minutes (100% ee) (Method X)

[0403] Example 66: 3,3-difluoro-1-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]piperidine-2-one The title compound was prepared at 60°C using a MeCN solution of I-08 (145 mg, 54% purity, 283 μmol), Ar-Cl 20 (70 mg, 283 μmol), and DIPEA (10 equivalents) in the same manner as in Example 1. The residue was purified by preparative HPLC to obtain Example 66 as a white solid (16 mg, 11%). Chiral SFC: RT minutes (100% ee) (Method X)

[0404] Example 70: 5-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one The title compound was prepared at 60°C using a MeCN solution of I-09 (629 mg, 54% purity, 123 μmol), Ar-Cl 17 (250 mg, 112 μmol), and DIPEA (10 equivalents) in the same manner as in Example 1. The residue was purified by preparative HPLC to obtain Example 70 as a white solid (159 mg, 30%). Chiral SFC: RT minutes (100% ee) (Method X)

[0405] Example 71: 1-[4-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-2-yl]pyrrolidine-2-one The title compound was prepared at 25°C using the same method as in Example 1, with a solution of I-09 (450 mg, 58% purity, 935 μmol), Ar-Cl4 (210 mg, 1.06 mmol), and TEA (10 equivalents) in DMF (6 mL). The residue was purified by preparative HPLC to obtain Example 71 as a white solid (80 mg, 17%). Chiral SFC: RT minutes (100%ee) (Method AK)

[0406] Example 72: 5-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2.5]octane-4-one The title compound was prepared at 60°C using the same method as in Example 1, with a solution of I-09 (427 mg, 66% purity, 1.01 mmol), Ar-Cl 19 (200 mg, 841 μmol), and TEA (α0 equivalent) in DMF (5 mL). The residue was purified by preparative HPLC to obtain Example 72 as a white solid (183 mg, 45%). Chiral SFC: RT minutes (100% ee) (Method X)

[0407] Example 73: 3,3-difluoro-1-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one The title compound was prepared in the same manner as in Example 1, using I-08 (263 mg, 54% purity, 514 μmol), Ar-Cl 17 (120 mg, 514 μmol), and DIPEA (10 equivalents) in MeCN at 60°C. The residue was purified by preparative HPLC to obtain Example 73 as a white solid (101 mg, 41%). Chiral SFC: RT minutes (100% ee) (Method X)

[0408] Example 74: 3,3-difluoro-1-[2-[4-[(3S)-3-(5-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one The title compound was prepared in the same manner as in Example 1, using I-34 (312 mg, 57% purity, 642 μmol), Ar-Cl 17 (150 mg, 642 μmol), and DIPEA (10 equivalents) in MeCN at 60°C. The residue was purified by preparative HPLC to obtain Example 74 as a white solid (151 mg, 50%). Chiral SFC: RT minutes (100%ee) (Method Z)

[0409] Example 75: 3,3-difluoro-1-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one The title compound was prepared in the same manner as in Example 1, using I-09 (460 mg, 39% purity, 642 μmol), Ar-Cl 17 (150 mg, 642 μmol), and DIPEA (10 equivalents) in MeCN at 60°C. The residue was purified by preparative HPLC to obtain Example 75 as a white solid (103 mg, 34%). Chiral SFC: RT minutes (100% ee) (Method X)

[0410] Example 76: 3,3-difluoro-1-[2-[4-[(3S)-3-(5-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]piperidine-2-one The title compound was prepared in the same manner as in Example 1, using I-34 (138 mg, 57% purity, 283 μmol) and Ar-Cl20 (100 mg, 283 μmol) in MeCN with 10 equivalents of DIPEA at 60°C. The residue was purified by preparative HPLC to obtain Example 76 as a white solid (25 mg, 18%). Chiral SFC: RT minutes (100% ee) (Method X)

[0411] Example 78: [5-[6-(2-methylimidazole-1-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone The title compound was prepared in the same manner as in Example 1, using I-11(R) (225 mg, 747 μmol), Ar-Cl 10 (160 mg, 822 μmol), and DIPEA (10 equivalents) in DMSO (3 mL). The residue was purified by preparative HPLC to obtain Example 78 as a white solid (307 mg, 81%). Chiral SFC: RT minutes (100% ee) (Method F)

[0412] Example 79: [5-[6-(2-methylimidazole-1-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone The title compound was prepared in the same manner as in Example 1, using I-11(S) (225 mg, 747 μmol), Ar-Cl 10 (160 mg, 822 μmol), and DIPEA (10 equivalents) in DMSO (3 mL). The residue was purified by preparative HPLC to obtain Example 79 as a white solid (294 mg, 78%). Chiral SFC: RT minutes (100% ee) (Method F)

[0413] Example 80: [5-[6-(2-methylpyrazole-3-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone The title compound was prepared at 60°C using the same method as in Example 1, with a solution of I-11(S) (800 mg, 28% purity, 747 μmol), Ar-Cl 13 (160 mg, 822 μmol), and DIPEA (10 equivalents) in DMSO (3 mL). The residue was purified by preparative HPLC to obtain Example 80 as a white solid (304 mg, 79%). Chiral SFC: RT minutes (100% ee) (Method F)

[0414] Example 83: [(8R)-5-[4-(4-methylpyrazole-1-yl)pyrimidine-2-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-pyrazine-2-yl-1,2-oxazolidine-2-yl]methanone The title compound was prepared in the same manner as in Example 1, using I-35(R) (178 mg, 617 μmol), Ar-Cl24 (167 mg, 60% purity, 360 μmol), and DIPEA (268 μL, 3 equivalents) in DMSO (1 mL). The residue was purified by preparative HPLC to obtain Example 83 as a white solid (154 mg, 67%). Chiral SFC: RT minutes (100% ee) (Method AB)

[0415] Example 84: 3,3-dimethyl-1-[4-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-2-yl]pyrrolidine-2-one The title compound was prepared at room temperature using the same method as in Example 1, with I-08 (588 mg, 78% purity, 166 μmol), Ar-Cl25 (268 mg, 78% purity, 923 μmol), and TEA (2.15 mL, 154 mmol) in EtOH (5 mL). The residue was purified by preparative HPLC to obtain Example 84 as a white solid (111 mg, 26%). Chiral SFC:RT 0.834 min (100% ee) (Method N)

[0416] Example 85: 1-[4-[(8R)-8-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]-5-azaspiro[2.5]octan-5-yl]pyrimidine-2-yl]pyrrolidine-2-one The title compound was prepared in the same manner as in Example 1, using I-11(R) (575 mg, 73% purity, 139 μmol), Ar-Cl4 (250 mg, 127 μmol), and TEA (1.41 μL, 8 equivalents) in EtOH (2 mL). The residue was purified by preparative HPLC to obtain Example 85 as a white solid (87 mg, 15%). Chiral SFC:RT 1,390 minutes (99.99% ee) (Method Z)

[0417] Example 87: 1-[4-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-2-yl]pyrrolidine-2-one The title compound was prepared in the same manner as in Example 1, using I-08 (492 mg, 78%, 139 μmol), Ar-Cl4 (275 mg, 139 μmol), and TEA DMF (10 ml). The residue was purified by preparative HPLC to obtain Example 87 as a white solid (54 mg, 9%). Chiral SFC:RT 1.894 min (99.99% ee) (Method Y)

[0418] Example 88: 5,5-dimethyl-1-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one The title compound was prepared in the same manner as in Example 1, using I-08 (680 mg, 54% purity, 133 μmol), Ar-Cl26 (250 mg, 111 μmol), and DIPEA (10 equivalents) in MeCN (5 mL). The residue was purified by preparative HPLC to obtain Example 88 as a white solid (143 mg, 28%). Chiral SFC:RT 1.678 min (100% ee) (Method P)

[0419] Example 89: 1-[2-[4-[(3S)-3-(5-fluoro-6-methylpyrrolidine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5,5-dimethylpyrrolidine-2-one The title compound was prepared at 60°C using the same method as in Example 1, with a solution of I-10 (450 mg, 63% purity, 966 μmol), Ar-Cl26 (240 mg, 106 μmol), and DIPEA (10 equivalents) in MeCN (4 mL). The residue was purified by preparative HPLC to obtain Example 89 as a white solid (161 mg, 35%). Chiral SFC:RT 1.619 min (100% ee) (Method P)

[0420] Example 90: 5-[4-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-2-yl]-5-azaspiro[2.5]octan-4-one The title compound was prepared at 25°C using the same method as in Example 1, with a solution of I-08 (881 mg, 54%, 172 μmol), Ar-Cl27 (341 mg, 143 μmol), and TEA (10 equivalents) in DMF (10 mL). The residue was purified by preparative HPLC to obtain Example 90 as a white solid (187 mg, 27%). Chiral SFC:RT 1.401 min (100% ee) (Method X)

[0421] Example 91: 3-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-1,3-oxazolidine-2-one The title compound was prepared at 60°C using the same method as in Example 1, with a solution of I-09 (254 mg, 1 mmol), Ar-Cl2 (200 mg, 1 mmol), and DIPEA (5 equivalents) in MeCN (10 mL). The residue was purified by preparative HPLC to obtain Example 91 as a white solid (171 mg, 39%). Chiral SFC:RT 1,910 minutes (100% ee) (Method X)

[0422] Example 92: 1-[2-[4-[(3S)-3-(2-methyl-1,3-thiazole-4-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one The title compound was prepared at 60°C using the same method as in Example 1, with a solution of I-07 (360 mg, 78% purity, 998 μmol), Ar-Cl3 (187 mg, 948 μmol), and DIPEA (10 equivalents) in MeCN (4 mL). The residue was purified by preparative HPLC to obtain Example 92 as a white solid (189 mg, 43%). Chiral SFC:RT 1.474 min (100% ee) (Method H)

[0423] Examples 98 and 99: [(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[4-(oxetan-2-yl)pyrimidine-2-yl]piperidine-4-yl]methanone (isomers 1 and 2) To a DMSO (6 ml) solution of intermediate I-10 (842 mg, crude product, purity approximately 44.9%, 0.00129 mol, 0.932 equivalents), TEA (2.88 ml, 0.0208 mol, 15.0 equivalents) and Ar-Cl 29 (333 mg, purity 89.0%, 0.00138 mol, 1.00 equivalent) were added at 25°C. The mixture was stirred at 90°C for 23 hours. The mixture was quenched with pre-cooled NH4Cl (saturated aqueous solution, 30 ml) and then extracted with RINKAN (3 × 30 ml). The combined organic layers were washed with brine (4 × 50 mL), dried over anhydrous Na2SO4 solids, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE / Â=1 / 1~0 / 1 to DCM / MeOH=1 / 0~6 / 1) and NPLC (column: Welch Ultimate XB-SiOH 250×50×10um; mobile phase: [hexane-EtOH]; gradient: 1%~30%B over 15 minutes), and then freeze-dried to obtain Example 98 (0.457g, 0.00107mol, yield 77.3%) as a yellow oily substance. The two isomers were separated by SFC: (conditions: DAIEL CHIRALPAK IC (250mm×30mm, 10um); mobile phase: (CO2-iPrOH(1‰NH3·H2O); B%: 65%, homogeneous concentration elution mode). Chiral SFC:RT 0.80 min (184.27 mg, 99.9% ee, Example 98) and RT: 1.11 min (192.32 mg, 98.9% ee, Example 99) (Method U)

[0424] Example 100: 1-[2-[(8R)-8-[(3S)-3-pyrazine-2-yl-1,2-oxazolidine-2-carbonyl]-5-azaspiro[2.5]octan-5-yl]pyrimidine-4-yl]pyrrolidine-2-one The title compound was prepared at 60°C using the same method as in Example 1, with a solution of I-35-(R) (150 mg, 520 μmol), Ar-Cl3 (103 mg, 520 μmol), and DIPEA (5 equivalents) in MeCN (3 mL). The residue was purified by preparative HPLC to obtain Example 100 as a white solid (109 mg, 47%). Chiral SFC:RT 1,590 minutes (100% ee) (Method W)

[0425] Example 101: [(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[4-(oxetan-3-yl)pyrimidine-2-yl]piperidine-4-yl]methanone The title compound was prepared at 90°C using the same method as in Example 1, with a solution of I-09 (354 mg, 90% purity, 1.09 mmol), Ar-Cl23 (250 mg, 1.17 mmol), and TEA (15 equivalents) in DMSO (5 mL). The residue was purified by preparative HPLC to obtain Example 101 as a yellow gum-like substance (101 mg, 20%). Chiral SFC:RT 1.804 min (100% ee) (Method P)

[0426] Example 103: 5-[5-fluoro-2-[4-[(3S)-3-(5-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one The title compound was prepared at 60°C using the same method as in Example 1, with a solution of I-34 (355 mg, 73% purity, 0.93 mmol), Ar-Cl 34 (150 mg, 0.62 mmol), and TEA (10 equivalents) in ACN (4 mL). The residue was purified by preparative HPLC to obtain Example 103 as a white solid (141 mg, 47%). Chiral SFC:RT 1.585 min (100% ee) (Method X)

[0427] Example 104: 5-[5-fluoro-2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one The title compound was prepared at 60°C using the same method as in Example 1, with a solution of I-10 (477 mg, 67% purity, 0.9 mmol), Ar-Cl34 (150 mg, 0.62 mmol), and TEA (10 equivalents) in ACN (4 mL). The residue was purified by preparative HPLC to obtain Example 103 as a white solid (121 mg, 41%). Chiral SFC:RT 1.542 min (100% ee) (Method X)

[0428] Example 105: 5-[5-fluoro-2-[4-[(3S)-3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one The title compound was prepared at 60°C using the same method as in Example 1, with a solution of I-36 (319 mg, 64% purity, 0.7 mmol), Ar-Cl 34 (150 mg, 0.62 mmol), and TEA (10 equivalents) in ACN (4 mL). The residue was purified by preparative HPLC to obtain Example 103 as a grayish-white solid (127 mg, 42%). Chiral SFC:RT 0.778 min (100% ee) (Method AC)

[0429] Example 106: [1-[4-[(3S)-3-fluoropyrrolidine-1-yl]pyrimidine-2-yl]piperidine-4-yl]-[(3S3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-yl]methanone The title compound was prepared at 80°C using the same method as in Example 1, with a solution of I-36 (212 mg, 64% purity, 0.49 mmol), Ar-Cl 36 (120 mg, 0.62 mmol), and TEA (10 equivalents) in ACN (4 mL). The residue was purified by preparative HPLC to obtain Example 103 as a grayish-white solid (70.8 mg, 32%). Chiral SFC:RT 2.089 min (100% ee) (Method X)

[0430] Example 107 [1-[4-[(3R)-3-methoxypyrrolidine-1-yl]pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-yl]methanone The title compound was prepared at 80°C using the same method as in Example 1, with a solution of I-36 (200 mg, 64% purity, 0.47 mmol), Ar-Cl 35 (R isomer) (120 mg, 0.56 mmol), and DEA (10 equivalents) in ACN (4 mL). The residue was purified by preparative HPLC to obtain Example 107 as a grayish-white solid (53 mg, 25%). Chiral SFC:RT 0.934 min (100% ee) (Method AH)

[0431] Example 108 [1-[4-[(3S)-3-methoxypyrrolidine-1-yl]pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-yl]methanone The title compound was prepared at 80°C using the same method as in Example 1, with a solution of I-36 (200 mg, 64% purity, 0.47 mmol), Ar-Cl 35 (S isomer) (120 mg, 0.56 mmol), and DEA (10 equivalents) in ACN (4 mL). The residue was purified by preparative HPLC to obtain Example 108 as a grayish-white solid (64 mg). Chiral SFC:RT 0.934 minutes (100% ee) (Method AC)

[0432] Example 109 5-[5-fluoro-2-[4-[(3S3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one The title compound was prepared at 60°C using the same method as in Example 1, with a solution of I-08 (2432 mg, 77% purity, 0.68 mmol), Ar-Cl34 (150 mg, 0.62 mmol), and TEA (10 equivalents) in ACN (4 mL). The residue was purified by preparative HPLC to obtain Example 109 as a white solid (83 mg, 28%). Chiral SFC:RT 1.504 min (100% ee) (Method M)

[0433] Example 110 1-[5-fluoro-2-[4-[(3S3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one The title compound was prepared at 60°C using the same method as in Example 1, with a solution of I-36 (298 mg, 65% purity, 0.69 mmol), Ar-Cl6 (150 mg, 0.69 mmol), and TEA (10 equivalents) in ACN (4 mL). The residue was purified by preparative HPLC to obtain Example 110 as a white solid (120 mg, 38%). Chiral SFC:RT 1.734 min (100% ee) (Method X)

[0434] Example 113 [1-[4-(3-methoxyazetidine-1-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-yl]methanone and The title compound was prepared at 60°C using the same method as in Example 1, with a solution of I-36 (200 mg, 65% purity, 0.62 mmol), Ar-Cl 33 (93 mg, 0.62 mmol), and TEA (10 equivalents) in ACN (4 mL). The residue was purified by preparative HPLC to obtain Example 113 as a white solid (47 mg, 23%). Chiral SFC:RT 1.485 min (100% ee) (Method X)

[0435] Example 114: 3-[5-fluoro-2-[4-[(3S3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-1,3-oxazolidine-2-one The title compound was prepared in the same manner as in Example 1, using I-09 (355 mg, 61% purity), Ar-Cl 5 (200 mg, 84%), and TEA (10 equivalents) in dioxane:H2O (4 ml) at 60°C. The residue was purified by preparative HPLC to obtain Example 114 as a white solid (57 mg, 13%). Chiral SFC:RT 1.783 min (100% ee) (Method X)

[0436] Example 25. [1-(5-fluoro-2-pyrimidine-5-ylpyrimidine-4-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone Step 1: Starting with a solution of intermediate I-06 (150 mg, 260 μmol) and 2,4-dichloro-5-fluoropyrimidine (29 mg, 280 mmol) and DIPEA (230 μL, 1.29 mmol) in MeCN (3 ml): after silica gel column chromatography at MW, 100 °C, 2 hours, [1-(2-chloro-5-fluoropyrimidine-4-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone (84 mg, 83%) was obtained. LCMS: m / z 393.2[M+1] + ;RT 1.68 (Method A)

[0437] Step 2: To a solution of [1-(2-chloro-5-fluoropyrimidine-4-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone (22 mg, 0.056 mmol, 1 equivalent) in dioxane (2 ml), Cs2CO3 (36 mg, 0.112 mmol, 2 equivalents), H2O (0.5 ml), and pyrimidine-5-boronic acid pinacol ester (12 mg, 0.058 mmol, 1 equivalent) were added. The mixture was rinsed with argon for 5 minutes, and then Pd(dppf)Cl2 (4 mg, 0.005 mmol) was added. The mixture was stirred at 100°C for 15 minutes. LC-MS showed that no starting material remained. The residue was quenched with saturated NaCl aqueous solution and extracted with EE. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography to obtain Example 25 (4.3 mg, 17%).

[0438] Example 27: (S)-(1-(5-fluoro-4-(thiazole-5-yl)pyrimidine-2-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone Step 1: Starting with a solution of intermediate I-06 (250 mg, 0.350 mmol), 2-chloro-5-fluoropyrimidine-4-ol (262 mg, 1.77 mmol), and DIPEA (360 μL, 2.12 mmol) in MeCN (4 ml), (S)-(1-(5-fluoro-4-hydroxypyrimidine-2-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone (83 mg, 68%) was obtained by silica gel column chromatography at MW, 120 °C, 1 hour. LCMS: m / z 375.2[M+1] + ;RT 1.00(Method A)

[0439] Step 2: To a solution of (S)-(1-(5-fluoro-4-hydroxypyrimidine-2-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone (85 mg, 230 μmol) in dichloromethane (5 mL), POCl3 (1.47 g, 11.35 mmol) was added, and the mixture was stirred at 70 °C for 1 hour. The reaction product was cooled in an ice bath and slowly quenched with saturated NaHCO3. The mixture was extracted with dichloromethane (3 ×), the combined organic layers were dried over MgSO4, and purified by silica gel chromatography to obtain (S)-(1-(4-chloro-5-fluoropyrimidine-2-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone (30 mg, 34%). LCMS: m / z 393.1[M+1] + ;RT2.03(Method A)

[0440] Step 3: To a solution of (S)-(1-(4-chloro-5-fluoropyrimidine-2-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone (25 mg, 60 μmol) in dioxane (2 mL), Cs2CO3 (42.3 mg, 130 μmol), H2O (0.5 mL), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (14 mg, 70 μmol) were added. The mixture was rinsed with argon for 5 minutes, and then Pd(dppf)Cl2(CH2Cl2) (5.3 g, 10 μmol) was added. The mixture was stirred at 100°C for 15 minutes. LC-MS showed that no starting material remained. The residue was quenched with saturated NaCl aqueous solution and extracted with EE. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel chromatography to obtain Example 27 (25 mg, 88%).

[0441] Example 28: (S)-(1-(6-(1-methyl-1H-pyrazole-5-yl)pyrimidine-4-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone Step 1: Starting with I-06 TFA (330 mg, 0.47 mmol), 4,6-dichloropyrimidine (78 mg, 0.51 mmol), and DIEA (4 equivalents), (S)-(1-(6-chloropyrimidine-4-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone (175 mg, 100%) was obtained. LC / MS: m / z 375.2 [M+1] + :RT 1.48 minutes (Method A) 1H NMR(400MHz,DMSO-d6)d ppm 8.62(s,1H),8.61(m,1H),8.57(d,J=2.45Hz,1H),8.31(s,1H),6.96(s,1H),5.43(dd,J=8.68,6.36H z,1H),4.34(td,J=7.61,7.61,3.48Hz,3H),4.00(m,1H),3.08(m,3H),2.85(m,1H),2.50(u),1.89(br d,J=12.84Hz,1H),1.77(br d,J=13.08Hz,1H),1.49(m,2H)

[0442] Step 2: (S)-(1-(6-(1-methyl-1H-pyrazole-5-yl)pyrimidine-4-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone To a mixture of (S)-(1-(6-chloropyrimidine-4-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone (40 mg, 110 μmol) in DME (2.25 mL), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (25 mg, 120 μmol, 1 equivalent), K2CO3 (46 mg, 0.43 mmol), Pd(dppf)Cl2 (17 mg, 20 μmol), and H2O (0.75 mL) were added, the mixture was degassed, and purged with N2. The mixture was heated in a MW at 100°C for 20 minutes. The reaction mixture was diluted with EA and extracted with water. The organic layer was concentrated, and the residue was purified by HPLC to obtain Example 28 (15.2 mg, 35%) as a white solid.

[0443] Example 48: [(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[(8R)-5-[4-(2-methylpyrazole-3-yl)-1,3,5-triazine-2-yl]-5-azaspiro[2.5]octan-8-yl]methanone (following SM2, then the Suzuki reaction) Step 1: Using the same method as in Example 1, I-32(R)HCl salt (370 mg, 78% purity, 892 μmol) and 2,4-dichloro-1,3,5-triazine (3134 mg, 892 μmol, 1.0 equivalent) were used with DIEA in DMF (1.55 ml, 10 equivalents) to obtain [(8R)-5-(4-chloro-1,3,5-triazine-2-yl)-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone as a grayish-white solid (242 mg, 63%). LCMS: m / z = 433.2[M+H] + . RT 0.609 min (Method Q).

[0444] Step 2: To a solution of [(8R)-5-(4-chloro-1,3,5-triazine-2-yl)-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone (242 mg, 0.559 mmol, 1.00 equivalent) in dioxane (6 mL) and water (0.5 mL), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (128 mg, 0.615 mmol, 1.00 equivalent), Pd(dppf)Cl2 (0.0409 g, 55.9 μmol, 10%) and K2CO3 (0.155 g, 1.12 mmol, 2.00 equivalent) was added. The mixture was stirred at 80°C for 12 hours under an N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE / Â=10 / 1 to  / MeOH=10 / 1) to obtain the crude product (120 mg, purity 93%). The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water(HCOOH)-ACN]; gradient: 41%~71%B over 10 minutes) to obtain Example 48 (89.40 mg, yield 33.4%) as a white solid.

[0445] Example 68: 5-[5-fluoro-2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one Starting with I-05 TFA salt (1 equivalent) and I-47 (200 mg, 0.59 mmol) and pyridine (0.38 mL, 8 equivalents), the desired product, Example 68, was obtained as a white solid (161.4 mg, 54%). Chiral SFC:RT 1.588 min (99.99% ee) (Method X)

[0446] Example 69: [(8R)-5-[4-(2-methylpyrazole-3-yl)-1,3,5-triazine-2-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone (following SM2, then the Suzuki reaction) Step 1: In the same manner as in Example 1, I-11(R)HCl salt (2.47 g, 73% purity, 5.82 mmol) and 2,4-dichloro-1,3,5-triazine (1.34 g, 8.97 mmol, 1.0 equivalent) were used with DIEA in DMF (8.33 ml, 8 equivalents) at 25°C to obtain [(8R)-5-(4-chloro-1,3,5-triazine-2-yl)-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone (1.05 g, 58% purity, 58%) as a yellow oily substance.

[0447] Step 2: [(8R)-5-(4-chloro-1,3,5-triazine-2-yl)-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone (1.05g, 58% purity, 147 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyra To a solution of zole (450 mg, 2.20 mmol, 1.00 equivalent), Pd(dppf)Cl2 (0.107 g, 0.000147 mol, 10%) and CuCl (0.174 g, 0.00176 mol, 1.20 equivalent) in DMF (8 mL), K3PO4 (0.935 g, 0.00440 mol, 3.00 equivalent) was added under an N2 atmosphere, and the resulting mixture was heated at 100 °C for 18 hours. The mixture was quenched with pre-cooled NH4Cl (saturated aqueous solution, 50 ml) and then extracted with SiO4 (3 × 50 ml). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous Na2SO4 solid, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150×25mm×10um; mobile phase: [water(0.5‰NH3·H2O)-ACN]; gradient: 31%~61%B over 10 minutes), further purified by preparative HPLC (column: Phenomenex Luna C18 150×25mm×10um; mobile phase: [water(2.25‰HCOOH)-ACN]; gradient: 21%~45%B over 10 minutes), and finally lyophilized to obtain Example 69 (297.58 mg, yield 29.5%) as a white solid. Chiral SFC:RT 1.414 min (98.66% ee) (Method X)

[0448] General scheme for the synthesis of Examples 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 24, 26, 28, 35, 37, 38, 45, 46, 47, 50, 54, 55, 56, 57, 64, 65, 67, 77, 81, 82, 86, 93, 94, 95, 96 and 97 from intermediates I-12 to I-27 and I-37 to I-46. Examples 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 24, 26, 28, and 35 were synthesized by coupling intermediates I-01 to I-05 with the corresponding intermediates I-12 to I-27 using a general procedure (Hatu coupling).

[0449] Example 7: [1-[6-(2-methylimidazole-1-yl)pyrimidine-4-yl]-4-piperidyl]-[(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-yl]methanone Starting with I-12 (146 mg, 0.51 mmol) and I-02 HCl salt (100 mg, 0.4838 mmol) and DIPEA (0.379 ml, 2.18 mmol, 4.5 equivalents), the desired product, Example 7 (76 mg, 36% yield), was obtained as a white solid.

[0450] Example 8: 1-[4-(2-methylpyrazole-3-yl)-1,3,5-triazine-2-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone Starting with I-03 HCl salt (146.16 mg, 728.40 μmol, 1.05 equivalents, HCl) and intermediate I-27 (200 mg, 693.71 μmol, 1 equivalent), Example 8 (115 mg, 263.35 μmol, yield 37.96%, purity 99.5%) was obtained as a white solid. Chiral SFC: 1.218 minutes (100%, Method F).

[0451] Example 9: [1-[4-(4-methylpyrazole-1-yl)pyrimidine-2-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone Starting with I-03 TFA salt (32 mg, 100 μmol) and I-23 (31 mg, 110 μmol, 1.1 equivalents) and DIPEA (4 equivalents), the desired product, Example 9, was obtained as a white solid (30 mg, 69%).

[0452] Example 10: [1-(5-fluoro-4-pyrazole-1-ylpyrimidine-2-yl)-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone Starting with I-03 (160 mg, 500 μmol) and I-14 (153 mg, 525 μmol, 1.1 equivalents) and DIPEA (4 eq), the desired product, Example 10, was obtained as a white solid (152 mg, 70%).

[0453] Example 11: [1-(4-oxazol-2-ylpyrimidine-2-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone Starting with I-01 (7.5 mg, 50 μmol) and I-21 (153 mg, 53 μmol, 1.1 equivalents) and DIPEA (4 eq), the desired product, Example 11, was obtained as a white solid (18 mg, 89%). Chiral SFC:RT 1.80 minutes (100%, method AD).

[0454] Example 12: [1-(5-fluoro-4-oxazol-2-ylpyrimidine-2-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone Starting with I-01 (7.5 mg, 50 μmol) and I-16 (153 mg, 53 μmol, 1.1 equivalents) and DIPEA (4 eq), the desired product, Example 12, was obtained as a white solid (19.5 mg / 61%).

[0455] Example 13: [1-(5-fluoro-2-oxazol-2-ylpyrimidine-4-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone Starting with I-01 (13 mg, 86 μmol) and I-17 (25 mg, 85 μmol) and DIPEA (4 equivalents), the desired product, Example 13, was obtained as a white solid (63%). Chiral SFC:RT 1.37 minutes (100%, Method X).

[0456] Example 14: [(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]-[1-(4-thiazole-2-yl-1,3,5-triazine-2-yl)-4-piperidyl]methanone Starting with I-01 (13 mg, 86 μmol) and I-18 (25 mg, 85 μmol) and DIPEA (4 eq), the desired product, Example 14, was obtained as a white solid (25 mg / 69%). Chiral SFC:RT 1.762 minutes (100%, Method AF).

[0457] Example 15: [1-[4-(2-methylpyrazole-3-yl)pyrimidine-2-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone Starting with I-03 TFA (32.27 mg, 100 μmol) and I-20 (0.17 mg, 110 μmol, 1.1 equivalents) and DIPEA (4 equivalents), the desired product, Example 15, was obtained as a white solid (27 mg / 62%).

[0458] Example 16: [1-[2-(4-methylpyrazole-1-yl)pyrimidine-4-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone Starting with I-03 TFA (32.27 mg, 100 μmol) and I-25 (32 mg, 110 μmol, 1.1 equivalents) and DIPEA (4 equivalents), the desired product, Example 16, was obtained as a white solid (29 mg / 67%).

[0459] Example 17: [1-[6-(4-methylpyrazole-1-yl)pyrimidine-4-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone Starting with I-03 TFA (32.27 mg, 100 μmol) and I-26 (31.5 mg, 110 μmol, 1.1 equivalents) and DIPEA (4 equivalents), the desired product, Example 17, was obtained as a white solid (40 mg / 92%).

[0460] Example 18: [1-[6-(2-methylpyrazole-3-yl)pyrimidine-4-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone- Starting with I-03 TFA (32.27 mg, 100 μmol) and I-13 (30.1 mg, 110 μmol, 1.1 equivalents) and DIPEA (4 equivalents), the desired product, Example 18, was obtained as a white solid.

[0461] Example 19: [1-[5-fluoro-4-(2-methylpyrazole-3-yl)pyrimidine-2-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone Starting with I-03 TFA (32.3 mg, 100 μmol) and I-15 (32.1 mg, 110 μmol, 1.1 equivalents) and DIPEA (4 equivalents), the desired product, Example 19, was obtained as a white solid.

[0462] Example 20: [(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-yl]-[1-[4-(2-methylimidazole-1-yl)pyrimidine-2-yl]-4-piperidyl]methanone Starting with I-05 TFA (29.6 mg, 100 μmol) and I-22 (30.1 mg, 110 μmol, 1.1 equivalents) and DIPEA (4 equivalents), the desired product, Example 20, was obtained as a white solid (27.6 mg, 69%). Chiral SFC:RT 1.024 minutes (100%, Method AN).

[0463] Example 21: [(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-yl]-[1-[6-(2-methylimidazole-1-yl)pyrimidine-4-yl]-4-piperidyl]methanone Starting with I-05 TFA (30.5 mg, 100 μmol) and I-12 (27.1 mg, 110 μmol, 1.1 equivalents) and DIPEA (4 equivalents), the desired product, Example 21, was obtained as a white solid (31.5 mg, 70%).

[0464] Example 24: [1-[2-(2-methylpyrazole-3-yl)pyrimidine-4-yl]-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone Starting with I-01 TFA (30.5 mg, 100 μmol) and I-24 (27.1 mg, 110 μmol, 1.1 equivalents) and DIPEA (4 equivalents), the desired product, Example 24, was obtained as a white solid (31.5 mg, 70%).

[0465] Example 26: (S)-(1-(4-(2-methyl-1H-imidazole-1-yl)-1,3,5-triazine-2-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone Starting with I-01 HCl (146.16 mg, 728.40 μmol) and I-19 (200 mg, 693.71 μmol) and DIEA (4 equivalents), the desired product, Example 26, was obtained as a white solid (155 mg, 51%).

[0466] Example 35: [1-[4-(2-methylimidazole-1-yl)-1,3,5-triazine-2-yl]piperidine-4-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone Starting with I-03 HCl salt (146.16 mg, 1.05 equivalents), I-19 (200 mg, 693.71 μmol, 1 equivalent), and DIEA (537.94 mg, 4.16 mmol, 724.99 μL, 6 equivalents), the desired product, Example 35, was obtained as a white solid (155 mg, 51%).

[0467] Example 37: [(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[4-(1,3-oxazole-2-yl)pyrimidine-2-yl]piperidine-4-yl]methanone Starting with I-03 HCl salt (1.1 equivalents) and I-12 (200 mg, 7687 μmol, 1 equivalent) and DIEA (6.87 mmol, 1.20 mL, 10 equivalents), the desired product, Example 37, was obtained as a white gum-like substance (99 mg, 40%). Chiral SFC:RT 0.979 min (98.66%ee) (Method X)

[0468] Example 38: [(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[4-(1,3-thiazole-2-yl)-1,3,5-triazine-2-yl]piperidine-4-yl]methanone Starting with I-03 HCl salt (1.1 equivalents), I-18 (200 mg, 687 μmol, 1 equivalent), and DIEA (6.87 mmol, 1.20 mL, 10 equivalents), the desired product, Example 38, was obtained as a white-gray gum-like substance (99 mg, 40%). Chiral SFC:RT 1.246 min (98.66% ee) (Method X)

[0469] Example 45: [(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[4-(2-methylpyrazole-3-yl)-1,3,5-triazine-2-yl]piperidine-4-yl]methanone Starting with I-05 HCl salt (1.0 equivalent), I-27 (243 mg, 842 μmol, 1 equivalent), and DIEA (7.01 mmol, 1.16 mL, 10 equivalents), the desired product, Example 45, was obtained as a white solid (199 mg, 51%). Chiral SFC:RT 1.478 min 99.99% ee) (Method AF)

[0470] Example 47: 1-[2-[4-[(3S)-3-pyrazine-2-yl-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]piperidine-2-one Starting with I-01 TFA salt (1 equivalent), I-37 (300 mg, 90% purity, 0.93 mmol, 1.0 equivalent), and DIEA (1.61 mL, 10 equivalents), the desired product, Example 47, was obtained as a grayish-white solid (173 mg, 43%). Chiral SFC:RT 1.421 min (99.99% ee) (Method AL)

[0471] Example 50: 1-[2-[4-[(3S)-3-(5-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one Starting with I-31 TFA salt (1 equivalent) and I-42 (475 mg, 1.5 mmol, 1.2 equivalents) and DIEA (3.63 mL, 16 equivalents), the desired product, Example 50, was obtained as a white solid (260.5 mg, 45%). Chiral SFC:RT 0.715 min (99.99%ee) (Method Z)

[0472] Example 54: 5-[2-[4-[(3S)-3-(2-methyl-1,3-oxazol-4-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2,4]heptan-4-one Starting with I-28 TFA salt (1 equivalent) and I-38 (564 mg, 1.1 mmol, 1.2 equivalents) and DIEA (1.88 mL, 9 equivalents), the desired product, Example 54, was obtained as a white solid (125.9 mg, 28%). Chiral SFC:RT 1.324 min (99.99%ee) (Method AG)

[0473] Example 55: 1-[2-[4-[(3S)-3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one Starting with I-29 TFA salt (1 equivalent) and I-42 (351 mg, 1.21 mmol, 1.2 equivalents) and DIEA (1.88 mL, 10⁹ equivalents), the desired product, Example 55, was obtained as a white solid (324.4 mg, 65%). Chiral SFC:RT 1.441 min (99.99% ee) (Method AJ)

[0474] Example 56: 1-[2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one Starting with I-05 HCl salt (1 equivalent), I-42 (270 mg, 1.0 mmol, 1.2 equivalents), and DIEA (1.62 mL, 10 equivalents), the desired product, Example 56, was obtained as a white solid (328 mg, 77%). Chiral SFC:RT 1.998 minutes (99.99%ee) (Method Z)

[0475] Example 57: 5-[2-[4-[(3S)-3-pyrazine-2-yl-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2.5]octane-4-one Starting with I-01 TFA salt (1 equivalent), I-39 (190 mg, 0.05 mmol, 1.2 equivalents), and DIEA (1.53 mL, 16 equivalents), the desired product, Example 57, was obtained as a white solid (140.2 mg, 56%). Chiral SFC:RT 2.014 minutes (99.99%ee) (Method Z)

[0476] Example 64: [1-[5-fluoro-4-(2-methylimidazole-1-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-yl]methanone Starting with I-04 TFA salt (1 equivalent), I-41 (341 mg, 1.1 mmol, 1.2 equivalents), and DIEA (3.12 mL, 16 equivalents), the desired product, Example 64, was obtained as a white solid (258.8 mg, 51%). Chiral SFC:RT 1.325 min (99.99% ee) (Method X)

[0477] Example 65: 3-[2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-1,3-oxazolidine-2-one Starting with I-05 TFA salt (1 equivalent) and I-40 (584 mg, 2.0 mmol, 1.2 equivalents, crude) and DIEA (1.45 mL, 5 equivalents), the desired product, Example 65, was obtained as a white solid (194 mg, 25%). Chiral SFC:RT 1.881 min (99.99% ee) (Method X)

[0478] Example 67: [1-[5-fluoro-2-(1,3-oxazol-2-yl)pyrimidine-4-yl]piperidine-4-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone Starting with I-03 HCl salt (1 equivalent), I-17 (119 mg, 0.41 mmol, 1.2 equivalents), and DIEA (1.06 mL, 15 equivalents), the desired product, Example 67, was obtained as a white solid (76.9 mg, 43%). Chiral SFC:RT 2.402 minutes (99.99%ee) (Method Z)

[0479] Example 77: [1-[5-fluoro-4-(2-methylimidazole-1-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone The desired product, Example 77, was obtained as a white solid (272 mg, 42%) by treatment with I-03 TFA salt (1 equivalent) and I-41 (440 mg, 1.4 mmol, 1.2 equivalents, crude) and DIEA (1.45 mL, 5 equivalents). Chiral SFC:RT 1.248 min (99.99% ee) (Method X)

[0480] Example 81: 1-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one Starting with I-03 TFA salt (1 equivalent) and I-42 (250 mg, 0.88 mmol, 1.2 equivalents, crude) and DIEA (1.5 mL, 10 equivalents), the desired product, Example 81, was obtained as a white solid (294.3 mg, 78%). Chiral SFC:RT 2.096 min (99.99% ee) (Method AL)

[0481] Example 82: 1-[6-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one Starting with I-03 TFA salt (1 equivalent) and I-43 (250 mg, 0.86 mmol, 1.2 equivalents, crude) and DIEA (1.50 mL, 10 equivalents), the desired product, Example 82, was obtained as a white solid (237.7 mg, 61%). Chiral SFC:RT 1.355 minutes (99.99% ee) (Method AC)

[0482] Example 86: 1-[6-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one Starting with I-04 TFA salt (1 equivalent, crude, 29% purity) and I-43 (260 mg, 897 mmol, 1.2 equivalents, crude) and DIEA (2.40 mL, 20 equivalents), the desired product, Example 86, was obtained as a white solid (141 mg, 46%). Chiral SFC:RT 1.390 minutes (99.99% ee) (Method X)

[0483] Example 93: (3R)-3-methoxy-1-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]piperidine-2-one and Example 94: (3S)-3-methoxy-1-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]piperidine-2-one Starting from DIEA (2.56 mL, 5 equivalents) from I-03 TFA salt (1 equivalent) and I-44 (1.12 mL crude solution), the desired product was obtained as a white solid as a mixture of Examples 93 and 94. The two diastereomers were separated by SFC (241 mg, 42%). Column: DAIEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: [CO2-MeOH (1‰NH3·H2O)]; B%: 60%, homogeneous concentration elution mode). Example 93: RT 2.02 (49.29 mg, 99.9% ee (Method AL)) Example 94: RT: 2.48 (50.64 mg, 98.5% ee) (Method AL)

[0484] Example 95: 1-[2-[4-[(3S)-3-(2-methyl-1,3-oxazol-4-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one Starting with I-28 TFA salt (1 equivalent) and I-42 (564 mg, 65% purity, 1.3 mmol, 1.2 equivalents) and DIEA (1.55 mL, 12 equivalents), the desired product, Example 95, was obtained as a white solid (107 mg, 32%). Chiral SFC:RT 1.416 min (99.99% ee) (Method AH)

[0485] Example 96: (3R)-1-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-3-methoxypiperidine-2-one and Example 97: (3S)-1-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-3-methoxypiperidine-2-one Starting with I-05 TFA salt (1 equivalent) and I-44 (1.77 mL crude solution) and DIEA (1.45 mL, 5 equivalents), the desired product was obtained as a white solid (243 mg, 40%) as a mixture of Example 96 + Example 97. The two diastereomers were separated by SFC and NPLC (conditions: column: DAISEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: [CO2-MeOH (1‰NH3·H2O)]; B%: 65%, homogeneous concentration elution mode). The first fraction was further purified by NPLC (column: Welch Ultimate XB-SiOH 250 × 50 × 10 μm; mobile phase: [hexane-EtOH]; gradient: 1% to 30% B over 15 minutes). Example 96: RT 1.82 (121.00 mg, 99.9% ee, (Method AM), yield 49.7%), as a grayish-white solid. Example 97: RT 1.33 (79.66 mg, 99.9% ee, (Method AM), yield 32.6%), as a grayish-white solid.

[0486] Example 102: [1-[4-(5-amino-2-methylpyrazole-3-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone Step 1: Starting with I-05 TFA salt (1 equivalent) and I-45 (490 mg, 61% purity, 0.88 mmol, 1.2 equivalents, crude) and pyridine (3 equivalents) in dichloromethane (5 ml), the desired intermediate was obtained as a white solid (350 mg, 69% purity, 55%). LCMS:m / z=497.3;RT 0.553(Method Q)

[0487] Step 2: To a solution of the crude intermediate from Step 1 (300 mg, purity 69.0%, 0.000417 mol, 1.00 equivalent) and NH4Cl (0.376 g, 0.0125 mol, 30.0 equivalents) in MeOH (10 ml), Zn powder (0.267 g, 0.00417 mol, 10.0 equivalents) was added little by little. The mixture was stirred at 25°C for 1 hour. The mixture was filtered and washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by HPLC to obtain Example 102 (65.91 mg, yield 34%) as a white solid. Chiral SFC:RT 1.734 min (100% ee) (Method X)

[0488] The following examples were synthesized using a specific route that includes coupling steps different from those of coupling methods A to K described above.

[0489] Example 111: [1-[4-(4-amino-5-methylpyrazole-1-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone Step 1. Synthesis of ethyl[2-[4-[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-yl]-5-methylpyrazole-4-carboxylate The title compound was prepared at 25°C using the same method as in Example 1, with a solution of I-10 (503 mg, 44% purity, 0.69 mmol), Ar-Cl 37 (200 mg, 1 equivalent), and DIEA (10 equivalents) in ACN (4 ml). The residue was purified by preparative HPLC to obtain the title compound as a white solid (340 mg, 86%). 1 H NMR(400MHz,CD3OD)δ=8.41(d,J=5.6Hz,1H),8.24(s,1H),8.01(s,1H),7.49(dd,J=10.4,1.6Hz,1H ),7.08(d,J=5.6Hz,1H),5.42(t,J=7.6Hz,1H),4.79-4.68(m,2H),4.37(td,J=8.0,3.2Hz,1H),4.3 2(q,J=7.2Hz,2H),4.07-3.99(m,1H),3.23-3.07(m,3H),3.01-2.93(m,4H),2.48(d,J=2.8Hz,3H), 2.41-2.31(m,1H),2.01-1.97(m,1H),1.90-1.79(m,1H),1.75-1.59(m,2H),1.37(t,J=7.2Hz,3H).

[0490] Step 2. Synthesis of [2-[4-[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-yl]-5-methylpyrazole-4-carboxylic acid The title compound was synthesized according to a general procedure for ester hydrolysis, and the above intermediate was obtained as a white solid (90 mg, 28%). LCMS: m / z=496.3[M+H]+, RT 0.459 (Method Q) 1H NMR(400MHz,CD3OD)δ=8.40(d,J=5.6Hz,1H),8.24(s,1H),8.00(s,1H),7.49(dd,J=10.0 ,1.6Hz,1H),7.08(d,J=5.6Hz,1H),5.42(t,J=7.6Hz,1H),4.77-4.70(m,2H),4.37(td,J= 7.6,3.2Hz,1H),4.07-3.99(m,1H),3.24-3.07(m,3H),3.02-2.93(m,4H),2.48(d,J=2.8 Hz,3H),2.41-2.31(m,1H),2.01(d,J=13.2Hz,1H),1.90-1.79(m,1H),1.75-1.60(m,2H). Chiral SFC:RT 0.960 min (100% ee) (Method N)

[0491] Step 3. Synthesis of tert-butyl N-[1-[2-[4-[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-yl]-5-methylpyrazole-4-yl]carbamate To a solution of [2-[4-[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-yl]-5-methylpyrazole-4-carboxylic acid (70.0 mg, 0.000141 mol, 1.00 equivalent) in t-BuOH (2 ml), TEA (0.0589 ml, 0.000424 mol, 3.00 equivalent) and DPPA (0.0971 g, 0.000353 mol, 2.50 equivalent) were sequentially added under an N2 atmosphere. The resulting mixture was stirred at 85°C for 16 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (Â / MeOH = 10 / 1) to obtain the title compound (35.0 mg, 6.18 umol, yield 43.7%) as a gray solid. LCMS RT 0.501 min, (ESI) m / z=567.4[M+H]+(Method Q).

[0492] Step 4. Synthesis of [1-[4-(4-amino-5-methylpyrazole-1-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone (Example 111) The mixture of tert-butyl N-[1-[2-[4-[(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-yl]-5-methylpyrazole-4-yl]carbamate (35.0 mg, 61.8 μmol, 1.00 equivalent) in HCl (4 M dioxane solution, 0.5 mL) was stirred at 25°C for 1 hour. The mixture was directly concentrated and then dissolved in saturated NaHCO3 aqueous solution (0.5 mL). The resulting mixture was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: water-ACN; B%: 18%~48% in 5 minutes; flow rate: 30 ml / min) to obtain Example 111 (3.97 mg, yield 13.8%) as a yellow solid. Chiral SFC:RT 0.737 min (100% ee) (Method N)

[0493] Example 112: [1-[4-(4-amino-5-methylpyrazole-1-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone The title compound was synthesized in the same manner as in Example 111, but Example 112 was obtained as a white solid (110 mg, 41%) using I-08 (499 mg, 1.8 mmol). Chiral SFC:RT 1.814 min (100% ee) (Method X)

[0494] Example 115 3-[5-fluoro-2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-1,3-oxazolidine-2-one Starting with I-05 TFA salt (1 equivalent), I-46 (200 mg, 0.65 mmol), and DIEA (0.9 mL, 8 equivalents), the desired product, Example 114, was obtained as a white solid (175.7 mg, 57%). Chiral SFC:RT 1.757 min (99.99% ee) (Method X)

[0495] Example 116: 3-[5-fluoro-2-[4-[(3S)-3-(5-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-1,3-oxazolidine-2-one The title compound was prepared at 65°C using the same method as in Example 1, with a solution of I-34 (376 mg, 61% purity), Ar-Cl 5 (200 mg, 84% purity), and TEA (10 equivalents) in DMF (4 ml). The residue was purified by preparative HPLC to obtain Example 116 as a white solid (106 mg, 30% purity). Chiral SFC:RT 1.712 minutes (100% ee) (Method X).

[0496] Solubility assay Prior to measuring the solubility of the compound batch, its purity was determined by UHPLC / MS.

[0497] The solubility buffer system was 50 mM phosphate buffer with a pH of 7.4.

[0498] Solubility was determined from a DMSO stock solution (10 mM) using the high-throughput HPLC method described below. Equipment: Waters Acquity UPLC with Binary Pump Software: Waters Empower 3 (Build 3471) Gradient: Eluent A: Water + 25 mM ammonium acetate, Eluent B: Acetonitrile. 0.05 minutes 98%A / 2%B; then 2.3 minutes 98%A to 98%B, then 0.65 minutes 98%B, then 0.05 minutes to 98%A, flow rate: 0.9 ml / min, column: 2.1 × 50 mm Waters ACQUITY UPLC BEH C18, 1.7 μm, 55℃. UV data: Retention time adλ = 220 nm (given in minutes)

[0499] Measurement of actual sample concentration using UPLC-ELSD: - Thaw the microtiter plate containing the sample and centrifuge (10 minutes, 4000 rcf). - Dilute DMSO stock solution with DMSO at a 1:40 ratio (5 + 195 μL). - Concentration measurement using UPLC-ELSD (evaporative light scattering detector), injection volume: 4 μL

[0500] calibration - UPLC-ELSD execution of 1:40 diluted DMSO stock solution using UPLC-UV 220nm analysis - Determination of the relationship between peak area and actual concentration (by UPLC-ELSD) for calibration.

[0501] Solubility measurement: - Re-plating the DMSO stock solution into a U-shaped multi-titer plate (96 wells) with the target amount of compound (100 μg) in each well (Conditions: DMSO stock solution concentration > 3 mM as measured by ELSD, LC-UV) 220nm Purity >75% - Evaporate DMSO solvent in a vacuum (SpeedVac) - Add 160 μL of buffer and magnetic beads to each well, then seal the plate with a heat sealer (peelable foil). - Store at 25°C, protected from light, and shake overnight (16 hours) at 600 rpm in an Eppendorf thermomixer. - After centrifugation (5 minutes, 4000 rcf), manually re-plating onto a filter plate (Millipore multi-screen filter plate 0.45 μm low-binding hydrophilic PTFE). - Filter by centrifugal separation (4000 rcf for 15 minutes), place in a V-shaped multi-titer plate, and seal the plate with a heat sealer (perforated foil). - UPLC-UV of filtered supernatant 220nm For analysis, inject 2-8 μL (depending on water solubility prediction by ACD software) into a photodiode array detector until an amplitude of 1 absorbance unit (AU) is reached. - Calculate the concentration of the filtered supernatant based on the ratio of peak area to actual concentration since the last calibration run.

[0502] The results of the solubility measurement are shown in Table 4 below.

[0503] [Table 37]

[0504] [Table 38]

[0505] The compounds disclosed herein exhibit solubility values ​​higher than 200 μM at pH 7.4 for the majority. Advantageously, most of the compounds exhibit solubility exceeding 1000 μM.

[0506] biological activity Evaluation of receptor interaction protein kinase 1 inhibition. The catalytic activity of RIPK1 was measured by monitoring the conversion of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) via autophosphorylation using the ADP-Glo ​​kinase kit (Promega, catalog number V9104).

[0507] In detail, 2 μl of recombinant hRIPK1(aa1-375) fusion protein (final concentration 3.6 μg / ml) and 2 μl of the compound (final concentration 33300-1.69 nM; DMSO final concentration 1%) were incubated at room temperature for 30 minutes, followed by the addition of 2 μl of ATP (ADP Glo kit, final concentration 50 μM). After a further 240 minutes of incubation at room temperature, the reaction was quenched by adding 5 μl of Promega ADP-Glo ​​reagent I to deplete any unused ATP. After a 30-minute incubation period, 10 μl of Promega ADP-Glo ​​detection reagent II was added, causing ADP to be converted to ATP and a photoreaction to occur between luciferase and luciferin. After 30 minutes, luminescence was quantified using Pherastar FS (BMG LABTECH, Ortenberg).

[0508] For dose-response experiments, use ICs with a 95% confidence interval. 50 The values ​​were calculated using a four-parameter logistic model according to Ratkowsky and Reedy, with constraints on asymptotic values ​​below and above 0% and 100%. Adjustments were obtained by nonlinear regression using the Levenberg Marquardt algorithm.

[0509] A cell assay in U937 cells to measure the activity of RIPK1 inhibitors against cell death (necroptosis). During TNF receptor I ligation, the Ser / Thr kinase RIPK1 is recruited to transient receptor complex I. Modification of RIPK1 promotes RIPK1 activation, which can lead to the formation of complex IIb, which is involved in the recruitment of RIPK3 and MLKL (mixed-series kinase domain-like protein), and subsequently translocates from the cytosol to the plasma membrane to carry out cell death (Cai, Z. et al, Nat. Cell Biol. (2014) 16:55-65).

[0510] Cell death in 96-well plates was quantified by determining the number of viable cells using the CellTiter 96 AQueous reagent (Promega), a calorimetry method that measures the number of viable cells by reducing the tetrazolium compound [3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, internal salt; MTS] to formazan. The absorbance of formazan was read at 490 nm. The inhibitory activity of the test compound was quantified by concentration-response curve (CRC) experiments.

[0511] The compound was obtained as a 10 mM stock solution and diluted with DMSO to 1 to 10 volumes to obtain a 1 mM solution. 2 μl of this solution was diluted with 998 μl of growth medium. 100 μl of the 2 μM compound solution was further diluted sequentially at a dilution factor of 2.5 by adding 150 μl of growth medium. A total of 10 concentrations in the range of 10 μM to 0.26 nM or 1 μM to 0.07 nM were tested.

[0512] U937 cells were cultured in RPMI 1640 Glutamax and 10% thermally inactivated FBS. 50 μl of cell suspension containing 1 × 10⁶ cells / ml, supplemented with 50 μM zVAD.fmk (benzyloxycarbonyl-Val-Ala-Asp(OMe) fluoromethyl ketone) and 100 ng / ml recombinant human TNFα, was dispensed into each well of a 96-well plate. As described in the cell assay for U937 cells, 50 μl of compound dilution was added, and the cell suspension was incubated overnight (18-24 hours) at 37°C and 5% CO₂ in a humidified atmosphere (95% rH). High control (no compound) and low control (no TNFα, no zVAD.fmk) were tested in 7-row sets, and all compound concentrations were tested in 2-row sets in each experimental plate.

[0513] CellTiter96 aqueous reagent was mixed (100 μl of PMS (phenazine methosulfate) solution / 2 ml of MTS (3-(4,5-dimethyldiazole-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, internal salt) solution), and 20 μl was added per well. After incubation at 37°C (5% CO2 95% rH) for 4 hours, the optical density was measured at 490 nm using a microplate reader (Tecan Infinite M1000).

[0514] The inhibition percentage is expressed as the percentage of the maximum inhibition value obtained in the absence of TNFα / zVAD.fmc. For each dose-response experiment, the IC with a 95% confidence interval is used. 50 The values ​​were calculated using a four-parameter logistic model according to Ratkowsky and Reedy without constraints, using an internal application (Biost@t-Speed ​​LTS V2.3).

[0515] The results of the biological activity are shown in Table 5 (ADP-Glo ​​IC). 50 (μM) and U937 IC 50 (μM)).

[0516] [Table 39]

[0517] [Table 40]

[0518] [Table 41]

[0519] All compounds disclosed herein exhibit RIPK1 reduction catalytic activity, as highlighted by the ADP Glo assay, and IC2. 50 Because its IC50 is less than 500 nM, it is a potent RIPK1 inhibitor. Most compounds have an IC50 of less than 50 nM. 50The values ​​are shown. Advantageously, most compounds have ICs of less than 30 nM, and even less than 20 nM. 50 Show the value.

[0520] All compounds disclosed herein exhibited cell death (necroptosis) in U937 cells and IC 50 Since its IC50 is less than 7000 nM, it is a potent RIPK1 inhibitor. Most compounds have an IC50 of less than 75 nM, and even less than 50 nM. 50 The values ​​are shown. Advantageously, most compounds have an IC50 of less than 30 nM. 50 Show the value.

Claims

1. Compound of formula (I): 【Chemistry 1】 (In the formula, X １ , X ２ , and X ３ CR ６ or selected independently of N; R １ represents a 5-membered or 6-membered heteroaryl group, where the heteroaryl is a halogen, (C １ -C ６ ) optionally substituted with one or two groups independently selected from alkyl groups and -CN groups; R ２ teeth, - a 4-, 5- or 6-membered heteroaryl in which 1 to 3 ring atoms are independently selected from nitrogen, oxygen or sulfur (said heteroaryl being optionally substituted by one or two R ７ groups); - A 5- or 6-membered heterocycle in which 1 to 3 ring atoms are independently selected from nitrogen and oxygen (the heterocycle has 1, 2, or 3 R ８ (It is replaced by an optional choice); or - Spiro(C) is a ring atom in which one or two ring atoms are selected from nitrogen or oxygen. ７ -C １０ ) Heterobicyclic compounds (the heterocycle consists of one or two R rings) ９ (It is replaced by optional selection.) It represents; R ３ is H- or (C １ -C ４ ) Represents an alkyl group; R ４ is H- or (C １ -C ４ ) Represents an alkyl group; Or, R ３ and R ４ These, together with the carbon atoms to which they are bonded, form a cyclopropyl ring or a cyclobutyl ring; R ５ and R ６ H, (C １ -C ６ ) Represents an alkyl group or halogen; Each R ７ (C １ -C ６ ) Alkyl, halogen, -NH ２ Or it represents -OH; Each R ９ (C １ -C ６ ) Represents an alkyl group, halogen, or oxo; Each R ８ These are independently OH, oxo, halogen, (C １ -C ６ ) alkyl, O-(C １ -C ６ ) alkyl, -NH ２ ,-NH(C １ -C ６ ) alkyl, -N[(C １ -C ６ ) Alkyl] ２ or (C １ -C ６ (representing fluoroalkyl groups); and / or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

2. R １ However, pyridinyl, pyrazinyl, pyrimidinyl, oxazolyl or thiazolyl group (halogen, (C １ -C ２ A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that it is optionally substituted with one or two groups independently selected from alkyl groups and -CN groups.

3. R ２ However, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl or pyrimidinyl group (one or two R ７ It is optionally replaced by the R ７ CH ３ These are groups and halogens, particularly CH ３ A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that it represents a group.

4. R ２ However, piperidinyl, morpholinyl, pyrrolidinyl, oxazolidinyl, azetidinyl, or oxetanyl group (one or two R ８ It is optionally replaced by the R ８ OH, oxo, halogen, (C １ -C ２ ) alkyl group, O-(C １ -C ２ ) alkyl groups, and CF ３ A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that it represents a compound independently selected from and, in particular, optionally substituted by an oxo.

5. R ２ R represents a 7-oxa-2-azaspiro[3.5]nonane-2-yl group, a 5-azaspiro[2.5]octane-4-on-yl group, a 5-azaspiro[2.4]heptane-4-on-yl group, or a 2-oxa-7-azaspiro[3.5]nonane-7-yl group, particularly a 5-azaspiro[2.5]octane-4-on-yl group or a 5-azaspiro[2.4]heptane-4-on-yl group, and one or two R selected from methyl or fluorine. ９ A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that it is optionally substituted by [a specific compound].

6. R ３ However, H or (C １ -C ２ ) is an alkyl group; R ４ However, H or (C １ -C ２ ) Represents an alkyl group; or R ３ and R ４ A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that these elements come together to form a cyclopropyl ring with the carbon atoms to which they are bonded.

7. (1) (S)-(3-(5-fluoropyridine-3-yl)isoxazolidine-2-yl)(1-(6-(pyridine-3-yl)pyrimidine-4-yl)piperidine-4-yl)methanone, (2) (S)-3-(2-(4-(3-(pyrazine-2-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-yl)oxazolidine-2-one, (3) (S)-1-(4-(4-(3-(pyrazine-2-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-2-yl)pyrrolidine-2-one, (4) (S)-1-(2-(4-(3-(pyrazine-2-yl)isoxazolidine-2-carbonyl)piperidine-1-yl)pyrimidine-4-yl)pyrrolidine-2-one, (5) 3-[5-fluoro-2-[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-yl]oxazolidine-2-one, (6) 1-[5-fluoro-2-[4-[(3S)-3-pyrazine-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-yl]pyrrolidine-2-one, (7) 1-[6-(2-methylimidazole-1-yl)pyrimidine-4-yl]-4-piperidyl]-[(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-yl]methanone, (8) 1-[4-(2-methylpyrazole-3-yl)-1,3,5-triazine-2-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone, (9) [1-[4-(4-methylpyrazole-1-yl)pyrimidine-2-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone, (10) [1-(5-fluoro-4-pyrazole-1-ylpyrimidine-2-yl)-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone, (11) [1-(4-oxazole-2-ylpyrimidine-2-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone, (12) [1-(5-fluoro-4-oxazole-2-ylpyrimidine-2-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone, (13) [1-(5-fluoro-2-oxazole-2-ylpyrimidine-4-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone, (14) [(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]-[1-(4-thiazole-2-yl-1,3,5-triazine-2-yl)-4-piperidyl]methanone, (15) [1-[4-(2-methylpyrazole-3-yl)pyrimidine-2-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone, (16) [1-[2-(4-methylpyrazole-1-yl)pyrimidine-4-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone, (17) [1-[6-(4-methylpyrazole-1-yl)pyrimidine-4-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone, (18) [1-[6-(2-methylpyrazole-3-yl)pyrimidine-4-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone, (19) [1-[5-fluoro-4-(2-methylpyrazole-3-yl)pyrimidine-2-yl]-4-piperidyl]-[(3S)-3-(6-methyl-3-pyridyl)isoxazolidine-2-yl]methanone, (20) [(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-yl]-[1-[4-(2-methylimidazole-1-yl)pyrimidine-2-yl]-4-piperidyl]methanone, (21) [(3S)-3-(5-fluoro-6-methyl-3-pyridyl)isoxazolidine-2-yl]-[1-[4-(2-methylimidazole-1-yl)pyrimidine-2-yl]-4-piperidyl]methanone, (22) [1-[4-(2,4-dimethylimidazole-1-yl)-5-fluoropyrimidine-2-yl]-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone, (23) [1-[4-(2-methylimidazole-1-yl)-1,3,5-triazine-2-yl]-4-piperidyl]-[(3S)-3-(2-methylthiazole-4-yl)isoxazolidine-2-yl]methanone, (24) [1-[2-(2-methylpyrazole-3-yl)pyrimidine-4-yl]-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone, (25) [1-(5-fluoro-2-pyrimidine-5-ylpyrimidine-4-yl)-4-piperidyl]-[(3S)-3-pyrazine-2-ylisoxazolidine-2-yl]methanone, (26) (S)-(1-(4-(2-methyl-1H-imidazole-1-yl)-1,3,5-triazine-2-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone, (27) (S)-(1-(5-fluoro-4-(thiazole-5-yl)pyrimidine-2-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone, (28) (S)-(1-(6-(1-methyl-1H-pyrazole-5-yl)pyrimidine-4-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone, (29) (S)-(1-(2-(2-methyl-1H-imidazole-1-yl)pyrimidine-4-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone, (30) (S)-(1-(4-(2-methyl-1H-imidazole-1-yl)pyrimidine-2-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone, (31) (S)-(1-(6-(2-methyl-1H-imidazole-1-yl)pyrimidine-4-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone, (32) (S)-(1-(5-fluoro-4-(1H-pyrazole-1-yl)pyrimidine-2-yl)piperidine-4-yl)(3-(pyrazine-2-yl)isoxazolidine-2-yl)methanone, (33) [5-[6-(2-methylimidazole-1-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (34) [5-[6-(2-methylpyrazole-3-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (35) [1-[4-(2-methylimidazole-1-yl)-1,3,5-triazine-2-yl]piperidine-4-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (36) 3-[2-[4-[(3S)-3-(5-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-yl]oxazolidine-2-one, (37) [(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[4-(1,3-oxazole-2-yl)pyrimidine-2-yl]piperidine-4-yl]methanone, (38) [(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[4-(1,3-thiazole-2-yl)-1,3,5-triazine-2-yl]piperidine-4-yl]methanone, (39) [(8R)-5-[6-(2-methylpyrazole-3-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-pyrazine-2-yl-1,2-oxazolidine-2-yl]methanone, (40) [(3S)-3-(2-methyl-1,3-thiazole-4-yl)-1,2-oxazolidine-2-yl]-[1-[6-(2-methyl-1,2,4-triazole-3-yl)pyrimidine-4-yl]piperidine-4-yl]methanone, (41) [(3S)-3-(2-methyl-1,3-thiazole-4-yl)-1,2-oxazolidine-2-yl]-[(8R)-5-[6-(2-methyl-1,2,4-triazole-3-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]methanone, (42) [(3S)-3-(2-methyl-1,3-thiazole-4-yl)-1,2-oxazolidine-2-yl]-[(8R)-5-[6-(3-methyltriazole-4-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]methanone, (43) [(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[(8R)-5-[6-(2-methyl-1,2,4-triazole-3-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]methanone, (44) 1-[2-[(8R)-8-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]-5-azaspiro[2.5]octan-5-yl]pyrimidine-4-yl]pyrrolidine-2-one, (45) [(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[4-(2-methylpyrazole-(3-yl)-1,3,5-triazine-2-yl]piperidine-4-yl]methanone, (46) 1-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (47) 1-[2-[4-[(3S)-3-pyrazine-2-yl-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]piperidine-2-one, (48) [(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[(8R)-5-[4-(2-methylpyrazole-3-yl)-1,3,5-triazine-2-yl]-5-azaspiro[2.5]octan-8-yl]methanone, (49) [(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[6-(2-methyl-1,2,4-triazole-3-yl)pyrimidine-4-yl]piperidine-4-yl]methanone, (50) 1-[2-[4-[(3S)-3-(5-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (51) 5-[2-[4-[(3S)-3-(5-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2.4]heptan-4-one, (52) 5-[2-[4-[(3S)-3-(2-methyl-1,3-thiazole-4-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2.4]heptan-4-one, (53) 5-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2.4]heptan-4-one, (54) 5-[2-[4-[(3S)-3-(2-methyl-1,3-oxazole-4-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2.4]heptan-4-one, (55) 1-[2-[4-[(3S)-3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (56) 1-[2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (57) 5-[2-[4-[(3S)-3-pyrazine-2-yl-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2.5]octan-4-one, (58) 3,3-difluoro-1-[2-[4-[(3S)-3-pyrazine-2-yl-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (59) 3,3-difluoro-1-[2-[4-[(3S)-3-(2-methyl-1,3-thiazole-4-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (60) 1-[2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-3,3-dimethylpyrrolidine-2-one, (61) 5-[2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2.4]heptan-4-one, (62) 1-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-3-methylimidazolidin-2-one, (63) 4-[2-[(8R)-8-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]-5-azaspiro[2.5]octan-5-yl]pyrimidine-4-yl]morpholin-3-one, (64) [1-[5-fluoro-4-(2-methylimidazole-1-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (65) 3-[2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-1,3-oxazolidine-2-one, (66) 3,3-difluoro-1-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]piperidine-2-one, (67) [1-[5-fluoro-2-(1,3-oxazole-2-yl)pyrimidine-4-yl]piperidine-4-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (68) 5-[5-fluoro-2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2.4]heptan-4-one, (69) [(8R)-5-[4-(2-methylpyrazole-3-yl)-1,3,5-triazine-2-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (70) 5-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2.4]heptan-4-one, (71) 1-[4-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-2-yl]pyrrolidine-2-one, (72) 5-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2.5]octan-4-one, (73) 3,3-difluoro-1-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (74) 3,3-difluoro-1-[2-[4-[(3S)-3-(5-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (75) 3,3-difluoro-1-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (76) 3,3-difluoro-1-[2-[4-[(3S)-3-(5-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]piperidine-2-one, (77) [1-[5-fluoro-4-(2-methylimidazole-1-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (78) [5-[6-(2-methylimidazole-1-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (79) [5-[6-(2-methylimidazole-1-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (80) [5-[6-(2-methylpyrazole-3-yl)pyrimidine-4-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (81) 1-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (82) 1-[6-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (83) [(8R)-5-[4-(4-methylpyrazole-1-yl)pyrimidine-2-yl]-5-azaspiro[2.5]octan-8-yl]-[(3S)-3-pyrazine-2-yl-1,2-oxazolidine-2-yl]methanone, (84) 3,3-dimethyl-1-[4-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-2-yl]pyrrolidine-2-one, (85) 1-[4-[(8R)-8-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]-5-azaspiro[2.5]octan-5-yl]pyrimidine-2-yl]pyrrolidine-2-one, (86) 1-[6-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (87) 1-[4-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-2-yl]pyrrolidine-2-one, (88) 5,5-dimethyl-1-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (89) 1-[2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5,5-dimethylpyrrolidine-2-one, (90) 5-[4-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-2-yl]-5-azaspiro[2.5]octan-4-one, (91) 3-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-1,3-oxazolidine-2-one, (92) 1-[2-[4-[(3S)-3-(2-methyl-1,3-thiazole-4-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (93) (3R)-3-methoxy-1-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]piperidine-2-one, (94) (3S)-3-methoxy-1-[2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]piperidine-2-one, (95) 1-[2-[4-[(3S)-3-(2-methyl-1,3-oxazole-4-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (96) (3R)-1-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-3-methoxypiperidine-2-one, (97) (3S)-1-[2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-3-methoxypiperidine-2-one, (98) [(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[4-(oxetan-2-yl)pyrimidine-2-yl]piperidine-4-yl]methanone, (99) [(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[4-(oxetan-2-yl)pyrimidine-2-yl]piperidine-4-yl]methanone, (100) 1-[2-[(8R)-8-[(3S)-3-pyrazine-2-yl-1,2-oxazolidine-2-carbonyl]-5-azaspiro[2.5]octan-5-yl]pyrimidine-4-yl]pyrrolidine-2-one, (101) [(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]-[1-[4-(oxetan-3-yl)pyrimidine-2-yl]piperidine-4-yl]methanone, (102) [1-[4-(5-amino-2-methylpyrazole-3-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (103) 5-[5-fluoro-2-[4-[(3S)-3-(5-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2.4]heptan-4-one, (104) 5-[5-fluoro-2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2.4]heptan-4-one, (105) 5-[5-fluoro-2-[4-[(3S)-3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2.4]heptan-4-one, (106) [1-[4-[(3S)-3-fluoropyrrolidine-1-yl]pyrimidine-2-yl]piperidine-4-yl]-[(3S3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-yl]methanone, (107) [1-[4-[(3R)-3-methoxypyrrolidine-1-yl]pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-yl]methanone, (108) [1-[4-[(3S)-3-methoxypyrrolidine-1-yl]pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-yl]methanone, (109) 5-[5-fluoro-2-[4-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-5-azaspiro[2.4]heptan-4-one, (110) 1-[5-fluoro-2-[4-[(3S)-3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]pyrrolidine-2-one, (111) [1-[4-(4-amino-5-methylpyrazole-1-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (112) [1-[4-(4-amino-5-methylpyrazole-1-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(6-methylpyridine-3-yl)-1,2-oxazolidine-2-yl]methanone, (113) [1-[4-(3-methoxyazetidine-1-yl)pyrimidine-2-yl]piperidine-4-yl]-[(3S)-3-(5-methylpyrazine-2-yl)-1,2-oxazolidine-2-yl]methanone, (114) 3-[5-fluoro-2-[4-[(3S)-3-(5-fluoropyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-1,3-oxazolidine-2-one, (115) 3-[5-fluoro-2-[4-[(3S)-3-(5-fluoro-6-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-1,3-oxazolidine-2-one, and (116) 3-[5-fluoro-2-[4-[(3S)-3-(5-methylpyridine-3-yl)-1,2-oxazolidine-2-carbonyl]piperidine-1-yl]pyrimidine-4-yl]-1,3-oxazolidine-2-one A compound of formula (I) according to any one of claims 1 to 6, selected from, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

8. A compound of formula (I) according to any one of claims 1 to 7, selected from the group consisting of compounds (3), (11), (14), (15), (38), (39), (40), (42), (43), (45), (48), (49), (52), (53), (54), (55), (57), (62), (65), (69), and (91), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

9. A compound of formula (I) according to any one of claims 1 to 8, selected from the group consisting of compounds (3), (11), (14), (15), (38), (39) to (40), (42), (43), (45), and (48), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

10. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

11. A compound of formula (I) as described in any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use as a pharmaceutical.

12. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in the treatment and / or prevention of diseases, disorders, or conditions at least partially mediated by receptor-interacting protein kinase 1.

13. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in the treatment and / or prevention of a disease selected from Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS).

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