WO2022086284A1 - Inhibiteur de protéine kinase et son utilisation - Google Patents

Inhibiteur de protéine kinase et son utilisation Download PDF

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WO2022086284A1
WO2022086284A1 PCT/KR2021/014942 KR2021014942W WO2022086284A1 WO 2022086284 A1 WO2022086284 A1 WO 2022086284A1 KR 2021014942 W KR2021014942 W KR 2021014942W WO 2022086284 A1 WO2022086284 A1 WO 2022086284A1
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amino
pyridin
phenyl
thiazol
methyl
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PCT/KR2021/014942
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Korean (ko)
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방극찬
서행수
신미선
안지윤
이현진
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(주)메디톡스
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Publication of WO2022086284A1 publication Critical patent/WO2022086284A1/fr

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    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines 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

Definitions

  • the present disclosure relates to compounds of formula (1) having activity of inhibiting protein kinases and uses thereof.
  • Protein kinases are enzymes that catalyze the phosphorylation of hydroxyl groups located at tyrosine, serine, and threonine residues of proteins, and play an important role in growth factor signaling that induces cell growth, differentiation and proliferation. Mutation or overexpression of specific protein kinases can cause various diseases by disrupting normal intracellular signal transduction systems.
  • the protein kinase includes 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 to 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 produce two secondary messengers, inositol triphosphate (IP3) and diacylglycerol (DAG). These second 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
  • a reversible non-covalent BTK inhibitor is being developed.
  • International Publication No. WO2017/103611 discloses a reversible BTK inhibitor, a preparation method and use thereof. Nevertheless, there is a need for alternative BTK inhibitors.
  • 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 a protein kinase comprising a compound of formula 1, a stereoisomer 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 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another aspect is to provide a method for treating a disease mediated by protein kinase in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof. .
  • Another aspect is to provide a method for inhibiting the activity of a protein kinase comprising contacting a compound of Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof, with the protein kinase.
  • 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, said C 3-12 aryl, C 3-12 cycloalkyl or C 3-10 heteroaryl is C 1-6 alkyl, may be substituted with one or more substituents selected from the group consisting of C 1-6 alkoxy, halo, cyano, 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 and CH when X is S;
  • Z 1 is C or N
  • Z 1 is N is absent, when Z 1 is C, m is an integer of 0 to 3, and R 1 may be substituted with one or more substituents selected from the group consisting of C 1-6 alkyl and C 1-6 alkylcarbonyl. is C 3-10 heterocycloalkyl, which may be substituted with one or more C 1-6 alkyl, amino, hydrogen, C 1-6 alkoxy, or halo;
  • 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 3-10 heteroaryl, or C 3-12 aryl, said C 3-12 cycloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 heterocycloalkyl, C 3-10 heteroaryl, or C 3 12 aryl is hydroxy, C 1-6 alkoxy, —NR 3 R 4 (wherein R 3 and R 4 independently of each other are hydrogen, C 1-6 alkyl, or C 1-6 alkylcarbonyl), cyano , halo, C 1-6 alkyl (wherein C 1-6 alkyl may be substituted with one or more halo or hydroxy), C 1-6 alkylsulfonyl, C 1-6 alkylphosphonyl, aminosulfonyl may be substituted with one or more substituents selected from
  • L 1 and L 2 are each independently NH, 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 pyrazolyl.
  • A can be a 5-membered ring having 2 to 4 N atoms, 2 or 3 N atoms and 1 O atom, or -CONH-.
  • A can be imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, or -CONH-.
  • A may be imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, or -CONH-.
  • A may be tetrazolyl, oxadiazolyl or -CONH-.
  • m may be 0 or 1.
  • R 1 is C 4-6 heterocycloalkyl, which may be substituted with one or more substituents selected from the group consisting of C 1-6 alkyl and C 1-6 alkylcarbonyl; amino which may be substituted with one or more C 1-6 alkyl; Hydrogen; Alternatively, it may be C 1-6 alkoxy.
  • R 1 is morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl, which may be substituted with one or more substituents selected from the group consisting of C 1-6 alkyl and C 1-6 alkylcarbonyl. ; amino which may be substituted with one or more C 1-6 alkyl; Hydrogen; Alternatively, it may be C 1-6 alkoxy.
  • R 2 can be C 3-12 cycloalkyl, C 1-6 alkyl, or C 3-12 aryl.
  • R 2 can be C 4-7 cycloalkyl, C 1-6 alkyl, or C 5-12 aryl.
  • R 2 is C 4-7 cycloalkyl, C 1-6 alkyl, or C 5-12 aryl, wherein said C 4-7 cycloalkyl, C 1-6 alkyl, or C 5-12 aryl is hydroxy or It may be substituted with aminosulfonyl.
  • L 1 and L 2 may be each independently NH or O.
  • the compound of Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof may be the following compound, a stereoisomer or a pharmaceutically acceptable salt thereof:
  • the compound of Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof may be the following compound, a stereoisomer 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.
  • the optical label is a material that generates a detectable optical signal, and may be a radioactive material or a chromogenic material such as a fluorescent material.
  • Indirect label refers to a substance capable of generating a detectable label as a result of binding to a specific substance, such as an enzyme that converts a substrate into a chromogenic substance or its substrate, antibody or antigen.
  • the optical label may be an isotope of an element constituting the compound of Formula 1.
  • one or more of the elements constituting the compound may be substituted with an isotope thereof, for example, a radioactive isotope.
  • the isotopes include 2 H (which may be represented by D for deuterium), 3 H (which may be represented as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, 131 I, and the like.
  • a compound of the present disclosure may be in the form of a pharmaceutically acceptable salt thereof.
  • These salts include the conventional 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 acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, including 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 conventional metal salt forms, for example salts derived from metals such as lithium, sodium, potassium, magnesium, or calcium.
  • the compounds of the present disclosure may also be in the form of their solvates.
  • “Solvate” means a complex or aggregate formed by one or more solute molecules, ie a compound of Formula 1, or a stereoisomer or pharmaceutically acceptable salt thereof, and one or more solvent molecules.
  • the solvate may be, for example, a complex or aggregate formed with water, methanol, ethanol, isopropanol, acetic acid, or dimethylsulfoxide (DMSO).
  • the compounds of the present disclosure may also be in the form of their stereoisomers.
  • the stereoisomer includes all stereoisomers such as enantiomers and diastereomers.
  • the compound may be in a stereoisomerically pure form or a mixture of one or more stereoisomers, for example a racemic mixture. Separation of specific stereoisomers can be carried out by one of the conventional methods known in the art.
  • Some examples of the compounds of the present disclosure may have a greater BTK inhibitory effect of a specific stereoisomer compared to the racemic mixture. 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, n-nonyl or n-decyl.
  • alkenyl means an alkyl having at least one carbon-carbon double bond. wherein alkyl is as defined above. Alkenyl can be, for example, ethenyl or propenyl.
  • alkynyl means an alkyl having at least one carbon-carbon triple bond. wherein alkyl is as defined above. Alkynyl can be, for example, ethynyl or 2-propynyl.
  • alkoxy refers to an (alkyl)O- group. wherein alkyl is as defined above.
  • aryl denotes an aromatic ring in which each atom forming the ring is a carbon atom.
  • the ring may be monocyclic or polycyclic.
  • the polycyclic ring may include one having a fused ring (eg, naphthalene) or one having an unfused ring (eg, 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 6 to 10 carbon ring atoms.
  • Such aryl groups include, for example, phenyl, naphthalenyl (eg, naphthalen-1-yl and naphthalen-2-yl), biphenyl, anthracenyl, and phenanthrenyl.
  • cycloalkyl denotes a non-aromatic carbocyclic ring in which each atom forming the ring 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 those fused to an aromatic ring.
  • the cycloalkyl is, 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.
  • Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norcanyl, and adamantyl.
  • heterocycloalkyl refers to a non-aromatic carbon ring comprising heteroatoms forming one to four rings each selected from N, O, and S. Heterocycloalkyl may be one that does not have two adjacent O or S. Heterocycloalkyl includes monocyclic or polycyclic structures, for example structures with 2, 3 or 4 fused rings.
  • heterocycloalkyl examples include morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo- 1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, oxanyl, and the like.
  • 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 contains atoms forming 7 or 5 to 6 rings.
  • Cyclic groups may be linear fused, bridged, or spirocyclic.
  • 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 include 1, 2 or 3 heteroatoms.
  • Heteroaryl is, for example, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, furanyl, benzo Furanonyl, thiazolyl, indolyl, pyryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl , isothiazolyl, benzothienyl, purinyl, benzimidazolyl, or indolinyl.
  • halo or halogen refers to fluoro, chloro, bromo, or iodo.
  • Another aspect provides a pharmaceutical composition for use in treating a disease mediated by a protein kinase comprising a compound of Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the disease may be caused by an increase in the protein kinase activity.
  • the protein kinase may catalyze a 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 a 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 family.
  • cSRC is a prototypical member of the SRC family of tyrosine kinases including Lyn, Fyn, Lck, Hck, Fgr, Blk, Syk, Yrk and Yes.
  • the 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 expression 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.
  • Aberrant BCR-mediated signaling can lead to deregulated B cell proliferation and/or the formation of etiological autoantibodies leading to multiple autoimmune and/or inflammatory diseases.
  • Mutations in BTK in humans 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 in response to 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 to the ATP-binding site of the kinase.
  • the protein kinase having a cysteine residue near the ATP-binding site may be BTK, BMX, TEC, TXK, ITK, EGFR, ErbB, JAK3, BLK, and the like.
  • 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 a BTK, in particular a C481 mutant BTK, for example a C481S BTK.
  • Inhibition of protein kinases, such as BTK activity may be useful for 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, eg, BTK activity may be useful for treating a B-cell proliferative disorder or a mast cell proliferative disorder.
  • Inhibition of protein kinases, such as BTK activity may be useful for treating cancers such as B cell lymphoma and leukemia.
  • the disease may be cancer, an inflammatory disease, or an autoimmune disease.
  • the cancer may be a solid cancer or a blood cancer.
  • the hematologic cancer may be lymphoma, leukemia, multiple myeloma, plasma cell myeloma or myelodysplastic syndrome.
  • the lymphoma is mantle cell lymphoma (MCL) or non-Hodgkin's lymphoma, lymphoplasmacytic lymphoma, marginal zone lymphoma, small lymphocytic lymphoma (SLL), high-risk cattle 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 large It may be intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid
  • Solid cancers include brain tumor, head and neck cancer, lung cancer, breast cancer, thymoma, mesothelioma, esophageal cancer, colorectal cancer, liver cancer, stomach cancer, pancreatic cancer, biliary tract cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, germ cell tumor, ovarian cancer, cervical cancer, endometrial cancer cancer, sarcoma, malignant melanoma and skin cancer.
  • the inflammatory disease and / or autoimmune disease is systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple vasculitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, asthma , chronic graft vs host disease, Multiple Screlosis, Sjogren's syndrome, Crohn's disease, Behcet's disease, or Type 1 Diabetes ) can be The above diseases only exemplify specific diseases to which the pharmaceutical composition of the present disclosure can be applied, and the scope of the present disclosure is not limited to the above diseases.
  • the disease may be a disease resistant or refractory to an irreversible BTK inhibitor, for example ibrutinib.
  • treatment means treating a disease or medical condition, eg, a BTK-associated disease, in a subject, eg, a mammal, including a human, including: (a) a disease or medical condition alleviation of, ie, the elimination or recovery of, a disease or medical condition in a patient; (b) inhibiting the disease or medical condition, ie, slowing or arresting the progression of the disease or medical condition in a subject; or (c) alleviating the disease or medical condition in the subject.
  • a disease or medical condition alleviation of, ie, the elimination or recovery of, a disease or medical condition in a patient
  • inhibiting the disease or medical condition ie, slowing or arresting the progression of the disease or medical condition in a subject
  • alleviating the disease or medical condition in the subject including: (a) a disease or medical condition alleviation of, ie, the elimination or recovery of, a disease or medical condition in a patient.
  • the amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof can be appropriately selected by those skilled in the art.
  • the amount may be 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 0.01 mg to 1 mg.
  • “pharmaceutically acceptable carrier” refers to a substance used in combination with the active ingredient to aid in application of the active ingredient, usually an inert substance.
  • the carrier includes conventional pharmaceutically acceptable excipients, additives or diluents.
  • the carrier may be, for example, a filler, a binder, a disintegrant, a buffer, a preservative, an antioxidant, a lubricant, a flavoring agent, a thickener, a coloring agent, an emulsifier, a suspending agent. It may include one or more selected from a topical agent, a stabilizer, and an isotonic agent.
  • composition of the present disclosure may be 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 may be usually added. In the case of capsules for oral administration, lactose and/or dry corn starch may be used as diluents. If an aqueous suspension for oral use is required, the active ingredient may be combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
  • a sterile solution of the active ingredient is usually prepared, and the pH of the solution can be appropriately adjusted and buffered.
  • the total concentration of solutes can be adjusted to render the formulation isotonic.
  • the composition according to the present disclosure may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier, such as saline of physiological pH. The solution may be introduced into the patient's intramuscular bloodstream by local bolus injection.
  • the compound of Formula 1 as defined in the present disclosure may exhibit an effect of inhibiting protein kinase activity.
  • “inhibition” includes reducing the kinase activity of a protein kinase.
  • the protein kinase may be BTK.
  • the protein kinase may be a C481 mutant BTK, for example C481S BTK.
  • the pharmaceutical composition may be combined with one or more other therapeutic agents to treat a disease associated with a protein kinase.
  • Other therapeutic agents include chemotherapeutic agents, anti-inflammatory agents, immunosuppressive agents, and anti-cancer 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, immune checkpoint inhibitors checkpoint inhibitor), anti-CD20 therapeutics, HDAC inhibitors, PIM inhibitors, and mTOR inhibitors.
  • Combination therapy may produce synergistic effects.
  • the agent for combination therapy may be used in combination with the protein kinase inhibitor in a single administration or in a continuous dosage form, or may be administered in separate dosage forms simultaneously or sequentially.
  • the protein kinase may be BTK.
  • Another aspect provides the use of a compound of formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof, as defined above, in the treatment of a disease associated with protein kinase.
  • Another aspect provides the use of a compound of formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof, as defined above, for the manufacture of a medicament for the treatment of a disease associated with protein kinase.
  • Another aspect provides a pharmaceutical composition for use in inhibiting the activity of a protein kinase comprising a compound of Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another aspect provides a method of treating a disease mediated by a protein kinase in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof.
  • the administration route may be appropriately selected by a person skilled in the art according to the condition of the patient.
  • the administration may be oral, parenteral, or topical administration.
  • the subject may be a mammal, such as a human, cow, pig, horse, or cat.
  • terapéuticaally effective amount means an amount sufficient to exhibit a therapeutic effect when administered to a subject in need of treatment.
  • the dosage may vary depending on various factors such as the patient's condition, administration route, judgment of the attending physician, and the like.
  • An effective dosage can be estimated from a dose-response curve obtained from an in vitro test or an animal model test.
  • the proportion and concentration of the compound present in the composition to be administered may depend on the chemical nature, route of administration, therapeutic dosage, and the like.
  • the dosage may be administered to an 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 dose may be changed according to the age, weight, sensitivity, or symptoms of the individual.
  • the disease may be the one described for the pharmaceutical composition.
  • the above diseases are merely illustrative of 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 a disease associated with a protein kinase, for example, BTK. .
  • Another aspect relates to the activity of 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, for example Bruton's tyrosine kinase (BTK).
  • BTK Bruton's tyrosine kinase
  • the contacting may be performed ex vivo or in vitro.
  • the contacting may include incubating in a medium containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof and a protein kinase, for example, Brutons tyrosine kinase (BTK).
  • the medium may be a liquid, for example water, or a liquid medium such as an organic solvent.
  • the contacting may include administering the compound of Formula 1 or a pharmaceutically acceptable salt thereof to an individual, and allowing it to contact a protein kinase, for example, Bruton's tyrosine kinase (BTK) in the individual.
  • a protein kinase for example, Bruton's tyrosine kinase (BTK) in the individual.
  • the BTK may be a C481 mutant BTK, for example C481S BTK.
  • a compound including methylene in which m is 1 may be prepared according to Scheme 1 below.
  • a compound of Formula 1-VIb may be prepared by reacting a compound of Formula 1-VIa with a compound of Formula 1-VII.
  • This reaction is an amide reaction with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, hydroxybenzotriazole, (1-[bis(dimethylamino)methylene]-1H-1,2,3 -triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, in the presence of 1,1'-carbonyldiimidazole in an organic solvent such as N,N-dimethylformamide, dichloromethane can be performed.
  • step (1-2) the compound of formula 1-IV may be prepared by reducing the carbonyl group of formula 1-VIb obtained in step (1-1). This reaction can be carried out in an organic solvent, for example, tetrahydrofuran in the presence of borane.
  • 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 a polar organic solvent, for example, dioxane in the presence of tris(dibenzylideneacetone)dipalladium, xantphos, and sodium-t-butoxide.
  • a polar organic solvent for example, dioxane in the presence of tris(dibenzylideneacetone)dipalladium, xantphos, and sodium-t-butoxide.
  • step (1-4) a compound of formula (1-IIb) in which the halogen group of the compound of formula 1-IIa is substituted with an amino group can be prepared.
  • This reaction may be carried out in an organic solvent, for example, a glycol solvent, particularly ethylene glycol, in the presence of potassium carbonate, copper peroxide, N,N'-dimethylethylenediamine, and aqueous ammonia.
  • step (1-5) the compound of formula I can be prepared by reacting the compound of formula 1-IIb obtained in step (1-4) with the compound of formula III. This reaction can be carried out using the same reagents or solvents as in step (1-3).
  • the compound in which m is 0 among the compounds of Formula 1 according to an aspect may be prepared according to Scheme 2 as follows.
  • a compound of Formula 2-IIa may be prepared by reacting a compound of Formula 2-IV with a compound of Formula V. This reaction can be carried out in a polar organic solvent, for example, dioxane in the presence of tris(dibenzylideneacetone)dipalladium, xantphos, and sodium-t-butoxide.
  • a polar organic solvent for example, dioxane in the presence of tris(dibenzylideneacetone)dipalladium, xantphos, and sodium-t-butoxide.
  • step (2-2) a compound of formula (2-IIb) in which the halogen group of the compound of formula 2-IIa is substituted with an amino group can be prepared.
  • This reaction may be carried out in an organic solvent, for example, a glycol solvent, particularly ethylene glycol, in the presence of potassium carbonate, copper peroxide, N,N'-dimethylethylenediamine, and aqueous ammonia.
  • step (2-3) the compound of formula I can be prepared by reacting the compound of formula 2-IIb obtained in step (2-2) with the compound of formula III. This reaction may be carried out using the same reagents or solvents as in step (2-1).
  • the compound in which Z2 is N among the compounds of Formula 1 according to an aspect may be prepared according to Scheme 3 below.
  • a compound of Formula 2-VIa can be prepared by reacting Formula 3-IVa with Compound 3-VII.
  • This reaction is carried out in the presence of a base such as diisopropylethylamine, triethylamine, pyridine, sodium hydride, sodium-t-butoxide, potassium carbonate, cesium carbonate, sodium hydrogen carbonate and a polar aprotic organic solvent such as For example, it can be carried out in tetrahydrofuran, ethyl acetate, acetone, N,N-dimethylformamide, acetonitrile, N,N-dimethylsulfoxide.
  • the compound of formula 3-VIc may be prepared by amidation reaction of the compound of formula 3-VIb with 3-VIII.
  • This reaction is an amide reaction in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 1,4,6-triazabicyclo[3.3.0]oct-4-ene It can be carried out in an organic solvent such as N,N-dimethylformamide, dichloromethane, tetrahydrofuran.
  • step (3-3) the compound of chemical formula 3-IV can be prepared by reducing the carbonyl group of formula 3-VIc obtained in step (3-2). This reaction can be carried out in an organic solvent, for example, tetrahydrofuran in the presence of borane.
  • step (3-4) the protecting group of formula 3-II obtained in step (3-3) is removed by carrying out in dichloromethane in an organic solvent in the presence of a strong acid such as trifluoroacetic acid or hydrochloric acid to formula 3-IV obtained in step (3-3).
  • a strong acid such as trifluoroacetic acid or hydrochloric acid
  • step (3-5) the compound of Formula 3-I may be prepared by reacting the compound of Formula 3-II obtained in Step (3-4) with the compound of Formula 3-III. This reaction can be carried out using the same reagent or solvent as in step (3-1).
  • step (3-6) the compound of formula (I) can be prepared by reacting the compound of formula (V) with the compound of formula (3-I) obtained in step (3-5) using microwaves. This reaction may be carried out in an organic solvent such as isopropyl alcohol or ethanol.
  • the compound of Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof according to an aspect may be used to treat a disease mediated by a protein kinase, for example, BTK.
  • the pharmaceutical composition according to another aspect may be used to treat a disease mediated by a protein kinase, for example, BTK.
  • a protein kinase for example, BTK
  • a disease mediated by a protein kinase eg, BTK
  • a protein kinase for example, BTK
  • the BTK may be a C481 mutant BTK, for example C481S BTK.
  • N'-((5-bromothiazol-2-yl)methylene)-4-methylbenzenesulfonehydrazide 500 mg, 1.39 mmol obtained in step 1) and aniline (0.13 mL, 1.46 mmol) were mixed with tetra After dissolving in a mixed solvent of hydrofuran (2.78 ml) and pyridine (1.39 ml), the mixture was stirred at room temperature for 30 minutes. After adding isoamyl nitrite (0.24 mL, 1.81 mmol) to this solution, the mixture was stirred at room temperature for an additional 25 hours.
  • the reaction solution was cooled to 0 °C, the pH was adjusted to about 8 with a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and washed with water. The obtained organic layer was dried over magnesium sulfate, and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (750 mg, 70%).
  • 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 (69 mg, 27%).
  • Step 2) (1R,4R)-4-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole-2 Synthesis of -yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol
  • the target compound (1.01 g, 75%) was obtained in the same manner as in Example 1, except that cis-2,6-dimethylmorpholine was used instead of morpholine in step 3).
  • Step 2) (1R,4R)-4-((6-((5-(2-(4-bromophenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4 Synthesis of -(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol
  • N'-((5-bromothiazol-2-yl)methylene)-4-methylbenzenesulfonehydrazide 500 mg, 1.39 mmol obtained in step 1) of Example 1 and 2-chloro-6- Methylaniline (0.18 mL, 1.46 mmol) was used in the same manner as in step 2) of Example 1 to obtain the target compound (310 mg, 62%).
  • Step 2) (1R,4R)-4-((6-((5-(2-(2-chloro-6-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino) Synthesis of -4-(morpholinomethyl)pyridin-2-yl)aminocyclohexan-1-ol
  • Ethyl 2-((tert-butoxycarbonyl)amino)thiazole-5-carboxylate (4.5 g, 16.52 mmol) and sodium hydroxide (62.78 mg, 62.78 mmol) obtained in step 1) were mixed with THF and water in a solvent. After mixing, the mixture was heated and refluxed for 12 hours. When the reaction was completed, 1 N hydrochloric acid solution was added to crystallize it, and the resulting crystal was filtered to obtain the target compound (2.9 g, 99 %).
  • step 2 After dissolving 2-((tert-butoxycarbonyl)amino)thiazole-5-carboxylic acid (234 mg, 1 mmol) obtained in step 2) in tetrahydrofuran as a solvent, a 2 M solution of oxalyl chloride in dichloromethane ( 1 mL, 2 mmol) was added slowly. 3 drops of N,N-dimethylformamide were added to this solution, and the mixture was stirred at room temperature for 4 hours.
  • Cupric bromide (134 mg, 0.6 mmol) was placed in an acetonitrile solvent under nitrogen, and the temperature was lowered to 0 °C.
  • 2-amino-N-phenylthiazole-5-carboxamide (109 mg, 0.5 mmol) obtained in step 4) dissolved in tert-butyl nitrite (89 ⁇ l, 0.75 mmol) and acetonitrile was added to this solution at room temperature After raising the temperature to , the mixture was stirred for 4 hours.
  • the solvent was distilled under reduced pressure, extracted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate, filtered, the solvent was distilled under reduced pressure, and the residue was purified by column chromatography to obtain the target compound (89 mg, 63%).
  • Benzamidoxime (79 mg, 0.58 mmol), 2-bromothiazole-5-carboxylic acid (100 mg, 0.48 mmol), EDCI (1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide) (138 mg, 0.72 mmol) and HOBt (Hydroxybenzotriazole) (98 mg, 0.72 mmol) were added to a microwave vial and mixed with 2.5 ml of dimethylformamide. The mixed solution was stirred in a microwave at 80° C. for 30 minutes.
  • the mixture 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 using column chromatography to obtain the target compound (100 mg, 67%).
  • Step 2) (1R,4R)-4-((4-(morpholinomethyl)-6-((5-(3-phenyl-1,2,4-oxadiazol-5-yl)thiazole-2 Synthesis of -yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol
  • 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%).
  • Example 1 (1R,3R)-3-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclobutan-1-ol (92 mg, 0.33 mmol) synthesized in step 2) and 2-bromo-5-(2-phenyl-2H-tetrazol-5-yl)thiazole (123 mg, 0.39 mmol) synthesized in step 2) of Example 1 was prepared in the same manner as in Step 7) of Example 1 method to obtain the target compound (30 mg, 18%).
  • 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 (136 mg, 41%).
  • 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 (127 mg, 38%).
  • 6-bromo-4-(morpholinomethyl)pyridin-2-amine (50 mg, 0.18 mmol) synthesized in step 1) and 3-hydroxyphenylboronic acid (28 mg, 0.20 mmol) in a microwave vial ), sodium carbonate (39 mg, 0.36 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (30 mg, 0.036 mmol) in 1,4-dioxane: water After dissolving in (1:1 solution, 2ml), the reaction solution was stirred in a microwave at 120°C for 1 hour.
  • 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 (51 mg, 98%).
  • Methyl 2,6-dichloropyrimidine-4-carboxylate (1.4 g, 10.14 mmol), tert-octylamine (1.31 g, 1.5 eq.) and DIPEA (1.77 mL, 1.5 eq.) were mixed with tetrahydro at room temperature After stirring in a furan (2 mL) solvent for 68 hours, the solvent was removed under reduced pressure, extracted with dichloromethane, washed with an aqueous sodium hydrogen carbonate solution, and distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (1.44 g, 71%).
  • 6-bromo-4-(morpholinomethyl)pyridin-2-amine (100 mg, 0.36 mmol) synthesized in step 1 of Example 12 and 4-hydroxyphenylboronic acid (56 mg, 0.40 mmol), sodium carbonate (80 mg, 0.73 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (60 mg, 0.073 mmol) with 1,4- After dissolving in dioxane:water (1:1 solution, 4mL), the reaction solution is stirred in a microwave at 120°C for 1 hour.
  • 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 (97 mg, 93%).
  • Step 2) 4-(4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine Synthesis of -2-yl)phenol
  • the target compound (0.32 g, 30%) was obtained from 4-fluorobenzohydrazide (0.5 g, 3.24 mmol) obtained in step 1 in the same manner as in step 1 of Example 2.
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the obtained 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 (417 mg, 66%).
  • 6-Bromo-4-(morpholinomethyl)-N-((1R,4R)-4-(trifluoromethyl)cyclohexyl)pyridin-2-amine (687 mg, 1.62 mmol), cupric acetyl Acetone (10 mol%) and cesium carbonate (1.06 mg, 3.25 mmol) are placed in a shrink tube, and a nitrogen environment is created, then acetylacetone (40 mol%), aqueous ammonia solution (3.8 mL, 32.53 mmol), anhydrous die Methylformamide (0.2M) is added sequentially, and the mixture is stirred overnight at 90°C.
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the obtained 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 (333 mg, 57%).
  • Step 1) 4-(morpholinomethyl)-N2-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-N6-((1R, Synthesis of 4R)-4-(trifluoromethyl)cyclohexyl)pyridine-2,6-diamine
  • 6-Bromo-N-((1R,4R)-4-methoxycyclohexyl)-4-(morpholinomethyl)pyridin-2-amine (466 mg, 1.21 mmol), cupric acetylacetone (10 mol %), cesium carbonate (790 mg, 2.42 mmol) is placed in a shrink tube, and a nitrogen environment is created, then acetylacetone (40 mol%), aqueous ammonia solution (2.83 mL, 24.24 mmol), anhydrous dimethylformamide ( 0.2 M) in sequence, and stirred overnight at 90 °C.
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the obtained 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 (132 mg, 34%).
  • N2-((1R,4R)-4-methoxycyclohexyl)-4-(morpholinomethyl)pyridine-2,6-diamine 130 mg, 0.40 mmol
  • the 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole 150 mg, 0.48 mmol
  • the target compound 88 mg, 39%).
  • 6-Bromo-N-cyclohexyl-4- (morpholinomethyl) pyridin-2-amine (487 mg, 1.37 mmol), cupric acetylacetone (10 mol%), cesium carbonate (895 mg, 2.74 mmol)
  • cupric acetylacetone (10 mol%)
  • cesium carbonate (895 mg, 2.74 mmol)
  • acetylacetone 40 mol%), aqueous ammonia solution (3.21 mL, 27.49 mmol), and anhydrous dimethylformamide (0.2M) are sequentially added, and stirred overnight at 90 ° C. do.
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the obtained 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 (259 mg, 64%).
  • 6-Bromo-N-((1R,4R)-4-fluorocyclohexyl)-4-(morpholinomethyl)pyridin-2-amine (426 mg, 1.14 mmol), cupric acetylacetone (10 mol %), cesium carbonate (745 mg, 2.28 mmol) is placed in a shrink tube, and a nitrogen environment is created, then acetylacetone (40 mol%), aqueous ammonia solution (2.67 mL, 22.88 mmol), anhydrous dimethylformamide ( 0.2M), and stirred overnight at 90°C.
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the obtained 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 (217 mg, 61%).
  • N2-((1R,4R)-4-fluorocyclohexyl)-4-(morpholinomethyl)pyridine-2,6-diamine (107 mg, 0.34 mmol) synthesized in step 2 and the 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (130 mg, 0.41 mmol) synthesized in step 1 was prepared in the same manner as in step 2 of Example 2 to obtain the target compound (33 mg, 17%).
  • the target compound (1.00 g) was reacted in the same manner as 2,6-dibromonicotinic acid (1.00 g, 3.55 mmol) except that 4-methylpiperidine was used instead of morpholine in step 3 of Example 1 , 80%) was obtained.
  • Example 23 4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-N2-(5-(5-phenyl-1,3,4-oxadiazol-2-yl) Synthesis of thiazol-2-yl)-N6-(tetrahydro-2H-pyran-4-yl)pyridine-2,6-diamine
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the obtained 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 (308 mg, 70%).
  • Step 3 4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-N2-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia Synthesis of zol-2-yl)-N6-(tetrahydro-2H-pyran-4-yl)pyridine-2,6-diamine
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the obtained 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 (328 mg, 61%).
  • the target compound (2.86 g, 87%) was reacted in the same manner as 2,6-dibromonicotinic acid (3.00 g, 10.68 mmol) except that dimethylamine was used instead of morpholine in step 3 of Example 1 ) was obtained.
  • step 1 1-(2,6-dibromopyridin-4-yl)-N,N-dimethylmethanamine (0.98 g, 3.33 mmol) synthesized in step 1 was prepared in the same manner as in step 4 of Example 1 to the target compound (0.67 g, 61%) was obtained.
  • Example 27 4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-N2-(5-(5-phenyl-1,3,4-oxadiazol-2-yl) Synthesis of thiazol-2-yl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)pyridine-2,6-diamine
  • 6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridine obtained in step 1 above -2-amine (624 mg, 1.56 mmol), cupric acetylacetone (10 mol%), and cesium carbonate (1.02 g, 3.13 mmol) are placed in a shrink tube, and a nitrogen environment is prepared, then acetylacetone (40 mol) %), aqueous ammonia solution (3.6 mL, 31.32 mmol), and anhydrous dimethylformamide (0.2M) are sequentially added, followed by stirring at 90°C overnight.
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the obtained 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 (393 mg, 75%).
  • Step 3) 4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-N2-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia Synthesis of zol-2-yl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2,6-diamine
  • Example 28 (1R,4R)-4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-(4-fluoro) Synthesis of phenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol
  • Step 1) (1R,4R)-4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-(4-fluorophenyl) Synthesis of )-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol
  • Step 1) ((1R,4R)-4-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclohexyl ) synthesis of methanol
  • Step 2 ((1R,4R)-4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclohexyl) methanol synthesis
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the obtained 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 (400 mg, 68%).
  • Step 3 ((1R,4R)-4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3) Synthesis of ,4-oxadiazol-2) -yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexyl)methanol
  • the target compound (1.83 g, 92%) was obtained in the same manner as in Example 15, except that sodium methyl 2-fluorobenzoate (2.00 g, 12.96 mmol) was used instead of sodium methyl 4-fluorobenzoate in step 1.
  • the target compound (0.12 g, 7%) was obtained from 2-fluorobenzohydrazide (1.00 g, 0.80 mmol) obtained in step 1 in the same manner as in step 1 of Example 2.
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the obtained 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 (40 mg, 25%).
  • Example 32 ((1R,4R)-4-(((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1) Synthesis of ,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)methyl)cyclohexyl)methanol
  • Step 2 ((1R,4R)-4-(((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)methyl) Cyclohexyl) methanol synthesis
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the obtained 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 (40 mg, 8%).
  • Step 3 ((1R,4R)-4-(((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1, Synthesis of 3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)methyl)cyclohexyl)methanol
  • step 5 of Example 1 2,6-dibromopyridine (0.5 g, 2.11 mmol) was used instead of 4-((2,6-dibromopyridin-4-yl)methyl)morpholine and trans-4
  • the target compound (0.23 g, 29.6%) was obtained in the same manner except that 1-N-Boc-trans-1,4-cyclohexylamine (0.45 g, 2.11 mmol) was used instead of -aminocyclohexanol.
  • step 2 of Example 2 (1R,4R)-4-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol obtained in step 2 above (1R ,4R)-4-((6-aminopyridin-2-yl)amino)cyclohexane-1-tertbutyl carbamate (110 mg, 0.36 mmol) was reacted in the same manner except that the target compound (20 mg , 10.5%) was obtained.
  • 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 (123 mg, 75%).
  • Step 3 (2-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazole- 2-yl) thiazol-2-yl) amino) pyridin-2-yl) phenyl) methanol synthesis
  • 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 (160 mg, 100%).
  • Step 3 (3-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazole- 2-yl) thiazol-2-yl) amino) pyridin-2-yl) phenyl) methanol synthesis
  • Example 36 (4-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazole) Synthesis of -2-yl) thiazol-2-yl) amino) pyridin-2-yl) phenyl) methanol
  • 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 (160 mg, 100%).
  • 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) phenyl) methanol synthesis
  • Example 37 5-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazole) Synthesis of -2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclooctan-1-ol
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the obtained 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 (340 mg, 77%).
  • Example 38 d(1R,3R)-3-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1, Synthesis of 3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclopentan-1-ol
  • Step 2) (1R,3R)-3-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclopentane-1 -All synthesis
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the obtained 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 (150 mg, 77%).
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the obtained 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 (270 mg, 70%).
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the obtained 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 (323 mg, 63%).
  • Step 1) ((2S,5R)-5-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)tetrahydro Synthesis of -2H-pyran-2-yl)methanol
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the obtained 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 (447 mg, 60%).
  • Step 2 ((2S,5R)-5-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)tetrahydro- 2H-pyran-2-yl) methanol synthesis
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the obtained 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 (323 mg, 63%).
  • Step 3 ((2S,5R)-5-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3) Synthesis of ,4-oxadiazol-2) -yl)thiazol-2-yl)amino)pyridin-2-yl)amino)tetrahydro-2H-pyran-2-yl)methanol
  • 6-bromo-4-(morpholinomethyl)pyridin-2-amine 50 mg, 0.18 mmol
  • 3-hydroxyphenylboronic acid 28 mg, 0.20 mmol
  • sodium carbonate 39 mg, 0.36 mmol
  • [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex 30 mg, 0.036 mmol
  • 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 (51 mg, 98%).
  • Step 2) 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)phenol synthesis
  • the target compound (0.05 g, 15%) was obtained from 2-chloro-6-methylbenzohydrazide (0.20 g, 1.08 mmol) obtained in step 1 in the same manner as in step 1 of Example 2.
  • 6-bromo-N-((1R,4R)-4-methylcyclohexyl)pyridin-2-amine (716 mg, 2.66 mmol) obtained in step 1 above, cupric acetylacetone (10 mol%), cesium carbonate (1.7 g, 5.32 mmol) is placed in a shrink tube, a nitrogen environment is created, and then acetylacetone (40 mol%), aqueous ammonia solution (2.6 mL, 53.26 mmol), and anhydrous dimethylformamide (0.2M) are sequentially added. and stirred overnight at 90 °C.
  • the reaction solution is cooled to room temperature, extracted with ethyl acetate, washed with water, the obtained 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 (450 mg, 82%).
  • the target compound (0.30 g, 64%) was obtained in the same manner except that 2-methoxyaniline was used instead of aniline in step 2 of Example 1.
  • Step 2) (1R,4R)-4-((6-((5-(2-(2-methoxyphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4 Synthesis of -(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol
  • the target compound (11.2 g, 94%) was reacted in the same manner as 2,6-dibromonicotinic acid (10.00 g, 35.60 mmol) except that pyrrolidine was used instead of morpholine in step 3 of Example 1 ) was obtained.
  • Proteins were extracted with a high-speed centrifuge, quantified with a bicinchoninic acid (BCA) solution (Thermo 23225), and 4 ⁇ sample buffer solution (Invitrogen NP0007) was added to prepare a sample. Proteins in each sample were electrophoresed and transferred to a membrane made of nitrocellulose (Invitrogen IB23001). To block the protein-free portion, a solution containing 5% bovine serum albumin (BSA) (GenDEPOT A0100-010) in TBS-T (TBS-Tween, Thermo 28360) was prepared and treated at room temperature for 30 minutes.
  • BSA bovine serum albumin
  • the primary antibody was diluted and put into a protein-attached membrane and reacted for 16-20 hours (or 1 hour at room temperature) on a low-temperature shaker. 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 3 times. HRP (horseradish peroxidase)-attached secondary antibody was diluted and put on the membrane, and reacted for 45 minutes. TBS-T was put on a shaker at room temperature for 10 minutes, and the process of removing the primary antibody and the non-attached secondary antibody was repeated 3 times.
  • HRP horseradish peroxidase
  • the HRP enzyme was reacted using an Enhanced chemiluminescent (ECL) solution (Thermo 34095), and the protein level of the membrane was checked.
  • ECL Enhanced chemiluminescent
  • the IC 50 was calculated based on the protein of the negative control and the positive control and through the calculated values. The results are shown in Table 1 below.
  • the BTK WT/C481S kinase enzyme system (Promega V9071, VA7033) was used. 1 ⁇ l of the BTK inhibitor was serially diluted and reacted with 2 ⁇ l of BTK kinase at room temperature for 10 minutes. Substrate/ATP mix (ATP) using BTK kinase buffer consisting of 40 mM Tris (pH 7.5), 20 mM MgCl 2 , 0.1 mg/mL bovine serum albumin (BSA), 2 mM MnCl 2 , and 50 ⁇ M dithiothreitol (DTT).
  • BSA bovine serum albumin
  • DTT dithiothreitol

Abstract

L'invention concerne : un composé de formule chimique 1, ayant une activité inhibitrice vis-à-vis de la protéine kinase, un stéréoisomère de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci ; et une utilisation de celui-ci.
PCT/KR2021/014942 2020-10-23 2021-10-22 Inhibiteur de protéine kinase et son utilisation WO2022086284A1 (fr)

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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
WO2017168454A2 (fr) * 2016-04-02 2017-10-05 Sun Pharma Advanced Research Company Limited Nouveaux composés utilisés comme inhibiteurs de btk
US20180016247A1 (en) * 1999-04-15 2018-01-18 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
KR20200140200A (ko) * 2019-06-05 2020-12-15 (주)메디톡스 단백질 키나제 저해제 및 그의 용도

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US20180016247A1 (en) * 1999-04-15 2018-01-18 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
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
WO2017168454A2 (fr) * 2016-04-02 2017-10-05 Sun Pharma Advanced Research Company Limited Nouveaux composés utilisés comme inhibiteurs de btk
KR20200140200A (ko) * 2019-06-05 2020-12-15 (주)메디톡스 단백질 키나제 저해제 및 그의 용도

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