WO2022131741A1 - Isoxazolidine derivative compound and use thereof - Google Patents

Isoxazolidine derivative compound and use thereof Download PDF

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WO2022131741A1
WO2022131741A1 PCT/KR2021/018956 KR2021018956W WO2022131741A1 WO 2022131741 A1 WO2022131741 A1 WO 2022131741A1 KR 2021018956 W KR2021018956 W KR 2021018956W WO 2022131741 A1 WO2022131741 A1 WO 2022131741A1
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Prior art keywords
pyrimidin
trifluoromethyl
amine
alkyl
phenylisoxazolidin
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PCT/KR2021/018956
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French (fr)
Korean (ko)
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류희선
김다미
김승수
조서현
손정범
김성환
김남두
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보로노이바이오 주식회사
보로노이 주식회사
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Publication of WO2022131741A1 publication Critical patent/WO2022131741A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to isoxazolidine derivative compounds and medicinal uses thereof. Specifically, the present invention relates to isoxazolidine derivative compounds having CDK2, CDK4, CDK6 and/or HPK1 inhibitory activity.
  • Protein kinase is an enzyme that catalyzes the phosphorylation reaction that transfers the gamma-phosphate group of ATP to the hydroxyl group of tyrosine, serine, or threonine of a protein. It is responsible for cell metabolism, gene expression, cell growth, differentiation, and cell division. It plays an important role in signal transduction, etc. (Thomas A. Hamilton, in Encyclopedia of Immunology (Second Edition), 1998, 2028-2033).
  • Protein kinases are involved in signaling pathways by acting as molecular switches, and the switching between the active and inactive states of the target protein by the kinase in the cell must be smoothly regulated. If the transition between the active and the inactive state is abnormally regulated, the intracellular signal transduction is excessively activated or inactivated to induce uncontrolled cell division and proliferation. In particular, abnormal activation by mutation, amplification and/or overexpression of protein kinase genes causes the development and progression of various tumors or plays a decisive role in the onset of various diseases such as inflammatory diseases, degenerative brain diseases, and autoimmune diseases.
  • Examples of kinases related thereto include ABL1, ABL2, BRAF, CDK2, CDK4, CDK6, CDK8, CDK11, CDKL2, CIT, CSF1R, DDR1, DDR2, FLT3, HPK1, KIT, LOK, LTK, MUSK, PAK3, PDGFRA, PDGFRB , RAF1, RIPK1, and the like.
  • cyclin-dependent kinase (Cyclin-Dependent Kinase, CDK) is an enzyme that performs essential functions regulating cell division and proliferation.
  • CDK is activated by the regulatory subunit cyclin, and heterodynes such as cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6 are important regulators of cell cycle progression, It is additionally known to have transcriptional, DNA repair, differentiation and apoptosis regulatory functions (Morgan DO. et al, Annu. Rev. Cell. Dev. Biol. 1997, 13, 261-291).
  • the CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib are being tested for cancer as a single drug or in combination with other therapeutic agents.
  • Palbociclib and ribociclib are approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with aromatase inhibitors in postmenopausal women (O') Leary et al., Nature Reviews, 2016, 13, 417-430).
  • HR hormone receptor
  • HER2 human epidermal growth factor receptor 2
  • CDK2 Overexpression of CDK2 is associated with aberrant regulation of the cell cycle, and the cyclin E/CDK2 complex plays an important role in the regulation of G1/S conversion, histone biosynthesis and centrosome replication. Progressive phosphorylation of Rb by cyclin D/CDK4/6 and cyclin E/CDK2 releases the G1 transcription factor E2F and promotes entry into S phase. Activation of cyclin A/CDK2 during early S phase promotes phosphorylation of endogenous substrates that enable DNA replication and inactivation of E2F for S phase completion (Asghar et al., Nat. Rev. Drug. Discov., 2015 , 14(2), 130-146).
  • hematopoietic progenitor kinase (Hematopoietic Progenitor Kinase 1, HPK1) is a serine/threonine kinase restricted to hematopoietic cells, and HPK1 activity can be induced by activation signals generated by various cell surface receptors found in hematopoietic cells upon ligand binding.
  • HPK1 can be a novel target for cancer immunotherapy.
  • HPK1 -/- T cells have increased Th1 cytokine production in response to TCR binding, proliferate rapidly, and are resistant to PGE2-mediated inhibition, and mice transplanted with HPK1 -/- T cells can grow lung tumors have resistance to When HPK1 is removed from dendritic cells, antigen-presenting ability is significantly increased, and when used as a cancer vaccine, a better anti-tumor immune response may be exhibited (Sawasdikosol et al., Immunol Res., 2012, 54(1-3), 262). -265).
  • HPK1 increases IKKbeta (IKappaB kinase beta) phosphorylation
  • IKKbeta IKappaB kinase beta
  • inhibition of HPK1 expression slows TCR-mediated NF-kappaB activity and increases apoptosis (Brenner et al., EMBO J. 2005) , 24, 4279).
  • compounds having inhibitory activity against CDK2, CDK4, CDK6 and/or HPK1 can be expected to have excellent effects as anticancer agents, and development of novel compounds for inhibiting them is continuously required.
  • An object of the present invention is to provide an isoxazolidine derivative having a novel structure, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a method for preparing the isoxazolidine derivative compound.
  • Another object of the present invention is to provide a pharmaceutical use of the isoxazolidine derivative compound, specifically for the treatment or treatment of CDK2, CDK4, CDK6 and/or HPK1-related diseases comprising the isoxazolidine derivative compound as an active ingredient.
  • a pharmaceutical composition for prophylaxis, the use of the compound for the treatment or prophylaxis of a CDK2, CDK4, CDK6 and/or HPK1-related disease, or the treatment or prevention of a CDK2, CDK4, CDK6 and/or HPK1-related disease comprising administering the compound to provide preventive measures.
  • the present invention provides a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
  • Ring A 2 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • R 1 is —H or —C 1-6 alkyl
  • R 2 is -H, -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -halo, or 5-7 membered ring and ⁇ wherein, one or more H of the 5-7 membered ring may be substituted with -C 1-6 alkyl, -C 1-6 haloalkyl, or halo ⁇ ;
  • R 3 to R 7 are each independently —H or —C 1-6 alkyl
  • R 8 is —H, —C 1-6 alkyl, phenyl or benzyl
  • R 9 and R 10 are each independently —H, —C 1-6 alkyl, —C 1-6 hydroxyalkyl, —C 1-6 alkyl-NR 24 R 25 , or heterocycloalkyl ⁇ wherein the hetero one or more H of the cycloalkyl ring may be substituted with —C 1-6 alkyl ⁇ ;
  • R 11 is —H or —C 1-6 alkyl
  • each R 14 is independently —H, —C 1-6 alkyl, —C 1-6 alkyl-NR 26 R 27 , heterocycloalkyl, or —C 1-6 alkyl-heterocycloalkyl ⁇ wherein the heterocyclo one or more H of an alkyl or —C 1-6 alkyl-heterocycloalkyl ring may be substituted with —C 1-6 alkyl;
  • R 15 to R 17 are each independently —H or —C 1-6 alkyl
  • R 18 and R 19 are each independently —C 1-6 alkyl or —C 1-6 alkyl-NR 28 R 29 ;
  • R 20 to R 29 are each independently —H or —C 1-6 alkyl.
  • the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
  • Ring A 1 is aryl or heteroaryl ⁇ wherein at least one H of said aryl or heteroaryl ring is -C 1-6 alkyl, -C 1-6 haloalkyl, -CN, -NR 6 R 7 , -OR 8 , or - may be substituted with halo ⁇ ;
  • Ring A 2 is aryl, heteroaryl, or heterocycloalkyl
  • R 1 is —H
  • R 2 is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -CN, -halo, or a 5-7 membered ring ⁇ wherein at least one H of the 5-7 membered ring is -C may be substituted with 1-6 alkyl or halo ⁇ ;
  • R 6 and R 7 are each independently —C 1-6 alkyl
  • R 8 is —H, —C 1-6 alkyl, or phenyl
  • R 9 and R 10 are each independently —H, —C 1-6 alkyl, —C 1-6 hydroxyalkyl, —C 1-6 alkyl-NR 24 R 25 , or heterocycloalkyl ⁇ wherein the hetero one or more H of the cycloalkyl ring may be substituted with —C 1-6 alkyl ⁇ ;
  • R 11 is —C 1-6 alkyl
  • each R 14 is independently —C 1-6 alkyl, —C 1-6 alkyl-NR 26 R 27 , heterocycloalkyl, or —C 1-6 alkyl-heterocycloalkyl ⁇ wherein said heterocycloalkyl or — one or more H of a C 1-6 alkyl-heterocycloalkyl ring may be substituted with —C 1-6 alkyl ⁇ ;
  • R 15 to R 17 are each independently —C 1-6 alkyl
  • R 18 and R 19 are each independently —C 1-6 alkyl or —C 1-6 alkyl-NR 28 R 29 ;
  • R 20 to R 23 , R 26 to R 29 are each independently —H or —C 1-6 alkyl.
  • the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
  • R 3 to R 7 are each independently —H or —C 1-6 alkyl
  • R 8 is -H, -C 1-6 alkyl, phenyl or benzyl.
  • the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
  • Ring A 2 is phenyl, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, or 3-7 membered heterocycloalkyl
  • R 9 and R 10 are each independently —H, —C 1-6 alkyl, —C 1-6 hydroxyalkyl, —C 1-6 alkyl-NR 24 R 25 , or heterocycloalkyl ⁇ wherein the hetero one or more H of the cycloalkyl ring may be substituted with —C 1-6 alkyl ⁇ ;
  • R 11 is —H or —C 1-6 alkyl
  • each R 14 is independently —H, —C 1-6 alkyl, —C 1-6 alkyl-NR 26 R 27 , heterocycloalkyl, or —C 1-6 alkyl-heterocycloalkyl ⁇ wherein the heterocyclo one or more H of an alkyl or —C 1-6 alkyl-heterocycloalkyl ring may be substituted with —C 1-6 alkyl;
  • R 15 to R 17 are each independently —H or —C 1-6 alkyl
  • R 18 and R 19 are each independently —C 1-6 alkyl or —C 1-6 alkyl-NR 28 R 29 ;
  • R 20 to R 29 are each independently —H or —C 1-6 alkyl.
  • the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
  • R 1 is -H.
  • the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
  • R 2 is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -CN, -halo, or a 5-6 membered ring ⁇ wherein at least one H of the 5-6 membered ring is -C may be substituted with 1-6 alkyl, —C 1-6 haloalkyl, or halo ⁇ .
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is the compound of Examples 1 to 240 described in [Table 1], [Table 2], and [Table 3], or It may be selected from the group consisting of pharmaceutically acceptable salts thereof.
  • alkyl may mean a straight or branched acyclic, cyclic, or saturated hydrocarbon to which they are bonded.
  • C 1-6 alkyl can mean an alkyl containing 1 to 6 carbon atoms.
  • Acyclic alkyl may include, as an example, methyl, ethyl, n -propyl, n -butyl, isopropyl, sec -butyl, isobutyl, or tert -butyl, etc., It is not limited thereto.
  • Cyclic alkyl may be used interchangeably with “cycloalkyl” herein, and may include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. doesn't happen
  • alkoxy may mean -(O-alkyl) as an alkyl ether group, wherein alkyl is as defined above.
  • C 1-6 alkoxy may mean alkoxy containing C 1-6 alkyl, that is, -(OC 1-6 alkyl).
  • alkoxy is methoxy ), ethoxy, n -propoxy, isopropoxy, n -butoxy , isobutoxy , sec -butoxy ), or tert - butoxy , etc., but is not limited thereto.
  • halo may be F, Cl, Br, or I.
  • haloalkyl may mean a straight or branched chain alkyl (hydrocarbon) having one or more halo substituted carbon atoms as defined herein.
  • haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl independently substituted with one or more halogens, such as F, Cl, Br, or I. .
  • aminoalkyl may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with amino-(NR'R"), wherein R' and R" are each independently hydrogen. , and may be selected from the group consisting of C 1-6 alkyl, wherein the selected R′ and R′′ may each independently be substituted or unsubstituted.
  • heterocycloalkyl may mean a ring containing 1 to 5 heteroatoms selected from N, O and S as atoms forming the ring, and may be saturated or partially unsaturated.
  • unsaturated it may be referred to as a heterocycloalkene.
  • heterocycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring or a fused ring.
  • heterocycloalkyl may mean a heterocycloalkyl containing 3 to 12 atoms forming a ring
  • heterocycloalkyl is pyrrolidine, piperidine, Imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4( 1H , 3H ) -Dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine- S -oxide, thiomorpholine- S , S -oxide, piperazine, pyran, pyridone, 3-pyrroline , thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3
  • arene may mean an aromatic hydrocarbon ring.
  • the arene may be a monocyclic arene or a polycyclic arene.
  • the ring carbon number of arene may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less.
  • examples of arenes include benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quaterbenzene, quinkbenzene, sexbenzene, triphenylene, pyrene, benzofluoranthene, chrysene, etc. , but not limited to these.
  • the residue obtained by removing one hydrogen atom from "arene” is referred to as "aryl".
  • heteroene may be a ring including at least one of O, N, P, Si, and S as a heterogeneous element.
  • the number of ring carbon atoms in the heteroarene may be 2 or more and 30 or less, or 2 or more and 20 or less.
  • the hetero arene may be a monocyclic hetero arene or a polycyclic hetero arene.
  • the polycyclic heteroarene may have, for example, a two- or three-ring structure.
  • heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, pyridazine , pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine , imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine or pyrazolopyridine, N -arylcarbazole, N -heteroarylcarbazole, N -alkylcarbazole, be
  • heteroarenes may also include bicyclic heterocyclo-arenes, including arene rings fused to heterocycloalkyl rings or heteroarenes fused to cycloalkyl rings.
  • heteroaryl the residue obtained by removing one hydrogen atom from the "heteroarene” is referred to as "heteroaryl”.
  • the above-mentioned homologous or heterogeneous substituents may be substituted one or more at the same position or different positions, and may also be substituted sequentially.
  • the term "sequentially” means that in the formula, one substituent is substituted and then another substituent is successively substituted in the substituent, for example, after the alkyl group is substituted, a cycloalkyl group is substituted in the alkyl group and the When a carbonyl group is sequentially substituted with a cycloalkyl group, it can be indicated that the sequential substitution is made by naming the cycloalkyl group as carbonylcycloalkylalkyl.
  • linking radicals do not specify the bonding direction, and the bonding direction is arbitrary.
  • the connected radical L is -MW-, where -MW- connects Ring A and Ring B in the same direction as the reading order from left to right. can be formed, and by connecting Ring A and Ring B in the reverse reading order from left to right, can form.
  • enantiomer means a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but sterically different. Each of these optical isomers and mixtures thereof are also included within the scope of the present invention.
  • a solid line bond (-) connecting an asymmetric carbon atom is a wedge-shaped solid line bond indicating the absolute configuration of the stereocenter. or wedge-dotted join may include
  • the compound of Formula 1 of the present invention may exist in the form of a "pharmaceutically acceptable salt".
  • a pharmaceutically acceptable salt As the salt, an acid addition salt formed with a pharmaceutically acceptable free acid is useful.
  • pharmaceutically acceptable salt refers to any of the compounds at a concentration having an effective action that is relatively non-toxic and harmless to a patient, and the side effects due to the salt do not reduce the beneficial efficacy of the compound represented by the formula (1). Any organic or inorganic acid addition salt of
  • Acid addition salts are prepared by conventional methods, for example by dissolving the compound in an aqueous solution of an excess of acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of compound and acid or alcohol in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction.
  • a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • an organic acid and an inorganic acid may be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid may be used as the inorganic acid.
  • organic acid methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glycolic acid, glue Conic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid, etc.
  • the present invention is not limited thereto.
  • a pharmaceutically acceptable metal salt can be prepared using a base.
  • the alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate.
  • it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt as the metal salt, but is not limited thereto.
  • the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • the pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in the compound of Formula 1, unless otherwise indicated.
  • pharmaceutically acceptable salts may include sodium, calcium and potassium salts of a hydroxyl group
  • other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts; It can be prepared through a method for preparing a known salt.
  • the present invention provides the use of a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the compound represented by Formula 1 of the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof exhibits inhibitory activity against various kinases (Experimental Example 1).
  • the isoxazolidine derivative compound represented by Formula 1 since the isoxazolidine derivative compound represented by Formula 1 exhibits excellent inhibitory activity against CDK2, CDK4, CDK6 and/or HPK1 among various kinases, CDK2, CDK4, CDK6 and/or Alternatively, it may be usefully used for treatment or prevention of HPK1-related diseases, particularly cancer.
  • the cancer includes all cancers capable of exhibiting therapeutic or prophylactic efficacy due to inhibition of CDK2, CDK4, CDK6 and/or HPK1 activity, and may be solid cancer or blood cancer.
  • pseudomyxoma intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell cancer, ovarian cancer Epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter
  • the present invention provides a CDK2, CDK4, CDK6 and/or HPK1-related disease containing the compound represented by Formula 1, an optical isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition for treatment or prevention is provided.
  • the CDK2, CDK4, CDK6 and/or HPK1-related disease may be cancer.
  • the types of cancer are as described above.
  • the pharmaceutical composition of the present invention may further include one or more pharmaceutically acceptable carriers in addition to the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for administration.
  • the pharmaceutically acceptable carrier may be used in a mixture of saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components. , and other conventional additives such as a bacteriostatic agent may be added.
  • compositions of the present invention may be a patch, solution, pill, capsule, granule, tablet, suppository, and the like.
  • formulations may be prepared by a conventional method used for formulation in the art or a method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA, and may be formulated into various formulations according to each disease or component. can
  • the pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar efficacy in addition to the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the step of administering to a subject in need thereof a therapeutically effective amount of the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof Provided is a method for treating or preventing a CDK2, CDK4, CDK6 and/or HPK1 related disease, comprising:
  • the subject may be a mammal including a human.
  • the term "therapeutically effective amount” refers to an amount of the compound represented by Formula 1 effective for the treatment or prevention of CDK2, CDK4, CDK6 and/or HPK1-related diseases.
  • “therapeutically effective amount” means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and effective dose level includes the subject type and severity, age, sex, type of disease, The activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of excretion, the duration of treatment, factors including concurrently used drugs, and other factors well known in the medical field may be determined according to factors.
  • the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents. and may be administered single or multiple. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, and can be easily determined by those skilled in the art.
  • the dosage of the pharmaceutical composition of the present invention may be determined by an expert according to various factors such as the patient's condition, age, sex, and complications. Since the active ingredient of the pharmaceutical composition of the present invention is excellent in safety, it can be used even more than the determined dosage.
  • the present invention provides a compound represented by Formula 1 for use in the manufacture of a medicament for use in the treatment or prevention of CDK2, CDK4, CDK6 and/or HPK1-related diseases , an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the compound represented by Formula 1 for the manufacture of a drug may be mixed with an acceptable adjuvant, diluent, carrier, etc., and may have a synergistic action of the active ingredients by being prepared as a complex formulation together with other active agents.
  • Embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below.
  • the embodiment of the present invention is provided in order to more completely explain the present invention to those of ordinary skill in the art.
  • "including" a certain element means that other elements may be further included, rather than excluding other elements, unless otherwise stated.
  • the isoxazolidine derivative compound of the present invention exhibits excellent inhibitory activity against CDK2, CDK4, CDK6 and/or HPK1, it can be usefully used for the treatment or prevention of CDK2, CDK4, CDK6 and/or HPK1-related diseases. .
  • the compound synthesized in the Examples of the present invention is purified by the following HPLC conditions or subjected to structural analysis:
  • Mobile phase A used water containing 0.1% formic acid
  • mobile phase B used acetonitrile containing 0.1% formic acid.
  • the Autopurification HPLC system manufactured by Waters (2767 sample manger, 2545 binary gradient module, 2998 Photodiode Array Detector) was equipped with a mass QDA Detector manufactured by Waters was used.
  • the column used was Waters' SunFire ® Prep C18 OBD TM (5 ⁇ m, 19 X 50 mm), and the column temperature was performed at room temperature.
  • Waters' Prep 150 LC system (2545 Quaternary gradient module, 2998 Photodiode Array Detector, Fraction collector III) was used with Waters' equipment.
  • the column used was Waters' XTERRA ® Prep RP18 OBD TM (10 ⁇ m, 30 X 300 mm) and the column temperature was carried out at room temperature.
  • room temperature refers to a temperature of about 1 ⁇ 35 °C.
  • a rotary evaporator was used for concentration under reduced pressure or solvent distillation.
  • Step 1 tert -Butyl ( R Preparation of )-(3-hydroxy-3-phenylpropoxy)carbamate
  • Step 3 ( S ) Preparation of -3-phenylisoxazolidine
  • tert -Butyl ( S )-3-phenylisoxazolidine-2-carboxylate (2.3 g) prepared in step 2 was dissolved in methylene chloride (90 mL), TFA (14 mL) was added, and 1 hour at room temperature reacted while The reaction mixture was neutralized with aqueous sodium bicarbonate solution, and then the organic layers were combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (THF/n - hexane) to obtain the target compound (1.3 g, 94 %).
  • TFA 14 mL-3-phenylisoxazolidine-2-carboxylate
  • Preparation Example 2 was prepared in a manner similar to Preparation Example 1, and was used in the preparation of Examples below.
  • the solvent was removed by concentration under reduced pressure, and the organic layer was extracted using methylene chloride (500 mL), HCl (500 mL, 2 N), and brine (200 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound (110 g, 94 %) as a yellow oil.
  • the organic layer was dried over sodium sulfate, and then concentrated under reduced pressure.
  • Step 4 ( R Preparation of -3-chloro-1- (3-fluorophenyl) propan-1-ol
  • Step 5 tert -Butyl ( R Preparation of )-(3-(3-fluorophenyl)-3-hydroxypropoxy)carbamate
  • tert -Butyl hydroxycarbamate (40.76 g, 306.16 mmol) was dissolved in dimethylformamide (400 mL), and then sodium hydride (12.83 g, 320.74 mmol, 60 % purity) was added at 0° C. under a nitrogen stream. The reaction mixture was stirred at 10 °C for 1 hour, and ( R )-3-chloro-1-(3-fluorophenyl)propan-1-ol (55) prepared in step 4 was added to dimethylformamide (150 mL). g, 291.58 mmol) was added dropwise at 0 °C and stirred at 10 °C for 16 hours.
  • Step 6 tert -Butyl ( S Preparation of )-3-(3-fluorophenyl)isoxazolidine-2-carboxylate
  • the target compound was purified through SFC (column: DAICEL CHIRALPAK AD-H (250 mm X 30 mm, 5 ⁇ m); mobile phase: [Neu-methanol]; B %: 15 %, 2.9 min; 760 min) to light yellow Solid tert -butyl ( S )-3-(3-fluorophenyl)isoxazolidine-2-carboxylate (25 g, 36 %, 98.37 % purity, 100 % ee) and tert -butyl ( R )- 3-(3-fluorophenyl)isoxazolidine-2-carboxylate (6.5 g, 8.7 %, 91.13 % purity, 100 % ee) was obtained.
  • Step 7 ( S Preparation of )-3-(3-fluorophenyl)isoxazolidine
  • Preparation Examples 4 to 25 were prepared in a manner similar to Preparation Examples 1 to 3, and the compound names, chemical structural formulas, and NMR analysis results of Preparation Examples 4 to 25 were shown below and were used in the preparation of Examples below.
  • Step 1 ( S Preparation of )-2-(2-chloropyrimidin-4-yl)-3-phenylisoxazolidine
  • Step 2 ( S )- N Preparation of -(4-(4-methylpiperidin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine
  • Step 1 ( S )-2-(2-chloropyrimidin-4-yl)-3-phenylisoxazolidin (100 mg, 0.38 mmol), 4-(4-methylpiperazin-1-yl) )
  • Aniline 110 mg, 0.57 mmol
  • potassium carbonate 158 mg, 1.152 mmol
  • Pd 2 (dba) 3 35 mg, 0.140 mmol
  • XPhos 36 mg, 0.04 mmol
  • the obtained filtrate was washed with brine, and the organic layers were collected and dried over sodium sulfate. After concentration under reduced pressure, it was purified by medium pressure liquid chromatography (methanol/methylene chloride 0 to 10%) to obtain the target compound (0.1 g, 63%).
  • Examples 2-44 were prepared in a manner similar to Example 1, and the compound names, chemical structural formulas, NMR and LC-MS analysis results of Examples 1-44 are summarized and shown in Table 1 below.
  • Step 1 ( S Preparation of )-2-(2-chloro-5-iodopyrimidin-4-yl)-3-phenylisoxazolidine
  • Step 2 ( S Preparation of )-2-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-3-phenylisoxazolidine
  • the obtained filtrate was washed with brine, and the organic layers were collected and dried over sodium sulfate. After concentration under reduced pressure, the mixture was purified by medium pressure liquid chromatography (ethyl acetate/n-hexane 0 to 60%) to obtain the target compound (1.15 g, 45%).
  • Step 3 ( S )- N Preparation of -(4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine
  • Examples 46 to 234 were prepared in a manner similar to that of Example 45, and the compound names, chemical structural formulas, NMR and LC-MS analysis results of Examples 45 to 234 are summarized and shown in Table 2 below.
  • Step 1 ( S )-2-(2-Chloro-5-(3,6-dihydro-2) H -Pyran-4-yl) pyrimidin-4-yl) -3-phenylisoxazolidine preparation
  • Step 2 ( S )-5-(3,6-dihydro-2 H -pyran-4-yl)- N Preparation of -(4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine
  • Examples 236 to 240 were prepared in a manner similar to that of Example 235, and the compound names, chemical structural formulas, NMR and LC-MS analysis results of Examples 235 to 240 are summarized in Table 3 below.
  • the positive control refers to a compound showing a percentage control of 0%
  • the negative control indicates a percentage control of 100% with DMSO.
  • the enzyme selectivity of the present invention was determined to have activity for the enzyme when the control percentage for the enzyme is ⁇ 20% (ie, less than 20%).
  • kinase Example 45 kinase Example 45 kinase Example 45 ARK5 8.8 FLT3 (D835V) 0 PIK3CA(C420R) 0 AURKA 6.9 FLT3 (D835Y) 1.1 PIK3CA (E545A) 0 AURKC 13 FLT3 (ITD) 0.65 RET(V804L) 10 AXL 7.3 FLT3 (ITD,D835V) 0.65 RET(V804M) 12 BIKE 16 FLT3 (ITD, F691L) 0.5 RIOK3 12 CDK4 0.95 FLT3(K663Q) 1.8 SLK 1.7 CDK4-cyclinD1 0.2 FLT3 (N841I) 0 SNARK 2.3 CDK4-cyclinD3 2 FLT3 (R834Q) 12 TAK1 8.1 CDK7 3.1 HIPK4 6.9 TAOK3 12 CDKL2 1.6 HPK1 14 TIE1 8.4 CLK
  • the example compounds according to the present invention are ALK, ALK (C1156Y), ALK (L1196M), AMPK-alpha1, AMPK-alpha2, ARK5, AURKA, AURKB, AURKC, AXL, BIKE , CDK4, CDK4-cyclinD1, CDK4-cyclinD3, CDK7, CDKL2, CLK1, CSNK2A2, DCAMKL1, DCAMKL3, DMPK, DRAK2, DYRK2, ERK5, ERK8, FAK, FER, FES, FGFR1, FGFR3 (G697C), FGFR3 (G697C) FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I),
  • Example compounds were reacted with purified human GST-CDK4/CyclinD3 (full-length human CDK4 and CyclinD3 were co-expressed protein, Signalchem) enzymes, and the enzyme inhibitory ability was evaluated as follows.
  • the reaction buffer was 40 mM Tris-HCl pH 7.4, 20 mM MgCl 2 , 0.5 mg/mL BSA, and 50 ⁇ M DTT composition. All test materials were reacted in the reaction buffer.
  • human GST-CDK4/CyclinD3 (10 ng) enzyme, purified ATP (200 ⁇ M), and a specific substrate solution were reacted at 30 ° C for 4 hours, followed by in vitro ADP-Glo TM kinase assay (promega).
  • the enzyme activity was confirmed.
  • the fluorescence was measured by reacting the enzyme activity reaction solution with the ADP-Glo reaction solution and the enzyme activity detection solution in a 2:2:1 ratio.
  • the degree of inhibition of enzyme activity according to the treatment concentration of each compound was calculated based on the fluorescence of the enzyme activity of the solvent control that was not treated with the compound. It was decided.
  • IC 50 of each compound was obtained using GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego) software. The results are shown in Table 6 below.
  • Example CDK4/D3 IC 50 (nM) Example CDK4/D3 IC 50 (nM)
  • Example CDK4/D3 IC 50 (nM) Example CDK4/D3 IC 50 (nM)
  • CDK2 Cyclin-Dependent Protein Kinase, CDK2
  • the following experiment was performed.
  • Example compounds were reacted with purified human GST-CDK2/CyclinE1 (full-length human CDK2 and CyclinE1 were co-expressed protein, SignalChem) enzymes, and the enzyme inhibitory ability was evaluated as follows.
  • the reaction buffer was 40 mM Tris-HCl pH 7.4, 20 mM MgCl 2 , 0.5 mg/mL BSA, and 50 ⁇ M DTT composition. All test materials were reacted in the reaction buffer.
  • Example CDK2/E1 IC 50 (nM) Example CDK2/E1 IC 50 (nM)
  • Example CDK2/E1 IC 50 (nM) 21 5350 81 722 129 944 168 1558 32 64 82 1376 131 656 170 64 33 69 83 1552 132 82 171 538 34 64 84 2362 133 79 175 990 44 755 85 1767 137 519 186 2295 45 591 86 444 138 2078 193 14 54 4959 88 6259 143 76 194 4579 55 2651 89 805 145 379 195 6615 56 3420 90 631 147 1691 196 255 57 3073 94 841 148 1393 198 413 58 6564 96 683 149 1585 199 107 59 411 97 3127 150 241 201 265 60 7009 98 668 151 102 202 708 63 4326 99 15
  • the example compound was reacted with purified human HPK1 (1-346, SignalChem) enzyme, and the enzyme inhibitory ability was evaluated as follows.
  • the reaction buffer was 40 mM Tris-HCl pH 7.4, 20 mM MgCl 2 , 0.5 mg/ml BSA, and 50 ⁇ M DTT composition, and all test materials were reacted in the reaction buffer.
  • Compounds were diluted in 12 steps from a 10 mM DMSO stock by serial dilution, and enzyme activity was measured at concentrations of 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003, 0.0001, 0.00003 ⁇ M of the final compound. .
  • the enzyme was reacted with human HPK1 (3 ng) enzyme, purified ATP (3 ⁇ M), and enzyme substrate (0.1 ⁇ g) at 25 °C for 2 hours, and then the enzyme was used in vitro ADP-Glo TM kinase assay (promega). Activity was confirmed.
  • the degree of inhibition of enzyme activity was measured by fluorescence. The degree of inhibition of enzyme activity according to the treatment concentration of each compound was calculated based on the fluorescence of the enzyme activity of the solvent control that was not treated with the compound. It was determined and obtained using GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego). The results are summarized in Table 8 below.
  • Example IC 50 (nM) Example IC 50 (nM)
  • Example IC 50 (nM) Example IC 50 (nM)
  • Example IC 50 (nM) 45 48 89 46 126 598 181 41 58 6227 90 33 127 28 182 63 59 407 91 107 128 15 183 735 64 100 92 46 129 609 184 913 66 23 93 5 132 3.9 185 704 68 7678 94 277 133 0.93 186 491 69 967 96 14 134 34 192 378 70 1606 97 140 135 44 210 143 73 254 98 36 136 13 211 10 74 569 99 59 138 22 212 29 79 39 101 309 139 5598 213 95 81 53 102 761 150 2165 214 16 82 12 103 143 151 42 215 39 83 13 106 1779 152 189 216 72 84 79 107 1199 157 7896 217 6802 85
  • MCF-7 breast cancer cells were planted in a clear bottom white 96-well plate (Corning) to 3 ⁇ 10 3 / 150 ⁇ l/well. Then, 0.5 ⁇ l/well of a culture solution containing 12 concentrations (0.00001 - 2 mM) of a compound or DMSO control serially diluted in 3 folds was added at a time to a final concentration of 0.00005 - 10 ⁇ M, followed by a 37 ° C CO 2 incubator incubated for 120 hours. After 120 hours, the plate treated with the compound was taken out, 150 ⁇ l/well of CellTiter-Glo® 2.0 Assay (Promega) solution was treated, and then mixed well.
  • a culture solution containing 12 concentrations (0.00001 - 2 mM) of a compound or DMSO control serially diluted in 3 folds was added at a time to a final concentration of 0.00005 - 10 ⁇ M, followed by a 37 ° C CO 2 incubator incubated for 120 hours. After 120 hours
  • Example GI 50 (nM) Example GI 50 (nM) Example GI 50 (nM) Example GI 50 (nM) Example GI 50 (nM) 2 5188 93 413 129 1056 183 1094 8 3362 94 1124 131 378 184 1270 15 5717 96 404 132 387 185 1161 34 151 98 1563 133 372 186 738 41 5639 99 1424 134 2640 187 2030 44 823 101 1480 135 2352 188 1174 45 362 102 1175 136 1316 191 1212 58 3418 103 1104 137 2006 192 4228 59 808 106 3122 138 2857 193 520 64 1145 107 1110 139 1612 194 1847 65 1971 108 1140 140 392 196 88 66 818 109 712 142 3181 201 405 68 8548 110 1544 150 2913 202 176 69 1612 111 5186 151 252 203 1152 70 1795 112 33
  • OVCAR-3 ovarian cancer cells were planted in a clear bottom white 96-well plate (Corning) at a volume of 5 ⁇ 10 3 /200 ⁇ l/well. Then, 0.5 ⁇ l/well of a culture solution containing 11 concentrations (0.00003 - 2 mM) of the compound or DMSO control, serially diluted in 3 folds, was added at a time to a final concentration of 0.0002 - 10 ⁇ M, followed by treatment at 37 ° C, CO 2 Incubated for 120 hours in an incubator.

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Abstract

The present invention relates to an isoxazolidine derivative compound and the use thereof. The isoxazolidine derivative compound of the present invention exhibits excellent inhibitory activity against CDK2, CDK4, CDK6 and/or HPK1, and thus can be utilized in treating or preventing diseases related to CDK2, CDK4, CDK6 and/or HPK1.

Description

아이소옥사졸리딘 유도체 화합물 및 이의 용도Isoxazolidine derivative compounds and uses thereof
본 발명은 아이소옥사졸리딘 유도체 화합물 및 이의 의약적 용도에 관한 것이다. 구체적으로, 본 발명은 CDK2, CDK4, CDK6 및/또는 HPK1 억제 활성을 갖는 아이소옥사졸리딘 유도체 화합물에 관한 것이다.The present invention relates to isoxazolidine derivative compounds and medicinal uses thereof. Specifically, the present invention relates to isoxazolidine derivative compounds having CDK2, CDK4, CDK6 and/or HPK1 inhibitory activity.
단백질 키나아제는 ATP의 감마-인산기를 단백질의 타이로신, 세린 또는 트레오닌의 하이드록시 그룹에 전달하는 인산화 반응을 촉매하는 효소로서, 세포의 대사, 유전자 발현, 세포 성장, 분화, 세포 분열 작용을 담당하며 세포 신호 전달 등에서 중요한 역할을 한다(Thomas A. Hamilton, in Encyclopedia of Immunology(Second Edition), 1998, 2028-2033). Protein kinase is an enzyme that catalyzes the phosphorylation reaction that transfers the gamma-phosphate group of ATP to the hydroxyl group of tyrosine, serine, or threonine of a protein. It is responsible for cell metabolism, gene expression, cell growth, differentiation, and cell division. It plays an important role in signal transduction, etc. (Thomas A. Hamilton, in Encyclopedia of Immunology (Second Edition), 1998, 2028-2033).
단백질 키나아제는 분자 스위치로 작용하여 신호전달경로에 관여하는데, 세포 내에서 키나아제에 의한 표적 단백질의 활성과 비활성 상태 사이의 전환은 원활하게 조절되어야 한다. 만약, 상기 활성과 비활성 상태 사이의 전환이 비정상적으로 조절되면 세포 내 신호 전달을 과도하게 활성화하거나 비활성화시켜 통제불능의 세포 분열 및 증식을 유도하게 된다. 특히, 단백질 키나아제 유전자의 변이, 증폭 및/또는 과발현에 의한 비정상적인 활성화는 다양한 종양의 발생 및 진행을 유발하거나 염증성 질환, 퇴행성 뇌질환, 자가면역 질환 등 다양한 질병의 발병에 결정적인 역할을 하게 된다. 이와 관련된 키나아제의 예를 들면 ABL1, ABL2, BRAF, CDK2, CDK4, CDK6, CDK8, CDK11, CDKL2, CIT, CSF1R, DDR1, DDR2, FLT3, HPK1, KIT, LOK, LTK, MUSK, PAK3, PDGFRA, PDGFRB, RAF1, RIPK1 등이 있다. Protein kinases are involved in signaling pathways by acting as molecular switches, and the switching between the active and inactive states of the target protein by the kinase in the cell must be smoothly regulated. If the transition between the active and the inactive state is abnormally regulated, the intracellular signal transduction is excessively activated or inactivated to induce uncontrolled cell division and proliferation. In particular, abnormal activation by mutation, amplification and/or overexpression of protein kinase genes causes the development and progression of various tumors or plays a decisive role in the onset of various diseases such as inflammatory diseases, degenerative brain diseases, and autoimmune diseases. Examples of kinases related thereto include ABL1, ABL2, BRAF, CDK2, CDK4, CDK6, CDK8, CDK11, CDKL2, CIT, CSF1R, DDR1, DDR2, FLT3, HPK1, KIT, LOK, LTK, MUSK, PAK3, PDGFRA, PDGFRB , RAF1, RIPK1, and the like.
특히, 사이클린-의존성 키나아제(Cyclin-Dependent Kinase, CDK)는 세포 분열 및 증식을 조절하는 필수적인 기능을 수행하는 효소이다. CDK는 조절 서브유닛인 사이클린에 의해 활성화되며, 사이클린 B/CDK1, 사이클린 A/CDK2, 사이클린 E/CDK2, 사이클린 D/CDK4, 사이클린 D/CDK6 등의 헤테로다인은 세포 주기 진행의 중요한 조절자이고, 추가적으로 전사, DNA 수선, 분화 및 세포자멸 조절 기능을 갖는 것으로 알려져 있다(Morgan DO. et al, Annu. Rev. Cell. Dev. Biol. 1997, 13, 261-291).In particular, cyclin-dependent kinase (Cyclin-Dependent Kinase, CDK) is an enzyme that performs essential functions regulating cell division and proliferation. CDK is activated by the regulatory subunit cyclin, and heterodynes such as cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6 are important regulators of cell cycle progression, It is additionally known to have transcriptional, DNA repair, differentiation and apoptosis regulatory functions (Morgan DO. et al, Annu. Rev. Cell. Dev. Biol. 1997, 13, 261-291).
CDK4/6 억제제인 팔보시클립, 리보시클립 및 아베마시클립은 단일 약품 또는 다른 치료제와 병용으로 암에 대한 임상 시험이 진행되고 있다. 팔보시클립 및 리보시클립은 폐경 후 여성에서 아로마타제 억제제와 병용으로 호르몬 수용체 (HR)-양성, 인간 표피 성장인자 수용체 2(HER2)-음성 진행성 또는 전이성 유방암의 치료에 대해 승인되었다(O'Leary et al., Nature Reviews, 2016, 13, 417-430). 또한 CDK4/6 억제제는 ER-양성 전이성 유방암에서 유의한 임상 효능을 나타내었다.The CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib are being tested for cancer as a single drug or in combination with other therapeutic agents. Palbociclib and ribociclib are approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with aromatase inhibitors in postmenopausal women (O') Leary et al., Nature Reviews, 2016, 13, 417-430). In addition, CDK4/6 inhibitors showed significant clinical efficacy in ER-positive metastatic breast cancer.
CDK2의 과발현은 세포 주기의 비정상적인 조절과 연관되며, 사이클린 E/CDK2 복합체는 G1/S 전환, 히스톤 생합성 및 중심체 복제의 조절에서 중요한 역할을 한다. 사이클린 D/CDK4/6 및 사이클린 E/CDK2에 의한 Rb의 진행성 인산화는 G1 전사인자인 E2F를 방출하고 S기로의 진입을 촉진한다. 초기 S기 중 사이클린 A/CDK2의 활성화는 S기 완료를 위해 E2F의 DNA 복제 및 불활성화를 가능하게 하는 내인성 기질의 인산화를 촉진한다(Asghar et al., Nat. Rev. Drug. Discov., 2015, 14(2), 130-146). Overexpression of CDK2 is associated with aberrant regulation of the cell cycle, and the cyclin E/CDK2 complex plays an important role in the regulation of G1/S conversion, histone biosynthesis and centrosome replication. Progressive phosphorylation of Rb by cyclin D/CDK4/6 and cyclin E/CDK2 releases the G1 transcription factor E2F and promotes entry into S phase. Activation of cyclin A/CDK2 during early S phase promotes phosphorylation of endogenous substrates that enable DNA replication and inactivation of E2F for S phase completion (Asghar et al., Nat. Rev. Drug. Discov., 2015 , 14(2), 130-146).
한편, 조혈 전구 키나아제(Hematopoietic Progenitor Kinase 1, HPK1)는 조혈 세포에 제한된 세린/트레오닌 키나아제로서, HPK1 활성은 리간드 결합시 조혈 세포에서 발견되는 다양한 세포 표면 수용체에 의해 생성된 활성화 신호에 의해 유도될 수 있다(Liou et al., Immunity, 2000, 12, 399; Wang et al., J. Biol. Chem., 1997, 272, 22771; Zhou et al., J. Biol. Chem., 1999, 274, 13133; Nagata et al., Blood, 1999, 93, 3347; Chen et al., Oncogene, 1999, 18, 7370). HPK1은 암 면역치료를 위한 신규 표적이 될 수 있다고 보고되고 있다. 구체적으로, HPK1-/- T 세포는 TCR 결합에 반응하여 Th1 사이토카인 생성이 증가되고, 빠르게 증식하며, PGE2-매개 억제에 저항성을 가지고, HPK1-/- T 세포를 이식받은 마우스는 폐 종양 성장에 저항성을 갖는다. 수지상 세포에서 HPK1을 제거한 경우 항원 제시 능력이 현저히 증가되어, 암 백신으로 사용할 경우 더욱 우수한 항종양 면역 반응을 보일 수 있다(Sawasdikosol et al., Immunol Res., 2012, 54(1-3), 262-265). 또한, 전장 HPK1은 IKK베타(IKappaB kinase beta) 인산화를 증가시키는 반면, HPK1 발현을 억제시킬 경우 TCR-매개 NF-카파B 활성을 둔화시키고 세포 사멸을 증가시킨다(Brenner et al., EMBO J. 2005, 24, 4279).On the other hand, hematopoietic progenitor kinase (Hematopoietic Progenitor Kinase 1, HPK1) is a serine/threonine kinase restricted to hematopoietic cells, and HPK1 activity can be induced by activation signals generated by various cell surface receptors found in hematopoietic cells upon ligand binding. (Liou et al., Immunity, 2000, 12, 399; Wang et al., J. Biol. Chem., 1997, 272, 22771; Zhou et al., J. Biol. Chem., 1999, 274, 13133 ; Nagata et al., Blood, 1999, 93, 3347; Chen et al., Oncogene, 1999, 18, 7370). It has been reported that HPK1 can be a novel target for cancer immunotherapy. Specifically, HPK1 -/- T cells have increased Th1 cytokine production in response to TCR binding, proliferate rapidly, and are resistant to PGE2-mediated inhibition, and mice transplanted with HPK1 -/- T cells can grow lung tumors have resistance to When HPK1 is removed from dendritic cells, antigen-presenting ability is significantly increased, and when used as a cancer vaccine, a better anti-tumor immune response may be exhibited (Sawasdikosol et al., Immunol Res., 2012, 54(1-3), 262). -265). In addition, while full-length HPK1 increases IKKbeta (IKappaB kinase beta) phosphorylation, inhibition of HPK1 expression slows TCR-mediated NF-kappaB activity and increases apoptosis (Brenner et al., EMBO J. 2005) , 24, 4279).
상술한 바와 같이, CDK2, CDK4, CDK6 및/또는 HPK1에 대해 억제 활성을 가지는 화합물은 항암제로서 우수한 효과를 기대할 수 있는바, 이들을 억제하는 신규 화합물에 대한 개발이 지속적으로 요구되고 있다.As described above, compounds having inhibitory activity against CDK2, CDK4, CDK6 and/or HPK1 can be expected to have excellent effects as anticancer agents, and development of novel compounds for inhibiting them is continuously required.
본 발명의 목적은 신규한 구조의 아이소옥사졸리딘 유도체, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.An object of the present invention is to provide an isoxazolidine derivative having a novel structure, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
본 발명의 다른 목적은 상기 아이소옥사졸리딘 유도체 화합물의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing the isoxazolidine derivative compound.
본 발명의 다른 목적은 상기 아이소옥사졸리딘 유도체 화합물의 의약용도를 제공하는 것으로서, 구체적으로 상기 아이소옥사졸리딘 유도체 화합물을 유효성분으로 포함하는 CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환의 치료 또는 예방용 약학적 조성물, 상기 화합물을 이용한 CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환의 치료 또는 예방 용도 또는 상기 화합물을 투여하는 단계를 포함하는 CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환의 치료 또는 예방방법을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical use of the isoxazolidine derivative compound, specifically for the treatment or treatment of CDK2, CDK4, CDK6 and/or HPK1-related diseases comprising the isoxazolidine derivative compound as an active ingredient. A pharmaceutical composition for prophylaxis, the use of the compound for the treatment or prophylaxis of a CDK2, CDK4, CDK6 and/or HPK1-related disease, or the treatment or prevention of a CDK2, CDK4, CDK6 and/or HPK1-related disease comprising administering the compound to provide preventive measures.
상기 목적을 달성하기 위하여, 본 발명자들이 연구 노력한 결과, 아래에서 언급하는 화학식 1로 표시되는 아이소옥사졸리딘 유도체 화합물들이 CDK2, CDK4, CDK6 및/또는 HPK1이 활성화된 세포의 증식을 저해하는 것을 확인함으로써 본 발명을 완성하였다.In order to achieve the above object, as a result of research efforts of the present inventors, it was confirmed that the isoxazolidine derivative compounds represented by Formula 1 mentioned below inhibit the proliferation of cells in which CDK2, CDK4, CDK6 and/or HPK1 are activated. Thus, the present invention was completed.
아이소옥사졸리딘 유도체 화합물Isooxazolidine Derivative Compounds
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염을 제공한다:The present invention provides a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2021018956-appb-img-000001
Figure PCTKR2021018956-appb-img-000001
상기 화학식 1에서,In Formula 1,
고리 A1은 아릴 또는 헤테로아릴이고 {여기서, 상기 아릴 또는 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -C1-6알킬-O-C1-6알킬, -CN, -(C=O)NR3R4, -(C=O)OR5, -NR6R7, -OR8, -할로, 아릴 또는 헤테로아릴로 치환될 수 있음}; Ring A 1 is aryl or heteroaryl {wherein at least one H of said aryl or heteroaryl ring is -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1 -6 Haloalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -CN, -(C=O)NR 3 R 4 , -(C=O)OR 5 , -NR 6 R 7 , -OR 8 , which may be substituted with halo, aryl or heteroaryl};
고리 A2는 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬이고 Ring A 2 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
{여기서, 상기 아릴 또는 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬, -C1-6하이드록시알킬, -C1-6아미노알킬, -C1-6할로알킬, -C1-6알킬-CN, -CN, -C1-6알킬-O-C1-6알킬, -C1-6알킬NR9R10, -(C=O)NR9R10, -C1-6알킬-(C=O)NR9R10, -(C=O)-C1-6알킬, -(C=O)OR11, -C1-6알킬-(C=O)OR11, -NR12R13, -OR14, -할로, -S-C1-6알킬, -SO2-C1-6알킬, -SO2-NR12R13, -SO2-할로, -(S=O)NH-C1-6알킬, -S(=O)(=NH)-C1-6알킬, 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C1-6알킬-사이클로알킬, -C1-6알킬-헤테로사이클로알킬, -(C=O)-사이클로알킬, -(C=O)-헤테로사이클로알킬, -NH(C=O)-사이클로알킬, -NH(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴로 치환될 수 있고 [이때, 상기 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C1-6알킬-사이클로알킬, -C1-6알킬-헤테로사이클로알킬, -(C=O)-사이클로알킬, -(C=O)-헤테로사이클로알킬, -NH(C=O)-사이클로알킬, -NH(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬, -(=O)-, -(C=O)-C1-6알킬, -(C=O)NR15R16, -(C=O)OR17, -NR18R19, -할로, -SO2-, 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬로 치환될 수 있음 (상기 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6하이드록시알킬, -C1-6아미노알킬, -C1-6할로알킬, -NR20R21, 또는 사이클로알킬로 치환될 수 있음)], 또는 상기 아릴 또는 헤테로아릴의 2 이상의 치환기가 서로 연결되어 융합 고리를 형성할 수 있고 [여기서, 상기 융합 고리의 하나 이상의 H는 -C1-6알킬, -(=O)-, -(C=O)-C1-6알킬, -(C=O)O-C1-6알킬, -NR22R23, -O-C1-6알킬, 할로, -SO2-C1-6알킬, 사이클로알킬, 또는 헤테로사이클로알킬로 치환될 수 있음]; {Wherein, at least one H of the aryl or heteroaryl ring is -C 1-6 alkyl, -C 1-6 hydroxyalkyl, -C 1-6 aminoalkyl, -C 1-6 haloalkyl, -C 1 6 alkyl-CN, -CN, -C 1-6 alkyl-OC 1-6 alkyl, -C 1-6 alkylNR 9 R 10 , -(C=O)NR 9 R 10 , -C 1-6 alkyl- (C=O)NR 9 R 10 , -(C=O)-C 1-6 alkyl, -(C=O)OR 11 , -C 1-6 alkyl-(C=O)OR 11 , -NR 12 R 13 , -OR 14 , -halo, -SC 1-6 alkyl, -SO 2 -C 1-6 alkyl, -SO 2 -NR 12 R 13 , -SO 2 -halo, -(S=O)NH- C 1-6 alkyl, -S(=O)(=NH)-C 1-6 alkyl, cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C 1-6 alkyl-cycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, -(C=O)-cycloalkyl, -(C=O)-heterocycloalkyl, -NH(C=O)-cycloalkyl, -NH(C=O)-heterocycloalkyl, may be substituted with aryl, -(C=O)-aryl, or heteroaryl [wherein said cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C 1-6 alkyl-cycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, -(C=O)-cycloalkyl, -(C=O)-heterocycloalkyl, -NH(C=O)-cycloalkyl, -NH(C=O)-heterocycloalkyl, At least one H of an aryl, -(C=O)-aryl, or heteroaryl ring is -C 1-6 alkyl, -(=O)-, -(C=O)-C 1-6 alkyl, -(C =O)NR 15 R 16 , -(C=O)OR 17 , -NR 18 R 19 , -halo, -SO 2 -, cycloalkyl, heterocycloalkyl, or heterobicycloalkyl (supra At least one H of a cycloalkyl, heterocycloalkyl, or heterobicycloalkyl ring is -C 1-6 alkyl, -C 1-6 hydroxyalkyl, -C 1-6 aminoalkyl, -C 1-6 haloalkyl, -NR 20 R 21 , or may be substituted with cycloalkyl)], or two or more substituents of the aryl or heteroaryl may be linked to each other to form a fused ring, wherein at least one H of the fused ring is —C 1-6 alkyl; -(=O)-, -(C=O)-C 1-6 alkyl, -(C=O)OC 1-6 alkyl, -NR 22 R 23 , -OC 1-6 alkyl, halo, -SO 2 -C 1-6 alkyl, cycloalkyl, or heterocycloalkyl];
상기 사이클로알킬 또는 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6하이드록시알킬, -(C=O)-C1-6알킬, -(C=O)O-C1-6알킬, 또는 -SO2-C1-6알킬로 치환될 수 있음}; at least one H of said cycloalkyl or heterocycloalkyl ring is -C 1-6 alkyl, -C 1-6 hydroxyalkyl, -(C=O)-C 1-6 alkyl, -(C=O)OC 1 -6 alkyl, or —SO 2 —C 1-6 alkyl};
R1은 -H 또는 -C1-6알킬이고;R 1 is —H or —C 1-6 alkyl;
R2는 -H, -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -할로, 또는 5-7원 고리이고 {여기서, 상기 5-7원 고리의 하나 이상의 H는 -C1-6알킬, -C1-6할로알킬, 또는 할로로 치환될 수 있음};R 2 is -H, -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -halo, or 5-7 membered ring and {wherein, one or more H of the 5-7 membered ring may be substituted with -C 1-6 alkyl, -C 1-6 haloalkyl, or halo};
R3 내지 R7은 각각 독립적으로 -H 또는 -C1-6알킬이고;R 3 to R 7 are each independently —H or —C 1-6 alkyl;
R8은 -H, -C1-6알킬, 페닐 또는 벤질이고;R 8 is —H, —C 1-6 alkyl, phenyl or benzyl;
R9 및 R10은 각각 독립적으로 -H, -C1-6알킬, -C1-6히드록시알킬, -C1-6알킬-NR24R25, 또는 헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};R 9 and R 10 are each independently —H, —C 1-6 alkyl, —C 1-6 hydroxyalkyl, —C 1-6 alkyl-NR 24 R 25 , or heterocycloalkyl {wherein the hetero one or more H of the cycloalkyl ring may be substituted with —C 1-6 alkyl};
R11은 -H 또는 -C1-6알킬이고;R 11 is —H or —C 1-6 alkyl;
R12 및 R13은 각각 독립적으로 -H, -C1-6알킬, -C1-6알킬-NR24R25, 또는 -(C=O)O-C1-6알킬이고;R 12 and R 13 are each independently —H, —C 1-6 alkyl, —C 1-6 alkyl-NR 24 R 25 , or —(C=O)OC 1-6 alkyl;
R14은 각각 독립적으로 -H, -C1-6알킬, -C1-6알킬-NR26R27, 헤테로사이클로알킬, 또는 -C1-6알킬-헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 또는 -C1-6알킬-헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};each R 14 is independently —H, —C 1-6 alkyl, —C 1-6 alkyl-NR 26 R 27 , heterocycloalkyl, or —C 1-6 alkyl-heterocycloalkyl {wherein the heterocyclo one or more H of an alkyl or —C 1-6 alkyl-heterocycloalkyl ring may be substituted with —C 1-6 alkyl;
R15 내지 R17은 각각 독립적으로 -H 또는 -C1-6알킬이고;R 15 to R 17 are each independently —H or —C 1-6 alkyl;
R18 및 R19은 각각 독립적으로 -C1-6알킬 또는 -C1-6알킬-NR28R29이고;R 18 and R 19 are each independently —C 1-6 alkyl or —C 1-6 alkyl-NR 28 R 29 ;
R20 내지 R29은 각각 독립적으로 -H 또는 -C1-6알킬이다.R 20 to R 29 are each independently —H or —C 1-6 alkyl.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 아래 범위일 수 있다:According to an embodiment of the present invention, the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
고리 A1은 아릴 또는 헤테로아릴이고 {여기서, 상기 아릴 또는 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬, -C1-6할로알킬, -CN, -NR6R7, -OR8, 또는 -할로로 치환될 수 있음}; Ring A 1 is aryl or heteroaryl {wherein at least one H of said aryl or heteroaryl ring is -C 1-6 alkyl, -C 1-6 haloalkyl, -CN, -NR 6 R 7 , -OR 8 , or - may be substituted with halo};
고리 A2는 아릴, 헤테로아릴, 또는 헤테로사이클로알킬이고Ring A 2 is aryl, heteroaryl, or heterocycloalkyl
{여기서, 상기 아릴 또는 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬, -C1-6할로알킬, -C1-6알킬-CN, -CN, -C1-6알킬-O-C1-6알킬, -C1-6알킬NR9R10, -(C=O)NR9R10, -C1-6알킬-(C=O)NR9R10, -(C=O)-C1-6알킬, -(C=O)OR11, -NR12R13, -OR14, -할로, -S-C1-6알킬, -SO2-C1-6알킬, -SO2-NR12R13, -SO2-할로, -S(=O)(=NH)-C1-6알킬, 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C1-6알킬-헤테로사이클로알킬, -(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴로 치환될 수 있고 [이때, 상기 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C1-6알킬-헤테로사이클로알킬, -(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬, -(=O)-, -(C=O)-C1-6알킬, -(C=O)NR15R16, -(C=O)OR17, -NR18R19, -할로, -SO2-, 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬로 치환될 수 있음 (상기 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6하이드록시알킬, 또는 -NR20R21로 치환될 수 있음)], 또는 상기 아릴 또는 헤테로아릴의 2 이상의 치환기가 서로 연결되어 융합 고리를 형성할 수 있고 [여기서, 상기 융합 고리의 하나 이상의 H는 -C1-6알킬, -(=O)-, -(C=O)-C1-6알킬, -(C=O)O-C1-6알킬, -NR22R23, -O-C1-6알킬, 할로, -SO2-C1-6알킬, 또는 사이클로알킬로 치환될 수 있음]; {wherein at least one H of the aryl or heteroaryl ring is -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-CN, -CN, -C 1-6 alkyl-OC 1 -6 alkyl, -C 1-6 alkylNR 9 R 10 , -(C=O)NR 9 R 10 , -C 1-6 alkyl-(C=O)NR 9 R 10 , -(C=O)- C 1-6 alkyl, -(C=O)OR 11 , -NR 12 R 13 , -OR 14 , -halo, -SC 1-6 alkyl, -SO 2 -C 1-6 alkyl, -SO 2 -NR 12 R 13 , —SO 2 -halo, —S(=O)(=NH)—C 1-6 alkyl, cycloalkyl, heterocycloalkyl, heterobicycloalkyl, —C 1-6 alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, aryl, -(C=O)-aryl, or heteroaryl [wherein said cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C 1 - At least one H of a 6 alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, aryl, -(C=O)-aryl, or heteroaryl ring is -C 1-6 alkyl, -(=O) -, -(C=O)-C 1-6 alkyl, -(C=O)NR 15 R 16 , -(C=O)OR 17 , -NR 18 R 19 , -halo, -SO 2 -, cyclo may be substituted with alkyl, heterocycloalkyl, or heterobicycloalkyl (one or more H of the cycloalkyl, heterocycloalkyl, or heterobicycloalkyl ring is -C 1-6 alkyl, -C 1-6 hydroxy alkyl, or -NR 20 R 21 )], or two or more substituents of the aryl or heteroaryl may be linked to each other to form a fused ring, wherein at least one H of the fused ring is -C 1-6 alkyl, -(=O)-, -(C=O)-C 1-6 alkyl, -(C=O)OC 1-6 alkyl, -NR 22 R 23 , -OC 1-6 alkyl, may be substituted with halo, —SO 2 —C 1-6 alkyl, or cycloalkyl];
상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6하이드록시알킬, -(C=O)-C1-6알킬, -(C=O)O-C1-6알킬, 또는 -SO2-C1-6알킬로 치환될 수 있음}; at least one H of the heterocycloalkyl ring is -C 1-6 alkyl, -C 1-6 hydroxyalkyl, -(C=O)-C 1-6 alkyl, -(C=O)OC 1-6 alkyl , or —SO 2 —C 1-6 alkyl};
R1은 -H이고;R 1 is —H;
R2는 -H, -C1-6알킬, -C1-6할로알킬, -CN, -할로, 또는 5-7원 고리이고 {여기서, 상기 5-7원 고리의 하나 이상의 H는 -C1-6알킬 또는 할로로 치환될 수 있음};R 2 is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -CN, -halo, or a 5-7 membered ring {wherein at least one H of the 5-7 membered ring is -C may be substituted with 1-6 alkyl or halo};
R6 및 R7은 각각 독립적으로 -C1-6알킬이고;R 6 and R 7 are each independently —C 1-6 alkyl;
R8은 -H, -C1-6알킬, 또는 페닐이고;R 8 is —H, —C 1-6 alkyl, or phenyl;
R9 및 R10은 각각 독립적으로 -H, -C1-6알킬, -C1-6하이드록시알킬, -C1-6알킬-NR24R25, 또는 헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};R 9 and R 10 are each independently —H, —C 1-6 alkyl, —C 1-6 hydroxyalkyl, —C 1-6 alkyl-NR 24 R 25 , or heterocycloalkyl {wherein the hetero one or more H of the cycloalkyl ring may be substituted with —C 1-6 alkyl};
R11은 -C1-6알킬이고;R 11 is —C 1-6 alkyl;
R12 및 R13은 각각 독립적으로 -H, -C1-6알킬, 또는 -(C=O)O-C1-6알킬이고;R 12 and R 13 are each independently —H, —C 1-6 alkyl, or —(C=O)OC 1-6 alkyl;
R14은 각각 독립적으로 -C1-6알킬, -C1-6알킬-NR26R27, 헤테로사이클로알킬, 또는 -C1-6알킬-헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 또는 -C1-6알킬-헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};each R 14 is independently —C 1-6 alkyl, —C 1-6 alkyl-NR 26 R 27 , heterocycloalkyl, or —C 1-6 alkyl-heterocycloalkyl {wherein said heterocycloalkyl or — one or more H of a C 1-6 alkyl-heterocycloalkyl ring may be substituted with —C 1-6 alkyl};
R15 내지 R17은 각각 독립적으로 -C1-6알킬이고;R 15 to R 17 are each independently —C 1-6 alkyl;
R18 및 R19은 각각 독립적으로 -C1-6알킬 또는 -C1-6알킬-NR28R29이고;R 18 and R 19 are each independently —C 1-6 alkyl or —C 1-6 alkyl-NR 28 R 29 ;
R20 내지 R23, R26 내지 R29은 각각 독립적으로 -H 또는 -C1-6알킬이다. R 20 to R 23 , R 26 to R 29 are each independently —H or —C 1-6 alkyl.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 아래 범위일 수 있다:According to an embodiment of the present invention, the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
고리 A1은 페닐 또는 피리디닐이고 {여기서, 상기 페닐 또는 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -C1-6알킬-O-C1-6알킬, -CN, -(C=O)NR3R4, -(C=O)OR5, -NR6R7, -OR8, -할로, 아릴 또는 헤테로아릴로 치환될 수 있음}; Ring A 1 is phenyl or pyridinyl {wherein at least one H of said phenyl or heteroaryl ring is -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1 -6 Haloalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -CN, -(C=O)NR 3 R 4 , -(C=O)OR 5 , -NR 6 R 7 , -OR 8 , which may be substituted with halo, aryl or heteroaryl};
R3 내지 R7은 각각 독립적으로 -H 또는 -C1-6알킬이고;R 3 to R 7 are each independently —H or —C 1-6 alkyl;
R8은 -H, -C1-6알킬, 페닐 또는 벤질이다. R 8 is -H, -C 1-6 alkyl, phenyl or benzyl.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 아래 범위일 수 있다:According to an embodiment of the present invention, the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
고리 A2는 페닐, 5-6원 헤테로아릴, 3-7원 사이클로알킬, 또는 3-7원 헤테로사이클로알킬이고 Ring A 2 is phenyl, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, or 3-7 membered heterocycloalkyl
{여기서, 상기 페닐 또는 5-6원 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬, -C1-6하이드록시알킬, -C1-6아미노알킬, -C1-6할로알킬, -C1-6알킬-CN, -CN, -C1-6알킬-O-C1-6알킬, -C1-6알킬NR9R10, -(C=O)NR9R10, -C1-6알킬-(C=O)NR9R10, -(C=O)-C1-6알킬, -(C=O)OR11, -C1-6알킬-(C=O)OR11, -NR12R13, -OR14, -할로, -S-C1-6알킬, -SO2-C1-6알킬, -SO2-NR12R13, -SO2-할로, -(S=O)NH-C1-6알킬, -S(=O)(=NH)-C1-6알킬, 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C1-6알킬-사이클로알킬, -C1-6알킬-헤테로사이클로알킬, -(C=O)-사이클로알킬, -(C=O)-헤테로사이클로알킬, -NH(C=O)-사이클로알킬, -NH(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴로 치환될 수 있고 [이때, 상기 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C1-6알킬-사이클로알킬, -C1-6알킬-헤테로사이클로알킬, -(C=O)-사이클로알킬, -(C=O)-헤테로사이클로알킬, -NH(C=O)-사이클로알킬, -NH(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬, -(=O)-, -(C=O)-C1-6알킬, -(C=O)NR15R16, -(C=O)OR17, -NR18R19, -할로, -SO2-, 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬로 치환될 수 있음 (상기 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6하이드록시알킬, -C1-6아미노알킬, -C1-6할로알킬, -NR20R21, 또는 사이클로알킬로 치환될 수 있음)], 또는 상기 아릴 또는 헤테로아릴의 2 이상의 치환기가 서로 연결되어 융합 고리를 형성할 수 있고 [여기서, 상기 융합 고리의 하나 이상의 H는 -C1-6알킬, -(=O)-, -(C=O)-C1-6알킬, -(C=O)O-C1-6알킬, -NR22R23, -O-C1-6알킬, 할로, -SO2-C1-6알킬, 사이클로알킬, 또는 헤테로사이클로알킬로 치환될 수 있음]; {Wherein, at least one H of the phenyl or 5-6 membered heteroaryl ring is -C 1-6 alkyl, -C 1-6 hydroxyalkyl, -C 1-6 aminoalkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-CN, -CN, -C 1-6 alkyl-OC 1-6 alkyl, -C 1-6 alkylNR 9 R 10 , -(C=O)NR 9 R 10 , -C 1 -6 alkyl-(C=O)NR 9 R 10 , -(C=O)-C 1-6 alkyl, -(C=O)OR 11 , -C 1-6 alkyl-(C=O)OR 11 , -NR 12 R 13 , -OR 14 , -halo, -SC 1-6 alkyl, -SO 2 -C 1-6 alkyl, -SO 2 -NR 12 R 13 , -SO 2 -halo, -(S= O)NH-C 1-6 alkyl, -S(=O)(=NH)-C 1-6 alkyl, cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C 1-6 alkyl-cycloalkyl, - C 1-6 Alkyl-heterocycloalkyl, -(C=O)-cycloalkyl, -(C=O)-heterocycloalkyl, -NH(C=O)-cycloalkyl, -NH(C=O)- which may be substituted with heterocycloalkyl, aryl, -(C=O)-aryl, or heteroaryl [wherein said cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C 1-6 alkyl-cycloalkyl, - C 1-6 Alkyl-heterocycloalkyl, -(C=O)-cycloalkyl, -(C=O)-heterocycloalkyl, -NH(C=O)-cycloalkyl, -NH(C=O)- At least one H of a heterocycloalkyl, aryl, -(C=O)-aryl, or heteroaryl ring is -C 1-6 alkyl, -(=O)-, -(C=O)-C 1-6 alkyl to be substituted with , -(C=O)NR 15 R 16 , -(C=O)OR 17 , -NR 18 R 19 , -halo, -SO 2 -, cycloalkyl, heterocycloalkyl, or heterobicycloalkyl can be (at least one H of the cycloalkyl, heterocycloalkyl, or heterobicycloalkyl ring is -C 1-6 alkyl, -C 1-6 hydroxyalkyl, -C 1-6 aminoalkyl, -C 1 6 haloalkyl, -NR 20 R 21 , or may be substituted with cycloalkyl)], or two or more substituents of the aryl or heteroaryl may be linked to each other to form a fused ring, wherein at least one H of the fused ring is —C 1-6 alkyl, -(=O)-, -(C=O)-C 1-6 alkyl, -(C=O)OC 1-6 alkyl, -NR 22 R 23 , -OC 1-6 alkyl, halo, - SO 2 -C 1-6 alkyl, cycloalkyl, or heterocycloalkyl];
상기 사이클로알킬 또는 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6하이드록시알킬, -(C=O)-C1-6알킬, -(C=O)O-C1-6알킬, 또는 -SO2-C1-6알킬로 치환될 수 있음}; at least one H of said cycloalkyl or heterocycloalkyl ring is -C 1-6 alkyl, -C 1-6 hydroxyalkyl, -(C=O)-C 1-6 alkyl, -(C=O)OC 1 -6 alkyl, or —SO 2 —C 1-6 alkyl};
R9 및 R10은 각각 독립적으로 -H, -C1-6알킬, -C1-6하이드록시알킬, -C1-6알킬-NR24R25, 또는 헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};R 9 and R 10 are each independently —H, —C 1-6 alkyl, —C 1-6 hydroxyalkyl, —C 1-6 alkyl-NR 24 R 25 , or heterocycloalkyl {wherein the hetero one or more H of the cycloalkyl ring may be substituted with —C 1-6 alkyl};
R11은 -H 또는 -C1-6알킬이고;R 11 is —H or —C 1-6 alkyl;
R12 및 R13은 각각 독립적으로 -H, -C1-6알킬, -C1-6알킬-NR24R25, 또는 -(C=O)O-C1-6알킬이고;R 12 and R 13 are each independently —H, —C 1-6 alkyl, —C 1-6 alkyl-NR 24 R 25 , or —(C=O)OC 1-6 alkyl;
R14은 각각 독립적으로 -H, -C1-6알킬, -C1-6알킬-NR26R27, 헤테로사이클로알킬, 또는 -C1-6알킬-헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 또는 -C1-6알킬-헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};each R 14 is independently —H, —C 1-6 alkyl, —C 1-6 alkyl-NR 26 R 27 , heterocycloalkyl, or —C 1-6 alkyl-heterocycloalkyl {wherein the heterocyclo one or more H of an alkyl or —C 1-6 alkyl-heterocycloalkyl ring may be substituted with —C 1-6 alkyl;
R15 내지 R17은 각각 독립적으로 -H 또는 -C1-6알킬이고;R 15 to R 17 are each independently —H or —C 1-6 alkyl;
R18 및 R19은 각각 독립적으로 -C1-6알킬 또는 -C1-6알킬-NR28R29이고;R 18 and R 19 are each independently —C 1-6 alkyl or —C 1-6 alkyl-NR 28 R 29 ;
R20 내지 R29은 각각 독립적으로 -H 또는 -C1-6알킬이다. R 20 to R 29 are each independently —H or —C 1-6 alkyl.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 아래 범위일 수 있다:According to an embodiment of the present invention, the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
R1은 -H이다. R 1 is -H.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 아래 범위일 수 있다:According to an embodiment of the present invention, the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:
R2는 -H, -C1-6알킬, -C1-6할로알킬, -CN, -할로, 또는 5-6원 고리이다 {여기서, 상기 5-6원 고리의 하나 이상의 H는 -C1-6알킬, -C1-6할로알킬, 또는 할로로 치환될 수 있음}.R 2 is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -CN, -halo, or a 5-6 membered ring {wherein at least one H of the 5-6 membered ring is -C may be substituted with 1-6 alkyl, —C 1-6 haloalkyl, or halo}.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염이 하기 [표 1], [표 2], 및 [표 3] 에 기재된 실시예 1 내지 240의 화합물 또는 이의 약학적으로 허용가능한 염으로 이루어진 군으로부터 선택된 것일 수 있다.According to an embodiment of the present invention, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is the compound of Examples 1 to 240 described in [Table 1], [Table 2], and [Table 3], or It may be selected from the group consisting of pharmaceutically acceptable salts thereof.
본 발명에 있어서, "알킬"은, 다른 기재가 없는 한, 직쇄 또는 분지쇄의 비고리형, 고리형 또는 이들이 결합된 포화 탄화수소를 의미할 수 있다. 예를 들어, "C1-6알킬"은 탄소 원자를 1 내지 6개 포함하는 알킬을 의미할 수 있다. 비고리형 알킬은, 일 예로서, 메틸, 에틸, n-프로필, n-부틸, 아이소프로필, 2급(sec)-부틸, 아이소부틸, 또는 3급(tert)-부틸 등을 포함할 수 있으나, 이에 제한되지 않는다. 고리형 알킬은 본 명세서에서 "사이클로알킬"과 교환적으로 사용될 수 있으며, 일 예로서, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸, 또는 사이클로옥틸 등을 포함할 수 있으나, 이에 제한되지 않는다. In the present invention, unless otherwise stated, "alkyl" may mean a straight or branched acyclic, cyclic, or saturated hydrocarbon to which they are bonded. For example, "C 1-6 alkyl" can mean an alkyl containing 1 to 6 carbon atoms. Acyclic alkyl may include, as an example, methyl, ethyl, n -propyl, n -butyl, isopropyl, sec -butyl, isobutyl, or tert -butyl, etc., It is not limited thereto. Cyclic alkyl may be used interchangeably with “cycloalkyl” herein, and may include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. doesn't happen
본 발명에 있어서, "알콕시"는 알킬 에터기로 -(O-알킬)을 의미할 수 있고, 여기서, 알킬은 상기에서 정의된 바와 같다. 예를 들어, "C1-6의 알콕시"는 C1-6의 알킬을 함유하는 알콕시, 즉, -(O-C1-6알킬)을 의미할 수 있으며, 일 예로서, 알콕시는 메톡시(methoxy), 에톡시(ethoxy), n-프로폭시(n-propoxy), 아이소프로폭시(isopropoxy), n-부톡시(n-butoxy), 아이소부톡시(isobutoxy), sec-부톡시(sec-butoxy), 또는 tert-부톡시(tert-butoxy) 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, "alkoxy" may mean -(O-alkyl) as an alkyl ether group, wherein alkyl is as defined above. For example, "C 1-6 alkoxy" may mean alkoxy containing C 1-6 alkyl, that is, -(OC 1-6 alkyl). For example, alkoxy is methoxy ), ethoxy, n -propoxy, isopropoxy, n -butoxy , isobutoxy , sec -butoxy ), or tert - butoxy , etc., but is not limited thereto.
본 발명에 있어서, "할로"는 F, Cl, Br, 또는 I일 수 있다.In the present invention, "halo" may be F, Cl, Br, or I.
본 발명에 있어서, "할로알킬"은 본원에 정의된 바와 같은 하나 이상의 할로로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다. 상기 할로알킬의 예로는 하나 이상의 할로겐, 예를 들어 F, Cl, Br, 또는 I로 독립적으로 치환된 메틸, 에틸, 프로필, 아이소프로필, 아이소부틸 또는 n-부틸을 포함하나, 이에 한정되는 것은 아니다.In the present invention, "haloalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having one or more halo substituted carbon atoms as defined herein. Examples of such haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl independently substituted with one or more halogens, such as F, Cl, Br, or I. .
본 명세서에서, "아미노알킬"은 아미노-(NR'R")로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다. 여기서, R' 및 R"은 각각 독립적으로 수소, 및 C1-6알킬로 이루어진 군으로부터 선택될 수 있으며, 상기 선택된 R' 및 R"은 각각 독립적으로 치환되거나 비치환될 수 있다. As used herein, "aminoalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with amino-(NR'R"), wherein R' and R" are each independently hydrogen. , and may be selected from the group consisting of C 1-6 alkyl, wherein the selected R′ and R″ may each independently be substituted or unsubstituted.
본 발명에 있어서, "헤테로사이클로알킬"은 고리를 형성하는 원자로 N, O 및 S로부터 선택된 1 내지 5 개의 헤테로 원자를 함유하는 고리를 의미할 수 있고, 포화 또는 부분적으로 불포화될 수 있다. 여기서, 불포화된 경우, 헤테로사이클로알켄으로 지칭될 수 있다. 달리 언급하지 않는 한, 헤테로사이클로알킬은 단일 고리이거나, 스파이로(spiro) 고리, 다리(bridged) 고리 또는 융합(fused) 고리와 같은 다중 고리일 수 있다. 또한, "3 내지 12 원자의 헤테로사이클로알킬"은 고리를 형성하는 원자를 3 내지 12 개 포함하는 헤테로사이클로알킬을 의미할 수 있으며, 일 예로서, 헤테로사이클로알킬은 피롤리딘, 피페리딘, 이미다졸리딘, 피라졸리딘, 부티로락탐, 발레로락탐, 이미다졸리딘온, 하이단토인, 다이옥솔란, 프탈이미드, 피페리딘, 피리미딘-2,4(1H,3H)-다이온, 1,4-다이옥산, 모르폴린, 싸이오모르폴린, 싸이오모르폴린-S-옥사이드, 싸이오모르폴린-S,S-옥사이드, 피페라진, 피란, 피리돈, 3-피롤린, 싸이오피란, 피론, 테트라하이드로퓨란, 테트라하이드로싸이오펜, 퀴누클리딘, 트로판, 2-아자스파이로[3.3]헵탄, (1R,5S)-3-아자바이사이클로[3.2.1]옥탄, (1s,4s)-2-아자바이사이클로[2.2.2]옥탄, 또는 (1R,4R)-2-옥사-5-아자바이사이클로[2.2.2]옥탄 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, "heterocycloalkyl" may mean a ring containing 1 to 5 heteroatoms selected from N, O and S as atoms forming the ring, and may be saturated or partially unsaturated. Here, when unsaturated, it may be referred to as a heterocycloalkene. Unless otherwise stated, heterocycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring or a fused ring. In addition, "3 to 12 membered heterocycloalkyl" may mean a heterocycloalkyl containing 3 to 12 atoms forming a ring, for example, heterocycloalkyl is pyrrolidine, piperidine, Imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4( 1H , 3H ) -Dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine- S -oxide, thiomorpholine- S , S -oxide, piperazine, pyran, pyridone, 3-pyrroline , thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1 R ,5 S )-3-azabicyclo [3.2.1 ]octane, (1 s ,4 s )-2-azabicyclo[2.2.2]octane, or ( 1R , 4R )-2-oxa-5-azabicyclo[2.2.2]octane, and the like. can, but is not limited thereto.
본 발명에 있어서, "아렌"은 방향족 탄화수소 고리를 의미할 수 있다. 아렌은 단환식 아렌 또는 다환식 아렌일 수 있다. 아렌의 고리 형성 탄소수는 5 이상 30 이하, 5 이상 20 이하, 또는 5 이상 15 이하일 수 있다. 아렌의 예로는 벤젠, 나프탈렌, 플루오렌, 안트라센, 페난트렌, 바이벤젠, 터벤젠, 쿼터벤젠, 퀸크벤젠, 섹시벤젠, 트라이페닐렌, 피렌, 벤조 플루오란텐, 크리센 등을 예시할 수 있지만, 이들에 한정되지 않는다. 본 명세서에서 상기 "아렌"에서 수소 원자 하나를 제거한 잔기를 "아릴"로 지칭한다.In the present invention, "arene" may mean an aromatic hydrocarbon ring. The arene may be a monocyclic arene or a polycyclic arene. The ring carbon number of arene may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less. Examples of arenes include benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quaterbenzene, quinkbenzene, sexbenzene, triphenylene, pyrene, benzofluoranthene, chrysene, etc. , but not limited to these. In the present specification, the residue obtained by removing one hydrogen atom from "arene" is referred to as "aryl".
본 발명에 있어서, "헤테로아렌"은 이종 원소로 O, N, P, Si, 및 S 중 1 개 이상을 포함하는 고리일 수 있다. 헤테로아렌의 고리 형성 탄소수는 2 이상 30 이하 또는 2 이상 20 이하일 수 있다. 헤테로 아렌은 단환식 헤테로 아렌 또는 다환식 헤테로 아렌일 수 있다. 다환식 헤테로아렌은 예를 들어, 2 환 또는 3 환 구조를 갖는 것일 수 있다. 헤테로아렌의 예로는 싸이오펜, 퓨린, 피롤, 피라졸, 이미다졸, 싸이아졸, 옥사졸, 아이소싸이아졸, 옥사다이아졸, 트라이아졸, 피리딘, 비피리딜, 트리아진, 아크리딜, 피리다진, 피라진, 퀴놀린, 퀴나졸린, 퀴녹살린, 페녹사진, 프탈라진, 피리미딘, 피리도 피리미딘, 피리도 피라진, 피라지노 피라진, 아이소퀴놀린, 인돌, 카바졸, 이미다조피리다진, 이미다조피리딘, 이미다조피리미딘, 피라졸로피리미딘, 이미다조피라진 또는 피라졸로피리딘, N-아릴카바졸, N-헤테로아릴카바졸, N-알킬카바졸, 벤조옥사졸, 벤조이미다졸, 벤조싸이아졸, 벤조카바졸, 벤조싸이오펜, 다이벤조싸이오펜, 싸이에노싸이오펜, 벤조퓨란, 페난트롤린, 아이소옥사졸, 옥사다이아졸, 싸이아다이아졸, 벤조싸이아졸, 테트라졸, 페노싸이아진, 다이벤조실롤 및 다이벤조퓨란 등이 있으나, 이들에 한정되지 않는다. 본 발명의 일 실시 태양에서 헤테로아렌은 또한 헤테로사이클로알킬 고리에 융합된 아렌 고리 또는 사이클로알킬 고리에 융합된 헤테로아렌을 포함하는 바이사이클릭 헤테로사이클로-아렌을 포함할 수 있다. 본 명세서에서 상기 "헤테로아렌"에서 수소 원자 하나를 제거한 잔기를 "헤테로아릴"로 지칭한다.In the present invention, "heteroarene" may be a ring including at least one of O, N, P, Si, and S as a heterogeneous element. The number of ring carbon atoms in the heteroarene may be 2 or more and 30 or less, or 2 or more and 20 or less. The hetero arene may be a monocyclic hetero arene or a polycyclic hetero arene. The polycyclic heteroarene may have, for example, a two- or three-ring structure. Examples of heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, pyridazine , pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine , imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine or pyrazolopyridine, N -arylcarbazole, N -heteroarylcarbazole, N -alkylcarbazole, benzoxazole, benzoimidazole, benzothiazole , benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine , dibenzosilol and dibenzofuran, but are not limited thereto. In one embodiment of the invention heteroarenes may also include bicyclic heterocyclo-arenes, including arene rings fused to heterocycloalkyl rings or heteroarenes fused to cycloalkyl rings. In the present specification, the residue obtained by removing one hydrogen atom from the "heteroarene" is referred to as "heteroaryl".
상기 언급된 동종 또는 이종의 치환기는 동일한 위치 또는 상이한 위치에 하나 이상 치환될 수 있고, 순차적으로도 치환될 수 있다. 상기 "순차적"으로의 의미는 화학식에서 하나의 치환기가 치환된 후 상기 치환기에 또 다른 치환기가 연속하여 치환되는 것을 의미하며, 예를 들면, 알킬기가 치환된 후 상기 알킬기에 사이클로알킬기가 치환되고 상기 사이클로알킬기에 카보닐기가 순차적으로 치환되는 경우에, 카보닐사이클로알킬알킬로 명명함으로써 순차적으로 치환된 것임을 나타낼 수 있다.The above-mentioned homologous or heterogeneous substituents may be substituted one or more at the same position or different positions, and may also be substituted sequentially. The term "sequentially" means that in the formula, one substituent is substituted and then another substituent is successively substituted in the substituent, for example, after the alkyl group is substituted, a cycloalkyl group is substituted in the alkyl group and the When a carbonyl group is sequentially substituted with a cycloalkyl group, it can be indicated that the sequential substitution is made by naming the cycloalkyl group as carbonylcycloalkylalkyl.
또한, 상기 나열된 연결 라디칼은 결합 방향을 명시하지 않았으며 결합방향은 임의적이다. 예를 들어
Figure PCTKR2021018956-appb-img-000002
에서 연결된 라디칼 L은 -M-W-이고, 이 때, -M-W-는 고리 A와 고리 B를 왼쪽에서 오른쪽으로 읽기 순서와 같은 방향으로 연결하여
Figure PCTKR2021018956-appb-img-000003
를 형성할 수 있고, 고리 A와 고리 B를 왼쪽에서 오른쪽으로 읽기 순서와 반대 방향으로 연결하여
Figure PCTKR2021018956-appb-img-000004
를 형성할 수 있다.In addition, the above-listed linking radicals do not specify the bonding direction, and the bonding direction is arbitrary. for example
Figure PCTKR2021018956-appb-img-000002
The connected radical L is -MW-, where -MW- connects Ring A and Ring B in the same direction as the reading order from left to right.
Figure PCTKR2021018956-appb-img-000003
can be formed, and by connecting Ring A and Ring B in the reverse reading order from left to right,
Figure PCTKR2021018956-appb-img-000004
can form.
본 발명에 있어서, 용어 "광학 이성질체(enantiomer)"는 동일한 화학식 또는 분자식을 가지지만 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미한다. 이러한 각각의 광학 이성질체 및 그것의 혼합물들 역시 본 발명의 범위에 포함된다. 다른 설명이 없는 한, 비대칭 탄소 원자와 연결되는 실선 결합 (-)은 입체 중심의 절대적 배열을 나타내는 쐐기형 실선 결합
Figure PCTKR2021018956-appb-img-000005
또는 쐐기형 점선 결합
Figure PCTKR2021018956-appb-img-000006
을 포함할 수 있다.In the present invention, the term "enantiomer" means a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but sterically different. Each of these optical isomers and mixtures thereof are also included within the scope of the present invention. Unless otherwise noted, a solid line bond (-) connecting an asymmetric carbon atom is a wedge-shaped solid line bond indicating the absolute configuration of the stereocenter.
Figure PCTKR2021018956-appb-img-000005
or wedge-dotted join
Figure PCTKR2021018956-appb-img-000006
may include
본 발명의 화학식 1의 화합물은 "약학적으로 허용가능한 염"의 형태로 존재할 수 있다. 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 본 발명의 용어 "약학적으로 허용가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 화학식 1로 표시되는 화합물의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기산 또는 무기산 부가염을 의미한다.The compound of Formula 1 of the present invention may exist in the form of a "pharmaceutically acceptable salt". As the salt, an acid addition salt formed with a pharmaceutically acceptable free acid is useful. As used herein, the term "pharmaceutically acceptable salt" refers to any of the compounds at a concentration having an effective action that is relatively non-toxic and harmless to a patient, and the side effects due to the salt do not reduce the beneficial efficacy of the compound represented by the formula (1). Any organic or inorganic acid addition salt of
산부가염은 통상의 방법, 예를 들어 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토나이트릴을 사용하여 침전시켜서 제조한다. 동 몰량의 화합물 및 물 중의 산 또는 알코올을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.Acid addition salts are prepared by conventional methods, for example by dissolving the compound in an aqueous solution of an excess of acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of compound and acid or alcohol in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction.
이때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 또는 질산 등을 사용할 수 있고 유기산으로는 메테인설폰산, p-톨루엔설폰산, 아세트산, 트라이플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산(fumaric acid), 만데르산, 프로피온산(propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 또는 아이오딘화수소산(hydroiodic acid) 등을 사용할 수 있다. 다만, 이들에 제한되지 않는다.In this case, an organic acid and an inorganic acid may be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid may be used as the inorganic acid. As the organic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glycolic acid, glue Conic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid, etc. can be used However, the present invention is not limited thereto.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속염 또는 알칼리 토금속염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 특히 나트륨, 칼륨, 또는 칼슘염을 제조하는 것이 제약상 적합하나 이들에 제한되는 것은 아니다. 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.In addition, a pharmaceutically acceptable metal salt can be prepared using a base. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt as the metal salt, but is not limited thereto. Also, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
본 발명의 약학적으로 허용가능한 염은, 달리 지시되지 않는 한, 상기 화학식 1의 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 포함한다. 예를 들어, 약학적으로 허용가능한 염으로는 하이드록시기의 나트륨, 칼슘 및 칼륨염 등이 포함될 수 있고, 아미노기의 기타 약학적으로 허용가능한 염으로는 하이드로브롬화물, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메테인설포네이트(메실레이트), 및 p-톨루엔설포네이트(토실레이트) 염 등이 있으며, 당업계에 알려진 염의 제조방법을 통하여 제조될 수 있다.The pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in the compound of Formula 1, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of a hydroxyl group, and other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts; It can be prepared through a method for preparing a known salt.
아이소옥사졸리딘 유도체 화합물의 용도Uses of isoxazolidine derivative compounds
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염의 용도를 제공한다.The present invention provides the use of a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2021018956-appb-img-000007
Figure PCTKR2021018956-appb-img-000007
본 발명의 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 다양한 키나아제에 대하여 억제 활성을 나타낸다(실험예 1). The compound represented by Formula 1 of the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof exhibits inhibitory activity against various kinases (Experimental Example 1).
본 발명의 일 구체예에 따르면, 상기 화학식 1로 표시되는 아이소옥사졸리딘 유도체 화합물은 여러 키나아제 중에서 CDK2, CDK4, CDK6 및/또는 HPK1에 대해 우수한 억제 활성을 나타내므로, CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환, 특히, 암에 대하여 치료 또는 예방에 유용하게 사용될 수 있다. According to one embodiment of the present invention, since the isoxazolidine derivative compound represented by Formula 1 exhibits excellent inhibitory activity against CDK2, CDK4, CDK6 and/or HPK1 among various kinases, CDK2, CDK4, CDK6 and/or Alternatively, it may be usefully used for treatment or prevention of HPK1-related diseases, particularly cancer.
본 발명에 있어서, 상기 암은 CDK2, CDK4, CDK6 및/또는 HPK1 활성 억제로 인해 치료 또는 예방 효능을 나타낼 수 있는 모든　암을 포함하며, 고형암　또는 혈액암일 수 있다. 예컨대, 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상인 것일 수 있으나, 이에 제한되지 않는다. 또한, 상기　암은 원발성　암뿐 아니라 전이성　암도 포함한다.In the present invention, the cancer includes all cancers capable of exhibiting therapeutic or prophylactic efficacy due to inhibition of CDK2, CDK4, CDK6 and/or HPK1 activity, and may be solid cancer or blood cancer. For example, pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell cancer, ovarian cancer Epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer, Parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain cancer, juvenile lymphoma, juvenile leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenum Cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms cancer , breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic schwannoma, Pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological cancer, and thymus cancer It may be at least one selected from the group consisting of, but is not limited thereto. In addition, the above cancers include not only primary cancers but also metastatic cancers.
본 발명의 일 구체예에 따르면, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환의 치료 또는 예방용 약학적 조성물을 제공한다. 구체적으로, 상기 CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환은 암일 수 있다. 상기 암의 종류는 위에서 언급한 바와 같다. According to one embodiment of the present invention, the present invention provides a CDK2, CDK4, CDK6 and/or HPK1-related disease containing the compound represented by Formula 1, an optical isomer, or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition for treatment or prevention is provided. Specifically, the CDK2, CDK4, CDK6 and/or HPK1-related disease may be cancer. The types of cancer are as described above.
본 발명의 약학적 조성물은 투여를 위해서 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염 외에 추가로 약학적으로 허용가능한 담체를 1종 이상 더 포함할 수 있다. 약학적으로 허용 가능한 담체는 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 따라서, 본 발명의 조성물은 패치제, 액제, 환약, 캡슐, 과립, 정제, 좌제 등일 수 있다. 이들 제제는 당 분야에서 제제화에 사용되는 통상의 방법 또는 문헌 [Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA]에 개시되어 있는 방법으로 제조될 수 있으며 각 질환에 따라 또는 성분에 따라 다양한 제제로 제제화될 수 있다. The pharmaceutical composition of the present invention may further include one or more pharmaceutically acceptable carriers in addition to the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for administration. The pharmaceutically acceptable carrier may be used in a mixture of saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components. , and other conventional additives such as a bacteriostatic agent may be added. In addition, diluents, dispersants, surfactants, binders and lubricants may be additionally added to form an injectable formulation such as an aqueous solution, suspension, emulsion, etc., pills, capsules, granules or tablets. Accordingly, the composition of the present invention may be a patch, solution, pill, capsule, granule, tablet, suppository, and the like. These formulations may be prepared by a conventional method used for formulation in the art or a method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA, and may be formulated into various formulations according to each disease or component. can
본 발명의 상기 약학적 조성물은 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염 외에 동일 또는 유사한 약효를 나타내는 유효성분을 1 종 이상을 더 포함할 수 있다. The pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar efficacy in addition to the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
또한 본 발명의 일 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 치료학적으로 유효한 양을, 이를 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는, CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환을 치료 또는 예방하는 방법을 제공한다. 상기 대상(subject)은 인간을 포함하는 포유류일 수 있다.Also, according to one embodiment of the present invention, the step of administering to a subject in need thereof a therapeutically effective amount of the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof Provided is a method for treating or preventing a CDK2, CDK4, CDK6 and/or HPK1 related disease, comprising: The subject may be a mammal including a human.
본 발명에서 사용되는 "치료학적으로 유효한 양"이라는 용어는 CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환의 치료 또는 예방에 유효한 상기 화학식 1로 표시되는 화합물의 양을 나타낸다. 구체적으로, "치료학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 질병의 종류, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 시판되는 치료제와는 순차적으로 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다. 본 발명의 약학적 조성물의 투여 용량은, 환자의 상태, 연령, 성별 및 합병증 등의 다양한 요인에 따라 전문가에 의해 결정될 수 있다. 본 발명의 약학적 조성물의 유효성분은 안전성이 우수하므로, 결정된 투여 용량 이상으로도 사용될 수 있다.As used herein, the term "therapeutically effective amount" refers to an amount of the compound represented by Formula 1 effective for the treatment or prevention of CDK2, CDK4, CDK6 and/or HPK1-related diseases. Specifically, "therapeutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and effective dose level includes the subject type and severity, age, sex, type of disease, The activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of excretion, the duration of treatment, factors including concurrently used drugs, and other factors well known in the medical field may be determined according to factors. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents. and may be administered single or multiple. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, and can be easily determined by those skilled in the art. The dosage of the pharmaceutical composition of the present invention may be determined by an expert according to various factors such as the patient's condition, age, sex, and complications. Since the active ingredient of the pharmaceutical composition of the present invention is excellent in safety, it can be used even more than the determined dosage.
또한 본 발명의 일 구체예에 따르면, 본 발명은 CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환의 치료 또는 예방에 사용하기 위한 약제(medicament)의 제조에 사용하기 위한, 상기 화학식 1 로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 용도(use)를 제공한다. 약제의 제조를 위한 상기 화학식 1로 표시되는 화합물은 허용되는 보조제, 희석제, 담체 등을 혼합할 수 있으며, 기타 활성제제와 함께 복합 제제로 제조되어 활성 성분들의 상승 작용을 가질 수 있다. Also, according to one embodiment of the present invention, the present invention provides a compound represented by Formula 1 for use in the manufacture of a medicament for use in the treatment or prevention of CDK2, CDK4, CDK6 and/or HPK1-related diseases , an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The compound represented by Formula 1 for the manufacture of a drug may be mixed with an acceptable adjuvant, diluent, carrier, etc., and may have a synergistic action of the active ingredients by being prepared as a complex formulation together with other active agents.
본 발명의 용도, 조성물, 치료 방법에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.Matters mentioned in the uses, compositions, and treatment methods of the present invention are equally applicable as long as they do not contradict each other.
본 발명의 실시 형태는 여러가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 이하 설명하는 실시 형태로 한정되는 것은 아니다. 또한 본 발명의 실시 형태는 당해 기술분야에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해서 제공되는 것이다. 나아가, 명세서 전체에서 어떤 구성요소를 "포함"한다는 것은 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있다는 것을 의미한다.Embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. In addition, the embodiment of the present invention is provided in order to more completely explain the present invention to those of ordinary skill in the art. Furthermore, in the entire specification, "including" a certain element means that other elements may be further included, rather than excluding other elements, unless otherwise stated.
본 발명의 아이소옥사졸리딘 유도체 화합물은 CDK2, CDK4, CDK6 및/또는 HPK1에 대해 우수한 억제 활성을 나타내므로, 상기 CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환의 치료 또는 예방에 유용하게 사용될 수 있다.Since the isoxazolidine derivative compound of the present invention exhibits excellent inhibitory activity against CDK2, CDK4, CDK6 and/or HPK1, it can be usefully used for the treatment or prevention of CDK2, CDK4, CDK6 and/or HPK1-related diseases. .
이하, 본 발명을 실시예 및 실험예에 의하여 상세히 설명한다. 단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 범위가 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by way of Examples and Experimental Examples. However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the scope of the present invention is not limited thereto.
본 발명의 실시예에서 합성된 화합물은 다음의 HPLC 조건에 의해 정제하거나 또는 구조 분석을 실시한 것이다: The compound synthesized in the Examples of the present invention is purified by the following HPLC conditions or subjected to structural analysis:
정제용 중압액체크로마토그래피(Medium pressure liquid chromatography; MPLC)Medium pressure liquid chromatography (MPLC) for purification
중압액체크로마토그래피는 TELEDYNE ISCO사의 CombiFlash Rf +UV을 사용하였다.Medium pressure liquid chromatography was performed using TELEDYNE ISCO's CombiFlash Rf +UV.
분석용 HPLC 조건(ACQUITY UPLC H-Class Core System)Analytical HPLC conditions (ACQUITY UPLC H-Class Core System)
Waters사 제조 UPLC system(ACQUITY UPLC PDA Detector)에 Waters사 제조 mass QDA Detector가 장착된 장비를 사용하였다. 사용 컬럼은 Waters사의 ACQUITY UPLC®BEH C18(1.7　㎛, 2.1 X 50 mm)였으며 컬럼온도는 30 ℃에서 진행하였다.An equipment equipped with a mass QDA Detector manufactured by Waters was used in the UPLC system (ACQUITY UPLC PDA Detector) manufactured by Waters. The column used was Waters' ACQUITY UPLC ® BEH C18 (1.7 ㎛, 2.1 X 50 mm), and the column temperature was 30 ℃.
이동상 A는 0.1 % 개미산이 포함된 물, 이동상 B는 0.1 %의 개미산이 포함된 아세토나이트릴을 사용하였다.Mobile phase A used water containing 0.1% formic acid, and mobile phase B used acetonitrile containing 0.1% formic acid.
Gradient condition(10 - 100 % B로 3 분, 이동속도 = 0.6 ml/min)Gradient condition (10 - 100 % B for 3 minutes, movement speed = 0.6 ml/min)
정제용 Prep-LCMS(Preparative-Liquid chromatography mass spectrometry)Preparative-Liquid chromatography mass spectrometry (Prep-LCMS) for purification
Waters사 제조 Autopurification HPLC system(2767 sample manger, 2545 binary gradient module, 2998 Photodiode Array Detector)에 Waters사 제조 mass QDA Detector가 장착된 장비를 사용하였다. 사용 컬럼은 Waters사의 SunFire®Prep C18 OBDTM(5　㎛, 19 X 50 mm)였으며 컬럼온도는 실온에서 진행하였다.The Autopurification HPLC system manufactured by Waters (2767 sample manger, 2545 binary gradient module, 2998 Photodiode Array Detector) was equipped with a mass QDA Detector manufactured by Waters was used. The column used was Waters' SunFire ® Prep C18 OBD TM (5 ㎛, 19 X 50 mm), and the column temperature was performed at room temperature.
이동상 A는 0.035 % 트라이플루오로아세트산이 포함된 물, 이동상 B는 0.035 %의 트라이플루오로아세트산이 포함된 메탄올을 사용하였다.Water containing 0.035% trifluoroacetic acid was used for mobile phase A, and methanol containing 0.035% trifluoroacetic acid was used for mobile phase B.
Gradient condition(15 - 100 % B로 10 분, 이동속도 = 25 ml/min)Gradient condition (15 - 10 minutes with 100 % B, movement speed = 25 ml/min)
정제용 Prep-150 LC System(Preparative-Liquid chromatography UV spectrometry)Prep-150 LC System for purification (Preparative-Liquid chromatography UV spectrometry)
Waters사 제조 Prep 150 LC system(2545 Quaternary gradient module, 2998 Photodiode Array Detector, Fraction collector Ⅲ에 Waters사 제조 장비를 사용하였다. 사용 컬럼은 Waters사의 XTERRA®Prep RP18 OBDTM(10　㎛, 30 X 300 mm)였으며 컬럼온도는 실온에서 진행하였다.Waters' Prep 150 LC system (2545 Quaternary gradient module, 2998 Photodiode Array Detector, Fraction collector Ⅲ) was used with Waters' equipment. The column used was Waters' XTERRA ® Prep RP18 OBD TM (10 ㎛, 30 X 300 mm) and the column temperature was carried out at room temperature.
Gradient condition(3 - 100 % B로 120 분, 이동속도 = 40 ml/min)Gradient condition (3 - 120 min with 100 % B, movement speed = 40 ml/min)
사용된 시판 시약은 추가 정제 없이 사용하였다. 본 발명에서 실온은 1 ~ 35 ℃ 정도의 온도를 말한다. 감압하 농축 또는 용매 증류 제거는, 회전식 증발기(rotary evaporator)를 사용하였다.Commercial reagents used were used without further purification. In the present invention, room temperature refers to a temperature of about 1 ~ 35 ℃. For concentration under reduced pressure or solvent distillation, a rotary evaporator was used.
<제조예 1> (S)-3-페닐아이소옥사졸리딘의 제조<Preparation Example 1> Preparation of (S)-3-phenylisoxazolidine
Figure PCTKR2021018956-appb-img-000008
Figure PCTKR2021018956-appb-img-000008
단계 1: Step 1: terttert -부틸 (-Butyl ( RR )-(3-하이드록시-3-페닐프로폭시)카바메이트의 제조Preparation of )-(3-hydroxy-3-phenylpropoxy)carbamate
tert-부틸 하이드록시카바메이트(7.8 g, 58.6 mmol)를 다이메틸포름아마이드(140 mL)에 녹인 후 0 ℃에서 수소화나트륨(2.58 g, 64.5 mmol)을 첨가하고 30 분 동안 반응하였다. 그리고 다이메틸포름아마이드(10 mL)에 녹인 (R)-3-클로로-1-페닐프로판-1-올(5 g, 29.3 mmol)을 0 ℃에서 10 분간 천천히 적가하고 실온에서 72 시간 동안 교반하였다. 반응 혼합물에 염화암모늄 수용액을 넣어 반응을 종결시키고, 아세트산에틸 및 소금물로 추출하여 유기층을 합하였다. 유기층을 황산나트륨으로 건조한 후 감압하여 농축 후 중압액체크로마토그래피(아세트산에틸/n-헥산)로 정제하여 목적 화합물(2.8 g, 68 %)을 수득하였다. tert -Butyl hydroxycarbamate (7.8 g, 58.6 mmol) was dissolved in dimethylformamide (140 mL), and sodium hydride (2.58 g, 64.5 mmol) was added at 0 °C, followed by reaction for 30 minutes. Then, ( R )-3-chloro-1-phenylpropan-1-ol (5 g, 29.3 mmol) dissolved in dimethylformamide (10 mL) was slowly added dropwise at 0° C. for 10 minutes, followed by stirring at room temperature for 72 hours. . The reaction was terminated by adding an aqueous ammonium chloride solution to the reaction mixture, followed by extraction with ethyl acetate and brine to combine the organic layers. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (ethyl acetate/n-hexane) to obtain the target compound (2.8 g, 68%).
MS (m/z): 150.17 [M+1]+ MS (m/z): 150.17 [M+1] +
1H NMR (400 MHz, CDCl3) δ = 7.43 - 7.39 (m, 2H), 7.38 - 7.32 (m, 2H), 7.27 - 7.24 (m, 1H), 5.05 - 4.97 (m, 1H), 4.15 - 4.08 (m, 1H), 4.07 - 4.00 (m, 1H), 2.10 - 1.93 (m, 2H), 1.54 - 1.48 (m, 9H) 1 H NMR (400 MHz, CDCl 3 ) δ = 7.43 - 7.39 (m, 2H), 7.38 - 7.32 (m, 2H), 7.27 - 7.24 (m, 1H), 5.05 - 4.97 (m, 1H), 4.15 - 4.08 (m, 1H), 4.07 - 4.00 (m, 1H), 2.10 - 1.93 (m, 2H), 1.54 - 1.48 (m, 9H)
단계 2: Step 2: terttert -부틸 (-Butyl ( SS )-3-페닐아이소옥사졸리딘-2-카복실레이트의 제조) Preparation of -3-phenylisoxazolidine-2-carboxylate
단계 1에서 제조한 tert-부틸 (R)-(3-하이드록시-3-페닐프로폭시)카바메이트(2.55 g, 9.54 mmol)와 트라이에틸아민(3.13 mL, 22.44 mmol)을 염화메틸렌(250 mL)에 녹인 후 0 ℃로 냉각하였다. 그리고 MsCl(1 mL, 13 mmol)를 적가하고 0 ℃에서 2 시간 동안 반응하였다. 반응 혼합물을 소금물 및 염화메틸렌으로 추출하여 유기층을 합하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하여 목적 화합물(2.3 g, crude)을 얻어 정제 없이 다음 반응에 사용하였다. tert -Butyl ( R )-(3-hydroxy-3-phenylpropoxy)carbamate (2.55 g, 9.54 mmol) prepared in step 1 and triethylamine (3.13 mL, 22.44 mmol) were mixed with methylene chloride (250 mL) ) and then cooled to 0 °C. Then, MsCl (1 mL, 13 mmol) was added dropwise and reacted at 0 °C for 2 hours. The reaction mixture was extracted with brine and methylene chloride, and the organic layers were combined. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound (2.3 g, crude), which was used in the next reaction without purification.
MS (m/z): 194.13 [M+1]+ MS (m/z): 194.13 [M+1] +
1H NMR (400 MHz, CDCl3) δ = 7.29 - 7.23 (m, 4H), 7.18 - 7.17 (m, 1H), 5.12 - 5.11 (m, 1H), 4.10 - 4.03 (m, 1H), 3.82- 3.80 (m, 1H), 2.75 - 2.65 (m, 1H), 2.29 - 2.15 (m, 1H), 1.37 (s, 9H) 1 H NMR (400 MHz, CDCl 3 ) δ = 7.29 - 7.23 (m, 4H), 7.18 - 7.17 (m, 1H), 5.12 - 5.11 (m, 1H), 4.10 - 4.03 (m, 1H), 3.82 3.80 (m, 1H), 2.75 - 2.65 (m, 1H), 2.29 - 2.15 (m, 1H), 1.37 (s, 9H)
단계 3: (Step 3: ( SS )-3-페닐아이소옥사졸리딘의 제조) Preparation of -3-phenylisoxazolidine
단계 2에서 제조한 tert-부틸 (S)-3-페닐아이소옥사졸리딘-2-카복실레이트(2.3 g)를 염화메틸렌(90 mL)에 녹인 후 TFA(14 mL)를 첨가하고 실온에서 1 시간 동안 반응하였다. 반응 혼합물을 중탄산나트륨 수용액으로 중화시킨 뒤 유기층을 합하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하여 중압액체크로마토그래피(THF/n-헥산)로 정제하여 목적 화합물(1.3 g, 94 %)을 수득하였다. tert -Butyl ( S )-3-phenylisoxazolidine-2-carboxylate (2.3 g) prepared in step 2 was dissolved in methylene chloride (90 mL), TFA (14 mL) was added, and 1 hour at room temperature reacted while The reaction mixture was neutralized with aqueous sodium bicarbonate solution, and then the organic layers were combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (THF/n - hexane) to obtain the target compound (1.3 g, 94 %).
MS (m/z): 150.08 [M+1]+ MS (m/z): 150.08 [M+1] +
1H NMR (400 MHz, DMSO-d 6) δ = 7.59 - 7.52 (m, 2H), 7.50 - 7.39 (m, 3H), 5.01 - 4.93 (m, 1H), 2.93 - 2.82 (m, 1H), 2.62 - 2.53 (m, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.59 - 7.52 (m, 2H), 7.50 - 7.39 (m, 3H), 5.01 - 4.93 (m, 1H), 2.93 - 2.82 (m, 1H), 2.62 - 2.53 (m, 2H)
<제조예2> (R)-3-페닐아이소옥사졸리딘의 제조<Preparation Example 2> Preparation of (R)-3-phenylisooxazolidine
Figure PCTKR2021018956-appb-img-000009
Figure PCTKR2021018956-appb-img-000009
상기 제조예 1과 유사한 방법으로 제조예 2를 제조하였으며, 이하 실시예의 제조시 사용하였다.Preparation Example 2 was prepared in a manner similar to Preparation Example 1, and was used in the preparation of Examples below.
MS (m/z) : 150.08 [M+1]+ MS (m/z): 150.08 [M+1] +
1H NMR (400 MHz, DMSO-d 6) δ = 7.59 - 7.52 (m, 2H), 7.50 - 7.39 (m, 3H), 5.01 - 4.93 (m, 1H), 2.93 - 2.82 (m, 1H), 2.62 - 2.53 (m, 2H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.59 - 7.52 (m, 2H), 7.50 - 7.39 (m, 3H), 5.01 - 4.93 (m, 1H), 2.93 - 2.82 (m, 1H), 2.62 - 2.53 (m, 2H)
<제조예 3> (<Preparation Example 3> ( SS )-3-(3-플루오로페닐)아이소옥사졸리딘)-3-(3-fluorophenyl)isoxazolidine
Figure PCTKR2021018956-appb-img-000010
Figure PCTKR2021018956-appb-img-000010
단계 1: 3-플루오로-Step 1: 3-Fluoro- N-N- 메톡시-methoxy- N-N- 메틸벤즈아마이드의 제조Preparation of methylbenzamide
3-플루오로벤조산(90 g, 642.3 mmol)을 피리딘(150 mL)에 녹인 후, N,O-다이메틸하이드록실아민 염산염(75.19 g, 770.81 mmol)을 첨가하였다. 그 후 15 ℃에서 EDCI(147.77 g, 770.8 mmol)를 첨가하였다. 반응 혼합물을 50 ℃에서 30 분 동안 교반하였다. TLC 분석결과(석유에터:아세트산에틸 = 3:1), 출발 물질이 모두 사라졌으며 낮은 극성을 가지는 새로운 스팟이 검출되었다. 감압 농축하여 용매를 제거하고, 염화메틸렌(500 mL)과 HCl(500 mL, 2 N), 소금물(200 mL)을 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하여 황색 오일의 목적 화합물(110 g, 94 %)을 수득하였다.3-fluorobenzoic acid (90 g, 642.3 mmol) was dissolved in pyridine (150 mL), and N,O -dimethylhydroxylamine hydrochloride (75.19 g, 770.81 mmol) was added thereto. EDCI (147.77 g, 770.8 mmol) was then added at 15 °C. The reaction mixture was stirred at 50 °C for 30 min. As a result of TLC analysis (petroleum ether:ethyl acetate = 3:1), all starting materials disappeared and a new spot with low polarity was detected. The solvent was removed by concentration under reduced pressure, and the organic layer was extracted using methylene chloride (500 mL), HCl (500 mL, 2 N), and brine (200 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound (110 g, 94 %) as a yellow oil.
단계 2: 1-(3-플루오로페닐)프로프-2-엔-1-온의 제조Step 2: Preparation of 1-(3-fluorophenyl)prop-2-en-1-one
단계 1에서 제조한 3-플루오로-N-메톡시-N-메틸벤즈아마이드(110 g, 600.5 mmol)를 THF(1 L)에 녹인 후, -78 ℃에서 브로모(비닐)마그네슘(1M, 630.53 mL)을 한 방울씩 적가하였다. 그 후, 반응 혼합물을 0 ℃에서 30 분 동안 교반하였다. TLC 분석 결과(석유에터:아세트산에틸 = 4:1), 출발 물질이 모두 사라졌으며, 낮은 극성을 가지는 새로운 스팟이 검출되었다. HCl(4 N, 500 mL)을 첨가하여 반응을 종결한 후, MTBE(2 L)와 소금물(500 mL)을 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후, 감압 농축하였다. 농축한 화합물을 중압크로마토그래피(석유에터/아세트산에틸 = 30/1)를 이용해 정제하여 황색 오일 상태의 목적 화합물(80 g, 89 %)을 수득하였다.After dissolving 3-fluoro- N -methoxy- N -methylbenzamide (110 g, 600.5 mmol) prepared in step 1 in THF (1 L), bromo(vinyl)magnesium (1M, 630.53 mL) was added dropwise. After that, the reaction mixture was stirred at 0 °C for 30 min. As a result of TLC analysis (petroleum ether:ethyl acetate = 4:1), all starting materials disappeared, and a new spot with low polarity was detected. After the reaction was terminated by addition of HCl (4 N, 500 mL), the organic layer was extracted using MTBE (2 L) and brine (500 mL). The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The concentrated compound was purified by medium pressure chromatography (petroleum ether/ethyl acetate = 30/1) to obtain the target compound as a yellow oil (80 g, 89%).
단계 3: 3-클로로-1-(3-플루오로페닐)프로판-1-온의 제조Step 3: Preparation of 3-chloro-1-(3-fluorophenyl)propan-1-one
단계 2에서 제조한 1-(3-플루오로페닐)프로프-2-엔-1-온(71 g, 472.86 mmol)을 염화메틸렌(71 mL)에 녹인 후, 0 ℃에서 HCl(4 M, 295.54 mL)을 첨가하였다. 그 후, 반응 혼합물을 15 ℃에서 1.5 시간 동안 교반하였다. TLC 분석 결과(석유에터:아세트산에틸 = 10:1), 출발 물질은 모두 사라졌으며, 목적 화합물이 검출되었다. 반응 혼합물을 감압 하에 농축한 후, 염화메틸렌(450 mL)과 물(200 mL * 5 회)을 첨가하여 유기층을 추출하였고, 황산나트륨으로 건조한 후 감압 농축하여 황색 고체의 목적 화합물 (73 g, 83 %)을 수득하였다.After dissolving 1-(3-fluorophenyl)prop-2-en-1-one (71 g, 472.86 mmol) prepared in step 2 in methylene chloride (71 mL), HCl (4 M, 295.54 mL) was added. After that, the reaction mixture was stirred at 15 °C for 1.5 hours. As a result of TLC analysis (petroleum ether:ethyl acetate = 10:1), all the starting materials disappeared, and the target compound was detected. After the reaction mixture was concentrated under reduced pressure, methylene chloride (450 mL) and water (200 mL * 5 times) were added to extract the organic layer, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a yellow solid (73 g, 83 %) ) was obtained.
1H NMR (400 MHz, CDCl3) δ = 7.78 - 7.72 (m, 1H), 7.69 - 7.60 (m, 1H), 7.53 - 7.44 (m, 1H), 7.37 - 7.24 (m, 1H), 3.93 (t, J = 6.8 Hz, 2H), 3.46 (t, J = 6.8 Hz, 2H) 1 H NMR (400 MHz, CDCl 3 ) δ = 7.78 - 7.72 (m, 1H), 7.69 - 7.60 (m, 1H), 7.53 - 7.44 (m, 1H), 7.37 - 7.24 (m, 1H), 3.93 ( t, J = 6.8 Hz, 2H), 3.46 (t, J = 6.8 Hz, 2H)
단계 4: (Step 4: ( RR )-3-클로로-1-(3-플루오로페닐)프로판-1-올의 제조Preparation of -3-chloro-1- (3-fluorophenyl) propan-1-ol
(S)-1-메틸-3,3-다이페닐테트라하이드로-1H,3H-피롤로[1,2-c][1,3,2]옥사자보롤(9.27 mL, 31.08 mmol)을 THF(380 mL)에 녹인 후, BH3.THF(1M, 186.48 mL)를 0 ℃에서 질소기류 하에 한 방울씩 첨가하였다. 반응 혼합물을 0 ℃에서 30 분간 교반하였다. 그 후, 반응 혼합물에 THF(390 mL)에 희석한 상기 단계 3에서 얻어진 3-클로로-1-(3-플루오로페닐)프로판-1-온(70 g, 375.11 mmol)을 0 ℃에서 한 방울씩 적가하였다. 반응 혼합물을 0 ℃에서 30 분 동안 교반하였다. TLC 분석 결과(석유에터:아세트산에틸 = 5:1), 출발 물질이 모두 사라졌으며, 목적 화합물 스팟이 검출되었다. 0 ℃에서 메탄올(100 mL)을 첨가하여 반응을 종결한 후, 용매를 감압 하에 날려주었다. 농축한 화합물을 염화메틸렌(100 mL * 3 회)과 염화암모늄 수용액(300 mL)을 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하였다. 농축한 화합물을 중압액체크로마토그래피(석유에터:아세트산에틸 = 50:1 내지 5:1)를 사용해 정제하여 무색의 오일(55 g, 92 %, 98.2 % purity, 54.1 % e.e.)을 수득하였다.( S )-1-methyl-3,3-diphenyltetrahydro- 1H , 3H -pyrrolo[1,2- c ][1,3,2]oxazaborol (9.27 mL, 31.08 mmol) After dissolving in THF (380 mL), BH 3 .THF (1M, 186.48 mL) was added dropwise at 0 °C under a nitrogen stream. The reaction mixture was stirred at 0 °C for 30 min. Thereafter, 3-chloro-1-(3-fluorophenyl)propan-1-one (70 g, 375.11 mmol) obtained in step 3 above diluted in THF (390 mL) was added to the reaction mixture at 0 ° C. dropwise. were added dropwise. The reaction mixture was stirred at 0 °C for 30 min. As a result of TLC analysis (petroleum ether:ethyl acetate = 5:1), all the starting materials disappeared, and a target compound spot was detected. After the reaction was terminated by adding methanol (100 mL) at 0 °C, the solvent was blown away under reduced pressure. The organic layer was extracted from the concentrated compound using methylene chloride (100 mL * 3 times) and ammonium chloride aqueous solution (300 mL). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The concentrated compound was purified using medium pressure liquid chromatography (petroleum ether:ethyl acetate = 50:1 to 5:1) to give a colorless oil (55 g, 92 %, 98.2 % purity, 54.1 % ee).
MS (m/z): 135.2 [M-56+H]＋ MS (m/z): 135.2 [M-56+H] +
1H NMR (400 MHz, CDCl3) δ = 7.35 - 7.28 (m, 1H), 7.19 - 7.04 (m, 2H), 7.01 - 6.91 (m, 1H), 5.00 - 4.88 (m, 1H), 3.76 - 3.70 (m, 1H), 3.60 - 3.51 (m, 1H), 2.24 - 2.13 (m, 1H), 2.12 - 1.98 (m, 2H) 1 H NMR (400 MHz, CDCl 3 ) δ = 7.35 - 7.28 (m, 1H), 7.19 - 7.04 (m, 2H), 7.01 - 6.91 (m, 1H), 5.00 - 4.88 (m, 1H), 3.76 - 3.70 (m, 1H), 3.60 - 3.51 (m, 1H), 2.24 - 2.13 (m, 1H), 2.12 - 1.98 (m, 2H)
단계 5: Step 5: terttert -부틸 (-Butyl ( RR )-(3-(3-플루오로페닐)-3-하이드록시프로폭시)카바메이트의 제조Preparation of )-(3-(3-fluorophenyl)-3-hydroxypropoxy)carbamate
tert-부틸 하이드록시카바메이트(40.76 g, 306.16 mmol)를 다이메틸포름아마이드(400 mL)에 녹인 후, 0 ℃에서 질소 기류 하에 수소화나트륨(12.83 g, 320.74 mmol, 60 % purity)을 첨가하였다. 반응 혼합물을 10 ℃에서 1 시간 동안 교반하고, 다이메틸포름아마이드(150 mL)에 단계 4에서 제조한 (R)-3-클로로-1-(3-플루오로페닐)프로판-1-올(55 g, 291.58 mmol)을 0 ℃에서 한 방울씩 첨가하고 10 ℃에서 16 시간 동안 교반하였다. TLC 분석 결과, 출발 물질은 모두 사라졌으며, 목적 화합물이 검출되었다. 물(800 mL)을 첨가하여 반응을 종결한 후, 생성된 고체를 필터하였다. 회수한 고체를 아세트산에틸(800 mL)과 물(100 mL), 소금물(100 mL)을 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하여 밝은 황색 고체의 목적 화합물(72 g, 65 %, 75.12 % purity)을 수득하였다. tert -Butyl hydroxycarbamate (40.76 g, 306.16 mmol) was dissolved in dimethylformamide (400 mL), and then sodium hydride (12.83 g, 320.74 mmol, 60 % purity) was added at 0° C. under a nitrogen stream. The reaction mixture was stirred at 10 °C for 1 hour, and ( R )-3-chloro-1-(3-fluorophenyl)propan-1-ol (55) prepared in step 4 was added to dimethylformamide (150 mL). g, 291.58 mmol) was added dropwise at 0 °C and stirred at 10 °C for 16 hours. As a result of TLC analysis, all the starting materials disappeared, and the target compound was detected. After the reaction was terminated by addition of water (800 mL), the resulting solid was filtered. The organic layer was extracted from the recovered solid using ethyl acetate (800 mL), water (100 mL), and brine (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound (72 g, 65 %, 75.12 % purity) as a light yellow solid.
MS (m/z) : 167.9 [M-118]＋ MS (m/z): 167.9 [M-118] +
1H NMR (400 MHz, CDCl3) δ = 7.17 - 7.06 (m, 1H), 7.01 - 6.93 (m, 2H), 6.80 - 6.73 (m, 1H), 4.89 - 4.79 (m, 1H), 3.95 - 3.89 (m, 1H), 3.88 - 3.82 (m, 1H), 1.89 - 1.81 (m, 1H), 1.80 - 1.69 (m, 1H), 1.32 (s, 9H) 1 H NMR (400 MHz, CDCl 3 ) δ = 7.17 - 7.06 (m, 1H), 7.01 - 6.93 (m, 2H), 6.80 - 6.73 (m, 1H), 4.89 - 4.79 (m, 1H), 3.95 - 3.89 (m, 1H), 3.88 - 3.82 (m, 1H), 1.89 - 1.81 (m, 1H), 1.80 - 1.69 (m, 1H), 1.32 (s, 9H)
단계 6: Step 6: terttert -부틸 (-Butyl ( SS )-3-(3-플루오로페닐)아이소옥사졸리딘-2-카복실레이트의 제조Preparation of )-3-(3-fluorophenyl)isoxazolidine-2-carboxylate
단계 5에서 제조한 tert-부틸 (R)-(3-(3-플루오로페닐)-3-하이드록시프로폭시)카바메이트(72 g, 252.36 mmol)와 트라이에틸아민(105.38 mL, 757.07 mmol)을 염화메틸렌(700 mL)에 녹인 후, 0 ℃에서 메테인설폰산 무수물(65.94 g, 378.53 mmol)을 천천히 첨가하였다. 반응 혼합물을 20 ℃에서 12 시간 동안 교반하였다. TLC 분석 결과(석유에터:아세트산에틸 = 3:1), 출발 물질은 모두 사라졌으며, 새로운 스팟이 검출되었다. 물(1000 mL)을 첨가하여 반응을 종결한 후, 염화메틸렌(200 mL * 3 회)을 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하였다. 농축한 화합물을 중압액체크로마토그래피(석유에터:아세트산에틸 = 50:1 내지 5:1)로 정제하여 57.7 % e.e 값을 가지는 목적 화합물 35 g을 추출하였다. 목적 화합물을 SFC(column : DAICEL CHIRALPAK AD-H (250 mm X 30 mm, 5 ㎛); mobile phase: [Neu-메탄올]; B % : 15 %, 2.9 min; 760 min)을 통해 정제하여 밝은 황색 고체의 tert-부틸 (S)-3-(3-플루오로페닐)아이소옥사졸리딘-2-카복실레이트(25 g, 36 %, 98.37 % purity, 100 % e.e.)와 tert-부틸 (R)-3-(3-플루오로페닐)아이소옥사졸리딘-2-카복실레이트(6.5 g, 8.7 %, 91.13 % purity, 100 % e.e.)를 수득하였다. tert -Butyl ( R )-(3-(3-fluorophenyl)-3-hydroxypropoxy)carbamate (72 g, 252.36 mmol) prepared in step 5 and triethylamine (105.38 mL, 757.07 mmol) was dissolved in methylene chloride (700 mL), and methanesulfonic anhydride (65.94 g, 378.53 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 20 °C for 12 h. As a result of TLC analysis (petroleum ether:ethyl acetate = 3:1), all starting materials disappeared and a new spot was detected. After the reaction was terminated by adding water (1000 mL), the organic layer was extracted using methylene chloride (200 mL * 3 times). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The concentrated compound was purified by medium pressure liquid chromatography (petroleum ether: ethyl acetate = 50:1 to 5:1) to extract 35 g of the target compound having a 57.7% ee value. The target compound was purified through SFC (column: DAICEL CHIRALPAK AD-H (250 mm X 30 mm, 5 μm); mobile phase: [Neu-methanol]; B %: 15 %, 2.9 min; 760 min) to light yellow Solid tert -butyl ( S )-3-(3-fluorophenyl)isoxazolidine-2-carboxylate (25 g, 36 %, 98.37 % purity, 100 % ee) and tert -butyl ( R )- 3-(3-fluorophenyl)isoxazolidine-2-carboxylate (6.5 g, 8.7 %, 91.13 % purity, 100 % ee) was obtained.
MS (m/z): 212.2 [M-56+H]＋ MS (m/z): 212.2 [M-56+H] +
1H NMR (400 MHz, CDCl3) δ = 7.34 - 7.27 (m, 1H), 7.17 - 7.05 (m, 2H), 6.99 - 6.91 (m, 1H), 5.20 (dd, J = 5.6, 8.8 Hz, 1H), 4.22 - 4.14 (m, 1H), 3.94 - 3.84 (m, 1H), 2.84 - 2.73 (m, 1H), 2.34 - 2.22 (m, 1H), 1.47 (s, 9H) 1 H NMR (400 MHz, CDCl 3 ) δ = 7.34 - 7.27 (m, 1H), 7.17 - 7.05 (m, 2H), 6.99 - 6.91 (m, 1H), 5.20 (dd, J = 5.6, 8.8 Hz, 1H), 4.22 - 4.14 (m, 1H), 3.94 - 3.84 (m, 1H), 2.84 - 2.73 (m, 1H), 2.34 - 2.22 (m, 1H), 1.47 (s, 9H)
단계 7: (Step 7: ( SS )-3-(3-플루오로페닐)아이소옥사졸리딘의 제조Preparation of )-3-(3-fluorophenyl)isoxazolidine
단계 6에서 제조한 tert-부틸 (S)-3-(3-플루오로페닐)아이소옥사졸리딘-2-카복실레이트(25 g, 93.53 mmol)를 아세트산에틸(50 mL)에 녹인 후, 0 ℃에서 HCl/아세트산에틸(4M, 250 mL)을 첨가하였다. 그 후, 반응 혼합물을 10 ℃에서 1 시간 동안 교반하였다. LCMS 분석 결과, 출발 물질이 모두 사라졌고 목적 스팟이 검출되었다. 고체를 얻기 위해 감압 농축하여 백색 고체의 목적 화합물(19.12 g, 93 %, 92.35 % purity, HCl, 99.91 % e.e.)을 수득하였다.After dissolving tert -butyl ( S )-3-(3-fluorophenyl)isoxazolidine-2-carboxylate (25 g, 93.53 mmol) prepared in step 6 in ethyl acetate (50 mL), 0 °C HCl/ethyl acetate (4M, 250 mL) was added. After that, the reaction mixture was stirred at 10 °C for 1 hour. As a result of LCMS analysis, all of the starting material disappeared and the target spot was detected. The target compound (19.12 g, 93 %, 92.35 % purity, HCl, 99.91 % ee) was obtained as a white solid by concentration under reduced pressure to obtain a solid.
MS (m/z): 168.3 [M+H]＋ MS (m/z): 168.3 [M+H] +
1H NMR (400 MHz, DMSO-d 6) δ = 12.51 (br s, 1H), 7.55 - 7.44 (m, 2H), 7.44 - 7.37 (m, 1H), 7.32 - 7.22 (m, 1H), 5.03 (t, J = 8.0 Hz, 1H), 4.54 - 4.43 (m, 1H), 4.34 - 4.24 (m, 1H), 2.95 - 2.83 (m, 1H), 2.64 - 2.52 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 12.51 (br s, 1H), 7.55 - 7.44 (m, 2H), 7.44 - 7.37 (m, 1H), 7.32 - 7.22 (m, 1H), 5.03 (t, J = 8.0 Hz, 1H), 4.54 - 4.43 (m, 1H), 4.34 - 4.24 (m, 1H), 2.95 - 2.83 (m, 1H), 2.64 - 2.52 (m, 1H)
상기 제조예 1 내지 3과 유사한 방법으로 제조예 4 내지 25를 제조하였으며, 제조예 4 내지 25의 화합물명, 화학구조식, NMR분석 결과를 아래에 나타내었고 이하 실시예의 제조시 사용하였다.Preparation Examples 4 to 25 were prepared in a manner similar to Preparation Examples 1 to 3, and the compound names, chemical structural formulas, and NMR analysis results of Preparation Examples 4 to 25 were shown below and were used in the preparation of Examples below.
<제조예 4> (<Preparation Example 4> ( SS )-3-(4-플루오로페닐)아이소옥사졸리딘)-3-(4-fluorophenyl)isoxazolidine
Figure PCTKR2021018956-appb-img-000011
Figure PCTKR2021018956-appb-img-000011
1H NMR (400 MHz, DMSO-d 6) δ 7.66 - 7.60 (m, 2H), 7.34 - 7.26 (m, 2H), 5.00 (t, J = 8.0 Hz, 1H), 4.49 (td, J = 8.1, 4.0 Hz, 1H), 4.29 (q, J = 7.7 Hz, 1H), 2.87 (dtd, J = 12.6, 7.5, 4.0 Hz, 1H), 2.62 - 2.52 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.66 - 7.60 (m, 2H), 7.34 - 7.26 (m, 2H), 5.00 (t, J = 8.0 Hz, 1H), 4.49 (td, J = 8.1) , 4.0 Hz, 1H), 4.29 (q, J = 7.7 Hz, 1H), 2.87 (dtd, J = 12.6, 7.5, 4.0 Hz, 1H), 2.62 - 2.52 (m, 1H)
<제조예 5> (<Preparation Example 5> ( SS )-3-(3,5-다이플루오로페닐)아이소옥사졸리딘)-3-(3,5-difluorophenyl)isoxazolidine
Figure PCTKR2021018956-appb-img-000012
Figure PCTKR2021018956-appb-img-000012
1H NMR (400 MHz, DMSO-d 6) δ = 7.36 - 7.28 (m, 3H), 5.04 - 4.98 (t, J = 7.6 Hz, 1H), 4.47 - 4.38 (m, 1H), 4.25 - 4.19 (dd, J = 7.6, 15.2 Hz, 1H), 2.89 - 2.81 (m, 1H), 2.58 - 2.51 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.36 - 7.28 (m, 3H), 5.04 - 4.98 (t, J = 7.6 Hz, 1H), 4.47 - 4.38 (m, 1H), 4.25 - 4.19 ( dd, J = 7.6, 15.2 Hz, 1H), 2.89 - 2.81 (m, 1H), 2.58 - 2.51 (m, 1H)
<제조예 6> (<Preparation Example 6> ( RR )-3-(3,5-다이플루오로페닐)아이소옥사졸리딘)-3-(3,5-difluorophenyl)isoxazolidine
Figure PCTKR2021018956-appb-img-000013
Figure PCTKR2021018956-appb-img-000013
1H NMR (400 MHz, DMSO-d 6) δ = 7.36 - 7.28 (m, 3H), 5.04 - 4.98 (t, J = 7.6 Hz, 1H), 4.47 - 4.38 (m, 1H), 4.25 - 4.19 (dd, J = 7.6, 15.2 Hz, 1H), 2.89 - 2.81 (m, 1H), 2.58 - 2.51 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.36 - 7.28 (m, 3H), 5.04 - 4.98 (t, J = 7.6 Hz, 1H), 4.47 - 4.38 (m, 1H), 4.25 - 4.19 ( dd, J = 7.6, 15.2 Hz, 1H), 2.89 - 2.81 (m, 1H), 2.58 - 2.51 (m, 1H)
<제조예 7> (<Preparation Example 7> ( SS )-3-(2,6-다이플루오로페닐)아이소옥사졸리딘)-3-(2,6-difluorophenyl)isoxazolidine
Figure PCTKR2021018956-appb-img-000014
Figure PCTKR2021018956-appb-img-000014
1H NMR (400 MHz, DMSO-d 6) δ 7.55 (tt, J = 8.5, 6.5 Hz, 1H), 7.27 - 7.15 (m, 2H), 5.19 (t, J = 8.2 Hz, 1H), 4.47 (td, J = 8.0, 3.9 Hz, 1H), 4.19 (q, J = 8.0 Hz, 1H), 2.95 - 2.77 (m, 1H), 2.57 (dq, J = 12.3, 8.0 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.55 (tt, J = 8.5, 6.5 Hz, 1H), 7.27 - 7.15 (m, 2H), 5.19 (t, J = 8.2 Hz, 1H), 4.47 ( td, J = 8.0, 3.9 Hz, 1H), 4.19 (q, J = 8.0 Hz, 1H), 2.95 - 2.77 (m, 1H), 2.57 (dq, J = 12.3, 8.0 Hz, 1H)
<제조예 8> (<Preparation Example 8> ( SS )-3-(2,3,4-트라이플루오로페닐)아이소옥사졸리딘)-3-(2,3,4-trifluorophenyl)isoxazolidine
Figure PCTKR2021018956-appb-img-000015
Figure PCTKR2021018956-appb-img-000015
1H NMR (400 MHz, DMSO-d 6) δ 7.37 - 7.21 (m, 2H), 6.59 (s, 1H), 4.70 - 4.57 (m, 1H), 3.95 (td, J = 8.0, 4.8 Hz, 1H), 3.74 - 3.57 (m, 1H), 2.65 (dtd, J = 12.0, 8.7, 4.8 Hz, 1H), 2.13 - 2.01 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.37 - 7.21 (m, 2H), 6.59 (s, 1H), 4.70 - 4.57 (m, 1H), 3.95 (td, J = 8.0, 4.8 Hz, 1H) ), 3.74 - 3.57 (m, 1H), 2.65 (dtd, J = 12.0, 8.7, 4.8 Hz, 1H), 2.13 - 2.01 (m, 1H)
<제조예 9> (<Preparation Example 9> ( SS )-3-(2-플루오로-3-메틸페닐)아이소옥사졸리딘)-3-(2-fluoro-3-methylphenyl)isoxazolidine
Figure PCTKR2021018956-appb-img-000016
Figure PCTKR2021018956-appb-img-000016
1H NMR (400 MHz, DMSO-d 6) δ 7.32 (td, J = 7.4, 1.8 Hz, 1H), 7.14 (td, J = 7.5, 1.9 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 4.59 (dd, J = 8.6, 4.7 Hz, 1H), 3.92 (td, J = 8.0, 5.0 Hz, 1H), 3.75 - 3.67 (m, 1H), 2.62 (dtd, J = 12.1, 8.6, 5.1 Hz, 1H), 2.22 (d, J = 2.2 Hz, 3H), 2.03 (ttd, J = 10.8, 5.9, 5.3, 2.4 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.32 (td, J = 7.4, 1.8 Hz, 1H), 7.14 (td, J = 7.5, 1.9 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 4.59 (dd, J = 8.6, 4.7 Hz, 1H), 3.92 (td, J = 8.0, 5.0 Hz, 1H), 3.75 - 3.67 (m, 1H), 2.62 (dtd, J = 12.1, 8.6, 5.1 Hz, 1H), 2.22 (d, J = 2.2 Hz, 3H), 2.03 (ttd, J = 10.8, 5.9, 5.3, 2.4 Hz, 1H)
<제조예 10> (<Production Example 10> ( SS )-3-(아이소옥사졸리딘-3-일)-)-3-(isoxazolidin-3-yl)- NN ,, NN -다이메틸아닐린-dimethylaniline
Figure PCTKR2021018956-appb-img-000017
Figure PCTKR2021018956-appb-img-000017
1H NMR (400 MHz, CDCl3) δ 7.23 - 7.17 (m, 1H), 6.81 - 6.60 (m, 3H), 4.46 - 4.34 (m, 1H), 4.02 (dq, J = 14.0, 7.5, 7.1 Hz, 2H), 2.94 (s, 6H), 2.63 (dtd, J = 12.2, 8.1, 6.7 Hz, 1H), 2.36 - 2.20 (m, 1H) 1 H NMR (400 MHz, CDCl 3 ) δ 7.23 - 7.17 (m, 1H), 6.81 - 6.60 (m, 3H), 4.46 - 4.34 (m, 1H), 4.02 (dq, J = 14.0, 7.5, 7.1 Hz) , 2H), 2.94 (s, 6H), 2.63 (dtd, J = 12.2, 8.1, 6.7 Hz, 1H), 2.36 - 2.20 (m, 1H)
<제조예 11> (<Preparation Example 11> ( SS )-3-(아이소옥사졸리딘-3-일)-)-3-(isoxazolidin-3-yl)- N,NN, N -다이메틸벤즈아마이드-Dimethylbenzamide
Figure PCTKR2021018956-appb-img-000018
Figure PCTKR2021018956-appb-img-000018
1H NMR (400 MHz, DMSO-d 6) δ = 7.96 (t, J = 2.8 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.67 - 7.58 (m, 1H), 7.46 (t, J = 7.7 Hz, 1H), 5.19 - 5.07 (m, 1H), 4.15 - 4.05 (m, 1H), 3.97 - 3.86 (m, 1H), 2.70 - 2.58 (m, 1H), 2.14 - 2.01 (m, 1H), 1.32 (d, J = 6.3 Hz, 6H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.96 (t, J = 2.8 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.67 - 7.58 (m, 1H), 7.46 (t) , J = 7.7 Hz, 1H), 5.19 - 5.07 (m, 1H), 4.15 - 4.05 (m, 1H), 3.97 - 3.86 (m, 1H), 2.70 - 2.58 (m, 1H), 2.14 - 2.01 (m) , 1H), 1.32 (d, J = 6.3 Hz, 6H)
<제조예 12> (<Preparation Example 12> ( SS )-3-(3-(트라이플루오로메틸)페닐)아이소옥사졸리딘)-3-(3-(trifluoromethyl)phenyl)isoxazolidine
Figure PCTKR2021018956-appb-img-000019
Figure PCTKR2021018956-appb-img-000019
1H NMR (400 MHz, CDCl3) δ 7.70 - 7.40 (m, 4H), 4.57 (dd, J = 8.4, 5.4 Hz, 1H), 4.10 (td, J = 8.3, 5.2 Hz, 1H), 3.99 - 3.86 (m, 1H), 2.82 - 2.59 (m, 1H), 2.28 (dddd, J = 12.4, 8.5, 7.1, 5.3 Hz, 1H) 1 H NMR (400 MHz, CDCl 3 ) δ 7.70 - 7.40 (m, 4H), 4.57 (dd, J = 8.4, 5.4 Hz, 1H), 4.10 (td, J = 8.3, 5.2 Hz, 1H), 3.99 - 3.86 (m, 1H), 2.82 - 2.59 (m, 1H), 2.28 (dddd, J = 12.4, 8.5, 7.1, 5.3 Hz, 1H)
<제조예 13> (<Preparation Example 13> ( SS )-3-(아이소옥사졸리딘-3-일)벤조나이트릴)-3-(isoxazolidin-3-yl)benzonitrile
Figure PCTKR2021018956-appb-img-000020
Figure PCTKR2021018956-appb-img-000020
1H NMR (400 MHz, DMSO-d 6) δ = 7.89 (m, 1H), 7.79 (s, 1H), 7.64 (m, 1H), 4.61 - 4.43 (m, 1H), 3.92 (td, J = 8.0, 4.8 Hz, 1H), 3.77 - 3.56 (m, 1H), 2.66 (dtd, J = 12.0, 8.6, 4.9 Hz, 1H), 2.06 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.89 (m, 1H), 7.79 (s, 1H), 7.64 (m, 1H), 4.61 - 4.43 (m, 1H), 3.92 (td, J = 8.0, 4.8 Hz, 1H), 3.77 - 3.56 (m, 1H), 2.66 (dtd, J = 12.0, 8.6, 4.9 Hz, 1H), 2.06 (m, 1H)
<제조예 14> (<Preparation Example 14> ( SS )-4-(아이소옥사졸리딘-3-일)벤조나이트릴)-4-(isoxazolidin-3-yl)benzonitrile
Figure PCTKR2021018956-appb-img-000021
Figure PCTKR2021018956-appb-img-000021
1H NMR (400 MHz, DMSO-d 6) δ 7.81 - 7.74 (m, 2H), 7.57 (d, J = 8.2 Hz, 2H), 6.55 (s, 1H), 4.61 - 4.43 (m, 1H), 3.92 (td, J = 8.0, 4.8 Hz, 1H), 3.77 - 3.56 (m, 1H), 2.66 (dtd, J = 12.0, 8.6, 4.9 Hz, 1H), 2.06 (dddd, J = 11.9, 8.5, 7.2, 4.6 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.81 - 7.74 (m, 2H), 7.57 (d, J = 8.2 Hz, 2H), 6.55 (s, 1H), 4.61 - 4.43 (m, 1H), 3.92 (td, J = 8.0, 4.8 Hz, 1H), 3.77 - 3.56 (m, 1H), 2.66 (dtd, J = 12.0, 8.6, 4.9 Hz, 1H), 2.06 (dddd, J = 11.9, 8.5, 7.2) , 4.6 Hz, 1H)
<제조예 15> (<Preparation Example 15> ( SS )-3-(3-메톡시페닐)아이소옥사졸리딘)-3-(3-methoxyphenyl)isoxazolidine
Figure PCTKR2021018956-appb-img-000022
Figure PCTKR2021018956-appb-img-000022
1H NMR (400 MHz, DMSO-d 6) δ = 7.37 (t, J = 8.0 Hz, 1H), 7.23 - 7.20 (m, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.01 (dd, J = 8.3, 2.5 Hz, 1H), 4.96 (t, J = 8.1 Hz, 1H), 4.49 (td, J = 8.1, 4.0 Hz, 1H), 4.30 (q, J = 7.7 Hz, 1H), 3.79 (s, 3H), 2.88 (dtd, J = 11.5, 7.4, 4.0 Hz, 1H), 2.58 (dq, J = 12.5, 8.5 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.37 (t, J = 8.0 Hz, 1H), 7.23 - 7.20 (m, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.01 (dd , J = 8.3, 2.5 Hz, 1H), 4.96 (t, J = 8.1 Hz, 1H), 4.49 (td, J = 8.1, 4.0 Hz, 1H), 4.30 (q, J = 7.7 Hz, 1H), 3.79 (s, 3H), 2.88 (dtd, J = 11.5, 7.4, 4.0 Hz, 1H), 2.58 (dq, J = 12.5, 8.5 Hz, 1H)
<제조예 16> (<Preparation Example 16> ( SS )-3-(피리딘-3-일)아이소옥사졸리딘)-3-(pyridin-3-yl)isoxazolidine
Figure PCTKR2021018956-appb-img-000023
Figure PCTKR2021018956-appb-img-000023
1H NMR (400 MHz, DMSO-d 6) δ = 9.09 - 9.08 (d, J = 1.6 Hz, 1H), 8.96 - 8.95 (d, J = 5.2 Hz 1H), 8.76 - 8.74 (m, 1H), 8.15 - 8.12 (dd, J = 5.6 Hz, 8.0 Hz, 1H), 5.34 - 5.30 (m, 1H), 4.52 - 4.48 (m, 1H), 4.29 - 4.25 (m, 1H), 2.94 - 2.91 (m, 1H), 2.69 - 2.66 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.09 - 9.08 (d, J = 1.6 Hz, 1H), 8.96 - 8.95 (d, J = 5.2 Hz 1H), 8.76 - 8.74 (m, 1H), 8.15 - 8.12 (dd, J = 5.6 Hz, 8.0 Hz, 1H), 5.34 - 5.30 (m, 1H), 4.52 - 4.48 (m, 1H), 4.29 - 4.25 (m, 1H), 2.94 - 2.91 (m, 1H), 2.69 - 2.66 (m, 1H)
<제조예 17><Production Example 17> (( SS )-3-(6-메틸피리딘-3-일)아이소옥사졸리딘)-3-(6-methylpyridin-3-yl)isoxazolidine
Figure PCTKR2021018956-appb-img-000024
Figure PCTKR2021018956-appb-img-000024
1H NMR (400 MHz, MeOD) δ = 8.98 (d, J = 2.0 Hz, 1H), 8.71 - 8.68 (dd, J = 2.0, 8.4 Hz, 1H), 8.09 - 8.07 (d, J = 8.4 Hz, 1H), 5.53 - 5.49 (dd, J = 6.8, 8.0 Hz, 1H), 4.79 - 4.75 (m, 1H), 4.49 - 4.43 (m, 1H), 3.17 - 3.11 (m, 1H), 2.94 - 2.78 (m, 4H) 1 H NMR (400 MHz, MeOD) δ = 8.98 (d, J = 2.0 Hz, 1H), 8.71 - 8.68 (dd, J = 2.0, 8.4 Hz, 1H), 8.09 - 8.07 (d, J = 8.4 Hz, 1H), 5.53 - 5.49 (dd, J = 6.8, 8.0 Hz, 1H), 4.79 - 4.75 (m, 1H), 4.49 - 4.43 (m, 1H), 3.17 - 3.11 (m, 1H), 2.94 - 2.78 ( m, 4H)
<제조예 18> (<Preparation Example 18> ( SS )-5-(아이소옥사졸리딘-3-일)니코티노나이트릴)-5-(isooxazolidin-3-yl)nicotinonitrile
Figure PCTKR2021018956-appb-img-000025
Figure PCTKR2021018956-appb-img-000025
1H NMR (400 MHz, CDCl3) δ = 8.79 - 8.76 (dd, J = 2.0, 12.4 Hz, 2H), 8.09 (s, 1H), 5.58 (br s, 1H), 4.67 - 4.66 (m, 1H), 4.19 - 4.14 (m, 1H), 3.84 - 3.82 (m, 1H), 2.82 - 2.77 (m, 1H), 2.29 - 2.25 (m, 1H) 1 H NMR (400 MHz, CDCl 3 ) δ = 8.79 - 8.76 (dd, J = 2.0, 12.4 Hz, 2H), 8.09 (s, 1H), 5.58 (br s, 1H), 4.67 - 4.66 (m, 1H) ), 4.19 - 4.14 (m, 1H), 3.84 - 3.82 (m, 1H), 2.82 - 2.77 (m, 1H), 2.29 - 2.25 (m, 1H)
<제조예 19> (<Production Example 19> ( SS )-3-(싸이오펜-2-일)아이소옥사졸리딘)-3-(thiophen-2-yl)isoxazolidine
Figure PCTKR2021018956-appb-img-000026
Figure PCTKR2021018956-appb-img-000026
1H NMR (400 MHz, DMSO-d 6) δ = 7.38 (m, 1H), 6.97 (m, 1H), 6.87 (m, 1H), 4.67 - 4.66 (m, 1H), 4.19 - 4.14 (m, 1H), 3.84 - 3.82 (m, 1H), 2.82 - 2.77 (m, 1H), 2.29 - 2.25 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.38 (m, 1H), 6.97 (m, 1H), 6.87 (m, 1H), 4.67 - 4.66 (m, 1H), 4.19 - 4.14 (m, 1H), 3.84 - 3.82 (m, 1H), 2.82 - 2.77 (m, 1H), 2.29 - 2.25 (m, 1H)
<제조예 20> (<Preparation Example 20> ( SS )-3-(나프탈렌-1-일)아이소옥사졸리딘)-3-(naphthalen-1-yl)isoxazolidine
Figure PCTKR2021018956-appb-img-000027
Figure PCTKR2021018956-appb-img-000027
1H NMR (400 MHz, DMSO-d 6) δ 8.13 (d, J = 8.2 Hz, 1H), 7.93 (dd, J = 7.6, 1.7 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.59 - 7.49 (m, 2H), 7.47 (dd, J = 8.2, 7.2 Hz, 1H), 6.61 (s, 1H), 5.08 (s, 1H), 3.94 (td, J = 8.0, 4.8 Hz, 1H), 3.76 (s, 1H), 2.93 - 2.76 (m, 1H), 2.07 (d, J = 11.5 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.13 (d, J = 8.2 Hz, 1H), 7.93 (dd, J = 7.6, 1.7 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H) , 7.70 (d, J = 7.2 Hz, 1H), 7.59 - 7.49 (m, 2H), 7.47 (dd, J = 8.2, 7.2 Hz, 1H), 6.61 (s, 1H), 5.08 (s, 1H), 3.94 (td, J = 8.0, 4.8 Hz, 1H), 3.76 (s, 1H), 2.93 - 2.76 (m, 1H), 2.07 (d, J = 11.5 Hz, 1H)
<제조예 21> (<Preparation Example 21> ( SS )-3-(4-(트라이플루오로메틸)싸이아졸-2-일)아이소옥사졸리딘)-3-(4-(trifluoromethyl)thiazol-2-yl)isoxazolidine
Figure PCTKR2021018956-appb-img-000028
Figure PCTKR2021018956-appb-img-000028
1H NMR (400 MHz, CDCl3) δ = 7.71 (s, 1H), 5.76 (br d, J = 4.4 Hz, 1H), 4.91 - 4.88 (m, 1H), 4.20 - 4.15 (m, 1H), 3.80 (m, 1H), 2.81 - 2.76 (m, 2H) 1 H NMR (400 MHz, CDCl 3 ) δ = 7.71 (s, 1H), 5.76 (br d, J = 4.4 Hz, 1H), 4.91 - 4.88 (m, 1H), 4.20 - 4.15 (m, 1H), 3.80 (m, 1H), 2.81 - 2.76 (m, 2H)
<제조예 22> (<Preparation Example 22> ( SS )-3-(나프탈렌-2-일)아이소옥사졸리딘)-3-(naphthalen-2-yl)isoxazolidine
Figure PCTKR2021018956-appb-img-000029
Figure PCTKR2021018956-appb-img-000029
1H NMR (400 MHz, DMSO-d 6) δ 7.93 - 7.82 (m, 4H), 7.60 - 7.40 (m, 3H), 6.47 (s, 1H), 4.49 (d, J = 36.8 Hz, 1H), 4.02 - 3.90 (m, 1H), 3.88 - 3.70 (m, 1H), 2.67 (dtd, J = 11.9, 8.4, 5.2 Hz, 1H), 2.19 (dddd, J = 12.1, 8.5, 6.9, 5.4 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.93 - 7.82 (m, 4H), 7.60 - 7.40 (m, 3H), 6.47 (s, 1H), 4.49 (d, J = 36.8 Hz, 1H), 4.02 - 3.90 (m, 1H), 3.88 - 3.70 (m, 1H), 2.67 (dtd, J = 11.9, 8.4, 5.2 Hz, 1H), 2.19 (dddd, J = 12.1, 8.5, 6.9, 5.4 Hz, 1H )
<제조예 23> (<Preparation Example 23> ( SS )-3-([1,1'-바이페닐]-3-일)아이소옥사졸리딘)-3-([1,1'-biphenyl]-3-yl)isoxazolidine
Figure PCTKR2021018956-appb-img-000030
Figure PCTKR2021018956-appb-img-000030
1H NMR (400 MHz, CDCl3) δ 7.59 (dt, J = 8.1, 1.6 Hz, 3H), 7.54 - 7.48 (m, 1H), 7.43 (dt, J = 7.5, 6.5 Hz, 3H), 7.39 - 7.31 (m, 2H), 4.53 (d, J = 14.4 Hz, 1H), 4.09 (s, 2H), 2.71 (dtd, J = 12.2, 8.1, 5.9 Hz, 1H), 2.35 (ddt, J = 12.5, 8.1, 6.4 Hz, 1H) 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (dt, J = 8.1, 1.6 Hz, 3H), 7.54 - 7.48 (m, 1H), 7.43 (dt, J = 7.5, 6.5 Hz, 3H), 7.39 - 7.31 (m, 2H), 4.53 (d, J = 14.4 Hz, 1H), 4.09 (s, 2H), 2.71 (dtd, J = 12.2, 8.1, 5.9 Hz, 1H), 2.35 (ddt, J = 12.5, 8.1, 6.4 Hz, 1H)
<제조예 24> (<Production Example 24> ( SS )-3-(3-페녹시페닐)아이소옥사졸리딘)-3-(3-phenoxyphenyl)isoxazolidine
Figure PCTKR2021018956-appb-img-000031
Figure PCTKR2021018956-appb-img-000031
1H NMR (400 MHz, DMSO-d 6) δ = 7.42 (m, 2H), 7.18 (m, 2H), 7.06 (m, 5H), 4.25 - 4.19 (dd, J = 7.6, 15.2 Hz, 1H), 2.89 - 2.81 (m, 1H), 2.58 - 2.51 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 7.42 (m, 2H), 7.18 (m, 2H), 7.06 (m, 5H), 4.25 - 4.19 (dd, J = 7.6, 15.2 Hz, 1H) , 2.89 - 2.81 (m, 1H), 2.58 - 2.51 (m, 1H)
<제조예 25> (<Production Example 25> ( SS )-3-(3-(벤질옥시)페닐)아이소옥사졸리딘)-3-(3-(benzyloxy)phenyl)isoxazolidine
Figure PCTKR2021018956-appb-img-000032
Figure PCTKR2021018956-appb-img-000032
1H NMR (400 MHz, DMSO-d 6) δ 7.50 - 7.28 (m, 5H), 7.22 (t, J = 7.9 Hz, 1H), 7.05 (s, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.91 - 6.83 (m, 1H), 5.08 (s, 2H), 4.36 (q, J = 20.5, 15.3 Hz, 1H), 3.89 (td, J = 8.0, 5.4 Hz, 1H), 3.37 (d, J = 10.2 Hz, 1H), 2.57 (tt, J = 8.1, 4.4 Hz, 1H), 2.06 (ddt, J = 12.2, 7.9, 6.0 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.50 - 7.28 (m, 5H), 7.22 (t, J = 7.9 Hz, 1H), 7.05 (s, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.91 - 6.83 (m, 1H), 5.08 (s, 2H), 4.36 (q, J = 20.5, 15.3 Hz, 1H), 3.89 (td, J = 8.0, 5.4 Hz, 1H), 3.37 (d) , J = 10.2 Hz, 1H), 2.57 (tt, J = 8.1, 4.4 Hz, 1H), 2.06 (ddt, J = 12.2, 7.9, 6.0 Hz, 1H)
실시예 1. (Example 1. ( SS )-)- NN -(4-(4-메틸피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민의 제조Preparation of -(4-(4-methylpiperidin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine
Figure PCTKR2021018956-appb-img-000033
Figure PCTKR2021018956-appb-img-000033
단계 1: (Step 1: ( SS )-2-(2-클로로피리미딘-4-일)-3-페닐아이소옥사졸리딘의 제조Preparation of )-2-(2-chloropyrimidin-4-yl)-3-phenylisoxazolidine
2,4-다이클로로피리미딘(1 g, 6.7 mmol), (S)-3-페닐아이소옥사졸리딘(1 g, 6.7 mmol)과 DIPEA(2.3 mL, 13.4 mmol)를 넣고 DMSO(20 mL)를 첨가하여 60 ℃에서 2 시간 동안 교반하였다. 반응 종결 후 반응 혼합물을 과량의 물에 넣고 생성된 고체를 필터하여 목적 화합물(1.2 g, 68 %)을 수득하였다.Add 2,4-dichloropyrimidine (1 g, 6.7 mmol), ( S )-3-phenylisoxazolidine (1 g, 6.7 mmol) and DIPEA (2.3 mL, 13.4 mmol), and DMSO (20 mL) was added and stirred at 60 °C for 2 hours. After completion of the reaction, the reaction mixture was added to excess water, and the resulting solid was filtered to obtain the target compound (1.2 g, 68%).
MS (m/z): 262.8 [M+1]+ MS (m/z): 262.8 [M+1] +
단계 2: (Step 2: ( SS )-)- NN -(4-(4-메틸피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민의 제조Preparation of -(4-(4-methylpiperidin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine
단계 1에서 제조한 (S)-2-(2-클로로피리미딘-4-일)-3-페닐아이소옥사졸리딘(100 mg, 0.38 mmol), 4-(4-메틸피페라진-1-일)아닐린(110 mg, 0.57 mmol) 및 탄산칼륨(158 mg, 1.152 mmol)을 sec-BuOH(1 mL)에 녹인 후 질소를 흘리면서 5 분 동안 초음파 처리하였다. 반응 혼합물에 Pd2(dba)3(35 mg, 0.140 mmol), XPhos(36 mg, 0.04 mmol)를 첨가한 후 100 ℃에서 2 시간 동안 교반하였다. 반응 혼합물을 Celite로 여과하고, 아세트산에틸로 씻어 주었다. 얻어진 여과액을 소금물로 씻어 유기층을 모아 황산나트륨으로 건조하였다. 감압 하에 농축한 후 중압액체크로마토그래피(메탄올/염화메틸렌 0 ~ 10 %)로 정제하여 목적 화합물(0.1 g, 63 %)을 수득하였다.Prepared in Step 1 ( S )-2-(2-chloropyrimidin-4-yl)-3-phenylisoxazolidin (100 mg, 0.38 mmol), 4-(4-methylpiperazin-1-yl) ) Aniline (110 mg, 0.57 mmol) and potassium carbonate (158 mg, 1.152 mmol) were dissolved in sec -BuOH (1 mL) and then sonicated for 5 minutes while flowing nitrogen. Pd 2 (dba) 3 (35 mg, 0.140 mmol) and XPhos (36 mg, 0.04 mmol) were added to the reaction mixture, followed by stirring at 100° C. for 2 hours. The reaction mixture was filtered through Celite and washed with ethyl acetate. The obtained filtrate was washed with brine, and the organic layers were collected and dried over sodium sulfate. After concentration under reduced pressure, it was purified by medium pressure liquid chromatography (methanol/methylene chloride 0 to 10%) to obtain the target compound (0.1 g, 63%).
MS (m/z): 417.4 [M+1]+ MS (m/z): 417.4 [M+1] +
1H NMR (400 MHz, DMSO-d6) δ = 9.87 (s, 1H), 9.54 (s, 1H), 8.59 (s, 2H), 7.92 - 7.88 (m, 2H), 7.65 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.50 (d, J = 0.9 Hz, 1H), 7.38 (dd, J = 7.2, 1.2 Hz, 4H), 7.35 - 7.32 (m, 1H), 7.31 - 7.25 (m, 1H), 7.18 (dt, J = 7.7, 1.3 Hz, 1H), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (d, J = 3.1 Hz, 1H), 3.92 - 3.87 (m, 1H), 3.81 (s, 3H), 2.86 (dddd, J = 12.0, 8.7, 7.0, 3.0 Hz, 1H), 2.28 - 2.19 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.87 (s, 1H), 9.54 (s, 1H), 8.59 (s, 2H), 7.92 - 7.88 (m, 2H), 7.65 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.50 (d, J = 0.9 Hz, 1H), 7.38 (dd, J = 7.2, 1.2 Hz, 4H), 7.35 - 7.32 (m, 1H), 7.31 - 7.25 (m) , 1H), 7.18 (dt, J = 7.7, 1.3 Hz, 1H), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (d, J = 3.1 Hz, 1H), 3.92 - 3.87 (m, 1H), 3.81 (s, 3H), 2.86 (dddd, J = 12.0, 8.7, 7.0, 3.0 Hz, 1H), 2.28 - 2.19 (m, 1H)
실시예 2 내지 44Examples 2 to 44
상기 실시예 1과 유사한 방법으로 실시예 2 내지 44를 제조하였으며, 실시예 1 내지 44의 화합물명, 화학구조식, NMR 및 LC-MS 분석 결과를 하기 표 1에 정리하여 나타내었다.Examples 2-44 were prepared in a manner similar to Example 1, and the compound names, chemical structural formulas, NMR and LC-MS analysis results of Examples 1-44 are summarized and shown in Table 1 below.
실시예Example 구조rescue 화합물명compound name 1H NMR 1 H NMR LC-MS
(m/z)LC-MS
(m/z)
1One
Figure PCTKR2021018956-appb-img-000034
Figure PCTKR2021018956-appb-img-000034
 		(S)-N-(4-(4-메틸피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민( S )-N-(4-(4- methylpiperidin -1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.87 (s, 1H), 9.54 (s, 1H), 8.59 (s, 2H), 7.92 - 7.88 (m, 2H), 7.65 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.50 (d, J = 0.9 Hz, 1H), 7.38 (dd, J = 7.2, 1.2 Hz, 4H), 7.35 - 7.32 (m, 1H), 7.31 - 7.25 (m, 1H), 7.18 (dt, J = 7.7, 1.3 Hz, 1H), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (d, J = 3.1 Hz, 1H), 3.92 - 3.87 (m, 1H), 3.81 (s, 3H), 2.86 (dddd, J = 12.0, 8.7, 7.0, 3.0 Hz, 1H), 2.28 - 2.19 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.87 (s, 1H), 9.54 (s, 1H), 8.59 (s, 2H), 7.92 - 7.88 (m, 2H), 7.65 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.50 (d, J = 0.9 Hz, 1H), 7.38 (dd, J = 7.2, 1.2 Hz, 4H), 7.35 - 7.32 (m, 1H), 7.31 - 7.25 (m) , 1H), 7.18 (dt, J = 7.7, 1.3 Hz, 1H), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (d, J = 3.1 Hz, 1H), 3.92 - 3.87 (m, 1H), 3.81 (s, 3H), 2.86 (dddd, J = 12.0, 8.7, 7.0, 3.0 Hz, 1H), 2.28 - 2.19 (m, 1H) 417.4 [M+1]+ 417.4 [M+1] +
22
Figure PCTKR2021018956-appb-img-000035
Figure PCTKR2021018956-appb-img-000035
 		(R)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민( R )-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine 1H NMR (400 MHz, Chloroform-d) δ 7.85 (d, J = 6.3 Hz, 1H), 7.40 - 7.31 (m, 5H), 7.25 - 7.21 (m, 2H), 6.72 - 6.67 (m, 2H), 6.45 (d, J = 6.3 Hz, 1H), 5.50 (dd, J = 8.7, 5.9 Hz, 1H), 4.29 (td, J = 7.6, 4.0 Hz, 1H), 3.22 (dd, J = 6.2, 4.0 Hz, 4H), 2.87 (t, J = 4.7 Hz, 4H), 2.84 (d, J = 3.9 Hz, 2H), 2.53 (s, 3H), 2.46 - 2.34 (m, 1H), 2.05 (s, 2H) 1 H NMR (400 MHz, Chloroform- d ) δ 7.85 (d, J = 6.3 Hz, 1H), 7.40 - 7.31 (m, 5H), 7.25 - 7.21 (m, 2H), 6.72 - 6.67 (m, 2H) , 6.45 (d, J = 6.3 Hz, 1H), 5.50 (dd, J = 8.7, 5.9 Hz, 1H), 4.29 (td, J = 7.6, 4.0 Hz, 1H), 3.22 (dd, J = 6.2, 4.0) Hz, 4H), 2.87 (t, J = 4.7 Hz, 4H), 2.84 (d, J = 3.9 Hz, 2H), 2.53 (s, 3H), 2.46 - 2.34 (m, 1H), 2.05 (s, 2H) ) 417.4
[M+H]+ 417.4
[M+H] +
33
Figure PCTKR2021018956-appb-img-000036
Figure PCTKR2021018956-appb-img-000036
 		(S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(3,4,5-트라이메톡시페닐)피리미딘-2-아민 트라이플루오로아세트산염( S )-4-(3- phenylisoxazolidin -2-yl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine trifluoroacetate 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.08 (d, J = 6.9 Hz, 1H), 7.39 - 7.26 (m, 5H), 6.82 (s, 2H), 6.52 (d, J = 6.8 Hz, 1H), 5.67 (dd, J = 8.6, 4.6 Hz, 1H), 4.32 (td, J = 7.5, 4.7 Hz, 1H), 4.08 (q, J = 7.6 Hz, 1H), 3.62 (s, 3H), 3.57 (s, 6H), 3.05 - 2.95 (m, 1H), 2.55 (s, 1H), 2.46 - 2.36 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.41 (s, 1H), 8.08 (d, J = 6.9 Hz, 1H), 7.39 - 7.26 (m, 5H), 6.82 (s, 2H), 6.52 ( d, J = 6.8 Hz, 1H), 5.67 (dd, J = 8.6, 4.6 Hz, 1H), 4.32 (td, J = 7.5, 4.7 Hz, 1H), 4.08 (q, J = 7.6 Hz, 1H), 3.62 (s, 3H), 3.57 (s, 6H), 3.05 - 2.95 (m, 1H), 2.55 (s, 1H), 2.46 - 2.36 (m, 1H) 409.2
[M+H]+ 409.2
[M+H] +
44
Figure PCTKR2021018956-appb-img-000037
Figure PCTKR2021018956-appb-img-000037
 		(S)-N-(4-(2-(다이에틸아미노)에톡시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 염산염( S )-N-(4-(2-( diethylamino )ethoxy)phenyl)-4-(3-phenylisooxazolidin-2-yl)pyrimidin-2-amine hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.77 (d, J = 26.2 Hz, 2H), 8.07 (d, J = 7.2 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.33 (dt, J = 7.2, 3.1 Hz, 3H), 7.19 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 6.52 (d, J = 7.1 Hz, 1H), 5.54 (dd, J = 8.6, 5.7 Hz, 1H), 4.50 - 4.41 (m, 1H), 4.38 (t, J = 5.2 Hz, 2H), 4.15 (q, J = 7.6 Hz, 1H), 3.49 (q, J = 5.1 Hz, 4H), 3.27 - 3.13 (m, 4H), 3.05 - 2.96 (m, 1H), 2.37 - 2.26 (m, 1H), 1.27 (t, J = 7.2 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.77 (d, J = 26.2 Hz, 2H), 8.07 (d, J = 7.2 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.33 (dt, J = 7.2, 3.1 Hz, 3H), 7.19 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 6.52 (d, J = 7.1 Hz, 1H), 5.54 (dd, J = 8.6, 5.7 Hz, 1H), 4.50 - 4.41 (m, 1H), 4.38 (t, J = 5.2 Hz, 2H), 4.15 (q, J = 7.6 Hz, 1H), 3.49 (q, J = 5.1) Hz, 4H), 3.27 - 3.13 (m, 4H), 3.05 - 2.96 (m, 1H), 2.37 - 2.26 (m, 1H), 1.27 (t, J = 7.2 Hz, 6H) 434.3
[M+H]+ 434.3
[M+H] +
55
Figure PCTKR2021018956-appb-img-000038
Figure PCTKR2021018956-appb-img-000038
 		(S)-N-(4-(3-(다이에틸아미노)프로폭시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 염산염( S )-N-(4-(3-( diethylamino )propoxy)phenyl)-4-(3-phenylisooxazolidin-2-yl)pyrimidin-2-amine hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 2H), 8.05 (d, J = 7.0 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.36 - 7.30 (m, 3H), 7.19 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 6.51 (d, J = 7.0 Hz, 1H), 5.53 (dd, J = 8.6, 5.8 Hz, 1H), 4.45 - 4.37 (m, 1H), 4.11 (q, J = 7.6 Hz, 1H), 4.05 (t, J = 6.1 Hz, 2H), 3.22 - 3.12 (m, 6H), 3.04 - 2.95 (m, 1H), 2.35 - 2.26 (m, 1H), 2.18 - 2.10 (m, 2H), 1.24 (t, J = 7.2 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.44 (s, 2H), 8.05 (d, J = 7.0 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.36 - 7.30 (m, 3H), 7.19 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 6.51 (d, J = 7.0 Hz, 1H), 5.53 (dd, J = 8.6, 5.8 Hz, 1H), 4.45 - 4.37 (m, 1H), 4.11 (q, J = 7.6 Hz, 1H), 4.05 (t, J = 6.1 Hz, 2H), 3.22 - 3.12 (m, 6H), 3.04 - 2.95 (m, 1H) , 2.35 - 2.26 (m, 1H), 2.18 - 2.10 (m, 2H), 1.24 (t, J = 7.2 Hz, 6H) 448.3
[M+H]+ 448.3
[M+H] +
66
Figure PCTKR2021018956-appb-img-000039
Figure PCTKR2021018956-appb-img-000039
 		(S)-N-(4-(2-(다이에틸아미노)에톡시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 염산염( S )-N-(4-(2-(diethylamino)ethoxy)-3,5- dimethylphenyl )-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.69 (d, J = 50.5 Hz, 2H), 8.11 (d, J = 7.1 Hz, 1H), 7.34 (dp, J = 21.4, 7.3 Hz, 5H), 7.08 (s, 2H), 6.55 (d, J = 7.0 Hz, 1H), 5.68 (dd, J = 8.7, 4.9 Hz, 1H), 4.36 (td, J = 7.4, 4.8 Hz, 1H), 4.16 - 4.05 (m, 3H), 3.48 (d, J = 5.2 Hz, 2H), 3.30 - 3.19 (m, 4H), 3.09 - 2.99 (m, 1H), 2.41 - 2.31 (m, 1H), 2.11 (s, 6H), 1.28 (t, J = 7.2 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.69 (d, J = 50.5 Hz, 2H), 8.11 (d, J = 7.1 Hz, 1H), 7.34 (dp, J = 21.4, 7.3 Hz, 5H) , 7.08 (s, 2H), 6.55 (d, J = 7.0 Hz, 1H), 5.68 (dd, J = 8.7, 4.9 Hz, 1H), 4.36 (td, J = 7.4, 4.8 Hz, 1H), 4.16 - 4.05 (m, 3H), 3.48 (d, J = 5.2 Hz, 2H), 3.30 - 3.19 (m, 4H), 3.09 - 2.99 (m, 1H), 2.41 - 2.31 (m, 1H), 2.11 (s, 6H), 1.28 (t, J = 7.2 Hz, 6H) 462.3
[M+H]+ 462.3
[M+H] +
77
Figure PCTKR2021018956-appb-img-000040
Figure PCTKR2021018956-appb-img-000040
 		(S)-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 염산염( S )-N-(4-(3-(diethylamino)propoxy)-3,5- dimethylphenyl )-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.84 - 10.73 (m, 2H), 8.11 (d, J = 7.3 Hz, 1H), 7.39 - 7.28 (m, 5H), 7.04 (s, 2H), 6.55 (d, J = 7.2 Hz, 1H), 5.69 (dd, J = 8.7, 4.9 Hz, 1H), 4.42 - 4.33 (m, 1H), 4.16 (q, J = 7.5 Hz, 1H), 3.76 (t, J = 6.0 Hz, 2H), 3.28 - 3.20 (m, 2H), 3.14 (tt, J = 7.2, 3.6 Hz, 4H), 3.08 - 3.02 (m, 1H), 2.41 - 2.32 (m, 1H), 2.18 - 2.12 (m, 2H), 2.08 (s, 6H), 1.26 (t, J = 7.2 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.84 - 10.73 (m, 2H), 8.11 (d, J = 7.3 Hz, 1H), 7.39 - 7.28 (m, 5H), 7.04 (s, 2H), 6.55 (d, J = 7.2 Hz, 1H), 5.69 (dd, J = 8.7, 4.9 Hz, 1H), 4.42 - 4.33 (m, 1H), 4.16 (q, J = 7.5 Hz, 1H), 3.76 (t) , J = 6.0 Hz, 2H), 3.28 - 3.20 (m, 2H), 3.14 (tt, J = 7.2, 3.6 Hz, 4H), 3.08 - 3.02 (m, 1H), 2.41 - 2.32 (m, 1H), 2.18 - 2.12 (m, 2H), 2.08 (s, 6H), 1.26 (t, J = 7.2 Hz, 6H) 476.3
[M+H]+ 476.3
[M+H] +
88
Figure PCTKR2021018956-appb-img-000041
Figure PCTKR2021018956-appb-img-000041
 		(S)-N-(4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민( S )-N-(4-(3- phenylisoxazolidin -2-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine 374.5 [M+H]+ 374.5 [M+H] +
99
Figure PCTKR2021018956-appb-img-000042
Figure PCTKR2021018956-appb-img-000042
 		(R)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-(3-페녹시페닐)아이소옥사졸리딘-2-일)피리미딘-2-아민( R )-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-(3-phenoxyphenyl)isoxazolidin-2-yl)pyrimidin-2-amine 1H NMR (400 MHz, Chloroform-d) δ 8.09 (d, J = 5.7 Hz, 1H), 7.34 - 7.28 (m, 5H), 7.24 - 7.16 (m, 2H), 7.13 - 7.05 (m, 1H), 7.05 - 6.97 (m, 3H), 6.90 (ddd, J = 8.0, 2.4, 1.0 Hz, 1H), 6.85 - 6.78 (m, 2H), 6.50 (d, J = 5.7 Hz, 1H), 5.53 (dd, J = 8.7, 6.0 Hz, 1H), 4.21 (td, J = 7.8, 3.4 Hz, 1H), 3.84 (ddd, J = 9.2, 8.1, 6.8 Hz, 1H), 3.10 (td, J = 4.4, 1.4 Hz, 4H), 2.83 - 2.71 (m, 1H), 2.54 (t, J = 5.0 Hz, 4H), 2.45 - 2.36 (m, 1H), 2.34 (s, 3H) 1 H NMR (400 MHz, Chloroform-d) δ 8.09 (d, J = 5.7 Hz, 1H), 7.34 - 7.28 (m, 5H), 7.24 - 7.16 (m, 2H), 7.13 - 7.05 (m, 1H) , 7.05 - 6.97 (m, 3H), 6.90 (ddd, J = 8.0, 2.4, 1.0 Hz, 1H), 6.85 - 6.78 (m, 2H), 6.50 (d, J = 5.7 Hz, 1H), 5.53 (dd , J = 8.7, 6.0 Hz, 1H), 4.21 (td, J = 7.8, 3.4 Hz, 1H), 3.84 (ddd, J = 9.2, 8.1, 6.8 Hz, 1H), 3.10 (td, J = 4.4, 1.4) Hz, 4H), 2.83 - 2.71 (m, 1H), 2.54 (t, J = 5.0 Hz, 4H), 2.45 - 2.36 (m, 1H), 2.34 (s, 3H) 509.4 [M+H]+ 509.4 [M+H] +
1010
Figure PCTKR2021018956-appb-img-000043
Figure PCTKR2021018956-appb-img-000043
 		(S)-5-메틸-4-(3-페닐아이소옥사졸리딘-2-일)-N-(3,4,5-트라이메톡시페닐)피리미딘-2-아민 염산염( S )-5-methyl-4-(3- phenylisooxazolidin -2-yl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 7.88 (s, 1H), 7.28 (q, J = 6.4 Hz, 5H), 6.79 (s, 2H), 6.57 (s, 1H), 5.73 (dd, J = 8.8, 4.7 Hz, 1H), 4.36 - 4.26 (m, 1H), 4.04 (q, J = 7.8 Hz, 1H), 3.64 (d, J = 2.1 Hz, 9H), 2.95 - 2.85 (m, 1H), 2.38 - 2.29 (m, 1H), 2.24 (s, 3H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.97 (s, 1H), 7.88 (s, 1H), 7.28 (q, J = 6.4 Hz, 5H), 6.79 (s, 2H), 6.57 (s, 1H), 5.73 (dd, J = 8.8, 4.7 Hz, 1H), 4.36 - 4.26 (m, 1H), 4.04 (q, J = 7.8 Hz, 1H), 3.64 (d, J = 2.1 Hz, 9H), 2.95 - 2.85 (m, 1H), 2.38 - 2.29 (m, 1H), 2.24 (s, 3H) 423.2
[M+H]+ 423.2
[M+H] +
1111
Figure PCTKR2021018956-appb-img-000044
Figure PCTKR2021018956-appb-img-000044
 		(S)-N-(4-(2-(다이에틸아미노)에톡시)페닐)-5-메틸-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 염산염( S )-N-(4-(2-( diethylamino )ethoxy)phenyl)-5-methyl-4-(3-phenylisooxazolidin-2-yl)pyrimidin-2-amine hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.11 (s, 1H), 7.98 (s, 1H), 7.55 - 7.43 (m, 4H), 7.38 (dd, J = 8.4, 6.8 Hz, 2H), 7.30 - 7.25 (m, 1H), 6.82 (d, J = 9.0 Hz, 2H), 5.73 (dd, J = 8.6, 5.3 Hz, 1H), 4.28 (d, J = 5.3 Hz, 2H), 4.20 - 4.15 (m, 1H), 3.84 (q, J = 7.9 Hz, 1H), 3.46 (s, 2H), 3.19 (s, 4H), 2.86 - 2.76 (m, 1H), 2.26 - 2.21 (m, 1H), 2.20 (s, 3H), 1.24 (t, J = 7.1 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.22 (s, 1H), 9.11 (s, 1H), 7.98 (s, 1H), 7.55 - 7.43 (m, 4H), 7.38 (dd, J = 8.4) , 6.8 Hz, 2H), 7.30 - 7.25 (m, 1H), 6.82 (d, J = 9.0 Hz, 2H), 5.73 (dd, J = 8.6, 5.3 Hz, 1H), 4.28 (d, J = 5.3 Hz) , 2H), 4.20 - 4.15 (m, 1H), 3.84 (q, J = 7.9 Hz, 1H), 3.46 (s, 2H), 3.19 (s, 4H), 2.86 - 2.76 (m, 1H), 2.26 - 2.21 (m, 1H), 2.20 (s, 3H), 1.24 (t, J = 7.1 Hz, 6H) 448.3
[M+H]+ 448.3
[M+H] +
1212
Figure PCTKR2021018956-appb-img-000045
Figure PCTKR2021018956-appb-img-000045
 		(S)-N-(4-(2-(다이에틸아미노)에톡시)-3,5-다이메틸페닐)-5-메틸-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 염산염( S )-N-(4-(2-(diethylamino)ethoxy)-3,5- dimethylphenyl )-5-methyl-4-(3-phenylisoxazolidin-2-yl)pyrimidine -2-amine hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.07 (s, 1H), 8.00 (s, 1H), 7.44 (d, J = 7.4 Hz, 2H), 7.36 (dd, J = 8.3, 6.8 Hz, 2H), 7.32 - 7.23 (m, 3H), 5.84 (dd, J = 8.8, 4.7 Hz, 1H), 4.17 (td, J = 7.9, 3.7 Hz, 1H), 3.95 (s, 2H), 3.84 (t, J = 8.1 Hz, 1H), 3.38 - 3.00 (m, 6H), 2.83 (tq, J = 8.1, 4.1 Hz, 2H), 2.27 (ddd, J = 12.2, 8.3, 4.6 Hz, 1H), 2.20 (s, 3H), 2.11 (d, J = 2.3 Hz, 7H), 1.22 (d, J = 21.8 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.36 (s, 1H), 9.07 (s, 1H), 8.00 (s, 1H), 7.44 (d, J = 7.4 Hz, 2H), 7.36 (dd, J = 8.3, 6.8 Hz, 2H), 7.32 - 7.23 (m, 3H), 5.84 (dd, J = 8.8, 4.7 Hz, 1H), 4.17 (td, J = 7.9, 3.7 Hz, 1H), 3.95 (s) , 2H), 3.84 (t, J = 8.1 Hz, 1H), 3.38 - 3.00 (m, 6H), 2.83 (tq, J = 8.1, 4.1 Hz, 2H), 2.27 (ddd, J = 12.2, 8.3, 4.6) Hz, 1H), 2.20 (s, 3H), 2.11 (d, J = 2.3 Hz, 7H), 1.22 (d, J = 21.8 Hz, 6H) 476.3
[M+H]+ 476.3
[M+H] +
1313
Figure PCTKR2021018956-appb-img-000046
Figure PCTKR2021018956-appb-img-000046
 		(S)-N-(4-(3-(다이에틸아미노)프로폭시)페닐)-5-메틸-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 염산염( S )-N-(4-(3-( diethylamino )propoxy)phenyl)-5-methyl-4-(3-phenylisooxazolidin-2-yl)pyrimidin-2-amine hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.76 (s, 1H), 7.88 (s, 1H), 7.42 - 7.33 (m, 4H), 7.32 - 7.24 (m, 3H), 6.78 (d, J = 9.0 Hz, 2H), 5.67 (dd, J = 8.7, 5.6 Hz, 1H), 4.30 (td, J = 7.6, 3.8 Hz, 1H), 4.03 (t, J = 6.1 Hz, 2H), 3.14 (qd, J = 7.4, 3.7 Hz, 5H), 2.97 - 2.84 (m, 1H), 2.26 (s, 3H), 2.22 (dd, J = 7.9, 4.9 Hz, 1H), 2.13 (dt, J = 10.8, 5.7 Hz, 2H), 1.24 (t, J = 7.2 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.32 (s, 1H), 9.76 (s, 1H), 7.88 (s, 1H), 7.42 - 7.33 (m, 4H), 7.32 - 7.24 (m, 3H) ), 6.78 (d, J = 9.0 Hz, 2H), 5.67 (dd, J = 8.7, 5.6 Hz, 1H), 4.30 (td, J = 7.6, 3.8 Hz, 1H), 4.03 (t, J = 6.1 Hz) , 2H), 3.14 (qd, J = 7.4, 3.7 Hz, 5H), 2.97 - 2.84 (m, 1H), 2.26 (s, 3H), 2.22 (dd, J = 7.9, 4.9 Hz, 1H), 2.13 ( dt, J = 10.8, 5.7 Hz, 2H), 1.24 (t, J = 7.2 Hz, 6H) 462.3
[M+H]+ 462.3
[M+H] +
1414
Figure PCTKR2021018956-appb-img-000047
Figure PCTKR2021018956-appb-img-000047
 		(S)-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)-5-메틸-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 염산염( S )-N-(4-(3-(diethylamino)propoxy)-3,5- dimethylphenyl )-5-methyl-4-(3-phenylisoxazolidin-2-yl)pyrimidine -2-amine hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 9.20 (s, 1H), 7.99 (s, 1H), 7.43 (d, J = 7.2 Hz, 2H), 7.36 (dd, J = 8.5, 6.8 Hz, 2H), 7.29 - 7.24 (m, 3H), 5.83 (dd, J = 8.8, 4.8 Hz, 1H), 4.19 (td, J = 7.9, 3.7 Hz, 1H), 3.86 (q, J = 8.0 Hz, 1H), 3.74 (t, J = 6.0 Hz, 2H), 3.24 (dt, J = 12.4, 4.6 Hz, 2H), 3.14 (dt, J = 11.7, 5.7 Hz, 4H), 2.85 (dtd, J = 11.9, 8.0, 3.7 Hz, 1H), 2.32 - 2.23 (m, 1H), 2.21 (s, 3H), 2.16 - 2.12 (m, 1H), 2.09 (s, 6H), 1.25 (t, J = 7.2 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.50 (s, 1H), 9.20 (s, 1H), 7.99 (s, 1H), 7.43 (d, J = 7.2 Hz, 2H), 7.36 (dd, J = 8.5, 6.8 Hz, 2H), 7.29 - 7.24 (m, 3H), 5.83 (dd, J = 8.8, 4.8 Hz, 1H), 4.19 (td, J = 7.9, 3.7 Hz, 1H), 3.86 (q) , J = 8.0 Hz, 1H), 3.74 (t, J = 6.0 Hz, 2H), 3.24 (dt, J = 12.4, 4.6 Hz, 2H), 3.14 (dt, J = 11.7, 5.7 Hz, 4H), 2.85 (dtd, J = 11.9, 8.0, 3.7 Hz, 1H), 2.32 - 2.23 (m, 1H), 2.21 (s, 3H), 2.16 - 2.12 (m, 1H), 2.09 (s, 6H), 1.25 (t) , J = 7.2 Hz, 6H) 490.3
[M+H]+ 490.3
[M+H] +
1515
Figure PCTKR2021018956-appb-img-000048
Figure PCTKR2021018956-appb-img-000048
 		(S)-5-메틸-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 트라이플루오로아세트산염( S )-5-methyl- N- (4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine trifluoro Roacetate 1H NMR (400 MHz, DMSO-d6) δ 10.48 (d, J = 56.2 Hz, 1H), 7.85 (s, 1H), 7.35 (d, J = 35.6 Hz, 5H), 7.11 (s, 2H), 6.85 (s, 2H), 5.63 (s, 1H), 4.27 (d, J = 109.1 Hz, 2H), 3.67 (d, J = 84.1 Hz, 4H), 3.19 (s, 1H), 2.93 (d, J = 26.8 Hz, 5H), 2.30 (s, 4H), 1.25 (s, 1H), 0.86 (s, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.48 (d, J = 56.2 Hz, 1H), 7.85 (s, 1H), 7.35 (d, J = 35.6 Hz, 5H), 7.11 (s, 2H) , 6.85 (s, 2H), 5.63 (s, 1H), 4.27 (d, J = 109.1 Hz, 2H), 3.67 (d, J = 84.1 Hz, 4H), 3.19 (s, 1H), 2.93 (d, J = 26.8 Hz, 5H), 2.30 (s, 4H), 1.25 (s, 1H), 0.86 (s, 1H) 431.3 [M+H]+ 431.3 [M+H] +
1616
Figure PCTKR2021018956-appb-img-000049
Figure PCTKR2021018956-appb-img-000049
 		(R)-5-메틸-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민( R )-5-methyl- N- (4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 7.95 (s, 1H), 7.44 (td, J = 9.1, 1.9 Hz, 4H), 7.37 (dd, J = 8.5, 6.8 Hz, 2H), 7.27 (t, J = 7.3 Hz, 1H), 6.77 (d, J = 9.1 Hz, 2H), 5.74 (dd, J = 8.7, 5.3 Hz, 1H), 4.16 (td, J = 7.8, 3.6 Hz, 1H), 3.83 (q, J = 7.9 Hz, 1H), 3.02 (t, J = 4.9 Hz, 4H), 2.79 (dq, J = 8.2, 4.2 Hz, 1H), 2.45 (t, J = 4.9 Hz, 3H), 2.20 (d, J = 10.1 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.96 (s, 1H), 7.95 (s, 1H), 7.44 (td, J = 9.1, 1.9 Hz, 4H), 7.37 (dd, J = 8.5, 6.8 Hz, 2H), 7.27 (t, J = 7.3 Hz, 1H), 6.77 (d, J = 9.1 Hz, 2H), 5.74 (dd, J = 8.7, 5.3 Hz, 1H), 4.16 (td, J = 7.8) , 3.6 Hz, 1H), 3.83 (q, J = 7.9 Hz, 1H), 3.02 (t, J = 4.9 Hz, 4H), 2.79 (dq, J = 8.2, 4.2 Hz, 1H), 2.45 (t, J ) = 4.9 Hz, 3H), 2.20 (d, J = 10.1 Hz, 6H) 431.3
[M+H]+ 431.3
[M+H] +
1717
Figure PCTKR2021018956-appb-img-000050
Figure PCTKR2021018956-appb-img-000050
 		(S)-5-메틸-N-(4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민( S )-5-methyl- N- (4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisoxazolidine-2 -yl) pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 7.95 (s, 1H), 7.46 - 7.34 (m, 6H), 7.29 - 7.24 (m, 1H), 6.79 - 6.73 (m, 2H), 5.74 (dd, J = 8.6, 5.3 Hz, 1H), 4.17 (td, J = 7.9, 3.6 Hz, 1H), 3.82 (q, J = 7.8 Hz, 1H), 3.57 (dd, J = 9.7, 6.1 Hz, 2H), 2.81 (tq, J = 8.2, 3.8 Hz, 1H), 2.61 - 2.51 (m, 5H), 2.37 - 2.19 (m, 7H), 2.19 (s, 3H), 2.13 (s, 3H), 1.83 (d, J = 11.8 Hz, 2H), 1.49 (qd, J = 12.0, 3.9 Hz, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.95 (s, 1H), 7.95 (s, 1H), 7.46 - 7.34 (m, 6H), 7.29 - 7.24 (m, 1H), 6.79 - 6.73 (m) , 2H), 5.74 (dd, J = 8.6, 5.3 Hz, 1H), 4.17 (td, J = 7.9, 3.6 Hz, 1H), 3.82 (q, J = 7.8 Hz, 1H), 3.57 (dd, J = 9.7, 6.1 Hz, 2H), 2.81 (tq, J = 8.2, 3.8 Hz, 1H), 2.61 - 2.51 (m, 5H), 2.37 - 2.19 (m, 7H), 2.19 (s, 3H), 2.13 (s) , 3H), 1.83 (d, J = 11.8 Hz, 2H), 1.49 (qd, J = 12.0, 3.9 Hz, 2H) 514.5 [M+H]+ 514.5 [M+H] +
1818
Figure PCTKR2021018956-appb-img-000051
Figure PCTKR2021018956-appb-img-000051
 		(S)-5-클로로-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민( S )-5-chloro- N- (4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine 451.3 [M+H]+ 451.3 [M+H] +
1919
Figure PCTKR2021018956-appb-img-000052
Figure PCTKR2021018956-appb-img-000052
 		(R)-5-클로로-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민( R )-5-chloro- N- (4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine 1H NMR (400 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.44 (d, J = 7.3 Hz, 2H), 7.39 - 7.33 (m, 4H), 7.30 - 7.25 (m, 1H), 6.79 (d, J = 9.0 Hz, 2H), 5.56 (dd, J = 8.6, 4.6 Hz, 1H), 4.22 (td, J = 7.8, 4.5 Hz, 1H), 4.11 (q, J = 7.8 Hz, 1H), 3.28 (t, J = 5.0 Hz, 4H), 3.05 (t, J = 4.9 Hz, 4H), 2.75 (dtd, J = 12.5, 8.1, 4.6 Hz, 1H), 2.65 (s, 3H), 2.38 (dtd, J = 12.3, 7.9, 4.6 Hz, 1H), 2.05 (s, 1H) 1 H NMR (400 MHz, Chloroform- d ) δ 8.01 (s, 1H), 7.44 (d, J = 7.3 Hz, 2H), 7.39 - 7.33 (m, 4H), 7.30 - 7.25 (m, 1H), 6.79 (d, J = 9.0 Hz, 2H), 5.56 (dd, J = 8.6, 4.6 Hz, 1H), 4.22 (td, J = 7.8, 4.5 Hz, 1H), 4.11 (q, J = 7.8 Hz, 1H) , 3.28 (t, J = 5.0 Hz, 4H), 3.05 (t, J = 4.9 Hz, 4H), 2.75 (dtd, J = 12.5, 8.1, 4.6 Hz, 1H), 2.65 (s, 3H), 2.38 ( dtd, J = 12.3, 7.9, 4.6 Hz, 1H), 2.05 (s, 1H) 451.3 [M+H]+ 451.3 [M+H] +
2020
Figure PCTKR2021018956-appb-img-000053
Figure PCTKR2021018956-appb-img-000053
 		(R)-5-클로로-N-(1-(2-메톡시에틸)-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 트라이플루오로아세트산염( R )-5-chloro- N- (1-(2-methoxyethyl) -1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine- 2-amine trifluoroacetate 401.3 [M+H]+ 401.3 [M+H] +
2121
Figure PCTKR2021018956-appb-img-000054
Figure PCTKR2021018956-appb-img-000054
 		(R)-2-(4-((5-클로로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-일)아미노)-1H-피라졸-1-일)-N,N-다이메틸아세트아마이드( R )-2-(4-((5-chloro-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-yl)amino) -1H -pyrazol-1-yl) -N , N -dimethylacetamide 428.3 [M+H]+ 428.3 [M+H] +
2222
Figure PCTKR2021018956-appb-img-000055
Figure PCTKR2021018956-appb-img-000055
 		(S)-5-클로로-4-(3-페닐아이소옥사졸리딘-2-일)-N-(3,4,5-트라이메톡시페닐)피리미딘-2-아민 트라이플루오로아세트산염( S )-5-chloro-4-(3- phenylisoxazolidin -2-yl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine trifluoroacetate 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.25 (s, 1H), 7.45 (d, J = 7.3 Hz, 2H), 7.36 (dd, J = 8.4, 6.8 Hz, 2H), 7.30 - 7.24 (m, 1H), 7.18 (s, 2H), 5.60 (dd, J = 8.6, 3.4 Hz, 1H), 4.16 (dt, J = 9.9, 6.4 Hz, 2H), 3.72 (s, 6H), 3.61 (s, 3H), 2.81 (dtt, J = 13.1, 8.6, 4.9 Hz, 1H), 2.33 (dtd, J = 11.8, 8.0, 3.5 Hz, 1H), 1.26 (t, J = 6.2 Hz, 3H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.58 (s, 1H), 8.25 (s, 1H), 7.45 (d, J = 7.3 Hz, 2H), 7.36 (dd, J = 8.4, 6.8 Hz, 2H), 7.30 - 7.24 (m, 1H), 7.18 (s, 2H), 5.60 (dd, J = 8.6, 3.4 Hz, 1H), 4.16 (dt, J = 9.9, 6.4 Hz, 2H), 3.72 (s) , 6H), 3.61 (s, 3H), 2.81 (dtt, J = 13.1, 8.6, 4.9 Hz, 1H), 2.33 (dtd, J = 11.8, 8.0, 3.5 Hz, 1H), 1.26 (t, J = 6.2) Hz, 3H) 443.1
[M+H]+ 443.1
[M+H] +
2323
Figure PCTKR2021018956-appb-img-000056
Figure PCTKR2021018956-appb-img-000056
 		(S)-5-클로로-N-(4-(2-(다이에틸아미노)에톡시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 염산염( S )-5-chloro- N- (4-(2-(diethylamino)ethoxy)phenyl)-4-(3-phenylisooxazolidin-2-yl)pyrimidin-2-amine hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.95 (s, 1H), 8.24 (s, 1H), 7.50 - 7.36 (m, 7H), 7.30 (h, J = 4.1 Hz, 1H), 6.91 - 6.84 (m, 2H), 5.60 (dd, J = 8.6, 4.8 Hz, 1H), 4.36 (t, J = 5.1 Hz, 2H), 4.28 (td, J = 7.7, 4.4 Hz, 1H), 4.12 (q, J = 7.7 Hz, 1H), 3.48 (q, J = 5.1 Hz, 2H), 3.26 - 3.14 (m, 4H), 2.87 (dtd, J = 12.2, 8.0, 4.4 Hz, 1H), 2.31 - 2.22 (m, 1H), 1.27 (t, J = 7.2 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.70 (s, 1H), 9.95 (s, 1H), 8.24 (s, 1H), 7.50 - 7.36 (m, 7H), 7.30 (h, J = 4.1) Hz, 1H), 6.91 - 6.84 (m, 2H), 5.60 (dd, J = 8.6, 4.8 Hz, 1H), 4.36 (t, J = 5.1 Hz, 2H), 4.28 (td, J = 7.7, 4.4 Hz) , 1H), 4.12 (q, J = 7.7 Hz, 1H), 3.48 (q, J = 5.1 Hz, 2H), 3.26 - 3.14 (m, 4H), 2.87 (dtd, J = 12.2, 8.0, 4.4 Hz, 1H), 2.31 - 2.22 (m, 1H), 1.27 (t, J = 7.2 Hz, 6H) 468.2
[M+H]+ 468.2
[M+H] +
2424
Figure PCTKR2021018956-appb-img-000057
Figure PCTKR2021018956-appb-img-000057
 		(S)-5-클로로-N-(4-(3-(다이에틸아미노)프로폭시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 염산염( S )-5-chloro- N- (4-(3-(diethylamino)propoxy)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 9.86 (s, 1H), 8.23 (s, 1H), 7.47 - 7.33 (m, 7H), 7.29 (dq, J = 8.7, 4.4, 3.9 Hz, 1H), 6.85 - 6.78 (m, 2H), 5.59 (dd, J = 8.6, 4.8 Hz, 1H), 4.27 (td, J = 7.7, 4.3 Hz, 1H), 4.11 (q, J = 7.7 Hz, 1H), 4.04 (t, J = 6.1 Hz, 2H), 3.15 (ddd, J = 12.0, 9.3, 5.5 Hz, 6H), 2.87 (dtd, J = 12.3, 7.9, 4.3 Hz, 1H), 2.31 - 2.21 (m, 1H), 2.18 - 2.09 (m, 2H), 1.24 (t, J = 7.2 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.50 (s, 1H), 9.86 (s, 1H), 8.23 (s, 1H), 7.47 - 7.33 (m, 7H), 7.29 (dq, J = 8.7 , 4.4, 3.9 Hz, 1H), 6.85 - 6.78 (m, 2H), 5.59 (dd, J = 8.6, 4.8 Hz, 1H), 4.27 (td, J = 7.7, 4.3 Hz, 1H), 4.11 (q, J = 7.7 Hz, 1H), 4.04 (t, J = 6.1 Hz, 2H), 3.15 (ddd, J = 12.0, 9.3, 5.5 Hz, 6H), 2.87 (dtd, J = 12.3, 7.9, 4.3 Hz, 1H) ), 2.31 - 2.21 (m, 1H), 2.18 - 2.09 (m, 2H), 1.24 (t, J = 7.2 Hz, 6H) 482.2
[M+H]+ 482.2
[M+H] +
2525
Figure PCTKR2021018956-appb-img-000058
Figure PCTKR2021018956-appb-img-000058
 		(S)-5-클로로-N-(4-(2-(다이에틸아미노)에톡시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 염산염( S )-5-chloro- N- (4-(2-(diethylamino)ethoxy)-3,5-dimethylphenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine -2-amine hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.93 - 9.80 (m, 1H), 8.26 (s, 1H), 7.41 - 7.35 (m, 4H), 7.27 (s, 2H), 5.67 (dd, J = 8.7, 4.2 Hz, 1H), 4.14 (d, J = 7.8 Hz, 1H), 4.11 - 4.08 (m, 2H), 3.48 (q, J = 5.4 Hz, 2H), 3.31 - 3.22 (m, 4H), 2.89 (dtd, J = 12.4, 8.2, 4.5 Hz, 1H), 2.33 (td, J = 7.9, 4.9 Hz, 1H), 2.30 (s, 1H), 2.16 (s, 6H), 1.27 (d, J = 7.2 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.79 (s, 1H), 9.93 - 9.80 (m, 1H), 8.26 (s, 1H), 7.41 - 7.35 (m, 4H), 7.27 (s, 2H) ), 5.67 (dd, J = 8.7, 4.2 Hz, 1H), 4.14 (d, J = 7.8 Hz, 1H), 4.11 - 4.08 (m, 2H), 3.48 (q, J = 5.4 Hz, 2H), 3.31 - 3.22 (m, 4H), 2.89 (dtd, J = 12.4, 8.2, 4.5 Hz, 1H), 2.33 (td, J = 7.9, 4.9 Hz, 1H), 2.30 (s, 1H), 2.16 (s, 6H) ), 1.27 (d, J = 7.2 Hz, 6H) 496.2
[M+H]+ 496.2
[M+H] +
2626
Figure PCTKR2021018956-appb-img-000059
Figure PCTKR2021018956-appb-img-000059
 		(S)-5-클로로-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 염산염( S )-5-chloro- N- (4-(3-(diethylamino)propoxy)-3,5-dimethylphenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine -2-amine hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.53 (s, 1H), 8.23 (s, 1H), 7.45 - 7.37 (m, 3H), 7.33 - 7.24 (m, 3H), 5.62 (dd, J = 8.6, 4.1 Hz, 1H), 4.20 (tt, J = 9.2, 4.5 Hz, 1H), 4.09 (q, J = 7.8 Hz, 1H), 3.87 - 3.82 (m, 1H), 3.76 (t, J = 6.0 Hz, 2H), 3.25 (dt, J = 12.6, 4.9 Hz, 3H), 3.19 - 3.11 (m, 6H), 2.84 (dtd, J = 12.5, 8.4, 4.5 Hz, 1H), 2.34 - 2.28 (m, 1H), 2.14 (s, 6H), 1.25 (d, J = 5.0 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.44 (s, 1H), 9.53 (s, 1H), 8.23 (s, 1H), 7.45 - 7.37 (m, 3H), 7.33 - 7.24 (m, 3H) ), 5.62 (dd, J = 8.6, 4.1 Hz, 1H), 4.20 (tt, J = 9.2, 4.5 Hz, 1H), 4.09 (q, J = 7.8 Hz, 1H), 3.87 - 3.82 (m, 1H) , 3.76 (t, J = 6.0 Hz, 2H), 3.25 (dt, J = 12.6, 4.9 Hz, 3H), 3.19 - 3.11 (m, 6H), 2.84 (dtd, J = 12.5, 8.4, 4.5 Hz, 1H) ), 2.34 - 2.28 (m, 1H), 2.14 (s, 6H), 1.25 (d, J = 5.0 Hz, 6H) 510.3
[M+H]+ 510.3
[M+H] +
2727
Figure PCTKR2021018956-appb-img-000060
Figure PCTKR2021018956-appb-img-000060
 		(S)-5-클로로-N-(4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민( S )-5-chloro- N- (4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisoxazolidine-2 -yl) pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.17 (s, 1H), 7.43 (dd, J = 8.0, 5.6 Hz, 4H), 7.37 (dd, J = 8.4, 6.8 Hz, 2H), 7.30 - 7.25 (m, 1H), 6.85 - 6.77 (m, 2H), 5.56 (dd, J = 8.5, 4.5 Hz, 1H), 4.18 (td, J = 7.8, 4.3 Hz, 1H), 4.05 (q, J = 7.8 Hz, 1H), 3.60 (d, J = 11.8 Hz, 2H), 2.85 - 2.78 (m, 1H), 2.57 (t, J = 12.1 Hz, 5H), 2.36 - 2.15 (m, 7H), 2.13 (s, 3H), 1.83 (d, J = 12.3 Hz, 2H), 1.50 (tt, J = 11.9, 6.1 Hz, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.37 (s, 1H), 8.17 (s, 1H), 7.43 (dd, J = 8.0, 5.6 Hz, 4H), 7.37 (dd, J = 8.4, 6.8) Hz, 2H), 7.30 - 7.25 (m, 1H), 6.85 - 6.77 (m, 2H), 5.56 (dd, J = 8.5, 4.5 Hz, 1H), 4.18 (td, J = 7.8, 4.3 Hz, 1H) , 4.05 (q, J = 7.8 Hz, 1H), 3.60 (d, J = 11.8 Hz, 2H), 2.85 - 2.78 (m, 1H), 2.57 (t, J = 12.1 Hz, 5H), 2.36 - 2.15 ( m, 7H), 2.13 (s, 3H), 1.83 (d, J = 12.3 Hz, 2H), 1.50 (tt, J = 11.9, 6.1 Hz, 2H) 534.5 [M+H]+ 534.5 [M+H] +
2828
Figure PCTKR2021018956-appb-img-000061
Figure PCTKR2021018956-appb-img-000061
 		5-클로로-N-(3-사이클로프로필-5-(((3S,5R)-3,5-다이메틸피페라진-1-일)메틸)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 염산염5-Chloro- N- (3-cyclopropyl-5-((( 3S,5R)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-((S ) -3 -Phenylisooxazolidin-2-yl)pyrimidin-2-amine hydrochloride 519.4 [M+H]+ 519.4 [M+H] +
2929
Figure PCTKR2021018956-appb-img-000062
Figure PCTKR2021018956-appb-img-000062
 		(S)-5-클로로-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민( S )-5-chloro- N- (3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenyliso Oxazolidin-2-yl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.27 (s, 1H), 7.66 (s, 1H), 7.46 - 7.43 (m, 2H), 7.40 - 7.34 (m, 2H), 7.31 - 7.26 (m, 1H), 7.23 (s, 1H), 7.13 (s, 1H), 5.61 - 5.58 (m, 1H), 4.22 - 4.18 (m, 1H), 4.12 (d, J = 7.8 Hz, 1H), 3.82 (s, 3H), 3.52 (d, J = 11.4 Hz, 8H), 3.09 (s, 6H), 2.85 (s, 3H), 2.81 (d, J = 4.1 Hz, 1H), 2.34 - 2.28 (m, 1H), 2.09 (d, J = 12.1 Hz, 2H), 1.86 (s, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.76 (s, 1H), 8.27 (s, 1H), 7.66 (s, 1H), 7.46 - 7.43 (m, 2H), 7.40 - 7.34 (m, 2H) ), 7.31 - 7.26 (m, 1H), 7.23 (s, 1H), 7.13 (s, 1H), 5.61 - 5.58 (m, 1H), 4.22 - 4.18 (m, 1H), 4.12 (d, J = 7.8 Hz, 1H), 3.82 (s, 3H), 3.52 (d, J = 11.4 Hz, 8H), 3.09 (s, 6H), 2.85 (s, 3H), 2.81 (d, J = 4.1 Hz, 1H), 2.34 - 2.28 (m, 1H), 2.09 (d, J = 12.1 Hz, 2H), 1.86 (s, 1H) 564.4 [M+H]+ 564.4 [M+H] +
3030
Figure PCTKR2021018956-appb-img-000063
Figure PCTKR2021018956-appb-img-000063
 		5-클로로-N-(3-메톡시-4-(4-((1S,4S)-5-메틸-2,5-다이아자바이사이클로[2.2.1]헵탄-2-일)피페리딘-1-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민5-Chloro- N- (3-methoxy-4-(4-(( 1S , 4S )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperi Din-1-yl)phenyl)-4-(( S )-3-phenylisoxazolidin-2-yl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.21 (s, 1H), 7.39 (s, 4H), 7.27 (s, 1H), 7.13 (s, 1H), 6.75 (s, 1H), 5.57 (s, 1H), 4.14 (d, J = 33.4 Hz, 2H), 3.72 (s, 4H), 3.55 (s, 1H), 3.24 (s, 4H), 2.82 (s, 3H), 2.33 (s, 4H), 1.87 (s, 9H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.47 (s, 1H), 8.21 (s, 1H), 7.39 (s, 4H), 7.27 (s, 1H), 7.13 (s, 1H), 6.75 ( s, 1H), 5.57 (s, 1H), 4.14 (d, J = 33.4 Hz, 2H), 3.72 (s, 4H), 3.55 (s, 1H), 3.24 (s, 4H), 2.82 (s, 3H) ), 2.33 (s, 4H), 1.87 (s, 9H) 576.4 [M+H]+ 576.4 [M+H] +
3131
Figure PCTKR2021018956-appb-img-000064
Figure PCTKR2021018956-appb-img-000064
 		(S)-5-클로로-N-(3-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민( S )-5-chloro- N- (3-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisooxa Jolidin-2-yl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.21 (s, 1H), 7.49 (d, J = 2.6 Hz, 1H), 7.44 (d, J = 7.4 Hz, 2H), 7.37 (t, J = 7.5 Hz, 3H), 7.30 - 7.26 (m, 1H), 6.92 (d, J = 8.7 Hz, 1H), 5.59 (dd, J = 8.5, 4.3 Hz, 1H), 4.23 - 4.15 (m, 1H), 4.08 (d, J = 7.9 Hz, 1H), 3.55 (s, 5H), 3.12 (d, J = 11.5 Hz, 6H), 2.84 (s, 1H), 2.82 (s, 3H), 2.66 (d, J = 12.5 Hz, 2H), 2.33 - 2.25 (m, 1H), 2.17 (s, 3H), 2.06 (d, J = 11.3 Hz, 2H), 1.72 (d, J = 12.0 Hz, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.48 (s, 1H), 8.21 (s, 1H), 7.49 (d, J = 2.6 Hz, 1H), 7.44 (d, J = 7.4 Hz, 2H) , 7.37 (t, J = 7.5 Hz, 3H), 7.30 - 7.26 (m, 1H), 6.92 (d, J = 8.7 Hz, 1H), 5.59 (dd, J = 8.5, 4.3 Hz, 1H), 4.23 - 4.15 (m, 1H), 4.08 (d, J = 7.9 Hz, 1H), 3.55 (s, 5H), 3.12 (d, J = 11.5 Hz, 6H), 2.84 (s, 1H), 2.82 (s, 3H) ), 2.66 (d, J = 12.5 Hz, 2H), 2.33 - 2.25 (m, 1H), 2.17 (s, 3H), 2.06 (d, J = 11.3 Hz, 2H), 1.72 (d, J = 12.0 Hz) , 2H) 548.4 [M+H]+ 548.4 [M+H] +
3232
Figure PCTKR2021018956-appb-img-000065
Figure PCTKR2021018956-appb-img-000065
 		(S)-N-(5-클로로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민( S )-N-(5-chloro-4-(3- phenylisoxazolidin -2-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-7-amine 1H NMR (400 MHz, Chloroform-d) δ = 8.09 (s, 1H), 7.47 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.29 (d, J = 7.3 Hz, 1H), 7.25 (s, 1H), 7.19 (dd, J = 8.3, 2.3 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.93 (s, 1H), 5.61 (dd, J = 8.6, 4.2 Hz, 1H), 4.23 (td, J = 7.8, 4.7 Hz, 1H), 4.16 (q, J = 7.8 Hz, 1H), 3.93 (s, 2H), 3.17 - 3.06 (m, 3H), 2.83 - 2.72 (m, 3H), 2.43 (dtd, J = 12.3, 8.0, 4.2 Hz, 1H) 1 H NMR (400 MHz, Chloroform-d) δ = 8.09 (s, 1H), 7.47 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.29 (d, J = 7.3 Hz, 1H), 7.25 (s, 1H), 7.19 (dd, J = 8.3, 2.3 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.93 (s, 1H), 5.61 (dd, J = 8.6, 4.2 Hz, 1H), 4.23 (td, J = 7.8, 4.7 Hz, 1H), 4.16 (q, J = 7.8 Hz, 1H), 3.93 (s, 2H), 3.17 - 3.06 (m, 3H) ), 2.83 - 2.72 (m, 3H), 2.43 (dtd, J = 12.3, 8.0, 4.2 Hz, 1H) 408.2 [M+H]+ 408.2 [M+H] +
3333
Figure PCTKR2021018956-appb-img-000066
Figure PCTKR2021018956-appb-img-000066
 		(S)-N-(5-클로로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-일)-2-메틸-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민( S )-N-(5-chloro-4-(3- phenylisooxazolidin -2-yl)pyrimidin-2-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline -7-amine 1H NMR (400 MHz, Chloroform-d) δ = 8.09 (s, 1H), 7.47 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.33 - 7.26 (m, 2H), 7.16 (dd, J = 8.3, 2.3 Hz, 1H), 7.02 - 6.94 (m, 2H), 5.63 (dd, J = 8.7, 4.4 Hz, 1H), 4.23 (td, J = 7.8, 4.6 Hz, 1H), 4.14 (q, J = 7.9 Hz, 1H), 3.45 (s, 1H), 3.09 (s, 1H), 2.86 (t, J = 5.9 Hz, 2H), 2.77 (ddd, J = 12.7, 8.4, 4.4 Hz, 1H), 2.67 (t, J = 5.9 Hz, 2H), 2.47 - 2.38 (m, 4H) 1 H NMR (400 MHz, Chloroform-d) δ = 8.09 (s, 1H), 7.47 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.33 - 7.26 (m, 2H), 7.16 (dd, J = 8.3, 2.3 Hz, 1H), 7.02 - 6.94 (m, 2H), 5.63 (dd, J = 8.7, 4.4 Hz, 1H), 4.23 (td, J = 7.8, 4.6 Hz) , 1H), 4.14 (q, J = 7.9 Hz, 1H), 3.45 (s, 1H), 3.09 (s, 1H), 2.86 (t, J = 5.9 Hz, 2H), 2.77 (ddd, J = 12.7, 8.4, 4.4 Hz, 1H), 2.67 (t, J = 5.9 Hz, 2H), 2.47 - 2.38 (m, 4H) 422.3 [M+H]+ 422.3 [M+H] +
3434
Figure PCTKR2021018956-appb-img-000067
Figure PCTKR2021018956-appb-img-000067
 		(S)-N-(5-클로로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민( S )-N-(5-chloro-4-(3- phenylisoxazolidin -2-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.22 (s, 1H), 7.51 - 7.24 (m, 8H), 6.85 (d, J = 8.3 Hz, 1H), 5.60 (dd, J = 8.6, 4.2 Hz, 1H), 4.19 (td, J = 7.8, 4.3 Hz, 1H), 4.07 (q, J = 7.8 Hz, 1H), 3.75 (s, 1H), 2.94 - 2.76 (m, 3H), 2.56 (d, J = 6.1 Hz, 2H), 2.28 (dtd, J = 12.2, 8.0, 4.3 Hz, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.50 (s, 1H), 8.22 (s, 1H), 7.51 - 7.24 (m, 8H), 6.85 (d, J = 8.3 Hz, 1H), 5.60 ( dd, J = 8.6, 4.2 Hz, 1H), 4.19 (td, J = 7.8, 4.3 Hz, 1H), 4.07 (q, J = 7.8 Hz, 1H), 3.75 (s, 1H), 2.94 - 2.76 (m) , 3H), 2.56 (d, J = 6.1 Hz, 2H), 2.28 (dtd, J = 12.2, 8.0, 4.3 Hz, 2H) 408.3 [M+H]+ 408.3 [M+H] +
3535
Figure PCTKR2021018956-appb-img-000068
Figure PCTKR2021018956-appb-img-000068
 		(S)-5-플루오로-4-(3-페닐아이소옥사졸리딘-2-일)-N-(3,4,5-트라이메톡시페닐)피리미딘-2-아민 트라이플루오로아세트산염( S )-5-fluoro-4-(3- phenylisooxazolidin -2-yl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine trifluoroacetate 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.21 (d, J = 5.0 Hz, 1H), 7.42 - 7.34 (m, 4H), 7.31 - 7.26 (m, 1H), 7.12 (s, 2H), 5.62 (dt, J = 7.8, 3.0 Hz, 1H), 4.25 (td, J = 7.8, 3.9 Hz, 1H), 4.00 (q, J = 7.9 Hz, 1H), 3.67 (s, 6H), 3.60 (s, 3H), 2.92 (dtd, J = 12.1, 8.0, 3.9 Hz, 1H), 2.33 (dtd, J = 12.5, 8.2, 4.6 Hz, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.47 (s, 1H), 8.21 (d, J = 5.0 Hz, 1H), 7.42 - 7.34 (m, 4H), 7.31 - 7.26 (m, 1H), 7.12 (s, 2H), 5.62 (dt, J = 7.8, 3.0 Hz, 1H), 4.25 (td, J = 7.8, 3.9 Hz, 1H), 4.00 (q, J = 7.9 Hz, 1H), 3.67 (s) , 6H), 3.60 (s, 3H), 2.92 (dtd, J = 12.1, 8.0, 3.9 Hz, 1H), 2.33 (dtd, J = 12.5, 8.2, 4.6 Hz, 1H) 427.2
[M+H]+ 427.2
[M+H] +
3636
Figure PCTKR2021018956-appb-img-000069
Figure PCTKR2021018956-appb-img-000069
 		(S)-N-(4-(2-(다이에틸아미노)에톡시)페닐)-5-플루오로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 염산염( S )-N-(4-(2-( diethylamino )ethoxy)phenyl)-5-fluoro-4-(3-phenylisooxazolidin-2-yl)pyrimidin-2-amine hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 10.08 (s, 1H), 8.25 (d, J = 6.0 Hz, 1H), 7.48 - 7.27 (m, 8H), 6.87 - 6.82 (m, 2H), 5.60 (dd, J = 8.7, 5.5 Hz, 1H), 4.36 (d, J = 5.1 Hz, 2H), 4.11 (d, J = 7.7 Hz, 2H), 3.48 (q, J = 5.0 Hz, 2H), 3.27 - 3.13 (m, 4H), 3.00 - 2.91 (m, 1H), 2.27 (dtd, J = 12.8, 7.7, 5.4 Hz, 1H), 1.27 (t, J = 7.2 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.72 (s, 1H), 10.08 (s, 1H), 8.25 (d, J = 6.0 Hz, 1H), 7.48 - 7.27 (m, 8H), 6.87 - 6.82 (m, 2H), 5.60 (dd, J = 8.7, 5.5 Hz, 1H), 4.36 (d, J = 5.1 Hz, 2H), 4.11 (d, J = 7.7 Hz, 2H), 3.48 (q, J ) = 5.0 Hz, 2H), 3.27 - 3.13 (m, 4H), 3.00 - 2.91 (m, 1H), 2.27 (dtd, J = 12.8, 7.7, 5.4 Hz, 1H), 1.27 (t, J = 7.2 Hz, 6H) 452.2
[M+H]+ 452.2
[M+H] +
3737
Figure PCTKR2021018956-appb-img-000070
Figure PCTKR2021018956-appb-img-000070
 		(S)-N-(4-(3-(다이에틸아미노)프로폭시)페닐)-5-플루오로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 염산염( S )-N-(4-(3-( diethylamino )propoxy)phenyl)-5-fluoro-4-(3-phenylisooxazolidin-2-yl)pyrimidin-2-amine hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 9.95 (s, 1H), 8.23 (d, J = 5.9 Hz, 1H), 7.47 - 7.27 (m, 8H), 6.82 - 6.77 (m, 2H), 5.60 (dd, J = 8.6, 5.5 Hz, 1H), 4.35 (td, J = 7.6, 4.1 Hz, 1H), 4.09 (t, J = 7.7 Hz, 1H), 4.03 (t, J = 6.1 Hz, 2H), 3.15 (dqd, J = 14.5, 7.2, 6.5, 3.8 Hz, 6H), 2.99 - 2.91 (m, 1H), 2.27 (dtd, J = 12.8, 7.7, 5.3 Hz, 1H), 2.17 - 2.10 (m, 2H), 1.24 (t, J = 7.2 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.50 (s, 1H), 9.95 (s, 1H), 8.23 (d, J = 5.9 Hz, 1H), 7.47 - 7.27 (m, 8H), 6.82 - 6.77 (m, 2H), 5.60 (dd, J = 8.6, 5.5 Hz, 1H), 4.35 (td, J = 7.6, 4.1 Hz, 1H), 4.09 (t, J = 7.7 Hz, 1H), 4.03 (t) , J = 6.1 Hz, 2H), 3.15 (dqd, J = 14.5, 7.2, 6.5, 3.8 Hz, 6H), 2.99 - 2.91 (m, 1H), 2.27 (dtd, J = 12.8, 7.7, 5.3 Hz, 1H) ), 2.17 - 2.10 (m, 2H), 1.24 (t, J = 7.2 Hz, 6H) 466.3
[M+H]+ 466.3
[M+H] +
3838
Figure PCTKR2021018956-appb-img-000071
Figure PCTKR2021018956-appb-img-000071
 		(S)-N-(4-(2-(다이에틸아미노)에톡시)-3,5-다이메틸페닐)-5-플루오로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 염산염( S )-N-(4-(2-(diethylamino)ethoxy)-3,5- dimethylphenyl )-5-fluoro-4-(3-phenylisoxazolidin-2-yl)pyri Midin-2-amine hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.19 (d, J = 4.9 Hz, 1H), 7.43 (d, J = 7.3 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.29 (d, J = 11.3 Hz, 3H), 5.64 (dd, J = 8.8, 5.2 Hz, 1H), 4.25 (dd, J = 7.9, 3.5 Hz, 1H), 3.98 - 3.91 (m, 3H), 3.24 (s, 2H), 3.03 (s, 4H), 2.92 (dt, J = 12.5, 4.4 Hz, 1H), 2.28 (dtd, J = 12.9, 8.3, 5.0 Hz, 1H), 1.20 (d, J = 7.4 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.28 (s, 1H), 8.19 (d, J = 4.9 Hz, 1H), 7.43 (d, J = 7.3 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.29 (d, J = 11.3 Hz, 3H), 5.64 (dd, J = 8.8, 5.2 Hz, 1H), 4.25 (dd, J = 7.9, 3.5 Hz, 1H), 3.98 - 3.91 ( m, 3H), 3.24 (s, 2H), 3.03 (s, 4H), 2.92 (dt, J = 12.5, 4.4 Hz, 1H), 2.28 (dtd, J = 12.9, 8.3, 5.0 Hz, 1H), 1.20 (d, J = 7.4 Hz, 6H) 480.3
[M+H]+ 480.3
[M+H] +
3939
Figure PCTKR2021018956-appb-img-000072
Figure PCTKR2021018956-appb-img-000072
 		(S)-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)-5-플루오로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 염산염( S )-N-(4-(3-(diethylamino)propoxy)-3,5- dimethylphenyl )-5-fluoro-4-(3-phenylisoxazolidin-2-yl)pyri Midin-2-amine hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.25 (s, 1H), 8.19 (d, J = 4.9 Hz, 1H), 7.44 - 7.35 (m, 4H), 7.28 (s, 2H), 5.64 (dd, J = 8.8, 5.1 Hz, 1H), 4.26 (td, J = 7.9, 3.4 Hz, 1H), 3.94 (q, J = 7.9 Hz, 1H), 3.73 (t, J = 6.0 Hz, 2H), 3.36 (s, 6H), 3.17 (d, J = 39.2 Hz, 6H), 2.93 (dtd, J = 11.7, 7.8, 3.3 Hz, 1H), 2.30 - 2.23 (m, 1H), 2.09 (s, 8H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.35 (s, 1H), 9.25 (s, 1H), 8.19 (d, J = 4.9 Hz, 1H), 7.44 - 7.35 (m, 4H), 7.28 ( s, 2H), 5.64 (dd, J = 8.8, 5.1 Hz, 1H), 4.26 (td, J = 7.9, 3.4 Hz, 1H), 3.94 (q, J = 7.9 Hz, 1H), 3.73 (t, J ) = 6.0 Hz, 2H), 3.36 (s, 6H), 3.17 (d, J = 39.2 Hz, 6H), 2.93 (dtd, J = 11.7, 7.8, 3.3 Hz, 1H), 2.30 - 2.23 (m, 1H) , 2.09 (s, 8H) 494.3
[M+H]+ 494.3
[M+H] +
4040
Figure PCTKR2021018956-appb-img-000073
Figure PCTKR2021018956-appb-img-000073
 		(S)-5-플루오로-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 트라이플루오로아세트산염( S )-5-fluoro- N- (4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisooxazolidin-2-yl)pyrimidin-2-amine tri Fluoroacetate 435.2 [M+H]+ 435.2 [M+H] +
4141
Figure PCTKR2021018956-appb-img-000074
Figure PCTKR2021018956-appb-img-000074
 		(R)-5-플루오로-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 염산염( R )-5-fluoro- N- (4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 10.43 (s, 1H), 8.29 (d, J = 6.6 Hz, 1H), 7.46 - 7.27 (m, 6H), 7.19 (d, J = 8.6 Hz, 2H), 5.62 (dd, J = 8.6, 5.5 Hz, 1H), 4.41 (td, J = 7.4, 4.4 Hz, 1H), 4.19 (q, J = 7.6 Hz, 1H), 3.75 (d, J = 10.2 Hz, 2H), 3.50 (d, J = 9.6 Hz, 2H), 3.26 - 3.09 (m, 4H), 3.04 - 2.94 (m, 1H), 2.81 (d, J = 3.7 Hz, 3H), 2.31 - 2.22 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.39 (s, 1H), 10.43 (s, 1H), 8.29 (d, J = 6.6 Hz, 1H), 7.46 - 7.27 (m, 6H), 7.19 ( d, J = 8.6 Hz, 2H), 5.62 (dd, J = 8.6, 5.5 Hz, 1H), 4.41 (td, J = 7.4, 4.4 Hz, 1H), 4.19 (q, J = 7.6 Hz, 1H), 3.75 (d, J = 10.2 Hz, 2H), 3.50 (d, J = 9.6 Hz, 2H), 3.26 - 3.09 (m, 4H), 3.04 - 2.94 (m, 1H), 2.81 (d, J = 3.7 Hz) , 3H), 2.31 - 2.22 (m, 1H) 435.2
[M+H]+ 435.2
[M+H] +
4242
Figure PCTKR2021018956-appb-img-000075
Figure PCTKR2021018956-appb-img-000075
 		(S)-5-플루오로-N-(4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민( S )-5-fluoro- N- (4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisoxazolidine- 2-yl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.13 (d, J = 4.9 Hz, 1H), 7.44 - 7.34 (m, 6H), 7.31 - 7.26 (m, 1H), 6.81 - 6.73 (m, 2H), 5.56 (dd, J = 8.6, 5.7 Hz, 1H), 4.25 (td, J = 7.7, 3.3 Hz, 1H), 3.97 - 3.90 (m, 1H), 3.57 (d, J = 11.9 Hz, 2H), 2.90 (ddd, J = 11.1, 7.5, 3.5 Hz, 1H), 2.55 (dd, J = 21.4, 9.7 Hz, 5H), 2.39 - 2.15 (m, 7H), 2.14 (s, 3H), 1.83 (d, J = 12.3 Hz, 2H), 1.54 - 1.44 (m, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.15 (s, 1H), 8.13 (d, J = 4.9 Hz, 1H), 7.44 - 7.34 (m, 6H), 7.31 - 7.26 (m, 1H), 6.81 - 6.73 (m, 2H), 5.56 (dd, J = 8.6, 5.7 Hz, 1H), 4.25 (td, J = 7.7, 3.3 Hz, 1H), 3.97 - 3.90 (m, 1H), 3.57 (d, J = 11.9 Hz, 2H), 2.90 (ddd, J = 11.1, 7.5, 3.5 Hz, 1H), 2.55 (dd, J = 21.4, 9.7 Hz, 5H), 2.39 - 2.15 (m, 7H), 2.14 (s) , 3H), 1.83 (d, J = 12.3 Hz, 2H), 1.54 - 1.44 (m, 2H) 518.4 [M+H]+ 518.4 [M+H] +
4343
Figure PCTKR2021018956-appb-img-000076
Figure PCTKR2021018956-appb-img-000076
 		N-(3-사이클로프로필-5-(((3S,5R)-3,5-다이메틸피페라진-1-일)메틸)페닐)-5-플루오로-4-((S)-3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민 N -(3-cyclopropyl-5-((( 3S,5R)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-5-fluoro-4-((S ) - 3-phenylisoxazolidin-2-yl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.21 (d, J = 4.8 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.40 - 7.30 (m, 5H), 7.30 - 7.25 (m, 1H), 6.55 (d, J = 1.7 Hz, 1H), 5.65 (dd, J = 8.9, 4.7 Hz, 1H), 4.26 (td, J = 7.9, 3.6 Hz, 1H), 3.97 (q, J = 7.9 Hz, 1H), 3.24 (q, J = 13.0 Hz, 2H), 2.90 (dtd, J = 12.4, 7.9, 3.6 Hz, 1H), 2.77 (t, J = 7.7 Hz, 2H), 2.61 (d, J = 10.7 Hz, 2H), 2.33 (ddt, J = 12.0, 8.0, 4.1 Hz, 1H), 1.73 (tt, J = 8.4, 5.1 Hz, 1H), 1.47 (q, J = 10.4 Hz, 2H), 0.94 - 0.89 (m, 6H), 0.89 - 0.83 (m, 2H), 0.62 - 0.53 (m, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.33 (s, 1H), 8.21 (d, J = 4.8 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.40 - 7.30 (m, 5H), 7.30 - 7.25 (m, 1H), 6.55 (d, J = 1.7 Hz, 1H), 5.65 (dd, J = 8.9, 4.7 Hz, 1H), 4.26 (td, J = 7.9, 3.6 Hz, 1H), 3.97 (q, J = 7.9 Hz, 1H), 3.24 (q, J = 13.0 Hz, 2H), 2.90 (dtd, J = 12.4, 7.9, 3.6 Hz, 1H), 2.77 (t, J = 7.7 Hz, 2H) , 2.61 (d, J = 10.7 Hz, 2H), 2.33 (ddt, J = 12.0, 8.0, 4.1 Hz, 1H), 1.73 (tt, J = 8.4, 5.1 Hz, 1H), 1.47 (q, J = 10.4) Hz, 2H), 0.94 - 0.89 (m, 6H), 0.89 - 0.83 (m, 2H), 0.62 - 0.53 (m, 2H) 503.4 [M+H]+ 503.4 [M+H] +
4444
Figure PCTKR2021018956-appb-img-000077
Figure PCTKR2021018956-appb-img-000077
 		(S)-N-(5-플루오로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민( S )-N-(5-fluoro-4-(3- phenylisoxazolidin -2-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline-6- amine 391.5 [M+H]+ 391.5 [M+H] +
실시예 45. (Example 45. ( SS )-)- NN -(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민의 제조Preparation of -(4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine
Figure PCTKR2021018956-appb-img-000078
Figure PCTKR2021018956-appb-img-000078
단계 1: (Step 1: ( SS )-2-(2-클로로-5-아이오도피리미딘-4-일)-3-페닐아이소옥사졸리딘의 제조Preparation of )-2-(2-chloro-5-iodopyrimidin-4-yl)-3-phenylisoxazolidine
2,4-다이클로로-5-아이오도피리미딘(10 g, 36.4 mmol), (S)-3-페닐아이소옥사졸리딘(5.9 g, 40.0 mmol)과 DIPEA(12.71 mL, 72.8 mmol)를 넣고 DMSO(75 mL)를 첨가하여 50 ℃에서 2 시간 동안 교반하였다. 물(1000 mL)을 첨가하여 반응을 종결한 후, 아세트산에틸(200 mL * 3 회)을 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하여 목적 화합물(13 g, 92 %)을 수득하였다.Add 2,4-dichloro-5-iodopyrimidine (10 g, 36.4 mmol), ( S )-3-phenylisoxazolidine (5.9 g, 40.0 mmol) and DIPEA (12.71 mL, 72.8 mmol) DMSO (75 mL) was added and stirred at 50 °C for 2 hours. After the reaction was terminated by adding water (1000 mL), the organic layer was extracted using ethyl acetate (200 mL * 3 times). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound (13 g, 92%).
MS (m/z): 388.6 [M+1]+ MS (m/z): 388.6 [M+1] +
단계 2: (Step 2: ( SS )-2-(2-클로로-5-(트라이플루오로메틸)피리미딘-4-일)-3-페닐아이소옥사졸리딘의 제조Preparation of )-2-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-3-phenylisoxazolidine
반응 용기에 아이오딘화구리(3 g, 15.48 mmol), 플루오린화칼륨(0.9 g, 15.48 mmol)을 넣은 후, 감압 하에 120 ℃에서 2 시간 동안 교반하였다. 반응 혼합물을 상온으로 식힌 후에 질소 기류 하에 단계 1에서 제조한 (S)-2-(2-클로로-5-아이오도피리미딘-4-일)-3-페닐아이소옥사졸리딘(3 g, 7.74 mmol), TMS-CF3(2.3 mL, 15.48 mmol)를 NMP(50 mL)에 녹여 첨가한 후 50 ℃에서 2 시간 동안 교반하였다. 반응 혼합물에 과량의 물을 첨가한 후 아세트산에틸로 추출하였다. 얻어진 여과액을 소금물로 씻어 유기층을 모아 황산나트륨으로 건조하였다. 감압 하에 농축한 후 중압액체크로마토그래피(아세트산에틸/n-헥산 0 ~ 60%)로 정제하여 목적 화합물(1.15 g, 45 %)을 수득하였다.Copper iodide (3 g, 15.48 mmol) and potassium fluoride (0.9 g, 15.48 mmol) were placed in a reaction vessel, and then stirred at 120° C. under reduced pressure for 2 hours. After the reaction mixture was cooled to room temperature, ( S )-2-(2-chloro-5-iodopyrimidin-4-yl)-3-phenylisoxazolidine prepared in step 1 under a nitrogen stream (3 g, 7.74) mmol), TMS-CF 3 (2.3 mL, 15.48 mmol) was dissolved in NMP (50 mL) and added, followed by stirring at 50 °C for 2 hours. An excess of water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained filtrate was washed with brine, and the organic layers were collected and dried over sodium sulfate. After concentration under reduced pressure, the mixture was purified by medium pressure liquid chromatography (ethyl acetate/n-hexane 0 to 60%) to obtain the target compound (1.15 g, 45%).
MS (m/z): 417.5 [M+1]+ MS (m/z): 417.5 [M+1] +
단계 3: (Step 3: ( SS )-)- NN -(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민의 제조Preparation of -(4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine
단계 2에서 제조한 (S)-2-(2-클로로-5-(트라이플루오로메틸)피리미딘-4-일)-3-페닐아이소옥사졸리딘(50 mg, 0.15 mmol), PTSA(58 mg, 0.30 mmol)를 sec-BuOH(1.5 mL)에 녹인 후 100 ℃에서 2 시간 교반하였다. 반응 혼합물을 아세트산에틸로 씻어 주었다. 얻어진 여과액을 소금물로 씻어 유기층을 모아 황산나트륨으로 건조하였다. 감압 하에 농축한 후 중압액체크로마토그래피(메탄올/염화메틸렌 0 ~ 10 %)로 정제하여 목적 화합물(50 mg, 68 %)을 수득하였다.( S )-2-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-3-phenylisoxazolidine (50 mg, 0.15 mmol) prepared in step 2, PTSA (58 mg, 0.30 mmol) was dissolved in sec-BuOH (1.5 mL) and stirred at 100 °C for 2 hours. The reaction mixture was washed with ethyl acetate. The obtained filtrate was washed with brine, and the organic layers were collected and dried over sodium sulfate. After concentration under reduced pressure, it was purified by medium pressure liquid chromatography (methanol/methylene chloride 0 to 10%) to obtain the target compound (50 mg, 68%).
MS (m/z): 485.5 [M+1]+ MS (m/z): 485.5 [M+1] +
1H NMR (400 MHz, DMSO-d 6) δ = 9.87 (s, 1H), 9.54 (s, 1H), 8.59 (s, 2H), 7.92 - 7.88 (m, 2H), 7.65 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.50 (d, J = 0.9 Hz, 1H), 7.38 (dd, J = 7.2, 1.2 Hz, 4H), 7.35 - 7.32 (m, 1H), 7.31 - 7.25 (m, 1H), 7.18 (dt, J = 7.7, 1.3 Hz, 1H), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (d, J = 3.1 Hz, 1H), 3.92 - 3.87 (m, 1H), 3.81 (s, 3H), 2.86 (dddd, J = 12.0, 8.7, 7.0, 3.0 Hz, 1H), 2.28 - 2.19 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.87 (s, 1H), 9.54 (s, 1H), 8.59 (s, 2H), 7.92 - 7.88 (m, 2H), 7.65 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.50 (d, J = 0.9 Hz, 1H), 7.38 (dd, J = 7.2, 1.2 Hz, 4H), 7.35 - 7.32 (m, 1H), 7.31 - 7.25 (m) , 1H), 7.18 (dt, J = 7.7, 1.3 Hz, 1H), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (d, J = 3.1 Hz, 1H), 3.92 - 3.87 (m, 1H), 3.81 (s, 3H), 2.86 (dddd, J = 12.0, 8.7, 7.0, 3.0 Hz, 1H), 2.28 - 2.19 (m, 1H)
실시예 46 내지 234Examples 46-234
상기 실시예 45과 유사한 방법으로 실시예 46 내지 234를 제조하였으며, 실시예 45 내지 234의 화합물명, 화학구조식, NMR 및 LC-MS 분석 결과를 하기 표 2에 정리하여 나타내었다.Examples 46 to 234 were prepared in a manner similar to that of Example 45, and the compound names, chemical structural formulas, NMR and LC-MS analysis results of Examples 45 to 234 are summarized and shown in Table 2 below.
실시예Example 구조rescue 화합물명compound name 1H NMR 1 H NMR LC-MS
(m/z)LC-MS
(m/z)
4545
Figure PCTKR2021018956-appb-img-000079
Figure PCTKR2021018956-appb-img-000079
 		(S)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine- 2-amine 1H NMR (400 MHz, DMSO-d 6) δ = 9.87 (s, 1H), 9.54 (s, 1H), 8.59 (s, 2H), 7.92 - 7.88 (m, 2H), 7.65 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.50 (d, J = 0.9 Hz, 1H), 7.38 (dd, J = 7.2, 1.2 Hz, 4H), 7.35 - 7.32 (m, 1H), 7.31 - 7.25 (m, 1H), 7.18 (dt, J = 7.7, 1.3 Hz, 1H), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (d, J = 3.1 Hz, 1H), 3.92 - 3.87 (m, 1H), 3.81 (s, 3H), 2.86 (dddd, J = 12.0, 8.7, 7.0, 3.0 Hz, 1H), 2.28 - 2.19 (m, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ = 9.87 (s, 1H), 9.54 (s, 1H), 8.59 (s, 2H), 7.92 - 7.88 (m, 2H), 7.65 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.50 (d, J = 0.9 Hz, 1H), 7.38 (dd, J = 7.2, 1.2 Hz, 4H), 7.35 - 7.32 (m, 1H), 7.31 - 7.25 (m) , 1H), 7.18 (dt, J = 7.7, 1.3 Hz, 1H), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (d, J = 3.1 Hz, 1H), 3.92 - 3.87 (m, 1H), 3.81 (s, 3H), 2.86 (dddd, J = 12.0, 8.7, 7.0, 3.0 Hz, 1H), 2.28 - 2.19 (m, 1H) 485.5 [M+1]+ 485.5 [M+1] +
4646
Figure PCTKR2021018956-appb-img-000080
Figure PCTKR2021018956-appb-img-000080
 		(R)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( R )-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine- 2-amine 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.41 (s, 1H), 7.42 - 7.19 (m, 7H), 6.72 (s, 2H), 5.72 (s, 1H), 4.29 (dt, J = 8.7, 4.3 Hz, 1H), 3.78 (ddd, J = 10.1, 8.0, 6.3 Hz, 1H), 3.35 (s, 2H), 3.09 - 3.01 (m, 4H), 2.93 (dddd, J = 11.5, 8.6, 6.3, 2.2 Hz, 1H), 2.48 (q, J = 4.9, 4.2 Hz, 4H), 2.24 (s, 3H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.63 (s, 1H), 8.41 (s, 1H), 7.42 - 7.19 (m, 7H), 6.72 (s, 2H), 5.72 (s, 1H), 4.29 (dt, J = 8.7, 4.3 Hz, 1H), 3.78 (ddd, J = 10.1, 8.0, 6.3 Hz, 1H), 3.35 (s, 2H), 3.09 - 3.01 (m, 4H), 2.93 (dddd, J = 11.5, 8.6, 6.3, 2.2 Hz, 1H), 2.48 (q, J = 4.9, 4.2 Hz, 4H), 2.24 (s, 3H) 485.2
[M+H]+ 485.2
[M+H] +
4747
Figure PCTKR2021018956-appb-img-000081
Figure PCTKR2021018956-appb-img-000081
 		(S)-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤조나이트릴( S )-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzonitrile 412.2
[M+H]+ 412.2
[M+H] +
4848
Figure PCTKR2021018956-appb-img-000082
Figure PCTKR2021018956-appb-img-000082
 		(S)-N1,N1-다이메틸-N4-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)벤젠-1,4-다이아민( S ) -N 1, N 1-dimethyl- N 4-(4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)benzene- 1,4-diamine 430.2
[M+H]+ 430.2
[M+H] +
4949
Figure PCTKR2021018956-appb-img-000083
Figure PCTKR2021018956-appb-img-000083
 		(S)-N-(4-플루오로페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (4-fluorophenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 405.2
[M+H]+ 405.2
[M+H] +
5050
Figure PCTKR2021018956-appb-img-000084
Figure PCTKR2021018956-appb-img-000084
 		(S)-N-(4-메톡시페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (4-methoxyphenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 417.2
[M+H]+ 417.2
[M+H] +
5151
Figure PCTKR2021018956-appb-img-000085
Figure PCTKR2021018956-appb-img-000085
 		(S)-N-(4-(메틸싸이오)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (4-(methylthio)phenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, Methanol-d 4) δ 8.26 - 8.21 (m, 1H), 7.28 (d, J = 5.7 Hz, 4H), 7.22 - 7.11 (m, 3H), 6.95 - 6.89 (m, 2H), 5.64 (t, J = 7.8 Hz, 1H), 4.20 - 4.13 (m, 1H), 3.77 (ddd, J = 10.1, 8.2, 6.2 Hz, 1H), 2.83 (dtd, J = 12.2, 6.3, 3.1 Hz, 1H), 2.32 (s, 3H), 2.17 (ddt, J = 12.0, 10.2, 7.5 Hz, 1H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.26 - 8.21 (m, 1H), 7.28 (d, J = 5.7 Hz, 4H), 7.22 - 7.11 (m, 3H), 6.95 - 6.89 (m, 2H) ), 5.64 (t, J = 7.8 Hz, 1H), 4.20 - 4.13 (m, 1H), 3.77 (ddd, J = 10.1, 8.2, 6.2 Hz, 1H), 2.83 (dtd, J = 12.2, 6.3, 3.1 Hz, 1H), 2.32 (s, 3H), 2.17 (ddt, J = 12.0, 10.2, 7.5 Hz, 1H) 433.1
[M+H]+ 433.1
[M+H] +
5252
Figure PCTKR2021018956-appb-img-000086
Figure PCTKR2021018956-appb-img-000086
 		(S)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)-N-(4-(트라이플루오로메틸)페닐)피리미딘-2-아민( S )-4-(3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine 1H NMR (400 MHz, Methanol-d 4) δ 8.43 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.44 - 7.39 (m, 4H), 7.36 - 7.31 (m, 3H), 5.78 (dd, J = 8.7, 7.0 Hz, 1H), 4.31 (td, J = 7.8, 2.5 Hz, 1H), 3.92 (ddd, J = 10.2, 8.1, 6.1 Hz, 1H), 3.00 (dddd, J = 11.5, 8.6, 6.0, 2.5 Hz, 1H), 2.31 (ddt, J = 12.0, 10.2, 7.3 Hz, 1H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.43 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.44 - 7.39 (m, 4H), 7.36 - 7.31 (m, 3H), 5.78 (dd, J = 8.7, 7.0 Hz, 1H), 4.31 (td, J = 7.8, 2.5 Hz, 1H), 3.92 (ddd, J = 10.2, 8.1, 6.1 Hz, 1H), 3.00 (dddd, J = 11.5, 8.6, 6.0, 2.5 Hz, 1H), 2.31 (ddt, J = 12.0, 10.2, 7.3 Hz, 1H) 455.2
[M+H]+ 455.2
[M+H] +
5353
Figure PCTKR2021018956-appb-img-000087
Figure PCTKR2021018956-appb-img-000087
 		tert-부틸 (S)-(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)카바메이트 tert -Butyl ( S )-(4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)carbamate 1H NMR (400 MHz, Methanol-d 4) δ 8.34 (s, 1H), 7.40 (d, J = 5.9 Hz, 4H), 7.32 - 7.18 (m, 6H), 5.77 (t, J = 7.9 Hz, 1H), 4.27 (td, J = 7.9, 2.6 Hz, 1H), 3.86 (ddd, J = 10.1, 8.2, 6.3 Hz, 1H), 2.91 (dtd, J = 12.3, 6.3, 3.2 Hz, 1H), 2.28 (ddt, J = 12.0, 10.1, 7.3 Hz, 1H), 1.55 (s, 9H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.34 (s, 1H), 7.40 (d, J = 5.9 Hz, 4H), 7.32 - 7.18 (m, 6H), 5.77 (t, J = 7.9 Hz, 1H), 4.27 (td, J = 7.9, 2.6 Hz, 1H), 3.86 (ddd, J = 10.1, 8.2, 6.3 Hz, 1H), 2.91 (dtd, J = 12.3, 6.3, 3.2 Hz, 1H), 2.28 (ddt, J = 12.0, 10.1, 7.3 Hz, 1H), 1.55 (s, 9H) 502.3
[M+H]+ 502.3
[M+H] +
5454
Figure PCTKR2021018956-appb-img-000088
Figure PCTKR2021018956-appb-img-000088
 		(S)-N1-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)벤젠-1,4-다이아민( S ) -N 1-(4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)benzene-1,4-diamine 402.2
[M+H]+ 402.2
[M+H] +
5555
Figure PCTKR2021018956-appb-img-000089
Figure PCTKR2021018956-appb-img-000089
 		(S)-N-(4-(4-에틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(4-(4-ethylpiperazin- 1 -yl)phenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine- 2-amine 499.3
[M+H]+ 499.3
[M+H] +
5656
Figure PCTKR2021018956-appb-img-000090
Figure PCTKR2021018956-appb-img-000090
 		(S)-1-(4-(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피페라진-1-일)에탄-1-온( S )-1-(4-(4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pipe Razin-1-yl)ethan-1-one 513.3
[M+H]+ 513.3
[M+H] +
5757
Figure PCTKR2021018956-appb-img-000091
Figure PCTKR2021018956-appb-img-000091
 		4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)-N-(4-((3S,5R)-3,4,5-트라이메틸피페라진-1-일)페닐)피리미딘-2-아민4-(( S )-3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl)-N-(4-(( 3S ,5R)-3,4,5-trimethyl piperazin-1-yl)phenyl)pyrimidin-2-amine 1H NMR (400 MHz, Methanol-d 4) δ 8.33 (s, 1H), 7.38 (dd, J = 4.8, 1.5 Hz, 5H), 7.33 - 7.16 (m, 4H), 6.82 - 6.73 (m, 2H), 5.77 (s, 1H), 4.27 (td, J = 7.8, 2.5 Hz, 1H), 3.86 (dddd, J = 10.1, 8.2, 6.2, 2.5 Hz, 1H), 3.52 - 3.37 (m, 2H), 2.92 (dtt, J = 11.9, 6.2, 2.8 Hz, 1H), 2.57 - 2.41 (m, 5H), 2.38 (d, J = 1.7 Hz, 4H), 1.24 - 1.21 (m, 6H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.33 (s, 1H), 7.38 (dd, J = 4.8, 1.5 Hz, 5H), 7.33 - 7.16 (m, 4H), 6.82 - 6.73 (m, 2H) ), 5.77 (s, 1H), 4.27 (td, J = 7.8, 2.5 Hz, 1H), 3.86 (dddd, J = 10.1, 8.2, 6.2, 2.5 Hz, 1H), 3.52 - 3.37 (m, 2H), 2.92 (dtt, J = 11.9, 6.2, 2.8 Hz, 1H), 2.57 - 2.41 (m, 5H), 2.38 (d, J = 1.7 Hz, 4H), 1.24 - 1.21 (m, 6H) 513.4
[M+H]+ 513.4
[M+H] +
5858
Figure PCTKR2021018956-appb-img-000092
Figure PCTKR2021018956-appb-img-000092
 		(S)-N1-(2-(다이메틸아미노)에틸)-N1-메틸-N4-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)벤젠-1,4-다이아민( S ) -N 1-(2-(dimethylamino)ethyl) -N 1-methyl- N 4-(4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl )pyrimidin-2-yl)benzene-1,4-diamine 487.3
[M+H]+ 487.3
[M+H] +
5959
Figure PCTKR2021018956-appb-img-000093
Figure PCTKR2021018956-appb-img-000093
 		(S)-N-(4-(2-(다이메틸아미노)에톡시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (4-(2-(dimethylamino)ethoxy)phenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine- 2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.66 (s, 1H), 8.43 (s, 1H), 7.39 (d, J = 6.1 Hz, 4H), 7.35 - 7.26 (m, 3H), 6.71 (s, 2H), 5.80 - 5.70 (m, 1H), 4.28 (dt, J = 7.7, 3.9 Hz, 1H), 3.98 (t, J = 5.7 Hz, 2H), 3.82 - 3.77 (m, 1H), 2.95 (d, J = 3.7 Hz, 1H), 2.61 (s, 2H), 2.23 (s, 6H), 1.85 (s, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.66 (s, 1H), 8.43 (s, 1H), 7.39 (d, J = 6.1 Hz, 4H), 7.35 - 7.26 (m, 3H), 6.71 (s, 2H), 5.80 - 5.70 (m, 1H), 4.28 (dt, J = 7.7, 3.9 Hz, 1H), 3.98 (t, J = 5.7 Hz, 2H), 3.82 - 3.77 (m, 1H), 2.95 (d, J = 3.7 Hz, 1H), 2.61 (s, 2H), 2.23 (s, 6H), 1.85 (s, 1H) 474.3
[M+H]+ 474.3
[M+H] +
6060
Figure PCTKR2021018956-appb-img-000094
Figure PCTKR2021018956-appb-img-000094
 		(S)-N-(4-몰포리노페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (4-morpholinophenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, Methanol-d 4) δ 8.33 (s, 1H), 7.42 - 7.33 (m, 4H), 7.33 - 7.18 (m, 3H), 6.78 (d, J = 8.5 Hz, 2H), 5.77 (s, 1H), 4.28 (td, J = 7.8, 2.5 Hz, 1H), 3.90 - 3.82 (m, 5H), 3.15 - 3.04 (m, 4H), 2.98 - 2.86 (m, 1H), 2.30 (ddt, J = 12.0, 10.1, 7.3 Hz, 1H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.33 (s, 1H), 7.42 - 7.33 (m, 4H), 7.33 - 7.18 (m, 3H), 6.78 (d, J = 8.5 Hz, 2H), 5.77 (s, 1H), 4.28 (td, J = 7.8, 2.5 Hz, 1H), 3.90 - 3.82 (m, 5H), 3.15 - 3.04 (m, 4H), 2.98 - 2.86 (m, 1H), 2.30 ( ddt, J = 12.0, 10.1, 7.3 Hz, 1H) 472.2
[M+H]+ 472.2
[M+H] +
6161
Figure PCTKR2021018956-appb-img-000095
Figure PCTKR2021018956-appb-img-000095
 		N-(4-((2S,6R)-2,6-다이메틸몰포리노)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민 N- (4-(( 2S ,6R)-2,6-dimethylmorpholino)phenyl)-4-(( S )-3- phenylisoxazolidin -2-yl)-5-(tri Fluoromethyl) pyrimidin-2-amine 500.3
[M+H]+ 500.3
[M+H] +
6262
Figure PCTKR2021018956-appb-img-000096
Figure PCTKR2021018956-appb-img-000096
 		N-(4-((1R,4R)-2-옥사-5-아자바이사이클로[2.2.1]헵탄-5-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민 N- (4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl)-4-(( S )-3-phenylisoxazolidine- 2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 484.2
[M+H]+ 484.2
[M+H] +
6363
Figure PCTKR2021018956-appb-img-000097
Figure PCTKR2021018956-appb-img-000097
 		(S)-N-(4-(3-(다이메틸아미노)아제티딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(4-(3-( dimethylamino )azetidin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl ) pyrimidin-2-amine 485.3
[M+H]+ 485.3
[M+H] +
6464
Figure PCTKR2021018956-appb-img-000098
Figure PCTKR2021018956-appb-img-000098
 		(S)-N-(4-(4-메틸피페라진-1-일)-3-(트라이플루오로메틸)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(4-(4-methylpiperazin- 1 -yl)-3-(trifluoromethyl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, Chloroform-d) δ = 8.41 (s, 1H), 7.50 (d, J = 9.7 Hz, 2H), 7.41 - 7.31 (m, 4H), 7.32 - 7.26 (m, 2H), 7.13 (d, J = 8.7 Hz, 1H), 5.74 (dd, J = 8.7, 6.3 Hz, 1H), 4.29 (td, J = 7.9, 3.1 Hz, 1H), 3.90 (ddd, J = 9.6, 8.2, 6.6 Hz, 1H), 2.93 (d, J = 20.0 Hz, 4H), 2.87 (ddt, J = 8.7, 5.4, 3.1 Hz, 1H), 2.65 (s, 2H), 2.43 (d, J = 6.6 Hz, 2H), 2.40 - 2.35 (m, 1H), 1.26 (s, 3H) 1 H NMR (400 MHz, Chloroform-d) δ = 8.41 (s, 1H), 7.50 (d, J = 9.7 Hz, 2H), 7.41 - 7.31 (m, 4H), 7.32 - 7.26 (m, 2H), 7.13 (d, J = 8.7 Hz, 1H), 5.74 (dd, J = 8.7, 6.3 Hz, 1H), 4.29 (td, J = 7.9, 3.1 Hz, 1H), 3.90 (ddd, J = 9.6, 8.2, 6.6 Hz, 1H), 2.93 (d, J = 20.0 Hz, 4H), 2.87 (ddt, J = 8.7, 5.4, 3.1 Hz, 1H), 2.65 (s, 2H), 2.43 (d, J = 6.6 Hz, 2H), 2.40 - 2.35 (m, 1H), 1.26 (s, 3H) 553.5
[M+H]+ 553.5
[M+H] +
6565
Figure PCTKR2021018956-appb-img-000099
Figure PCTKR2021018956-appb-img-000099
 		(S)-N-(2-메톡시-4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(2-methoxy-4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoro methyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 8.48 (s, 1H), 8.36 (s, 1H), 7.32 (d, J = 7.1 Hz, 3H), 7.29 - 7.17 (m, 3H), 6.68 (d, J = 2.6 Hz, 1H), 6.41 (d, J = 8.6 Hz, 1H), 5.59 (s, 1H), 4.30 (dd, J = 7.8, 2.4 Hz, 1H), 3.79 - 3.76 (m, 1H), 3.74 (s, 3H), 3.54 - 3.18 (m, 8H), 2.89 (s, 3H), 2.84 (ddd, J = 8.5, 6.4, 2.6 Hz, 1H), 2.22 (d, J = 9.5 Hz, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.48 (s, 1H), 8.36 (s, 1H), 7.32 (d, J = 7.1 Hz, 3H), 7.29 - 7.17 (m, 3H), 6.68 (d, J = 2.6 Hz, 1H), 6.41 (d, J = 8.6 Hz, 1H), 5.59 (s, 1H), 4.30 (dd, J = 7.8, 2.4 Hz, 1H), 3.79 - 3.76 (m, 1H), 3.74 (s, 3H), 3.54 - 3.18 (m, 8H), 2.89 (s, 3H), 2.84 (ddd, J = 8.5, 6.4, 2.6 Hz, 1H), 2.22 (d, J = 9.5 Hz) , 1H) 515.4
[M+H]+ 515.4
[M+H] +
6666
Figure PCTKR2021018956-appb-img-000100
Figure PCTKR2021018956-appb-img-000100
 		(S)-N-(3-메톡시-4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(3-methoxy-4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoro methyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.61 (s, 1H), 8.44 (s, 1H), 7.36 (d, J = 4.8 Hz, 4H), 7.31 - 7.26 (m, 1H), 7.05 (s, 2H), 6.63 (s, 1H), 5.83 (s, 1H), 4.26 (dt, J = 7.8, 3.9 Hz, 1H), 3.83 - 3.76 (m, 1H), 3.62 (s, 3H), 2.97 - 2.82 (m, 6H), 2.44 (s, 4H), 2.21 (s, 3H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.61 (s, 1H), 8.44 (s, 1H), 7.36 (d, J = 4.8 Hz, 4H), 7.31 - 7.26 (m, 1H), 7.05 (s, 2H), 6.63 (s, 1H), 5.83 (s, 1H), 4.26 (dt, J = 7.8, 3.9 Hz, 1H), 3.83 - 3.76 (m, 1H), 3.62 (s, 3H), 2.97 - 2.82 (m, 6H), 2.44 (s, 4H), 2.21 (s, 3H) 515.3
[M+H]+ 515.3
[M+H] +
6767
Figure PCTKR2021018956-appb-img-000101
Figure PCTKR2021018956-appb-img-000101
 		(S)-N-(4-(4-사이클로프로필피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(4-(4-cyclopropylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine -2-amine 511.3
[M+H]+ 511.3
[M+H] +
6868
Figure PCTKR2021018956-appb-img-000102
Figure PCTKR2021018956-appb-img-000102
 		(S)-N-(3-메톡시-4-몰포리노페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (3-methoxy-4-morpholinophenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.75 (s, 1H), 8.47 (s, 1H), 7.37 (d, J = 5.7 Hz, 4H), 7.30 (dd, J = 5.9, 2.7 Hz, 1H), 7.13 (s, 2H), 6.79 (s, 1H), 5.84 (s, 1H), 4.28 (td, J = 7.8, 2.6 Hz, 1H), 3.82 (dt, J = 8.0, 1.3 Hz, 1H), 3.77 (t, J = 4.6 Hz, 4H), 3.66 (s, 3H), 3.03 (d, J = 4.8 Hz, 4H), 2.97 - 2.90 (m, 1H), 2.28 - 2.20 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.75 (s, 1H), 8.47 (s, 1H), 7.37 (d, J = 5.7 Hz, 4H), 7.30 (dd, J = 5.9, 2.7 Hz) , 1H), 7.13 (s, 2H), 6.79 (s, 1H), 5.84 (s, 1H), 4.28 (td, J = 7.8, 2.6 Hz, 1H), 3.82 (dt, J = 8.0, 1.3 Hz, 1H), 3.77 (t, J = 4.6 Hz, 4H), 3.66 (s, 3H), 3.03 (d, J = 4.8 Hz, 4H), 2.97 - 2.90 (m, 1H), 2.28 - 2.20 (m, 1H) ) 502.3
[M+H]+ 502.3
[M+H] +
6969
Figure PCTKR2021018956-appb-img-000103
Figure PCTKR2021018956-appb-img-000103
 		(R)-3-메틸-N-(4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-아민( R )-3-methyl- N- (4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2 ,3,4,4a,5-hexahydrobenzo[ b ]pyrazino[1,2- d ][1,4]oxazin-8-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.65 (s, 1H), 8.42 (s, 1H), 7.43 - 7.35 (m, 4H), 7.30 - 7.25 (m, 1H), 7.03 (d, J = 31.0 Hz, 2H), 6.77 (s, 1H), 5.78 (d, J = 19.1 Hz, 1H), 4.35 - 4.29 (m, 2H), 3.85 - 3.77 (m, 4H), 3.58 (d, J = 12.2 Hz, 1H), 3.52 (d, J = 11.8 Hz, 1H), 3.34 (dd, J = 11.3, 7.9 Hz, 1H), 3.13 (s, 1H), 2.93 (s, 2H), 2.87 (s, 3H), 2.22 (s, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.65 (s, 1H), 8.42 (s, 1H), 7.43 - 7.35 (m, 4H), 7.30 - 7.25 (m, 1H), 7.03 (d, J = 31.0 Hz, 2H), 6.77 (s, 1H), 5.78 (d, J = 19.1 Hz, 1H), 4.35 - 4.29 (m, 2H), 3.85 - 3.77 (m, 4H), 3.58 (d, J ) = 12.2 Hz, 1H), 3.52 (d, J = 11.8 Hz, 1H), 3.34 (dd, J = 11.3, 7.9 Hz, 1H), 3.13 (s, 1H), 2.93 (s, 2H), 2.87 (s) , 3H), 2.22 (s, 1H) 513.3
[M+H]+ 513.3
[M+H] +
7070
Figure PCTKR2021018956-appb-img-000104
Figure PCTKR2021018956-appb-img-000104
 		(S)-3-메틸-N-(4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-아민( S )-3-methyl- N- (4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2 ,3,4,4a,5-hexahydrobenzo[ b ]pyrazino[1,2- d ][1,4]oxazin-8-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.57 (s, 1H), 8.41 (s, 1H), 7.41 - 7.36 (m, 4H), 7.30 - 7.25 (m, 1H), 6.98 (d, J = 29.4 Hz, 2H), 6.68 (s, 1H), 5.79 (s, 1H), 4.30 - 4.23 (m, 2H), 3.96 - 3.90 (m, 1H), 3.82 - 3.75 (m, 2H), 3.13 (s, 4H), 2.91 (ddt, J = 7.4, 4.8, 2.5 Hz, 1H), 2.70 (d, J = 13.0 Hz, 1H), 2.20 (s, 1H), 1.91 (s, 4H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.57 (s, 1H), 8.41 (s, 1H), 7.41 - 7.36 (m, 4H), 7.30 - 7.25 (m, 1H), 6.98 (d, J = 29.4 Hz, 2H), 6.68 (s, 1H), 5.79 (s, 1H), 4.30 - 4.23 (m, 2H), 3.96 - 3.90 (m, 1H), 3.82 - 3.75 (m, 2H), 3.13 (s, 4H), 2.91 (ddt, J = 7.4, 4.8, 2.5 Hz, 1H), 2.70 (d, J = 13.0 Hz, 1H), 2.20 (s, 1H), 1.91 (s, 4H) 513.3
[M+H]+ 513.3
[M+H] +
7171
Figure PCTKR2021018956-appb-img-000105
Figure PCTKR2021018956-appb-img-000105
 		메틸 (S)-8-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-2,3-다이하이드로벤조[b][1,4]다이옥신-5-카복실레이트Methyl ( S )-8-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3-dihydrobenzo [ b ][1,4]dioxin-5-carboxylate 503.3
[M+H]+ 503.3
[M+H] +
7272
Figure PCTKR2021018956-appb-img-000106
Figure PCTKR2021018956-appb-img-000106
 		메틸 (S)-7-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-2,3-다이하이드로벤조퓨란-4-카복실레이트Methyl ( S )-7-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3-dihydrobenzo Furan-4-carboxylate 487.3
[M+H]+ 487.3
[M+H] +
7373
Figure PCTKR2021018956-appb-img-000107
Figure PCTKR2021018956-appb-img-000107
 		N-(4-((R)-3-(다이메틸아미노)피롤리딘-1-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민 N- (4-(( R )-3-(dimethylamino)pyrrolidin-1-yl)phenyl)-4-(( S )-3-phenylisoxazolidin-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine 499.4
[M+H]+ 499.4
[M+H] +
7474
Figure PCTKR2021018956-appb-img-000108
Figure PCTKR2021018956-appb-img-000108
 		N-(4-((S)-3-(다이메틸아미노)피롤리딘-1-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민 N- (4-(( S )-3-(dimethylamino)pyrrolidin-1-yl)phenyl)-4-(( S )-3-phenylisoxazolidin-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine 499.2
[M+H]+ 499.2
[M+H] +
7575
Figure PCTKR2021018956-appb-img-000109
Figure PCTKR2021018956-appb-img-000109
 		(S)-1-(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피롤리딘-2-온( S )-1-(4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyrrolidine- 2-on 1H NMR (400 MHz, Methanol-d 4) δ 8.36 (s, 1H), 7.47 - 7.23 (m, 10H), 5.77 - 5.69 (m, 1H), 4.40 (td, J = 7.7, 3.0 Hz, 1H), 4.03 (ddd, J = 9.6, 8.1, 6.4 Hz, 1H), 3.91 (t, J = 7.1 Hz, 2H), 3.05 - 2.96 (m, 1H), 2.66 (d, J = 12.2 Hz, 2H), 2.66 - 2.57 (m, 2H), 2.34 (dddd, J = 12.2, 9.7, 7.5, 6.5 Hz, 1H), 2.20 (qd, J = 8.1, 6.8 Hz, 2H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.36 (s, 1H), 7.47 - 7.23 (m, 10H), 5.77 - 5.69 (m, 1H), 4.40 (td, J = 7.7, 3.0 Hz, 1H) ), 4.03 (ddd, J = 9.6, 8.1, 6.4 Hz, 1H), 3.91 (t, J = 7.1 Hz, 2H), 3.05 - 2.96 (m, 1H), 2.66 (d, J = 12.2 Hz, 2H) , 2.66 - 2.57 (m, 2H), 2.34 (dddd, J = 12.2, 9.7, 7.5, 6.5 Hz, 1H), 2.20 (qd, J = 8.1, 6.8 Hz, 2H) 470.4
[M+H]+ 470.4
[M+H] +
7676
Figure PCTKR2021018956-appb-img-000110
Figure PCTKR2021018956-appb-img-000110
 		(S)-2-(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)아이소싸이아졸리딘 1,1-다이옥사이드( S )-2-(4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)isothiazoli din 1,1-dioxide 506.2
[M+H]+ 506.2
[M+H] +
7777
Figure PCTKR2021018956-appb-img-000111
Figure PCTKR2021018956-appb-img-000111
 		(S)-N-(3-메톡시-4-(1-메틸-1H-피라졸-5-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (3-methoxy-4-(1-methyl- 1H -pyrazol-5-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ= 9.99 (s, 1H), 8.53 (s, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.41 - 7.35 (m, 4H), 7.33 - 7.24 (m, 3H), 6.97 (d, J = 8.2 Hz, 1H), 6.18 (d, J = 1.9 Hz, 1H), 5.92 - 5.86 (m, 1H), 4.33 - 4.27 (m, 1H), 3.88 - 3.82 (m, 1H), 3.63 (s, 3H), 3.61 (s, 3H), 2.97 (dt, J = 6.0, 2.7 Hz, 1H), 2.30 - 2.22 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ= 9.99 (s, 1H), 8.53 (s, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.41 - 7.35 (m, 4H), 7.33 - 7.24 (m, 3H), 6.97 (d, J = 8.2 Hz, 1H), 6.18 (d, J = 1.9 Hz, 1H), 5.92 - 5.86 (m, 1H), 4.33 - 4.27 (m, 1H), 3.88 - 3.82 (m, 1H), 3.63 (s, 3H), 3.61 (s, 3H), 2.97 (dt, J = 6.0, 2.7 Hz, 1H), 2.30 - 2.22 (m, 1H) 497.2
[M+H]+ 497.2
[M+H] +
7878
Figure PCTKR2021018956-appb-img-000112
Figure PCTKR2021018956-appb-img-000112
 		(S)-N-(4-(4-(다이메틸아미노)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(4-(4-( dimethylamino )piperidin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoro methyl)pyrimidin-2-amine 513.4
[M+H]+ 513.4
[M+H] +
7979
Figure PCTKR2021018956-appb-img-000113
Figure PCTKR2021018956-appb-img-000113
 		(S)-N-(4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)- 5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, Chloroform-d) δ = 8.37 (s, 1H), 7.42 - 7.34 (m, 4H), 7.29 (ddd, J = 8.2, 4.0, 1.9 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 6.96 (s, 1H), 6.76 (d, J = 8.5 Hz, 2H), 5.74 (t, J = 7.7 Hz, 1H), 4.28 (td, J = 7.6, 2.5 Hz, 1H), 3.84 (ddd, J = 9.9, 8.2, 6.4 Hz, 1H), 3.65 (d, J = 12.0 Hz, 2H), 2.86 - 2.78 (m, 1H), 2.67 (td, J = 10.6, 9.0, 4.8 Hz, 5H), 2.49 (s, 2H), 2.36 (dt, J = 11.9, 3.8 Hz, 2H), 2.31 (s, 3H), 1.95 (d, J = 12.3 Hz, 2H), 1.79 - 1.59 (m, 5H) 1 H NMR (400 MHz, Chloroform-d) δ = 8.37 (s, 1H), 7.42 - 7.34 (m, 4H), 7.29 (ddd, J = 8.2, 4.0, 1.9 Hz, 1H), 7.14 (d, J ) = 8.4 Hz, 2H), 6.96 (s, 1H), 6.76 (d, J = 8.5 Hz, 2H), 5.74 (t, J = 7.7 Hz, 1H), 4.28 (td, J = 7.6, 2.5 Hz, 1H) ), 3.84 (ddd, J = 9.9, 8.2, 6.4 Hz, 1H), 3.65 (d, J = 12.0 Hz, 2H), 2.86 - 2.78 (m, 1H), 2.67 (td, J = 10.6, 9.0, 4.8) Hz, 5H), 2.49 (s, 2H), 2.36 (dt, J = 11.9, 3.8 Hz, 2H), 2.31 (s, 3H), 1.95 (d, J = 12.3 Hz, 2H), 1.79 - 1.59 (m) , 5H) 568.5
[M+H]+ 568.5
[M+H] +
8080
Figure PCTKR2021018956-appb-img-000114
Figure PCTKR2021018956-appb-img-000114
 		(S)-N-(2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisoxazolidine- 2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 8.58 (s, 1H), 8.38 (s, 1H), 7.32 (d, J = 7.2 Hz, 2H), 7.27 (d, J = 7.1 Hz, 4H), 6.70 (d, J = 2.5 Hz, 1H), 6.43 (d, J = 8.7 Hz, 1H), 5.63 (s, 1H), 4.34 - 4.28 (m, 1H), 3.85 - 3.77 (m, 3H), 3.74 (s, 3H), 3.60 - 3.07 (m, 9H), 2.92 - 2.86 (m, 1H), 2.84 (s, 3H), 2.78 (t, J = 12.3 Hz, 2H), 2.24 (d, J = 10.3 Hz, 1H), 2.10 (d, J = 11.9 Hz, 2H), 1.73 (t, J = 10.5 Hz, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.58 (s, 1H), 8.38 (s, 1H), 7.32 (d, J = 7.2 Hz, 2H), 7.27 (d, J = 7.1 Hz, 4H) ), 6.70 (d, J = 2.5 Hz, 1H), 6.43 (d, J = 8.7 Hz, 1H), 5.63 (s, 1H), 4.34 - 4.28 (m, 1H), 3.85 - 3.77 (m, 3H) , 3.74 (s, 3H), 3.60 - 3.07 (m, 9H), 2.92 - 2.86 (m, 1H), 2.84 (s, 3H), 2.78 (t, J = 12.3 Hz, 2H), 2.24 (d, J ) = 10.3 Hz, 1H), 2.10 (d, J = 11.9 Hz, 2H), 1.73 (t, J = 10.5 Hz, 2H) 598.5
[M+H]+ 598.5
[M+H] +
8181
Figure PCTKR2021018956-appb-img-000115
Figure PCTKR2021018956-appb-img-000115
 		(S)-N-(3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisoxazolidine- 2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, Chloroform-d) δ = 8.38 (s, 1H), 7.43 - 7.35 (m, 4H), 7.31 - 7.28 (m, 1H), 7.24 (s, 1H), 7.04 (s, 1H), 6.86 (d, J = 8.7 Hz, 1H), 6.76 (t, J = 9.0 Hz, 1H), 5.77 (dd, J = 8.8, 6.3 Hz, 1H), 4.30 (td, J = 7.9, 2.8 Hz, 1H), 3.87 (ddd, J = 9.8, 8.2, 6.6 Hz, 1H), 3.44 (d, J = 11.2 Hz, 2H), 2.90 - 2.81 (m, 1H), 2.69 - 2.61 (m, 5H), 2.50 (s, 2H), 2.42 - 2.34 (m, 2H), 2.31 (s, 3H), 1.93 (d, J = 12.4 Hz, 2H), 1.85 - 1.71 (m, 5H) 1 H NMR (400 MHz, Chloroform-d) δ = 8.38 (s, 1H), 7.43 - 7.35 (m, 4H), 7.31 - 7.28 (m, 1H), 7.24 (s, 1H), 7.04 (s, 1H) ), 6.86 (d, J = 8.7 Hz, 1H), 6.76 (t, J = 9.0 Hz, 1H), 5.77 (dd, J = 8.8, 6.3 Hz, 1H), 4.30 (td, J = 7.9, 2.8 Hz) , 1H), 3.87 (ddd, J = 9.8, 8.2, 6.6 Hz, 1H), 3.44 (d, J = 11.2 Hz, 2H), 2.90 - 2.81 (m, 1H), 2.69 - 2.61 (m, 5H), 2.50 (s, 2H), 2.42 - 2.34 (m, 2H), 2.31 (s, 3H), 1.93 (d, J = 12.4 Hz, 2H), 1.85 - 1.71 (m, 5H) 586.5
[M+H]+ 586.5
[M+H] +
8282
Figure PCTKR2021018956-appb-img-000116
Figure PCTKR2021018956-appb-img-000116
 		(S)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisoxazolidine- 2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.62 (s, 1H), 8.44 (s, 1H), 7.36 (d, J = 4.7 Hz, 4H), 7.30 - 7.26 (m, 1H), 7.05 (s, 2H), 6.65 (s, 1H), 5.83 (s, 1H), 4.29 (d, J = 2.5 Hz, 1H), 3.82 - 3.76 (m, 1H), 3.63 (s, 3H), 3.36 (d, J = 11.2 Hz, 8H), 3.09 - 2.75 (m, 9H), 2.62 - 2.54 (m, 3H), 2.46 (s, 1H), 2.24 (s, 1H), 1.61 (d, J = 11.9 Hz, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.62 (s, 1H), 8.44 (s, 1H), 7.36 (d, J = 4.7 Hz, 4H), 7.30 - 7.26 (m, 1H), 7.05 (s, 2H), 6.65 (s, 1H), 5.83 (s, 1H), 4.29 (d, J = 2.5 Hz, 1H), 3.82 - 3.76 (m, 1H), 3.63 (s, 3H), 3.36 ( d, J = 11.2 Hz, 8H), 3.09 - 2.75 (m, 9H), 2.62 - 2.54 (m, 3H), 2.46 (s, 1H), 2.24 (s, 1H), 1.61 (d, J = 11.9 Hz) , 2H) 598.5
[M+H]+ 598.5
[M+H] +
8383
Figure PCTKR2021018956-appb-img-000117
Figure PCTKR2021018956-appb-img-000117
 		(S)-N-(3-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (3-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisoxazolidine-2 -yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.72 (s, 1H), 8.45 (s, 1H), 7.38 (d, J = 4.7 Hz, 4H), 7.29 (dt, J = 4.7, 2.7 Hz, 3H), 6.82 (s, 1H), 5.83 (s, 1H), 4.31 - 4.25 (m, 1H), 3.82 - 3.77 (m, 1H), 3.70 - 3.32 (m, 7H), 3.27 (s, 2H), 3.11 (s, 3H), 2.99 - 2.92 (m, 1H), 2.87 (s, 3H), 2.63 (td, J = 12.0, 11.5, 4.0 Hz, 2H), 2.28 - 2.19 (m, 1H), 2.12 (s, 1H), 2.09 - 2.05 (m, 3H), 1.81 - 1.73 (m, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.72 (s, 1H), 8.45 (s, 1H), 7.38 (d, J = 4.7 Hz, 4H), 7.29 (dt, J = 4.7, 2.7 Hz) , 3H), 6.82 (s, 1H), 5.83 (s, 1H), 4.31 - 4.25 (m, 1H), 3.82 - 3.77 (m, 1H), 3.70 - 3.32 (m, 7H), 3.27 (s, 2H) ), 3.11 (s, 3H), 2.99 - 2.92 (m, 1H), 2.87 (s, 3H), 2.63 (td, J = 12.0, 11.5, 4.0 Hz, 2H), 2.28 - 2.19 (m, 1H), 2.12 (s, 1H), 2.09 - 2.05 (m, 3H), 1.81 - 1.73 (m, 2H) 582.4
[M+H]+ 582.4
[M+H] +
8484
Figure PCTKR2021018956-appb-img-000118
Figure PCTKR2021018956-appb-img-000118
 		(S)-N-(3-메톡시-4-(4-몰포리노피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (3-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(tri Fluoromethyl) pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ= 9.87 (s, 1H), 8.49 (s, 1H), 7.38 (d, J = 5.9 Hz, 4H), 7.32 - 7.27 (m, 1H), 7.13 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 8.6 Hz, 1H), 5.84 (t, J = 7.3 Hz, 1H), 4.30 (td, J = 7.8, 2.6 Hz, 1H), 4.03 (s, 2H), 3.87 - 3.81 (m, 1H), 3.78 (s, 1H), 3.69 (s, 3H), 3.51 (t, J = 8.9 Hz, 4H), 3.43 - 3.37 (m, 1H), 3.16 (s, 2H), 2.95 (dt, J = 6.0, 2.7 Hz, 1H), 2.89 - 2.79 (m, 2H), 2.32 - 2.25 (m, 1H), 2.22 (d, J = 12.7 Hz, 2H), 1.95 (s, 1H), 1.92 - 1.84 (m, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.87 (s, 1H), 8.49 (s, 1H), 7.38 (d, J = 5.9 Hz, 4H), 7.32 - 7.27 (m, 1H), 7.13 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 8.6 Hz, 1H), 5.84 (t, J = 7.3 Hz, 1H), 4.30 (td, J = 7.8, 2.6 Hz, 1H), 4.03 (s, 2H), 3.87 - 3.81 (m, 1H), 3.78 (s, 1H), 3.69 (s, 3H), 3.51 (t, J = 8.9 Hz, 4H), 3.43 - 3.37 (m, 1H), 3.16 (s, 2H), 2.95 (dt, J = 6.0, 2.7 Hz, 1H), 2.89 - 2.79 (m, 2H), 2.32 - 2.25 (m, 1H), 2.22 (d, J = 12.7 Hz, 2H) , 1.95 (s, 1H), 1.92 - 1.84 (m, 2H) 585.4
[M+H]+ 585.4
[M+H] +
8585
Figure PCTKR2021018956-appb-img-000119
Figure PCTKR2021018956-appb-img-000119
 		(S)-N1-(1-(2-메톡시-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피페리딘-4-일)-N1,N2,N2-트라이메틸에탄-1,2-다이아민( S ) -N 1-(1-(2-methoxy-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl) )amino)phenyl)piperidin-4-yl) -N 1, N 2, N 2-trimethylethane-1,2-diamine 600.4
[M+H]+ 600.4
[M+H] +
8686
Figure PCTKR2021018956-appb-img-000120
Figure PCTKR2021018956-appb-img-000120
 		N-(3-메톡시-4-(4-((1S,4S)-5-메틸-2,5-다이아자바이사이클로[2.2.1]헵탄-2-일)피페리딘-1-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민 N -(3-methoxy-4-(4-((1 S ,4 S )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidine-1- yl)phenyl)-4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.66 (s, 1H), 8.45 (s, 1H), 7.37 (d, J = 4.5 Hz, 4H), 7.31 - 7.25 (m, 1H), 7.08 (s, 2H), 6.68 (s, 1H), 5.83 (s, 1H), 4.29 - 4.25 (m, 1H), 3.82 - 3.77 (m, 1H), 3.64 (s, 3H), 3.40 - 3.39 (m, 11H), 2.95 - 2.90 (m, 1H), 2.86 (s, 3H), 2.56 (s, 2H), 2.24 (s, 2H), 1.99 (s, 1H), 1.64 (s, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.66 (s, 1H), 8.45 (s, 1H), 7.37 (d, J = 4.5 Hz, 4H), 7.31 - 7.25 (m, 1H), 7.08 (s, 2H), 6.68 (s, 1H), 5.83 (s, 1H), 4.29 - 4.25 (m, 1H), 3.82 - 3.77 (m, 1H), 3.64 (s, 3H), 3.40 - 3.39 (m , 11H), 2.95 - 2.90 (m, 1H), 2.86 (s, 3H), 2.56 (s, 2H), 2.24 (s, 2H), 1.99 (s, 1H), 1.64 (s, 2H) 610.5
[M+H]+ 610.5
[M+H] +
8787
Figure PCTKR2021018956-appb-img-000121
Figure PCTKR2021018956-appb-img-000121
 		N-(3-메톡시-4-(4-((1R,4R)-5-메틸-2,5-다이아자바이사이클로[2.2.1]헵탄-2-일)피페리딘-1-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민 N -(3-methoxy-4-(4-((1 R ,4 R )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidine-1- yl)phenyl)-4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ= 9.71 (s, 1H), 8.46 (s, 1H), 7.37 (d, J = 4.8 Hz, 4H), 7.31 - 7.26 (m, 1H), 7.09 (s, 2H), 6.74 (s, 1H), 5.84 (d, J = 9.0 Hz, 1H), 4.69 (s, 1H), 4.47 (s, 1H), 4.29 (dt, J = 9.1, 4.5 Hz, 2H), 3.87 - 3.75 (m, 2H), 3.66 (s, 4H), 3.44 (d, J = 12.7 Hz, 3H), 3.23 (s, 1H), 2.94 (t, J = 2.9 Hz, 1H), 2.92 - 2.86 (m, 3H), 2.58 (d, J = 22.3 Hz, 2H), 2.42 (s, 2H), 2.24 (s, 2H), 2.15 - 2.04 (m, 2H), 2.00 (d, J = 5.0 Hz, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.71 (s, 1H), 8.46 (s, 1H), 7.37 (d, J = 4.8 Hz, 4H), 7.31 - 7.26 (m, 1H), 7.09 (s, 2H), 6.74 (s, 1H), 5.84 (d, J = 9.0 Hz, 1H), 4.69 (s, 1H), 4.47 (s, 1H), 4.29 (dt, J = 9.1, 4.5 Hz, 2H), 3.87 - 3.75 (m, 2H), 3.66 (s, 4H), 3.44 (d, J = 12.7 Hz, 3H), 3.23 (s, 1H), 2.94 (t, J = 2.9 Hz, 1H), 2.92 - 2.86 (m, 3H), 2.58 (d, J = 22.3 Hz, 2H), 2.42 (s, 2H), 2.24 (s, 2H), 2.15 - 2.04 (m, 2H), 2.00 (d, J = 5.0 Hz, 1H) 610.5
[M+H]+ 610.5
[M+H] +
8888
Figure PCTKR2021018956-appb-img-000122
Figure PCTKR2021018956-appb-img-000122
 		(S)-2-(4-(1-(2-메톡시-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피페리딘-4-일)피페라진-1-일)에탄-1-올( S )-2-(4-(1-(2-methoxy-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine-2) -yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethan-1-ol 1H NMR (400 MHz, DMSO-d6) δ = 9.61 (s, 1H), 8.44 (s, 1H), 7.36 (d, J = 5.0 Hz, 4H), 7.30 - 7.25 (m, 1H), 7.04 (s, 2H), 6.63 (s, 1H), 5.83 (s, 1H), 4.27 (d, J = 2.6 Hz, 1H), 3.80 - 3.77 (m, 1H), 3.70 (s, 1H), 3.62 (s, 3H), 3.48 (t, J = 6.3 Hz, 3H), 3.32 (d, J = 11.0 Hz, 3H), 2.91 (ddd, J = 8.0, 5.6, 2.9 Hz, 1H), 2.50 (dq, J = 4.6, 2.7, 2.2 Hz, 6H), 2.42 (d, J = 9.9 Hz, 4H), 2.35 (d, J = 6.4 Hz, 2H), 2.24 (t, J = 3.7 Hz, 2H), 1.52 (dd, J = 11.9, 3.8 Hz, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.61 (s, 1H), 8.44 (s, 1H), 7.36 (d, J = 5.0 Hz, 4H), 7.30 - 7.25 (m, 1H), 7.04 (s, 2H), 6.63 (s, 1H), 5.83 (s, 1H), 4.27 (d, J = 2.6 Hz, 1H), 3.80 - 3.77 (m, 1H), 3.70 (s, 1H), 3.62 ( s, 3H), 3.48 (t, J = 6.3 Hz, 3H), 3.32 (d, J = 11.0 Hz, 3H), 2.91 (ddd, J = 8.0, 5.6, 2.9 Hz, 1H), 2.50 (dq, J ) = 4.6, 2.7, 2.2 Hz, 6H), 2.42 (d, J = 9.9 Hz, 4H), 2.35 (d, J = 6.4 Hz, 2H), 2.24 (t, J = 3.7 Hz, 2H), 1.52 (dd , J = 11.9, 3.8 Hz, 2H) 628.4
[M+H]+ 628.4
[M+H] +
8989
Figure PCTKR2021018956-appb-img-000123
Figure PCTKR2021018956-appb-img-000123
 		(S)-1'-(2-메톡시-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)-N,N-다이메틸-[1,4'-바이피페리딘]-4-아민( S )-1'-(2-methoxy-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino) Phenyl) -N , N -dimethyl-[1,4'-bipiperidin]-4-amine 600.5
[M+H]+ 600.5
[M+H] +
9090
Figure PCTKR2021018956-appb-img-000124
Figure PCTKR2021018956-appb-img-000124
 		(S)-N-(4-(4-(3-(다이메틸아미노)아제티딘-1-일)피페리딘-1-일)-3-메톡시페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(4-(4-(3-( dimethylamino )azetidin-1-yl)piperidin-1-yl)-3-methoxyphenyl)-4-(3-phenyliso Oxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.61 (s, 1H), 8.44 (s, 1H), 7.36 (d, J = 4.8 Hz, 4H), 7.30 - 7.25 (m, 1H), 7.04 (s, 2H), 6.64 (s, 1H), 5.83 (s, 1H), 4.27 (td, J = 7.8, 2.6 Hz, 1H), 3.79 - 3.78 (m, 1H), 3.62 (s, 3H), 3.56 (s, 4H), 3.21 (d, J = 7.3 Hz, 2H), 3.04 (s, 2H), 2.94 - 2.86 (m, 2H), 2.34 (d, J = 13.8 Hz, 1H), 2.23 (s, 1H), 2.07 (s, 6H), 1.81 - 1.74 (m, 2H), 1.33 (d, J = 10.9 Hz, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.61 (s, 1H), 8.44 (s, 1H), 7.36 (d, J = 4.8 Hz, 4H), 7.30 - 7.25 (m, 1H), 7.04 (s, 2H), 6.64 (s, 1H), 5.83 (s, 1H), 4.27 (td, J = 7.8, 2.6 Hz, 1H), 3.79 - 3.78 (m, 1H), 3.62 (s, 3H), 3.56 (s, 4H), 3.21 (d, J = 7.3 Hz, 2H), 3.04 (s, 2H), 2.94 - 2.86 (m, 2H), 2.34 (d, J = 13.8 Hz, 1H), 2.23 (s) , 1H), 2.07 (s, 6H), 1.81 - 1.74 (m, 2H), 1.33 (d, J = 10.9 Hz, 2H) 598.4
[M+H]+ 598.4
[M+H] +
9191
Figure PCTKR2021018956-appb-img-000125
Figure PCTKR2021018956-appb-img-000125
 		(S)-2-(4-(1-(2-플루오로-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피페리딘-4-일)피페라진-1-일)에탄-1-올( S )-2-(4-(1-(2-fluoro-4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine-2) -yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethan-1-ol 1H NMR (400 MHz, DMSO-d6) δ = 9.84 (s, 1H), 8.47 (s, 1H), 7.43 - 7.35 (m, 5H), 7.29 (dt, J = 6.1, 2.8 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 6.83 (s, 1H), 5.81 (s, 1H), 4.34 - 4.28 (m, 1H), 3.85 - 3.78 (m, 1H), 3.73 (d, J = 5.3 Hz, 2H), 3.59 - 3.24 (m, 8H), 3.16 (d, J = 12.0 Hz, 5H), 3.02 - 2.91 (m, 2H), 2.67 (d, J = 11.8 Hz, 2H), 2.21 (s, 1H), 2.06 (d, J = 10.4 Hz, 2H), 1.73 (d, J = 12.6 Hz, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.84 (s, 1H), 8.47 (s, 1H), 7.43 - 7.35 (m, 5H), 7.29 (dt, J = 6.1, 2.8 Hz, 1H) , 7.18 (d, J = 8.8 Hz, 1H), 6.83 (s, 1H), 5.81 (s, 1H), 4.34 - 4.28 (m, 1H), 3.85 - 3.78 (m, 1H), 3.73 (d, J ) = 5.3 Hz, 2H), 3.59 - 3.24 (m, 8H), 3.16 (d, J = 12.0 Hz, 5H), 3.02 - 2.91 (m, 2H), 2.67 (d, J = 11.8 Hz, 2H), 2.21 (s, 1H), 2.06 (d, J = 10.4 Hz, 2H), 1.73 (d, J = 12.6 Hz, 2H) 616.4
[M+H]+ 616.4
[M+H] +
9292
Figure PCTKR2021018956-appb-img-000126
Figure PCTKR2021018956-appb-img-000126
 		(S)-N-(4-(4-(1-메틸피페리딘-4-일)피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (4-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)- 5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.58 (s, 1H), 8.40 (s, 1H), 7.38 (d, J = 6.1 Hz, 5H), 7.31 - 7.21 (m, 4H), 6.71 (s, 1H), 4.31 - 4.25 (m, 1H), 3.79 (dt, J = 10.0, 7.6 Hz, 1H), 3.03 (t, J = 5.2 Hz, 4H), 2.93 (dd, J = 6.6, 3.4 Hz, 1H), 2.81 (d, J = 11.1 Hz, 2H), 2.61 (t, J = 4.9 Hz, 4H), 2.16 (s, 3H), 1.94 - 1.83 (m, 4H), 1.76 (d, J = 11.9 Hz, 3H), 1.47 - 1.42 (m, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.58 (s, 1H), 8.40 (s, 1H), 7.38 (d, J = 6.1 Hz, 5H), 7.31 - 7.21 (m, 4H), 6.71 (s, 1H), 4.31 - 4.25 (m, 1H), 3.79 (dt, J = 10.0, 7.6 Hz, 1H), 3.03 (t, J = 5.2 Hz, 4H), 2.93 (dd, J = 6.6, 3.4 Hz, 1H), 2.81 (d, J = 11.1 Hz, 2H), 2.61 (t, J = 4.9 Hz, 4H), 2.16 (s, 3H), 1.94 - 1.83 (m, 4H), 1.76 (d, J ) = 11.9 Hz, 3H), 1.47 - 1.42 (m, 2H) 568.4
[M+H]+ 568.4
[M+H] +
9393
Figure PCTKR2021018956-appb-img-000127
Figure PCTKR2021018956-appb-img-000127
 		(S)-N-(3-메톡시-4-(4-(1-메틸피페리딘-4-일)피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (3-methoxy-4-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)-4-(3-phenylisoxazolidine- 2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, Chloroform-d) δ = 8.41 (s, 1H), 7.36 (d, J = 4.5 Hz, 3H), 7.29 (d, J = 8.6 Hz, 2H), 6.94 - 6.86 (m, 2H), 6.74 (d, J = 8.6 Hz, 1H), 5.81 (dd, J = 8.7, 6.1 Hz, 1H), 4.30 - 4.22 (m, 1H), 3.85 (q, J = 8.1 Hz, 1H), 3.68 (s, 3H), 3.05 (s, 3H), 2.94 (s, 2H), 2.85 - 2.80 (m, 1H), 2.77 (s, 3H), 2.37 (d, J = 10.1 Hz, 1H), 2.28 (s, 3H), 1.97 (s, 2H), 1.86 (d, J = 12.0 Hz, 2H), 1.58 (s, 5H) 1 H NMR (400 MHz, Chloroform-d) δ = 8.41 (s, 1H), 7.36 (d, J = 4.5 Hz, 3H), 7.29 (d, J = 8.6 Hz, 2H), 6.94 - 6.86 (m, 2H), 6.74 (d, J = 8.6 Hz, 1H), 5.81 (dd, J = 8.7, 6.1 Hz, 1H), 4.30 - 4.22 (m, 1H), 3.85 (q, J = 8.1 Hz, 1H), 3.68 (s, 3H), 3.05 (s, 3H), 2.94 (s, 2H), 2.85 - 2.80 (m, 1H), 2.77 (s, 3H), 2.37 (d, J = 10.1 Hz, 1H), 2.28 (s, 3H), 1.97 (s, 2H), 1.86 (d, J = 12.0 Hz, 2H), 1.58 (s, 5H) 598.4
[M+H]+ 598.4
[M+H] +
9494
Figure PCTKR2021018956-appb-img-000128
Figure PCTKR2021018956-appb-img-000128
 		(S)-N-(4-(3-(4-메틸피페라진-1-일)아제티딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(4-(3-(4-methylpiperazin- 1 -yl)azetidin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5 -(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.52 (s, 1H), 8.38 (s, 1H), 7.37 (dd, J = 5.5, 3.2 Hz, 4H), 7.29 (d, J = 6.6 Hz, 1H), 7.21 (d, J = 4.2 Hz, 2H), 6.24 (s, 2H), 5.73 (d, J = 22.7 Hz, 1H), 4.30 - 4.25 (m, 1H), 3.87 (dt, J = 6.9, 3.5 Hz, 2H), 3.81 - 3.74 (m, 1H), 3.52 - 3.47 (m, 2H), 3.34 (s, 6H), 3.24 (s, 1H), 2.91 (ddt, J = 9.2, 6.4, 3.2 Hz, 1H), 2.40 (s, 2H), 2.30 (s, 3H), 2.22 - 2.15 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.52 (s, 1H), 8.38 (s, 1H), 7.37 (dd, J = 5.5, 3.2 Hz, 4H), 7.29 (d, J = 6.6 Hz) , 1H), 7.21 (d, J = 4.2 Hz, 2H), 6.24 (s, 2H), 5.73 (d, J = 22.7 Hz, 1H), 4.30 - 4.25 (m, 1H), 3.87 (dt, J = 6.9, 3.5 Hz, 2H), 3.81 - 3.74 (m, 1H), 3.52 - 3.47 (m, 2H), 3.34 (s, 6H), 3.24 (s, 1H), 2.91 (ddt, J = 9.2, 6.4, 3.2 Hz, 1H), 2.40 (s, 2H), 2.30 (s, 3H), 2.22 - 2.15 (m, 1H) 540.4
[M+H]+ 540.4
[M+H] +
9595
Figure PCTKR2021018956-appb-img-000129
Figure PCTKR2021018956-appb-img-000129
 		(S)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)-N-(3,4,5-트라이메톡시페닐)피리미딘-2-아민( S )-4-(3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.50 (s, 1H), 7.36 - 7.24 (m, 5H), 6.89 (s, 2H), 5.92 (dd, J = 8.9, 5.4 Hz, 1H), 4.28 (td, J = 7.9, 3.0 Hz, 1H), 3.86 - 3.77 (m, 1H), 3.59 (d, J = 17.7 Hz, 9H), 2.98 - 2.89 (m, 1H), 2.33 (dtd, J = 12.0, 8.4, 5.3 Hz, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.86 (s, 1H), 8.50 (s, 1H), 7.36 - 7.24 (m, 5H), 6.89 (s, 2H), 5.92 (dd, J = 8.9 , 5.4 Hz, 1H), 4.28 (td, J = 7.9, 3.0 Hz, 1H), 3.86 - 3.77 (m, 1H), 3.59 (d, J = 17.7 Hz, 9H), 2.98 - 2.89 (m, 1H) , 2.33 (dtd, J = 12.0, 8.4, 5.3 Hz, 1H) 477.2
[M+H]+ 477.2
[M+H] +
9696
Figure PCTKR2021018956-appb-img-000130
Figure PCTKR2021018956-appb-img-000130
 		(S)-N-(4-(2-(다이에틸아미노)에톡시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(4-(2-( diethylamino )ethoxy)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine- 2-amine 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.75 (s, 1H), 8.43 (s, 1H), 7.46 - 7.27 (m, 7H), 6.77 (s, 1H), 5.74 (s, 1H), 4.36 - 4.26 (m, 3H), 3.80 (ddd, J = 10.1, 8.0, 6.3 Hz, 1H), 3.47 (s, 2H), 3.26 - 3.13 (m, 4H), 3.05 (qd, J = 7.3, 3.9 Hz, 1H), 2.95 (dtd, J = 12.6, 6.3, 3.1 Hz, 1H), 1.26 (t, J = 7.2 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.60 (s, 1H), 9.75 (s, 1H), 8.43 (s, 1H), 7.46 - 7.27 (m, 7H), 6.77 (s, 1H), 5.74 (s, 1H), 4.36 - 4.26 (m, 3H), 3.80 (ddd, J = 10.1, 8.0, 6.3 Hz, 1H), 3.47 (s, 2H), 3.26 - 3.13 (m, 4H), 3.05 ( qd, J = 7.3, 3.9 Hz, 1H), 2.95 (dtd, J = 12.6, 6.3, 3.1 Hz, 1H), 1.26 (t, J = 7.2 Hz, 6H) 502.2
[M+H]+ 502.2
[M+H] +
9797
Figure PCTKR2021018956-appb-img-000131
Figure PCTKR2021018956-appb-img-000131
 		(S)-N-(4-(2-(다이에틸아미노)에톡시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(4-(2-(diethylamino)ethoxy)-3,5- dimethylphenyl )-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoro Rhomethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 9.84 (s, 1H), 8.49 (s, 1H), 7.37 (d, J = 5.6 Hz, 4H), 7.28 (ddt, J = 6.6, 5.0, 2.9 Hz, 1H), 7.19 (s, 1H), 5.91 (dd, J = 8.9, 6.0 Hz, 1H), 4.29 (td, J = 8.0, 2.6 Hz, 1H), 4.05 (t, J = 5.3 Hz, 2H), 3.86 - 3.75 (m, 6H), 3.47 (q, J = 5.2 Hz, 2H), 3.32 - 3.20 (m, 4H), 3.00 (d, J = 8.9 Hz, 1H), 2.27 (tdd, J = 13.9, 9.5, 5.1 Hz, 1H), 1.27 (t, J = 7.2 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.47 (s, 1H), 9.84 (s, 1H), 8.49 (s, 1H), 7.37 (d, J = 5.6 Hz, 4H), 7.28 (ddt, J = 6.6, 5.0, 2.9 Hz, 1H), 7.19 (s, 1H), 5.91 (dd, J = 8.9, 6.0 Hz, 1H), 4.29 (td, J = 8.0, 2.6 Hz, 1H), 4.05 (t) , J = 5.3 Hz, 2H), 3.86 - 3.75 (m, 6H), 3.47 (q, J = 5.2 Hz, 2H), 3.32 - 3.20 (m, 4H), 3.00 (d, J = 8.9 Hz, 1H) , 2.27 (tdd, J = 13.9, 9.5, 5.1 Hz, 1H), 1.27 (t, J = 7.2 Hz, 6H) 530.3
[M+H]+ 530.3
[M+H] +
9898
Figure PCTKR2021018956-appb-img-000132
Figure PCTKR2021018956-appb-img-000132
 		(S)-N-(4-(3-(다이에틸아미노)프로폭시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(4-(3-( diethylamino )propoxy)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine- 2-amine 1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 9.87 (s, 1H), 8.45 (s, 1H), 7.44 - 7.27 (m, 7H), 6.73 (s, 1H), 5.83 - 5.64 (m, 1H), 4.35 - 4.27 (m, 1H), 4.03 (td, J = 6.1, 2.0 Hz, 2H), 3.83 (q, J = 7.9 Hz, 1H), 3.14 (ddp, J = 11.8, 7.2, 4.5 Hz, 7H), 2.96 (dtd, J = 12.5, 6.2, 3.3 Hz, 1H), 2.15 (dt, J = 7.9, 5.6 Hz, 2H), 1.26 (d, J = 7.2 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.71 (s, 1H), 9.87 (s, 1H), 8.45 (s, 1H), 7.44 - 7.27 (m, 7H), 6.73 (s, 1H), 5.83 - 5.64 (m, 1H), 4.35 - 4.27 (m, 1H), 4.03 (td, J = 6.1, 2.0 Hz, 2H), 3.83 (q, J = 7.9 Hz, 1H), 3.14 (ddp, J = 11.8, 7.2, 4.5 Hz, 7H), 2.96 (dtd, J = 12.5, 6.2, 3.3 Hz, 1H), 2.15 (dt, J = 7.9, 5.6 Hz, 2H), 1.26 (d, J = 7.2 Hz, 6H) ) 516.3
[M+H]+ 516.3
[M+H] +
9999
Figure PCTKR2021018956-appb-img-000133
Figure PCTKR2021018956-appb-img-000133
 		(S)-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(4-(3-(diethylamino)propoxy)-3,5- dimethylphenyl )-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoro Rhomethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.76 (s, 1H), 8.47 (s, 1H), 7.38 - 7.27 (m, 5H), 7.17 (s, 1H), 5.91 (dd, J = 8.8, 6.0 Hz, 1H), 4.28 (td, J = 7.9, 2.5 Hz, 1H), 3.82 - 3.77 (m, 1H), 3.69 - 3.56 (m, 6H), 3.24 (dt, J = 12.2, 4.8 Hz, 2H), 3.15 (qd, J = 7.2, 4.5 Hz, 4H), 3.03 - 2.95 (m, 1H), 2.33 - 2.23 (m, 1H), 2.02 (s, 4H), 1.23 (d, J = 7.3 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.30 (s, 1H), 9.76 (s, 1H), 8.47 (s, 1H), 7.38 - 7.27 (m, 5H), 7.17 (s, 1H), 5.91 (dd, J = 8.8, 6.0 Hz, 1H), 4.28 (td, J = 7.9, 2.5 Hz, 1H), 3.82 - 3.77 (m, 1H), 3.69 - 3.56 (m, 6H), 3.24 (dt, J = 12.2, 4.8 Hz, 2H), 3.15 (qd, J = 7.2, 4.5 Hz, 4H), 3.03 - 2.95 (m, 1H), 2.33 - 2.23 (m, 1H), 2.02 (s, 4H), 1.23 (d, J = 7.3 Hz, 6H) 544.3
[M+H]+ 544.3
[M+H] +
100100
Figure PCTKR2021018956-appb-img-000134
Figure PCTKR2021018956-appb-img-000134
 		(R)-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( R )-N-(4-(3-(diethylamino)propoxy)-3,5- dimethylphenyl )-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoro Rhomethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 10.04 (s, 1H), 8.51 (s, 1H), 7.38 - 7.26 (m, 5H), 7.14 (s, 1H), 5.89 (dd, J = 8.8, 5.9 Hz, 1H), 4.32 (td, J = 7.9, 2.7 Hz, 1H), 3.89 - 3.80 (m, 1H), 3.74 (t, J = 6.0 Hz, 2H), 3.24 (dt, J = 12.0, 4.9 Hz, 2H), 3.14 (qd, J = 7.3, 4.4 Hz, 4H), 3.01 (s, 1H), 2.35 - 2.23 (m, 1H), 2.12 (dt, J = 14.5, 5.8 Hz, 2H), 2.04 (s, 6H), 1.25 (t, J = 7.2 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.57 (s, 1H), 10.04 (s, 1H), 8.51 (s, 1H), 7.38 - 7.26 (m, 5H), 7.14 (s, 1H), 5.89 (dd, J = 8.8, 5.9 Hz, 1H), 4.32 (td, J = 7.9, 2.7 Hz, 1H), 3.89 - 3.80 (m, 1H), 3.74 (t, J = 6.0 Hz, 2H), 3.24 (dt, J = 12.0, 4.9 Hz, 2H), 3.14 (qd, J = 7.3, 4.4 Hz, 4H), 3.01 (s, 1H), 2.35 - 2.23 (m, 1H), 2.12 (dt, J = 14.5) , 5.8 Hz, 2H), 2.04 (s, 6H), 1.25 (t, J = 7.2 Hz, 6H) 544.3
[M+H]+ 544.3
[M+H] +
101101
Figure PCTKR2021018956-appb-img-000135
Figure PCTKR2021018956-appb-img-000135
 		(S)-N-(3,5-다이메틸-4-(3-(4-메틸피페라진-1-일)프로폭시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(3,5- dimethyl -4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-4-(3-phenylisoxazolidin-2-yl )-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.66 (s, 1H), 8.46 (s, 1H), 7.36 (d, J = 4.5 Hz, 4H), 7.28 (d, J = 4.3 Hz, 1H), 7.18 (s, 2H), 5.92 (dd, J = 8.9, 6.0 Hz, 1H), 4.26 (td, J = 7.8, 2.6 Hz, 1H), 3.81 - 3.75 (m, 1H), 3.69 (t, J = 6.2 Hz, 2H), 3.56 - 3.05 (m, 7H), 3.02 - 2.86 (m, 4H), 2.75 (s, 3H), 2.31 - 2.23 (m, 1H), 2.02 (s, 6H), 1.97 (s, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.66 (s, 1H), 8.46 (s, 1H), 7.36 (d, J = 4.5 Hz, 4H), 7.28 (d, J = 4.3 Hz, 1H) ), 7.18 (s, 2H), 5.92 (dd, J = 8.9, 6.0 Hz, 1H), 4.26 (td, J = 7.8, 2.6 Hz, 1H), 3.81 - 3.75 (m, 1H), 3.69 (t, J = 6.2 Hz, 2H), 3.56 - 3.05 (m, 7H), 3.02 - 2.86 (m, 4H), 2.75 (s, 3H), 2.31 - 2.23 (m, 1H), 2.02 (s, 6H), 1.97 (s, 2H) 571.5
[M+H]+ 571.5
[M+H] +
102102
Figure PCTKR2021018956-appb-img-000136
Figure PCTKR2021018956-appb-img-000136
 		(S)-N-(4-(3-(다이에틸아미노)프로폭시)-3-(트라이플루오로메틸)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(4-(3-( diethylamino )propoxy)-3-(trifluoromethyl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, Chloroform-d) δ = 8.38 (s, 1H), 7.51 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.39 - 7.26 (m, 6H), 6.70 (d, J = 8.9 Hz, 1H), 5.76 - 5.67 (m, 1H), 4.29 (td, J = 7.8, 3.0 Hz, 1H), 4.08 (s, 2H), 3.92 - 3.86 (m, 1H), 2.97 - 2.79 (m, 7H), 2.38 (t, J = 10.1 Hz, 1H), 2.14 (d, J = 5.5 Hz, 2H), 1.19 (t, J = 7.2 Hz, 6H) 1 H NMR (400 MHz, Chloroform-d) δ = 8.38 (s, 1H), 7.51 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.39 - 7.26 (m, 6H), 6.70 ( d, J = 8.9 Hz, 1H), 5.76 - 5.67 (m, 1H), 4.29 (td, J = 7.8, 3.0 Hz, 1H), 4.08 (s, 2H), 3.92 - 3.86 (m, 1H), 2.97 - 2.79 (m, 7H), 2.38 (t, J = 10.1 Hz, 1H), 2.14 (d, J = 5.5 Hz, 2H), 1.19 (t, J = 7.2 Hz, 6H) 584.4
[M+H]+ 584.4
[M+H] +
103103
Figure PCTKR2021018956-appb-img-000137
Figure PCTKR2021018956-appb-img-000137
 		(S)-N-(3-플루오로-4-((1-메틸피페리딘-4-일)옥시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (3-fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ= 9.91 (s, 1H), 8.48 (s, 1H), 7.51 (s, 1H), 7.43 - 7.36 (m, 4H), 7.32 - 7.27 (m, 1H), 7.22 (s, 1H), 7.04 (s, 1H), 5.82 (s, 1H), 4.31 (td, J = 7.9, 2.4 Hz, 1H), 3.83 (dd, J = 9.5, 6.8 Hz, 1H), 3.53 (d, J = 12.6 Hz, 1H), 3.40 (d, J = 12.4 Hz, 1H), 3.19 (s, 3H), 2.97 (ddt, J = 9.2, 6.4, 3.3 Hz, 1H), 2.87 - 2.85 (m, 1H), 2.82 (s, 1H), 2.22 (d, J = 13.0 Hz, 2H), 2.05 (d, J = 3.4 Hz, 2H), 1.83 - 1.72 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ=9.91 (s, 1H), 8.48 (s, 1H), 7.51 (s, 1H), 7.43 - 7.36 (m, 4H), 7.32 - 7.27 (m, 1H), 7.22 (s, 1H), 7.04 (s, 1H), 5.82 (s, 1H), 4.31 (td, J = 7.9, 2.4 Hz, 1H), 3.83 (dd, J = 9.5, 6.8 Hz, 1H) ), 3.53 (d, J = 12.6 Hz, 1H), 3.40 (d, J = 12.4 Hz, 1H), 3.19 (s, 3H), 2.97 (ddt, J = 9.2, 6.4, 3.3 Hz, 1H), 2.87 - 2.85 (m, 1H), 2.82 (s, 1H), 2.22 (d, J = 13.0 Hz, 2H), 2.05 (d, J = 3.4 Hz, 2H), 1.83 - 1.72 (m, 1H) 518.3
[M+H]+ 518.3
[M+H] +
104104
Figure PCTKR2021018956-appb-img-000138
Figure PCTKR2021018956-appb-img-000138
 		tert-부틸 (S)-4-(2-플루오로-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피페리딘-1-카복실레이트 tert -Butyl ( S )-4-(2-fluoro-4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl) Amino)phenyl)piperidine-1-carboxylate 588.4
[M+H]+ 588.4
[M+H] +
105105
Figure PCTKR2021018956-appb-img-000139
Figure PCTKR2021018956-appb-img-000139
 		(S)-N-(3-플루오로-4-(피페리딘-4-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (3-fluoro-4-(piperidin-4-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine 488.3
[M+H]+ 488.3
[M+H] +
106106
Figure PCTKR2021018956-appb-img-000140
Figure PCTKR2021018956-appb-img-000140
 		(S)-N-(4-(4-에틸피페라진-1-일)-3,5-다이플루오로페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(4-(4-ethylpiperazin- 1 -yl)-3,5-difluorophenyl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, Chloroform-d) δ = 8.39 (s, 1H), 7.44 - 7.33 (m, 4H), 7.30 - 7.26 (m, 1H), 7.20 (s, 1H), 6.95 (d, J = 10.6 Hz, 2H), 5.78 (dd, J = 8.8, 6.1 Hz, 1H), 4.31 (td, J = 7.9, 3.1 Hz, 1H), 3.89 (ddd, J = 9.7, 8.2, 6.6 Hz, 1H), 3.27 (s, 4H), 2.89 (dddd, J = 12.1, 9.4, 6.6, 3.1 Hz, 1H), 2.71 (d, J = 33.7 Hz, 6H), 2.41 - 2.34 (m, 1H), 1.22 (t, J = 6.8 Hz, 3H) 1 H NMR (400 MHz, Chloroform-d) δ = 8.39 (s, 1H), 7.44 - 7.33 (m, 4H), 7.30 - 7.26 (m, 1H), 7.20 (s, 1H), 6.95 (d, J ) = 10.6 Hz, 2H), 5.78 (dd, J = 8.8, 6.1 Hz, 1H), 4.31 (td, J = 7.9, 3.1 Hz, 1H), 3.89 (ddd, J = 9.7, 8.2, 6.6 Hz, 1H) , 3.27 (s, 4H), 2.89 (dddd, J = 12.1, 9.4, 6.6, 3.1 Hz, 1H), 2.71 (d, J = 33.7 Hz, 6H), 2.41 - 2.34 (m, 1H), 1.22 (t) , J = 6.8 Hz, 3H) 535.4
[M+H]+ 535.4
[M+H] +
107107
Figure PCTKR2021018956-appb-img-000141
Figure PCTKR2021018956-appb-img-000141
 		(S)-N-(3,5-다이플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (3,5-difluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisooxa Jolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 10.00 (s, 1H), 8.50 (s, 1H), 7.37 (d, J = 6.5 Hz, 4H), 7.28 (dq, J = 5.6, 1.7 Hz, 1H), 7.23 (d, J = 11.6 Hz, 2H), 5.84 (t, J = 7.6 Hz, 1H), 4.30 (d, J = 2.6 Hz, 1H), 3.86 - 3.79 (m, 5H), 3.08 (d, J = 12.5 Hz, 2H), 3.02 - 2.93 (m, 4H), 2.35 - 2.19 (m, 7H), 2.14 (s, 3H), 1.51 (d, J = 4.0 Hz, 1H), 1.48 (d, J = 4.1 Hz, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 10.00 (s, 1H), 8.50 (s, 1H), 7.37 (d, J = 6.5 Hz, 4H), 7.28 (dq, J = 5.6, 1.7 Hz) , 1H), 7.23 (d, J = 11.6 Hz, 2H), 5.84 (t, J = 7.6 Hz, 1H), 4.30 (d, J = 2.6 Hz, 1H), 3.86 - 3.79 (m, 5H), 3.08 (d, J = 12.5 Hz, 2H), 3.02 - 2.93 (m, 4H), 2.35 - 2.19 (m, 7H), 2.14 (s, 3H), 1.51 (d, J = 4.0 Hz, 1H), 1.48 ( d, J = 4.1 Hz, 1H) 604.5
[M+H]+ 604.5
[M+H] +
108108
Figure PCTKR2021018956-appb-img-000142
Figure PCTKR2021018956-appb-img-000142
 		(S)-N-(4-(4-(다이메틸아미노)피페리딘-1-일)-3,5-다이플루오로페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(4-(4-( dimethylamino )piperidin-1-yl)-3,5-difluorophenyl)-4-(3-phenylisoxazolidin-2-yl )-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.50 (s, 1H), 7.41 - 7.33 (m, 4H), 7.31 - 7.16 (m, 3H), 5.84 (t, J = 7.6 Hz, 1H), 4.31 (td, J = 7.8, 2.5 Hz, 1H), 3.82 (ddd, J = 9.8, 8.0, 6.6 Hz, 1H), 3.08 (q, J = 6.2, 3.8 Hz, 2H), 3.03 - 2.91 (m, 3H), 2.49 (d, J = 4.3 Hz, 1H), 2.26 (dd, J = 6.9, 2.4 Hz, 1H), 2.22 (s, 6H), 1.84 - 1.70 (m, 2H), 1.48 (qd, J = 11.8, 4.2 Hz, 2H)1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.50 (s, 1H), 7.41 - 7.33 (m, 4H), 7.31 - 7.16 (m, 3H), 5.84 (t, J = 7.6 Hz, 1H), 4.31 (td, J = 7.8, 2.5 Hz, 1H), 3.82 (ddd, J = 9.8, 8.0, 6.6 Hz, 1H), 3.08 (q, J = 6.2, 3.8 Hz, 2H), 3.03 - 2.91 (m, 3H), 2.49 (d, J = 4.3 Hz, 1H), 2.26 (dd, J = 6.9, 2.4 Hz, 1H), 2.22 (s, 6H), 1.84 - 1.70 (m, 2H), 1.48 (qd, J = 11.8, 4.2 Hz, 2H) 549.5
[M+H]+ 549.5
[M+H] +
109109
Figure PCTKR2021018956-appb-img-000143
Figure PCTKR2021018956-appb-img-000143
 		N-(4-((R)-3-(다이메틸아미노)피롤리딘-1-일)-3,5-다이플루오로페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민 N- (4-(( R )-3-(dimethylamino)pyrrolidin-1-yl)-3,5-difluorophenyl)-4-(( S )-3-phenylisoxazolidine -2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.92 (s, 1H), 8.49 (s, 1H), 7.37 (dd, J = 8.1, 1.5 Hz, 4H), 7.29 - 7.26 (m, 1H), 7.22 (d, J = 11.2 Hz, 2H), 5.83 (d, J = 7.6 Hz, 1H), 4.33 - 4.28 (m, 1H), 3.87 - 3.79 (m, 1H), 3.41 - 3.29 (m, 4H), 3.05 (t, J = 7.4 Hz, 1H), 3.01 - 2.94 (m, 1H), 2.34 (s, 6H), 2.27 - 2.20 (m, 1H), 2.15 - 2.08 (m, 1H), 1.81 (dt, J = 8.3, 4.2 Hz, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.92 (s, 1H), 8.49 (s, 1H), 7.37 (dd, J = 8.1, 1.5 Hz, 4H), 7.29 - 7.26 (m, 1H) , 7.22 (d, J = 11.2 Hz, 2H), 5.83 (d, J = 7.6 Hz, 1H), 4.33 - 4.28 (m, 1H), 3.87 - 3.79 (m, 1H), 3.41 - 3.29 (m, 4H) ), 3.05 (t, J = 7.4 Hz, 1H), 3.01 - 2.94 (m, 1H), 2.34 (s, 6H), 2.27 - 2.20 (m, 1H), 2.15 - 2.08 (m, 1H), 1.81 ( dt, J = 8.3, 4.2 Hz, 1H) 535.4
[M+H]+ 535.4
[M+H] +
110110
Figure PCTKR2021018956-appb-img-000144
Figure PCTKR2021018956-appb-img-000144
 		N-(4-((S)-3-(다이메틸아미노)피롤리딘-1-일)-3,5-다이플루오로페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민 N- (4-(( S )-3-(dimethylamino)pyrrolidin-1-yl)-3,5-difluorophenyl)-4-(( S )-3-phenylisoxazolidine -2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.94 (s, 1H), 8.49 (s, 1H), 7.37 (dd, J = 7.8, 1.5 Hz, 4H), 7.30 - 7.20 (m, 3H), 5.84 (t, J = 7.6 Hz, 1H), 4.30 (dt, J = 7.8, 3.9 Hz, 1H), 3.85 - 3.79 (m, 1H), 3.40 - 3.28 (m, 4H), 3.18 (dd, J = 7.7, 5.4 Hz, 1H), 3.02 - 2.94 (m, 1H), 2.41 (s, 6H), 2.26 - 2.20 (m, 1H), 2.16 - 2.10 (m, 1H), 1.88 - 1.80 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.94 (s, 1H), 8.49 (s, 1H), 7.37 (dd, J = 7.8, 1.5 Hz, 4H), 7.30 - 7.20 (m, 3H) , 5.84 (t, J = 7.6 Hz, 1H), 4.30 (dt, J = 7.8, 3.9 Hz, 1H), 3.85 - 3.79 (m, 1H), 3.40 - 3.28 (m, 4H), 3.18 (dd, J ) = 7.7, 5.4 Hz, 1H), 3.02 - 2.94 (m, 1H), 2.41 (s, 6H), 2.26 - 2.20 (m, 1H), 2.16 - 2.10 (m, 1H), 1.88 - 1.80 (m, 1H) ) 535.4
[M+H]+ 535.4
[M+H] +
111111
Figure PCTKR2021018956-appb-img-000145
Figure PCTKR2021018956-appb-img-000145
 		(S)-1-(2,6-다이플루오로-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피롤리딘-2-온( S )-1-(2,6-difluoro-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl) amino)phenyl)pyrrolidin-2-one 1H NMR (400 MHz, DMSO-d6) δ = 10.21 (s, 1H), 8.54 (s, 1H), 7.40 - 7.34 (m, 6H), 7.28 (dd, J = 6.2, 2.5 Hz, 1H), 5.85 (dd, J = 8.7, 6.3 Hz, 1H), 4.33 (dd, J = 7.7, 2.5 Hz, 1H), 3.87 - 3.81 (m, 1H), 3.61 (t, J = 7.1 Hz, 2H), 3.01 (dq, J = 8.5, 2.5 Hz, 1H), 2.44 - 2.39 (m, 2H), 2.26 - 2.20 (m, 1H), 2.18 - 2.10 (m, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 10.21 (s, 1H), 8.54 (s, 1H), 7.40 - 7.34 (m, 6H), 7.28 (dd, J = 6.2, 2.5 Hz, 1H) , 5.85 (dd, J = 8.7, 6.3 Hz, 1H), 4.33 (dd, J = 7.7, 2.5 Hz, 1H), 3.87 - 3.81 (m, 1H), 3.61 (t, J = 7.1 Hz, 2H), 3.01 (dq, J = 8.5, 2.5 Hz, 1H), 2.44 - 2.39 (m, 2H), 2.26 - 2.20 (m, 1H), 2.18 - 2.10 (m, 2H) 506.4
[M+H]+ 506.4
[M+H] +
112112
Figure PCTKR2021018956-appb-img-000146
Figure PCTKR2021018956-appb-img-000146
 		(S)-N-(3,5-다이플루오로-4-(4-메틸-1,4-다이아제판-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (3,5-difluoro-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl )-5-(trifluoromethyl)pyrimidin-2-amine 535.4
[M+H]+ 535.4
[M+H] +
113113
Figure PCTKR2021018956-appb-img-000147
Figure PCTKR2021018956-appb-img-000147
 		(S)-N-(3,5-다이플루오로-4-((1-메틸피페리딘-4-일)옥시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (3,5-difluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-4-(3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.50 (s, 1H), 7.40 - 7.22 (m, 7H), 5.83 (t, J = 7.7 Hz, 1H), 4.31 (td, J = 7.9, 2.5 Hz, 1H), 3.97 (s, 1H), 3.83 (ddd, J = 9.9, 8.0, 6.5 Hz, 1H), 3.04 - 2.95 (m, 1H), 2.66 - 2.57 (m, 2H), 2.20 (d, J = 10.6 Hz, 1H), 2.16 (s, 3H), 2.12 - 2.03 (m, 2H), 1.84 (s, 2H), 1.65 (ddt, J = 14.6, 10.2, 5.1 Hz, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.01 (s, 1H), 8.50 (s, 1H), 7.40 - 7.22 (m, 7H), 5.83 (t, J = 7.7 Hz, 1H), 4.31 ( td, J = 7.9, 2.5 Hz, 1H), 3.97 (s, 1H), 3.83 (ddd, J = 9.9, 8.0, 6.5 Hz, 1H), 3.04 - 2.95 (m, 1H), 2.66 - 2.57 (m, 2H), 2.20 (d, J = 10.6 Hz, 1H), 2.16 (s, 3H), 2.12 - 2.03 (m, 2H), 1.84 (s, 2H), 1.65 (ddt, J = 14.6, 10.2, 5.1 Hz) , 2H) 536.4
[M+H]+ 536.4
[M+H] +
114114
Figure PCTKR2021018956-appb-img-000148
Figure PCTKR2021018956-appb-img-000148
 		(S)-N-(3,5-다이플루오로-4-((1-메틸피페리딘-4-일)메톡시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (3,5-difluoro-4-((1-methylpiperidin-4-yl)methoxy)phenyl)-4-(3-phenylisoxazolidin-2-yl )-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 10.02 (s, 1H), 8.51 (s, 1H), 7.43 - 7.23 (m, 7H), 5.88 - 5.78 (m, 1H), 4.31 (td, J = 7.8, 2.5 Hz, 1H), 3.90 - 3.78 (m, 3H), 3.33 (s, 2H), 3.10 (d, J = 11.6 Hz, 2H), 2.99 (dddd, J = 11.7, 9.0, 6.5, 2.5 Hz, 1H), 2.46 (s, 3H), 2.27 - 2.17 (m, 1H), 1.89 - 1.73 (m, 3H), 1.46 (dd, J = 13.0, 9.6 Hz, 2H)1H NMR (400 MHz, DMSO-d 6 ) δ = 10.02 (s, 1H), 8.51 (s, 1H), 7.43 - 7.23 (m, 7H), 5.88 - 5.78 (m, 1H), 4.31 (td, J ) = 7.8, 2.5 Hz, 1H), 3.90 - 3.78 (m, 3H), 3.33 (s, 2H), 3.10 (d, J = 11.6 Hz, 2H), 2.99 (dddd, J = 11.7, 9.0, 6.5, 2.5 Hz, 1H), 2.46 (s, 3H), 2.27 - 2.17 (m, 1H), 1.89 - 1.73 (m, 3H), 1.46 (dd, J = 13.0, 9.6 Hz, 2H) 550.4
[M+H]+ 550.4
[M+H] +
115115
Figure PCTKR2021018956-appb-img-000149
Figure PCTKR2021018956-appb-img-000149
 		(S)-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이플루오로페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(4-(3-( diethylamino )propoxy)-3,5-difluorophenyl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 10.01 (s, 1H), 8.50 (s, 1H), 7.42 - 7.24 (m, 7H), 5.83 (t, J = 7.5 Hz, 1H), 4.31 (td, J = 7.8, 2.5 Hz, 1H), 4.04 (t, J = 6.2 Hz, 2H), 3.83 (dt, J = 9.5, 7.5 Hz, 1H), 2.99 (dtt, J = 9.0, 6.7, 3.4 Hz, 1H), 2.69 - 2.51 (m, 6H), 2.24 - 2.17 (m, 1H), 1.79 (q, J = 6.9 Hz, 2H), 0.98 (t, J = 7.2 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 10.01 (s, 1H), 8.50 (s, 1H), 7.42 - 7.24 (m, 7H), 5.83 (t, J = 7.5 Hz, 1H), 4.31 (td, J = 7.8, 2.5 Hz, 1H), 4.04 (t, J = 6.2 Hz, 2H), 3.83 (dt, J = 9.5, 7.5 Hz, 1H), 2.99 (dtt, J = 9.0, 6.7, 3.4 Hz, 1H), 2.69 - 2.51 (m, 6H), 2.24 - 2.17 (m, 1H), 1.79 (q, J = 6.9 Hz, 2H), 0.98 (t, J = 7.2 Hz, 6H) 552.5
[M+H]+ 552.5
[M+H] +
116116
Figure PCTKR2021018956-appb-img-000150
Figure PCTKR2021018956-appb-img-000150
 		(S)-N-(3,5-다이플루오로-4-(4-메틸-1H-이미다졸-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (3,5-difluoro-4-(4-methyl-1 H -imidazol-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-amine 503.4
[M+H]+ 503.4
[M+H] +
117117
Figure PCTKR2021018956-appb-img-000151
Figure PCTKR2021018956-appb-img-000151
 		(S)-N-(5-(4-메틸피페라진-1-일)피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(5-(4-methylpiperazin- 1 -yl)pyridin-2-yl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl ) pyrimidin-2-amine 1H NMR (400 MHz, Methanol-d 4) δ 8.47 (d, J = 5.0 Hz, 1H), 7.96 (t, J = 2.8 Hz, 1H), 7.53 (d, J = 9.1 Hz, 1H), 7.43 (d, J = 4.4 Hz, 4H), 7.37 - 7.29 (m, 2H), 7.06 (dd, J = 9.1, 3.0 Hz, 1H), 5.75 (dd, J = 8.6, 7.1 Hz, 1H), 4.33 (td, J = 7.7, 2.5 Hz, 1H), 3.94 (ddd, J = 10.3, 8.1, 6.1 Hz, 1H), 3.20 (t, J = 5.1 Hz, 4H), 2.99 (dddd, J = 11.6, 8.6, 6.0, 2.5 Hz, 1H), 2.73 (dq, J = 5.1, 2.5 Hz, 4H), 2.45 (d, J = 1.7 Hz, 3H), 2.32 (ddt, J = 12.1, 10.3, 7.5 Hz, 1H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.47 (d, J = 5.0 Hz, 1H), 7.96 (t, J = 2.8 Hz, 1H), 7.53 (d, J = 9.1 Hz, 1H), 7.43 (d, J = 4.4 Hz, 4H), 7.37 - 7.29 (m, 2H), 7.06 (dd, J = 9.1, 3.0 Hz, 1H), 5.75 (dd, J = 8.6, 7.1 Hz, 1H), 4.33 ( td, J = 7.7, 2.5 Hz, 1H), 3.94 (ddd, J = 10.3, 8.1, 6.1 Hz, 1H), 3.20 (t, J = 5.1 Hz, 4H), 2.99 (dddd, J = 11.6, 8.6, 6.0, 2.5 Hz, 1H), 2.73 (dq, J = 5.1, 2.5 Hz, 4H), 2.45 (d, J = 1.7 Hz, 3H), 2.32 (ddt, J = 12.1, 10.3, 7.5 Hz, 1H) 485.5
[M+H]+ 485.5
[M+H] +
118118
Figure PCTKR2021018956-appb-img-000152
Figure PCTKR2021018956-appb-img-000152
 		(S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(5-(피페라진-1-일)피리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-4-(3- phenylisoxazolidin -2-yl)-N-(5-(piperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)pyrimidine -2-amine 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 0.8 Hz, 1H), 7.75 (dd, J = 3.0, 0.8 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.35 (ddd, J = 7.7, 6.8, 1.2 Hz, 2H), 7.29 - 7.27 (m, 1H), 7.16 (dd, J = 8.8, 2.9 Hz, 1H), 6.48 (dd, J = 8.8, 0.7 Hz, 1H), 5.66 - 5.56 (m, 1H), 4.32 - 4.25 (m, 1H), 4.22 (s, 2H), 3.89 (ddd, J = 9.6, 8.2, 6.5 Hz, 2H), 3.78 (s, 3H), 2.98 - 2.75 (m, 5H), 2.39 (dddd, J = 12.0, 9.6, 7.6, 6.8 Hz, 1H) 1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (d, J = 0.8 Hz, 1H), 7.75 (dd, J = 3.0, 0.8 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.35 (ddd, J = 7.7, 6.8, 1.2 Hz, 2H), 7.29 - 7.27 (m, 1H), 7.16 (dd, J = 8.8, 2.9 Hz, 1H), 6.48 (dd, J = 8.8, 0.7 Hz, 1H), 5.66 - 5.56 (m, 1H), 4.32 - 4.25 (m, 1H), 4.22 (s, 2H), 3.89 (ddd, J = 9.6, 8.2, 6.5 Hz, 2H), 3.78 (s, 3H), 2.98 - 2.75 (m, 5H), 2.39 (dddd, J = 12.0, 9.6, 7.6, 6.8 Hz, 1H) 472.3
[M+H]+472.3
[M+H]+
119119
Figure PCTKR2021018956-appb-img-000153
Figure PCTKR2021018956-appb-img-000153
 		(S)-N-(5-몰포리노피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (5-morpholinopyridin-2-yl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, Methanol-d 4) δ 8.42 (s, 1H), 7.91 (d, J = 3.0 Hz, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.41 (d, J = 4.4 Hz, 5H), 7.30 (dt, J = 8.7, 4.2 Hz, 2H), 7.05 (dd, J = 9.1, 3.0 Hz, 1H), 5.74 (dd, J = 8.7, 7.0 Hz, 1H), 4.31 (td, J = 7.7, 2.5 Hz, 1H), 3.92 (ddd, J = 10.2, 8.2, 6.1 Hz, 1H), 3.89 - 3.82 (m, 4H), 3.13 - 3.06 (m, 4H), 3.03 - 2.92 (m, 1H), 2.31 (ddt, J = 12.0, 10.1, 7.2 Hz, 1H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.42 (s, 1H), 7.91 (d, J = 3.0 Hz, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.41 (d, J = 4.4 Hz, 5H), 7.30 (dt, J = 8.7, 4.2 Hz, 2H), 7.05 (dd, J = 9.1, 3.0 Hz, 1H), 5.74 (dd, J = 8.7, 7.0 Hz, 1H), 4.31 ( td, J = 7.7, 2.5 Hz, 1H), 3.92 (ddd, J = 10.2, 8.2, 6.1 Hz, 1H), 3.89 - 3.82 (m, 4H), 3.13 - 3.06 (m, 4H), 3.03 - 2.92 ( m, 1H), 2.31 (ddt, J = 12.0, 10.1, 7.2 Hz, 1H) 472.5
[M+H]+ 472.5
[M+H] +
120120
Figure PCTKR2021018956-appb-img-000154
Figure PCTKR2021018956-appb-img-000154
 		(S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(5-(테트라하이드로-2H-피란-4-일)피리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-4-(3-phenylisoxazolidin-2-yl) -N- (5-(tetrahydro- 2H -pyran-4-yl)pyridin-2-yl)-5-(trifluoro Rhomethyl)pyrimidin-2-amine 471.5
[M+H]+ 471.5
[M+H] +
121121
Figure PCTKR2021018956-appb-img-000155
Figure PCTKR2021018956-appb-img-000155
 		(S)-N-(5-(4-아이소프로필피페라진-1-일)피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(5-(4-isopropylpiperazin- 1 -yl)pyridin-2-yl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoro methyl)pyrimidin-2-amine 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 2.4 Hz, 1H), 8.34 (s, 1H), 7.97 (t, J = 2.5 Hz, 1H), 7.61 (d, J = 6.6 Hz, 1H), 7.45 - 7.36 (m, 4H), 7.32 (qt, J = 6.6, 2.6 Hz, 2H), 6.93 (d, J = 9.0 Hz, 1H), 5.71 (dd, J = 8.6, 6.9 Hz, 1H), 4.31 (td, J = 7.8, 2.6 Hz, 1H), 3.89 (ddd, J = 10.1, 8.3, 6.2 Hz, 1H), 3.28 (s, 4H), 3.01 (s, 3H), 2.88 (dddd, J = 11.6, 8.8, 6.1, 2.6 Hz, 2H), 2.38 (ddt, J = 12.0, 10.1, 7.3 Hz, 1H), 1.32 - 1.20 (m, 6H) 1 H NMR (400 MHz, CDCl 3 ) δ 8.51 (d, J = 2.4 Hz, 1H), 8.34 (s, 1H), 7.97 (t, J = 2.5 Hz, 1H), 7.61 (d, J = 6.6 Hz) , 1H), 7.45 - 7.36 (m, 4H), 7.32 (qt, J = 6.6, 2.6 Hz, 2H), 6.93 (d, J = 9.0 Hz, 1H), 5.71 (dd, J = 8.6, 6.9 Hz, 1H), 4.31 (td, J = 7.8, 2.6 Hz, 1H), 3.89 (ddd, J = 10.1, 8.3, 6.2 Hz, 1H), 3.28 (s, 4H), 3.01 (s, 3H), 2.88 (dddd , J = 11.6, 8.8, 6.1, 2.6 Hz, 2H), 2.38 (ddt, J = 12.0, 10.1, 7.3 Hz, 1H), 1.32 - 1.20 (m, 6H) 514.4
[M+H]+ 514.4
[M+H] +
122122
Figure PCTKR2021018956-appb-img-000156
Figure PCTKR2021018956-appb-img-000156
 		(S)-N-(5-(4-사이클로프로필피페라진-1-일)피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(5-(4-cyclopropylpiperazin- 1 -yl)pyridin-2-yl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoro methyl)pyrimidin-2-amine 511.6
[M+H]+ 511.6
[M+H] +
123123
Figure PCTKR2021018956-appb-img-000157
Figure PCTKR2021018956-appb-img-000157
 		(S)-N-(5-(4-(옥세탄-3-일)피페라진-1-일)피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(5-(4-( oxetan -3-yl)piperazin-1-yl)pyridin-2-yl)-4-(3-phenylisoxazolidin-2-yl)- 5-(trifluoromethyl)pyrimidin-2-amine 527.6
[M+H]+ 527.6
[M+H] +
124124
Figure PCTKR2021018956-appb-img-000158
Figure PCTKR2021018956-appb-img-000158
 		(S)-N-(5-((4-에틸피페라진-1-일)메틸)피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(5-((4-ethylpiperazin- 1 -yl)methyl)pyridin-2-yl)-4-(3-phenylisoxazolidin-2-yl)-5-(tri Fluoromethyl) pyrimidin-2-amine -- 514.5
[M+H]+514.5
[M+H]+
125125
Figure PCTKR2021018956-appb-img-000159
Figure PCTKR2021018956-appb-img-000159
 		(S)-N-(5-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N-(5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)-4-(3-phenylisoxazolidin-2 -yl)-5-(trifluoromethyl)pyrimidin-2-amine 569.4
[M+H]+ 569.4
[M+H] +
126126
Figure PCTKR2021018956-appb-img-000160
Figure PCTKR2021018956-appb-img-000160
 		(S)-N-(6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N-(6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)-4-(3-phenylisoxazolidin-2 -yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.88 (s, 1H), 8.47 (s, 1H), 8.26 (s, 1H), 7.82 (s, 1H), 7.41 - 7.31 (m, 4H), 7.30 - 7.24 (m, 1H), 6.99 (s, 1H), 5.84 - 5.60 (m, 1H), 4.39 - 4.28 (m, 3H), 3.84 (t, J = 8.2 Hz, 1H), 3.54 (s, 9H), 2.99 (d, J = 13.5 Hz, 2H), 2.92 (d, J = 2.9 Hz, 1H), 2.90 (s, 3H), 2.30 - 2.21 (m, 1H), 2.18 (d, J = 12.2 Hz, 2H), 1.73 - 1.59 (m, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.88 (s, 1H), 8.47 (s, 1H), 8.26 (s, 1H), 7.82 (s, 1H), 7.41 - 7.31 (m, 4H) , 7.30 - 7.24 (m, 1H), 6.99 (s, 1H), 5.84 - 5.60 (m, 1H), 4.39 - 4.28 (m, 3H), 3.84 (t, J = 8.2 Hz, 1H), 3.54 (s) , 9H), 2.99 (d, J = 13.5 Hz, 2H), 2.92 (d, J = 2.9 Hz, 1H), 2.90 (s, 3H), 2.30 - 2.21 (m, 1H), 2.18 (d, J = 12.2 Hz, 2H), 1.73 - 1.59 (m, 2H) 569.4
[M+H]+ 569.4
[M+H] +
127127
Figure PCTKR2021018956-appb-img-000161
Figure PCTKR2021018956-appb-img-000161
 		(S)-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민( S )-N-(4-(3- phenylisooxazolidin -2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydroiso Quinolin-6-amine 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.48 (s, 1H), 7.45 - 7.22 (m, 7H), 6.94 (d, J = 8.7 Hz, 1H), 5.85 (t, J = 7.7 Hz, 1H), 4.29 (td, J = 7.8, 2.5 Hz, 1H), 4.07 (s, 2H), 3.80 (ddd, J = 9.9, 8.0, 6.5 Hz, 1H), 3.19 (t, J = 6.2 Hz, 2H), 2.98 (dtt, J = 10.0, 7.3, 3.8 Hz, 1H), 2.77 - 2.57 (m, 2H), 2.29 - 2.18 (m, 1H)1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.48 (s, 1H), 7.45 - 7.22 (m, 7H), 6.94 (d, J = 8.7 Hz, 1H), 5.85 (t, J = 7.7 Hz, 1H), 4.29 (td, J = 7.8, 2.5 Hz, 1H), 4.07 (s, 2H), 3.80 (ddd, J = 9.9, 8.0, 6.5 Hz, 1H), 3.19 (t, J ) = 6.2 Hz, 2H), 2.98 (dtt, J = 10.0, 7.3, 3.8 Hz, 1H), 2.77 - 2.57 (m, 2H), 2.29 - 2.18 (m, 1H) 442.4
[M+H]+ 442.4
[M+H] +
128128
Figure PCTKR2021018956-appb-img-000162
Figure PCTKR2021018956-appb-img-000162
 		(S)-2-메틸-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민( S )-2-methyl- N- (4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4 -tetrahydroisoquinolin-6-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.71 (s, 1H), 8.45 (s, 1H), 7.38 (d, J = 5.3 Hz, 4H), 7.29 (td, J = 5.5, 3.2 Hz, 1H), 7.23 (t, J = 7.9 Hz, 2H), 6.80 (d, J = 8.2 Hz, 1H), 5.84 (s, 1H), 4.29 - 4.27 (m, 1H), 4.03 (d, J = 7.1 Hz, 2H), 3.82 - 3.79 (m, 1H), 3.78 - 3.75 (m, 1H), 3.38 (s, 2H), 3.00 - 2.93 (m, 1H), 2.56 (s, 1H), 2.30 (s, 3H), 2.21 (d, J = 10.3 Hz, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.71 (s, 1H), 8.45 (s, 1H), 7.38 (d, J = 5.3 Hz, 4H), 7.29 (td, J = 5.5, 3.2 Hz) , 1H), 7.23 (t, J = 7.9 Hz, 2H), 6.80 (d, J = 8.2 Hz, 1H), 5.84 (s, 1H), 4.29 - 4.27 (m, 1H), 4.03 (d, J = 7.1 Hz, 2H), 3.82 - 3.79 (m, 1H), 3.78 - 3.75 (m, 1H), 3.38 (s, 2H), 3.00 - 2.93 (m, 1H), 2.56 (s, 1H), 2.30 (s) , 3H), 2.21 (d, J = 10.3 Hz, 1H) 456.3
[M+H]+ 456.3
[M+H] +
129129
Figure PCTKR2021018956-appb-img-000163
Figure PCTKR2021018956-appb-img-000163
 		(S)-1-(6-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-3,4-다이하이드로아이소퀴놀린-2(1H)-일)에탄-1-온( S )-1-(6-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-di Hydroisoquinolin-2(1 H )-yl)ethan-1-one 484.2
[M+H]+ 484.2
[M+H] +
130130
Figure PCTKR2021018956-appb-img-000164
Figure PCTKR2021018956-appb-img-000164
 		(S)-2-(메틸설포닐)-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민( S )-2-(methylsulfonyl)-N-(4-(3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2 ,3,4-Tetrahydroisoquinolin-6-amine 520.2
[M+H]+ 520.2
[M+H] +
131131
Figure PCTKR2021018956-appb-img-000165
Figure PCTKR2021018956-appb-img-000165
 		(S)-2-사이클로프로필-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민( S )-2-cyclopropyl- N- (4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3, 4-tetrahydroisoquinolin-6-amine 482.2
[M+H]+ 482.2
[M+H] +
132132
Figure PCTKR2021018956-appb-img-000166
Figure PCTKR2021018956-appb-img-000166
 		(S)-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민( S )-N-(4-(3- phenylisooxazolidin -2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydroiso Quinolin-7-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.88 (s, 1H), 9.00 (s, 1H), 8.48 (s, 1H), 7.43 - 7.36 (m, 5H), 7.31 (dd, J = 6.2, 2.5 Hz, 2H), 7.00 (d, J = 8.3 Hz, 1H), 5.84 (t, J = 7.6 Hz, 1H), 4.29 (td, J = 7.8, 2.5 Hz, 1H), 4.07 - 3.88 (m, 2H), 3.81 (ddd, J = 9.9, 8.0, 6.6 Hz, 1H), 3.36 - 3.31 (m, 2H), 3.00 - 2.94 (m, 1H), 2.90 (t, J = 6.3 Hz, 2H), 2.28 - 2.21 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.88 (s, 1H), 9.00 (s, 1H), 8.48 (s, 1H), 7.43 - 7.36 (m, 5H), 7.31 (dd, J = 6.2, 2.5 Hz, 2H), 7.00 (d, J = 8.3 Hz, 1H), 5.84 (t, J = 7.6 Hz, 1H), 4.29 (td, J = 7.8, 2.5 Hz, 1H), 4.07 - 3.88 ( m, 2H), 3.81 (ddd, J = 9.9, 8.0, 6.6 Hz, 1H), 3.36 - 3.31 (m, 2H), 3.00 - 2.94 (m, 1H), 2.90 (t, J = 6.3 Hz, 2H) , 2.28 - 2.21 (m, 1H) 442.2
[M+H]+ 442.2
[M+H] +
133133
Figure PCTKR2021018956-appb-img-000167
Figure PCTKR2021018956-appb-img-000167
 		(S)-2-메틸-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민( S )-2-methyl- N- (4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4 -tetrahydroisoquinolin-7-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.75 (s, 1H), 8.45 (d, J = 2.8 Hz, 1H), 7.39 (q, J = 3.1 Hz, 4H), 7.32 - 7.28 (m, 1H), 7.24 (s, 1H), 7.16 (s, 1H), 6.87 (d, J = 8.3 Hz, 1H), 5.85 (d, J = 7.6 Hz, 1H), 4.29 - 4.25 (m, 1H), 3.80 - 3.76 (m, 2H), 3.60 (s, 1H), 3.05 - 2.94 (m, 2H), 2.88 (t, J = 5.9 Hz, 1H), 2.69 (t, J = 5.9 Hz, 2H), 2.59 (d, J = 5.9 Hz, 1H), 2.26 (s, 3H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.75 (s, 1H), 8.45 (d, J = 2.8 Hz, 1H), 7.39 (q, J = 3.1 Hz, 4H), 7.32 - 7.28 (m) , 1H), 7.24 (s, 1H), 7.16 (s, 1H), 6.87 (d, J = 8.3 Hz, 1H), 5.85 (d, J = 7.6 Hz, 1H), 4.29 - 4.25 (m, 1H) , 3.80 - 3.76 (m, 2H), 3.60 (s, 1H), 3.05 - 2.94 (m, 2H), 2.88 (t, J = 5.9 Hz, 1H), 2.69 (t, J = 5.9 Hz, 2H), 2.59 (d, J = 5.9 Hz, 1H), 2.26 (s, 3H) 456.3
[M+H]+ 456.3
[M+H] +
134134
Figure PCTKR2021018956-appb-img-000168
Figure PCTKR2021018956-appb-img-000168
 		(S)-6-메톡시-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민( S )-6-methoxy- N- (4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3, 4-Tetrahydroisoquinolin-7-amine 1H NMR (400 MHz, DMSO-d6) δ = 8.44 (s, 1H), 8.41 (s, 1H), 7.32 (d, J = 7.2 Hz, 2H), 7.28 - 7.23 (m, 4H), 6.72 (s, 1H), 5.77 - 5.71 (m, 1H), 4.27 (d, J = 2.6 Hz, 1H), 3.78 - 3.75 (m, 1H), 3.72 (s, 3H), 3.56 (d, J = 19.2 Hz, 2H), 2.92 (td, J = 5.1, 2.8 Hz, 4H), 2.67 (t, J = 5.9 Hz, 2H), 2.29 - 2.21 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.44 (s, 1H), 8.41 (s, 1H), 7.32 (d, J = 7.2 Hz, 2H), 7.28 - 7.23 (m, 4H), 6.72 (s, 1H), 5.77 - 5.71 (m, 1H), 4.27 (d, J = 2.6 Hz, 1H), 3.78 - 3.75 (m, 1H), 3.72 (s, 3H), 3.56 (d, J = 19.2) Hz, 2H), 2.92 (td, J = 5.1, 2.8 Hz, 4H), 2.67 (t, J = 5.9 Hz, 2H), 2.29 - 2.21 (m, 1H) 472.3
[M+H]+ 472.3
[M+H] +
135135
Figure PCTKR2021018956-appb-img-000169
Figure PCTKR2021018956-appb-img-000169
 		(S)-6-메톡시-2-메틸-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민( S )-6-methoxy-2-methyl- N- (4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1, 2,3,4-tetrahydroisoquinolin-7-amine 1H NMR (400 MHz, DMSO-d6) δ = 8.42 (s, 1H), 8.38 (s, 1H), 7.38 - 7.32 (m, 2H), 7.29 - 7.23 (m, 4H), 6.73 (s, 1H), 5.76 (s, 1H), 4.30 - 4.24 (m, 1H), 3.79 - 3.74 (m, 2H), 3.73 (s, 3H), 3.03 (s, 2H), 2.95 (ddt, J = 10.2, 7.5, 3.8 Hz, 2H), 2.75 (t, J = 6.0 Hz, 2H), 2.27 (s, 3H), 2.26 - 2.21 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.42 (s, 1H), 8.38 (s, 1H), 7.38 - 7.32 (m, 2H), 7.29 - 7.23 (m, 4H), 6.73 (s, 1H), 5.76 (s, 1H), 4.30 - 4.24 (m, 1H), 3.79 - 3.74 (m, 2H), 3.73 (s, 3H), 3.03 (s, 2H), 2.95 (ddt, J = 10.2, 7.5, 3.8 Hz, 2H), 2.75 (t, J = 6.0 Hz, 2H), 2.27 (s, 3H), 2.26 - 2.21 (m, 1H) 486.3
[M+H]+ 486.3
[M+H] +
136136
Figure PCTKR2021018956-appb-img-000170
Figure PCTKR2021018956-appb-img-000170
 		(S)-6-플루오로-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민( S )-6-fluoro- N- (4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3, 4-Tetrahydroisoquinolin-7-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.37 (s, 1H), 8.42 (s, 1H), 7.32 (dd, J = 8.0, 6.6 Hz, 2H), 7.27 - 7.18 (m, 4H), 7.03 (d, J = 11.2 Hz, 1H), 5.66 (s, 1H), 4.28 (td, J = 7.8, 2.5 Hz, 1H), 3.86 (s, 2H), 3.80 - 3.73 (m, 1H), 3.16 (t, J = 6.1 Hz, 3H), 2.85 (q, J = 7.8, 6.1 Hz, 3H), 2.28 - 2.21 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.37 (s, 1H), 8.42 (s, 1H), 7.32 (dd, J = 8.0, 6.6 Hz, 2H), 7.27 - 7.18 (m, 4H) , 7.03 (d, J = 11.2 Hz, 1H), 5.66 (s, 1H), 4.28 (td, J = 7.8, 2.5 Hz, 1H), 3.86 (s, 2H), 3.80 - 3.73 (m, 1H), 3.16 (t, J = 6.1 Hz, 3H), 2.85 (q, J = 7.8, 6.1 Hz, 3H), 2.28 - 2.21 (m, 1H) 460.2
[M+H]+ 460.2
[M+H] +
137137
Figure PCTKR2021018956-appb-img-000171
Figure PCTKR2021018956-appb-img-000171
 		(S)-6-플루오로-7-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-3,4-다이하이드로아이소퀴놀린-1(2H)-온( S )-6-fluoro-7-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4 -dihydroisoquinolin-1( 2H )-one 1H NMR (400 MHz, DMSO-d6) δ = 9.49 (s, 1H), 8.43 (s, 1H), 7.99 (d, J = 2.8 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.28 - 7.19 (m, 4H), 7.16 (s, 1H), 5.64 (s, 1H), 4.29 (td, J = 7.9, 2.6 Hz, 1H), 3.82 - 3.77 (m, 1H), 3.40 (d, J = 2.7 Hz, 2H), 2.91 (t, J = 6.6 Hz, 2H), 2.84 (d, J = 6.8 Hz, 1H), 2.24 (d, J = 10.1 Hz, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.49 (s, 1H), 8.43 (s, 1H), 7.99 (d, J = 2.8 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H) ), 7.28 - 7.19 (m, 4H), 7.16 (s, 1H), 5.64 (s, 1H), 4.29 (td, J = 7.9, 2.6 Hz, 1H), 3.82 - 3.77 (m, 1H), 3.40 ( d, J = 2.7 Hz, 2H), 2.91 (t, J = 6.6 Hz, 2H), 2.84 (d, J = 6.8 Hz, 1H), 2.24 (d, J = 10.1 Hz, 1H) 474.2
[M+H]+ 474.2
[M+H] +
138138
Figure PCTKR2021018956-appb-img-000172
Figure PCTKR2021018956-appb-img-000172
 		(S)-6-플루오로-2-메틸-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민( S )-6-fluoro-2-methyl- N- (4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1, 2,3,4-tetrahydroisoquinolin-7-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.29 (s, 1H), 8.42 (s, 1H), 7.32 - 7.23 (m, 4H), 7.20 - 7.17 (m, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 11.3 Hz, 1H), 5.63 (s, 1H), 4.31 - 4.25 (m, 1H), 3.76 - 3.74 (m, 1H), 2.89 (dd, J = 6.2, 3.1 Hz, 1H), 2.78 (t, J = 5.9 Hz, 2H), 2.55 (dd, J = 5.9, 2.2 Hz, 2H), 2.30 (s, 3H), 2.26 - 2.21 (m, 1H), 1.78 (s, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.29 (s, 1H), 8.42 (s, 1H), 7.32 - 7.23 (m, 4H), 7.20 - 7.17 (m, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 11.3 Hz, 1H), 5.63 (s, 1H), 4.31 - 4.25 (m, 1H), 3.76 - 3.74 (m, 1H), 2.89 (dd, J ) = 6.2, 3.1 Hz, 1H), 2.78 (t, J = 5.9 Hz, 2H), 2.55 (dd, J = 5.9, 2.2 Hz, 2H), 2.30 (s, 3H), 2.26 - 2.21 (m, 1H) , 1.78 (s, 2H) 474.3
[M+H]+ 474.3
[M+H] +
139139
Figure PCTKR2021018956-appb-img-000173
Figure PCTKR2021018956-appb-img-000173
 		6-메톡시-N2,N2-다이메틸-N5-(4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-2,3-다이하이드로-1H-인덴-2,5-다이아민6-Methoxy- N 2, N 2-dimethyl- N 5-(4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine-2 -yl) -2,3-dihydro-1 H -indene-2,5-diamine 500.4
[M+H]+ 500.4
[M+H] +
140140
Figure PCTKR2021018956-appb-img-000174
Figure PCTKR2021018956-appb-img-000174
 		(S)-5-메톡시-2-메틸-6-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)아이소인돌린-1-온( S )-5-methoxy-2-methyl-6-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino) Isoindolin-1-one 1H NMR (400 MHz, DMSO-d6) δ = 8.61 (s, 1H), 8.46 (s, 1H), 8.04 (s, 1H), 7.33 (d, J = 7.4 Hz, 2H), 7.28 - 7.19 (m, 4H), 5.73 (s, 1H), 4.42 (s, 2H), 4.30 (td, J = 7.9, 2.8 Hz, 1H), 3.83 (s, 3H), 3.81 - 3.76 (m, 1H), 3.09 (s, 3H), 2.84 (s, 1H), 2.28 - 2.20 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.61 (s, 1H), 8.46 (s, 1H), 8.04 (s, 1H), 7.33 (d, J = 7.4 Hz, 2H), 7.28 - 7.19 (m, 4H), 5.73 (s, 1H), 4.42 (s, 2H), 4.30 (td, J = 7.9, 2.8 Hz, 1H), 3.83 (s, 3H), 3.81 - 3.76 (m, 1H), 3.09 (s, 3H), 2.84 (s, 1H), 2.28 - 2.20 (m, 1H) 486.2
[M+H]+ 486.2
[M+H] +
141141
Figure PCTKR2021018956-appb-img-000175
Figure PCTKR2021018956-appb-img-000175
 		(S)-5'-메톡시-6'-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)스파이로[사이클로프로판-1,3'-인돌린]-2'-온( S )-5'-methoxy-6'-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)spiro [Cyclopropane-1,3'-indolin]-2'-one 498.3
[M+H]+ 498.3
[M+H] +
142142
Figure PCTKR2021018956-appb-img-000176
Figure PCTKR2021018956-appb-img-000176
 		(S)-3,3-다이메틸-5-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)아이소벤조퓨란-1(3H)-온( S )-3,3-dimethyl-5-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)isobenzo furan-1( 3H )-one 1H NMR (400 MHz, DMSO-d6) δ = 10.40 (s, 1H), 8.59 (s, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.66 (dd, J = 8.4, 1.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.43 - 7.40 (m, 4H), 7.34 - 7.30 (m, 1H), 5.93 (dd, J = 8.8, 6.0 Hz, 1H), 4.30 (d, J = 2.8 Hz, 1H), 3.90 - 3.83 (m, 1H), 3.06 - 3.00 (m, 1H), 2.37 - 2.29 (m, 1H), 1.44 (s, 3H), 1.33 (s, 3H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 10.40 (s, 1H), 8.59 (s, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.66 (dd, J = 8.4, 1.8 Hz) , 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.43 - 7.40 (m, 4H), 7.34 - 7.30 (m, 1H), 5.93 (dd, J = 8.8, 6.0 Hz, 1H), 4.30 ( d, J = 2.8 Hz, 1H), 3.90 - 3.83 (m, 1H), 3.06 - 3.00 (m, 1H), 2.37 - 2.29 (m, 1H), 1.44 (s, 3H), 1.33 (s, 3H) 471.3
[M+H]+ 471.3
[M+H] +
143143
Figure PCTKR2021018956-appb-img-000177
Figure PCTKR2021018956-appb-img-000177
 		(S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(1H-피라졸-4-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-4-(3- phenylisoxazolidin -2-yl)-N-(1 H -pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine 377.2
[M+H]+ 377.2
[M+H] +
144144
Figure PCTKR2021018956-appb-img-000178
Figure PCTKR2021018956-appb-img-000178
 		(S)-N-(1-메틸-1H-피라졸-3-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N-(1-methyl- 1H -pyrazol-3-yl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine-2 -amine 391.2
[M+H]+ 391.2
[M+H] +
145145
Figure PCTKR2021018956-appb-img-000179
Figure PCTKR2021018956-appb-img-000179
 		(S)-N-(1-메틸-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (1-methyl- 1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine-2 -amine 391.2
[M+H]+ 391.2
[M+H] +
146146
Figure PCTKR2021018956-appb-img-000180
Figure PCTKR2021018956-appb-img-000180
 		(S)-N-(1-아이소프로필-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (1-isopropyl- 1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine- 2-amine 419.2
[M+H]+ 419.2
[M+H] +
147147
Figure PCTKR2021018956-appb-img-000181
Figure PCTKR2021018956-appb-img-000181
 		(S)-N-(1-사이클로프로필-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (1-cyclopropyl- 1H -pyrazol-4-yl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine- 2-amine 419.3
[M+H]+ 419.3
[M+H] +
148148
Figure PCTKR2021018956-appb-img-000182
Figure PCTKR2021018956-appb-img-000182
 		(S)-N-(1-(2,2-다이플루오로에틸)-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N-(1-(2,2-difluoroethyl) -1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine 441.2
[M+H]+ 441.2
[M+H] +
149149
Figure PCTKR2021018956-appb-img-000183
Figure PCTKR2021018956-appb-img-000183
 		(S)-N-메틸-2-(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-1H-피라졸-1-일)아세트아마이드( S ) -N -methyl-2-(4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1 H -pyrazol-1-yl)acetamide 448.2
[M+H]+ 448.2
[M+H] +
150150
Figure PCTKR2021018956-appb-img-000184
Figure PCTKR2021018956-appb-img-000184
 		(S)-N-(1-(2-메톡시에틸)-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N-(1-(2-methoxyethyl) -1H -pyrazol-4-yl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoro methyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.78 (s, 1H), 8.39 (s, 1H), 7.44 - 7.39 (m, 4H), 7.37 (s, 1H), 7.30 (s, 2H), 5.88 - 5.83 (m, 1H), 4.27 (d, J = 7.3 Hz, 1H), 3.97 (d, J = 5.3 Hz, 2H), 3.79 (t, J = 8.4 Hz, 1H), 3.55 - 3.45 (m, 2H), 3.18 (s, 3H), 3.00 (s, 1H), 2.25 - 2.15 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.78 (s, 1H), 8.39 (s, 1H), 7.44 - 7.39 (m, 4H), 7.37 (s, 1H), 7.30 (s, 2H) , 5.88 - 5.83 (m, 1H), 4.27 (d, J = 7.3 Hz, 1H), 3.97 (d, J = 5.3 Hz, 2H), 3.79 (t, J = 8.4 Hz, 1H), 3.55 - 3.45 ( m, 2H), 3.18 (s, 3H), 3.00 (s, 1H), 2.25 - 2.15 (m, 1H) 435.3
[M+H]+ 435.3
[M+H] +
151151
Figure PCTKR2021018956-appb-img-000185
Figure PCTKR2021018956-appb-img-000185
 		(S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(1-(피페리딘-4-일)-1H-피라졸-4-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-4-(3-phenylisoxazolidin-2-yl) -N- (1-(piperidin-4-yl) -1H -pyrazol-4-yl)-5-(tri Fluoromethyl) pyrimidin-2-amine 460.3
[M+H]+ 460.3
[M+H] +
152152
Figure PCTKR2021018956-appb-img-000186
Figure PCTKR2021018956-appb-img-000186
 		(S)-N-(1-(2-몰포리노에틸)-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N-(1-(2-morpholinoethyl) -1H -pyrazol-4-yl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoro methyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.84 (s, 1H), 8.40 (s, 1H), 7.42 (d, J = 3.8 Hz, 4H), 7.35 (s, 1H), 7.31 (t, J = 4.5 Hz, 2H), 5.87 (d, J = 8.1 Hz, 1H), 4.28 (t, J = 7.8 Hz, 1H), 4.10 (s, 2H), 3.83 - 3.79 (m, 1H), 3.68 (s, 4H), 3.37 (s, 5H), 3.01 (s, 2H), 2.21 (s, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.84 (s, 1H), 8.40 (s, 1H), 7.42 (d, J = 3.8 Hz, 4H), 7.35 (s, 1H), 7.31 (t) , J = 4.5 Hz, 2H), 5.87 (d, J = 8.1 Hz, 1H), 4.28 (t, J = 7.8 Hz, 1H), 4.10 (s, 2H), 3.83 - 3.79 (m, 1H), 3.68 (s, 4H), 3.37 (s, 5H), 3.01 (s, 2H), 2.21 (s, 1H) 490.3
[M+H]+ 490.3
[M+H] +
153153
Figure PCTKR2021018956-appb-img-000187
Figure PCTKR2021018956-appb-img-000187
 		(S)-N-(1-(3-(다이에틸아미노)프로필)-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(1-(3-( diethylamino )propyl) -1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine 490.4
[M+H]+ 490.4
[M+H] +
154154
Figure PCTKR2021018956-appb-img-000188
Figure PCTKR2021018956-appb-img-000188
 		4-((S)-3-페닐아이소옥사졸리딘-2-일)-N-(1-(((R)-테트라하이드로퓨란-2-일)메틸)-1H-피라졸-4-일)-5-(트라이플루오로메틸)피리미딘-2-아민4-(( S )-3- phenylisoxazolidin -2-yl)-N-(1-((( R )-tetrahydrofuran-2-yl)methyl) -1H -pyrazole-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine 461.3
[M+H]+ 461.3
[M+H] +
155155
Figure PCTKR2021018956-appb-img-000189
Figure PCTKR2021018956-appb-img-000189
 		tert-부틸 (S)-3-((4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-1H-피라졸-1-일)메틸)아제티딘-1-카복실레이트 tert -Butyl ( S )-3-((4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1 H -pyrazol-1-yl)methyl)azetidine-1-carboxylate 546.4
[M+H]+ 546.4
[M+H] +
156156
Figure PCTKR2021018956-appb-img-000190
Figure PCTKR2021018956-appb-img-000190
 		(S)-N-(1-(아제티딘-3-일메틸)-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N-(1-(azetidin-3-ylmethyl) -1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl)-5-(tri Fluoromethyl) pyrimidin-2-amine 446.3
[M+H]+ 446.3
[M+H] +
157157
Figure PCTKR2021018956-appb-img-000191
Figure PCTKR2021018956-appb-img-000191
 		(S)-6-메틸-2-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-5,6-다이하이드로-4H-피라졸로[1,5-d][1,4]다이아제핀-7(8H)-온( S )-6-methyl-2-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5,6- Dihydro- 4H -pyrazolo[1,5- d ][1,4]diazepin-7( 8H )-one 1H NMR (400 MHz, DMSO-d6) δ = 10.03 (s, 1H), 8.41 (s, 1H), 7.40 (d, J = 4.7 Hz, 4H), 7.34 (t, J = 1.4 Hz, 1H), 7.32 - 7.26 (m, 1H), 5.79 (d, J = 9.1 Hz, 1H), 4.88 (d, J = 4.2 Hz, 2H), 4.29 (td, J = 7.8, 2.2 Hz, 1H), 3.82 - 3.76 (m, 3H), 3.35 (s, 2H), 2.98 (s, 1H), 2.94 (s, 3H), 2.23 - 2.15 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 10.03 (s, 1H), 8.41 (s, 1H), 7.40 (d, J = 4.7 Hz, 4H), 7.34 (t, J = 1.4 Hz, 1H) ), 7.32 - 7.26 (m, 1H), 5.79 (d, J = 9.1 Hz, 1H), 4.88 (d, J = 4.2 Hz, 2H), 4.29 (td, J = 7.8, 2.2 Hz, 1H), 3.82 - 3.76 (m, 3H), 3.35 (s, 2H), 2.98 (s, 1H), 2.94 (s, 3H), 2.23 - 2.15 (m, 1H) 474.3
[M+H]+ 474.3
[M+H] +
158158
Figure PCTKR2021018956-appb-img-000192
Figure PCTKR2021018956-appb-img-000192
 		(S)-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-4-(피페리딘-4-일)싸이아졸-2-아민( S )-N-(4-(3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-4-(piperidin-4-yl) Thiazol-2-amine 477.2
[M+H]+ 477.2
[M+H] +
159159
Figure PCTKR2021018956-appb-img-000193
Figure PCTKR2021018956-appb-img-000193
 		tert-부틸 (S)-2-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-6,7-다이하이드로싸이아졸로[5,4-c]피리딘-5(4H)-카복실레이트 tert -Butyl ( S )-2-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6,7-di Hydrothiazolo[5,4-c]pyridine-5( 4H )-carboxylate 1H NMR (400 MHz, Methanol-d 4) δ 8.53 (s, 1H), 7.47 - 7.24 (m, 9H), 6.02 (dd, J = 8.8, 6.2 Hz, 1H), 4.39 (s, 2H), 4.31 (td, J = 7.8, 3.0 Hz, 2H), 3.95 (ddd, J = 9.7, 8.1, 6.4 Hz, 1H), 3.75 - 3.64 (m, 3H), 3.05 (dddd, J = 11.8, 9.0, 6.4, 2.7 Hz, 1H), 2.63 (t, J = 5.9 Hz, 2H), 2.55 (ddt, J = 5.8, 3.7, 2.1 Hz, 1H), 2.41 - 2.32 (m, 1H), 1.52 (s, 9H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.53 (s, 1H), 7.47 - 7.24 (m, 9H), 6.02 (dd, J = 8.8, 6.2 Hz, 1H), 4.39 (s, 2H), 4.31 (td, J = 7.8, 3.0 Hz, 2H), 3.95 (ddd, J = 9.7, 8.1, 6.4 Hz, 1H), 3.75 - 3.64 (m, 3H), 3.05 (dddd, J = 11.8, 9.0, 6.4 , 2.7 Hz, 1H), 2.63 (t, J = 5.9 Hz, 2H), 2.55 (ddt, J = 5.8, 3.7, 2.1 Hz, 1H), 2.41 - 2.32 (m, 1H), 1.52 (s, 9H) 549.4
[M+H]+ 549.4
[M+H] +
160160
Figure PCTKR2021018956-appb-img-000194
Figure PCTKR2021018956-appb-img-000194
 		(S)-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-4,5,6,7-테트라하이드로싸이아졸로[5,4-c]피리딘-2-아민(S)-N-(4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydrothio Azolo[5,4-c]pyridin-2-amine 1H NMR (400 MHz, Methanol-d 4) δ 8.60 (s, 1H), 7.45 - 7.35 (m, 4H), 7.33 - 7.26 (m, 1H), 6.02 (dd, J = 8.8, 6.0 Hz, 1H), 4.36 - 4.26 (m, 2H), 4.19 - 4.07 (m, 1H), 3.98 (ddd, J = 9.6, 8.2, 6.7 Hz, 1H), 3.57 - 3.46 (m, 2H), 3.05 (dddd, J = 12.0, 9.3, 6.6, 3.0 Hz, 1H), 2.96 (tt, J = 6.4, 2.0 Hz, 2H), 2.38 (dddd, J = 12.0, 9.6, 7.6, 6.0 Hz, 1H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.60 (s, 1H), 7.45 - 7.35 (m, 4H), 7.33 - 7.26 (m, 1H), 6.02 (dd, J = 8.8, 6.0 Hz, 1H) ), 4.36 - 4.26 (m, 2H), 4.19 - 4.07 (m, 1H), 3.98 (ddd, J = 9.6, 8.2, 6.7 Hz, 1H), 3.57 - 3.46 (m, 2H), 3.05 (dddd, J = 12.0, 9.3, 6.6, 3.0 Hz, 1H), 2.96 (tt, J = 6.4, 2.0 Hz, 2H), 2.38 (dddd, J = 12.0, 9.6, 7.6, 6.0 Hz, 1H) 449.3
[M+H]+ 449.3
[M+H] +
161161
Figure PCTKR2021018956-appb-img-000195
Figure PCTKR2021018956-appb-img-000195
 		(S)-5-메틸-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-4,5,6,7-테트라하이드로싸이아졸로[5,4-c]피리딘-2-아민( S )-5-methyl- N- (4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7 -tetrahydrothiazolo[5,4-c]pyridin-2-amine 463.2
[M+H]+ 463.2
[M+H] +
162162
Figure PCTKR2021018956-appb-img-000196
Figure PCTKR2021018956-appb-img-000196
 		메틸 (S)-5-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)싸이오펜-2-카복실레이트methyl ( S )-5-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)thiophene-2-carboxylate 451.2
[M+H]+ 451.2
[M+H] +
163163
Figure PCTKR2021018956-appb-img-000197
Figure PCTKR2021018956-appb-img-000197
 		(S)-1-(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)에탄-1-온( S )-1-(4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)ethane-1- On 429.2
[M+H]+ 429.2
[M+H] +
164164
Figure PCTKR2021018956-appb-img-000198
Figure PCTKR2021018956-appb-img-000198
 		(S)-페닐(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)메탄온( S )-phenyl(4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)methanone 491.2
[M+H]+ 491.2
[M+H] +
165165
Figure PCTKR2021018956-appb-img-000199
Figure PCTKR2021018956-appb-img-000199
 		(S)-N,N-다이메틸-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤즈아마이드( S ) -N , N -dimethyl-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide 458.2
[M+H]+ 458.2
[M+H] +
166166
Figure PCTKR2021018956-appb-img-000200
Figure PCTKR2021018956-appb-img-000200
 		(S)-(4-메틸피페라진-1-일)(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)메탄온( S )-(4-methylpiperazin-1-yl)(4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl )amino)phenyl)methanone 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 15.8 Hz, 1H), 7.76 (d, J = 7.8 Hz, 2H), 7.46 - 7.28 (m, 7H), 7.20 (dd, J = 8.4, 3.5 Hz, 4H), 5.71 (dd, J = 8.7, 6.4 Hz, 1H), 4.35 (td, J = 7.8, 3.1 Hz, 1H), 3.96 (td, J = 8.8, 6.4 Hz, 2H), 2.98 - 2.82 (m, 4H), 2.36 (s, 5H) 1 H NMR (400 MHz, CDCl 3 ) δ 8.32 (d, J = 15.8 Hz, 1H), 7.76 (d, J = 7.8 Hz, 2H), 7.46 - 7.28 (m, 7H), 7.20 (dd, J = 8.4, 3.5 Hz, 4H), 5.71 (dd, J = 8.7, 6.4 Hz, 1H), 4.35 (td, J = 7.8, 3.1 Hz, 1H), 3.96 (td, J = 8.8, 6.4 Hz, 2H), 2.98 - 2.82 (m, 4H), 2.36 (s, 5H) 513.4
[M+H]+ 513.4
[M+H] +
167167
Figure PCTKR2021018956-appb-img-000201
Figure PCTKR2021018956-appb-img-000201
 		(S)-N-(2-하이드록시에틸)-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤즈아마이드( S ) -N-(2-hydroxyethyl)-4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) benzamide 1H NMR (400 MHz, Methanol-d 4) δ 8.42 (s, 1H), 7.68 - 7.62 (m, 2H), 7.53 - 7.47 (m, 2H), 7.47 - 7.40 (m, 4H), 7.31 (tt, J = 5.1, 3.3 Hz, 1H), 5.82 (dd, J = 8.7, 6.7 Hz, 1H), 4.30 (td, J = 7.8, 2.6 Hz, 1H), 3.91 (ddd, J = 10.0, 8.1, 6.3 Hz, 1H), 3.74 (t, J = 5.8 Hz, 2H), 3.52 (t, J = 5.9 Hz, 2H), 2.96 (dddd, J = 11.7, 8.9, 6.3, 2.6 Hz, 1H), 2.31 (ddt, J = 12.0, 10.0, 7.2 Hz, 1H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.42 (s, 1H), 7.68 - 7.62 (m, 2H), 7.53 - 7.47 (m, 2H), 7.47 - 7.40 (m, 4H), 7.31 (tt , J = 5.1, 3.3 Hz, 1H), 5.82 (dd, J = 8.7, 6.7 Hz, 1H), 4.30 (td, J = 7.8, 2.6 Hz, 1H), 3.91 (ddd, J = 10.0, 8.1, 6.3) Hz, 1H), 3.74 (t, J = 5.8 Hz, 2H), 3.52 (t, J = 5.9 Hz, 2H), 2.96 (dddd, J = 11.7, 8.9, 6.3, 2.6 Hz, 1H), 2.31 (ddt) , J = 12.0, 10.0, 7.2 Hz, 1H) 474.2
[M+H]+ 474.2
[M+H] +
168168
Figure PCTKR2021018956-appb-img-000202
Figure PCTKR2021018956-appb-img-000202
 		(S)-N-(3-하이드록시프로필)-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤즈아마이드( S ) -N- (3-hydroxypropyl)-4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) benzamide 1H NMR (400 MHz, Methanol-d 4) δ 8.42 (s, 1H), 7.69 - 7.57 (m, 2H), 7.54 - 7.37 (m, 6H), 7.32 (tt, J = 5.2, 3.2 Hz, 1H), 5.83 (dd, J = 8.7, 6.7 Hz, 1H), 4.31 (td, J = 7.7, 2.6 Hz, 1H), 3.91 (ddd, J = 10.0, 8.1, 6.3 Hz, 1H), 3.69 (t, J = 6.3 Hz, 2H), 3.49 (t, J = 6.9 Hz, 2H), 2.97 (dddd, J = 11.7, 8.8, 6.2, 2.7 Hz, 1H), 2.40 - 2.23 (m, 1H), 1.86 (p, J = 6.6 Hz, 2H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.42 (s, 1H), 7.69 - 7.57 (m, 2H), 7.54 - 7.37 (m, 6H), 7.32 (tt, J = 5.2, 3.2 Hz, 1H ), 5.83 (dd, J = 8.7, 6.7 Hz, 1H), 4.31 (td, J = 7.7, 2.6 Hz, 1H), 3.91 (ddd, J = 10.0, 8.1, 6.3 Hz, 1H), 3.69 (t, J = 6.3 Hz, 2H), 3.49 (t, J = 6.9 Hz, 2H), 2.97 (dddd, J = 11.7, 8.8, 6.2, 2.7 Hz, 1H), 2.40 - 2.23 (m, 1H), 1.86 (p , J = 6.6 Hz, 2H) 488.2
[M+H]+ 488.2
[M+H] +
169169
Figure PCTKR2021018956-appb-img-000203
Figure PCTKR2021018956-appb-img-000203
 		(S)-N-(2-(메틸아미노)에틸)-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤즈아마이드( S )-N-(2-(methylamino)ethyl)-4-((4-(3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl)pyrimidin-2-yl ) amino) benzamide 487.2
[M+H]+ 487.2
[M+H] +
170170
Figure PCTKR2021018956-appb-img-000204
Figure PCTKR2021018956-appb-img-000204
 		이미노(메틸)(4-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)-λ6-설판온imino(methyl)(4-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)- λ 6 -sulfanone 463.5
[M+H]+ 463.5
[M+H] +
171171
Figure PCTKR2021018956-appb-img-000205
Figure PCTKR2021018956-appb-img-000205
 		1-(4-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)-4,5-다이하이드로-3H-아이소싸이아졸 1-옥사이드1-(4-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-4,5 -dihydro-3 H -isothiazole 1-oxide 490.2
[M+H]+ 490.2
[M+H] +
172172
Figure PCTKR2021018956-appb-img-000206
Figure PCTKR2021018956-appb-img-000206
 		(S)-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤젠설포닐 플로라이드( S )-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonyl fluoride 467.2
[M+H]+ 467.2
[M+H] +
173173
Figure PCTKR2021018956-appb-img-000207
Figure PCTKR2021018956-appb-img-000207
 		(S)-N,N-다이메틸-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤젠설폰아마이드( S ) -N , N -dimethyl-4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfone amide 494.2
[M+H]+ 494.2
[M+H] +
174174
Figure PCTKR2021018956-appb-img-000208
Figure PCTKR2021018956-appb-img-000208
 		(S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(3-(피리딘-3-일)페닐)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-4-(3- phenylisoxazolidin -2-yl)-N-(3-(pyridin-3-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.94 (s, 1H), 8.82 (d, J = 2.3 Hz, 1H), 8.61 - 8.57 (m, 1H), 8.51 (s, 1H), 7.97 (dt, J = 7.9, 2.0 Hz, 1H), 7.81 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.47 (dd, J = 7.9, 4.7 Hz, 1H), 7.35 - 7.22 (m, 7H), 5.84 (t, J = 7.6 Hz, 1H), 4.29 (td, J = 7.8, 2.6 Hz, 1H), 3.83 (ddd, J = 9.7, 8.0, 6.6 Hz, 1H), 2.94 (dtt, J = 9.0, 6.4, 3.3 Hz, 1H), 2.21 (ddd, J = 10.6, 6.8, 3.4 Hz, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.94 (s, 1H), 8.82 (d, J = 2.3 Hz, 1H), 8.61 - 8.57 (m, 1H), 8.51 (s, 1H), 7.97 (dt, J = 7.9, 2.0 Hz, 1H), 7.81 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.47 (dd, J = 7.9, 4.7 Hz, 1H), 7.35 - 7.22 ( m, 7H), 5.84 (t, J = 7.6 Hz, 1H), 4.29 (td, J = 7.8, 2.6 Hz, 1H), 3.83 (ddd, J = 9.7, 8.0, 6.6 Hz, 1H), 2.94 (dtt) , J = 9.0, 6.4, 3.3 Hz, 1H), 2.21 (ddd, J = 10.6, 6.8, 3.4 Hz, 1H) 464.3
[M+H]+ 464.3
[M+H] +
175175
Figure PCTKR2021018956-appb-img-000209
Figure PCTKR2021018956-appb-img-000209
 		(S)-N-(3-메톡시-5-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(3-methoxy-5-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoro methyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ= 9.62 (s, 1H), 8.49 (s, 1H), 7.40 (d, J = 7.2 Hz, 2H), 7.37 - 7.32 (m, 2H), 7.29 - 7.24 (m, 1H), 6.79 (d, J = 27.8 Hz, 2H), 6.16 (t, J = 2.2 Hz, 1H), 5.97 (dd, J = 8.8, 5.2 Hz, 1H), 4.25 (d, J = 3.2 Hz, 1H), 3.82 - 3.77 (m, 1H), 3.62 (s, 3H), 3.05 (dd, J = 6.6, 3.8 Hz, 4H), 2.92 - 2.83 (m, 1H), 2.38 (t, J = 5.0 Hz, 4H), 2.33 - 2.27 (m, 1H), 2.19 (s, 3H), 1.52 - 1.41 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.62 (s, 1H), 8.49 (s, 1H), 7.40 (d, J = 7.2 Hz, 2H), 7.37 - 7.32 (m, 2H), 7.29 - 7.24 (m, 1H), 6.79 (d, J = 27.8 Hz, 2H), 6.16 (t, J = 2.2 Hz, 1H), 5.97 (dd, J = 8.8, 5.2 Hz, 1H), 4.25 (d, J = 3.2 Hz, 1H), 3.82 - 3.77 (m, 1H), 3.62 (s, 3H), 3.05 (dd, J = 6.6, 3.8 Hz, 4H), 2.92 - 2.83 (m, 1H), 2.38 (t) , J = 5.0 Hz, 4H), 2.33 - 2.27 (m, 1H), 2.19 (s, 3H), 1.52 - 1.41 (m, 1H) 515.4
[M+H]+ 515.4
[M+H] +
176176
Figure PCTKR2021018956-appb-img-000210
Figure PCTKR2021018956-appb-img-000210
 		(S)-N-(3-(4-메틸피페라진-1-일)-5-(트라이플루오로메틸)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(3-(4-methylpiperazin- 1 -yl)-5-(trifluoromethyl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, Methanol-d 4) δ 8.54 (s, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.49 - 7.34 (m, 5H), 7.34 - 7.27 (m, 1H), 6.92 (t, J = 1.8 Hz, 1H), 6.06 (dd, J = 8.8, 5.0 Hz, 1H), 4.28 (td, J = 7.9, 3.6 Hz, 1H), 3.96 (dt, J = 8.7, 7.6 Hz, 1H), 3.27 (td, J = 4.5, 1.7 Hz, 4H), 2.92 (dddd, J = 12.3, 8.8, 7.4, 3.7 Hz, 1H), 2.61 (t, J = 5.0 Hz, 4H), 2.46 (ddt, J = 11.9, 8.2, 4.2 Hz, 1H), 2.39 (s, 3H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.54 (s, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.49 - 7.34 (m, 5H), 7.34 - 7.27 (m, 1H), 6.92 (t, J = 1.8 Hz, 1H), 6.06 (dd, J = 8.8, 5.0 Hz, 1H), 4.28 (td, J = 7.9, 3.6 Hz, 1H), 3.96 (dt, J = 8.7, 7.6 Hz) , 1H), 3.27 (td, J = 4.5, 1.7 Hz, 4H), 2.92 (dddd, J = 12.3, 8.8, 7.4, 3.7 Hz, 1H), 2.61 (t, J = 5.0 Hz, 4H), 2.46 ( ddt, J = 11.9, 8.2, 4.2 Hz, 1H), 2.39 (s, 3H) 552.5
[M+H]+ 552.5
[M+H] +
177177
Figure PCTKR2021018956-appb-img-000211
Figure PCTKR2021018956-appb-img-000211
 		(S)-N-(3-((4-메틸피페라진-1-일)메틸)-5-(트라이플루오로메틸)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-N-(3-((4-methylpiperazin- 1 -yl)methyl)-5-(trifluoromethyl)phenyl)-4-(3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-amine 566.6
[M+H]+ 566.6
[M+H] +
178178
Figure PCTKR2021018956-appb-img-000212
Figure PCTKR2021018956-appb-img-000212
 		(S)-2-메틸-2-(3-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)프로판나이트릴( S )-2-methyl-2-(3-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl) propanenitrile 453.5
[M+H]+ 453.5
[M+H] +
179179
Figure PCTKR2021018956-appb-img-000213
Figure PCTKR2021018956-appb-img-000213
 		(S)-2-메틸-2-(3-(4-메틸피페라진-1-일)-5-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)프로판나이트릴( S )-2-methyl-2-(3-(4-methylpiperazin-1-yl)-5-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoro Rhomethyl)pyrimidin-2-yl)amino)phenyl)propanenitrile 1H NMR (400 MHz, Methanol-d 4) δ 8.32 (s, 1H), 7.30 - 7.24 (m, 2H), 7.24 - 7.17 (m, 2H), 7.16 - 7.10 (m, 2H), 7.03 (t, J = 2.0 Hz, 1H), 6.66 (t, J = 2.0 Hz, 1H), 5.96 (dd, J = 8.8, 5.0 Hz, 1H), 4.13 - 4.05 (m, 1H), 3.77 (dt, J = 8.8, 7.7 Hz, 1H), 3.11 - 3.04 (m, 4H), 2.76 (dddd, J = 12.2, 8.8, 7.5, 3.6 Hz, 1H), 2.46 (t, J = 5.1 Hz, 4H), 2.36 - 2.27 (m, 1H), 2.24 (s, 3H), 1.52 (d, J = 9.4 Hz, 6H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.32 (s, 1H), 7.30 - 7.24 (m, 2H), 7.24 - 7.17 (m, 2H), 7.16 - 7.10 (m, 2H), 7.03 (t) , J = 2.0 Hz, 1H), 6.66 (t, J = 2.0 Hz, 1H), 5.96 (dd, J = 8.8, 5.0 Hz, 1H), 4.13 - 4.05 (m, 1H), 3.77 (dt, J = 8.8, 7.7 Hz, 1H), 3.11 - 3.04 (m, 4H), 2.76 (dddd, J = 12.2, 8.8, 7.5, 3.6 Hz, 1H), 2.46 (t, J = 5.1 Hz, 4H), 2.36 - 2.27 (m, 1H), 2.24 (s, 3H), 1.52 (d, J = 9.4 Hz, 6H) 551.6
[M+H]+ 551.6
[M+H] +
180180
Figure PCTKR2021018956-appb-img-000214
Figure PCTKR2021018956-appb-img-000214
 		(S)-2-메틸-2-(3-((4-메틸피페라진-1-일)메틸)-5-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)프로판나이트릴( S )-2-methyl-2-(3-((4-methylpiperazin-1-yl)methyl)-5-((4-(3-phenylisoxazolidin-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)propanenitrile 565.6
[M+H]+ 565.6
[M+H] +
181181
Figure PCTKR2021018956-appb-img-000215
Figure PCTKR2021018956-appb-img-000215
 		N-(3-((1R,4R)-5-메틸-2,5-다이아자바이사이클로[2.2.1]헵탄-2-일)-5-(메틸설포닐)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민 N -(3-((1 R ,4 R )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-(methylsulfonyl)phenyl)-4-( ( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, Methanol-d 4) δ 8.45 (s, 1H), 7.67 (t, J = 1.7 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.26 - 7.18 (m, 1H), 6.97 (t, J = 2.1 Hz, 1H), 6.75 (t, J = 1.9 Hz, 1H), 6.08 (dd, J = 8.8, 4.9 Hz, 1H), 4.20 (p, J = 4.1 Hz, 2H), 3.90 (q, J = 8.0 Hz, 1H), 3.50 (d, J = 2.3 Hz, 1H), 3.36 (dd, J = 9.5, 2.4 Hz, 1H), 3.29 - 3.23 (m, 1H), 3.00 (s, 3H), 2.95 - 2.83 (m, 1H), 2.80 - 2.64 (m, 2H), 2.46 - 2.30 (m, 4H), 1.99 - 1.79 (m, 2H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.45 (s, 1H), 7.67 (t, J = 1.7 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.26 - 7.18 (m, 1H), 6.97 (t, J = 2.1 Hz, 1H), 6.75 (t, J = 1.9 Hz, 1H), 6.08 (dd, J = 8.8, 4.9 Hz, 1H), 4.20 (p, J = 4.1 Hz, 2H), 3.90 (q, J = 8.0 Hz, 1H), 3.50 (d, J = 2.3 Hz, 1H), 3.36 (dd, J = 9.5, 2.4 Hz, 1H), 3.29 - 3.23 (m, 1H), 3.00 (s, 3H), 2.95 - 2.83 (m, 1H), 2.80 - 2.64 (m, 2H), 2.46 - 2.30 (m, 4H), 1.99 - 1.79 (m, 2H) ) 574.6
[M+H]+ 574.6
[M+H] +
182182
Figure PCTKR2021018956-appb-img-000216
Figure PCTKR2021018956-appb-img-000216
 		N-(3-((1S,4S)-5-메틸-2,5-다이아자바이사이클로[2.2.1]헵탄-2-일)-5-(메틸설포닐)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민 N -(3-(( 1S , 4S )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-(methylsulfonyl)phenyl)-4-( ( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 574.6
[M+H]+ 574.6
[M+H] +
183183
Figure PCTKR2021018956-appb-img-000217
Figure PCTKR2021018956-appb-img-000217
 		(S)-N-(3-(4-(4-메틸피페라진-1-일)피페리딘-1-일)-5-(메틸설포닐)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N-(3-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-(methylsulfonyl)phenyl)-4-(3-phenylisooxa Jolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, Methanol-d 4) δ 8.46 (s, 1H), 7.81 (t, J = 1.7 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.32 (dd, J = 8.3, 6.6 Hz, 3H), 7.27 - 7.20 (m, 1H), 7.12 (t, J = 1.9 Hz, 1H), 6.08 (dd, J = 8.8, 4.9 Hz, 1H), 4.23 (td, J = 7.9, 3.7 Hz, 1H), 3.92 (q, J = 8.0 Hz, 1H), 3.85 - 3.70 (m, 2H), 3.01 (s, 3H), 2.96 - 2.87 (m, 1H), 2.81 - 2.32 (m, 12H), 2.30 (s, 3H), 2.01 - 1.85 (m, 2H), 1.63 - 1.44 (m, 2H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.46 (s, 1H), 7.81 (t, J = 1.7 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.32 (dd, J = 8.3, 6.6 Hz, 3H), 7.27 - 7.20 (m, 1H), 7.12 (t, J = 1.9 Hz, 1H), 6.08 (dd, J = 8.8, 4.9 Hz, 1H), 4.23 (td, J = 7.9, 3.7 Hz) , 1H), 3.92 (q, J = 8.0 Hz, 1H), 3.85 - 3.70 (m, 2H), 3.01 (s, 3H), 2.96 - 2.87 (m, 1H), 2.81 - 2.32 (m, 12H), 2.30 (s, 3H), 2.01 - 1.85 (m, 2H), 1.63 - 1.44 (m, 2H) 645.7
[M+H]+ 645.7
[M+H] +
184184
Figure PCTKR2021018956-appb-img-000218
Figure PCTKR2021018956-appb-img-000218
 		N-(2-플루오로-5-((1R,4R)-5-메틸-2,5-다이아자바이사이클로[2.2.1]헵탄-2-일)피리딘-3-일)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민 N -(2-fluoro-5-((1 R ,4 R )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-4- (( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, Methanol-d 4) δ 8.44 (s, 1H), 7.57 (dd, J = 8.6, 2.7 Hz, 1H), 7.39 - 7.21 (m, 5H), 7.18 (t, J = 2.6 Hz, 1H), 5.88 (dd, J = 8.7, 5.6 Hz, 1H), 4.28 - 4.19 (m, 1H), 4.03 (s, 1H), 3.90 (ddd, J = 9.2, 8.0, 7.1 Hz, 1H), 3.55 (d, J = 2.7 Hz, 1H), 3.22 - 3.17 (m, 1H), 2.89 (dddd, J = 12.1, 8.8, 7.1, 3.3 Hz, 1H), 2.73 (d, J = 1.9 Hz, 2H), 2.45 - 2.34 (m, 4H), 1.99 - 1.85 (m, 2H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.44 (s, 1H), 7.57 (dd, J = 8.6, 2.7 Hz, 1H), 7.39 - 7.21 (m, 5H), 7.18 (t, J = 2.6) Hz, 1H), 5.88 (dd, J = 8.7, 5.6 Hz, 1H), 4.28 - 4.19 (m, 1H), 4.03 (s, 1H), 3.90 (ddd, J = 9.2, 8.0, 7.1 Hz, 1H) , 3.55 (d, J = 2.7 Hz, 1H), 3.22 - 3.17 (m, 1H), 2.89 (dddd, J = 12.1, 8.8, 7.1, 3.3 Hz, 1H), 2.73 (d, J = 1.9 Hz, 2H) ), 2.45 - 2.34 (m, 4H), 1.99 - 1.85 (m, 2H) 515.5
[M+H]+ 515.5
[M+H] +
185185
Figure PCTKR2021018956-appb-img-000219
Figure PCTKR2021018956-appb-img-000219
 		N-(3-(3,3-다이플루오로피롤리딘-1-일)-5-((R)-피롤리딘-3-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민 N- (3-(3,3-difluoropyrrolidin-1-yl)-5-(( R )-pyrrolidin-3-yl)phenyl)-4-(( S )-3-phenyl Isooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.62 (s, 1H), 8.49 (s, 1H), 7.35 (d, J = 4.5 Hz, 4H), 7.28 (d, J = 4.4 Hz, 1H), 6.89 (s, 1H), 6.18 (t, J = 1.8 Hz, 1H), 5.99 (dd, J = 8.8, 5.2 Hz, 1H), 4.22 (d, J = 3.2 Hz, 1H), 3.81 - 3.76 (m, 2H), 3.27 (s, 3H), 3.10 (d, J = 4.8 Hz, 1H), 3.04 - 3.00 (m, 1H), 2.91 (dd, J = 8.0, 3.3 Hz, 2H), 2.88 (d, J = 3.0 Hz, 1H), 2.70 - 2.63 (m, 1H), 2.41 (dt, J = 15.3, 7.6 Hz, 2H), 2.33 (td, J = 5.2, 2.6 Hz, 1H), 2.07 - 2.01 (m, 1H), 1.70 (dt, J = 12.3, 8.6 Hz, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.62 (s, 1H), 8.49 (s, 1H), 7.35 (d, J = 4.5 Hz, 4H), 7.28 (d, J = 4.4 Hz, 1H) ), 6.89 (s, 1H), 6.18 (t, J = 1.8 Hz, 1H), 5.99 (dd, J = 8.8, 5.2 Hz, 1H), 4.22 (d, J = 3.2 Hz, 1H), 3.81 - 3.76 (m, 2H), 3.27 (s, 3H), 3.10 (d, J = 4.8 Hz, 1H), 3.04 - 3.00 (m, 1H), 2.91 (dd, J = 8.0, 3.3 Hz, 2H), 2.88 ( d, J = 3.0 Hz, 1H), 2.70 - 2.63 (m, 1H), 2.41 (dt, J = 15.3, 7.6 Hz, 2H), 2.33 (td, J = 5.2, 2.6 Hz, 1H), 2.07 - 2.01 (m, 1H), 1.70 (dt, J = 12.3, 8.6 Hz, 2H) 561.4
[M+H]+ 561.4
[M+H] +
186186
Figure PCTKR2021018956-appb-img-000220
Figure PCTKR2021018956-appb-img-000220
 		N-(3-(3,3-다이플루오로피롤리딘-1-일)-5-((S)-피롤리딘-3-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민 N- (3-(3,3-difluoropyrrolidin-1-yl)-5-(( S )-pyrrolidin-3-yl)phenyl)-4-(( S )-3-phenyl Isooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ= 9.66 (s, 1H), 8.50 (s, 1H), 7.36 (d, J = 4.5 Hz, 4H), 7.28 (d, J = 4.4 Hz, 1H), 6.92 (s, 1H), 6.71 (s, 1H), 6.22 (t, J = 1.7 Hz, 1H), 5.99 (dd, J = 8.8, 5.3 Hz, 1H), 4.22 (dt, J = 7.9, 4.0 Hz, 1H), 3.78 (d, J = 1.6 Hz, 1H), 3.59 (t, J = 13.3 Hz, 2H), 3.35 - 3.24 (m, 3H), 3.16 (d, J = 10.4 Hz, 1H), 2.93 (ddt, J = 12.6, 8.7, 4.1 Hz, 2H), 2.44 (t, J = 7.2 Hz, 1H), 2.36 - 2.29 (m, 1H), 2.01 (d, J = 10.7 Hz, 1H), 1.84 (s, 4H), 1.77 - 1.69 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.66 (s, 1H), 8.50 (s, 1H), 7.36 (d, J = 4.5 Hz, 4H), 7.28 (d, J = 4.4 Hz, 1H) ), 6.92 (s, 1H), 6.71 (s, 1H), 6.22 (t, J = 1.7 Hz, 1H), 5.99 (dd, J = 8.8, 5.3 Hz, 1H), 4.22 (dt, J = 7.9, 4.0 Hz, 1H), 3.78 (d, J = 1.6 Hz, 1H), 3.59 (t, J = 13.3 Hz, 2H), 3.35 - 3.24 (m, 3H), 3.16 (d, J = 10.4 Hz, 1H) , 2.93 (ddt, J = 12.6, 8.7, 4.1 Hz, 2H), 2.44 (t, J = 7.2 Hz, 1H), 2.36 - 2.29 (m, 1H), 2.01 (d, J = 10.7 Hz, 1H), 1.84 (s, 4H), 1.77 - 1.69 (m, 1H) 561.4
[M+H]+ 561.4
[M+H] +
187187
Figure PCTKR2021018956-appb-img-000221
Figure PCTKR2021018956-appb-img-000221
 		(S)-N-(2-메톡시-5-(1-메틸-1H-피라졸-4-일)-4-몰포리노페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (2-methoxy-5-(1-methyl-1 H -pyrazol-4-yl)-4-morpholinophenyl)-4-(3-phenylisoxazolidine-2- yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 8.05 (d, J = 34.8 Hz, 3H), 7.38 (s, 1H), 7.22 (t, J = 7.3 Hz, 1H), 7.15 (t, J = 7.4 Hz, 2H), 6.83 (d, J = 7.5 Hz, 2H), 6.79 (s, 1H), 5.50 (s, 1H), 4.48 (s, 1H), 4.19 (s, 3H), 3.86 (t, J = 4.3 Hz, 4H), 3.72 (s, 3H), 2.99 (d, J = 4.7 Hz, 5H), 2.42 (d, J = 11.0 Hz, 1H), 2.08 (s, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.88 (s, 1H), 8.05 (d, J = 34.8 Hz, 3H), 7.38 (s, 1H), 7.22 (t, J = 7.3 Hz, 1H), 7.15 (t, J = 7.4 Hz, 2H), 6.83 (d, J = 7.5 Hz, 2H), 6.79 (s, 1H), 5.50 (s, 1H), 4.48 (s, 1H), 4.19 (s, 3H) , 3.86 (t, J = 4.3 Hz, 4H), 3.72 (s, 3H), 2.99 (d, J = 4.7 Hz, 5H), 2.42 (d, J = 11.0 Hz, 1H), 2.08 (s, 1H) . 582.4
[M+H]+ 582.4
[M+H] +
188188
Figure PCTKR2021018956-appb-img-000222
Figure PCTKR2021018956-appb-img-000222
 		(S)-N-(2-메톡시-5-(1-메틸-1H-피라졸-4-일)-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (2-methoxy-5-(1-methyl-1 H -pyrazol-4-yl)-4-(4-(4-methylpiperazin-1-yl)piperidin- 1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.96 (s, 1H), 7.78 (s, 1H), 7.68 (s, 1H), 7.18 (d, J = 25.1 Hz, 4H), 6.58 (s, 1H), 5.83 (s, 1H), 4.27 (td, J = 8.0, 3.9 Hz, 1H), 3.95 (s, 4H), 3.83 (s, 3H), 3.62 (s, 4H), 3.45 (s, 4H), 3.28 (s, 3H), 2.80 (s, 4H), 2.62 (dt, J = 26.5, 12.1 Hz, 3H), 2.44 - 2.30 (m, 2H), 2.13 (s, 2H), 1.99 (s, 2H) 1 H NMR (400 MHz, CDCl 3 ) δ 8.37 (s, 1H), 7.96 (s, 1H), 7.78 (s, 1H), 7.68 (s, 1H), 7.18 (d, J = 25.1 Hz, 4H) , 6.58 (s, 1H), 5.83 (s, 1H), 4.27 (td, J = 8.0, 3.9 Hz, 1H), 3.95 (s, 4H), 3.83 (s, 3H), 3.62 (s, 4H), 3.45 (s, 4H), 3.28 (s, 3H), 2.80 (s, 4H), 2.62 (dt, J = 26.5, 12.1 Hz, 3H), 2.44 - 2.30 (m, 2H), 2.13 (s, 2H) , 1.99 (s, 2H) 678.5
[M+H]+ 678.5
[M+H] +
189189
Figure PCTKR2021018956-appb-img-000223
Figure PCTKR2021018956-appb-img-000223
 		(R)-N-(2-메톡시-5-(1-메틸-1H-피라졸-4-일)-4-몰포리노페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( R ) -N- (2-methoxy-5-(1-methyl-1 H -pyrazol-4-yl)-4-morpholinophenyl)-4-(3-phenylisoxazolidine-2- yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, CDCl3) δ 9.85 (s, 1H), 8.15 - 7.89 (m, 3H), 7.36 (s, 1H), 7.22 (t, J = 7.3 Hz, 1H), 7.15 (t, J = 7.4 Hz, 2H), 6.83 (d, J = 7.5 Hz, 2H), 6.76 (s, 1H), 5.47 (s, 1H), 4.47 (s, 1H), 4.14 (s, 4H), 3.86 (t, J = 4.5 Hz, 4H), 3.73 (s, 3H), 2.99 (d, J = 4.7 Hz, 5H), 2.43 (s, 1H) 1 H NMR (400 MHz, CDCl 3 ) δ 9.85 (s, 1H), 8.15 - 7.89 (m, 3H), 7.36 (s, 1H), 7.22 (t, J = 7.3 Hz, 1H), 7.15 (t, J = 7.4 Hz, 2H), 6.83 (d, J = 7.5 Hz, 2H), 6.76 (s, 1H), 5.47 (s, 1H), 4.47 (s, 1H), 4.14 (s, 4H), 3.86 ( t, J = 4.5 Hz, 4H), 3.73 (s, 3H), 2.99 (d, J = 4.7 Hz, 5H), 2.43 (s, 1H) 582.4
[M+H]+ 582.4
[M+H] +
190190
Figure PCTKR2021018956-appb-img-000224
Figure PCTKR2021018956-appb-img-000224
 		(R)-N-(2-메톡시-5-(1-메틸-1H-피라졸-4-일)-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( R ) -N- (2-methoxy-5-(1-methyl-1 H -pyrazol-4-yl)-4-(4-(4-methylpiperazin-1-yl)piperidin- 1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.68 (s, 1H), 7.21 (s, 3H), 7.13 (s, 1H), 6.58 (s, 1H), 5.80 (s, 1H), 4.28 (td, J = 8.0, 3.9 Hz, 1H), 4.01 - 3.89 (m, 4H), 3.83 (s, 3H), 3.71 (s, 3H), 3.48 (s, 4H), 3.29 (d, J = 11.3 Hz, 3H), 2.88 - 2.74 (m, 4H), 2.61 (q, J = 12.3 Hz, 3H), 2.38 (ddt, J = 12.0, 8.1, 4.2 Hz, 2H), 2.15 (s, 2H), 2.01 (s, 3H) 1 H NMR (400 MHz, CDCl 3 ) δ 8.36 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.68 (s, 1H), 7.21 (s, 3H), 7.13 (s, 1H), 6.58 (s, 1H), 5.80 (s, 1H), 4.28 (td, J = 8.0, 3.9 Hz, 1H), 4.01 - 3.89 (m, 4H), 3.83 (s, 3H), 3.71 (s) , 3H), 3.48 (s, 4H), 3.29 (d, J = 11.3 Hz, 3H), 2.88 - 2.74 (m, 4H), 2.61 (q, J = 12.3 Hz, 3H), 2.38 (ddt, J = 12.0, 8.1, 4.2 Hz, 2H), 2.15 (s, 2H), 2.01 (s, 3H) 678.5
[M+H]+ 678.5
[M+H] +
191191
Figure PCTKR2021018956-appb-img-000225
Figure PCTKR2021018956-appb-img-000225
 		(S)-2-플루오로-N-(1-아이소프로필피페리딘-4-일)-5-메톡시-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤즈아마이드( S )-2-fluoro- N- (1-isopropylpiperidin-4-yl)-5-methoxy-4-((4-(3-phenylisoxazolidin-2-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide 1H NMR (400 MHz, DMSO-d6) δ = 8.52 (s, 1H), 8.48 (s, 1H), 7.91 (dd, J = 7.8, 3.2 Hz, 1H), 7.79 (d, J = 12.2 Hz, 1H), 7.37 - 7.35 (m, 3H), 7.30 - 7.23 (m, 2H), 7.15 (d, J = 6.6 Hz, 1H), 5.81 (dd, J = 8.7, 6.1 Hz, 1H), 4.32 (td, J = 7.8, 2.6 Hz, 1H), 3.84 (s, 4H), 3.74 - 3.68 (m, 1H), 2.94 (ddt, J = 9.1, 6.4, 3.2 Hz, 1H), 2.76 (d, J = 11.3 Hz, 2H), 2.71 - 2.67 (m, 1H), 2.28 - 2.23 (m, 1H), 2.19 (td, J = 11.4, 2.4 Hz, 2H), 1.83 - 1.77 (m, 2H), 1.50 (td, J = 11.2, 7.6 Hz, 2H), 0.97 (d, J = 6.5 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.52 (s, 1H), 8.48 (s, 1H), 7.91 (dd, J = 7.8, 3.2 Hz, 1H), 7.79 (d, J = 12.2 Hz) , 1H), 7.37 - 7.35 (m, 3H), 7.30 - 7.23 (m, 2H), 7.15 (d, J = 6.6 Hz, 1H), 5.81 (dd, J = 8.7, 6.1 Hz, 1H), 4.32 ( td, J = 7.8, 2.6 Hz, 1H), 3.84 (s, 4H), 3.74 - 3.68 (m, 1H), 2.94 (ddt, J = 9.1, 6.4, 3.2 Hz, 1H), 2.76 (d, J = 11.3 Hz, 2H), 2.71 - 2.67 (m, 1H), 2.28 - 2.23 (m, 1H), 2.19 (td, J = 11.4, 2.4 Hz, 2H), 1.83 - 1.77 (m, 2H), 1.50 (td) , J = 11.2, 7.6 Hz, 2H), 0.97 (d, J = 6.5 Hz, 6H) 603.5
[M+H]+ 603.5
[M+H] +
192192
Figure PCTKR2021018956-appb-img-000226
Figure PCTKR2021018956-appb-img-000226
 		N-(3-사이클로프로필-5-(((3S,5R)-3,5-다이메틸피페라진-1-일)메틸)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민 N- (3-cyclopropyl-5-(((3S, 5R )-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(( S )-3- phenylisooxa Jolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.71 (s, 1H), 8.48 (s, 1H), 7.35 (td, J = 9.2, 8.0, 6.5 Hz, 4H), 7.29 (d, J = 1.8 Hz, 1H), 7.28 - 7.24 (m, 1H), 7.19 (s, 1H), 6.58 (s, 1H), 5.97 (dd, J = 8.9, 5.5 Hz, 1H), 4.26 (td, J = 7.9, 2.9 Hz, 1H), 3.80 (dt, J = 9.4, 7.5 Hz, 1H), 3.23 (d, J = 13.2 Hz, 2H), 3.13 (d, J = 13.2 Hz, 1H), 2.94 (dtt, J = 9.0, 6.6, 3.6 Hz, 1H), 2.72 (ddt, J = 12.1, 8.5, 4.1 Hz, 2H), 2.56 (t, J = 9.6 Hz, 2H), 2.37 - 2.27 (m, 1H), 1.64 (s, 1H), 1.41 (dd, J = 21.4, 10.6 Hz, 2H), 0.91 - 0.83 (m, 8H), 0.55 (qd, J = 5.0, 3.0 Hz, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.71 (s, 1H), 8.48 (s, 1H), 7.35 (td, J = 9.2, 8.0, 6.5 Hz, 4H), 7.29 (d, J = 1.8 Hz, 1H), 7.28 - 7.24 (m, 1H), 7.19 (s, 1H), 6.58 (s, 1H), 5.97 (dd, J = 8.9, 5.5 Hz, 1H), 4.26 (td, J = 7.9) , 2.9 Hz, 1H), 3.80 (dt, J = 9.4, 7.5 Hz, 1H), 3.23 (d, J = 13.2 Hz, 2H), 3.13 (d, J = 13.2 Hz, 1H), 2.94 (dtt, J ) = 9.0, 6.6, 3.6 Hz, 1H), 2.72 (ddt, J = 12.1, 8.5, 4.1 Hz, 2H), 2.56 (t, J = 9.6 Hz, 2H), 2.37 - 2.27 (m, 1H), 1.64 ( s, 1H), 1.41 (dd, J = 21.4, 10.6 Hz, 2H), 0.91 - 0.83 (m, 8H), 0.55 (qd, J = 5.0, 3.0 Hz, 2H) 553.5
[M+H]+ 553.5
[M+H] +
193193
Figure PCTKR2021018956-appb-img-000227
Figure PCTKR2021018956-appb-img-000227
 		(S)-N-(1-(메틸설포닐)피페리딘-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (1-(methylsulfonyl)piperidin-4-yl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine- 2-amine 471.5
[M+H]+ 471.5
[M+H] +
194194
Figure PCTKR2021018956-appb-img-000228
Figure PCTKR2021018956-appb-img-000228
 		(S)-N-(1-아이소프로필피페리딘-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (1-isopropylpiperidin-4-yl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 435.5
[M+H]+ 435.5
[M+H] +
195195
Figure PCTKR2021018956-appb-img-000229
Figure PCTKR2021018956-appb-img-000229
 		(3S,4S)-1-(메틸설포닐)-4-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피페리딘-3-올( 3S,4S)-1-(methylsulfonyl)-4-((4-((S ) -3 -phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine -2-yl)amino)piperidin-3-ol 488.2
[M+H]+ 488.2
[M+H] +
196196
Figure PCTKR2021018956-appb-img-000230
Figure PCTKR2021018956-appb-img-000230
 		(3R,4R)-1-(메틸설포닐)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피페리딘-4-올( 3R , 4R )-1-(methylsulfonyl)-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine -2-yl)amino)piperidin-4-ol 488.2
[M+H]+ 488.2
[M+H] +
197197
Figure PCTKR2021018956-appb-img-000231
Figure PCTKR2021018956-appb-img-000231
 		tert-부틸 (S)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피페리딘-1-카복실레이트 tert -Butyl ( S )-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin din-1-carboxylate 494.2
[M+H]+ 494.2
[M+H] +
198198
Figure PCTKR2021018956-appb-img-000232
Figure PCTKR2021018956-appb-img-000232
 		tert-부틸 (S)-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피페리딘-1-카복실레이트 tert -Butyl ( S )-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1- carboxylate 1H NMR (400 MHz, Methanol-d 4) δ 8.19 (s, 1H), 7.42 - 7.32 (m, 5H), 7.27 (dt, J = 7.9, 3.3 Hz, 1H), 5.62 (s, 1H), 4.29 (s, 1H), 4.09 - 3.97 (m, 1H), 3.91 (s, 1H), 3.78 (d, J = 12.8 Hz, 1H), 3.57 (s, 1H), 2.88 (d, J = 39.3 Hz, 3H), 2.51 (s, 1H), 2.35 - 2.21 (m, 1H), 1.96 - 1.81 (m, 1H), 1.47 (s, 9H), 1.43 - 1.35 (m, 2H), 1.09 (tdd, J = 9.5, 4.6, 3.0 Hz, 1H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.19 (s, 1H), 7.42 - 7.32 (m, 5H), 7.27 (dt, J = 7.9, 3.3 Hz, 1H), 5.62 (s, 1H), 4.29 (s, 1H), 4.09 - 3.97 (m, 1H), 3.91 (s, 1H), 3.78 (d, J = 12.8 Hz, 1H), 3.57 (s, 1H), 2.88 (d, J = 39.3 Hz) , 3H), 2.51 (s, 1H), 2.35 - 2.21 (m, 1H), 1.96 - 1.81 (m, 1H), 1.47 (s, 9H), 1.43 - 1.35 (m, 2H), 1.09 (tdd, J ) = 9.5, 4.6, 3.0 Hz, 1H) 494.2
[M+H]+ 494.2
[M+H] +
199199
Figure PCTKR2021018956-appb-img-000233
Figure PCTKR2021018956-appb-img-000233
 		tert-부틸 (S)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피롤리딘-1-카복실레이트 tert -Butyl ( S )-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrroly din-1-carboxylate 1H NMR (400 MHz, Methanol-d 4) δ 8.21 (s, 1H), 7.43 - 7.30 (m, 4H), 7.30 - 7.22 (m, 1H), 5.61 (s, 1H), 4.31 (s, 1H), 3.94 (s, 2H), 3.66 (dd, J = 10.9, 6.6 Hz, 1H), 3.38 (s, 1H), 3.26 - 3.10 (m, 2H), 2.92 (s, 1H), 2.33 (q, J = 8.9 Hz, 1H), 1.50 (s, 9H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.21 (s, 1H), 7.43 - 7.30 (m, 4H), 7.30 - 7.22 (m, 1H), 5.61 (s, 1H), 4.31 (s, 1H) ), 3.94 (s, 2H), 3.66 (dd, J = 10.9, 6.6 Hz, 1H), 3.38 (s, 1H), 3.26 - 3.10 (m, 2H), 2.92 (s, 1H), 2.33 (q, J = 8.9 Hz, 1H), 1.50 (s, 9H) 480.2
[M+H]+ 480.2
[M+H] +
200200
Figure PCTKR2021018956-appb-img-000234
Figure PCTKR2021018956-appb-img-000234
 		tert-부틸 (R)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피롤리딘-1-카복실레이트 tert -Butyl ( R )-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrroly din-1-carboxylate 480.2
[M+H]+ 480.2
[M+H] +
201201
Figure PCTKR2021018956-appb-img-000235
Figure PCTKR2021018956-appb-img-000235
 		4-((S)-3-페닐아이소옥사졸리딘-2-일)-N-((S)-피페리딘-3-일)-5-(트라이플루오로메틸)피리미딘-2-아민4-(( S )-3-phenylisoxazolidin-2-yl) -N -(( S )-piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, Methanol-d 4) δ 8.28 (s, 1H), 7.44 - 7.32 (m, 4H), 7.31 - 7.22 (m, 1H), 5.74 (s, 1H), 4.30 (s, 1H), 3.93 (s, 2H), 3.38 (d, J = 12.2 Hz, 1H), 3.26 (dt, J = 12.6, 4.5 Hz, 1H), 3.08 - 2.86 (m, 3H), 2.34 (dddd, J = 12.1, 9.7, 7.6, 6.6 Hz, 1H), 1.62 (t, J = 94.3 Hz, 4H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.28 (s, 1H), 7.44 - 7.32 (m, 4H), 7.31 - 7.22 (m, 1H), 5.74 (s, 1H), 4.30 (s, 1H) ), 3.93 (s, 2H), 3.38 (d, J = 12.2 Hz, 1H), 3.26 (dt, J = 12.6, 4.5 Hz, 1H), 3.08 - 2.86 (m, 3H), 2.34 (dddd, J = 12.1, 9.7, 7.6, 6.6 Hz, 1H), 1.62 (t, J = 94.3 Hz, 4H) 394.2
[M+H]+ 394.2
[M+H] +
202202
Figure PCTKR2021018956-appb-img-000236
Figure PCTKR2021018956-appb-img-000236
 		(S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(피페리딘-4-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-4-(3- phenylisoxazolidin -2-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine 394.2
[M+H]+ 394.2
[M+H] +
203203
Figure PCTKR2021018956-appb-img-000237
Figure PCTKR2021018956-appb-img-000237
 		4-((S)-3-페닐아이소옥사졸리딘-2-일)-N-((S)-피롤리딘-3-일)-5-(트라이플루오로메틸)피리미딘-2-아민4-(( S )-3-phenylisoxazolidin-2-yl) -N -(( S )-pyrrolidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, Methanol-d 4) δ 8.29 (s, 1H), 7.43 - 7.33 (m, 4H), 7.31 - 7.24 (m, 1H), 5.69 (s, 1H), 4.32 (s, 2H), 3.95 (s, 1H), 3.48 (dd, J = 12.2, 6.6 Hz, 2H), 3.26 (s, 1H), 3.00 - 2.87 (m, 1H), 2.33 (ddt, J = 12.1, 9.9, 7.3 Hz, 1H), 1.82 (s, 2H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.29 (s, 1H), 7.43 - 7.33 (m, 4H), 7.31 - 7.24 (m, 1H), 5.69 (s, 1H), 4.32 (s, 2H) ), 3.95 (s, 1H), 3.48 (dd, J = 12.2, 6.6 Hz, 2H), 3.26 (s, 1H), 3.00 - 2.87 (m, 1H), 2.33 (ddt, J = 12.1, 9.9, 7.3) Hz, 1H), 1.82 (s, 2H) 380.2
[M+H]+ 380.2
[M+H] +
204204
Figure PCTKR2021018956-appb-img-000238
Figure PCTKR2021018956-appb-img-000238
 		4-((S)-3-페닐아이소옥사졸리딘-2-일)-N-((R)-피롤리딘-3-일)-5-(트라이플루오로메틸)피리미딘-2-아민4-(( S )-3-phenylisoxazolidin-2-yl) -N -(( R )-pyrrolidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine 380.2
[M+H]+ 380.2
[M+H] +
205205
Figure PCTKR2021018956-appb-img-000239
Figure PCTKR2021018956-appb-img-000239
 		3-((S)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피롤리딘-1-일)프로판-1-올3-(( S )-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrroly Din-1-yl)propan-1-ol 438.2
[M+H]+ 438.2
[M+H] +
206206
Figure PCTKR2021018956-appb-img-000240
Figure PCTKR2021018956-appb-img-000240
 		tert-부틸 (R)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피페리딘-1-카복실레이트 tert -Butyl ( R )-3-((4-(( S )-3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin din-1-carboxylate 494.2
[M+H]+ 494.2
[M+H] +
207207
Figure PCTKR2021018956-appb-img-000241
Figure PCTKR2021018956-appb-img-000241
 		1-((S)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피페리딘-1-일)에탄-1-온1-(( S )-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin Din-1-yl)ethan-1-one 436.2
[M+H]+ 436.2
[M+H] +
208208
Figure PCTKR2021018956-appb-img-000242
Figure PCTKR2021018956-appb-img-000242
 		4-((S)-3-페닐아이소옥사졸리딘-2-일)-N-((R)-피페리딘-3-일)-5-(트라이플루오로메틸)피리미딘-2-아민4-(( S )-3-phenylisoxazolidin-2-yl) -N -(( R )-piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, Methanol-d 4) δ 8.30 (s, 1H), 7.40 (d, J = 3.7 Hz, 4H), 7.35 - 7.24 (m, 1H), 5.79 (s, 1H), 4.36 (s, 1H), 3.99 (s, 2H), 3.17 (s, 1H), 3.00 (ddd, J = 12.2, 8.7, 3.1 Hz, 2H), 2.67 (t, J = 29.3 Hz, 2H), 2.35 (dddd, J = 12.1, 9.5, 7.5, 6.4 Hz, 1H), 2.03 (tdt, J = 13.1, 6.9, 3.3 Hz, 2H), 1.91 - 1.66 (m, 2H) 1 H NMR (400 MHz, Methanol- d 4 ) δ 8.30 (s, 1H), 7.40 (d, J = 3.7 Hz, 4H), 7.35 - 7.24 (m, 1H), 5.79 (s, 1H), 4.36 ( s, 1H), 3.99 (s, 2H), 3.17 (s, 1H), 3.00 (ddd, J = 12.2, 8.7, 3.1 Hz, 2H), 2.67 (t, J = 29.3 Hz, 2H), 2.35 (dddd , J = 12.1, 9.5, 7.5, 6.4 Hz, 1H), 2.03 (tdt, J = 13.1, 6.9, 3.3 Hz, 2H), 1.91 - 1.66 (m, 2H) 394.3
[M+H]+ 394.3
[M+H] +
209209
Figure PCTKR2021018956-appb-img-000243
Figure PCTKR2021018956-appb-img-000243
 		N-((S)-1-메틸피페리딘-3-일)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민 N -(( S )-1-methylpiperidin-3-yl)-4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine- 2-amine 408.3
[M+H]+ 408.3
[M+H] +
210210
Figure PCTKR2021018956-appb-img-000244
Figure PCTKR2021018956-appb-img-000244
 		(S)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-(3-메톡시페닐)아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-(3-methoxyphenyl) )isoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ= 9.61 (s, 1H), 8.43 (s, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.07 (s, 2H), 6.93 (d, J = 6.8 Hz, 2H), 6.88 - 6.84 (m, 1H), 6.63 (s, 1H), 5.77 (d, J = 8.1 Hz, 1H), 4.30 - 4.23 (m, 1H), 3.78 (d, J = 8.8 Hz, 1H), 3.74 (s, 3H), 3.63 (s, 3H), 3.32 (d, J = 10.1 Hz, 2H), 2.91 (d, J = 9.0 Hz, 1H), 2.47 - 2.42 (m, 2H), 2.35 - 2.24 (m, 4H), 2.14 (s, 3H), 1.83 - 1.70 (m, 8H), 1.52 (d, J = 11.4 Hz, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.61 (s, 1H), 8.43 (s, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.07 (s, 2H), 6.93 (d , J = 6.8 Hz, 2H), 6.88 - 6.84 (m, 1H), 6.63 (s, 1H), 5.77 (d, J = 8.1 Hz, 1H), 4.30 - 4.23 (m, 1H), 3.78 (d, J = 8.8 Hz, 1H), 3.74 (s, 3H), 3.63 (s, 3H), 3.32 (d, J = 10.1 Hz, 2H), 2.91 (d, J = 9.0 Hz, 1H), 2.47 - 2.42 ( m, 2H), 2.35 - 2.24 (m, 4H), 2.14 (s, 3H), 1.83 - 1.70 (m, 8H), 1.52 (d, J = 11.4 Hz, 2H) 628.5
[M+H]+ 628.5
[M+H] +
211211
Figure PCTKR2021018956-appb-img-000245
Figure PCTKR2021018956-appb-img-000245
 		(S)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-(피리딘-3-일)아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-(pyridin-3-yl) )isoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 599.3
[M+H]+ 599.3
[M+H] +
212212
Figure PCTKR2021018956-appb-img-000246
Figure PCTKR2021018956-appb-img-000246
 		(S)-4-(3-(3-플루오로페닐)아이소옥사졸리딘-2-일)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-4-(3-(3-fluorophenyl)isoxazolidin-2-yl ) -N-(3-methoxy-4-(4-(4-methylpiperazin-1-yl) piperidin-1-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ= 9.75 (s, 1H), 8.48 (s, 1H), 7.42 (td, J = 7.9, 6.0 Hz, 1H), 7.24 - 7.17 (m, 2H), 7.12 (td, J = 8.7, 2.7 Hz, 3H), 6.80 (s, 1H), 5.82 (s, 1H), 4.28 (td, J = 7.9, 2.5 Hz, 1H), 3.84 - 3.77 (m, 1H), 3.68 (s, 3H), 3.44 (d, J = 10.6 Hz, 4H), 3.07 (d, J = 21.5 Hz, 2H), 2.98 - 2.90 (m, 2H), 2.79 (s, 4H), 2.70 (d, J = 24.2 Hz, 2H), 2.24 (s, 1H), 2.02 (d, J = 11.4 Hz, 2H), 1.91 (s, 3H), 1.74 (s, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.75 (s, 1H), 8.48 (s, 1H), 7.42 (td, J = 7.9, 6.0 Hz, 1H), 7.24 - 7.17 (m, 2H) , 7.12 (td, J = 8.7, 2.7 Hz, 3H), 6.80 (s, 1H), 5.82 (s, 1H), 4.28 (td, J = 7.9, 2.5 Hz, 1H), 3.84 - 3.77 (m, 1H) ), 3.68 (s, 3H), 3.44 (d, J = 10.6 Hz, 4H), 3.07 (d, J = 21.5 Hz, 2H), 2.98 - 2.90 (m, 2H), 2.79 (s, 4H), 2.70 (d, J = 24.2 Hz, 2H), 2.24 (s, 1H), 2.02 (d, J = 11.4 Hz, 2H), 1.91 (s, 3H), 1.74 (s, 2H) 616.4
[M+H]+ 616.4
[M+H] +
213213
Figure PCTKR2021018956-appb-img-000247
Figure PCTKR2021018956-appb-img-000247
 		(S)-4-(3-(4-플루오로페닐)아이소옥사졸리딘-2-일)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-4-(3-(4-fluorophenyl)isoxazolidin-2-yl ) -N-(3-methoxy-4-(4-(4-methylpiperazin-1-yl) piperidin-1-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.62 (s, 1H), 8.44 (s, 1H), 7.42 - 7.36 (m, 2H), 7.18 (t, J = 8.8 Hz, 2H), 7.03 (s, 2H), 6.64 (s, 1H), 5.81 (s, 1H), 4.26 (d, J = 2.6 Hz, 1H), 3.80 - 3.77 (m, 1H), 3.63 (s, 3H), 3.34 - 3.30 (m, 4H), 3.23 (s, 2H), 2.93 - 2.89 (m, 1H), 2.48 - 2.44 (m, 2H), 2.35 - 2.21 (m, 6H), 2.14 (s, 3H), 1.80 (d, J = 12.8 Hz, 2H), 1.52 (dd, J = 11.9, 3.7 Hz, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.62 (s, 1H), 8.44 (s, 1H), 7.42 - 7.36 (m, 2H), 7.18 (t, J = 8.8 Hz, 2H), 7.03 (s, 2H), 6.64 (s, 1H), 5.81 (s, 1H), 4.26 (d, J = 2.6 Hz, 1H), 3.80 - 3.77 (m, 1H), 3.63 (s, 3H), 3.34 - 3.30 (m, 4H), 3.23 (s, 2H), 2.93 - 2.89 (m, 1H), 2.48 - 2.44 (m, 2H), 2.35 - 2.21 (m, 6H), 2.14 (s, 3H), 1.80 ( d, J = 12.8 Hz, 2H), 1.52 (dd, J = 11.9, 3.7 Hz, 2H) 616.4
[M+H]+ 616.4
[M+H] +
214214
Figure PCTKR2021018956-appb-img-000248
Figure PCTKR2021018956-appb-img-000248
 		(S)-4-(3-(2,6-다이플루오로페닐)아이소옥사졸리딘-2-일)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-4-(3-(2,6-difluorophenyl)isoxazolidin-2-yl) -N- (3-methoxy-4-(4-(4-methylpiperazine-1) -yl)piperidin-1-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.48 (s, 1H), 8.40 (s, 1H), 7.43 - 7.36 (m, 1H), 7.11 - 7.05 (m, 3H), 6.89 (s, 1H), 6.65 (d, J = 8.5 Hz, 1H), 5.99 (t, J = 8.1 Hz, 1H), 4.34 (td, J = 7.8, 2.0 Hz, 1H), 3.81 (dd, J = 6.6, 4.2 Hz, 1H), 3.67 (s, 3H), 3.39 - 3.29 (m, 10H), 2.88 (dd, J = 6.1, 2.8 Hz, 1H), 2.37 - 2.24 (m, 7H), 1.82 (d, J = 12.0 Hz, 2H), 1.53 (dd, J = 12.0, 3.8 Hz, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.48 (s, 1H), 8.40 (s, 1H), 7.43 - 7.36 (m, 1H), 7.11 - 7.05 (m, 3H), 6.89 (s, 1H), 6.65 (d, J = 8.5 Hz, 1H), 5.99 (t, J = 8.1 Hz, 1H), 4.34 (td, J = 7.8, 2.0 Hz, 1H), 3.81 (dd, J = 6.6, 4.2) Hz, 1H), 3.67 (s, 3H), 3.39 - 3.29 (m, 10H), 2.88 (dd, J = 6.1, 2.8 Hz, 1H), 2.37 - 2.24 (m, 7H), 1.82 (d, J = 12.0 Hz, 2H), 1.53 (dd, J = 12.0, 3.8 Hz, 2H) 634.5
[M+H]+ 634.5
[M+H] +
215215
Figure PCTKR2021018956-appb-img-000249
Figure PCTKR2021018956-appb-img-000249
 		(S)-4-(3-(3-(다이메틸아미노)페닐)아이소옥사졸리딘-2-일)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-5-(트라이플루오로메틸)피리미딘-2-아민( S )-4-(3-(3-(dimethylamino)phenyl)isoxazolidin-2-yl) -N- (3-methoxy-4-(4-(4-methylpiperazine-1) -yl)piperidin-1-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.59 (s, 1H), 8.41 (s, 1H), 7.15 (t, J = 7.9 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.00 (s, 1H), 6.71 (t, J = 2.0 Hz, 1H), 6.66 - 6.57 (m, 3H), 5.76 (s, 1H), 4.26 (dt, J = 7.7, 3.9 Hz, 1H), 3.83 - 3.75 (m, 2H), 3.64 (s, 3H), 3.35 - 3.24 (m, 3H), 2.88 (s, 6H), 2.42 (dd, J = 11.6, 2.3 Hz, 2H), 2.32 (s, 3H), 2.24 (d, J = 4.1 Hz, 2H), 2.14 (s, 3H), 1.89 (s, 4H), 1.79 (d, J = 12.2 Hz, 2H), 1.52 (dd, J = 12.2, 3.8 Hz, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.59 (s, 1H), 8.41 (s, 1H), 7.15 (t, J = 7.9 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H) ), 7.00 (s, 1H), 6.71 (t, J = 2.0 Hz, 1H), 6.66 - 6.57 (m, 3H), 5.76 (s, 1H), 4.26 (dt, J = 7.7, 3.9 Hz, 1H) , 3.83 - 3.75 (m, 2H), 3.64 (s, 3H), 3.35 - 3.24 (m, 3H), 2.88 (s, 6H), 2.42 (dd, J = 11.6, 2.3 Hz, 2H), 2.32 (s) , 3H), 2.24 (d, J = 4.1 Hz, 2H), 2.14 (s, 3H), 1.89 (s, 4H), 1.79 (d, J = 12.2 Hz, 2H), 1.52 (dd, J = 12.2, 3.8 Hz, 2H) 641.5
[M+H]+ 641.5
[M+H] +
216216
Figure PCTKR2021018956-appb-img-000250
Figure PCTKR2021018956-appb-img-000250
 		(S)-3-(2-(2-((3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-(트라이플루오로메틸)피리미딘-4-일)아이소옥사졸리딘-3-일)벤조나이트릴( S )-3-(2-(2-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)isoxazolidin-3-yl)benzonitrile 1H NMR (400 MHz, DMSO-d6) δ = 9.71 (s, 1H), 8.47 (s, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.79 - 7.76 (m, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.05 (s, 2H), 6.70 (s, 1H), 5.84 (s, 1H), 4.30 (td, J = 7.9, 2.3 Hz, 1H), 3.83 (dt, J = 8.1, 1.7 Hz, 1H), 3.67 (s, 3H), 3.40 (s, 8H), 3.07 - 2.85 (m, 4H), 2.77 - 2.71 (m, 3H), 2.62 (s, 2H), 2.24 (s, 1H), 1.97 (d, J = 11.7 Hz, 2H), 1.73 - 1.63 (m, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.71 (s, 1H), 8.47 (s, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.79 - 7.76 (m, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.05 (s, 2H), 6.70 (s, 1H), 5.84 (s, 1H), 4.30 (td, J = 7.9, 2.3 Hz, 1H), 3.83 (dt, J = 8.1, 1.7 Hz, 1H), 3.67 (s, 3H), 3.40 (s, 8H), 3.07 - 2.85 (m, 4H), 2.77 - 2.71 (m) , 3H), 2.62 (s, 2H), 2.24 (s, 1H), 1.97 (d, J = 11.7 Hz, 2H), 1.73 - 1.63 (m, 2H) 623.5
[M+H]+ 623.5
[M+H] +
217217
Figure PCTKR2021018956-appb-img-000251
Figure PCTKR2021018956-appb-img-000251
 		(S)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-(3-페녹시페닐)아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민( S ) -N- (3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-(3-phenoxyphenyl) )isoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine 690.4
[M+H]+ 690.4
[M+H] +
218218
Figure PCTKR2021018956-appb-img-000252
Figure PCTKR2021018956-appb-img-000252
 		(S)-3-(2-(2-((1,2,3,4-테트라하이드로아이소퀴놀린-7-일)아미노)-5-(트라이플루오로메틸)피리미딘-4-일)아이소옥사졸리딘-3-일)벤조나이트릴( S )-3-(2-(2-((1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)iso oxazolidin-3-yl)benzonitrile 1H NMR (400 MHz, DMSO-d6) δ = 9.89 (s, 1H), 9.03 (s, 1H), 8.50 (s, 1H), 7.83 - 7.76 (m, 2H), 7.75 - 7.69 (m, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.25 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 5.83 (t, J = 7.6 Hz, 1H), 4.35 - 4.27 (m, 1H), 4.06 (s, 2H), 3.87 - 3.78 (m, 1H), 3.31 - 3.25 (m, 1H), 3.04 - 2.96 (m, 1H), 2.92 (t, J = 6.2 Hz, 2H), 2.29 - 2.20 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.89 (s, 1H), 9.03 (s, 1H), 8.50 (s, 1H), 7.83 - 7.76 (m, 2H), 7.75 - 7.69 (m, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.25 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 5.83 (t, J = 7.6 Hz, 1H), 4.35 - 4.27 (m, 1H), 4.06 (s, 2H), 3.87 - 3.78 (m, 1H), 3.31 - 3.25 (m, 1H), 3.04 - 2.96 (m, 1H), 2.92 ( t, J = 6.2 Hz, 2H), 2.29 - 2.20 (m, 1H) 467.2
[M+H]+ 467.2
[M+H] +
219219
Figure PCTKR2021018956-appb-img-000253
Figure PCTKR2021018956-appb-img-000253
 		(S)-4-(3-페닐아이소옥사졸리딘-2-일)-2-((3,4,5-트라이메톡시페닐)아미노)피리미딘-5-카보나이트릴 염산염( S )-4-(3-phenylisoxazolidin-2-yl)-2-((3,4,5-trimethoxyphenyl)amino)pyrimidine-5-carbonitrile hydrochloride 434.2
[M+H]+ 434.2
[M+H] +
220220
Figure PCTKR2021018956-appb-img-000254
Figure PCTKR2021018956-appb-img-000254
 		(S)-2-((4-(2-(다이에틸아미노)에톡시)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴 염산염( S )-2-((4-(2-(diethylamino)ethoxy)phenyl)amino)-4-(3-phenylisooxazolidin-2-yl)pyrimidine-5-carbonitrile hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 9.98 (s, 1H), 8.49 (s, 1H), 7.46 - 7.31 (m, 7H), 6.75 (s, 1H), 5.56 (s, 1H), 4.37 (d, J = 10.0 Hz, 1H), 4.35 - 4.30 (m, 2H), 3.98 (q, J = 7.9 Hz, 1H), 3.47 (t, J = 5.1 Hz, 2H), 3.20 (p, J = 7.0 Hz, 4H), 2.96 (dddd, J = 11.8, 9.1, 6.4, 2.7 Hz, 1H), 2.23 (s, 1H), 1.26 (t, J = 7.2 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.52 (s, 1H), 9.98 (s, 1H), 8.49 (s, 1H), 7.46 - 7.31 (m, 7H), 6.75 (s, 1H), 5.56 (s, 1H), 4.37 (d, J = 10.0 Hz, 1H), 4.35 - 4.30 (m, 2H), 3.98 (q, J = 7.9 Hz, 1H), 3.47 (t, J = 5.1 Hz, 2H) ), 3.20 (p, J = 7.0 Hz, 4H), 2.96 (dddd, J = 11.8, 9.1, 6.4, 2.7 Hz, 1H), 2.23 (s, 1H), 1.26 (t, J = 7.2 Hz, 6H) 459.2
[M+H]+ 459.2
[M+H] +
221221
Figure PCTKR2021018956-appb-img-000255
Figure PCTKR2021018956-appb-img-000255
 		(S)-2-((4-(2-(다이에틸아미노)에톡시)-3,5-다이메틸페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴 염산염( S )-2-((4-(2-(diethylamino)ethoxy)-3,5-dimethylphenyl)amino)-4-(3-phenylisoxazolidin-2-yl)pyrimidine- 5-Carbonitrile Hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.96 (s, 1H), 8.53 (s, 1H), 7.38 (d, J = 5.2 Hz, 3H), 7.33 - 7.24 (m, 2H), 7.21 (s, 1H), 5.76 (d, J = 4.9 Hz, 1H), 4.34 (td, J = 7.8, 3.2 Hz, 1H), 4.04 - 3.96 (m, 2H), 3.94 (dd, J = 8.5, 6.5 Hz, 1H), 3.84 - 3.50 (m, 2H), 3.46 (s, 2H), 3.24 (s, 3H), 3.02 (s, 1H), 2.31 - 2.21 (m, 1H), 2.01 (s, 3H), 1.94 (d, J = 20.0 Hz, 2H), 1.26 (t, J = 7.3 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.25 (s, 1H), 9.96 (s, 1H), 8.53 (s, 1H), 7.38 (d, J = 5.2 Hz, 3H), 7.33 - 7.24 ( m, 2H), 7.21 (s, 1H), 5.76 (d, J = 4.9 Hz, 1H), 4.34 (td, J = 7.8, 3.2 Hz, 1H), 4.04 - 3.96 (m, 2H), 3.94 (dd , J = 8.5, 6.5 Hz, 1H), 3.84 - 3.50 (m, 2H), 3.46 (s, 2H), 3.24 (s, 3H), 3.02 (s, 1H), 2.31 - 2.21 (m, 1H), 2.01 (s, 3H), 1.94 (d, J = 20.0 Hz, 2H), 1.26 (t, J = 7.3 Hz, 6H) 487.3
[M+H]+ 487.3
[M+H] +
222222
Figure PCTKR2021018956-appb-img-000256
Figure PCTKR2021018956-appb-img-000256
 		(S)-2-((4-(3-(다이에틸아미노)프로폭시)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴 염산염( S )-2-((4-(3-(diethylamino)propoxy)phenyl)amino)-4-(3-phenylisooxazolidin-2-yl)pyrimidine-5-carbonitrile hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.95 (s, 1H), 8.48 (s, 1H), 7.43 - 7.34 (m, 8H), 6.68 (d, J = 7.9 Hz, 1H), 5.56 (s, 1H), 4.39 (d, J = 10.1 Hz, 1H), 3.99 (q, J = 9.5, 7.8 Hz, 4H), 3.09 (s, 4H), 2.95 (ddt, J = 11.7, 6.4, 2.8 Hz, 2H), 2.25 (td, J = 8.8, 8.0, 4.6 Hz, 1H), 2.07 (s, 2H), 1.18 (d, J = 8.7 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.31 (s, 1H), 9.95 (s, 1H), 8.48 (s, 1H), 7.43 - 7.34 (m, 8H), 6.68 (d, J = 7.9) Hz, 1H), 5.56 (s, 1H), 4.39 (d, J = 10.1 Hz, 1H), 3.99 (q, J = 9.5, 7.8 Hz, 4H), 3.09 (s, 4H), 2.95 (ddt, J ) = 11.7, 6.4, 2.8 Hz, 2H), 2.25 (td, J = 8.8, 8.0, 4.6 Hz, 1H), 2.07 (s, 2H), 1.18 (d, J = 8.7 Hz, 6H) 473.3
[M+H]+ 473.3
[M+H] +
223223
Figure PCTKR2021018956-appb-img-000257
Figure PCTKR2021018956-appb-img-000257
 		(S)-2-((4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴 염산염( S )-2-((4-(3-(diethylamino)propoxy)-3,5-dimethylphenyl)amino)-4-(3-phenylisoxazolidin-2-yl)pyrimidine- 5-Carbonitrile Hydrochloride 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.93 (s, 1H), 8.52 (s, 1H), 7.41 - 7.34 (m, 4H), 7.29 (ddt, J = 8.6, 5.4, 3.0 Hz, 1H), 7.18 (s, 1H), 5.76 (d, J = 6.3 Hz, 1H), 4.34 (td, J = 7.8, 2.9 Hz, 1H), 3.95 (dt, J = 9.3, 7.3 Hz, 1H), 3.71 (s, 2H), 3.35 (s, 2H), 3.23 - 3.08 (m, 4H), 3.01 (s, 1H), 2.27 (d, J = 23.9 Hz, 1H), 2.10 - 1.92 (m, 8H), 1.22 (d, J = 9.5 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.24 (s, 1H), 9.93 (s, 1H), 8.52 (s, 1H), 7.41 - 7.34 (m, 4H), 7.29 (ddt, J = 8.6) , 5.4, 3.0 Hz, 1H), 7.18 (s, 1H), 5.76 (d, J = 6.3 Hz, 1H), 4.34 (td, J = 7.8, 2.9 Hz, 1H), 3.95 (dt, J = 9.3, 7.3 Hz, 1H), 3.71 (s, 2H), 3.35 (s, 2H), 3.23 - 3.08 (m, 4H), 3.01 (s, 1H), 2.27 (d, J = 23.9 Hz, 1H), 2.10 - 1.92 (m, 8H), 1.22 (d, J = 9.5 Hz, 6H) 501.3
[M+H]+ 501.3
[M+H] +
224224
Figure PCTKR2021018956-appb-img-000258
Figure PCTKR2021018956-appb-img-000258
 		(S)-2-((4-(3-(다이에틸아미노)프로폭시)-3,5-다이플루오로페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴( S )-2-((4-(3-(diethylamino)propoxy)-3,5-difluorophenyl)amino)-4-(3-phenylisoxazolidin-2-yl)pyri Midin-5-carbonitrile 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.56 (s, 1H), 7.43 - 7.32 (m, 5H), 7.30 - 7.25 (m, 2H), 5.67 (d, J = 7.7 Hz, 1H), 4.40 (d, J = 9.7 Hz, 1H), 4.02 (dt, J = 13.1, 7.0 Hz, 3H), 3.04 - 2.97 (m, 1H), 2.56 - 2.53 (m, 2H), 2.49 - 2.43 (m, 4H), 2.28 - 2.21 (m, 1H), 1.79 - 1.71 (m, 2H), 0.95 (t, J = 7.1 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.21 (s, 1H), 8.56 (s, 1H), 7.43 - 7.32 (m, 5H), 7.30 - 7.25 (m, 2H), 5.67 (d, J ) = 7.7 Hz, 1H), 4.40 (d, J = 9.7 Hz, 1H), 4.02 (dt, J = 13.1, 7.0 Hz, 3H), 3.04 - 2.97 (m, 1H), 2.56 - 2.53 (m, 2H) , 2.49 - 2.43 (m, 4H), 2.28 - 2.21 (m, 1H), 1.79 - 1.71 (m, 2H), 0.95 (t, J = 7.1 Hz, 6H) 509.4
[M+H]+ 509.4
[M+H] +
225225
Figure PCTKR2021018956-appb-img-000259
Figure PCTKR2021018956-appb-img-000259
 		(R)-2-((4-(4-메틸피페라진-1-일)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴( R )-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-4-(3-phenylisooxazolidin-2-yl)pyrimidine-5-carbonitrile 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.45 (s, 1H), 7.39 (d, J = 5.4 Hz, 5H), 7.33 - 7.23 (m, 3H), 6.69 (d, J = 8.5 Hz, 2H), 5.55 (s, 1H), 4.36 (d, J = 8.1 Hz, 1H), 3.96 (q, J = 8.1, 7.4 Hz, 1H), 3.35 (s, 1H), 3.05 (t, J = 4.8 Hz, 4H), 2.94 (dddd, J = 11.6, 8.8, 6.2, 2.7 Hz, 1H), 2.47 (t, J = 4.9 Hz, 4H), 2.24 (s, 3H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.87 (s, 1H), 8.45 (s, 1H), 7.39 (d, J = 5.4 Hz, 5H), 7.33 - 7.23 (m, 3H), 6.69 ( d, J = 8.5 Hz, 2H), 5.55 (s, 1H), 4.36 (d, J = 8.1 Hz, 1H), 3.96 (q, J = 8.1, 7.4 Hz, 1H), 3.35 (s, 1H), 3.05 (t, J = 4.8 Hz, 4H), 2.94 (dddd, J = 11.6, 8.8, 6.2, 2.7 Hz, 1H), 2.47 (t, J = 4.9 Hz, 4H), 2.24 (s, 3H) 442.2
[M+H]+ 442.2
[M+H] +
226226
Figure PCTKR2021018956-appb-img-000260
Figure PCTKR2021018956-appb-img-000260
 		(R)-2-((4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴( R )-2-((4-(3-(diethylamino)propoxy)-3,5-dimethylphenyl)amino)-4-(3-phenylisoxazolidin-2-yl)pyrimidine- 5-Carbonitrile 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.51 (s, 1H), 7.37 (d, J = 5.2 Hz, 4H), 7.29 (dt, J = 6.4, 3.0 Hz, 1H), 7.16 (s, 2H), 5.74 (dd, J = 8.8, 5.8 Hz, 1H), 4.34 (td, J = 7.8, 3.0 Hz, 1H), 3.94 (dt, J = 9.3, 7.2 Hz, 1H), 3.66 (t, J = 6.4 Hz, 2H), 3.36 (s, 2H), 3.00 (s, 1H), 2.57 (t, J = 7.1 Hz, 2H), 2.50 - 2.46 (m, 3H), 2.27 (p, J = 7.8 Hz, 1H), 1.97 (s, 5H), 1.80 (t, J = 6.9 Hz, 2H), 0.96 (t, J = 7.1 Hz, 6H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.51 (s, 1H), 7.37 (d, J = 5.2 Hz, 4H), 7.29 (dt, J = 6.4, 3.0 Hz, 1H), 7.16 (s, 2H), 5.74 (dd, J = 8.8, 5.8 Hz, 1H), 4.34 (td, J = 7.8, 3.0 Hz, 1H), 3.94 (dt, J = 9.3, 7.2 Hz, 1H) ), 3.66 (t, J = 6.4 Hz, 2H), 3.36 (s, 2H), 3.00 (s, 1H), 2.57 (t, J = 7.1 Hz, 2H), 2.50 - 2.46 (m, 3H), 2.27 (p, J = 7.8 Hz, 1H), 1.97 (s, 5H), 1.80 (t, J = 6.9 Hz, 2H), 0.96 (t, J = 7.1 Hz, 6H) 501.3
[M+H]+ 501.3
[M+H] +
227227
Figure PCTKR2021018956-appb-img-000261
Figure PCTKR2021018956-appb-img-000261
 		(S)-2-((4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴( S )-2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-4-(3-phenylisoxazolidine-2- 1) Pyrimidine-5-carbonitrile 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.44 (s, 1H), 7.39 (d, J = 5.2 Hz, 5H), 7.32 - 7.28 (m, 1H), 7.25 (s, 1H), 6.68 (s, 2H), 5.55 (s, 1H), 4.37 (s, 1H), 4.00 - 3.92 (m, 1H), 3.60 (d, J = 12.3 Hz, 2H), 2.98 - 2.92 (m, 1H), 2.59 (ddd, J = 12.4, 9.6, 2.9 Hz, 5H), 2.35 - 2.15 (m, 7H), 2.14 (s, 3H), 1.83 (d, J = 12.3 Hz, 2H), 1.48 (dd, J = 11.8, 3.8 Hz, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 8.44 (s, 1H), 7.39 (d, J = 5.2 Hz, 5H), 7.32 - 7.28 (m, 1H), 7.25 ( s, 1H), 6.68 (s, 2H), 5.55 (s, 1H), 4.37 (s, 1H), 4.00 - 3.92 (m, 1H), 3.60 (d, J = 12.3 Hz, 2H), 2.98 - 2.92 (m, 1H), 2.59 (ddd, J = 12.4, 9.6, 2.9 Hz, 5H), 2.35 - 2.15 (m, 7H), 2.14 (s, 3H), 1.83 (d, J = 12.3 Hz, 2H), 1.48 (dd, J = 11.8, 3.8 Hz, 2H) 525.5
[M+H]+ 525.5
[M+H] +
228228
Figure PCTKR2021018956-appb-img-000262
Figure PCTKR2021018956-appb-img-000262
 		(S)-2-((3,5-다이메틸-4-(3-(피롤리딘-1-일)프로폭시)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴( S )-2-((3,5-dimethyl-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)amino)-4-(3-phenylisoxazolidine-2- 1) Pyrimidine-5-carbonitrile 498.6
[M+H]+ 498.6
[M+H] +
229229
Figure PCTKR2021018956-appb-img-000263
Figure PCTKR2021018956-appb-img-000263
 		(S)-2-((3,5-다이메틸-4-(3-(피페리딘-1-일)프로폭시)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴( S )-2-((3,5-dimethyl-4-(3-(piperidin-1-yl)propoxy)phenyl)amino)-4-(3-phenylisoxazolidine-2- 1) Pyrimidine-5-carbonitrile 512.7
[M+H]+ 512.7
[M+H] +
230230
Figure PCTKR2021018956-appb-img-000264
Figure PCTKR2021018956-appb-img-000264
 		(S)-2-((3,5-다이메틸-4-(3-몰포리노프로폭시)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴( S )-2-((3,5-dimethyl-4-(3-morpholinopropoxy)phenyl)amino)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-5- carbonitrile 514.6
[M+H]+ 514.6
[M+H] +
231231
Figure PCTKR2021018956-appb-img-000265
Figure PCTKR2021018956-appb-img-000265
 		(S)-2-((3,5-다이메틸-4-(3-(4-메틸피페라진-1-일)프로폭시)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴( S )-2-((3,5-dimethyl-4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)amino)-4-(3-phenylisoxazolidine- 2-yl) pyrimidine-5-carbonitrile 527.7
[M+H]+ 527.7
[M+H] +
232232
Figure PCTKR2021018956-appb-img-000266
Figure PCTKR2021018956-appb-img-000266
 		(S)-4-(3-페닐아이소옥사졸리딘-2-일)-2-((4-(피페라진-1-일)-3-(트라이플루오로메틸)페닐)아미노)피리미딘-5-카보나이트릴( S )-4-(3-phenylisoxazolidin-2-yl)-2-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)pyrimidine- 5-Carbonitrile 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.41 - 7.32 (m, 5H), 7.28 - 7.23 (m, 1H), 7.19 (d, J = 8.6 Hz, 1H), 6.82 (d, J = 2.7 Hz, 1H), 6.74 (dd, J = 8.6, 2.7 Hz, 1H), 5.53 (dd, J = 8.4, 6.6 Hz, 1H), 5.38 (s, 2H), 4.39 (td, J = 7.7, 2.9 Hz, 1H), 3.97 (ddd, J = 9.5, 7.9, 6.5 Hz, 1H), 3.57 (s, 2H), 2.88 (dtd, J = 12.1, 6.3, 3.2 Hz, 1H), 2.65 (d, J = 35.1 Hz, 4H), 2.35 - 2.28 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.43 (s, 1H), 7.41 - 7.32 (m, 5H), 7.28 - 7.23 (m, 1H), 7.19 (d, J = 8.6 Hz, 1H), 6.82 (d, J = 2.7 Hz, 1H), 6.74 (dd, J = 8.6, 2.7 Hz, 1H), 5.53 (dd, J = 8.4, 6.6 Hz, 1H), 5.38 (s, 2H), 4.39 (td) , J = 7.7, 2.9 Hz, 1H), 3.97 (ddd, J = 9.5, 7.9, 6.5 Hz, 1H), 3.57 (s, 2H), 2.88 (dtd, J = 12.1, 6.3, 3.2 Hz, 1H), 2.65 (d, J = 35.1 Hz, 4H), 2.35 - 2.28 (m, 1H) 496.4
[M+H]+ 496.4
[M+H] +
233233
Figure PCTKR2021018956-appb-img-000267
Figure PCTKR2021018956-appb-img-000267
 		(S)-2-((4-(4-메틸피페라진-1-일)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴 트라이플루오로아세트산염( S )-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-4-(3-phenylisooxazolidin-2-yl)pyrimidine-5-carbonitrile trifluoro Roacetate 1H NMR (400 MHz, DMSO-d 6) δ 9.93 (s, 1H), 8.48 (s, 1H), 7.41 (d, J = 5.6 Hz, 5H), 7.33 - 7.29 (m, 2H), 6.84 - 6.72 (m, 2H), 5.56 (s, 1H), 4.37 (d, J = 8.6 Hz, 1H), 3.97 (d, J = 8.2 Hz, 1H), 3.73 (d, J = 13.2 Hz, 2H), 3.54 (d, J = 12.0 Hz, 2H), 3.17 (s, 2H), 2.93 (dd, J = 5.6, 3.0 Hz, 2H), 2.87 (s, 5H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.93 (s, 1H), 8.48 (s, 1H), 7.41 (d, J = 5.6 Hz, 5H), 7.33 - 7.29 (m, 2H), 6.84 - 6.72 (m, 2H), 5.56 (s, 1H), 4.37 (d, J = 8.6 Hz, 1H), 3.97 (d, J = 8.2 Hz, 1H), 3.73 (d, J = 13.2 Hz, 2H), 3.54 (d, J = 12.0 Hz, 2H), 3.17 (s, 2H), 2.93 (dd, J = 5.6, 3.0 Hz, 2H), 2.87 (s, 5H) 442.2
[M+H]+ 442.2
[M+H] +
234234
Figure PCTKR2021018956-appb-img-000268
Figure PCTKR2021018956-appb-img-000268
 		(S)-4-(3-페닐아이소옥사졸리딘-2-일)-2-((1,2,3,4-테트라하이드로아이소퀴놀린-6-일)아미노)피리미딘-5-카보나이트릴( S )-4-(3-phenylisoxazolidin-2-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidine-5-carbonitrile 399.2
[M+H]+ 399.2
[M+H] +
실시예 235. (Example 235. ( SS )-5-(3,6-다이하이드로-2)-5-(3,6-dihydro-2 HH -피란-4-일)--pyran-4-yl)- NN -(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민의 제조Preparation of -(4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine
Figure PCTKR2021018956-appb-img-000269
Figure PCTKR2021018956-appb-img-000269
단계 1: (Step 1: ( SS )-2-(2-클로로-5-(3,6-다이하이드로-2)-2-(2-Chloro-5-(3,6-dihydro-2) HH -피란-4-일)피리미딘-4-일)-3-페닐아이소옥사졸리딘의 제조-Pyran-4-yl) pyrimidin-4-yl) -3-phenylisoxazolidine preparation
(S)-2-(5-브로모-2-클로로피리미딘-4-일)-3-페닐아이소옥사졸리딘(190 mg, 0.056 mmol), 탄산나트륨(177 mg, 1.7 mmol) 및 2-(3,6-다이하이드로-2H-피란-4-일)-4,4,5,5-테트라메틸-1,3,2-다이옥사보로란(141 mg, 0.67 mmol)을 1,4-다이옥세인(4 mL)와 물(1 mL)에 녹인 후 질소를 흘리면서 5 분 동안 초음파 처리하였다. 반응 혼합물에 Pd(PPh3)4(65 mg, 0.056 mmol)을 첨가한 후 100 ℃에서 2 시간 동안 교반하였다. 반응 혼합물을 Celite로 여과하고, 아세트산에틸로 씻어 주었다. 얻어진 여과액을 소금물로 씻어 유기층을 모아 황산나트륨으로 건조하였다. 농축한 후 중압액체크로마토그래피(아세트산에틸/n-헥산 0 ~ 50 %)로 정제하여 목적 화합물(78 mg, 41 %)을 수득하였다.( S )-2-(5-bromo-2-chloropyrimidin-4-yl)-3-phenylisoxazolidine (190 mg, 0.056 mmol), sodium carbonate (177 mg, 1.7 mmol) and 2-( 3,6-dihydro- 2H -pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (141 mg, 0.67 mmol) was mixed with 1,4- After dissolving in dioxane (4 mL) and water (1 mL), it was sonicated for 5 minutes while flowing nitrogen. After adding Pd(PPh 3 ) 4 (65 mg, 0.056 mmol) to the reaction mixture, the mixture was stirred at 100° C. for 2 hours. The reaction mixture was filtered through Celite and washed with ethyl acetate. The obtained filtrate was washed with brine, and the organic layers were collected and dried over sodium sulfate. After concentration, it was purified by medium pressure liquid chromatography (ethyl acetate/n-hexane 0 to 50%) to obtain the target compound (78 mg, 41%).
MS (m/z): 388.6 [M+1]+ MS (m/z): 388.6 [M+1] +
단계 2: (Step 2: ( SS )-5-(3,6-다이하이드로-2)-5-(3,6-dihydro-2 HH -피란-4-일)--pyran-4-yl)- NN -(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민의 제조Preparation of -(4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine
단계 1에서 제조한 (S)-2-(2-클로로-5-(3,6-다이하이드로-2H-피란-4-일)피리미딘-4-일)-3-페닐아이소옥사졸리딘(78 mg, 0.23 mmol), PTSA(86 mg, 0.45 mmol)를 sec-BuOH(3 mL)에 녹인 후 80 ℃에서 12 시간 동안 교반하였다. 반응 혼합물을 아세트산에틸로 씻어 주었다. 얻어진 여과액을 소금물로 씻어 유기층을 모아 황산나트륨으로 건조하였다. 회전식 증발기를 이용하여 감압 하에 농축한 후 중압액체크로마토그래피(메탄올/염화메틸렌 0 ~ 10 %)로 정제하여 목적 화합물(35 mg, 31 %)을 수득하였다.( S )-2-(2-chloro-5-(3,6-dihydro- 2H -pyran-4-yl)pyrimidin-4-yl)-3-phenylisoxazolidine prepared in step 1 (78 mg, 0.23 mmol) and PTSA (86 mg, 0.45 mmol) were dissolved in sec -BuOH (3 mL) and stirred at 80 °C for 12 hours. The reaction mixture was washed with ethyl acetate. The obtained filtrate was washed with brine, and the organic layers were collected and dried over sodium sulfate. After concentration under reduced pressure using a rotary evaporator, the target compound (35 mg, 31%) was obtained by purification by medium pressure liquid chromatography (methanol/methylene chloride 0 to 10%).
MS (m/z): 499.4 [M+1]+ MS (m/z): 499.4 [M+1] +
1H NMR (400 MHz, DMSO-d6) δ = 9.16 (s, 1H), 7.87 (s, 1H), 7.45 - 7.36 (m, 6H), 7.30 - 7.25 (m, 1H), 6.80 - 6.74 (m, 2H), 5.63 (d, J = 8.4 Hz, 2H), 4.11 (td, J = 7.7, 7.1, 3.3 Hz, 3H), 3.76 - 3.69 (m, 1H), 3.65 (h, J = 5.2, 4.5 Hz, 2H), 3.03 (t, J = 5.0 Hz, 4H), 2.83 - 2.74 (m, 1H), 2.45 (t, J = 5.0 Hz, 4H), 2.22 (s, 3H), 2.21 - 2.07 (m, 3H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.16 (s, 1H), 7.87 (s, 1H), 7.45 - 7.36 (m, 6H), 7.30 - 7.25 (m, 1H), 6.80 - 6.74 ( m, 2H), 5.63 (d, J = 8.4 Hz, 2H), 4.11 (td, J = 7.7, 7.1, 3.3 Hz, 3H), 3.76 - 3.69 (m, 1H), 3.65 (h, J = 5.2, 4.5 Hz, 2H), 3.03 (t, J = 5.0 Hz, 4H), 2.83 - 2.74 (m, 1H), 2.45 (t, J = 5.0 Hz, 4H), 2.22 (s, 3H), 2.21 - 2.07 ( m, 3H)
실시예 236 내지 240Examples 236 to 240
상기 실시예 235와 유사한 방법으로 실시예 236 내지 240을 제조하였으며, 실시예 235 내지 240의 화합물명, 화학구조식, NMR 및 LC-MS 분석 결과를 하기 표 3에 정리하여 나타내었다.Examples 236 to 240 were prepared in a manner similar to that of Example 235, and the compound names, chemical structural formulas, NMR and LC-MS analysis results of Examples 235 to 240 are summarized in Table 3 below.
실시예Example 구조rescue 화합물명compound name 1H NMR 1 H NMR LC-MS
(m/z)LC-MS
(m/z)
235235
Figure PCTKR2021018956-appb-img-000270
Figure PCTKR2021018956-appb-img-000270
 		(S)-5-(3,6-다이하이드로-2H-피란-4-일)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민( S )-5-(3,6-dihydro-2H-pyran-4-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisooxa Jolidin-2-yl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ = 9.16 (s, 1H), 7.87 (s, 1H), 7.45 - 7.36 (m, 6H), 7.30 - 7.25 (m, 1H), 6.80 - 6.74 (m, 2H), 5.63 (d, J = 8.4 Hz, 2H), 4.11 (td, J = 7.7, 7.1, 3.3 Hz, 3H), 3.76 - 3.69 (m, 1H), 3.65 (h, J = 5.2, 4.5 Hz, 2H), 3.03 (t, J = 5.0 Hz, 4H), 2.83 - 2.74 (m, 1H), 2.45 (t, J = 5.0 Hz, 4H), 2.22 (s, 3H), 2.21 - 2.07 (m, 3H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.16 (s, 1H), 7.87 (s, 1H), 7.45 - 7.36 (m, 6H), 7.30 - 7.25 (m, 1H), 6.80 - 6.74 ( m, 2H), 5.63 (d, J = 8.4 Hz, 2H), 4.11 (td, J = 7.7, 7.1, 3.3 Hz, 3H), 3.76 - 3.69 (m, 1H), 3.65 (h, J = 5.2, 4.5 Hz, 2H), 3.03 (t, J = 5.0 Hz, 4H), 2.83 - 2.74 (m, 1H), 2.45 (t, J = 5.0 Hz, 4H), 2.22 (s, 3H), 2.21 - 2.07 ( m, 3H) 499.4
[M+1]+ 499.4
[M+1] +
236236
Figure PCTKR2021018956-appb-img-000271
Figure PCTKR2021018956-appb-img-000271
 		(S)-5-(사이클로헥산-1-엔-1-일)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민( S )-5-(cyclohexane-1- en -1-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidine-2 -yl) pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 7.81 (s, 1H), 7.49 - 7.43 (m, 2H), 7.43 - 7.35 (m, 4H), 7.30 - 7.24 (m, 1H), 6.80 - 6.74 (m, 2H), 5.59 - 5.52 (m, 2H), 4.07 (td, J = 7.9, 3.6 Hz, 1H), 3.76 (q, J = 7.9 Hz, 1H), 3.02 (t, J = 5.0 Hz, 4H), 2.76 (tq, J = 8.3, 4.3, 3.9 Hz, 1H), 2.44 (t, J = 5.0 Hz, 4H), 2.35 (d, J = 17.4 Hz, 1H), 2.21 (s, 3H), 2.15 (ddt, J = 12.8, 8.2, 4.1 Hz, 1H), 2.07 - 1.94 (m, 3H), 1.58 - 1.41 (m, 4H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.10 (s, 1H), 7.81 (s, 1H), 7.49 - 7.43 (m, 2H), 7.43 - 7.35 (m, 4H), 7.30 - 7.24 (m) , 1H), 6.80 - 6.74 (m, 2H), 5.59 - 5.52 (m, 2H), 4.07 (td, J = 7.9, 3.6 Hz, 1H), 3.76 (q, J = 7.9 Hz, 1H), 3.02 ( t, J = 5.0 Hz, 4H), 2.76 (tq, J = 8.3, 4.3, 3.9 Hz, 1H), 2.44 (t, J = 5.0 Hz, 4H), 2.35 (d, J = 17.4 Hz, 1H), 2.21 (s, 3H), 2.15 (ddt, J = 12.8, 8.2, 4.1 Hz, 1H), 2.07 - 1.94 (m, 3H), 1.58 - 1.41 (m, 4H) 497.4
[M+H]+ 497.4
[M+H] +
237237
Figure PCTKR2021018956-appb-img-000272
Figure PCTKR2021018956-appb-img-000272
 		(S)-5-(1-메틸-1H-피라졸-4-일)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민( S )-5-(1-methyl- 1H -pyrazol-4-yl)-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazoli Din-2-yl)pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.24 (s, 1H), 7.71 (s, 1H), 7.60 (s, 1H), 7.55 - 7.49 (m, 2H), 7.36 (d, J = 4.4 Hz, 4H), 7.26 (h, J = 4.2 Hz, 1H), 6.84 (d, J = 9.1 Hz, 2H), 5.38 (dd, J = 8.6, 4.4 Hz, 1H), 4.04 (td, J = 7.8, 5.0 Hz, 1H), 3.96 (q, J = 7.7 Hz, 1H), 3.70 (s, 3H), 3.05 (dd, J = 6.2, 3.9 Hz, 4H), 2.72 (dtd, J = 12.0, 8.3, 5.1 Hz, 1H), 2.45 (t, J = 4.9 Hz, 4H), 2.22 (s, 3H), 2.14 (td, J = 7.6, 4.2 Hz, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.25 (s, 1H), 8.24 (s, 1H), 7.71 (s, 1H), 7.60 (s, 1H), 7.55 - 7.49 (m, 2H), 7.36 (d, J = 4.4 Hz, 4H), 7.26 (h, J = 4.2 Hz, 1H), 6.84 (d, J = 9.1 Hz, 2H), 5.38 (dd, J = 8.6, 4.4 Hz, 1H), 4.04 (td, J = 7.8, 5.0 Hz, 1H), 3.96 (q, J = 7.7 Hz, 1H), 3.70 (s, 3H), 3.05 (dd, J = 6.2, 3.9 Hz, 4H), 2.72 (dtd , J = 12.0, 8.3, 5.1 Hz, 1H), 2.45 (t, J = 4.9 Hz, 4H), 2.22 (s, 3H), 2.14 (td, J = 7.6, 4.2 Hz, 1H) 497.4
[M+H]+ 497.4
[M+H] +
238238
Figure PCTKR2021018956-appb-img-000273
Figure PCTKR2021018956-appb-img-000273
 		(S)-5-(퓨란-3-일)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민( S )-5-(furan-3-yl)-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine -2-amine 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.23 (s, 1H), 7.76 (t, J = 1.2 Hz, 1H), 7.60 (t, J = 1.7 Hz, 1H), 7.48 (d, J = 9.0 Hz, 2H), 7.43 - 7.39 (m, 2H), 7.38 - 7.33 (m, 2H), 7.29 - 7.23 (m, 1H), 6.85 - 6.79 (m, 2H), 6.74 (d, J = 1.8 Hz, 1H), 5.51 (dd, J = 8.6, 4.7 Hz, 1H), 4.01 (td, J = 7.7, 4.8 Hz, 1H), 3.87 (q, J = 7.6 Hz, 1H), 3.05 (t, J = 5.0 Hz, 4H), 2.75 (ddt, J = 11.7, 7.7, 4.0 Hz, 1H), 2.45 (t, J = 5.0 Hz, 4H), 2.22 (s, 3H), 2.17 (dq, J = 8.5, 4.5, 3.8 Hz, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.29 (s, 1H), 8.23 (s, 1H), 7.76 (t, J = 1.2 Hz, 1H), 7.60 (t, J = 1.7 Hz, 1H) , 7.48 (d, J = 9.0 Hz, 2H), 7.43 - 7.39 (m, 2H), 7.38 - 7.33 (m, 2H), 7.29 - 7.23 (m, 1H), 6.85 - 6.79 (m, 2H), 6.74 (d, J = 1.8 Hz, 1H), 5.51 (dd, J = 8.6, 4.7 Hz, 1H), 4.01 (td, J = 7.7, 4.8 Hz, 1H), 3.87 (q, J = 7.6 Hz, 1H) , 3.05 (t, J = 5.0 Hz, 4H), 2.75 (ddt, J = 11.7, 7.7, 4.0 Hz, 1H), 2.45 (t, J = 5.0 Hz, 4H), 2.22 (s, 3H), 2.17 ( dq, J = 8.5, 4.5, 3.8 Hz, 1H) 483.3
[M+H]+ 483.3
[M+H] +
239239
Figure PCTKR2021018956-appb-img-000274
Figure PCTKR2021018956-appb-img-000274
 		(S)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(피리딘-3-일)피리미딘-2-아민( S )-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(pyridin-3-yl)pyrimidine -2-amine 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.60 (d, J = 2.3 Hz, 1H), 8.42 (dd, J = 4.8, 1.7 Hz, 1H), 8.06 (s, 1H), 7.80 (dt, J = 7.9, 2.0 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.39 - 7.32 (m, 5H), 7.27 (ddd, J = 8.5, 5.5, 2.3 Hz, 1H), 6.78 (d, J = 8.7 Hz, 2H), 5.66 (t, J = 7.4 Hz, 1H), 3.87 (td, J = 7.8, 3.5 Hz, 1H), 3.60 (q, J = 7.9 Hz, 1H), 3.05 (d, J = 4.8 Hz, 4H), 2.77 (dtd, J = 11.8, 7.5, 3.3 Hz, 1H), 2.47 - 2.44 (m, 4H), 2.22 (s, 3H), 2.11 (d, J = 7.4 Hz, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.31 (s, 1H), 8.60 (d, J = 2.3 Hz, 1H), 8.42 (dd, J = 4.8, 1.7 Hz, 1H), 8.06 (s, 1H), 7.80 (dt, J = 7.9, 2.0 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.39 - 7.32 (m, 5H), 7.27 (ddd, J = 8.5, 5.5, 2.3 Hz, 1H) , 6.78 (d, J = 8.7 Hz, 2H), 5.66 (t, J = 7.4 Hz, 1H), 3.87 (td, J = 7.8, 3.5 Hz, 1H), 3.60 (q, J = 7.9 Hz, 1H) , 3.05 (d, J = 4.8 Hz, 4H), 2.77 (dtd, J = 11.8, 7.5, 3.3 Hz, 1H), 2.47 - 2.44 (m, 4H), 2.22 (s, 3H), 2.11 (d, J ) = 7.4 Hz, 1H) 494.4
[M+H]+ 494.4
[M+H] +
240240
Figure PCTKR2021018956-appb-img-000275
Figure PCTKR2021018956-appb-img-000275
 		(S)-5-(6-플루오로피리딘-3-일)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민( S )-5-(6-fluoropyridin-3-yl)-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidine-2- Day) pyrimidin-2-amine 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.22 (d, J = 2.5 Hz, 1H), 8.06 (s, 1H), 7.99 (td, J = 8.3, 2.6 Hz, 1H), 7.44 - 7.34 (m, 6H), 7.27 (ddd, J = 8.5, 5.5, 2.3 Hz, 1H), 7.13 (dd, J = 8.5, 2.8 Hz, 1H), 6.77 (d, J = 8.6 Hz, 2H), 5.64 (t, J = 7.4 Hz, 1H), 3.90 (td, J = 7.7, 3.4 Hz, 1H), 3.61 (q, J = 7.9 Hz, 1H), 3.04 (t, J = 5.1 Hz, 4H), 2.82 - 2.74 (m, 1H), 2.45 (t, J = 5.0 Hz, 4H), 2.22 (s, 3H), 2.13 - 2.05 (m, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.32 (s, 1H), 8.22 (d, J = 2.5 Hz, 1H), 8.06 (s, 1H), 7.99 (td, J = 8.3, 2.6 Hz, 1H), 7.44 - 7.34 (m, 6H), 7.27 (ddd, J = 8.5, 5.5, 2.3 Hz, 1H), 7.13 (dd, J = 8.5, 2.8 Hz, 1H), 6.77 (d, J = 8.6 Hz) , 2H), 5.64 (t, J = 7.4 Hz, 1H), 3.90 (td, J = 7.7, 3.4 Hz, 1H), 3.61 (q, J = 7.9 Hz, 1H), 3.04 (t, J = 5.1 Hz) , 4H), 2.82 - 2.74 (m, 1H), 2.45 (t, J = 5.0 Hz, 4H), 2.22 (s, 3H), 2.13 - 2.05 (m, 1H) 512.4
[M+H]+ 512.4
[M+H] +
실험예 1. 본 발명에 따른 화합물의 키나아제 저해 활성 평가Experimental Example 1. Evaluation of the kinase inhibitory activity of the compound according to the present invention
본 발명에 따른 화합물의 키나아제 저해 활성을 평가하기 위해 하기와 같은 실험을 수행하였다. 구체적으로, 본 발명의 실시예 화합물 중, 선별된 실시예 45 및 46에 대하여, DiscoverX 사에 의뢰하여 효소(kinase) 선택성을 측정하기로 하고, scanMAXTM Kinase 분석용 패널을 사용하여 실험을 진행하였다. 이때, 효소에 처리되는 약물의 농도는 DMSO에 1 μM로 하였고, 하기 식 1과 같은 방법으로 조절 백분율(% control)을 정하였고, 그 결과를 하기 표 4 및 표 5에 나타내었다.In order to evaluate the kinase inhibitory activity of the compound according to the present invention, the following experiment was performed. Specifically, among the example compounds of the present invention, selected Examples 45 and 46 were commissioned by DiscoverX to measure enzyme (kinase) selectivity, and experiments were conducted using a scanMAX TM Kinase analysis panel. . At this time, the concentration of the drug treated with the enzyme was 1 μM in DMSO, and the control percentage (% control) was determined in the same way as in Equation 1 below, and the results are shown in Tables 4 and 5 below.
[식 1][Equation 1]
(실시예 화합물 - 양성 대조군) / (음성 대조군- 양성 대조군) x 100(Example compound - positive control) / (negative control - positive control) x 100
여기서, 상기 양성 대조군은 0 %의 조절 백분율을 나타내는 화합물을 말하며, 음성 대조군은 DMSO로 100 %의 조절 백분율을 나타낸다. 또한, 본 발명의 효소 선택성은 효소에 대하여 조절 백분율이 < 20 % (즉 20 % 미만)이면 해당 효소에 대하여 활성을 갖는 것으로 판단하였다.Here, the positive control refers to a compound showing a percentage control of 0%, and the negative control indicates a percentage control of 100% with DMSO. In addition, the enzyme selectivity of the present invention was determined to have activity for the enzyme when the control percentage for the enzyme is <20% (ie, less than 20%).
키나아제kinase 실시예 45Example 45 키나아제kinase 실시예 45Example 45 키나아제kinase 실시예 45Example 45
ARK5ARK5 8.88.8 FLT3(D835V)FLT3 (D835V) 00 PIK3CA(C420R)PIK3CA(C420R) 00
AURKAAURKA 6.96.9 FLT3(D835Y)FLT3 (D835Y) 1.11.1 PIK3CA(E545A)PIK3CA (E545A) 00
AURKCAURKC 1313 FLT3(ITD)FLT3 (ITD) 0.650.65 RET(V804L)RET(V804L) 1010
AXLAXL 7.37.3 FLT3
(ITD,D835V)FLT3
(ITD,D835V) 		0.650.65 RET(V804M)RET(V804M) 1212
BIKEBIKE 1616 FLT3
(ITD,F691L)FLT3
(ITD, F691L) 		0.50.5 RIOK3RIOK3 1212
CDK4CDK4 0.950.95 FLT3(K663Q)FLT3(K663Q) 1.81.8 SLKSLK 1.71.7
CDK4-cyclinD1CDK4-cyclinD1 0.20.2 FLT3(N841I)FLT3 (N841I) 00 SNARKSNARK 2.32.3
CDK4-cyclinD3CDK4-cyclinD3 22 FLT3(R834Q)FLT3 (R834Q) 1212 TAK1TAK1 8.18.1
CDK7CDK7 3.13.1 HIPK4HIPK4 6.96.9 TAOK3TAOK3 1212
CDKL2CDKL2 1.61.6 HPK1HPK1 1414 TIE1TIE1 8.48.4
CLK1CLK1 1212 JAK1
(JH2domain-
pseudokinase)JAK1
(JH2domain-
pseudokinase) 		9.49.4 TNK1TNK1 1313
DCAMKL3DCAMKL3 2.92.9 JAK3
(JH1domain-
catalytic)JAK3
(JH1domain-
catalytic) 		1414 TRKATRKA 7.87.8
DMPKDMPK 1010 MARK4MARK4 1414 TYK2
(JH1domain-catalytic)TYK2
(JH1domain-catalytic) 		1919
ERK5ERK5 1010 MERTKMERTK 1919 ULK1ULK1 22
ERK8ERK8 1515 MUSKMUSK 88 ULK2ULK2 0.10.1
FGFR1FGFR1 1414 NEK10NEK10 00 ULK3ULK3 1313
FLT3FLT3 00 PCTK1PCTK1 1818
FLT3(D835H)FLT3 (D835H) 1313 PCTK2PCTK2 1212
키나아제kinase 실시예 46Example 46 키나아제kinase 실시예 46Example 46 키나아제kinase 실시예 46Example 46
ALKALK 4.54.5 FLT4FLT4 1.81.8 RETRET 0.10.1
ALK(C1156Y)ALK (C1156Y) 0.950.95 IKK-epsilonIKK-epsilon 1616 RET(M918T)RET(M918T) 0.80.8
ALK(L1196M)ALK (L1196M) 6.76.7 IRAK3IRAK3 1717 RET(V804L)RET(V804L) 0.30.3
AMPK-alpha1AMPK-alpha1 1212 JAK2(JH1domain-catalytic)JAK2 (JH1 domain-catalytic) 00 RET(V804M)RET(V804M) 0.40.4
AMPK-alpha2AMPK-alpha2 55 JAK3(JH1domain-catalytic)JH1 domain-catalytic (JAK3) 00 RIOK3RIOK3 1313
ARK5ARK5 1.21.2 KITKIT 4.34.3 ROS1ROS1 8.48.4
AURKAAURKA 00 KIT(A829P)KIT(A829P) 00 RPS6KA4
(Kin.Dom.2-C-terminal)RPS6KA4
(Kin.Dom.2-C-terminal) 		6.96.9
AURKBAURKB 1.41.4 KIT(D816H)KIT(D816H) 6.46.4 RPS6KA5
(Kin.Dom.2-C-terminal)RPS6KA5
(Kin.Dom.2-C-terminal) 		6.86.8
AURKCAURKC 8.98.9 KIT(L576P)KIT(L576P) 4.54.5 RSK1
(Kin.Dom.1-N-terminal)RSK1
(Kin.Dom.1-N-terminal) 		1414
AXLAXL 1717 KIT(V559D)KIT(V559D) 1.71.7 RSK2
(Kin.Dom.1-N-terminal)RSK2
(Kin.Dom.1-N-terminal) 		0.90.9
CDK4-cyclinD1CDK4-cyclinD1 3.73.7 KIT
(V559D,T670I)KIT
(V559D, T670I) 		6.96.9 RSK3
(Kin.Dom.1-N-terminal)RSK3
(Kin.Dom.1-N-terminal) 		9.79.7
CDKL2CDKL2 00 KIT
(V559D,V654A)KIT
(V559D,V654A) 		1212 RSK4
(Kin.Dom.1-N-terminal)RSK4
(Kin.Dom.1-N-terminal) 		2.72.7
CSNK2A2CSNK2A2 9.29.2 LATS2LATS2 00 S6K1S6K1 4.34.3
DCAMKL1DCAMKL1 5.85.8 LRRK2LRRK2 5.15.1 SBK1SBK1 1515
DCAMKL3DCAMKL3 1.51.5 LRRK2(G2019S)LRRK2(G2019S) 88 SGKSGK 1.61.6
DRAK2DRAK2 3.93.9 MAP3K2MAP3K2 2.62.6 SGK3SGK3 3.73.7
DYRK2DYRK2 1717 MAP3K3MAP3K3 1414 SIK2SIK2 1111
FAKFAK 1.91.9 MERTKMERTK 1717 SNARKSNARK 0.750.75
FERFER 8.28.2 MKNK2MKNK2 6.36.3 SRPK1SRPK1 1919
FESFES 5.85.8 MLCKMLCK 1313 STK16STK16 6.46.4
FGFR1FGFR1 0.550.55 MLK1MLK1 5.15.1 TAK1TAK1 1.31.3
FGFR3(G697C)FGFR3 (G697C) 6.46.4 MLK2MLK2 3.43.4 TAOK3TAOK3 1616
FGFR4FGFR4 1717 MLK3MLK3 4.64.6 TIE1TIE1 3.13.1
FLT1FLT1 5.35.3 MUSKMUSK 1.61.6 TNK1TNK1 1.11.1
FLT3FLT3 00 PDGFRBPDGFRB 2.12.1 TRKATRKA 2.12.1
FLT3(D835H)FLT3 (D835H) 1.61.6 PKN1PKN1 3.53.5 TRKBTRKB 1515
FLT3(D835V)FLT3 (D835V) 0.150.15 PKN2PKN2 1717 TTKTTK 4.14.1
FLT3(D835Y)FLT3 (D835Y) 0.950.95 PKNB
(M.tuberculosis)PKNB
(M. tuberculosis) 		0.70.7 TYK2
(JH1domain-catalytic)TYK2
(JH1domain-catalytic) 		00
FLT3(ITD)FLT3 (ITD) 0.750.75 PLK4PLK4 2.22.2 ULK1ULK1 1414
FLT3
(ITD,D835V)FLT3
(ITD,D835V) 		0.10.1 PRKCEPRKCE 1313 ULK2ULK2 1111
FLT3
(ITD,F691L)FLT3
(ITD, F691L) 		00 PRKCQPRKCQ 5.95.9 ULK3ULK3 66
FLT3(K663Q)FLT3(K663Q) 0.20.2 PRKD2PRKD2 2.22.2 VEGFR2VEGFR2 2.22.2
FLT3(N841I)FLT3 (N841I) 00 PRKD3PRKD3 00 VPS34VPS34 0.20.2
FLT3(R834Q)FLT3 (R834Q) 00 PYK2PYK2 7.17.1 YSK4YSK4 0.10.1
상기 표 4 및 표 5에서 확인할 수 있듯이, 본 발명에 따른 실시예 화합물은 ALK, ALK(C1156Y), ALK(L1196M), AMPK-alpha1, AMPK-alpha2, ARK5, AURKA, AURKB, AURKC, AXL, BIKE, CDK4, CDK4-cyclinD1, CDK4-cyclinD3, CDK7, CDKL2, CLK1, CSNK2A2, DCAMKL1, DCAMKL3, DMPK, DRAK2, DYRK2, ERK5, ERK8, FAK, FER, FES, FGFR1, FGFR3(G697C), FGFR4, FLT1, FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT4, HIPK4, HPK1, IKK-epsilon, IRAK3, JAK1(JH2domain-pseudokinase), JAK2(JH1domain-catalytic), JAK3(JH1domain-catalytic), KIT, KIT(A829P), KIT(D816H), KIT(L576P), KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A), LATS2, LRRK2, LRRK2(G2019S), MAP3K2, MAP3K3, MARK4, MERTK, MKNK2, MLCK, MLK1, MLK2, MLK3, MUSK, NEK10, PCTK1, PCTK2, PIK3CA(C420R), PIK3CA(E545A), PDGFRB, PKN1, PKN2, PKNB(M.tuberculosis), PLK4, PRKCE, PRKCQ, PRKD2, PRKD3, PYK2, RET, RET(M918T), RET(V804L), RET(V804M), RIOK3, ROS1, RPS6KA4(Kin.Dom.2-C-terminal), RPS6KA5(Kin.Dom.2-C-terminal), RSK1(Kin.Dom.1-N-terminal), RSK2(Kin.Dom.1-N-terminal), RSK3(Kin.Dom.1-N-terminal), RSK4(Kin.Dom.1-N-terminal), S6K1, SBK1, SGK, SGK3, SIK2, SLK, SNARK, SRPK1, STK16, TAK1, TAOK3, TIE1, TNK1, TRKA, TRKB, TTK, TYK2(JH1domain-catalytic), ULK1, ULK2, ULK3, VEGFR2, VPS34, YSK4에 대하여 조절 백분율 20 %보다 작은 값을 가지므로, 상기 나열된 효소에 대하여 활성을 가짐을 알 수 있다. 이는 본 발명에 따른 실시예 화합물을 상기 나열된 효소에 관련된 질환에 사용할 경우 유용한 효과가 있음을 암시하는 것이며, 따라서, 상기 나열된 효소 관련 질환의 치료 또는 예방용 조성물로 유용하게 사용할 수 있다.As can be seen in Tables 4 and 5, the example compounds according to the present invention are ALK, ALK (C1156Y), ALK (L1196M), AMPK-alpha1, AMPK-alpha2, ARK5, AURKA, AURKB, AURKC, AXL, BIKE , CDK4, CDK4-cyclinD1, CDK4-cyclinD3, CDK7, CDKL2, CLK1, CSNK2A2, DCAMKL1, DCAMKL3, DMPK, DRAK2, DYRK2, ERK5, ERK8, FAK, FER, FES, FGFR1, FGFR3 (G697C), FGFR3 (G697C) FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q) , FLT4, HIPK4, HPK1, IKK-epsilon, IRAK3, JAK1 (JH2domain-pseudokinase), JAK2 (JH1domain-catalytic), JAK3 (JH1domain-catalytic), KIT, KIT (A829P), KIT (D816H), KIT (L576P) , KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A), LATS2, LRRK2, LRRK2(G2019S), MAP3K2, MAP3K3, MARK4, MERTK, MKNK2, MLCK, MLK1, MLK2, MLK10 , PCTK1, PCTK2, PIK3CA(C420R), PIK3CA(E545A), PDGFRB, PKN1, PKN2, PKNB(M.tuberculosis), PLK4, PRKCE, PRKCQ, PRKD2, PRKD3, PYK2, RET, RET(M918T), RET(M918T) ), RET(V804M), RIOK3, ROS1, RPS6KA4(Kin.Dom.2-C-terminal), RPS6KA5(Kin.Dom.2-C-terminal), RSK1(Kin.Dom) .1-N-terminal), RSK2 (Kin.Dom.1-N-terminal), RSK3 (Kin.Dom.1-N-terminal), RSK4 (Kin.Dom.1-N-terminal), S6K1, SBK1 Regulates against , SGK, SGK3, SIK2, SLK, SNARK, SRPK1, STK16, TAK1, TAOK3, TIE1, TNK1, TRKA, TRKB, TTK, TYK2 (JH1domain-catalytic), ULK1, ULK2, ULK3, VEGFR2, V Since it has a value less than the percentage 20%, it can be seen that it has activity against the enzymes listed above. This suggests that the example compound according to the present invention has a useful effect when used in the diseases related to the enzymes listed above, and thus can be usefully used as a composition for treating or preventing the diseases related to the enzymes listed above.
실험예 2. CDK4(Cyclin-Dependent protein Kinase, CDK4) 효소 저해능 평가 Experimental Example 2. CDK4 (Cyclin-Dependent Protein Kinase, CDK4) enzyme inhibitory ability evaluation
본 발명에 따른 실시예 화합물의 CDK4(Cyclin-Dependent protein Kinase, CDK4) 효소에 대한 저해능을 평가하기 위해 하기와 같은 실험을 수행하였다.In order to evaluate the inhibitory ability of the Example compound according to the present invention to the CDK4 (Cyclin-Dependent Protein Kinase, CDK4) enzyme, the following experiment was performed.
실시예 화합물을 정제된 human GST-CDK4/CyclinD3 (full-length human CDK4 and CyclinD3 were co-expressed protein, Signalchem) 효소와 반응하여, 하기와 같은 방법으로 효소 저해능을 평가하였다. 반응 버퍼는 40 mM Tris-HCl pH 7.4, 20 mM MgCl2, 0.5 mg/mL BSA, 및 50 μM DTT 조성을 사용하였으며 모든 시험물은 반응 버퍼상에서 반응을 수행하였다. 시험 시 human GST-CDK4/CyclinD3(10 ng) 효소와 정제된 ATP(200 μM), 특이적인 기질용액을 30 ℃ 상에서 4 시간 동안 반응시킨 후, in vitro ADP-GloTM kinase assay(promega)를 이용하여 효소활성을 확인하였다. 2:2:1 비율로 효소활성 반응액과 ADP-Glo 반응액, 효소능 검출용액을 반응시켜서 형광도를 측정하였다. 화합물을 처리하지 않은 용매 대조군 효소활성의 형광도를 기준으로 각 화합물들의 처리 농도에 따른 효소활성 저해 정도를 산출하였으며, 이때 효소활성을 50 % 억제하는 각 화합물의 농도를 IC50(nM) 값으로 결정하였다. 각 화합물의 IC50는 GraphPad Prism 8.3.0(GraphPad software Inc., San Diego) 소프트웨어를 이용하여 구하였다. 그 결과는 하기 표 6에 나타내었다.Example compounds were reacted with purified human GST-CDK4/CyclinD3 (full-length human CDK4 and CyclinD3 were co-expressed protein, Signalchem) enzymes, and the enzyme inhibitory ability was evaluated as follows. The reaction buffer was 40 mM Tris-HCl pH 7.4, 20 mM MgCl 2 , 0.5 mg/mL BSA, and 50 μM DTT composition. All test materials were reacted in the reaction buffer. For testing, human GST-CDK4/CyclinD3 (10 ng) enzyme, purified ATP (200 μM), and a specific substrate solution were reacted at 30 ° C for 4 hours, followed by in vitro ADP-Glo TM kinase assay (promega). Thus, the enzyme activity was confirmed. The fluorescence was measured by reacting the enzyme activity reaction solution with the ADP-Glo reaction solution and the enzyme activity detection solution in a 2:2:1 ratio. The degree of inhibition of enzyme activity according to the treatment concentration of each compound was calculated based on the fluorescence of the enzyme activity of the solvent control that was not treated with the compound. It was decided. IC 50 of each compound was obtained using GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego) software. The results are shown in Table 6 below.
실시예Example CDK4/D3CDK4/D3
ICIC 5050 (nM)(nM) 		실시예Example CDK4/D3CDK4/D3
ICIC 5050 (nM)(nM) 		실시예Example CDK4/D3CDK4/D3
ICIC 5050 (nM)(nM) 		실시예Example CDK4/D3CDK4/D3
ICIC 5050 (nM)(nM)
1One 12971297 4242 412412 130130 55725572 199199 348348
22 444444 4444 274274 131131 6969 202202 4141
44 58855885 4545 3232 132132 3232 203203 168168
55 64476447 4646 47464746 133133 3535 204204 23242324
1111 431431 5454 33543354 134134 79537953 205205 78767876
1212 12581258 5858 10721072 136136 113113 210210 151151
1313 422422 5959 8585 137137 138138 211211 314314
1414 989989 6464 144144 138138 8989 212212 355355
1515 5353 6565 586586 139139 17481748 213213 168168
1616 29092909 6666 9393 144144 614614 214214 20082008
1717 152152 6969 13201320 145145 2222 215215 233233
1818 6262 7070 163163 146146 5757 216216 9292
2020 52635263 7373 293293 150150 977977 217217 34583458
2121 263263 7979 2424 151151 3535 218218 2727
2323 161161 9696 9494 152152 212212 220220 7171
2424 135135 9999 461461 157157 286286 221221 255255
2525 10241024 100100 211211 158158 175175 222222 5353
2626 12921292 103103 8383 165165 699699 223223 330330
2727 8484 105105 169169 166166 179179 224224 765765
2828 80948094 109109 18301830 170170 640640 225225 18831883
2929 16321632 115115 113113 171171 989989 227227 4242
3030 369369 117117 128128 179179 27162716 228228 438438
3131 352352 119119 472472 182182 216216 229229 381381
3232 3838 120120 6161 189189 62736273 230230 13321332
3333 4242 121121 9595 193193 5656 231231 482482
3434 1616 124124 4141 194194 15921592 233233 2020
3636 14821482 125125 31563156 195195 10331033 234234 7.77.7
3737 10151015 127127 2121 196196 2.12.1
3838 36893689 128128 2828 197197 17201720
4141 359359 129129 11281128 198198 601601
실험예 3. CDK2(Cyclin-Dependent protein Kinase, CDK2) 효소 저해능 평가Experimental Example 3. CDK2 (Cyclin-Dependent Protein Kinase, CDK2) enzyme inhibitory ability evaluation
본 발명에 따른 실시예 화합물의 CDK2(Cyclin-Dependent protein Kinase, CDK2) 효소 저해능을 평가하기 위해 하기와 같은 실험을 수행하였다.In order to evaluate the CDK2 (Cyclin-Dependent Protein Kinase, CDK2) enzyme inhibitory ability of the Example compound according to the present invention, the following experiment was performed.
실시예 화합물을 정제된 human GST-CDK2/CyclinE1(full-length human CDK2 and CyclinE1 were co-expressed protein, SignalChem) 효소와 반응하여, 하기와 같은 방법으로 효소 저해능을 평가하였다. 반응 버퍼는 40 mM Tris-HCl pH 7.4, 20 mM MgCl2, 0.5 mg/mL BSA, 및 50 μM DTT 조성을 사용하였으며 모든 시험물은 반응 버퍼상에서 반응을 수행하였다. 시험 시 human GST-CDK2/CyclinE1(1.5 ng) 효소와 정제된 ATP(50 μM), 특이적인 기질용액을 30 ℃ 상에서 4 시간 동안 반응시킨 후, in vitro ADP-GloTM kinase assay (promega)를 이용하여 효소활성을 확인하였다. 2:2:1 비율로 효소활성 반응액과 ADP-Glo 반응액, 효소능 검출용액을 반응시켜서 형광도를 측정하였다. 화합물을 처리하지 않은 용매 대조군 효소활성의 형광도를 기준으로 각 화합물들의 처리 농도에 따른 효소활성 저해 정도를 산출하였으며, 이때 효소활성을 50 % 억제하는 각 화합물의 농도를 IC50(nM) 값으로 결정하였다. 각 화합물의 IC50는 GraphPad Prism 8.3.0(GraphPad software Inc., San Diego) 소프트웨어를 이용하여 구하였다. 그 결과는 하기 표 7에 나타내었다.Example compounds were reacted with purified human GST-CDK2/CyclinE1 (full-length human CDK2 and CyclinE1 were co-expressed protein, SignalChem) enzymes, and the enzyme inhibitory ability was evaluated as follows. The reaction buffer was 40 mM Tris-HCl pH 7.4, 20 mM MgCl 2 , 0.5 mg/mL BSA, and 50 μM DTT composition. All test materials were reacted in the reaction buffer. In the test, human GST-CDK2/CyclinE1 (1.5 ng) enzyme, purified ATP (50 μM), and a specific substrate solution were reacted at 30 °C for 4 hours, followed by in vitro ADP-Glo TM kinase assay (promega) Thus, the enzyme activity was confirmed. The fluorescence was measured by reacting the enzyme activity reaction solution with the ADP-Glo reaction solution and the enzyme activity detection solution in a 2:2:1 ratio. The degree of inhibition of enzyme activity according to the treatment concentration of each compound was calculated based on the fluorescence of the enzyme activity of the solvent control that was not treated with the compound. It was decided. IC 50 of each compound was obtained using GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego) software. The results are shown in Table 7 below.
실시예Example CDK2/E1CDK2/E1
ICIC 5050 (nM)(nM) 		실시예Example CDK2/E1CDK2/E1
ICIC 5050 (nM)(nM) 		실시예Example CDK2/E1CDK2/E1
ICIC 5050 (nM)(nM) 		실시예Example CDK2/E1CDK2/E1
ICIC 5050 (nM)(nM)
2121 53505350 8181 722722 129129 944944 168168 15581558
3232 6464 8282 13761376 131131 656656 170170 6464
3333 6969 8383 15521552 132132 8282 171171 538538
3434 6464 8484 23622362 133133 7979 175175 990990
4444 755755 8585 17671767 137137 519519 186186 22952295
4545 591591 8686 444444 138138 20782078 193193 1414
5454 49594959 8888 62596259 143143 7676 194194 45794579
5555 26512651 8989 805805 145145 379379 195195 66156615
5656 34203420 9090 631631 147147 16911691 196196 255255
5757 30733073 9494 841841 148148 13931393 198198 413413
5858 65646564 9696 683683 149149 15851585 199199 107107
5959 411411 9797 31273127 150150 241241 201201 265265
6060 70097009 9898 668668 151151 102102 202202 708708
6363 43264326 9999 15241524 153153 14151415 203203 181181
6464 11031103 103103 23362336 154154 10801080 204204 57585758
6666 366366 105105 11141114 156156 584584 207207 20992099
6969 19451945 106106 51865186 160160 15811581 208208 30313031
7070 13221322 108108 10481048 161161 31903190 209209 12981298
7373 39793979 109109 20312031 163163 48464846 210210 21102110
7474 17341734 113113 693693 165165 3636 213213 18231823
7676 54365436 127127 4242 166166 385385 218218 178178
7979 958958 128128 3939 167167 12371237 234234 5050
실험예 4. HPK1(Hematopoietic Progenitor Kinase 1) 효소 저해능 평가Experimental Example 4. HPK1 (Hematopoietic Progenitor Kinase 1) enzyme inhibition evaluation
본 발명에 따른 실시예 화합물의 HPK1 효소 저해능을 평가하기 위하여 다음과 같은 방법으로 수행하였다.In order to evaluate the HPK1 enzyme inhibitory ability of the example compounds according to the present invention, the following method was performed.
실시예 화합물을 정제된 human HPK1(1-346, SignalChem) 효소와 반응하여, 하기와 같은 방법으로 효소 저해능을 평가하였다. 반응 버퍼는 40 mM Tris-HCl pH 7.4, 20 mM MgCl2, 0.5 mg/ml BSA, 50 μM DTT 조성으로 사용하였으며, 모든 시험물의 반응은 반응 버퍼상에서 이루어졌다. 화합물은 10 mM DMSO 스톡을 계열 희석법으로 12 단계로 희석하였으며, 최종 화합물의 농도 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003, 0.0001, 0.00003 μM에서 효소 활성을 측정하였다. 시험 시 human HPK1(3 ng) 효소와 정제된 ATP(3 μM), 효소 기질(0.1 μg)과 25 ℃에서 2 시간 동안 반응시킨 후, in vitro ADP-GloTM kinase assay(promega)을 이용하여 효소활성을 확인하였다. 2:2:1 비율로 효소활성 반응액과 ADP-Glo 반응액, 효소활성 검출용액을 반응시켜서 효소의 활성 저해도를 형광도로 측정하였다. 화합물을 처리하지 않은 용매 대조군 효소활성의 형광도를 기준으로 각 화합물들의 처리 농도에 따른 효소활성 저해 정도를 산출하였으며, 이때 효소활성을 50 % 억제하는 각 화합물의 농도를 IC50(nM) 값으로 결정하였고, GraphPad Prism 8.3.0(GraphPad software Inc., San Diego)을 이용하여 구하였다. 그 결과를 하기 표 8에 정리하여 나타내었다.The example compound was reacted with purified human HPK1 (1-346, SignalChem) enzyme, and the enzyme inhibitory ability was evaluated as follows. The reaction buffer was 40 mM Tris-HCl pH 7.4, 20 mM MgCl 2 , 0.5 mg/ml BSA, and 50 μM DTT composition, and all test materials were reacted in the reaction buffer. Compounds were diluted in 12 steps from a 10 mM DMSO stock by serial dilution, and enzyme activity was measured at concentrations of 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003, 0.0001, 0.00003 μM of the final compound. . In the test, the enzyme was reacted with human HPK1 (3 ng) enzyme, purified ATP (3 μM), and enzyme substrate (0.1 μg) at 25 °C for 2 hours, and then the enzyme was used in vitro ADP-Glo TM kinase assay (promega). Activity was confirmed. By reacting the enzyme activity reaction solution with the ADP-Glo reaction solution and the enzyme activity detection solution in a 2:2:1 ratio, the degree of inhibition of enzyme activity was measured by fluorescence. The degree of inhibition of enzyme activity according to the treatment concentration of each compound was calculated based on the fluorescence of the enzyme activity of the solvent control that was not treated with the compound. It was determined and obtained using GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego). The results are summarized in Table 8 below.
실시예Example ICIC 5050 (nM)(nM) 실시예Example ICIC 5050 (nM)(nM) 실시예Example ICIC 5050 (nM)(nM) 실시예Example ICIC 5050 (nM)(nM)
4545 4848 8989 4646 126126 598598 181181 4141
5858 62276227 9090 3333 127127 2828 182182 6363
5959 407407 9191 107107 128128 1515 183183 735735
6464 100100 9292 4646 129129 609609 184184 913913
6666 2323 9393 55 132132 3.93.9 185185 704704
6868 76787678 9494 277277 133133 0.930.93 186186 491491
6969 967967 9696 1414 134134 3434 192192 378378
7070 16061606 9797 140140 135135 4444 210210 143143
7373 254254 9898 3636 136136 1313 211211 1010
7474 569569 9999 5959 138138 2222 212212 2929
7979 3939 101101 309309 139139 55985598 213213 9595
8181 5353 102102 761761 150150 21652165 214214 1616
8282 1212 103103 143143 151151 4242 215215 3939
8383 1313 106106 17791779 152152 189189 216216 7272
8484 7979 107107 11991199 157157 78967896 217217 68026802
8585 1717 108108 113113 158158 16351635 218218 4343
8686 1515 113113 8181 175175 49844984
8787 4949 114114 933933 179179 872872
8888 245245 115115 238238 180180 11361136
실험예 5. MCF-7 세포 성장 저해능 평가Experimental Example 5. MCF-7 cell growth inhibitory ability evaluation
MCF-7 유방암세포(한국세포주은행)를 clear bottom white 96-웰 플레이트(Corning)에 3 Х 103 / 150 μl/웰이 되도록 심었다. 그 다음, 3 배수로 연속 희석된 12 가지 농도(0.00001 - 2 mM)의 화합물 또는 DMSO 대조군이 포함된 배양액을 0.5 μl/웰씩 첨가하여 최종농도가 0.00005 - 10 μM이 되도록 처리한 뒤 37 ℃ CO2 배양기에서 120 시간 동안 배양하였다. 120 시간 후, 화합물을 처리한 플레이트를 꺼내어, CellTiter-Glo® 2.0 Assay(Promega) 용액을 150 μl/웰씩 처리한 후, 잘 섞어 주었다. 상온에서 10 분 정도 잘 섞어 주고, 마이크로플레이트 판독기로 형광도를 측정하였다. 데이터는 비히클 기준 처리된 세포에 비례하여 백분율로 나타내었고, GraphPad Prism 8.3.0(GraphPad software Inc., San Diego)을 이용하여 GI50(nM) 값을 산출하였다. 그 결과를 표 9에 정리하여 나타내었다.MCF-7 breast cancer cells (Korea Cell Line Bank) were planted in a clear bottom white 96-well plate (Corning) to 3 Х 10 3 / 150 μl/well. Then, 0.5 μl/well of a culture solution containing 12 concentrations (0.00001 - 2 mM) of a compound or DMSO control serially diluted in 3 folds was added at a time to a final concentration of 0.00005 - 10 μM, followed by a 37 ° C CO 2 incubator incubated for 120 hours. After 120 hours, the plate treated with the compound was taken out, 150 μl/well of CellTiter-Glo® 2.0 Assay (Promega) solution was treated, and then mixed well. After mixing well for about 10 minutes at room temperature, the fluorescence was measured with a microplate reader. Data were expressed as a percentage relative to the treated cells relative to the vehicle standard, and GI 50 (nM) values were calculated using GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego). The results are summarized in Table 9 and shown.
실시예Example GIGI 5050 (nM)(nM) 실시예Example GIGI 5050 (nM)(nM) 실시예Example GIGI 5050 (nM)(nM) 실시예Example GIGI 5050 (nM)(nM)
22 51885188 9393 413413 129129 10561056 183183 10941094
88 33623362 9494 11241124 131131 378378 184184 12701270
1515 57175717 9696 404404 132132 387387 185185 11611161
3434 151151 9898 15631563 133133 372372 186186 738738
4141 56395639 9999 14241424 134134 26402640 187187 20302030
4444 823823 101101 14801480 135135 23522352 188188 11741174
4545 362362 102102 11751175 136136 13161316 191191 12121212
5858 34183418 103103 11041104 137137 20062006 192192 42284228
5959 808808 106106 31223122 138138 28572857 193193 520520
6464 11451145 107107 11101110 139139 16121612 194194 18471847
6565 19711971 108108 11401140 140140 392392 196196 8888
6666 818818 109109 712712 142142 31813181 201201 405405
6868 85488548 110110 15441544 150150 29132913 202202 176176
6969 16121612 111111 51865186 151151 252252 203203 11521152
7070 17951795 112112 33223322 152152 915915 210210 249249
7373 239239 113113 11821182 157157 35743574 212212 21992199
7474 33413341 114114 12561256 158158 11611161 213213 12751275
7979 178178 115115 266266 165165 43684368 214214 10861086
8080 18881888 116116 18211821 166166 11131113 215215 12821282
8181 18621862 117117 767767 170170 11671167 216216 28412841
8282 13021302 118118 21242124 174174 11661166 217217 12811281
8383 24262426 119119 13661366 175175 32453245 218218 636636
8484 22052205 121121 15791579 176176 19311931 223223 13581358
8585 135135 122122 28672867 177177 14501450 225225 39403940
8686 12161216 123123 20182018 178178 97049704 233233 35153515
8787 17541754 124124 697697 179179 762762 234234 124124
8989 11081108 126126 11601160 180180 11411141
9090 11241124 127127 7474 181181 26792679
9191 11991199 128128 6262 182182 15231523
실험예 6. CCNE 과발현 세포 성장 저해능 평가Experimental Example 6. Evaluation of CCNE overexpression cell growth inhibitory ability
OVCAR-3 난소암 세포(한국세포주은행)를 clear bottom white 96-웰 플레이트(Corning)에 5 Х 103/200 μl/웰이 되도록 심었다. 그 다음, 3 배수로 연속 희석된 11 가지 농도(0.00003 - 2 mM)의 화합물 또는 DMSO 대조군이 포함된 배양액을 0.5 μl/웰씩 첨가하여 최종농도가 0.0002 - 10 μM이 되도록 처리한 뒤 37 ℃, CO2 배양기에서 120 시간 동안 배양하였다. 120 시간 후, 화합물을 처리한 플레이트를 꺼내어, 각 well에 CellTiter-Glo® 2.0 Assay (Promega) 용액을 100 μl씩 처리한 후, 잘 섞어 주었다. 상온에서 10 분 정도 잘 섞어 주고, 마이크로플레이트 판독기로 형광도를 측정하였다. GI50 (nM)는 측정된 luminescence 값을 토대로 GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego)을 이용하여 산출하였다. 그 결과를 표 10에 정리하여 나타내었다.OVCAR-3 ovarian cancer cells (Korea Cell Line Bank) were planted in a clear bottom white 96-well plate (Corning) at a volume of 5 Х 10 3 /200 μl/well. Then, 0.5 μl/well of a culture solution containing 11 concentrations (0.00003 - 2 mM) of the compound or DMSO control, serially diluted in 3 folds, was added at a time to a final concentration of 0.0002 - 10 μM, followed by treatment at 37 ° C, CO 2 Incubated for 120 hours in an incubator. After 120 hours, the plate treated with the compound was taken out, and 100 μl of CellTiter-Glo® 2.0 Assay (Promega) solution was treated in each well, and then mixed well. After mixing well for about 10 minutes at room temperature, the fluorescence was measured with a microplate reader. GI 50 (nM) was calculated using GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego) based on the measured luminescence value. The results are summarized in Table 10 and shown.
실시예Example GIGI 5050 (nM)(nM)
127127 409409

Claims (12)

  1. 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염:A compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2021018956-appb-img-000276
    Figure PCTKR2021018956-appb-img-000276
    상기 화학식 1에서,In Formula 1,
    고리 A1은 아릴 또는 헤테로아릴이고 {여기서, 상기 아릴 또는 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -C1-6알킬-O-C1-6알킬, -CN, -(C=O)NR3R4, -(C=O)OR5, -NR6R7, -OR8, -할로, 아릴 또는 헤테로아릴로 치환될 수 있음}; Ring A 1 is aryl or heteroaryl {wherein at least one H of said aryl or heteroaryl ring is -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1 -6 Haloalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -CN, -(C=O)NR 3 R 4 , -(C=O)OR 5 , -NR 6 R 7 , -OR 8 , which may be substituted with halo, aryl or heteroaryl};
    고리 A2는 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬이고 Ring A 2 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
    {여기서, 상기 아릴 또는 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬, -C1-6하이드록시알킬, -C1-6아미노알킬, -C1-6할로알킬, -C1-6알킬-CN, -CN, -C1-6알킬-O-C1-6알킬, -C1-6알킬NR9R10, -(C=O)NR9R10, -C1-6알킬-(C=O)NR9R10, -(C=O)-C1-6알킬, -(C=O)OR11, -C1-6알킬-(C=O)OR11, -NR12R13, -OR14, -할로, -S-C1-6알킬, -SO2-C1-6알킬, -SO2-NR12R13, -SO2-할로, -(S=O)NH-C1-6알킬, -S(=O)(=NH)-C1-6알킬, 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C1-6알킬-사이클로알킬, -C1-6알킬-헤테로사이클로알킬, -(C=O)-사이클로알킬, -(C=O)-헤테로사이클로알킬, -NH(C=O)-사이클로알킬, -NH(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴로 치환될 수 있고 [이때, 상기 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C1-6알킬-사이클로알킬, -C1-6알킬-헤테로사이클로알킬, -(C=O)-사이클로알킬, -(C=O)-헤테로사이클로알킬, -NH(C=O)-사이클로알킬, -NH(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬, -(=O)-, -(C=O)-C1-6알킬, -(C=O)NR15R16, -(C=O)OR17, -NR18R19, -할로, -SO2-, 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬로 치환될 수 있음 (상기 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6하이드록시알킬, -C1-6아미노알킬, -C1-6할로알킬, -NR20R21, 또는 사이클로알킬로 치환될 수 있음)], 또는 상기 아릴 또는 헤테로아릴의 2 이상의 치환기가 서로 연결되어 융합 고리를 형성할 수 있고 [여기서, 상기 융합 고리의 하나 이상의 H는 -C1-6알킬, -(=O)-, -(C=O)-C1-6알킬, -(C=O)O-C1-6알킬, -NR22R23, -O-C1-6알킬, 할로, -SO2-C1-6알킬, 사이클로알킬, 또는 헤테로사이클로알킬로 치환될 수 있음]; {Wherein, at least one H of the aryl or heteroaryl ring is -C 1-6 alkyl, -C 1-6 hydroxyalkyl, -C 1-6 aminoalkyl, -C 1-6 haloalkyl, -C 1 6 alkyl-CN, -CN, -C 1-6 alkyl-OC 1-6 alkyl, -C 1-6 alkylNR 9 R 10 , -(C=O)NR 9 R 10 , -C 1-6 alkyl- (C=O)NR 9 R 10 , -(C=O)-C 1-6 alkyl, -(C=O)OR 11 , -C 1-6 alkyl-(C=O)OR 11 , -NR 12 R 13 , -OR 14 , -halo, -SC 1-6 alkyl, -SO 2 -C 1-6 alkyl, -SO 2 -NR 12 R 13 , -SO 2 -halo, -(S=O)NH- C 1-6 alkyl, -S(=O)(=NH)-C 1-6 alkyl, cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C 1-6 alkyl-cycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, -(C=O)-cycloalkyl, -(C=O)-heterocycloalkyl, -NH(C=O)-cycloalkyl, -NH(C=O)-heterocycloalkyl, may be substituted with aryl, -(C=O)-aryl, or heteroaryl [wherein said cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C 1-6 alkyl-cycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, -(C=O)-cycloalkyl, -(C=O)-heterocycloalkyl, -NH(C=O)-cycloalkyl, -NH(C=O)-heterocycloalkyl, At least one H of an aryl, -(C=O)-aryl, or heteroaryl ring is -C 1-6 alkyl, -(=O)-, -(C=O)-C 1-6 alkyl, -(C =O)NR 15 R 16 , -(C=O)OR 17 , -NR 18 R 19 , -halo, -SO 2 -, cycloalkyl, heterocycloalkyl, or heterobicycloalkyl (supra At least one H of a cycloalkyl, heterocycloalkyl, or heterobicycloalkyl ring is -C 1-6 alkyl, -C 1-6 hydroxyalkyl, -C 1-6 aminoalkyl, -C 1-6 haloalkyl, -NR 20 R 21 , or may be substituted with cycloalkyl)], or two or more substituents of the aryl or heteroaryl may be linked to each other to form a fused ring, wherein at least one H of the fused ring is —C 1-6 alkyl; -(=O)-, -(C=O)-C 1-6 alkyl, -(C=O)OC 1-6 alkyl, -NR 22 R 23 , -OC 1-6 alkyl, halo, -SO 2 -C 1-6 alkyl, cycloalkyl, or heterocycloalkyl];
    상기 사이클로알킬 또는 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6하이드록시알킬, -(C=O)-C1-6알킬, -(C=O)O-C1-6알킬, 또는 -SO2-C1-6알킬로 치환될 수 있음}; at least one H of said cycloalkyl or heterocycloalkyl ring is -C 1-6 alkyl, -C 1-6 hydroxyalkyl, -(C=O)-C 1-6 alkyl, -(C=O)OC 1 -6 alkyl, or —SO 2 —C 1-6 alkyl};
    R1은 -H 또는 -C1-6알킬이고;R 1 is —H or —C 1-6 alkyl;
    R2는 -H, -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -CN, -할로, 또는 5-7원 고리이고 {여기서, 상기 5-7원 고리의 하나 이상의 H는 -C1-6알킬, -C1-6할로알킬, 또는 할로로 치환될 수 있음};R 2 is -H, -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1-6 haloalkyl, -CN, -halo, or 5-7 membered ring and {wherein, one or more H of the 5-7 membered ring may be substituted with -C 1-6 alkyl, -C 1-6 haloalkyl, or halo};
    R3 내지 R7은 각각 독립적으로 -H 또는 -C1-6알킬이고;R 3 to R 7 are each independently —H or —C 1-6 alkyl;
    R8은 -H, -C1-6알킬, 페닐 또는 벤질이고;R 8 is —H, —C 1-6 alkyl, phenyl or benzyl;
    R9 및 R10은 각각 독립적으로 -H, -C1-6알킬, -C1-6하이드록시알킬, -C1-6알킬-NR24R25, 또는 헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};R 9 and R 10 are each independently —H, —C 1-6 alkyl, —C 1-6 hydroxyalkyl, —C 1-6 alkyl-NR 24 R 25 , or heterocycloalkyl {wherein the hetero one or more H of the cycloalkyl ring may be substituted with —C 1-6 alkyl};
    R11은 -H 또는 -C1-6알킬이고;R 11 is —H or —C 1-6 alkyl;
    R12 및 R13은 각각 독립적으로 -H, -C1-6알킬, -C1-6알킬-NR24R25, 또는 -(C=O)O-C1-6알킬이고;R 12 and R 13 are each independently —H, —C 1-6 alkyl, —C 1-6 alkyl-NR 24 R 25 , or —(C=O)OC 1-6 alkyl;
    R14은 각각 독립적으로 -H, -C1-6알킬, -C1-6알킬-NR26R27, 헤테로사이클로알킬, 또는 -C1-6알킬-헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 또는 -C1-6알킬-헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};each R 14 is independently —H, —C 1-6 alkyl, —C 1-6 alkyl-NR 26 R 27 , heterocycloalkyl, or —C 1-6 alkyl-heterocycloalkyl {wherein the heterocyclo one or more H of an alkyl or —C 1-6 alkyl-heterocycloalkyl ring may be substituted with —C 1-6 alkyl;
    R15 내지 R17은 각각 독립적으로 -H 또는 -C1-6알킬이고;R 15 to R 17 are each independently —H or —C 1-6 alkyl;
    R18 및 R19은 각각 독립적으로 -C1-6알킬 또는 -C1-6알킬-NR28R29이고;R 18 and R 19 are each independently —C 1-6 alkyl or —C 1-6 alkyl-NR 28 R 29 ;
    R20 내지 R29은 각각 독립적으로 -H 또는 -C1-6알킬이다.R 20 to R 29 are each independently —H or —C 1-6 alkyl.
  2. 제 1 항에 있어서, The method of claim 1,
    고리 A1은 아릴 또는 헤테로아릴이고 {여기서, 상기 아릴 또는 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬, -C1-6할로알킬, -CN, -NR6R7, -OR8, 또는 -할로로 치환될 수 있음}; Ring A 1 is aryl or heteroaryl {wherein at least one H of said aryl or heteroaryl ring is -C 1-6 alkyl, -C 1-6 haloalkyl, -CN, -NR 6 R 7 , -OR 8 , or - may be substituted with halo};
    고리 A2는 아릴, 헤테로아릴, 또는 헤테로사이클로알킬이고ring A 2 is aryl, heteroaryl, or heterocycloalkyl;
    {여기서, 상기 아릴 또는 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬, -C1-6할로알킬, -C1-6알킬-CN, -CN, -C1-6알킬-O-C1-6알킬, -C1-6알킬NR9R10, -(C=O)NR9R10, -C1-6알킬-(C=O)NR9R10, -(C=O)-C1-6알킬, -(C=O)OR11, -NR12R13, -OR14, -할로, -S-C1-6알킬, -SO2-C1-6알킬, -SO2-NR12R13, -SO2-할로, -S(=O)(=NH)-C1-6알킬, 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C1-6알킬-헤테로사이클로알킬, -(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴로 치환될 수 있고 [이때, 상기 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C1-6알킬-헤테로사이클로알킬, -(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬, -(=O)-, -(C=O)-C1-6알킬, -(C=O)NR15R16, -(C=O)OR17, -NR18R19, -할로, -SO2-, 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬로 치환될 수 있음 (상기 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6하이드록시알킬, 또는 -NR20R21로 치환될 수 있음)], 또는 상기 아릴 또는 헤테로아릴의 2 이상의 치환기가 서로 연결되어 융합 고리를 형성할 수 있고 [여기서, 상기 융합 고리의 하나 이상의 H는 -C1-6알킬, -(=O)-, -(C=O)-C1-6알킬, -(C=O)O-C1-6알킬, -NR22R23, -O-C1-6알킬, 할로, -SO2-C1-6알킬, 또는 사이클로알킬로 치환될 수 있음]; {wherein at least one H of the aryl or heteroaryl ring is -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-CN, -CN, -C 1-6 alkyl-OC 1 -6 alkyl, -C 1-6 alkylNR 9 R 10 , -(C=O)NR 9 R 10 , -C 1-6 alkyl-(C=O)NR 9 R 10 , -(C=O)- C 1-6 alkyl, -(C=O)OR 11 , -NR 12 R 13 , -OR 14 , -halo, -SC 1-6 alkyl, -SO 2 -C 1-6 alkyl, -SO 2 -NR 12 R 13 , —SO 2 -halo, —S(=O)(=NH)—C 1-6 alkyl, cycloalkyl, heterocycloalkyl, heterobicycloalkyl, —C 1-6 alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, aryl, -(C=O)-aryl, or heteroaryl [wherein said cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C 1 - At least one H of a 6 alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, aryl, -(C=O)-aryl, or heteroaryl ring is -C 1-6 alkyl, -(=O) -, -(C=O)-C 1-6 alkyl, -(C=O)NR 15 R 16 , -(C=O)OR 17 , -NR 18 R 19 , -halo, -SO 2 -, cyclo may be substituted with alkyl, heterocycloalkyl, or heterobicycloalkyl (one or more H of the cycloalkyl, heterocycloalkyl, or heterobicycloalkyl ring is -C 1-6 alkyl, -C 1-6 hydroxy alkyl, or -NR 20 R 21 )], or two or more substituents of the aryl or heteroaryl may be linked to each other to form a fused ring, wherein at least one H of the fused ring is -C 1-6 alkyl, -(=O)-, -(C=O)-C 1-6 alkyl, -(C=O)OC 1-6 alkyl, -NR 22 R 23 , -OC 1-6 alkyl, may be substituted with halo, —SO 2 —C 1-6 alkyl, or cycloalkyl];
    상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6하이드록시알킬, -(C=O)-C1-6알킬, -(C=O)O-C1-6알킬, 또는 -SO2-C1-6알킬로 치환될 수 있음}; at least one H of the heterocycloalkyl ring is -C 1-6 alkyl, -C 1-6 hydroxyalkyl, -(C=O)-C 1-6 alkyl, -(C=O)OC 1-6 alkyl , or —SO 2 —C 1-6 alkyl};
    R1은 -H이고;R 1 is —H;
    R2는 -H, -C1-6알킬, -C1-6할로알킬, -CN, -할로, 또는 5-7원 고리이고 {여기서, 상기 5-7원 고리의 하나 이상의 H는 -C1-6알킬 또는 할로로 치환될 수 있음};R 2 is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -CN, -halo, or a 5-7 membered ring {wherein at least one H of the 5-7 membered ring is -C may be substituted with 1-6 alkyl or halo};
    R6 및 R7은 각각 독립적으로 -C1-6알킬이고;R 6 and R 7 are each independently —C 1-6 alkyl;
    R8은 -H, -C1-6알킬, 또는 페닐이고;R 8 is —H, —C 1-6 alkyl, or phenyl;
    R9 및 R10은 각각 독립적으로 -H, -C1-6알킬, -C1-6하이드록시알킬, -C1-6알킬-NR24R25, 또는 헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};R 9 and R 10 are each independently —H, —C 1-6 alkyl, —C 1-6 hydroxyalkyl, —C 1-6 alkyl-NR 24 R 25 , or heterocycloalkyl {wherein the hetero one or more H of the cycloalkyl ring may be substituted with —C 1-6 alkyl};
    R11은 -C1-6알킬이고;R 11 is —C 1-6 alkyl;
    R12 및 R13은 각각 독립적으로 -H, -C1-6알킬, 또는 -(C=O)O-C1-6알킬이고;R 12 and R 13 are each independently —H, —C 1-6 alkyl, or —(C=O)OC 1-6 alkyl;
    R14은 각각 독립적으로 -C1-6알킬, -C1-6알킬-NR26R27, 헤테로사이클로알킬, 또는 -C1-6알킬-헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 또는 -C1-6알킬-헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};each R 14 is independently —C 1-6 alkyl, —C 1-6 alkyl-NR 26 R 27 , heterocycloalkyl, or —C 1-6 alkyl-heterocycloalkyl {wherein said heterocycloalkyl or — one or more H of a C 1-6 alkyl-heterocycloalkyl ring may be substituted with —C 1-6 alkyl};
    R15 내지 R17은 각각 독립적으로 -C1-6알킬이고;R 15 to R 17 are each independently —C 1-6 alkyl;
    R18 및 R19은 각각 독립적으로 -C1-6알킬 또는 -C1-6알킬-NR28R29이고;R 18 and R 19 are each independently —C 1-6 alkyl or —C 1-6 alkyl-NR 28 R 29 ;
    R20 내지 R23, R26 내지 R29은 각각 독립적으로 -H 또는 -C1-6알킬인;R 20 to R 23 , R 26 to R 29 are each independently —H or —C 1-6 alkyl;
    화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  3. 제 1 항에 있어서, The method of claim 1,
    고리 A1은 페닐 또는 피리디닐이고 {여기서, 상기 페닐 또는 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬, -C1-6아미노알킬, -C1-6하이드록시알킬, -C1-6할로알킬, -C1-6알킬-O-C1-6알킬, -CN, -(C=O)NR3R4, -(C=O)OR5, -NR6R7, -OR8, -할로, 아릴 또는 헤테로아릴로 치환될 수 있음}; Ring A 1 is phenyl or pyridinyl {wherein at least one H of said phenyl or heteroaryl ring is -C 1-6 alkyl, -C 1-6 aminoalkyl, -C 1-6 hydroxyalkyl, -C 1 -6 Haloalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -CN, -(C=O)NR 3 R 4 , -(C=O)OR 5 , -NR 6 R 7 , -OR 8 , which may be substituted with halo, aryl or heteroaryl};
    R3 내지 R7은 각각 독립적으로 -H 또는 -C1-6알킬이고;R 3 to R 7 are each independently —H or —C 1-6 alkyl;
    R8은 -H, -C1-6알킬, 페닐 또는 벤질인;R 8 is -H, -C 1-6 alkyl, phenyl or benzyl;
    화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  4. 제 1 항에 있어서, The method of claim 1,
    고리 A2는 페닐, 5-6원 헤테로아릴, 3-7원 사이클로알킬, 또는 3-7원 헤테로사이클로알킬이고 Ring A 2 is phenyl, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, or 3-7 membered heterocycloalkyl
    {여기서, 상기 페닐 또는 5-6원 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬, -C1-6하이드록시알킬, -C1-6아미노알킬, -C1-6할로알킬, -C1-6알킬-CN, -CN, -C1-6알킬-O-C1-6알킬, -C1-6알킬NR9R10, -(C=O)NR9R10, -C1-6알킬-(C=O)NR9R10, -(C=O)-C1-6알킬, -(C=O)OR11, -C1-6알킬-(C=O)OR11, -NR12R13, -OR14, -할로, -S-C1-6알킬, -SO2-C1-6알킬, -SO2-NR12R13, -SO2-할로, -(S=O)NH-C1-6알킬, -S(=O)(=NH)-C1-6알킬, 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C1-6알킬-사이클로알킬, -C1-6알킬-헤테로사이클로알킬, -(C=O)-사이클로알킬, -(C=O)-헤테로사이클로알킬, -NH(C=O)-사이클로알킬, -NH(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴로 치환될 수 있고 [이때, 상기 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C1-6알킬-사이클로알킬, -C1-6알킬-헤테로사이클로알킬, -(C=O)-사이클로알킬, -(C=O)-헤테로사이클로알킬, -NH(C=O)-사이클로알킬, -NH(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴 고리의 하나 이상의 H는 -C1-6알킬, -(=O)-, -(C=O)-C1-6알킬, -(C=O)NR15R16, -(C=O)OR17, -NR18R19, -할로, -SO2-, 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬로 치환될 수 있음 (상기 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6하이드록시알킬, -C1-6아미노알킬, -C1-6할로알킬, -NR20R21, 또는 사이클로알킬로 치환될 수 있음)], 또는 상기 아릴 또는 헤테로아릴의 2 이상의 치환기가 서로 연결되어 융합 고리를 형성할 수 있고 [여기서, 상기 융합 고리의 하나 이상의 H는 -C1-6알킬, -(=O)-, -(C=O)-C1-6알킬, -(C=O)O-C1-6알킬, -NR22R23, -O-C1-6알킬, 할로, -SO2-C1-6알킬, 사이클로알킬, 또는 헤테로사이클로알킬로 치환될 수 있음]; {Wherein, at least one H of the phenyl or 5-6 membered heteroaryl ring is -C 1-6 alkyl, -C 1-6 hydroxyalkyl, -C 1-6 aminoalkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-CN, -CN, -C 1-6 alkyl-OC 1-6 alkyl, -C 1-6 alkylNR 9 R 10 , -(C=O)NR 9 R 10 , -C 1 -6 alkyl-(C=O)NR 9 R 10 , -(C=O)-C 1-6 alkyl, -(C=O)OR 11 , -C 1-6 alkyl-(C=O)OR 11 , -NR 12 R 13 , -OR 14 , -halo, -SC 1-6 alkyl, -SO 2 -C 1-6 alkyl, -SO 2 -NR 12 R 13 , -SO 2 -halo, -(S= O)NH-C 1-6 alkyl, -S(=O)(=NH)-C 1-6 alkyl, cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C 1-6 alkyl-cycloalkyl, - C 1-6 Alkyl-heterocycloalkyl, -(C=O)-cycloalkyl, -(C=O)-heterocycloalkyl, -NH(C=O)-cycloalkyl, -NH(C=O)- which may be substituted with heterocycloalkyl, aryl, -(C=O)-aryl, or heteroaryl [wherein said cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C 1-6 alkyl-cycloalkyl, - C 1-6 Alkyl-heterocycloalkyl, -(C=O)-cycloalkyl, -(C=O)-heterocycloalkyl, -NH(C=O)-cycloalkyl, -NH(C=O)- At least one H of a heterocycloalkyl, aryl, -(C=O)-aryl, or heteroaryl ring is -C 1-6 alkyl, -(=O)-, -(C=O)-C 1-6 alkyl to be substituted with , -(C=O)NR 15 R 16 , -(C=O)OR 17 , -NR 18 R 19 , -halo, -SO 2 -, cycloalkyl, heterocycloalkyl, or heterobicycloalkyl can be (at least one H of the cycloalkyl, heterocycloalkyl, or heterobicycloalkyl ring is -C 1-6 alkyl, -C 1-6 hydroxyalkyl, -C 1-6 aminoalkyl, -C 1 6 haloalkyl, -NR 20 R 21 , or may be substituted with cycloalkyl)], or two or more substituents of the aryl or heteroaryl may be linked to each other to form a fused ring, wherein at least one H of the fused ring is —C 1-6 alkyl, -(=O)-, -(C=O)-C 1-6 alkyl, -(C=O)OC 1-6 alkyl, -NR 22 R 23 , -OC 1-6 alkyl, halo, - SO 2 -C 1-6 alkyl, cycloalkyl, or heterocycloalkyl];
    상기 사이클로알킬 또는 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬, -C1-6하이드록시알킬, -(C=O)-C1-6알킬, -(C=O)O-C1-6알킬, 또는 -SO2-C1-6알킬로 치환될 수 있음}; at least one H of said cycloalkyl or heterocycloalkyl ring is -C 1-6 alkyl, -C 1-6 hydroxyalkyl, -(C=O)-C 1-6 alkyl, -(C=O)OC 1 -6 alkyl, or —SO 2 —C 1-6 alkyl};
    R9 및 R10은 각각 독립적으로 -H, -C1-6알킬, -C1-6하이드록시알킬, -C1-6알킬-NR24R25, 또는 헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};R 9 and R 10 are each independently —H, —C 1-6 alkyl, —C 1-6 hydroxyalkyl, —C 1-6 alkyl-NR 24 R 25 , or heterocycloalkyl {wherein the hetero one or more H of the cycloalkyl ring may be substituted with —C 1-6 alkyl};
    R11은 -H 또는 -C1-6알킬이고;R 11 is —H or —C 1-6 alkyl;
    R12 및 R13은 각각 독립적으로 -H, -C1-6알킬, -C1-6알킬-NR24R25, 또는 -(C=O)O-C1-6알킬이고;R 12 and R 13 are each independently —H, —C 1-6 alkyl, —C 1-6 alkyl-NR 24 R 25 , or —(C=O)OC 1-6 alkyl;
    R14은 각각 독립적으로 -H, -C1-6알킬, -C1-6알킬-NR26R27, 헤테로사이클로알킬, 또는 -C1-6알킬-헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 또는 -C1-6알킬-헤테로사이클로알킬 고리의 하나 이상의 H는 -C1-6알킬로 치환될 수 있음};each R 14 is independently —H, —C 1-6 alkyl, —C 1-6 alkyl-NR 26 R 27 , heterocycloalkyl, or —C 1-6 alkyl-heterocycloalkyl {wherein the heterocyclo one or more H of an alkyl or —C 1-6 alkyl-heterocycloalkyl ring may be substituted with —C 1-6 alkyl;
    R15 내지 R17은 각각 독립적으로 -H 또는 -C1-6알킬이고;R 15 to R 17 are each independently —H or —C 1-6 alkyl;
    R18 및 R19은 각각 독립적으로 -C1-6알킬 또는 -C1-6알킬-NR28R29이고;R 18 and R 19 are each independently —C 1-6 alkyl or —C 1-6 alkyl-NR 28 R 29 ;
    R20 내지 R29은 각각 독립적으로 -H 또는 -C1-6알킬인;R 20 to R 29 are each independently —H or —C 1-6 alkyl;
    화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  5. 제 1 항에 있어서,The method of claim 1,
    R1은 -H인;R 1 is -H;
    화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  6. 제 1 항에 있어서,The method of claim 1,
    R2는 -H, -C1-6알킬, -C1-6할로알킬, -CN, -할로, 또는 5-6원 고리인 {여기서, 상기 5-6원 고리의 하나 이상의 H는 -C1-6알킬, -C1-6할로알킬, 또는 할로로 치환될 수 있음};R 2 is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -CN, -halo, or a 5-6 membered ring {wherein at least one H of the 5-6 membered ring is -C may be substituted with 1-6 alkyl, —C 1-6 haloalkyl, or halo};
    화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  7. 제 1 항에 있어서,The method of claim 1,
    상기 화학식 1로 표시되는 화합물이 하기 화합물로 이루어진 군으로부터 선택된 것인, 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염:The compound represented by Formula 1 is selected from the group consisting of the following compounds, a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
    (1) (S)-N-(4-(4-메틸피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(1) ( S )-N-(4-(4- methylpiperidin -1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine;
    (2) (R)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(2) ( R )-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisooxazolidin-2-yl)pyrimidin-2-amine;
    (3) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(3,4,5-트라이메톡시페닐)피리미딘-2-아민;(3) ( S )-4-(3- phenylisooxazolidin -2-yl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine;
    (4) (S)-N-(4-(2-(다이에틸아미노)에톡시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(4) ( S )-N-(4-(2-( diethylamino )ethoxy)phenyl)-4-(3-phenylisooxazolidin-2-yl)pyrimidin-2-amine;
    (5) (S)-N-(4-(3-(다이에틸아미노)프로폭시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(5) ( S )-N-(4-(3-( diethylamino )propoxy)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine;
    (6) (S)-N-(4-(2-(다이에틸아미노)에톡시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(6) ( S )-N-(4-(2-(diethylamino)ethoxy)-3,5- dimethylphenyl )-4-(3-phenylisoxazolidin-2-yl)pyrimidine- 2-amine;
    (7) (S)-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(7) ( S )-N-(4-(3-(diethylamino)propoxy)-3,5- dimethylphenyl )-4-(3-phenylisoxazolidin-2-yl)pyrimidine- 2-amine;
    (8) (S)-N-(4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민;(8) ( S )-N-(4-(3- phenylisooxazolidin -2-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine;
    (9) (R)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-(3-페녹시페닐)아이소옥사졸리딘-2-일)피리미딘-2-아민;(9) ( R )-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-(3-phenoxyphenyl)isoxazolidin-2-yl)pyrimidine- 2-amine;
    (10) (S)-5-메틸-4-(3-페닐아이소옥사졸리딘-2-일)-N-(3,4,5-트라이메톡시페닐)피리미딘-2-아민;(10) ( S )-5-methyl-4-(3- phenylisooxazolidin -2-yl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine;
    (11) (S)-N-(4-(2-(다이에틸아미노)에톡시)페닐)-5-메틸-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(11) ( S )-N-(4-(2-( diethylamino )ethoxy)phenyl)-5-methyl-4-(3-phenylisooxazolidin-2-yl)pyrimidine-2- amines;
    (12) (S)-N-(4-(2-(다이에틸아미노)에톡시)-3,5-다이메틸페닐)-5-메틸-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(12) ( S )-N-(4-(2-(diethylamino)ethoxy)-3,5- dimethylphenyl )-5-methyl-4-(3-phenylisoxazolidin-2-yl ) pyrimidin-2-amine;
    (13) (S)-N-(4-(3-(다이에틸아미노)프로폭시)페닐)-5-메틸-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(13) ( S )-N-(4-(3-( diethylamino )propoxy)phenyl)-5-methyl-4-(3-phenylisooxazolidin-2-yl)pyrimidine-2- amines;
    (14) (S)-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)-5-메틸-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(14) ( S )-N-(4-(3-(diethylamino)propoxy)-3,5- dimethylphenyl )-5-methyl-4-(3-phenylisoxazolidin-2-yl ) pyrimidin-2-amine;
    (15) (S)-5-메틸-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(15) ( S )-5-methyl- N- (4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-2- amines;
    (16) (R)-5-메틸-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(16) ( R )-5-methyl- N- (4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-2- amines;
    (17) (S)-5-메틸-N-(4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(17) ( S )-5-methyl- N- (4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisoxazoli din-2-yl)pyrimidin-2-amine;
    (18) (S)-5-클로로-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(18) ( S )-5-chloro- N- (4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-2- amines;
    (19) (R)-5-클로로-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(19) ( R )-5-chloro- N- (4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-2- amines;
    (20) (R)-5-클로로-N-(1-(2-메톡시에틸)-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(20) ( R )-5-chloro- N- (1-(2-methoxyethyl) -1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl) pyrimidin-2-amine;
    (21) (R)-2-(4-((5-클로로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-일)아미노)-1H-피라졸-1-일)-N,N-다이메틸아세트아마이드;(21) ( R )-2-(4-((5-chloro-4-(3-phenylisooxazolidin-2-yl)pyrimidin-2-yl)amino) -1H -pyrazole-1 -yl) -N , N -dimethylacetamide;
    (22) (S)-5-클로로-4-(3-페닐아이소옥사졸리딘-2-일)-N-(3,4,5-트라이메톡시페닐)피리미딘-2-아민;(22) ( S )-5-chloro-4-(3- phenylisooxazolidin -2-yl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine;
    (23) (S)-5-클로로-N-(4-(2-(다이에틸아미노)에톡시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(23) ( S )-5-chloro- N- (4-(2-(diethylamino)ethoxy)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-2- amines;
    (24) (S)-5-클로로-N-(4-(3-(다이에틸아미노)프로폭시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(24) ( S )-5-chloro- N- (4-(3-(diethylamino)propoxy)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-2- amines;
    (25) (S)-5-클로로-N-(4-(2-(다이에틸아미노)에톡시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(25) ( S )-5-chloro- N- (4-(2-(diethylamino)ethoxy)-3,5-dimethylphenyl)-4-(3-phenylisoxazolidin-2-yl ) pyrimidin-2-amine;
    (26) (S)-5-클로로-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(26) ( S )-5-chloro- N- (4-(3-(diethylamino)propoxy)-3,5-dimethylphenyl)-4-(3-phenylisoxazolidin-2-yl ) pyrimidin-2-amine;
    (27) (S)-5-클로로-N-(4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(27) ( S )-5-chloro- N- (4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisoxazoli din-2-yl)pyrimidin-2-amine;
    (28) 5-클로로-N-(3-사이클로프로필-5-(((3S,5R)-3,5-다이메틸피페라진-1-일)메틸)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(28) 5-chloro- N- (3-cyclopropyl-5-((( 3S , 5R )-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(( S )-3-phenylisoxazolidin-2-yl)pyrimidin-2-amine;
    (29) (S)-5-클로로-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(29) ( S )-5-chloro- N- (3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3 -phenylisoxazolidin-2-yl)pyrimidin-2-amine;
    (30) 5-클로로-N-(3-메톡시-4-(4-((1S,4S)-5-메틸-2,5-다이아자바이사이클로[2.2.1]헵탄-2-일)피페리딘-1-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(30) 5-chloro- N -(3-methoxy-4-(4-(( 1S , 4S )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl) )piperidin-1-yl)phenyl)-4-(( S )-3-phenylisooxazolidin-2-yl)pyrimidin-2-amine;
    (31) (S)-5-클로로-N-(3-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(31) ( S )-5-chloro- N- (3-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3- phenylisoxazolidin-2-yl)pyrimidin-2-amine;
    (32) (S)-N-(5-클로로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민;(32) ( S )-N-(5-chloro-4-(3- phenylisooxazolidin -2-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline- 7-amine;
    (33) (S)-N-(5-클로로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-일)-2-메틸-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민;(33) ( S )-N-(5-chloro-4-(3- phenylisoxazolidin -2-yl)pyrimidin-2-yl)-2-methyl-1,2,3,4-tetra hydroisoquinolin-7-amine;
    (34) (S)-N-(5-클로로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민;(34) ( S )-N-(5-chloro-4-(3- phenylisooxazolidin -2-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline- 6-amine;
    (35) (S)-5-플루오로-4-(3-페닐아이소옥사졸리딘-2-일)-N-(3,4,5-트라이메톡시페닐)피리미딘-2-아민;(35) ( S )-5-fluoro-4-(3- phenylisooxazolidin -2-yl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine;
    (36) (S)-N-(4-(2-(다이에틸아미노)에톡시)페닐)-5-플루오로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(36) ( S )-N-(4-(2-( diethylamino )ethoxy)phenyl)-5-fluoro-4-(3-phenylisoxazolidin-2-yl)pyrimidine-2 -amines;
    (37) (S)-N-(4-(3-(다이에틸아미노)프로폭시)페닐)-5-플루오로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(37) ( S )-N-(4-(3-( diethylamino )propoxy)phenyl)-5-fluoro-4-(3-phenylisooxazolidin-2-yl)pyrimidine-2 -amines;
    (38) (S)-N-(4-(2-(다이에틸아미노)에톡시)-3,5-다이메틸페닐)-5-플루오로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(38) ( S )-N-(4-(2-(diethylamino)ethoxy)-3,5- dimethylphenyl )-5-fluoro-4-(3-phenylisoxazolidine-2- yl) pyrimidin-2-amine;
    (39) (S)-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)-5-플루오로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(39) ( S )-N-(4-(3-(diethylamino)propoxy)-3,5- dimethylphenyl )-5-fluoro-4-(3-phenylisoxazolidine-2- yl) pyrimidin-2-amine;
    (40) (S)-5-플루오로-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(40) ( S )-5-fluoro- N- (4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-2 -amines;
    (41) (R)-5-플루오로-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(41) ( R )-5-fluoro- N- (4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-2 -amines;
    (42) (S)-5-플루오로-N-(4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(42) ( S )-5-fluoro- N- (4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisooxa zolidin-2-yl)pyrimidin-2-amine;
    (43) N-(3-사이클로프로필-5-(((3S,5R)-3,5-다이메틸피페라진-1-일)메틸)페닐)-5-플루오로-4-((S)-3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(43) N- (3-cyclopropyl-5-((( 3S , 5R )-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-5-fluoro-4-(( S )-3-phenylisoxazolidin-2-yl)pyrimidin-2-amine;
    (44) (S)-N-(5-플루오로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민;(44) ( S )-N-(5-fluoro-4-(3- phenylisooxazolidin -2-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline -6-amine;
    (45) (S)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(45) ( S )-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
    (46) (R)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(46) ( R )-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
    (47) (S)-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤조나이트릴;(47) ( S )-4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzonitrile;
    (48) (S)-N1,N1-다이메틸-N4-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)벤젠-1,4-다이아민;(48) ( S ) -N 1, N 1-dimethyl- N 4-(4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl )benzene-1,4-diamine;
    (49) (S)-N-(4-플루오로페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(49) ( S ) -N- (4-fluorophenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (50) (S)-N-(4-메톡시페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(50) ( S ) -N- (4-methoxyphenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (51) (S)-N-(4-(메틸싸이오)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(51) ( S ) -N- (4-(methylthio)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine ;
    (52) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)-N-(4-(트라이플루오로메틸)페닐)피리미딘-2-아민;(52) ( S )-4-(3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl)-N-(4-(trifluoromethyl)phenyl)pyrimidine-2- amines;
    (53) tert-부틸 (S)-(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)카바메이트;(53) tert -butyl ( S )-(4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl) carbamate;
    (54) (S)-N1-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)벤젠-1,4-다이아민;(54) ( S ) -N 1-(4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)benzene-1,4-diamine ;
    (55) (S)-N-(4-(4-에틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(55) ( S )-N-(4-(4-ethylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
    (56) (S)-1-(4-(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피페라진-1-일)에탄-1-온;(56) ( S )-1-(4-(4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino) phenyl)piperazin-1-yl)ethan-1-one;
    (57) 4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)-N-(4-((3S,5R)-3,4,5-트라이메틸피페라진-1-일)페닐)피리미딘-2-아민;(57) 4-(( S )-3- phenylisoxazolidin - 2 -yl)-5-(trifluoromethyl)-N-(4-((3S,5R)-3,4,5 -trimethylpiperazin-1-yl)phenyl)pyrimidin-2-amine;
    (58) (S)-N1-(2-(다이메틸아미노)에틸)-N1-메틸-N4-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)벤젠-1,4-다이아민;(58) ( S ) -N 1-(2-(dimethylamino)ethyl) -N 1-methyl- N 4-(4-(3-phenylisoxazolidin-2-yl)-5-(tri fluoromethyl)pyrimidin-2-yl)benzene-1,4-diamine;
    (59) (S)-N-(4-(2-(다이메틸아미노)에톡시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(59) ( S ) -N- (4-(2-(dimethylamino)ethoxy)phenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
    (60) (S)-N-(4-몰포리노페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(60) ( S ) -N- (4-morpholinophenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (61) N-(4-((2S,6R)-2,6-다이메틸몰포리노)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(61) N- (4-(( 2S ,6R)-2,6-dimethylmorpholino)phenyl)-4-(( S )-3- phenylisoxazolidin -2-yl)-5 -(trifluoromethyl)pyrimidin-2-amine;
    (62) N-(4-((1R,4R)-2-옥사-5-아자바이사이클로[2.2.1]헵탄-5-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(62) N- (4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl)-4-(( S )-3-phenylisooxa zolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (63) (S)-N-(4-(3-(다이메틸아미노)아제티딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(63) ( S )-N-(4-(3-( dimethylamino )azetidin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(tri fluoromethyl)pyrimidin-2-amine;
    (64) (S)-N-(4-(4-메틸피페라진-1-일)-3-(트라이플루오로메틸)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(64) ( S )-N-(4-(4-methylpiperazin- 1 -yl)-3-(trifluoromethyl)phenyl)-4-(3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-amine;
    (65) (S)-N-(2-메톡시-4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(65) ( S )-N-(2-methoxy-4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine;
    (66) (S)-N-(3-메톡시-4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(66) ( S )-N-(3-methoxy-4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine;
    (67) (S)-N-(4-(4-사이클로프로필피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(67) ( S )-N-(4-(4-cyclopropylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl ) pyrimidin-2-amine;
    (68) (S)-N-(3-메톡시-4-몰포리노페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(68) ( S ) -N- (3-methoxy-4-morpholinophenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine-2 -amines;
    (69) (R)-3-메틸-N-(4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-아민;(69) ( R )-3-methyl- N- (4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)- 1,2,3,4,4a,5-hexahydrobenzo[ b ]pyrazino[1,2- d ][1,4]oxazin-8-amine;
    (70) (S)-3-메틸-N-(4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-아민;(70) ( S )-3-methyl- N- (4-(( S )-3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)- 1,2,3,4,4a,5-hexahydrobenzo[ b ]pyrazino[1,2- d ][1,4]oxazin-8-amine;
    (71) 메틸 (S)-8-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-2,3-다이하이드로벤조[b][1,4]다이옥신-5-카복실레이트;(71) methyl ( S )-8-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3- dihydrobenzo[ b ][1,4]dioxine-5-carboxylate;
    (72) 메틸 (S)-7-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-2,3-다이하이드로벤조퓨란-4-카복실레이트;(72) methyl ( S )-7-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3- dihydrobenzofuran-4-carboxylate;
    (73) N-(4-((R)-3-(다이메틸아미노)피롤리딘-1-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(73) N- (4-(( R )-3-(dimethylamino)pyrrolidin-1-yl)phenyl)-4-(( S )-3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-amine;
    (74) N-(4-((S)-3-(다이메틸아미노)피롤리딘-1-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(74) N- (4-(( S )-3-(dimethylamino)pyrrolidin-1-yl)phenyl)-4-(( S )-3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-amine;
    (75) (S)-1-(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피롤리딘-2-온;(75) ( S )-1-(4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)p rollidin-2-one;
    (76) (S)-2-(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)아이소싸이아졸리딘 1,1-다이옥사이드;(76) ( S )-2-(4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)iso thiazolidine 1,1-dioxide;
    (77) (S)-N-(3-메톡시-4-(1-메틸-1H-피라졸-5-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(77) ( S ) -N- (3-methoxy-4-(1-methyl- 1H -pyrazol-5-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-amine;
    (78) (S)-N-(4-(4-(다이메틸아미노)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(78) ( S )-N-(4-(4-( dimethylamino )piperidin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine;
    (79) (S)-N-(4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(79) ( S ) -N-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisoxazolidine-2- yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (80) (S)-N-(2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(80) ( S ) -N- (2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisooxa zolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (81) (S)-N-(3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(81) ( S ) -N- (3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisooxa zolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (82) (S)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(82) ( S ) -N- (3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisooxa zolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (83) (S)-N-(3-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(83) ( S ) -N-(3-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisoxazoli din-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (84) (S)-N-(3-메톡시-4-(4-몰포리노피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(84) ( S ) -N- (3-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5 -(trifluoromethyl)pyrimidin-2-amine;
    (85) (S)-N1-(1-(2-메톡시-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피페리딘-4-일)-N1,N2,N2-트라이메틸에탄-1,2-다이아민;(85) ( S ) -N 1-(1-(2-methoxy-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine- 2-yl)amino)phenyl)piperidin-4-yl) -N 1, N 2, N 2-trimethylethane-1,2-diamine;
    (86) N-(3-메톡시-4-(4-((1S,4S)-5-메틸-2,5-다이아자바이사이클로[2.2.1]헵탄-2-일)피페리딘-1-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(86) N -(3-methoxy-4-(4-(( 1S , 4S )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidine -1-yl)phenyl)-4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (87) N-(3-메톡시-4-(4-((1R,4R)-5-메틸-2,5-다이아자바이사이클로[2.2.1]헵탄-2-일)피페리딘-1-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(87) N -(3-methoxy-4-(4-((1 R ,4 R )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidine -1-yl)phenyl)-4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (88) (S)-2-(4-(1-(2-메톡시-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피페리딘-4-일)피페라진-1-일)에탄-1-올;(88) ( S )-2-(4-(1-(2-methoxy-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyri) midin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethan-1-ol;
    (89) (S)-1'-(2-메톡시-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)-N,N-다이메틸-[1,4'-바이피페리딘]-4-아민;(89) ( S )-1'-(2-methoxy-4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl )amino)phenyl) -N , N -dimethyl-[1,4′-bipiperidin]-4-amine;
    (90) (S)-N-(4-(4-(3-(다이메틸아미노)아제티딘-1-일)피페리딘-1-일)-3-메톡시페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(90) ( S )-N-(4-(4-(3-( dimethylamino )azetidin-1-yl)piperidin-1-yl)-3-methoxyphenyl)-4-(3 -phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (91) (S)-2-(4-(1-(2-플루오로-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피페리딘-4-일)피페라진-1-일)에탄-1-올;(91) ( S )-2-(4-(1-(2-fluoro-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyri) midin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethan-1-ol;
    (92) (S)-N-(4-(4-(1-메틸피페리딘-4-일)피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(92) ( S ) -N- (4-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)-4-(3-phenylisoxazolidine-2- yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (93) (S)-N-(3-메톡시-4-(4-(1-메틸피페리딘-4-일)피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(93) ( S ) -N- (3-methoxy-4-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)-4-(3-phenylisooxa zolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (94) (S)-N-(4-(3-(4-메틸피페라진-1-일)아제티딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(94) ( S )-N-(4-(3-(4-methylpiperazin- 1 -yl)azetidin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl )-5-(trifluoromethyl)pyrimidin-2-amine;
    (95) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)-N-(3,4,5-트라이메톡시페닐)피리미딘-2-아민;(95) ( S )-4-(3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl)-N-(3,4,5-trimethoxyphenyl)pyrimidine-2 -amines;
    (96) (S)-N-(4-(2-(다이에틸아미노)에톡시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(96) ( S )-N-(4-(2-( diethylamino )ethoxy)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
    (97) (S)-N-(4-(2-(다이에틸아미노)에톡시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(97) ( S )-N-(4-(2-(diethylamino)ethoxy)-3,5- dimethylphenyl )-4-(3-phenylisoxazolidin-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine;
    (98) (S)-N-(4-(3-(다이에틸아미노)프로폭시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(98) ( S )-N-(4-(3-( diethylamino )propoxy)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
    (99) (S)-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(99) ( S )-N-(4-(3-(diethylamino)propoxy)-3,5- dimethylphenyl )-4-(3-phenylisoxazolidin-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine;
    (100) (R)-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(100) ( R )-N-(4-(3-(diethylamino)propoxy)-3,5- dimethylphenyl )-4-(3-phenylisoxazolidin-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine;
    (101) (S)-N-(3,5-다이메틸-4-(3-(4-메틸피페라진-1-일)프로폭시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(101) ( S )-N-(3,5- dimethyl -4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-4-(3-phenylisoxazolidine- 2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (102) (S)-N-(4-(3-(다이에틸아미노)프로폭시)-3-(트라이플루오로메틸)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(102) ( S )-N-(4-(3-( diethylamino )propoxy)-3-(trifluoromethyl)phenyl)-4-(3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-amine;
    (103) (S)-N-(3-플루오로-4-((1-메틸피페리딘-4-일)옥시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(103) ( S ) -N- (3-fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-4-(3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-amine;
    (104) tert-부틸 (S)-4-(2-플루오로-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피페리딘-1-카복실레이트;(104) tert -Butyl ( S )-4-(2-fluoro-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine-2 -yl)amino)phenyl)piperidine-1-carboxylate;
    (105) (S)-N-(3-플루오로-4-(피페리딘-4-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(105) ( S ) -N- (3-fluoro-4-(piperidin-4-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoro romethyl)pyrimidin-2-amine;
    (106) (S)-N-(4-(4-에틸피페라진-1-일)-3,5-다이플루오로페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(106) ( S )-N-(4-(4-ethylpiperazin- 1 -yl)-3,5-difluorophenyl)-4-(3-phenylisoxazolidin-2-yl)- 5-(trifluoromethyl)pyrimidin-2-amine;
    (107) (S)-N-(3,5-다이플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(107) ( S ) -N- (3,5-difluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3- phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (108) (S)-N-(4-(4-(다이메틸아미노)피페리딘-1-일)-3,5-다이플루오로페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(108) ( S )-N-(4-(4-( dimethylamino )piperidin-1-yl)-3,5-difluorophenyl)-4-(3-phenylisoxazolidine- 2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (109) N-(4-((R)-3-(다이메틸아미노)피롤리딘-1-일)-3,5-다이플루오로페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(109) N- (4-(( R )-3-(dimethylamino)pyrrolidin-1-yl)-3,5-difluorophenyl)-4-(( S )-3-phenyliso oxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (110) N-(4-((S)-3-(다이메틸아미노)피롤리딘-1-일)-3,5-다이플루오로페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(110) N- (4-(( S )-3-(dimethylamino)pyrrolidin-1-yl)-3,5-difluorophenyl)-4-(( S )-3-phenyliso oxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (111) (S)-1-(2,6-다이플루오로-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피롤리딘-2-온;(111) ( S )-1-(2,6-difluoro-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine-2 -yl)amino)phenyl)pyrrolidin-2-one;
    (112) (S)-N-(3,5-다이플루오로-4-(4-메틸-1,4-다이아제판-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(112) ( S ) -N- (3,5-difluoro-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-4-(3-phenylisoxazolidine- 2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (113) (S)-N-(3,5-다이플루오로-4-((1-메틸피페리딘-4-일)옥시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(113) ( S ) -N- (3,5-difluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-4-(3-phenylisoxazolidine-2 -yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (114) (S)-N-(3,5-다이플루오로-4-((1-메틸피페리딘-4-일)메톡시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(114) ( S ) -N- (3,5-difluoro-4-((1-methylpiperidin-4-yl)methoxy)phenyl)-4-(3-phenylisoxazolidine- 2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (115) (S)-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이플루오로페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(115) ( S )-N-(4-(3-( diethylamino )propoxy)-3,5-difluorophenyl)-4-(3-phenylisoxazolidin-2-yl)- 5-(trifluoromethyl)pyrimidin-2-amine;
    (116) (S)-N-(3,5-다이플루오로-4-(4-메틸-1H-이미다졸-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(116) ( S ) -N- (3,5-difluoro-4-(4-methyl-1 H -imidazol-1-yl)phenyl)-4-(3-phenylisoxazolidine-2 -yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (117) (S)-N-(5-(4-메틸피페라진-1-일)피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(117) ( S )-N-(5-(4-methylpiperazin- 1 -yl)pyridin-2-yl)-4-(3-phenylisoxazolidin-2-yl)-5-(tri fluoromethyl)pyrimidin-2-amine;
    (118) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(5-(피페라진-1-일)피리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(118) ( S )-4-(3- phenylisoxazolidin -2-yl)-N-(5-(piperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl ) pyrimidin-2-amine;
    (119) (S)-N-(5-몰포리노피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(119) ( S ) -N- (5-morpholinopyridin-2-yl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine-2- amines;
    (120) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(5-(테트라하이드로-2H-피란-4-일)피리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(120) ( S )-4-(3-phenylisooxazolidin-2-yl) -N- (5-(tetrahydro- 2H -pyran-4-yl)pyridin-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine;
    (121) (S)-N-(5-(4-아이소프로필피페라진-1-일)피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(121) ( S )-N-(5-(4-isopropylpiperazin- 1 -yl)pyridin-2-yl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine;
    (122) (S)-N-(5-(4-사이클로프로필피페라진-1-일)피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(122) ( S )-N-(5-(4-cyclopropylpiperazin- 1 -yl)pyridin-2-yl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine;
    (123) (S)-N-(5-(4-(옥세탄-3-일)피페라진-1-일)피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(123) ( S )-N-(5-(4-( oxetan -3-yl)piperazin-1-yl)pyridin-2-yl)-4-(3-phenylisoxazolidin-2- yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (124) (S)-N-(5-((4-에틸피페라진-1-일)메틸)피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(124) ( S )-N-(5-((4-ethylpiperazin- 1 -yl)methyl)pyridin-2-yl)-4-(3-phenylisoxazolidin-2-yl)-5 -(trifluoromethyl)pyrimidin-2-amine;
    (125) (S)-N-(5-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(125) ( S ) -N-(5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)-4-(3-phenylisoxazoli din-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (126) (S)-N-(6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(126) ( S ) -N-(6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)-4-(3-phenylisoxazoli din-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (127) (S)-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민;(127) ( S )-N-(4-(3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4- tetrahydroisoquinolin-6-amine;
    (128) (S)-2-메틸-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민;(128) ( S )-2-methyl- N- (4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2, 3,4-tetrahydroisoquinolin-6-amine;
    (129) (S)-1-(6-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-3,4-다이하이드로아이소퀴놀린-2(1H)-일)에탄-1-온;(129) ( S )-1-(6-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3, 4-dihydroisoquinolin-2(1 H )-yl)ethan-1-one;
    (130) (S)-2-(메틸설포닐)-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민;(130) ( S )-2-(methylsulfonyl)-N-(4-(3- phenylisooxazolidin -2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)- 1,2,3,4-tetrahydroisoquinolin-6-amine;
    (131) (S)-2-사이클로프로필-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민;(131) ( S )-2-cyclopropyl- N- (4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2 ,3,4-tetrahydroisoquinolin-6-amine;
    (132) (S)-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민;(132) ( S )-N-(4-(3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4- tetrahydroisoquinolin-7-amine;
    (133) (S)-2-메틸-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민;(133) ( S )-2-methyl- N- (4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2, 3,4-tetrahydroisoquinolin-7-amine;
    (134) (S)-6-메톡시-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민;(134) ( S )-6-methoxy- N- (4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2 ,3,4-tetrahydroisoquinolin-7-amine;
    (135) (S)-6-메톡시-2-메틸-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민;(135) ( S )-6-methoxy-2-methyl- N- (4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl) -1,2,3,4-tetrahydroisoquinolin-7-amine;
    (136) (S)-6-플루오로-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민;(136) ( S )-6-fluoro- N- (4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2 ,3,4-tetrahydroisoquinolin-7-amine;
    (137) (S)-6-플루오로-7-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-3,4-다이하이드로아이소퀴놀린-1(2H)-온;(137) ( S )-6-fluoro-7-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 3,4-dihydroisoquinolin-1( 2H )-one;
    (138) (S)-6-플루오로-2-메틸-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민;(138) ( S )-6-fluoro-2-methyl- N- (4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl) -1,2,3,4-tetrahydroisoquinolin-7-amine;
    (139) 6-메톡시-N2,N2-다이메틸-N5-(4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-2,3-다이하이드로-1H-인덴-2,5-다이아민;(139) 6-methoxy- N 2, N 2-dimethyl- N 5-(4-(( S )-3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyri midin-2-yl)-2,3-dihydro-1 H -indene-2,5-diamine;
    (140) (S)-5-메톡시-2-메틸-6-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)아이소인돌린-1-온;(140) ( S )-5-methoxy-2-methyl-6-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl )amino)isoindolin-1-one;
    (141) (S)-5'-메톡시-6'-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)스파이로[사이클로프로판-1,3'-인돌린]-2'-온;(141) ( S )-5'-methoxy-6'-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) spiro[cyclopropane-1,3'-indolin]-2'-one;
    (142) (S)-3,3-다이메틸-5-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)아이소벤조퓨란-1(3H)-온;(142) ( S )-3,3-dimethyl-5-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) isobenzofuran-1(3 H )-one;
    (143) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(1H-피라졸-4-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(143) ( S )-4-(3- phenylisoxazolidin -2-yl)-N-( 1H -pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2- amines;
    (144) (S)-N-(1-메틸-1H-피라졸-3-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(144) ( S ) -N-(1-methyl- 1H -pyrazol-3-yl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyri midin-2-amine;
    (145) (S)-N-(1-메틸-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(145) ( S ) -N- (1-methyl- 1H -pyrazol-4-yl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyri midin-2-amine;
    (146) (S)-N-(1-아이소프로필-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(146) ( S ) -N- (1-isopropyl- 1H -pyrazol-4-yl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
    (147) (S)-N-(1-사이클로프로필-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(147) ( S ) -N- (1-cyclopropyl- 1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
    (148) (S)-N-(1-(2,2-다이플루오로에틸)-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(148) ( S ) -N-(1-(2,2-difluoroethyl) -1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl)- 5-(trifluoromethyl)pyrimidin-2-amine;
    (149) (S)-N-메틸-2-(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-1H-피라졸-1-일)아세트아마이드;(149) ( S ) -N -methyl-2-(4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino )-1 H -pyrazol-1-yl)acetamide;
    (150) (S)-N-(1-(2-메톡시에틸)-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(150) ( S ) -N-(1-(2-methoxyethyl) -1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine;
    (151) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(1-(피페리딘-4-일)-1H-피라졸-4-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(151) ( S )-4-(3-phenylisoxazolidin-2-yl) -N- (1-(piperidin-4-yl) -1H -pyrazol-4-yl)-5 -(trifluoromethyl)pyrimidin-2-amine;
    (152) (S)-N-(1-(2-몰포리노에틸)-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(152) ( S ) -N-(1-(2-morpholinoethyl) -1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine;
    (153) (S)-N-(1-(3-(다이에틸아미노)프로필)-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(153) ( S )-N-(1-(3-( diethylamino )propyl) -1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl)- 5-(trifluoromethyl)pyrimidin-2-amine;
    (154) 4-((S)-3-페닐아이소옥사졸리딘-2-일)-N-(1-(((R)-테트라하이드로퓨란-2-일)메틸)-1H-피라졸-4-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(154) 4-(( S )-3- phenylisoxazolidin -2-yl)-N-(1-((( R )-tetrahydrofuran-2-yl)methyl) -1H -pyrazole -4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (155) tert-부틸 (S)-3-((4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-1H-피라졸-1-일)메틸)아제티딘-1-카복실레이트;(155) tert -butyl ( S )-3-((4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino )-1 H -pyrazol-1-yl)methyl)azetidine-1-carboxylate;
    (156) (S)-N-(1-(아제티딘-3-일메틸)-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(156) ( S ) -N-(1-(azetidin-3-ylmethyl) -1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl)-5 -(trifluoromethyl)pyrimidin-2-amine;
    (157) (S)-6-메틸-2-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-5,6-다이하이드로-4H-피라졸로[1,5-d][1,4]다이아제핀-7(8H)-온;(157) ( S )-6-methyl-2-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5 ,6-dihydro- 4H -pyrazolo[1,5- d ][1,4]diazepin-7( 8H )-one;
    (158) (S)-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-4-(피페리딘-4-일)싸이아졸-2-아민;(158) ( S )-N-(4-(3- phenylisooxazolidin -2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-4-(piperidin-4 -yl) thiazol-2-amine;
    (159) tert-부틸 (S)-2-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-6,7-다이하이드로싸이아졸로[5,4-c]피리딘-5(4H)-카복실레이트;(159) tert -butyl ( S )-2-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6, 7-dihydrothiazolo[5,4-c]pyridine-5( 4H )-carboxylate;
    (160) (S)-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-4,5,6,7-테트라하이드로싸이아졸로[5,4-c]피리딘-2-아민;(160) ( S )-N-(4-(3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7- tetrahydrothiazolo[5,4-c]pyridin-2-amine;
    (161) (S)-5-메틸-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-4,5,6,7-테트라하이드로싸이아졸로[5,4-c]피리딘-2-아민;(161) ( S )-5-methyl- N- (4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-4,5, 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-amine;
    (162) 메틸 (S)-5-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)싸이오펜-2-카복실레이트;(162) methyl ( S )-5-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)thiophene-2- carboxylate;
    (163) (S)-1-(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)에탄-1-온;(163) ( S )-1-(4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)ethane -1-one;
    (164) (S)-페닐(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)메탄온;(164) ( S )-phenyl(4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)methanone ;
    (165) (S)-N,N-다이메틸-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤즈아마이드;(165) ( S ) -N , N -dimethyl-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino )benzamide;
    (166) (S)-(4-메틸피페라진-1-일)(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)메탄온;(166) ( S )-(4-methylpiperazin-1-yl)(4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine- 2-yl)amino)phenyl)methanone;
    (167) (S)-N-(2-하이드록시에틸)-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤즈아마이드;(167) ( S ) -N-(2-hydroxyethyl)-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine-2- yl)amino)benzamide;
    (168) (S)-N-(3-하이드록시프로필)-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤즈아마이드;(168) ( S ) -N- (3-hydroxypropyl)-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine-2- yl)amino)benzamide;
    (169) (S)-N-(2-(메틸아미노)에틸)-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤즈아마이드;(169) ( S )-N-(2-(methylamino)ethyl)-4-((4-(3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl)pyrimidine- 2-yl)amino)benzamide;
    (170) 이미노(메틸)(4-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)-λ6-설판온;(170) imino(methyl)(4-((4-(( S )-3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino) phenyl)-λ 6 -sulfanone;
    (171) 1-(4-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)-4,5-다이하이드로-3H-아이소싸이아졸 1-옥사이드;(171) 1-(4-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)- 4,5-dihydro-3 H -isothiazole 1-oxide;
    (172) (S)-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤젠설포닐 플로라이드;(172) ( S )-4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonyl fluoride;
    (173) (S)-N,N-다이메틸-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤젠설폰아마이드;(173) ( S ) -N , N -dimethyl-4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) benzenesulfonamide;
    (174) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(3-(피리딘-3-일)페닐)-5-(트라이플루오로메틸)피리미딘-2-아민;(174) ( S )-4-(3- phenylisooxazolidin -2-yl)-N-(3-(pyridin-3-yl)phenyl)-5-(trifluoromethyl)pyrimidine-2 -amines;
    (175) (S)-N-(3-메톡시-5-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(175) ( S )-N-(3-methoxy-5-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine;
    (176) (S)-N-(3-(4-메틸피페라진-1-일)-5-(트라이플루오로메틸)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(176) ( S )-N-(3-(4-methylpiperazin- 1 -yl)-5-(trifluoromethyl)phenyl)-4-(3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-amine;
    (177) (S)-N-(3-((4-메틸피페라진-1-일)메틸)-5-(트라이플루오로메틸)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(177) ( S )-N-(3-((4-methylpiperazin- 1 -yl)methyl)-5-(trifluoromethyl)phenyl)-4-(3-phenylisoxazolidine-2 -yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (178) (S)-2-메틸-2-(3-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)프로판나이트릴;(178) ( S )-2-methyl-2-(3-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino )phenyl)propanenitrile;
    (179) (S)-2-메틸-2-(3-(4-메틸피페라진-1-일)-5-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)프로판나이트릴;(179) ( S )-2-methyl-2-(3-(4-methylpiperazin-1-yl)-5-((4-(3-phenylisoxazolidin-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)propanenitrile;
    (180) (S)-2-메틸-2-(3-((4-메틸피페라진-1-일)메틸)-5-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)프로판나이트릴;(180) ( S )-2-methyl-2-(3-((4-methylpiperazin-1-yl)methyl)-5-((4-(3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)propanenitrile;
    (181) N-(3-((1R,4R)-5-메틸-2,5-다이아자바이사이클로[2.2.1]헵탄-2-일)-5-(메틸설포닐)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(181) N -(3-(( 1R , 4R )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-(methylsulfonyl)phenyl)- 4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (182) N-(3-((1S,4S)-5-메틸-2,5-다이아자바이사이클로[2.2.1]헵탄-2-일)-5-(메틸설포닐)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(182) N -(3-(( 1S , 4S )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-(methylsulfonyl)phenyl)- 4-(( S )-3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (183) (S)-N-(3-(4-(4-메틸피페라진-1-일)피페리딘-1-일)-5-(메틸설포닐)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(183) ( S ) -N-(3-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-(methylsulfonyl)phenyl)-4-(3- phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (184) N-(2-플루오로-5-((1R,4R)-5-메틸-2,5-다이아자바이사이클로[2.2.1]헵탄-2-일)피리딘-3-일)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(184) N -(2-fluoro-5-((1 R ,4 R )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl) -4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (185) N-(3-(3,3-다이플루오로피롤리딘-1-일)-5-((R)-피롤리딘-3-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(185) N -(3-(3,3-difluoropyrrolidin-1-yl)-5-(( R )-pyrrolidin-3-yl)phenyl)-4-(( S )- 3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (186) N-(3-(3,3-다이플루오로피롤리딘-1-일)-5-((S)-피롤리딘-3-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(186) N -(3-(3,3-difluoropyrrolidin-1-yl)-5-(( S )-pyrrolidin-3-yl)phenyl)-4-(( S )- 3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (187) (S)-N-(2-메톡시-5-(1-메틸-1H-피라졸-4-일)-4-몰포리노페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(187) ( S ) -N- (2-methoxy-5-(1-methyl-1 H -pyrazol-4-yl)-4-morpholinophenyl)-4-(3-phenylisoxazolidine -2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (188) (S)-N-(2-메톡시-5-(1-메틸-1H-피라졸-4-일)-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(188) ( S ) -N- (2-methoxy-5-(1-methyl-1 H -pyrazol-4-yl)-4-(4-(4-methylpiperazin-1-yl)p peridin-1-yl)phenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (189) (R)-N-(2-메톡시-5-(1-메틸-1H-피라졸-4-일)-4-몰포리노페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(189) ( R ) -N- (2-methoxy-5-(1-methyl-1 H -pyrazol-4-yl)-4-morpholinophenyl)-4-(3-phenylisoxazolidine -2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (190) (R)-N-(2-메톡시-5-(1-메틸-1H-피라졸-4-일)-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(190) ( R ) -N- (2-methoxy-5-(1-methyl-1 H -pyrazol-4-yl)-4-(4-(4-methylpiperazin-1-yl)pi peridin-1-yl)phenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (191) (S)-2-플루오로-N-(1-아이소프로필피페리딘-4-일)-5-메톡시-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤즈아마이드;(191) ( S )-2-fluoro- N- (1-isopropylpiperidin-4-yl)-5-methoxy-4-((4-(3-phenylisoxazolidine-2- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide;
    (192) N-(3-사이클로프로필-5-(((3S,5R)-3,5-다이메틸피페라진-1-일)메틸)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(192) N- (3-cyclopropyl-5-((( 3S,5R)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-((S ) -3- phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (193) (S)-N-(1-(메틸설포닐)피페리딘-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(193) ( S ) -N- (1-(methylsulfonyl)piperidin-4-yl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
    (194) (S)-N-(1-아이소프로필피페리딘-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(194) ( S ) -N- (1-isopropylpiperidin-4-yl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine- 2-amine;
    (195) (3S,4S)-1-(메틸설포닐)-4-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피페리딘-3-올;(195) (3S, 4S )-1-(methylsulfonyl)-4-((4-(( S )-3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl) )pyrimidin-2-yl)amino)piperidin-3-ol;
    (196) (3R,4R)-1-(메틸설포닐)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피페리딘-4-올;(196) ( 3R , 4R )-1-(methylsulfonyl)-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) )pyrimidin-2-yl)amino)piperidin-4-ol;
    (197) tert-부틸 (S)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피페리딘-1-카복실레이트;(197) tert -butyl ( S )-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) piperidine-1-carboxylate;
    (198) tert-부틸 (S)-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피페리딘-1-카복실레이트;(198) tert -butyl ( S )-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine -1-carboxylate;
    (199) tert-부틸 (S)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피롤리딘-1-카복실레이트;(199) tert -butyl ( S )-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) pyrrolidine-1-carboxylate;
    (200) tert-부틸 (R)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피롤리딘-1-카복실레이트;(200) tert -butyl ( R )-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) pyrrolidine-1-carboxylate;
    (201) 4-((S)-3-페닐아이소옥사졸리딘-2-일)-N-((S)-피페리딘-3-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(201) 4-(( S )-3-phenylisoxazolidin-2-yl) -N -(( S )-piperidin-3-yl)-5-(trifluoromethyl)pyrimidine- 2-amine;
    (202) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(피페리딘-4-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(202) ( S )-4-(3- phenylisooxazolidin -2-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (203) 4-((S)-3-페닐아이소옥사졸리딘-2-일)-N-((S)-피롤리딘-3-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(203) 4-(( S )-3-phenylisoxazolidin-2-yl) -N -(( S )-pyrrolidin-3-yl)-5-(trifluoromethyl)pyrimidine- 2-amine;
    (204) 4-((S)-3-페닐아이소옥사졸리딘-2-일)-N-((R)-피롤리딘-3-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(204) 4-(( S )-3-phenylisoxazolidin-2-yl) -N -(( R )-pyrrolidin-3-yl)-5-(trifluoromethyl)pyrimidine- 2-amine;
    (205) 3-((S)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피롤리딘-1-일)프로판-1-올;(205) 3-(( S )-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino )pyrrolidin-1-yl)propan-1-ol;
    (206) tert-부틸 (R)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피페리딘-1-카복실레이트;(206) tert -butyl ( R )-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) piperidine-1-carboxylate;
    (207) 1-((S)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피페리딘-1-일)에탄-1-온;(207) 1-(( S )-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino )piperidin-1-yl)ethan-1-one;
    (208) 4-((S)-3-페닐아이소옥사졸리딘-2-일)-N-((R)-피페리딘-3-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(208) 4-(( S )-3-phenylisoxazolidin-2-yl) -N -(( R )-piperidin-3-yl)-5-(trifluoromethyl)pyrimidine- 2-amine;
    (209) N-((S)-1-메틸피페리딘-3-일)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(209) N -(( S )-1-methylpiperidin-3-yl)-4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
    (210) (S)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-(3-메톡시페닐)아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(210) ( S ) -N- (3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-(3- methoxyphenyl)isooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (211) (S)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-(피리딘-3-일)아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(211) ( S ) -N- (3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-(pyridine- 3-yl)isoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (212) (S)-4-(3-(3-플루오로페닐)아이소옥사졸리딘-2-일)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-5-(트라이플루오로메틸)피리미딘-2-아민;(212) ( S )-4-(3-(3-fluorophenyl)isoxazolidin-2-yl) -N- (3-methoxy-4-(4-(4-methylpiperazine-1) -yl)piperidin-1-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (213) (S)-4-(3-(4-플루오로페닐)아이소옥사졸리딘-2-일)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-5-(트라이플루오로메틸)피리미딘-2-아민;(213) ( S )-4-(3-(4-fluorophenyl)isoxazolidin-2-yl) -N- (3-methoxy-4-(4-(4-methylpiperazine-1) -yl)piperidin-1-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (214) (S)-4-(3-(2,6-다이플루오로페닐)아이소옥사졸리딘-2-일)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-5-(트라이플루오로메틸)피리미딘-2-아민;(214) ( S )-4-(3-(2,6-difluorophenyl)isoxazolidin-2-yl) -N- (3-methoxy-4-(4-(4-methylpipette) Razin-1-yl)piperidin-1-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (215) (S)-4-(3-(3-(다이메틸아미노)페닐)아이소옥사졸리딘-2-일)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-5-(트라이플루오로메틸)피리미딘-2-아민;(215) ( S )-4-(3-(3-(dimethylamino)phenyl)isoxazolidin-2-yl) -N- (3-methoxy-4-(4-(4-methylpipette) Razin-1-yl)piperidin-1-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (216) (S)-3-(2-(2-((3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-(트라이플루오로메틸)피리미딘-4-일)아이소옥사졸리딘-3-일)벤조나이트릴;(216) ( S )-3-(2-(2-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino) -5-(trifluoromethyl)pyrimidin-4-yl)isooxazolidin-3-yl)benzonitrile;
    (217) (S)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-(3-페녹시페닐)아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;(217) ( S ) -N- (3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-(3- phenoxyphenyl)isoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
    (218) (S)-3-(2-(2-((1,2,3,4-테트라하이드로아이소퀴놀린-7-일)아미노)-5-(트라이플루오로메틸)피리미딘-4-일)아이소옥사졸리딘-3-일)벤조나이트릴;(218) ( S )-3-(2-(2-((1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4- day) isoxazolidin-3-yl) benzonitrile;
    (219) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-2-((3,4,5-트라이메톡시페닐)아미노)피리미딘-5-카보나이트릴;(219) ( S )-4-(3-phenylisooxazolidin-2-yl)-2-((3,4,5-trimethoxyphenyl)amino)pyrimidine-5-carbonitrile;
    (220) (S)-2-((4-(2-(다이에틸아미노)에톡시)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;(220) ( S )-2-((4-(2-(diethylamino)ethoxy)phenyl)amino)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-5-carbonite reel;
    (221) (S)-2-((4-(2-(다이에틸아미노)에톡시)-3,5-다이메틸페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;(221) ( S )-2-((4-(2-(diethylamino)ethoxy)-3,5-dimethylphenyl)amino)-4-(3-phenylisoxazolidin-2-yl) pyrimidine-5-carbonitrile;
    (222) (S)-2-((4-(3-(다이에틸아미노)프로폭시)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;(222) ( S )-2-((4-(3-(diethylamino)propoxy)phenyl)amino)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-5-carbonite reel;
    (223) (S)-2-((4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;(223) ( S )-2-((4-(3-(diethylamino)propoxy)-3,5-dimethylphenyl)amino)-4-(3-phenylisoxazolidin-2-yl) pyrimidine-5-carbonitrile;
    (224) (S)-2-((4-(3-(다이에틸아미노)프로폭시)-3,5-다이플루오로페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;(224) ( S )-2-((4-(3-(diethylamino)propoxy)-3,5-difluorophenyl)amino)-4-(3-phenylisoxazolidine-2- I) pyrimidine-5-carbonitrile;
    (225) (R)-2-((4-(4-메틸피페라진-1-일)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;(225) ( R )-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-5-carbonite reel;
    (226) (R)-2-((4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;(226) ( R )-2-((4-(3-(diethylamino)propoxy)-3,5-dimethylphenyl)amino)-4-(3-phenylisoxazolidin-2-yl) pyrimidine-5-carbonitrile;
    (227) (S)-2-((4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;(227) ( S )-2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-4-(3-phenylisoxazolidine -2-yl)pyrimidine-5-carbonitrile;
    (228) (S)-2-((3,5-다이메틸-4-(3-(피롤리딘-1-일)프로폭시)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;(228) ( S )-2-((3,5-dimethyl-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)amino)-4-(3-phenylisoxazolidine -2-yl)pyrimidine-5-carbonitrile;
    (229) (S)-2-((3,5-다이메틸-4-(3-(피페리딘-1-일)프로폭시)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;(229) ( S )-2-((3,5-dimethyl-4-(3-(piperidin-1-yl)propoxy)phenyl)amino)-4-(3-phenylisoxazolidine -2-yl)pyrimidine-5-carbonitrile;
    (230) (S)-2-((3,5-다이메틸-4-(3-몰포리노프로폭시)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;(230) ( S )-2-((3,5-dimethyl-4-(3-morpholinopropoxy)phenyl)amino)-4-(3-phenylisoxazolidin-2-yl)pyrimidine -5-carbonitrile;
    (231) (S)-2-((3,5-다이메틸-4-(3-(4-메틸피페라진-1-일)프로폭시)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;(231) ( S )-2-((3,5-dimethyl-4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)amino)-4-(3-phenylisooxa zolidin-2-yl)pyrimidine-5-carbonitrile;
    (232) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-2-((4-(피페라진-1-일)-3-(트라이플루오로메틸)페닐)아미노)피리미딘-5-카보나이트릴;(232) ( S )-4-(3-phenylisoxazolidin-2-yl)-2-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino) pyrimidine-5-carbonitrile;
    (233) (S)-2-((4-(4-메틸피페라진-1-일)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;(233) ( S )-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-5-carbonite reel;
    (234) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-2-((1,2,3,4-테트라하이드로아이소퀴놀린-6-일)아미노)피리미딘-5-카보나이트릴;(234) ( S )-4-(3-phenylisooxazolidin-2-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidine-5 -carbonitrile;
    (235) (S)-5-(3,6-다이하이드로-2H-피란-4-일)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(235) ( S )-5-(3,6-dihydro-2H-pyran-4-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-4-(3- phenylisoxazolidin-2-yl)pyrimidin-2-amine;
    (236) (S)-5-(사이클로헥산-1-엔-1-일)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(236) ( S )-5-(cyclohexane-1- en -1-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazoli din-2-yl)pyrimidin-2-amine;
    (237) (S)-5-(1-메틸-1H-피라졸-4-일)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(237) ( S )-5-(1-methyl- 1H -pyrazol-4-yl)-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenyl) isoxazolidin-2-yl)pyrimidin-2-amine;
    (238) (S)-5-(퓨란-3-일)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;(238) ( S )-5-(furan-3-yl)-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl ) pyrimidin-2-amine;
    (239) (S)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(피리딘-3-일)피리미딘-2-아민; 및(239) ( S )-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(pyridin-3-yl) ) pyrimidin-2-amine; and
    (240) (S)-5-(6-플루오로피리딘-3-일)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민.(240) ( S )-5-(6-fluoropyridin-3-yl)-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidine -2-yl)pyrimidin-2-amine.
  8. 제 1 항 내지 제 7 항 중 어느 하나의 항에 따른 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는, 암의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating cancer, comprising the compound according to any one of claims 1 to 7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  9. 제 8 항에 있어서,9. The method of claim 8,
    CDK2, CDK4, CDK6, 및/또는 HKP1을 억제하는 것인, 약학적 조성물.A pharmaceutical composition that inhibits CDK2, CDK4, CDK6, and/or HKP1.
  10. 제 8 항에 있어서,9. The method of claim 8,
    상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상인, 약학적 조성물.The cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, Ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer ; Duodenal cancer, malignant soft tissue cancer, malignant bone cancer, lymphoma malignant, mesothelioma malignant, melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilm Breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic schwannoma , pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological cancer, and thymus At least one selected from the group consisting of cancer, a pharmaceutical composition.
  11. 암의 치료 또는 예방에 사용하기 위한 약제의 제조에 사용하기 위한, 제 1 항 내지 제 7 항 중 어느 하나의 항에 따른 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 용도.Use of a compound according to any one of claims 1 to 7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment or prevention of cancer.
  12. 제 1 항 내지 제 7 항 중 어느 하나의 항에 따른 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 치료학적으로 유효한 양을, 이를 필요로 하는 대상에게 투여하는 단계를 포함하는, 암을 치료 또는 예방하는 방법.Claims 1 to 7, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1 to 7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. How to treat or prevent.
PCT/KR2021/018956 2020-12-14 2021-12-14 Isoxazolidine derivative compound and use thereof WO2022131741A1 (en)

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