WO2023204642A1 - Inhibiteur de protéine kinase et son utilisation - Google Patents

Inhibiteur de protéine kinase et son utilisation Download PDF

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WO2023204642A1
WO2023204642A1 PCT/KR2023/005401 KR2023005401W WO2023204642A1 WO 2023204642 A1 WO2023204642 A1 WO 2023204642A1 KR 2023005401 W KR2023005401 W KR 2023005401W WO 2023204642 A1 WO2023204642 A1 WO 2023204642A1
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amino
phenyl
oxadiazol
thiazol
alkyl
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Korean (ko)
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방극찬
서행수
신미선
안지윤
이현진
전혜림
민재홍
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(주)메디톡스
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    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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 disclosure relates to compounds of formula 1 having protein kinase inhibitory activity and their uses.
  • Protein kinase is an enzyme that catalyzes the phosphorylation of hydroxy groups located on tyrosine, serine, and threonine residues of proteins, and plays an important role in growth factor signal transduction that causes cell growth, differentiation, and proliferation. Mutation or overexpression of specific protein kinases can cause various diseases by disrupting the normal intracellular signaling system.
  • the protein kinases include Bruton's tyrosine kinase (BTK).
  • BTK is an enzyme encoded by the BTK gene in humans.
  • BTK is a kinase that plays an important role in B cell development.
  • BTK plays an important role in B cell maturation as well as mast cell activation through the high-affinity IgE receptor.
  • BTK contains a PH domain that binds phosphatidylinositol (3,4,5)-triphosphate (PIP3). When PIP3 binds to BTK, it induces BTK to phosphorylate phospholipase C.
  • PIP3 phosphatidylinositol
  • Phosphorylated phospholipase C hydrolyzes PIP2 and phosphatidylinositol to generate two secondary messengers, inositol triphosphate (IP3) and diacylglycerol (DAG). These secondary messengers regulate the activity of downstream proteins during B cell signaling.
  • IP3 inositol triphosphate
  • DAG diacylglycerol
  • Ibrutinib is the first approved BTK inhibitor and is being used to treat leukemia (CLL) and lymphoma (MCL).
  • CLL leukemia
  • MCL lymphoma
  • ibrutinib is an irreversible inhibitor that covalently binds to C481 in BTK, so there is a problem in that it cannot treat patients with C481 mutation. Accordingly, reversible non-covalent BTK inhibitors are being developed.
  • International Publication No. WO2017/103611 discloses a reversible BTK inhibitor, its preparation method, and its use. Nevertheless, alternative BTK inhibitors are needed.
  • the present inventors conducted research with support from the National New Drug Development Project of the National New Drug Development Project funded by the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, and the Ministry of Health and Welfare, and completed the present invention for a novel compound (project specific). Number HN2C0823).
  • One aspect is to provide a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • Another aspect is to provide a pharmaceutical composition for use in treating a disease mediated by protein kinases, comprising a compound of Formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. .
  • Another aspect is to provide a pharmaceutical composition for use in inhibiting the activity of a protein kinase comprising a compound of Formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another aspect provides a method of treating a disease mediated by protein kinases in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. .
  • Another aspect is to provide a method of inhibiting the activity of a protein kinase comprising contacting the protein kinase with a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • One aspect provides a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • Cy is C 3-12 aryl, C 3-12 cycloalkyl or C 3-10 heteroaryl, and the C 3-12 aryl, C 3-12 cycloalkyl or C 3-10 heteroaryl is C 1-6 alkyl, C 1-6 alkoxy, halo, cyano, -NR 3 R 4 (where R 3 and R 4 are each independently hydrogen, C 1-6 alkyl, or C 1-6 alkylcarbonyl), C 1- 6 alkylNR 3 - (wherein R 3 is hydrogen, C 1-6 alkyl, or C 1-6 alkylcarbonyl) and hydroxy;
  • A is a 5-membered ring having 2 or more N atoms or -CONH-;
  • X is CH or S
  • Y is NH or O when X is CH, or CH when X is S;
  • R 1 is C 1-6 alkyl (where C 1-6 alkyl may be substituted with one or more halo or hydroxy), hydroxyC 1-6 alkyl (where C 1-6 alkyl may be substituted with one or more halo or hydroxy), may be substituted with halo or hydroxy), NR 3 R 4 C 1-6 alkyl (where R 3 and R 4 are each independently hydrogen, C 1-6 alkyl, or C 1-6 alkylcarbonyl) , -NR 3 R 4 (wherein R 3 and R 4 are each independently hydrogen, C 1-6 alkyl, or C 1-6 alkylcarbonyl), NR 3 R 4 C 1-6 alkylcarbonyl (here R 3 and R 4 are each independently hydrogen, C 1-6 alkyl, or C 1-6 alkylcarbonyl), cyano, hydroxy, C 1-6 alkoxy, halo, C 3-6 cycloether, and C 3-10 heterocycloalkyl-(CH 2 )n1 (n1 is an integer of 0 to
  • Z 2 is CH or N
  • R 2 is C 3-12 cycloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 heterocycloalkyl, C 3 formed by combining the N of L 2 with carbon.
  • -10 heterocycloalkyl, C 3-10 heteroaryl, or C 3-12 aryl and the C 3-12 cycloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 heterocycloalkyl, C 3-10 heterocycloalkyl formed by combining the N of L 2 with carbon, C 3-10 heteroaryl, or C 3-12 aryl is hydroxy, C 1-6 alkoxy, -NR 3 R 4 (where R 3 and R 4 are independently hydrogen, C 1-6 alkyl, or C 1-6 alkylcarbonyl), cyano, halo, C 1-6 alkyl (where C 1-6 6 alkyl may be substituted with one or more halo or hydroxy), C 1-6
  • L 1 and L 2 are independently NH, N, O, or S;
  • n is an integer of 0 or 1.
  • Cy can be C 5-12 aryl, C 5-12 cycloalkyl, or C 3-6 heteroaryl.
  • Cy can be phenyl, cyclohexyl, pyrazolyl, or pyridyl.
  • Cy may be phenyl or pyridyl.
  • Cy is substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, halo or -NR 3 R 4 (wherein R 3 and R 4 are each independently hydrogen or C 1-6 alkyl) It can be.
  • A can be a 5-membered heteroaryl having two or more N atoms.
  • A may be a 5-membered ring having 2 to 4 N atoms, or 2 or 3 N atoms and 1 O atom, or -CONH-.
  • A can have 2 to 4 N atoms, or can be a 5-membered heteroaryl with 2 or 3 N atoms and 1 O atom.
  • A can be imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, or -CONH-.
  • A is -CONH-, N may be bonding to Cy, and C may be bonding to Cy.
  • A may be imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, or -CONH-.
  • A may be tetrazolyl, oxadiazolyl, or -CONH-.
  • R 1 is C 1-6 alkyl (wherein C 1-6 alkyl may be substituted with one or more halo or hydroxy), hydroxyC 1-6 alkyl (wherein C 1-6 alkyl may be substituted with one or more halo or hydroxy), NR 3 R 4 C 1-6 alkyl (where R 3 and R 4 are each independently hydrogen, C 1-6 alkyl, or C 1-6 alkyl carbonyl), -NR 3 R 4 (where R 3 and R 4 are each independently hydrogen, C 1-6 alkyl, or C 1-6 alkylcarbonyl), NR 3 R 4 C 1-6 alkyl carbonyl (wherein R 3 and R 4 are each independently hydrogen, C 1-6 alkyl, or C 1-6 alkylcarbonyl), cyano, hydroxy, C 1-6 alkoxy, halo, C 3- 6 C 3-10 heterocycloalkyl-(CH 2 )n1 (n1 is an integer from 0 to 6), which may be substituted with one or more substituents selected from
  • R 1 is C 1-6 alkyl (wherein C 1-6 alkyl may be substituted with one or more halo or hydroxy), hydroxyC 1-6 alkyl (wherein C 1-6 alkyl may be substituted with one or more halo or hydroxy), NR 3 R 4 C 1-6 alkyl (where R 3 and R 4 are each independently hydrogen, C 1-6 alkyl, or C 1-6 alkyl carbonyl), -NR 3 R 4 (where R 3 and R 4 are each independently hydrogen, C 1-6 alkyl, or C 1-6 alkylcarbonyl), NR 3 R 4 C 1-6 alkyl carbonyl (wherein R 3 and R 4 are each independently hydrogen, C 1-6 alkyl, or C 1-6 alkylcarbonyl), cyano, hydroxy, halo, C 3-6 cycloether, and C morpholinyl, morpholinomethyl, piperazinyl, piperidinyl or pyrrolidinyl, which may be substituted with one or more substituent
  • R 1 when R 1 is C 3-10 heterocycloalkyl, one of the heteroatoms of C 3-10 heterocycloalkyl may be bonded to the carbon of Z 1 .
  • One of the heteroatoms may be N, O, or S.
  • R 2 is C 3-12 cycloalkyl, C 1-6 alkyl, C 3-10 heterocycloalkyl, C 3-10 heterocycloalkyl formed by combining the N of L 2 with carbon, or C 3- 12 Can be aryl.
  • the C 3-12 cycloalkyl may be bicyclic or spiro.
  • R 2 is C 4-7 cycloalkyl, C 1-6 alkyl, C 4-7 heterocycloalkyl, C 4-7 heterocycloalkyl formed by combining the N and carbon of L 2 , or C 5- 12 Can be aryl.
  • R 2 is C 4-7 cycloalkyl, C 1-6 alkyl, C 4-7 heterocycloalkyl, C 4-7 heterocycloalkyl formed by combining N and carbon of L 2, or C 5-12 aryl
  • the C 4-7 cycloalkyl, C 1-6 alkyl, C 4-7 heterocycloalkyl, C 4-7 heterocycloalkyl formed by combining N and carbon of L 2 , or C 5-12 aryl is hydroxy, It may be substituted with hydroxymethyl, cyano, -CONH 2 , or aminosulfonyl.
  • L 1 and L 2 may be independently NH, N, or O.
  • the compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be the following compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • the compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be the following compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, but the scope of the present disclosure is not limited thereto:
  • the compound of Formula 1 may be substituted with a detectable label.
  • the detectable label may be an optical label, an electrical label, a magnetic label, or an indirect label.
  • An optical label is a substance that generates a detectable optical signal and may be a radioactive substance or a coloring substance such as a fluorescent substance.
  • An indirect label refers to a substance that can generate a detectable label as a result of binding to a specific substance, such as an enzyme that converts a substrate into a coloring substance or its substrate, antibody, or antigen.
  • the optical label may be an isotope of an element constituting the compound of Formula 1. Accordingly, the compound of Formula 1 may have one or more of the elements constituting it replaced with its isotope, for example, a radioactive isotope.
  • Examples of these isotopes include 2 H (which can be represented by D for deuterium), 3 H (which can be represented by T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, Includes 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, 131 I, etc.
  • the compounds of the present disclosure may be in the form of their pharmaceutically acceptable salts.
  • Said salts include the usual acid addition salts used in the pharmaceutical field, for example salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid or nitric acid, and salts derived from acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, Contains salts derived from organic acids such as citric acid, maleic acid, malonic acid, methanesulfonic acid, tartaric acid, malic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, oxalic acid or trifluoroacetic acid. do.
  • the salts also include common metal salt forms, for example salts derived from metals such as lithium, sodium, potassium, magnesium, or calcium
  • Solvate means a complex or aggregate formed by one or more solute molecules, i.e. a compound of Formula 1, or a stereoisomer or pharmaceutically acceptable salt thereof, and one or more solvent molecules.
  • Solvates may be complexes or aggregates formed with, for example, water, methanol, ethanol, isopropanol, acetic acid, or dimethyl sulfoxide (DMSO).
  • Stereoisomers include all stereoisomers such as enantiomers and diastereomers.
  • the compound may be in stereoisomerically pure form or a mixture of one or more stereoisomers, for example a racemic mixture. Separation of specific stereoisomers can be performed by any of the conventional methods known in the art.
  • Some examples of compounds of the present disclosure may have a greater BTK inhibitory effect of specific stereoisomers than their racemic mixtures. In this case, the dosage can be reduced by using a specific stereoisomer.
  • alkyl refers to a straight-chain or branched saturated hydrocarbon group.
  • the alkyl may contain 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • Alkyl is for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, It may contain n-nonyl or n-decyl.
  • alkenyl refers to alkyl having at least one carbon-carbon double bond. where alkyl is as defined above. Alkenyl may be, for example, ethenyl or propenyl.
  • alkynyl refers to alkyl having at least one carbon-carbon triple bond. where alkyl is as defined above. Alkynyl may be, for example, ethynyl or 2-propynyl.
  • alkoxy refers to an (alkyl)O-group. where alkyl is as defined above.
  • aryl refers to an aromatic ring in which each ring-forming atom is a carbon atom.
  • the ring may be monocyclic or polycyclic.
  • the polycyclic ring may include one having a fused ring (e.g. naphthalene) or one having an unfused ring (e.g. biphenyl).
  • the polycyclic ring may have, for example, 2, 3, or 4 rings.
  • the aryl group is, for example, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 5 to 20, 5 to 15, 5 to 12, 5 to 10. , or has 6 to 10 carbon ring atoms.
  • Such aryl groups include, for example, phenyl, naphthalenyl (e.g., naphthalen-1-yl and naphthalen-2-yl), biphenyl, anthracenyl, and phenanthrenyl.
  • cycloalkyl refers to a non-aromatic carbon ring in which each ring-forming atom is a carbon atom.
  • the cycloalkyl may be monocyclic or polycyclic.
  • the polycyclic ring is one having, for example, 2, 3 or 4 fused rings.
  • the cycloalkyl may include one fused to an aromatic ring.
  • the cycloalkyl has, for example, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 3 to 10, 3 to 7, 5 to 7, or 5 to 6 ring carbons. Contains atoms.
  • Cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norcanyl, and adamantyl.
  • the “cycloalkyl” may include a spiro ring.
  • the spiro ring may include a C7, C8, or C10 ring.
  • heterocycloalkyl refers to a carbon ring containing 1 to 4 ring-forming heteroatoms each selected from N, O, and S. Heterocycloalkyl may be one that does not have two adjacent O or S. Heterocycloalkyls include monocyclic or polycyclic structures, for example, structures having two, three or four fused rings.
  • heterocycloalkyl examples include morpholinyl, thiomorpholinyl, piperazinyl, imidazolidinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, oxadiazolyl , oxanyl, etc.
  • the heterocycloalkyl is, for example, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 3 to 10, 4 to 10, 3 to 7, 5 to 5. It contains 7 or 5 to 6 ring-forming atoms.
  • Cyclic groups may be linearly fused, bridged, or spirocyclic.
  • cycloalkyls include adamantyl, bicyclo[1.1.1]fentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and spiro[4.4].
  • ]octanyl or spiro[5.5]undecanyl and heterocycloalkyl may include 2-oxa-5-azabicyclo[2.2.1]heptane or cyclopenta[c]pyrrole.
  • heteroaryl refers to an aromatic carbon ring having 1 to 4 heteroatoms selected from N, O and S as ring members. Heteroaryl includes monocyclic or polycyclic structures. The polycyclic ring may have, for example, 2, 3 or 4 condensed rings. The heteroaryl contains, for example, 3 to 10, 5 to 10, 5 to 8, 5 to 7, 5, 6, or 7 ring atoms. The heteroaryl may contain 1, 2, or 3 heteroatoms.
  • Heteroaryl is, for example, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, furanyl, benzoyl.
  • halo or halogen refers to fluoro, chloro, bromo, or iodo.
  • Another aspect provides a pharmaceutical composition for use in treating a disease mediated by protein kinases, comprising a compound of Formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the disease may be caused by an increase in protein kinase activity.
  • the protein kinase may catalyze the reaction of adding a phosphate group to another protein.
  • the protein kinase may be a serine/threonine-specific protein kinase, a tyrosine-specific protein kinase, or a serine/threonine and tyrosine protein kinase.
  • the protein kinase may be a receptor or non-receptor protein kinase.
  • Receptor protein kinases include, for example, PDGFR or VEGFR.
  • the non-receptor protein kinase may be a member of an intracellular protein.
  • the non-receptor protein kinase may be a member of the Syk, SRC, or Tec families.
  • cSRC is the prototypical member of the SRC family of tyrosine kinases, which includes Lyn, Fyn, Lck, Hck, Fgr, Blk, Syk, Yrk, and Yes.
  • Tec kinase may be a non-receptor tyrosine kinase expressed primarily in cells of hematological origin.
  • the Tec family includes Tec, Btk, inducible T-cell kinase (Itk), resting lymphocyte kinase (Rlk/Txk), and myeloid expressed kinase (Bmx/Etk).
  • Bruton's Tyrosine Kinase is a member of the Tec family of tyrosine kinases and is a key regulator of early B cell development, mature B cell activation, signaling and survival.
  • B cell signaling through the B cell receptor (BCR) results in a wide range of biological outputs.
  • Abnormal BCR-mediated signaling can lead to deregulated B cell proliferation and/or formation of pathogenic autoantibodies that lead to multiple autoimmune and/or inflammatory diseases.
  • mutations in BTK can cause X-linked agammaglobulinaemia (XLA). The disease is associated with impaired maturation of B cells, reduced immunoglobulin production, T cell-independent immune responses, and marked attenuation of sustained calcium signaling upon BCR stimulation.
  • XLA X-linked agammaglobulinaemia
  • the protein kinase may be a cysteine-containing kinase.
  • the protein kinase may have a cysteine residue near the ATP-binding site of the kinase.
  • the cysteine residue may be in close spatial proximity near the ATP-binding site of the kinase.
  • Protein kinases with cysteine residues near the ATP-binding site may be BTK, BMX, TEC, TXK, ITK, EGFR, ErbB, JAK3, BLK, etc.
  • the protein kinase is ABL, ACK1, ALK, Aurora A, Aurora B, Aurora C, BLK, BMX/ETK, BRSK1, BTK, c-Src, CAMKK, CDK1, CDK2, CDK5, CLK, DDR, DYRK1B , EPHA, EPHB, FAK/PTK2, FER, FES/FPS, FGFR, FGR, FLT3, FLT4/VEGFR3, FMS, FRK/PTK5, FYN, GSK3b, HCK, IGF1R, IR, IRAK1, IRR/INSRR, ITK, JAK2 , KHS/MAP4K5, LCK, LYN, PHKg, PLK4/SAK, PYK2, RET, ROS/ROS1, TIE2/TEK, TRK, TXK, TYK, YES/YES1, or a combination thereof.
  • the protein kinase may be BTK, especially C481 mutant BTK, for example C481S BTK.
  • Inhibition of protein kinase activity may be useful in treating the following autoimmune and/or inflammatory diseases.
  • protein kinases, such as BTK have been reported to play a role in apoptosis.
  • Inhibition of protein kinase activity, such as BTK may be useful in treating B-cell proliferative disorders or mast cell proliferative disorders.
  • Inhibition of protein kinase activity, such as BTK may be useful in treating cancers such as B cell lymphoma and leukemia.
  • the disease may be cancer, inflammatory disease, or autoimmune disease.
  • the cancer may be a solid cancer or a hematological cancer.
  • the blood cancer may be lymphoma, leukemia, multiple myeloma, plasma cell myeloma, or myelodysplastic syndrome.
  • lymphomas include mantle cell lymphoma (MCL) or non-Hodgkin's lymphoma, lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma, small lymphocytic lymphoma (SLL), and high-risk small lymphoma.
  • MCL mantle cell lymphoma
  • SLL small lymphocytic lymphoma
  • High-risk small lymphocytic lymphoma follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), Waldenstrom's macroglobulinemia, Burkitt's lymphoma ( Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma , precursor B-lymphoblastic lymphoma, splenic marginal zone lymphoma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravenous giant It may be intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
  • the leukemia may be chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or B cell prolymphocytic leukemia.
  • Solid cancers include brain tumor, head and neck cancer, lung cancer, breast cancer, thymoma, mesothelioma, esophageal cancer, colon cancer, liver cancer, stomach cancer, pancreas cancer, biliary tract cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, germ cell tumor, ovarian cancer, cervical cancer, and endometrium.
  • the inflammatory diseases and/or autoimmune diseases include systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple vasculitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, and asthma. , chronic graft vs host disease, multiple sclerosis, Sjogren's syndrome, Crohn's disease, Behcet's Disease, or Type 1 Diabetes. ) can be.
  • SLE systemic lupus erythematosus
  • ITP idiopathic thrombocytopenic purpura
  • myasthenia gravis and asthma.
  • chronic graft vs host disease multiple sclerosis
  • Sjogren's syndrome Sjogren's syndrome
  • Crohn's disease Crohn's disease
  • Behcet's Disease or Type 1 Diabetes.
  • the above diseases merely exemplify specific diseases to which the pharmaceutical composition of the present disclosure can be applied, and the scope of the present
  • the disease may be resistant or refractory to an irreversible BTK inhibitor, such as ibrutinib.
  • treatment means treating a disease or medical condition, e.g., a BTK-related disease, in an individual, e.g., a mammal, including a human, and includes: (a) the disease or medical condition; Alleviation, i.e., causing elimination or recovery of a disease or medical condition in a patient; (b) inhibition of a disease or medical condition, i.e., slowing or halting the progression of a disease or medical condition in an individual; or (c) alleviating a disease or medical condition in an individual.
  • a disease or medical condition e.g., a BTK-related disease
  • Alleviation i.e., causing elimination or recovery of a disease or medical condition in a patient
  • inhibition of a disease or medical condition i.e., slowing or halting the progression of a disease or medical condition in an individual
  • alleviating a disease or medical condition in an individual alleviating a disease or medical condition in an individual.
  • the amount of the compound of Formula 1 or its pharmaceutically acceptable salt can be appropriately selected by a person skilled in the art.
  • the amount is 0.01 mg to 10,000 mg, 0.1 mg to 1,000 mg, 1 mg to 100 mg, 0.01 mg to 1,000 mg, 0.01 mg to 100 mg, 0.01 mg to 10 mg, or 0. It may be .01 mg to 1 mg.
  • “pharmaceutically acceptable carrier” refers to a substance, generally an inert substance, used in combination with the active ingredient to aid in the application of the active ingredient.
  • the carrier includes conventional pharmaceutically acceptable excipients, additives or diluents.
  • the carrier includes, for example, fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, flavoring agents, thickeners, coloring agents, emulsifiers, and suspending agents. It may contain one or more selected from topical agents, stabilizers, and isotonic agents.
  • composition of the present disclosure may be in an oral dosage form, or a parenteral dosage form, including intravenous, intraperitoneal, subcutaneous, rectal, and topical administration. Accordingly, the composition of the present disclosure may be formulated in various forms such as tablets, capsules, aqueous solutions, or suspensions. In the case of oral tablets, excipients such as lactose and corn starch and lubricants such as magnesium stearate can usually be added. For capsules for oral administration, lactose and/or dried corn starch may be used as diluents. When an aqueous suspension for oral use is required, the active ingredient may be combined with an emulsifying and/or suspending agent.
  • compositions according to the present disclosure may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier, such as saline solution at physiological pH.
  • a pharmaceutically acceptable carrier such as saline solution at physiological pH.
  • the solution can be introduced into the patient's intramuscular bloodstream by local bolus injection.
  • the compound of Formula 1 defined in the present disclosure may exhibit an effect of inhibiting protein kinase activity.
  • “Inhibition” herein includes reducing the kinase activity of a protein kinase.
  • the protein kinase may be BTK.
  • the protein kinase may be C481 mutant BTK, for example C481S BTK.
  • the pharmaceutical composition can be combined with one or more other therapeutic agents to treat diseases associated with protein kinases.
  • Other therapeutic agents include chemotherapy agents, anti-inflammatory agents, immunosuppressants, and anticancer agents.
  • examples of other therapeutic agents include anti-angiogenic agents, MALT1, MCL-1 or IDH1 inhibitors, TLR9 inhibitors, Bcl-2, JAK2, ALK or Hsp90 inhibitors, CYP3A4 inhibitors, BET inhibitors, and immune checkpoint inhibitors. checkpoint inhibitor), anti-CD20 treatment, HDAC inhibitor, PIM inhibitor, and mTOR inhibitor.
  • Combination treatment may produce synergistic effects.
  • the drug for combination treatment can be administered in combination with the protein kinase inhibitor in a single dose or sequential dosage form, or can be administered simultaneously or sequentially in separate dosage forms.
  • the protein kinase may be BTK.
  • Another aspect provides the use of a compound of formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as defined above, in the treatment of diseases associated with protein kinases.
  • Another aspect provides the use of a compound of formula (1) as defined above, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diseases associated with protein kinases.
  • Another aspect provides a pharmaceutical composition for use in inhibiting the activity of a protein kinase comprising a compound of Formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another aspect provides a method of treating a protein kinase-mediated disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the administration route can be appropriately selected by a person skilled in the art depending on the patient's condition.
  • the administration may be oral, parenteral, or topical.
  • the subject may be a mammal, such as a human, cow, pig, horse, or cat.
  • “therapeutically effective amount” means an amount sufficient to produce a therapeutic effect when administered to an individual in need of treatment.
  • the dosage may vary depending on various factors such as the patient's condition, route of administration, and the judgment of the attending physician. Effective doses can be estimated from dose-response curves obtained from in vitro experiments or animal model tests. The proportion and concentration of compounds present in the administered composition may be determined depending on the chemical nature, route of administration, therapeutic dosage, etc.
  • the dosage may be administered to the individual in an effective amount of about 1 ⁇ g/kg to about 1 g/kg per day, or about 0.1 mg/kg to about 500 mg/kg per day. The dosage may vary depending on the individual's age, weight, sensitivity, or symptoms.
  • the disease may be one described for the pharmaceutical composition.
  • the above diseases merely exemplify specific diseases to which the method of the present disclosure can be applied, and the scope of the present disclosure is not limited to the above diseases.
  • a therapeutically effective amount of a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be administered in combination with one or more other therapeutic agents for treating diseases associated with protein kinases, such as BTK. .
  • Another aspect is activating Bruton's Tyrosine Kinase (BTK) comprising contacting a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof with a protein kinase, such as Bruton's Tyrosine Kinase (BTK).
  • BTK Bruton's Tyrosine Kinase
  • the contacting step may be performed ex vivo or in vitro.
  • the contacting step may include incubation in a medium containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof and a protein kinase, such as Bruton's tyrosine kinase (BTK).
  • the medium may be a liquid, for example water, or an organic solvent.
  • the contacting step may include administering the compound of Formula 1 or a pharmaceutically acceptable salt thereof to an individual and allowing it to come into contact with a protein kinase, for example, Bruton's tyrosine kinase (BTK), within the individual.
  • a protein kinase for example, Bruton's tyrosine kinase (BTK)
  • the BTK may be C481 mutant BTK, for example, C481S BTK.
  • a compound of Formula 1 according to one aspect may be prepared according to Scheme 1 below.
  • the compound of Formula 1-IIa can be prepared by reacting the compound of Formula 1-IV with the compound of Formula V. This reaction can be carried out in the presence of tris(dibenzylideneacetone)dipalladium, xantphos, and sodium-t-butoxide in a polar organic solvent such as dioxane.
  • a compound of formula (1-IIb) can be prepared in which the halogen group of the compound of formula (1-IIa) is replaced with an amino group.
  • This reaction can be carried out in the presence of potassium carbonate, copper oxide, N,N'-dimethylethylenediamine, and aqueous ammonia in an organic solvent, such as a glycol solvent, especially ethylene glycol.
  • step (1-3) the compound of formula I can be prepared by reacting the compound of formula 1-IIb obtained in step (1-2) with the compound of formula III. This reaction can be performed using the same reagent or solvent as step (1-1).
  • the compound in which Z 2 is N may be prepared according to Scheme 2 below.
  • a compound of formula 2-IIb can be prepared by reacting formula 2-IV with compound V.
  • This reaction is carried out in a polar aprotic organic solvent in the presence of a base such as diisopropylethylamine, triethylamine, pyridine, sodium hydride, sodium-t-butoxide, potassium carbonate, cesium carbonate, sodium bicarbonate, or combinations thereof.
  • a base such as diisopropylethylamine, triethylamine, pyridine, sodium hydride, sodium-t-butoxide, potassium carbonate, cesium carbonate, sodium bicarbonate, or combinations thereof.
  • a base such as diisopropylethylamine, triethylamine, pyridine, sodium hydride, sodium-t-butoxide, potassium carbonate, cesium carbonate, sodium bicarbonate, or combinations thereof.
  • it can be carried out in tetrahydrofuran, ethyl acetate, acetone, N,
  • a compound of formula (2-IIa) can be prepared in which the halogen group of the compound of formula 2-IIb is replaced with an R 1 group.
  • Polar aprotic organic solvents in the presence of bases such as diisopropylethylamine, triethylamine, pyridine, sodium hydrochloride, sodium-t-butoxide, potassium carbonate, cesium carbonate, sodium bicarbonate, or combinations thereof.
  • bases such as diisopropylethylamine, triethylamine, pyridine, sodium hydrochloride, sodium-t-butoxide, potassium carbonate, cesium carbonate, sodium bicarbonate, or combinations thereof.
  • bases such as diisopropylethylamine, triethylamine, pyridine, sodium hydrochloride, sodium-t-butoxide, potassium carbonate, cesium carbonate, sodium bicarbonate, or combinations thereof.
  • it may be carried out in tetrahydrofuran, ethyl acetate,
  • a compound of Formula I can be prepared by reacting a compound of Formula 2-IIa with a compound of Formula 2-III. This reaction can be carried out in the presence of tris(dibenzylideneacetone)dipalladium, xantphos, and sodium-t-butoxide in a polar organic solvent such as dioxane.
  • the compound of Formula 1, its stereoisomer or its pharmaceutically acceptable salt can be used to treat diseases mediated by protein kinases, such as BTK.
  • compositions according to other aspects can be used to treat diseases mediated by protein kinases, such as BTK.
  • a disease mediated by a protein kinase such as BTK
  • a disease mediated by a protein kinase, such as BTK can be efficiently treated in an individual.
  • the activity of a protein kinase for example, BTK
  • the activity of a protein kinase for example, BTK
  • the BTK may be C481 mutant BTK, for example, C481S BTK.
  • the reaction mixture is stirred at 80° C. for 2 hours.
  • extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure.
  • the obtained residue was purified using column chromatography to obtain the target compound (0.08 g, 21%).
  • step 2 of Example 1 the target compound (1.20 g, 16%) was reacted in the same manner, except that tert-butyl piperazine-1-carboxylate (3.31 g, 17.80 mmol) was used instead of 1-methyl piperazine. ) was obtained.
  • the reaction mixture is neutralized using an aqueous sodium carbonate solution. After extraction using dichloromethane, washing with water, the obtained organic layer was dried with sodium sulfate, and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.01 g, 60%).
  • Step 1) (1R,4R)-4-((4-(4-isopropylpiperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2 Synthesis of -yl)thiazol-2-yl))amino)pyridin-2-yl)amino)cyclohexan-1-ol
  • the target compound (3.00 mg, 14%) was obtained by reacting in the same manner, except that iodoethane (0.01 ml, 0.11 mmol) was used instead of 2-iodopropane in Step 1 of Example 3.
  • Ethyl 2-aminothiazole-5-carboxylate (3.60 g, 20.93 mmol) and di-tert-butyl dicarboate (13.70 g, 62.79 mmol) were mixed with isopropanol solvent and stirred at 50°C for 24 hours. When the reaction was completed, the solvent was concentrated under reduced pressure to obtain the target compound (5.30 g, 93%).
  • 2,4,6-Trichloropyrimidine (12.00 g, 65.42 mmol), trans-4-aminocyclohexanol (8.29 g, 71.97 mmol) and triethylamine (13.68 ml, 98.13 mmol) were dissolved in 130 ml of dichloromethane. After dissolving in , it reacts at room temperature. When the reaction is completed, it is extracted with ethyl acetate, washed with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (4.80 g, 28%).
  • Step 2) (1R,4R)-4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4- Synthesis of oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol
  • the target compound (0.60 g, 96%) was reacted in the same manner, except that 1-methylpiperazine (0.32 ml, 2.86 mmol) was used instead of 1-(2-hydroxyethyl)piperazine in step 6 of Example 5. ) was obtained.
  • Step 2) (1R,4R)-4-((4-(4-methylpiperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2- Synthesis of 1) thiazol-2-yl)) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol
  • Step 1 4-Fluorobenzohydrazide (0.5 g, 3.24 mmol) obtained in Step 1 was reacted in the same manner as Step 1 of Example 1 to obtain the target compound (0.32 g, 30%).
  • the target compound (0.34 g, 94%) was obtained by reacting in the same manner, except that morpholine (0.15 ml, 1.71 mmol) was used instead of 1-(2-hydroxyethyl)piperazine in step 6 of Example 5. .
  • Step 2) (1R,4R)-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl ) Amino) pyrimidin-2-yl) amino) cyclohexan-1-ol synthesis
  • the extract is extracted using ethyl acetate, washed with water, the resulting organic layer is dried over magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.17 g, 56%).
  • the reaction mixture is stirred at 80° C. for 2 hours.
  • extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure.
  • the obtained residue was purified using column chromatography to obtain the target compound (0.16 g, 16%).
  • the target compound (0.20 g, 51 mmol) was reacted in the same manner, except that 4-aminocyclohexanol (0.20 g, 1.71 mmol) was used instead of 1-(2-hydroxyethyl)piperazine in Step 6 of Example 5. %) was obtained.
  • Step 2) (1R,4R)-4-((4-((4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazole-2- Synthesis of 1) thiazol-2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol
  • 2,4,6-Trichloropyrimidine (12.00 g, 65.42 mmol) was dissolved in 130 ml of dichloromethane, then 4-fluoropiperidine (7.64 mL, 71.91 mmol) and TEA (13.68 ml, 98.13 mmol). Add slowly at 0°C. Stir for 3 hours at the same temperature. When the reaction was completed, it was extracted using ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (4.80 g, 28%).
  • Step 2) (1R,4R)-4-((4-chloro-6-(4-fluoropiperidin-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol
  • 2,4-dichloro-6-(4-fluoropiperidin-1-yl)pyrimidine (0.30 g, 1.14 mmol) and cesium carbonate (0.74 g, 2.28 mmol) obtained in step 1 were mixed with 2.0 ml of aceto. After dissolving in nitrile, stir at room temperature for 30 minutes. Afterwards, 4-fluoropiperidine is slowly added and reacted in the microwave at 9°C for three hours. When the reaction was completed, it was extracted using ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (250 mg, 68%).
  • 2,4,6-Trichloropyrimidine (1.00 g, 5.45 mmol) was dissolved in 76 ml of dichloromethane, then cis-2,6-dimethylmorpholine (0.74 ml, 6.00 mmol) and DIPEA (3.13 ml, 18 mmol) is added slowly. Stir for 3 hours at the same temperature. When the reaction was completed, it was extracted using ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (1.06 g, 74%).
  • Step 2) (1R,4R)-4-((4-chloro-6-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-2-yl)amino)cyclohexan-1-ol
  • the target compound (1.00 g, 79%) was obtained in the same manner as in Step 1 of Example 14, except that piperidine (0.59 ml, 6.00 mmol) was used instead of 2,6-dimethylmorpholine.
  • Step 2) (1R,4R)-4-((4-chloro-6-(piperidin-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol
  • 2,6-Dibromo-4-nitropyridine (0.10 g, 0.36 mmol) and potassium carbonate (0.15 g, 1.07 mmol) were dissolved in 1 ml of dimethylformamide and stirred for 30 minutes. Afterwards, morpholine (0.03 ml, 0.36 mmol) was slowly added and stirred at room temperature for an additional 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (80 mg, 70%).
  • Step 1) N-(2-chloro-6-methylphenyl)-2-((6-(4-fluoropiperidin-1-yl)-2-(((1R,4R)-4-hydroxycyclo hexyl) amino) pyrimidin-4-yl) amino) thiazole-5-carboxamide
  • Step 1) (1R,4R)-4-((4-((5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl )Amino)-6-morpholinopyrimidin- 2-yl)amino)cyclohexan-1-ol
  • Example 9 (1R,4R)-4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)cyclohexan-1-ol (0.06 g, 0.21 mmol) synthesized in step 1 of the synthesis ) and 5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-amine (0.06 g, 0.23 mmol) obtained in step 3 of Example 8 was reacted in the same manner as step 3 of Example 12 to obtain the target compound (16 mg, 14%).
  • Step 2) (1R,4R)-4-((4-(methylamino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2- yl) amino) pyrimidin-2 -yl) amino) cyclohexan-1-ol
  • Step 2) (1R,4R)-4-((4-(dimethylamino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2- yl) amino) pyrimidin-2 -yl) amino) cyclohexan-1-ol
  • step 1 (1R,4R)-4-((4-chloro-6-(dimethylamino)pyrimidin-2-yl)amino)cyclohexan-1-ol (0.10 g, 0.37 mmol) obtained in step 1 was used as an example By reacting in the same manner as step 3 in 12, the target compound (104 mg, 59%) was obtained.
  • Step 2) (1R,4R)-4-((4-chloro-6-thiomopolinopyrimidin-2-yl)amino)cyclohexan-1-ol
  • 2,4,6-Trichloropyrimidine (7.00 g, 38.17 mmol) was dissolved in 76 ml of dichloromethane, and then morpholine (3.46 ml, 40.07 mmol) and DIPEA (19.95 ml, 114.50 mmol) were slowly added. Stir for 3 hours at the same temperature. When the reaction was completed, it was extracted using ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (8.60 g, 67%).
  • Step 2) (1R,3R)-3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl ) Amino) pyrimidin-2-yl ) Amino) cyclobutan-1-ol synthesis
  • Step 2) 6-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine- Synthesis of 2-yl)amino)spiro[3.3]heptan-2-ol
  • Step 2) (1S,3S)-3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl ) Amino) pyrimidin-2-yl ) Amino) cyclopentan-1-ol synthesis
  • Step 2) (1S,4 R )-4-((4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-chloropyrimidine-2 Synthesis of -yl)amino)cyclohexane-1ol
  • Example 27 (One R ,4 R )-4-((4-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl ) Synthesis of thiazol-2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol
  • Step 2) (1 R ,4 R )-4-((4-chloro-6-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyrimidin-2-yl)amino)cyclohexane- Synthesis of 1-ol
  • Step 3) (1 R ,4 R )-4-((4-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-6-((5-(5-phenyl-1,3, Synthesis of 4-oxadiazol-2-yl) thiazol-2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol
  • Step 1 of Example 22 the same method as 2,4,6-trichloropyrimidine (0.30 g, 1.60 mmol) was used, except that 4-piperidiol (0.50 g, 3.20 mmol) was used instead of morpholine.
  • the target compound (0.24 g, 61.7%) was obtained.
  • Step 2) Synthesis of 1-(6-chloro-2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)pyrimidin-4-yl)piperidin-4-ol
  • the target compound (430 mg, 26%) was obtained.
  • Step 2) (1R,4R)-4-((4-chloro-6-(2,2,6,6-tetrafluoromorpholino)pyrimidin-2-yl)amino)cyclohexan-1-ol
  • the target compound (630 mg, 52%) was obtained using the same method except that 2-methoxyethylamine (0.52 ml, 6.00 mmol) was used instead of 2,6-dimethylmorpholine in Step 1 of Example 22. .
  • Step 2) (1R,4R)-4-((4-chloro-6-((2-methoxyethyl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol
  • Step 2) 1-(6-chloro-2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)pyrimidin-4-yl)-5-methylpyrrolidin-2-one synthesis
  • Step 3 1-(2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazole-2 Synthesis of -yl)thiazol-2-yl)amino)pyrimidin-4-yl)-5-methylpyrrolidin-2-one
  • 2,4,6-trichloropyrimidine (0.30 g, 1.60 mmol), except that piperidine-4-carbonitrile hydrochloride (0.30 g, 1.90 mmol) was used instead of morpholine in Step 1 of Example 22.
  • the target compound (0.35 g, 85.4%) was obtained using the same method.
  • Step 2) Synthesis of 1-(6-chloro-2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)pyrimidin-4-yl)piperidine-4-carbonitrile
  • Step 3 1-(2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazole-2 Synthesis of -1)thiazol-2-yl)amino)pyrimidin-4-yl)piperidine-4-carbonitrile
  • Step 2) (1R,4R)-4-((4-methoxy-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl) Amino) pyridin-2-yl) Amino) cyclohexan-1-ol
  • Example 34 1-(4-(2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine-4 Synthesis of -1) piperazine-1-yl) ethane-1-one
  • Step 1 of Example 22 the same method as 2,4,6-trichloropyrimidine (0.15 g, 0.80 mmol) was used, except that 1-acetylpiperazine (0.12 g, 1.00 mmol) was used instead of morpholine.
  • the target compound (0.17 g, 77.7%) was obtained.
  • Step 3) 1-(4-(2-(((1 R ,4 R )-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadia Synthesis of sol-2-yl)thiazol-2-yl)amino)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one
  • Example 35 (One R ,4 R )-4-((4-(4-methoxypiperidin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2 Synthesis of -yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol
  • Step 2) Synthesis of (1 R ,4 R )-4-((4-chloro-6-(4-methoxypiperidin-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol
  • Step 3) (1 R ,4 R )-4-((4-(4-methoxypiperidin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole Synthesis of -2-yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol
  • Example 36 (One R ,4 R )-4-((4-(4-(dimethylamino)piperidin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia Synthesis of sol-2-yl) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol
  • Step 2) (1 R ,4 R )-4-((4-chloro-6-(4-(dimethylamino)piperidin-1-yl)pyrimidin-2-yl)amino)cyclohexane-1- synthesis of all
  • Step 3) (1 R ,4 R )-4-((4-(4-(dimethylamino)piperidin-1-yl)-6-((5-(5-phenyl-1,3,4- Synthesis of oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol
  • Example 37 (One R ,4 R )-4-((4-(1H-imidazol-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl ) Amino) pyrimidin-2-yl) amino) cyclohexan-1-ol synthesis
  • Step 2) Synthesis of (1 R ,4 R )-4-((4-chloro-6-(1 H -imidazol-1-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol
  • Step 3) (1 R ,4 R )-4-((4-(1H-imidazol-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2 Synthesis of -yl)thiazol-2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol
  • Example 38 4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)methyl)-3,4-dihydropyridin-2-yl)amino)bicyclo[2.2.2]octan-1-ol
  • the reaction solution was adjusted to pH 1 with 1M aqueous hydrochloric acid solution and stirred at 80°C for 1 hour. After cooling the reaction solution to 0°C, adjust the pH to about 8 using saturated aqueous sodium bicarbonate solution, extract using ethyl acetate, and wash with water. The obtained organic layer is dried with magnesium sulfate and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (750 mg, 70%).
  • Step 4) 4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)methyl)bicyclo[2.2.2]octane-1 -all
  • the reaction solution was cooled to room temperature, extracted with ethyl acetate, washed with water, and the resulting organic layer was dried over magnesium sulfate and the solvent was distilled under reduced pressure.
  • the obtained residue was purified by column chromatography to obtain the target compound (53 mg, 23%).
  • Step 6 4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazole- 2-yl)thiazol-2-yl)methyl)-3,4-dihydropyridin-2-yl)amino)bicyclo[2.2.2]octan-1-ol
  • Example 39 4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)amino)pyridin-2-yl)amino)adamantane-1-ol
  • Step 1) 4-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)adamantan-1-ol
  • Step 2) 4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)adamantan-1-ol
  • Step 3) 4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazole- 2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)adamantane-1-ol
  • step 2 4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)adamantan-1-ol synthesized in step 2 (0.10 g, 0.25 mmol) was reacted in the same manner as step 6 of Example 38 to obtain the target compound (158 mg, 64%).
  • Example 40 4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)amino)pyridin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol
  • Step 2) 4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)bicyclo[2.2.1]heptane-1 -all
  • Step 3) 4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazole- 2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol
  • 2,4,6-Trichloropyrimidine (7.00 g, 38.17 mmol) was dissolved in 76 ml of dichloromethane, and then 1-piperazineethanol (4.96 ml, 40.07 mmol) and DIPEA (19.95 ml, 114.50 mmol) were slowly added thereto. Add. Stir for 3 hours at the same temperature. When the reaction was completed, it was extracted using ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (7.40 g, 70%).
  • Step 2) (S)-2-((4-chloro-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-2-yl)amino)propan-1-ol
  • Example 38 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (0.50 g, 1.62 mmol) obtained in step 5 of synthesis was dissolved in 3.2 ml of ethanol. After this, aqueous ammonia (1.85 ml, 16.20 mmol) is added at room temperature and the tube is sealed. Afterwards, heat it at 15°C for 16 hours. After the reaction was completed, the obtained residue was adsorbed on silica and purified using column chromatography to obtain the target compound (225 mg, 57%).
  • Example 42 4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia sol-2-yl) amino) pyrimidin-2-yl) amino) bicyclo [2.2.2] octan-1-ol
  • Step 1) 4-((4-chloro-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-2-yl)amino)bicyclo[2.2.2]octane-1- all
  • Example 41 2-(4-(2,6-dichloropyrimidin-4-yl)piperazin-1-yl)ethan-1-ol (0.5 g, 1.80 mmol) obtained in synthesis step 1 was added to 2 ml of 1. -Dissolves in propanol. Then, 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (0.33 g, 1.89 mmol) and DIPEA (1.88 ml, 10.8 mmol) were added. The mixed solution is reacted at 16°C for 16 hours.
  • Step 2) 4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2- I) thiazol-2-yl) amino) pyrimidin-2-yl) amino) bicyclo [2.2.2] octan-1-ol
  • tert-Butyl (3S)-3-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexane-1-carboxylate obtained in step 3 (380 mg, 0.84 mmol), cupric acetylacetone (10 mol%), and cesium carbonate (551 mg, 1.69 mmol) were placed in a shrink tube, and a nitrogen environment was created. Then, acetylacetone (40 mol%), aqueous ammonia solution (0.65 mL, 16.91 mmol) and anhydrous dimethylformamide (4 mL) were sequentially added, and stirred at 90°C overnight.
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the resulting organic layer is dried over magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (88 mg, 27%).
  • Example 38 Compound synthesized in step 5 of the synthesis (285 mg, 0.92 mmol) and tert-butyl (3S)-3-((6-amino-4-(morpholinomethyl)pyridine-2 synthesized in step 4 above -yl)amino)cyclonucleic acid-1-carboxylate (300 mg, 0.77 mmol) is dissolved in 2 ml of dioxane. To this solution, tris(dibenzylindenacetone)dipalladium (70 mg, 10 mol%), xantphos (44 mg, 10 mol%), and sodium-tert-butoxyte (111 mg, 0.89 mmol) were added, and then 80 Stir at °C for 2 hours.
  • the extract is extracted using dichloromethane and methanol, washed with water, the resulting organic layer is dried over sodium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (296 mg, 98%).
  • 2,4,6-Trichloropyrimidine (7.00 g, 38.17 mmol) was dissolved in 76 ml of dichloromethane, and then morpholine (3.49 ml, 40.07 mmol) and DIPEA (19.95 ml, 114.50 mmol) were slowly dissolved at 0°C. Add. Stir for 3 hours at the same temperature. When the reaction was completed, it was extracted using ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (7.14 g, 80%).
  • Step 2) 4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)bicyclo[2.2.2]octan-1-ol
  • Step 3) 4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine- 2-yl)amino)bicyclo[2.2.2]octan-1-ol
  • step 2 4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)bicyclo[2.2.2]octan-1-ol (0.10 g, 0.25 mmol) synthesized in step 2 was used as an example. By reacting in the same manner as step 4 in 41, the target compound (82 mg, 60%) was obtained.
  • the reaction solution was cooled to room temperature, extracted with ethyl acetate, washed with water, and the resulting organic layer was dried over magnesium sulfate and the solvent was distilled under reduced pressure.
  • the obtained residue was purified by column chromatography to obtain the target compound (93 mg, 40%).
  • Example 45 Instead of 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.25 g, 1.10 mmol) obtained in step 1 of synthesis and aminobicyclocyclo[2.2.2]octan-1-ol hydrochloride.
  • the target compound (0.12 g, 36.3%) was obtained by reacting in the same manner as step 2 of synthesis in Example 45, except that 4-aminophenol (0.14 g, 1.30 mmol) was used.
  • Step 2) 4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine- Synthesis of 2-yl)amino)phenol
  • step 1 4-((4-Chloro-6-morpholinopyrimidin-2-yl)amino)phenol (44.0 mg, 0.18 mmol) obtained in step 1 was reacted in the same manner as step 4 of Example 41 to obtain the target compound. (0.50 mg, 3.2%) was obtained.
  • Example 46 4-((2,6-dibromopyridin-4-yl)methyl)morpholine (200 mg. 0.59 mmol), 4-piperidinemethanol (0.08 mL, 0.71%) synthesized in step 2 of synthesis mmol), tris(dibenzylideneacetone)dipalladium (27 mg, 10 mol%), xantphos (17 mg, 10 mol%), and sodium-tert-butoxide (85 mg, 0.89 mmol) in anhydrous 1,4 -Dissolved in 1.5 ml of dioxane and stirred at room temperature for 4 hours.
  • Example 46 (1-(6-bromo-4-(morpholinomethyl)pyridin-2-yl)piperidin-4-yl)methanol (0.92 g, 0.25 mmol) synthesized in step 1 was prepared in Example 46. By reacting in the same manner as step 4, the target compound (57 mg, 75%) was obtained.
  • Step 3 (1-(4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) Pyridin-2-yl)piperidin-4-yl)methanol
  • Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, (S)-(+)-2-amino-1-propanol (0.17 mL, 1.89 mmol) and DIPEA (0.94 ml, 5.4 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.37 mg, 77%).
  • Step 2) (S)-2-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino )pyrimidin-2-yl)amino)propan-1-ol
  • Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, (-)-3-pyrrolidinol (0.15 mL, 1.89 mmol) and DIPEA (0.94 ml, 5.4 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.39 mg, 77%).
  • Step 2) (R)-N-(2-chloro-6-methylphenyl)-2-((2-(3-hydroxypyrrolidin-1-yl)-6-morpholinopyrimidin-4-yl )Amino)thiazole-5-carboxamide
  • step 1 (R)-1-(4-chloro-6-morpholinopyrimidin-2-yl)pyrrolidin-3-ol (0.7 g, 0.25 mmol) synthesized in step 1 was mixed with 2-(2-amino Example using 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide instead of thiazol-5-yl)-5-phenyl-1,3,4-oxadiazole By reacting in the same manner as step 4 in 41, the target compound (96 mg, 75%) was obtained.
  • Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, trans-4-methylamino-cyclohexanol (0.44 g, 1.89 mmol) and DIPEA (0.94 ml, 5.4 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.45 mg, 77%).
  • Step 2) (1R,4R)-4-(methyl(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2- ) amino) pyrimidin-2-yl) amino) cyclohexan-1-ol
  • Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, (3R)-3-pyrrolidinemethanol (0.19 mL, 1.89 mmol) and DIPEA (0.94 ml, 5.4 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.43 mg, 80%).
  • Step 2) (R)-(1-(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino )pyrimidin-2-yl)pyrrolidin-3-yl)methanol
  • Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, (3S)-3-pyrrolidinemethanol (0.19 mL, 1.89 mmol) and DIPEA (0.94 ml, 5.4 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.43 mg, 80%).
  • Step 2 (S)-(1-(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino )pyrimidin-2-yl)pyrrolidin-3-yl)methanol
  • Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, (S)-3-pyrrolidine-2-carboxamide hydrochloride (0.28 g, 1.89 mmol) and DIPEA (1.88 ml, 10.8 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.28 mg, 5%).
  • Step 2) (S)-1-(4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) Pyrimidine-2-yl)pyrrolidine-2-carboxamide
  • Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, (R)-(+)-2-amino-1-propanol (0.17 mL, 1.89 mmol) and DIPEA (0.94 ml, 5.4 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.37 mg, 77%).
  • Step 2) (R)-2-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino )pyrimidin-2-yl)amino)propan-1-ol
  • Example 56 4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidin-2-yl )Amino)bicyclo[2.2.1]heptan-1-ol
  • Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, 4-aminobicyclo[2.2.1]heptan-1-ol hydrochloride (0.39 g, 1.89 mmol) and DIPEA (1.88 ml, 10.8 mmol) were added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.43 mg, 75%).
  • Step 2) 4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine- 2-yl)amino)bicyclo[2.2.1]heptan-1-ol
  • step 1 4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol (0.10 g, 0.25 mmol) synthesized in step 1 was used as an example. By reacting in the same manner as step 4 in 41, the target compound (93 mg, 70%) was obtained.
  • Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Trans-4-amino-1-adamantanol hydrochloride (0.38 g, 1.89 mmol) and DIPEA (1.88 ml, 10.8 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.50 mg, 77%).
  • Step 2) 4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine- 2-yl)amino)adamantane-1-ol
  • step 1 4-((4-Chloro-6-morpholinopyrimidin-2-yl)amino)adamantan-1-ol (0.09 g, 0.25 mmol) synthesized in step 1 was mixed with step 4 of Example 41. By reacting in the same way, the target compound (102 mg, 72%) was obtained.
  • Example 58 4-((4-((2S,6R)-2,6-dimethylmorpholino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl)amino)pyrimidin-2-yl)amino)bicyclo[2.2.2]octan-1-ol
  • 2,4,6-Trichloropyrimidine (7.00 g, 38.17 mmol) was dissolved in 76 ml of dichloromethane, then cis-2,6-dimethylmorpholine (4.96 ml, 40.07 mmol) and DIPEA (19.95 ml, 114.50 mmol) is added slowly. Stir for 3 hours at the same temperature. When the reaction was completed, it was extracted using ethyl acetate, washed with water, and the resulting organic layer was dried with magnesium sulfate and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (7.14 g, 80%).
  • Step 2) 4-((4-chloro-6-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-2-yl)amino)bicyclo[2.2.2]octan-1-ol
  • Step 3) 4-((4-((2S,6R)-2,6-dimethylmorpholino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)amino)pyrimidin-2-yl)amino)bicyclo[2.2.2]octan-1-ol
  • Step 1) 4-((4-chloro-6-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-2-yl)amino)adamantan-1-ol
  • Example 58 4-(2,6-dichloropyrimidin-4-yl)-2,6,-dimethylmorpholine (0.42 g, 1.80 mmol) obtained in step 1 of synthesis was dissolved in 2 ml of 1-propanol. do. Then, trans-5-amino-1-adamantanol hydrochloride (0.38 g, 1.89 mmol) and DIPEA (1.88 ml, 10.8 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.56 mg, 80%).
  • Step 3 4-((4-((2S,6R)-2,6-dimethylmorpholino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl )thiazol-2-yl)amino)pyrimidin-2-yl)amino)adamantane-1-ol
  • Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, trans-4-amino-1-methylcyclohexanol (0.24 g, 1.89 mmol) and DIPEA (0.94 ml, 5.4 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.39 mg, 67%).
  • Step 2) (1R,4R)-1-methyl-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole -2-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol
  • Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, 4-amino-3-methyl-1-butanol (0.21 mL, 1.89 mmol) and DIPEA (0.94 ml, 5.4 mmol) are added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.37 mg, 70%).
  • Step 2) 3-methyl-4-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino )pyrimidin-2-yl)amino)butan-1-ol
  • Example 57 4-((4-chloro-6-morpholinopyrimidin-2-yl)amino)adamantan-1-ol (0907 g, 0.25 mmol) synthesized in step 1 of synthesis was 2-( Instead of 2-aminothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole, use 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide. The reaction was carried out in the same manner as step 4 of Example 41 to obtain the target compound (92 mg, 65%).
  • Example 45 4-(2,6-dichloropyrimidin-4-yl)morpholine (0.42 g, 1.80 mmol) obtained in step 1 of the synthesis was dissolved in 2 ml of 1-propanol. Then, 3-aminobicyclo[1.1.1]pentan-1-ol hydrochloride (0.25 g, 1.89 mmol) and DIPEA (1.88 ml, 10.8 mmol) were added. The mixed solution is reacted at 16°C for 16 hours. When the reaction is completed, extraction is performed using ethyl acetate, washing with water, the resulting organic layer is dried with magnesium sulfate, and the solvent is distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.46 mg, 88%).
  • Step 2) 3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine- 2-yl)amino)bicyclo[1.1.1]pentan-1-ol
  • step 1 3-((4-chloro-6-morpholinopyrimidin-2-yl)amino)bicyclo[1.1.1]pentan-1-ol (0.10 g, 0.25 mmol) synthesized in step 1 was used as an example. By reacting in the same manner as step 4 in 41, the target compound (94 mg, 75%) was obtained.
  • the target compound (0.41 g, 63.9%) was obtained in the same manner as step 2 of synthesis in Example 14, except that 3-aminophenol (0.30 g, 2.50 mmol) was used instead of trans-4-aminocyclohexanol.
  • Step 2) 3-((4-morpholino-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrimidine- Synthesis of 2-yl)amino)phenol
  • step 2 3-((4-Chloro-6-morpholinopyrimidin-2-yl)amino)phenol (0.37 g, 0.90 mmol) obtained in step 2 was reacted in the same manner as step 4 of Example 12 to obtain the target compound. (48.8 mg, 10.5%) was obtained.
  • Ramos cells were added to culture medium without the addition of fetal bovine serum, BTK inhibitors were serially diluted, and reacted in an incubator at 37°C for 4 hours.
  • the Ramos cells are a B lymphocyte cell line derived from a 3-year-old, white male patient with Burkitt's Lymphoma. Afterwards, cells were treated with 15 ⁇ g/ml of anti-human IgM (SouthernBiotech 2020-01) and stimulated for 10 minutes at a low temperature of 2-8°C.
  • the culture medium remaining in the cells was removed with low-temperature DPBS (Dulbecco's Phosphate-Buffered Saline), and the cell membrane was incubated at low temperature for 30 minutes with RIPA buffer (Radioimmunoprecipitation assay buffer, Thermo 89901) containing protease and phosphatase inhibitors (Thermo 78442). dissolved.
  • RIPA buffer Radioimmunoprecipitation assay buffer, Thermo 89901
  • Proteins were extracted using a high-speed centrifuge, quantified using bicinchoninic acid (BCA) solution (Thermo 23225), and samples were prepared by adding 4x sample buffer solution (Invitrogen NP0007). Proteins from each sample were electrophoresed and then transferred to a membrane composed of nitrocellulose (Invitrogen IB23001). To block protein-free areas, a solution containing 5% bovine serum albumin (BSA) (GenDEPOT A0100-010) was prepared in TBS-T (TBS-Tween, Thermo 28360) and treated at room temperature for 30 minutes.
  • BSA bovine serum albumin
  • the primary antibody was diluted and added to the protein-attached membrane and reacted on a shaker at a low temperature for 16 to 20 hours (or 1 hour at room temperature). TBS-T was added and the primary antibody not attached to the membrane was removed on a shaker at room temperature for 10 minutes, and this process was repeated three times.
  • a secondary antibody tagged with horseradish peroxidase (HRP) was diluted and added to the membrane and reacted for 45 minutes. TBS-T was added and left on a shaker at room temperature for 10 minutes to remove primary antibodies and unattached secondary antibodies. The process was repeated three times.
  • the HRP enzyme was reacted using an enhanced chemiluminescent (ECL) solution (Thermo 34095), and the protein level of the membrane was confirmed.
  • IC 50 was calculated based on the proteins of the negative and positive controls and using the calculated values. The results are shown in Table 1 below.
  • BTK WT/C481S kinase enzyme system Promega V9071, VA7033
  • BTK inhibitor was serially diluted to prepare 1 ⁇ l each and reacted with 2 ⁇ l of BTK kinase for 10 minutes at room temperature.
  • BTK kinase buffer consisting of 40mM Tris (pH 7.5), 20mM MgCl 2 , 0.1mg/ml bovine serum albumin (BSA), 2mM MnCl 2 , and 50 ⁇ M dithiothreitol (DTT).
  • the compounds of Examples 1 to 64 had excellent activity in inhibiting BTK activity in in vitro enzyme or cell experiments. Additionally, the example compounds were confirmed to exhibit excellent pharmacodynamic (PK) efficacy. Specifically, the example compounds showed C max values and AUC last sufficient to demonstrate efficacy when orally administered to mice at a dose of 25 mg/kg.
  • PK pharmacodynamic

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Abstract

L'invention concerne : un composé de formule chimique 1, ayant une activité inhibitrice contre la protéine kinase, un stéréoisomère de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci; et son utilisation.
PCT/KR2023/005401 2022-04-20 2023-04-20 Inhibiteur de protéine kinase et son utilisation WO2023204642A1 (fr)

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WO2022071772A1 (fr) * 2020-09-29 2022-04-07 (주)메디톡스 Inhibiteur de protéine kinase et son utilisation
KR20220054066A (ko) * 2020-10-23 2022-05-02 (주)메디톡스 단백질 키나제 저해제 및 그의 용도

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CN106279143A (zh) * 2015-05-11 2017-01-04 天津国际生物医药联合研究院 噻唑杂环类化合物及其制备方法和应用
WO2022071772A1 (fr) * 2020-09-29 2022-04-07 (주)메디톡스 Inhibiteur de protéine kinase et son utilisation
KR20220054066A (ko) * 2020-10-23 2022-05-02 (주)메디톡스 단백질 키나제 저해제 및 그의 용도

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