WO2022086284A1 - Protein kinase inhibitor and use thereof - Google Patents

Protein kinase inhibitor and use thereof Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
amino
pyridin
phenyl
thiazol
methyl
Prior art date
Application number
PCT/KR2021/014942
Other languages
French (fr)
Korean (ko)
Inventor
방극찬
서행수
신미선
안지윤
이현진
Original Assignee
(주)메디톡스
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by (주)메디톡스 filed Critical (주)메디톡스
Publication of WO2022086284A1 publication Critical patent/WO2022086284A1/en

Links

Classifications

    • 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

Provided are: a compound of chemical formula 1, having inhibitory activity against protein kinase, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; and a use thereof.

Description

단백질 키나제 저해제 및 그의 용도Protein kinase inhibitors and uses thereof
본 개시는 단백질 키나제를 저해하는 활성을 갖는 화학식 1의 화합물 및 그의 용도에 관한 것이다.The present disclosure relates to compounds of formula (1) having activity of inhibiting protein kinases and uses thereof.
단백질 키나제는 단백질의 티로신, 세린 및 트레오닌 잔기에 위치하는 하이드록시 그룹의 인산화를 촉매하는 효소로서, 세포의 성장, 분화 및 증식을 유발하는 성장 인자 신호 전달에 중요한 역할을 담당하고 있다. 특정 단백질 키나제의 돌연변이나 과발현은 정상적인 세포 내 신호 전달체계를 붕괴시켜서 다양한 질병을 유발할 수 있다.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.
상기 단백질 키나제는 브루톤스 티로신 키나제(BTK)를 포함한다. BTK는 사람에서 BTK 유전자에 의하여 코딩되는 효소이다. BTK는 B 세포 발생에 중요한 역할을 하는 키나제이다. BTK는 고친화성 IgE 수용체를 통한 마스트 세포 활성화뿐만 아니라 B 세포 성숙화에 중요한 역할을 한다. BTK는 포스파티딜이노시톨(3,4,5)-트리포스페이트(PIP3)에 결합하는 PH 도메인을 포함한다. PIP3가 BTK에 결합하면, BTK가 포스포리파제 C를 인산화하도록 유도한다. 인산화된 포스포리파제 C는 PIP2와 포스파티딜이노시톨을 가수분해하여 2개의 2차 메신저, 이노시톨트리포스페이트(IP3)와 디아실글리세롤(DAG)을 생성한다. 이들 2차 메신저는 B 세포 신호전달 동안 하류 단백질의 활성을 조절한다.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. 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.
이브루티닙(ibrutinib)은 최초로 승인된 BTK 저해제로서 백혈병(CLL)과 림프종(MCL) 치료제로 사용 중이다. 그러나, 이브루티닙은 BTK 내 C481에 공유적으로 결합하는 비가역적(irreversible) 저해제로서 C481 돌연변이 발현 환자는 치료할 수 없다는 문제점이 있다. 이에, 가역적 비공유적(reversible non-covalent) BTK 저해제가 개발되고 있는바, 예를 들어 국제공개 WO2017/103611호는 가역적 BTK 저해제, 그의 제조방법 및 용도를 개시하고 있다. 그럼에도 불구하고, 대안적 BTK 저해제가 요구되고 있다.Ibrutinib is the first approved BTK inhibitor and is being used to treat leukemia (CLL) and lymphoma (MCL). However, since ibrutinib is an irreversible inhibitor that covalently binds to C481 in BTK, there is a problem that patients expressing C481 mutations cannot be treated. Accordingly, a reversible non-covalent BTK inhibitor is being developed. For example, 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.
일 양상은 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염을 제공하는 것이다.One aspect is to provide a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
다른 양상은 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염, 및 약제학적으로 허용가능한 담체를 포함하는 단백질 키나제에 의하여 매개되는 질환을 치료하는데 사용하기 위한 약제학적 조성물을 제공하는 것이다.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. .
다른 양상은 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염, 및 약제학적으로 허용가능한 담체를 포함하는 단백질 키나제의 활성을 저해하는데 사용하기 위한 약제학적 조성물을 제공하는 것이다.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.
다른 양상은 치료학적 유효량의 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염을 개체에 투여하는 단계를 포함하는, 개체에서 단백질 키나제에 의하여 매개되는 질환을 치료하는 방법을 제공하는 것이다.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. .
다른 양상은 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염을 단백질 키나제와 접촉시키는 단계를 포함하는 단백질 키나제의 활성을 저해하는 방법을 제공하는 것이다.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.
일 양상은 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염을 제공한다:One aspect provides a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure PCTKR2021014942-appb-C000001
Figure PCTKR2021014942-appb-C000001
상기 화학식 1에서,In Formula 1,
Cy는 C3-12아릴, C3-12사이클로알킬 또는 C3-10헤테로아릴이고, 상기 C3-12아릴, C3-12사이클로알킬 또는 C3-10헤테로아릴은 C1-6알킬, C1-6알콕시, 할로, 시아노, 및 하이드록시로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있고;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;
A는 2개 이상의 N 원자를 갖는 5-원 환 또는 -CONH-이며;A is a 5-membered ring having 2 or more N atoms or -CONH-;
X는 CH 또는 S이고;X is CH or S;
Y는 X가 CH인 경우 NH 또는 O이고, X가 S인 경우 CH이며;Y is NH or O when X is CH and CH when X is S;
Z1은 C 또는 N이고;Z 1 is C or N;
Z1이 N인 경우
Figure PCTKR2021014942-appb-I000001
은 부재하고, Z1이 C인 경우, m은 0~3의 정수이고, R1은 C1-6알킬 및 C1-6알킬카보닐로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있는 C3-10헤테로사이클로알킬, 1개 이상의 C1-6알킬로 치환될 수 있는 아미노, 수소, C1-6알콕시, 또는 할로이며;If Z 1 is N
Figure PCTKR2021014942-appb-I000001
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;
Z2는 CH 또는 N이고;Z 2 is CH or N;
R2는 C3-12사이클로알킬, C1-6알킬, C2-6알케닐, C2-6알키닐, C3-10헤테로사이클로알킬, C3-10헤테로아릴, 또는 C3-12아릴이고, 상기 C3-12사이클로알킬, C1-6알킬, C2-6알케닐, C2-6알키닐, C3-10헤테로사이클로알킬, C3-10헤테로아릴, 또는 C3-12아릴은 하이드록시, C1-6알콕시, -NR3R4(여기에서 R3 및 R4는 서로 독립적으로 수소, C1-6알킬, 또는 C1-6알킬카보닐이다), 시아노, 할로, C1-6알킬(여기에서 C1-6알킬은 1개 이상의 할로 또는 하이드록시로 치환될 수 있다), C1-6알킬설포닐, C1-6알킬포스포닐, 아미노설포닐, 또는 C3-12사이클로알킬(여기에서 C3-12사이클로알킬은 하이드록시 또는 하이드록시C1-6알킬로 치환될 수 있다)로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있으며;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 the group consisting of , or C 3-12 cycloalkyl, wherein C 3-12 cycloalkyl may be substituted with hydroxy or hydroxyC 1-6 alkyl;
L1 및 L2는 서로 독립적으로 NH, O, 또는 S이며;L 1 and L 2 are each independently NH, O, or S;
n은 0 또는 1의 정수이다.n is an integer of 0 or 1.
구체예에서, Cy는 C5-12아릴, C5-12사이클로알킬 또는 C3-6헤테로아릴일 수 있다,In embodiments, Cy can be C 5-12 aryl, C 5-12 cycloalkyl or C 3-6 heteroaryl,
특정 예에서, Cy는 페닐, 사이클로헥실, 피라졸릴 또는 피리딜일 수 있다.In certain instances, Cy can be phenyl, cyclohexyl, pyrazolyl or pyridyl.
특히, Cy는 페닐 또는 피라졸릴일 수 있다.In particular, Cy may be phenyl or pyrazolyl.
구체예에서, A는 2개 내지 4개의 N 원자를 갖거나, 2개 또는 3개의 N 원자와 1개의 O 원자를 갖는 5-원 환, 또는 -CONH-일 수 있다.In an embodiment, A can be a 5-membered ring having 2 to 4 N atoms, 2 or 3 N atoms and 1 O atom, or -CONH-.
특정 예에서, A는 이미다졸릴, 피라졸릴, 트리아졸릴, 테트라졸릴, 옥사디아졸릴, 또는 -CONH-일 수 있다.In certain instances, A can be imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, or -CONH-.
특히, A는 이미다졸릴, 트리아졸릴, 테트라졸릴, 옥사디아졸릴, 또는 -CONH-일 수 있다.In particular, A may be imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, or -CONH-.
보다 특히, A는 테트라졸릴, 옥사디아졸릴 또는 -CONH-일 수 있다.More particularly, A may be tetrazolyl, oxadiazolyl or -CONH-.
구체예에서, m은 0 또는 1일 수 있다.In embodiments, m may be 0 or 1.
구체예에서, R1은 C1-6알킬 및 C1-6알킬카보닐로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있는 C4-6헤테로사이클로알킬; 1개 이상의 C1-6알킬로 치환될 수 있는 아미노; 수소; 또는, C1-6알콕시일 수 있다.In embodiments, 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.
특정 예에서, R1은 C1-6알킬 및 C1-6알킬카보닐로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있는 몰포리닐, 피페라지닐, 피페리디닐 또는 피롤리디닐; 1개 이상의 C1-6알킬로 치환될 수 있는 아미노; 수소; 또는, C1-6알콕시일 수 있다.In certain instances, 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.
구체예에서, R2는 C3-12사이클로알킬, C1-6알킬, 또는 C3-12아릴일 수 있다.In embodiments, R 2 can be C 3-12 cycloalkyl, C 1-6 alkyl, or C 3-12 aryl.
특정 예에서, R2는 C4-7사이클로알킬, C1-6알킬, 또는 C5-12아릴일 수 있다.In certain instances, R 2 can be C 4-7 cycloalkyl, C 1-6 alkyl, or C 5-12 aryl.
특히, R2는 C4-7사이클로알킬, C1-6알킬, 또는 C5-12아릴이고, 상기 C4-7사이클로알킬, C1-6알킬, 또는 C5-12아릴은 하이드록시 또는 아미노설포닐로 치환될 수 있다.In particular, 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.
구체예에서, L1 및 L2는 서로 독립적으로 NH 또는 O일 수 있다.In embodiments, L 1 and L 2 may be each independently NH or O.
예를 들어, 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염은 하기 화합물, 그의 입체이성질체 또는 그의 약제학으로 허용가능한 염일 수 있다:For example, 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:
(1R,4R)-4-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올;(1R,4R)-4-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin-2 -yl)amino)cyclohexan-1-ol;
(1R,4R)-4-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올;(1R,4R)-4-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl) amino)pyridin-2-yl)amino)cyclohexan-1-ol;
(1R,4R)-4-((4-(((2S,6R)-2,6-디메틸몰포리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올;(1R,4R)-4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadia) zol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol;
(1R,4R)-4-((6-((5-(2-(4-브로모페닐)-2H-테트라놀-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올;(1R,4R)-4-((6-((5-(2-(4-bromophenyl)-2H-tetranol-5-yl)thiazol-2-yl)amino)-4-(morpho rinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol;
(1R,4R)-4-((6-((5-(2-(2-클로로-6-메틸펜닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노사이클로헥산-올;(1R,4R)-4-((6-((5-(2-(2-chloro-6-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4 -(morpholinomethyl)pyridin-2-yl)aminocyclohexan-ol;
2-((6-(((1R,4R)-4-히드록시사이클로헥실)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)-N-페닐싸이아졸-5-카복스아미드;2-((6-(((1R,4R)-4-hydroxycyclohexyl)amino)-4-(morpholinomethyl)pyridin-2-yl)amino)-N-phenylthiazole-5-carbox amides;
(1R,4R)-4-((4-(몰포리노메틸)-6-((5-(3-페닐-1,2,4-옥사디아졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올;(1R,4R)-4-((4-(morpholinomethyl)-6-((5-(3-phenyl-1,2,4-oxadiazol-5-yl)thiazol-2-yl) amino)pyridin-2-yl)amino)cyclohexan-1-ol;
(1r,3r)-3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로부탄-1-올;(1r,3r)-3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin-2 -yl)amino)cyclobutan-1-ol;
6-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)스피로[3.3]헵탄-2-올;6-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)spiro [3.3]heptan-2-ol;
6-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)스피로[3.3]헵탄-2-올;6-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2- yl)amino)spiro[3.3]heptan-2-ol;
2-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)에탄-1-설폰아미드;2-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2- yl)amino)ethane-1-sulfonamide;
3-(4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)페놀;3-(4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl )phenol;
(1R,4R)-4-((4-(모르폴리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)티아졸-2-일)아미노)피리미딘-2-일)아미노)시클로헥산-1-올;(1R,4R)-4-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyrimidine -2-yl)amino)cyclohexan-1-ol;
4-(4-(모르폴리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)페놀;4-(4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2- 1) phenol;
(1R,4R)-4-((6-((5-(5-(4-플루오로페닐)-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)-4-(모르폴리노메틸)피리딘-2-일)아미노)시클로헥산-1-올;(1R,4R)-4-((6-((5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) -4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol;
(1s,4s)-4-((4-(모르폴리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2 -일)아미노)사이클로헥산-1-올;(1s,4s)-4-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl )amino)pyridin-2-yl)amino)cyclohexan-1-ol;
4-(모르폴리노메틸)-N2-(5-(2-페닐-2H-테트라졸-5-일)티아졸-2-일)-N6-((1R,4R)-4-(트리플루오로메틸)시클로헥실)피리딘-2,6-디아민;4-(morpholinomethyl)-N2-(5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)-N6-((1R,4R)-4-(trifluoro romethyl)cyclohexyl)pyridine-2,6-diamine;
4-(모르폴리노메틸)-N2-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)-N6-((1R,4R)-4-(트리플루오로메틸)시클로헥실)피리딘-2,6-디아민;4-(morpholinomethyl)-N2-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-N6-((1R,4R)- 4-(trifluoromethyl)cyclohexyl)pyridine-2,6-diamine;
N2-((1R,4R)-4-메톡시시클로헥실)-4-(모르폴리노메틸)-N6-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)피리딘-2,6-디아민;N2-((1R,4R)-4-methoxycyclohexyl)-4-(morpholinomethyl)-N6-(5-(5-phenyl-1,3,4-oxadiazol-2-yl) thiazol-2-yl)pyridin-2,6-diamine;
N2-시클로헥실-4-(모르폴리노메틸)-N6-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)피리딘-2,6-디아민;N2-Cyclohexyl-4-(morpholinomethyl)-N6-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)pyridin-2,6 -diamine;
N2-((1R,4R)-4-플루오로시클로헥실)-4-(모르폴리노메틸)-N6-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)피리딘- 2,6-디아민;N2-((1R,4R)-4-fluorocyclohexyl)-4-(morpholinomethyl)-N6-(5-(5-phenyl-1,3,4-oxadiazol-2-yl) thiazol-2-yl)pyridin-2,6-diamine;
(1R,4R)-4-((4-((4-메틸피페리딘-1-일)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올;(1R,4R)-4-((4-((4-methylpiperidin-1-yl)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2) -yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol;
4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-N2-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)-N6- (테트라히드로-2H-피란-4-일)피리딘-2,6-디아민;4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-N2-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole-2 -yl)-N6-(tetrahydro-2H-pyran-4-yl)pyridin-2,6-diamine;
3-((4-(모르폴리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로헥산 -1-올;3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2 -yl)amino)cyclohexan-1-ol;
(1R,4R)-4-((4-((디메틸아미노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로헥산-1-올;(1R,4R)-4-((4-((dimethylamino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole-2- yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol;
(1R,4R)-4-((6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)-4-(피페라진-1-일메틸)피리딘-2-일)아미노)시클로헥산-1-올;(1R,4R)-4-((6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-4-(piperazine -1-ylmethyl)pyridin-2-yl)amino)cyclohexan-1-ol;
4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-N2-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)-N6-((테트라히드로-2H-피란-4-일)메틸)피리딘-2,6-디아민;4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-N2-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole-2 -yl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2,6-diamine;
(1R,4R)-4-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-(4-플루오로페닐)-1,3,4- 옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로헥산-1-올;(1R,4R)-4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-(4-fluorophenyl)-1 ,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol;
((1R,4R)-4-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2)-일)티아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥실)메탄올;((1R,4R)-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)cyclohexyl)methanol;
(1R,4R)-4-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-(2-플루오로페닐)-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로헥산-1-올;(1R,4R)-4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-(2-fluorophenyl)-1 ,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol;
(1R,4R)-4-(((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2)-일)티아졸-2-일)아미노)피리딘-2-일)아미노)메틸);(1R,4R)-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)methyl);
((1R,4R)-4-(((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸- 2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)메틸)사이클로헥실)메탄올;((1R,4R)-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)methyl)cyclohexyl)methanol;
(1R,4R)-4-((4-(((2S,6R)-2,6-디메틸몰포리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올;(1R,4R)-4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadia) zol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol;
(2-(4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)페닐)메탄올;(2-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl) )thiazol-2-yl)amino)pyridin-2-yl)phenyl)methanol;
(3-(4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)페닐)메탄올;(3-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl) )thiazol-2-yl)amino)pyridin-2-yl)phenyl)methanol;
(4-(4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)페닐)메탄올;(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)phenyl)methanol;
5-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로옥탄-1-올;5-((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)cyclooctan-1-ol;
d(1R,3R)-3-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로펜탄-1-올;d(1R,3R)-3-((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)cyclopentan-1-ol;
(1S,3S)-3-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)사이클로펜탄-1-올;(1S,3S)-3-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxa) diazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclopentan-1-ol;
(1R,4R)-4-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-카보니트릴;(1R,4R)-4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxa) diazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexane-1-carbonitrile;
((2S,5R)-5-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2)-일)티아졸-2-일)아미노)피리딘-2-일)아미노)테트라하이드로-2H-피란-2-일)메탄올;((2S,5R)-5-((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)tetrahydro-2H-pyran-2-yl)methanol;
4-(4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)페놀;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)phenol;
(1R,4R)-4-((6-((5-(5-(2-클로로-6-메틸페닐)-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)-4-(모르폴리노메틸)피리딘-2-일)아미노)시클로헥산-1-올;(1R,4R)-4-((6-((5-(5-(2-chloro-6-methylphenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl) amino)-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol;
N2-((1R,4R)-4-메틸시클로헥실)-N6-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)피리딘-2,6-디아민;N2-((1R,4R)-4-methylcyclohexyl)-N6-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)pyridin-2 ,6-diamine;
(1R,4R)-4-((6-((5-(2-(2-메톡시페닐)-2H-테트라졸-5-일)티아졸-2-일)아미노)-4-(모르폴리노메틸)피리딘-2 -일)아미노)사이클로헥산-1-올; 및,(1R,4R)-4-((6-((5-(2-(2-methoxyphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4-(don't know polynomethyl)pyridin-2-yl)amino)cyclohexan-1-ol; and,
(1R,4R)-4-((6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)-4-(피롤리딘-1-일메틸)피리딘-2-일)아미노)시클로헥산-1-올.(1R,4R)-4-((6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-4-(pyrroly Din-1-ylmethyl)pyridin-2-yl)amino)cyclohexan-1-ol.
예를 들어, 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염은 하기 화합물, 그의 입체이성질체 또는 그의 약제학으로 허용가능한 염일 수 있으나, 본 개시의 범위가 이들로 제한되는 것은 아니다:For example, 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:
Figure PCTKR2021014942-appb-I000002
Figure PCTKR2021014942-appb-I000002
Figure PCTKR2021014942-appb-I000003
Figure PCTKR2021014942-appb-I000003
Figure PCTKR2021014942-appb-I000004
Figure PCTKR2021014942-appb-I000005
Figure PCTKR2021014942-appb-I000006
Figure PCTKR2021014942-appb-I000007
Figure PCTKR2021014942-appb-I000008
Figure PCTKR2021014942-appb-I000009
Figure PCTKR2021014942-appb-I000010
Figure PCTKR2021014942-appb-I000011
Figure PCTKR2021014942-appb-I000012
Figure PCTKR2021014942-appb-I000013
Figure PCTKR2021014942-appb-I000014
Figure PCTKR2021014942-appb-I000015
Figure PCTKR2021014942-appb-I000016
Figure PCTKR2021014942-appb-I000017
Figure PCTKR2021014942-appb-I000018
Figure PCTKR2021014942-appb-I000019
Figure PCTKR2021014942-appb-I000020
Figure PCTKR2021014942-appb-I000021
Figure PCTKR2021014942-appb-I000022
Figure PCTKR2021014942-appb-I000004
Figure PCTKR2021014942-appb-I000005
Figure PCTKR2021014942-appb-I000006
Figure PCTKR2021014942-appb-I000007
Figure PCTKR2021014942-appb-I000008
Figure PCTKR2021014942-appb-I000009
Figure PCTKR2021014942-appb-I000010
Figure PCTKR2021014942-appb-I000011
Figure PCTKR2021014942-appb-I000012
Figure PCTKR2021014942-appb-I000013
Figure PCTKR2021014942-appb-I000014
Figure PCTKR2021014942-appb-I000015
Figure PCTKR2021014942-appb-I000016
Figure PCTKR2021014942-appb-I000017
Figure PCTKR2021014942-appb-I000018
Figure PCTKR2021014942-appb-I000019
Figure PCTKR2021014942-appb-I000020
Figure PCTKR2021014942-appb-I000021
Figure PCTKR2021014942-appb-I000022
학식 1의 화합물은 검출가능한 표지로 치환된 것일 수 있다. 상기 검출가능한 표지는 광학적 표지, 전기적 표지, 자기적 표지, 또는 간접 표지일 수 있다. 광학적 표지는 검출가능한 광학적 신호를 발생시키는 물질로서, 방사성 물질, 또는 형광 물질과 같은 발색 물질일 수 있다. 간접 표지는 기질을 발색 물질로 전환시키는 효소 또는 그 기질, 항체 또는 항원과 같이 특정 물질과 결합한 결과, 검출가능한 표지를 발생시킬 수 있는 물질을 나타낸다. 상기 광학적 표지는 화학식 1의 화합물을 구성하는 원소의 동위원소일 수 있다. 따라서, 화학식 1의 화합물은 그를 구성하는 원소 중 하나 이상이 그의 동위원소, 예를 들면 방사성 동위원소로 치환된 것일 수 있다. 상기 동위원소의 예는 2H(중수소를 의미하는 D로 나타낼 수 있음),　3H(삼중수소를 의미하는 T로 나타낼 수 있음), 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36Cl, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I, 131I 등을 포함한다. 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. Accordingly, in 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. Examples of 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.
본 개시의 화합물은 그의 약제학적으로 허용가능한 염의 형태일 수 있다. 상기 염은 제약 분야에서 사용되는 통상의 산 부가염, 예를 들면 염산, 브롬산, 황산, 설팜산, 인산 또는 질산과 같은 무기산으로부터 유도된 염 및 아세트산, 프로피온산, 숙신산, 글리콜산, 스테아르산, 시트르산, 말레산, 말론산, 메탄술폰산, 타르타르산, 말산, 페닐아세트산, 글루탐산, 벤조산, 살리실산, 2-아세톡시벤조산, 푸마르산, 톨루엔술폰산, 옥살산 또는 트리플루오로아세트산과 같은 유기산으로부터 유도된 염을 포함한다. 또한, 상기 염은 통상의 금속 염 형태, 예를 들면 리튬, 소듐, 칼륨, 마그네슘, 또는 칼슘과 같은 금속으로부터 유도된 염을 포함한다. 상기 산 부가염 또는 금속염은 통상의 방법에 따라 제조될 수 있다. 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 acid addition salt or metal salt may be prepared according to a conventional method.
본 개시의 화합물은 또한 그의 용매화물(solvate)의 형태일 수 있다. "용매화물"이란 하나 이상의 용질 분자, 즉 화학식 1의 화합물, 또는 그의 입체이성질체 또는 약제학적으로 허용가능한 염, 및 하나 이상의 용매 분자에 의해 형성되는 복합체 또는 집합체를 의미한다. 용매화물은 예를 들면 물, 메탄올, 에탄올, 이소프로판올, 아세트산, 또는 디메틸술폭시드(DMSO)와 형성된 복합체 또는 집합체일 수 있다.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).
본 개시의 화합물은 또한 그의 입체이성질체의 형태일 수 있다. 상기 입체이성질체는 거울상 이성질체(enantiomer) 및 부분입체이성질체(diastereomer)와 같은 모든 입체이성질체를 포함한다. 상기 화합물은 입체이성질체의 순수 형태(stereoisomerically pure form) 또는 하나 이상의 입체이성질체의 혼합물, 예를 들면 라세미 혼합물일 수 있다. 특정 입체이성질체의 분리는 당해 분야에 공지된 통상의 방법 중 하나에 의해 수행될 수 있다. 본 개시의 화합물의 일부 예는 그 라세미 혼합물에 비하여 특정 입체이성질체의 BTK 억제 효과가 더 큰 것일 수 있다. 이 경우, 특정 입체이성질체를 사용함으로써, 투여량을 줄일 수 있다.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.
본 개시의 화합물, 조성물 및 방법과 관련하여, 달리 나타내지 않는다면 하기의 용어는 하기의 의미를 갖는다. With respect to the compounds, compositions and methods of the present disclosure, unless otherwise indicated, the following terms have the following meanings.
용어 "알킬(alkyl)"은 직쇄상 또는 분지상의 포화 탄화수소기를 의미한다. 상기 알킬은 1 내지 10개, 1 내지 8개, 1 내지 6개, 1 내지 4개, 또는 1 내지 3개의 탄소 원자를 포함할 수 있다. 알킬은 예를 들면, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, t-부틸, n-펜틸, 이소펜틸, 네오펜틸, n-헥실, n-헵틸, n-옥틸, n-노닐 또는 n-데실을 포함할 수 있다. The term “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.
용어 "알케닐(alkenyl)"은 적어도 하나의 탄소-탄소 이중 결합을 갖는 알킬을 의미한다. 여기서 알킬은 위에서 정의된 바와 같다. 알케닐은 예를 들면, 에테닐 또는 프로페닐일 수 있다.The term “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.
용어 "알키닐(alkynyl)"은 적어도 하나의 탄소-탄소 삼중 결합을 갖는 알킬을 의미한다. 여기서 알킬은 위에서 정의된 바와 같다. 알키닐은 예를 들면, 에티닐 또는 2-프로피닐일 수 있다.The term “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.
용어 "알콕시(alkoxy)"는 (알킬)O-기를 나타낸다. 여기서 알킬은 위에서 정의된 바와 같다. The term "alkoxy" refers to an (alkyl)O- group. wherein alkyl is as defined above.
용어 "아릴(aryl)"은 고리를 형성하는 각 원자가 탄소 원자인 방향족 고리를 나타낸다. 상기 고리는 단환 또는 다환일 수 있다. 상기 다환은 융합된 고리(fused ring)를 갖는 것(예; 나프탈렌) 또는 융합되지 않은 고리를 갖는 것(예; 비페닐)을 포함할 수 있다. 상기 다환은 예를 들면, 2개, 3개 또는 4개의 고리를 갖는 것일 수 있다. 상기 아릴기는 예를 들면, 5개 이상, 6개 이상, 7개 이상, 8개 이상, 9개 이상, 10개 이상, 5 내지 20개, 5 내지 15개, 5 내지 12개, 5 내지 10개, 또는 6 내지 10개의 탄소 고리 원자를 가진다. 상기 아릴기는 예를 들면, 페닐, 나프탈레닐(예, 나프탈렌-1-일 및 나프탈렌-2-일), 비페닐, 안트라세닐, 및 페난트레닐을 포함한다. The term "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.
용어 "사이클로알킬(cycloalkyl)"은 고리를 형성하는 각 원자가 탄소 원자인 비방향성 탄소 고리를 나타낸다. 상기 사이클로알킬은 단환 또는 다환일 수 있다. 상기 다환은 예를 들면, 2개, 3개 또는 4개의 융합된 고리를 갖는 것이다. 상기 사이클로알킬은 방향족 고리에 융합된 것을 포함할 수 있다. 상기 사이클로알킬은 예를 들면, 3개 이상, 4개 이상, 5개 이상, 6개 이상, 7개 이상, 3 내지 10개, 3 내지 7개, 5 내지 7개, 또는 5 내지 6개의 고리 탄소 원자를 포함한다. 사이클로알킬은 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸, 사이클로헥사디에닐, 사이클로헵타트리에닐, 노르보르닐, 노르카닐, 및 아다만틸을 포함한다. The term “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.
용어 "헤테로사이클로알킬(heterocycloalkyl)"은 각각 N, O, 및 S로부터 선택된 1 내지 4개의 고리를 형성하는 헤테로원자를 포함하는 비방향족 탄소 고리를 의미한다. 헤테로사이클로알킬은 2개의 이웃하는 O 또는 S를 갖지 않는 것일 수 있다. 헤테로사이클로알킬은 단환 혹은 다환 구조, 예를 들면, 2개, 3개 또는 4개의 융합된 고리를 갖는 구조를 포함한다. "헤테로사이클로알킬"의 예는 몰포리닐, 티오몰포리닐, 피페라지닐, 테트라히드로푸라닐, 테트라히드로티에닐, 2,3-디히드로벤조푸릴, 1,3-벤조디옥솔, 벤조-1,4-디옥세인, 피페리디닐, 피롤리디닐, 이소옥사졸리디닐, 이소티아졸리디닐, 피라졸리디닐, 옥사졸리디닐, 티아졸리디닐, 옥사닐 등을 포함한다. 상기 헤테로사이클로알킬은 예를 들면, 3개 이상, 4개 이상, 5개 이상, 6개 이상, 7개 이상, 3개 내지 10개, 4개 내지 10개, 3개 내지 7개, 5개 내지 7개 또는 5개 내지 6개의 고리를 형성하는 원자를 포함한다.The term “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. Examples of "heterocycloalkyl" 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.
사이클릭 그룹(예를 들면, 지환족 및 헤테로사이클)은 선형 융합되거나(fused), 브릿징되거나 또는　스피로사이클릭일 수 있다.Cyclic groups (eg, cycloaliphatic and heterocycle) may be linear fused, bridged, or spirocyclic.
용어 "헤테로아릴(heteroaryl)"은 N, O 및 S로부터 선택된 1 내지 4개의 헤테로 원자를 고리 구성원으로 갖는 방향성 탄소 고리를 의미한다. 헤테로아릴은 단환 혹은 다환 구조를 포함한다. 상기 다환은 예를 들면, 2개, 3개 또는 4개의 축합 고리를 갖는 것일 수 있다. 상기 헤테로아릴은 예를 들면, 3 내지 10개, 5 내지 10개, 5 내지 8개, 5 내지 7개, 5개, 6개, 또는 7개의 고리 원자를 포함한다. 상기 헤테로아릴은 1개, 2개 또는 3개의 헤테로원자를 포함하는 것일 수 있다. 헤테로아릴은 예를 들면, 피리딜, N-옥소피리딜, 피리미디닐, 피라지닐, 피리다지닐, 트리아지닐, 푸릴, 퀴놀릴, 이소퀴놀릴, 티에닐, 이미다졸릴, 푸라닐, 벤조푸라노닐, 티아졸릴, 인돌릴, 피릴, 옥사졸릴, 벤조푸릴, 벤조티에닐, 벤즈티아졸릴, 이소옥사졸릴, 피라졸릴, 트리아졸릴, 테트라졸릴, 인다졸릴, 1,2,4-티아디아졸릴, 이소티아졸릴, 벤조티에닐, 푸리닐, 벤즈이미다졸릴, 또는 인돌리닐을 포함한다. The term "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.
용어 "할로(halo)" 또는 “할로겐(halogen)”은 플루오로, 클로로, 브로모, 또는 요오도를 나타낸다.The term “halo” or “halogen” refers to fluoro, chloro, bromo, or iodo.
다른 양상은 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염, 및 약제학적으로 허용가능한 담체를 포함하는 단백질 키나제에 의하여 매개되는 질환을 치료하는데 사용하기 위한 약제학적 조성물을 제공한다. 상기 질환은 상기 단백질 키나제 활성의 증가에 의하여 발생하는 것일 수 있다.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.
상기 단백질 키나제는 다른 단백질에 인산기를 부가하는 반응을 촉매하는 것일 수 있다. 상기 단백질 키나제는 세린/트레오닌-특이적 단백질 키나제, 티로신-특이적 단백질 키나제, 또는 세린/트레오닌 및 티로신 단백질 키나제일 수 있다. 상기 단백질 키나제는 수용체 또는 비수용체 단백질 키나제일 수 있다. 수용체 단백질 키나제는 예를 들면, PDGFR 또는 VEGFR을 포함한다. 상기 비수용체 단백질 키나제는 세포내 단백질의 구성원일 수 있다. 상기 비수용체 단백질 키나제는 Syk, SRC, 또는 Tec 패밀리의 구성원일 수 있다.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.
cSRC는 Lyn, Fyn, Lck, Hck, Fgr, Blk, Syk, Yrk 및 Yes를 포함하는 티로신 키나제의 SRC 패밀리의 원형 구성원이다. cSRC is a prototypical member of the SRC family of tyrosine kinases including Lyn, Fyn, Lck, Hck, Fgr, Blk, Syk, Yrk and Yes.
Tec 키나제는 혈액학적 기원의 세포에서 주로 발현되는 비수용체 티로신 키나제일 수 있다. Tec 패밀리는 Tec, Btk, 유도성 T-세포 키나제(Itk), 휴식 림프구 키나제(Rlk/Txk) 및 골수 발현 키나제(Bmx/Etk)를 포함한다.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).
상기 조성물에 있어서, 브루톤스 티로신 키나제(Bruton's Tyrosine Kinase: BTK)는 티로신 키나제의 Tec 패밀리의 일원이고, 초기 B 세포 발생, 성숙한 B 세포 활성화, 신호전달 및 생존의 핵심적 조절자이다. B 세포 수용체(BCR)를 통한 B 세포 신호전달은 넓은 범위의 생물학적 아웃풋을 야기한다. 비정상적 BCR-매개 신호전달은 조절이 해제된 B 세포 증식 및/또는 다중 자가면역 질환 및/또는 염증질환을 야기하는 병인성 자가항체의 형성을 야기할 수 있다. 사람에서 BTK의 돌연변이는 X-연관 무감마글로불린혈증(X-linked agammaglobulinaemia: XLA)을 야기할 수 있다. 이 질병은 B 세포의 손상된 성숙, 감소된 면역글로불린 생산, T 세포 독립적 면역 반응, 및 BCR 자극에 대한 지속된 칼슘 신호의 현저한 약화와 연관된다.In the composition, Bruton's Tyrosine Kinase (BTK) 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.
상기 단백질 키나제는 시스테인-함유 키나제일 수 있다. 상기 단백질 키나제는 키나제의 ATP-결합 부위 근처에 시스테인 잔기를 갖는 것일 수 있다. 상기 시스테인 잔기는 키나제의 ATP-결합 부위 근처에 가까운 공간적 근접(close spatial proximity)에 있는 것일 수 있다. ATP-결합 부위 근처에 시스테인 잔기를 갖는 단백질 키나제는 BTK, BMX, TEC, TXK, ITK, EGFR, ErbB, JAK3, BLK 등일 수 있다.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.
구체예에서, 상기 단백질 키나제는 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, 또는 이들의 조합일 수 있다.In an embodiment, 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.
상기 단백질 키나제는 BTK, 특히 C481 돌연변이 BTK, 예를 들어 C481S BTK일 수 있다.The protein kinase may be a BTK, in particular a C481 mutant BTK, for example a C481S BTK.
단백질 키나제, 예를 들면 BTK 활성의 저해는 하기 자가면역 및/또는 염증 질환을 치료하는데 유용할 수 있다. 더욱이, 단백질 키나제, 예를 들면 BTK는 세포자가사(apoptosis)에 역할을 하는 것으로 보고되었다. 단백질 키나제, 예를 들면 BTK 활성의 저해는 B-세포 증식성 장애 또는 비만세포 증식성 장애를 치료하는데 유용할 수 있다. 단백질 키나제, 예를 들면 BTK 활성의 저해는 B 세포 림프종 및 백혈병(leukemia)과 같은 암을 치료하는데 유용할 수 있다. 상기 조성물에 있어서, 상기 질환은 암, 염증 질환, 또는 자가면역 질환일 수 있다. 상기 암은 고형암 또는 혈액암일 수 있다. 상기 혈액암은 림프종, 백혈병, 다발성 골수종, 형질세포 골수종(plasma cell myeloma) 또는 골수이형성증후군일 수 있다.Inhibition of protein kinases, such as BTK activity, may be useful for treating the following autoimmune and/or inflammatory diseases. Moreover, 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. In the composition, 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.
상기 림프종은 맨틀세포 림프종(mantle cell lymphoma, MCL) 또는 비호지킨 림프종, 림프형질 림프종(lymphoplasmacytic lymphoma), 변연부B세포림프종(marginal zone lymphoma), 소 림프성 림프종(small lymphocytic lymphoma, SLL), 고위험 소 림프성 림프종(high-risk small lymphocytic lymphoma), 여포성 림프종(follicular lymphoma, FL), 미만성거대 B 세포 림프종(diffuse large B cell lymphoma, DLBCL), 발덴스트롬 거대글로불린혈증(Waldenstrom's macroglobulinemia), 버킷 림프종(Burkitt's lymphoma), 비버킷 고도 B세포 림프종(non-Burkitt high grade B cell lymphoma), 원발 원격동 B세포 림프종(primary mediastinal B-cell lymphoma, PMBL), 면역모세포성 대세포 림프종(immunoblastic large cell lymphoma), 전구 B 림프모구성 림프종(precursor B-lymphoblastic lymphoma), 비장변연부 림프종(splenic marginal zone lymphoma), 형질세포종(plasmacytoma), 종격동 거대 B 세포 림프종(mediastinal(thymic) large B cell lymphoma), 정맥내 거대 B 세포 림프종(intravascular large B cell lymphoma), 일차성 삼출 림프종(primary effusion lymphoma), 또는 림프종양 육아종증(lymphomatoid granulomatosis)일 수 있다. 상기 백혈병은 만성림프성 백혈병(chronic lymphocytic leukemia, CLL), 급성 림프모구성 백혈병(acute lymphoblastic leukemia, ALL), 또는 B 세포 전림프구성 백혈병(B cell prolymphocytic leukemia)일 수 있다.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 granulomatosis. The leukemia may be chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or B cell prolymphocytic leukemia.
고형암은 뇌종양, 두경부암, 폐암, 유방암, 흉선종, 중피종, 식도암, 대장암, 간암, 위암, 췌장암, 담도암, 신장암, 방광암, 전립선암, 고환암, 생식세포종, 난소암, 자궁 경부암, 자궁 내막암, 육종, 악성 흑색종 및 피부암을 포함한다.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.
상기 염증 질환 및/또는 자가면역 질환은 전신성 홍반성 루푸스(SLE), 류마티스 관절염, 다발혈관염(multiple vasculitis), 특발저혈소판자색반병(idiopathic thrombocytopenic purpura, ITP), 중증근육무력증(myasthenia gravis), 천식, 만성이식편대숙주 질병(chronic graft vs host disease), 다발성 경화증(Multiple Screlosis), 쇼그렌 증후군(Sjogren's syndrome), 크론병(Crohn's disease), 베체트병(Behcet's Disease), 또는 1형 당뇨(Type 1 Diabetes)일 수 있다. 상기 질환은 본 개시의 약제학적 조성물이 적용될 수 있는 구체적인 질환을 예시한 것일 뿐, 본 개시의 범위가 상기 질환들로 제한되는 것은 아니다.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.
상기 질환은 비가역적 BTK 저해제, 예를 들어 이브루티닙에 대한 내성 또는 불응성 질환일 수 있다.The disease may be a disease resistant or refractory to an irreversible BTK inhibitor, for example ibrutinib.
용어 "치료(treatment)"는 개체, 예를 들면 사람을 포함한 포유류에서 질환 또는 의학적 증상, 예를 들면 BTK-연관 질병을 치료함을 의미하고, 이는 다음을 포함한다: (a) 질환 또는 의학적 증상의 완화, 즉, 환자에서 질환 또는 의학적 증상의 제거 또는 회복 야기; (b) 질환 또는 의학적 증상의 억제, 즉, 개체에서 질환 또는 의학적 증상의 진행을 늦춤 또는 정지; 또는 (c) 개체에서 질환 또는 의학적 증상을 경감.The term "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.
상기한 화학식 1의 화합물 또는 그의 약제학적으로 허용가능한 염의 양은 당업자가 적절하게 선택할 수 있다. 상기 양은 0.01 ㎎ 내지 10,000 ㎎, 0.1 ㎎ 내지 1,000 ㎎, 1 ㎎ 내지 100 ㎎, 0.01 ㎎ 내지 1,000 ㎎, 0.01 ㎎ 내지 100 ㎎, 0.01 ㎎ 내지 10 ㎎, 또는 0.01 ㎎ 내지 1 ㎎일 수 있다.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.
상기 조성물에 있어서, "약제학적으로 허용가능한 담체"는 활성 성분의 적용을 돕기 위하여 활성 성분과 조합되어 사용되는 물질, 일반적으로 불활성 물질을 나타낸다. 상기 담체는 통상적인 약제학적으로 허용가능한 부형제, 첨가제 또는 희석제를 포함한다. 상기 담체는 예를 들면 충전제(filler), 결합제(binder), 붕해제(disintegrant), 버퍼, 보존제, 항산화제, 활택제, 향미제, 점증제(thickener), 발색제(coloring agent), 유화제, 현탁화제, 안정화제, 및 등장화제로부터 선택된 하나 이상을 포함하는 것일 수 있다.In the above compositions, "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.
본 개시의 조성물은 경구 투여 제형, 또는 정맥내, 복강내, 피하, 직장 및 국소투여를 포함한 비경구 투여 제형일 수 있다. 따라서, 본 개시의 조성물은 정제, 캡슐제, 수성액제 또는 현탁제 등의 다양한 형태로 제제화될 수 있다. 경구용 정제의 경우 락토즈, 옥수수 전분 등의 부형제 및 마그네슘 스테아레이트와 같은 활택제가 통상 가해질 수 있다. 경구투여용 캡슐제의 경우, 락토즈 및/또는 건조 옥수수 전분이 희석제로서 사용될 수 있다. 경구용 수성 현탁제가 필요할 경우, 활성성분을 유화제 및/또는 현탁화제와 결합시킬 수 있다. 필요할 경우, 특정 감미제 및/또는 향미제를 가할 수 있다. 근육내, 복강내, 피하 및 정맥내 투여의 경우, 활성성분의 멸균 용액이 통상 제조되며, 용액의 pH를 적합하게 조절하고 완충시킬 수 있다. 정맥내 투여의 경우, 용질의 총 농도는 제제에 등장성이 부여되도록 조절될 수 있다. 본 개시에 따른 조성물은 생리적 pH의 염수와 같은 약제학적으로 허용되는 담체를 포함하는 수용액제의 형태일 수 있다. 상기 용액은 국소 주사(local bolus injection)로 환자의 근육내 혈류에 도입될 수 있다.The 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. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, a sterile solution of the active ingredient is usually prepared, and the pH of the solution can be appropriately adjusted and buffered. For intravenous administration, 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.
본 개시에서 정의된 화학식 1의 화합물은 단백질 키나제 활성을 억제하는 효과를 보일 수 있다. 여기서 "억제(inhibition)"는 단백질 키나제의 키나제 활성을 감소시키는 것을 포함한다. 상기 단백질 키나제는 BTK일 수 있다. 상기 단백질 키나제는 C481 돌연변이 BTK, 예를 들어 C481S BTK일 수 있다.The compound of Formula 1 as defined in the present disclosure may exhibit an effect of inhibiting protein kinase activity. As used herein, “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.
약제학적 조성물은 단백질 키나제와 관련된 질환을 치료하기 위한 하나 이상의 다른 치료제와 함께 조합될 수 있다. 다른 치료제는 화학요법제, 항염증제, 면역억제제, 및 항암제를 포함한다. 다른 치료제의 예들은 신생혈관 형성 억제제(anti-angiogenic agent), MALT1, MCL-1 또는 IDH1 저해제, TLR9 저해제, Bcl-2, JAK2, ALK 또는 Hsp90 저해제, CYP3A4 저해제, BET 저해제, 면역 관문 억제제(immune checkpoint inhibitor), 항-CD20 치료제, HDAC 저해제, PIM 저해제, mTOR 저해제를 포함할 수 있다. 병용치료는 상승효과를 발생시킬 수 있다. 병용치료를 위한 약제는 단백질 키나제 억제제와 단회 투여 또는 연속적인 투여 형태로 병용할 수 있거나, 또는 동시에 또는 순차적으로 분리된 투여 형태로서 투여할 수 있다. 상기 단백질 키나제는 BTK일 수 있다. 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.
다른 양상은 단백질 키나제와 연관된 질병의 치료에 있어서의 상기에서 정의된 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염의 용도를 제공한다. 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.
다른 양상은 단백질 키나제와 연관된 질병을 치료하기 위한 의약을 제조하는데 있어서, 상기에서 정의된 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염의 용도를 제공한다. 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.
다른 양상은 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염, 및 약제학적으로 허용가능한 담체를 포함하는 단백질 키나제의 활성을 저해하는데 사용하기 위한 약제학적 조성물을 제공한다.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.
다른 양상은 치료학적 유효량의 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염을 개체에 투여하는 단계를 포함하는, 개체에서 단백질 키나제에 의하여 매개되는 질환을 치료하는 방법을 제공한다.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.
상기 방법에 있어서, 투여경로는 환자의 상태에 따라 당업자가 적절하게 선택할 수 있다. 상기 투여는 경구, 비경구, 또는 국부 투여일 수 있다. 상기 개체는 포유동물, 예를 들면, 사람, 소, 돼지, 말, 또는 고양이일 수 있다.In the above method, 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.
상기 방법에 있어서, "치료학적 유효량"은 치료를 필요로 하는 개체에게 투여되는 경우 치료 효과를 나타내기에 충분한 양을 의미한다. 투여량은 전술한 바와 같이 환자의 상태, 투여 경로, 주치의의 판단 등과 같은 다양한 인자들에 따라서 달라질 수 있다. 효과적인 투여량은 체외실험 또는 동물 모델 시험에서 얻어진 용량-반응곡선으로부터 추정할 수 있다. 투여되는 조성물에 존재하는 화합물의 비율 및 농도는 화학적 특성, 투여 경로, 치료적 투여량 등에 따라 결정될 수 있다. 상기 투여량은 개체에게 약 1 ㎍/㎏ 내지 약 1 g/㎏ per day, 또는 약 0.1 ㎎/㎏ 내지 약 500 ㎎/㎏ per day의 유효량으로 투여될 수 있다. 상기 용량은 개체의 나이, 체중, 감수성, 또는 증상에 따라 변경될 수 있다.In the above method, "therapeutically effective amount" means an amount sufficient to exhibit a therapeutic effect when administered to a subject in need of treatment. As described above, 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 μg/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.
상기 방법에 있어서, 상기 질환은 상기 약제학적 조성물에 대해 기재된 것일 수 있다. 상기 질환은 본 개시의 방법이 적용될 수 있는 구체적인 질환을 예시한 것일 뿐, 본 개시의 범위가 상기 질환들로 제한되는 것은 아니다.In the method, 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.
또한, 치료학적으로 유효량의 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염은 단백질 키나제, 예를 들면 BTK와 관련된 질환을 치료하기 위한 하나 이상의 다른 치료제와 함께 조합되어 투여될 수 있다. In addition, 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. .
다른 양상은 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염을 단백질 키나제, 예를 들면 브루톤스 티로신 키나제(BTK)와 접촉시키는 단계를 포함하는 브루톤스 티로신 키나제(BTK)의 활성을 저해하는 방법을 제공한다. 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). provide a way to inhibit it.
상기 접촉시키는 단계는 엑스 비보 또는 인 비트로에서 수행되는 것일 수 있다. 상기 접촉시키는 단계는 화학식 1의 화합물 또는 그의 약제학적으로 허용가능한 염 및 단백질 키나제, 예를 들면 브루톤스 티로신 키나제(BTK)을 포함하는 매질 중에서 인큐베이션하는 단계를 포함할 수 있다. 상기 매질은 액체, 예를 들면, 물, 또는 유기 용매와 같은 액체 매질일 수 있다. 상기 접촉시키는 단계는 상기 화학식 1의 화합물 또는 그의 약제학적으로 허용가능한 염을 개체에게 투여하고, 개체 내에서 단백질 키나제, 예를 들면 브루톤스 티로신 키나제(BTK)와 접촉하도록 하는 것을 포함할 수 있다. 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.
상기 BTK는 C481 돌연변이 BTK, 예를 들어 C481S BTK일 수 있다.The BTK may be a C481 mutant BTK, for example C481S BTK.
구체예에서, 일 양상에 따른 화학식 1의 화합물 중 m이 1인 메틸렌을 포함하는 화합물은 아래와 같은 반응식 1에 따라 제조될 수 있다.In an embodiment, among the compounds of Formula 1 according to an aspect, a compound including methylene in which m is 1 may be prepared according to Scheme 1 below.
[반응식 1][Scheme 1]
Figure PCTKR2021014942-appb-I000023
Figure PCTKR2021014942-appb-I000023
상기 반응식 1에서, Hal은 할로겐을 나타낸다. 상기 반응식 1에서, Cy, R1, R2, L1, L2, A, X, Y, Z 및 n은 화학식 1에서 정의된 바와 같다.In Scheme 1, Hal represents halogen. In Scheme 1, Cy, R 1 , R 2 , L 1 , L 2 , A, X, Y, Z and n are as defined in Formula 1.
상기 반응식 1에 있어서, 단계 (1-1)에서는 화학식 1-Ⅵa와 화학식 1-Ⅶ의 화합물을 반응시켜 화학식 1-Ⅵb의 화합물을 제조할 수 있다. 본 반응은 아미드 반응으로 N-(3-디메틸아미노프로필)-N′-에틸카보디이미드 염산염, 하이드록시벤조트리아졸, (1-[비스(디메틸아미노)메틸렌]-1H-1,2,3-트리아졸로[4,5-b]피리디늄 3-옥시드 헥사플루오로포스페이트, 1,1'-카보닐디이미다졸 존재 하에 유기용매, 예를 들어. N,N-디메틸포름아미드, 디클로로메탄 중에서 수행될 수 있다. In Scheme 1, in step (1-1), 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.
단계 (1-2)에서는 단계 (1-1)에서 얻은 화학식 1-Ⅵb의 카보닐 그룹을 환원시켜 화학식 1-Ⅳ의 화합물을 제조할 수 있다. 본 반응은 보란 존재 하에 유기용매, 예를들어 테트라하이드로퓨란 중에서 수행될 수 있다.In 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.
단계 (1-3)에서는 화학식 1-Ⅳ의 화합물과 화학식 Ⅴ의 화합물을 반응시켜 화학식 1-Ⅱa의 화합물을 제조할 수 있다. 본 반응은 트리스(디벤질리덴아세톤)디팔라듐, 잔트포스, 및 나트륨-t-부톡사이드 존재 하에 극성 유기용매, 예를 들어 디옥산 중에서 수행될 수 있다.In step (1-3), 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.
단계 (1-4)에서는 화학식 1-Ⅱa의 화합물의 할로겐 그룹이 아미노 그룹으로 치환된 화학식(1-Ⅱb)의 화합물을 제조할 수 있다. 본 반응은 포타슘카보네이트, 커퍼옥사이드, N,N'-디메틸에틸렌디아민, 및 암모니아수 존재 하에 유기용매, 예를 들어 글리콜 용매, 특히 에틸렌글리콜 중에서 수행될 수 있다.In 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.
단계 (1-5)에서는, 단계 (1-4)에서 얻은 화학식 1-Ⅱb의 화합물과 화학식 Ⅲ의 화합물을 반응시켜 화학식 Ⅰ의 화합물을 제조할 수 있다. 본 반응은 단계 (1-3)과 동일한 시약이나 용매를 사용하여 수행될 수 있다.In 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).
구체예에서, 일 양상에 따른 화학식 1의 화합물 중 m이 0인 화합물은 아래와 같은 반응식 2에 따라 제조될 수 있다.In an embodiment, 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.
[반응식 2][Scheme 2]
Figure PCTKR2021014942-appb-I000024
Figure PCTKR2021014942-appb-I000024
상기 반응식 2에서, Hal은 할로겐을 나타낸다. 상기 반응식 2에서, Cy, R1, R2, L1, L2, A, X, Y, Z 및 n은 화학식 1에서 정의된 바와 같다.In Scheme 2, Hal represents halogen. In Scheme 2, Cy, R 1 , R 2 , L 1 , L 2 , A, X, Y, Z and n are as defined in Formula 1.
단계 (2-1)에서는 화학식 2-Ⅳ의 화합물과 화학식 Ⅴ의 화합물을 반응시켜 화학식 2-Ⅱa의 화합물을 제조할 수 있다. 본 반응은 트리스(디벤질리덴아세톤)디팔라듐, 잔트포스, 및 나트륨-t-부톡사이드 존재 하에 극성 유기용매, 예를 들어 디옥산 중에서 수행될 수 있다.In step (2-1), 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.
단계 (2-2)에서는 화학식 2-Ⅱa의 화합물의 할로겐 그룹이 아미노 그룹으로 치환된 화학식 (2-Ⅱb)의 화합물을 제조할 수 있다. 본 반응은 포타슘카보네이트, 커퍼옥사이드, N,N'-디메틸에틸렌디아민, 및 암모니아수 존재 하에 유기용매, 예를 들어 글리콜 용매, 특히 에틸렌글리콜 중에서 수행될 수 있다.In 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.
단계 (2-3)에서는, 단계 (2-2)에서 얻은 화학식 2-Ⅱb의 화합물과 화학식 Ⅲ의 화합물을 반응시켜 화학식 Ⅰ의 화합물을 제조할 수 있다. 본 반응은 단계 (2-1)과 동일한 시약이나 용매를 사용하여 수행될 수 있다.In 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).
구체예에서, 일 양상에 따른 화학식 1의 화합물 중 Z2가 N인 화합물은 아래와 같은 반응식3 에 따라 제조될 수 있다.In an embodiment, 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.
[반응식 3][Scheme 3]
Figure PCTKR2021014942-appb-I000025
Figure PCTKR2021014942-appb-I000025
단계 (3-1) 에서는 화학식 3-IVa와 화합물 3-VII를 반응시켜 화학식 2-VIa의 화합물을 제조할 수 있다. 본 반응은 염기 예를들어 디아이소프로필에틸아민, 트라이에틸아민, 피리딘, 수호화나트륨, 나트륨-t-부톡사이드, 탄산칼륨, 탄산세슘, 탄산수소나트륨 존재하에 극성 비양자성 유기용매 예를들어, 예를 들어 테트라히드로퓨란, 에틸아세테이트, 아세톤, N,N-디메틸포름아미드, 아세토니트릴, N,N-디메틸설폭사이드 중에서 수행될 수 있다.In step (3-1), 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.
단계 (3-2)에서는 화학식 3-VIb 화합물을 3-VIII과 아미드화 반응시켜 화학식 3-VIc의 화합물을 제조할 수 있다. 본 반응은 아미드 반응으로 1,5,7-트리아자비사이클로[4.4.0]데크-5-엔 (TBD), 1,4,6-트리아자비사이클로[3.3.0]옥트-4-엔 존재 하에 유기용매 예를들어 N,N-디메틸포름아미드, 디클로로메탄, 테트라히드로퓨란 중에서 수행될 수 있다. In step (3-2), 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.
단계 (3-3) 에서는 단계 (3-2)에서 얻은 화학식 3-VIc의 카르보닐 그룹을 환원시켜 화학시 3-IV의 화합물을 제조할 수 있다. 본 반응은 보란 존재 하에 유기용매, 예를들어 테트라히드로퓨란 중에서 수행될 수 있다.In 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.
단계 (3-4) 에서는 단계 (3-3)에서 얻은 화학식 3-IV에, 강산, 예를 들어 트리플로로아세트산, 염산 존재 하에 유기용매 디클로로메탄 중에서 수행하여 보호기가 제거된 화학식 3-II의 화합물을 제조할 수 있다.In 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). compounds can be prepared.
단계(3-5)에서는, 단계(3-4)에서 얻은 화학식 3-II 화합물과 화학식 3-III의 화합물을 반응시켜 화학식 3-I 화합물을 제조할 수 있다. 본 반응은 단계 (3-1)와 동일한 시약이나 용매를 사용하여 수행될 수 있다.In 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).
단계(3-6)에서는, 단계(3-5)에서 얻은 화학식 3-I 화합물을 마이크로웨이브를 이용하여 화학식 V 의 화합물을 반응시켜 화학식(I)의 화합물을 제조할 수 있다. 본 반응에서 유기용매 예를들어 이소프로필알콜, 에탄올 중에서 수행될 수 있다.In 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.
일 양상에 따른 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염은 단백질 키나제, 예를 들어 BTK에 의하여 매개되는 질환을 치료하는데 사용될 수 있다.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.
다른 양상에 따른 약제학적 조성물은 단백질 키나제, 예를 들어 BTK에 의하여 매개되는 질환을 치료하는데 사용될 수 있다.The pharmaceutical composition according to another aspect may be used to treat a disease mediated by a protein kinase, for example, BTK.
다른 양상에 따른 단백질 키나제, 예를 들어 BTK에 의하여 매개되는 질환을 치료하는 방법에 의하면, 개체에서 단백질 키나제, 예를 들어 BTK에 의하여 매개되는 질환을 효율적으로 치료할 수 있다.According to the method for treating a disease mediated by a protein kinase, eg, BTK, according to another aspect, it is possible to efficiently treat a disease mediated by a protein kinase, eg, BTK, in a subject.
다른 양상에 따른 단백질 키나제, 예를 들어 BTK의 활성을 저해하는 방법에 의하면, 단백질 키나제, 예를 들어 BTK의 활성을 효율적으로 저해할 수 있다.According to the method for inhibiting the activity of a protein kinase, for example, BTK, according to another aspect, it is possible to efficiently inhibit the activity of a protein kinase, for example, BTK.
상기 BTK는 C481 돌연변이 BTK, 예를 들어 C481S BTK일 수 있다.The BTK may be a C481 mutant BTK, for example C481S BTK.
이하 본 개시를 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 예시적으로 설명하기 위한 것으로 본 개시의 범위가 이들 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present disclosure will be described in more detail through examples. However, these examples are for illustrative purposes only, and the scope of the present disclosure is not limited by these examples.
실시예 1: (1R,4R)-4-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Example 1: (1R,4R)-4-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino Synthesis of )pyridin-2-yl)amino)cyclohexan-1-ol
단계 1) N'-((5-브로모싸이아졸-2-일)메틸렌)-4-메틸벤젠설폰하이드라자이드의 합성Step 1) Synthesis of N'-((5-bromothiazol-2-yl)methylene)-4-methylbenzenesulfonehydrazide
2-브로모-5-포밀싸이아졸(100 ㎎, 0.52 mmol)과 p-톨루엔설포닐 하이드라자이드(183 ㎎, 0.98 mmol)를 마이크로파 바이알에 첨가한 후 에탄올 용매와 혼합하였다. 이 용액에 1 M의 염산(0.02 ㎖, 0.02 mmol)을 천천히 첨가하고 마이크로파로 80 ℃에서 1 시간 교반하였다. 반응이 완결되면 상온으로 냉각시킨 뒤 3 시간 추가 교반한 후 용액을 날려주었다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물(150 ㎎, 80%)을 얻었다.2-Bromo-5-formylthiazole (100 mg, 0.52 mmol) and p-toluenesulfonyl hydrazide (183 mg, 0.98 mmol) were added to a microwave vial and mixed with an ethanol solvent. To this solution, 1 M hydrochloric acid (0.02 ml, 0.02 mmol) was slowly added, followed by stirring in a microwave at 80° C. for 1 hour. When the reaction was completed, the solution was blown off after cooling to room temperature and further stirring for 3 hours. The obtained residue was purified using column chromatography to obtain the target compound (150 mg, 80%).
단계 2) 2-브로모-5-(2-페닐-2H-테트라졸-5-일)싸이아졸의 합성Step 2) Synthesis of 2-bromo-5-(2-phenyl-2H-tetrazol-5-yl)thiazole
단계 1)에서 얻은 N'-((5-브로모싸이아졸-2-일)메틸렌)-4-메틸벤젠설폰하이드라자이드(500 ㎎, 1.39 mmol)와 아닐린(0.13 ㎖, 1.46 mmol)을 테트라하이드로퓨란(2.78 ㎖)과 피리딘(1.39 ㎖) 혼합용매에 녹인 후 상온에서 30 분 교반하였다. 이 용액에 아이소아밀 나이트라이트(0.24 ㎖, 1.81 mmol)를 첨가한 후 상온에서 추가 25 시간 교반하였다. 반응이 종료되면 에틸아세테이트를 이용하여 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적화합물(172 ㎎, 56%)을 얻었다.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. Upon completion of the reaction, extraction was performed with ethyl acetate, 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 (172 mg, 56%).
단계 3) (2,6-디브로모피리딘-4-일)(몰포리노)메탄온의 합성Step 3) Synthesis of (2,6-dibromopyridin-4-yl)(morpholino)methanone
2,6-디브로모니코티닉 산(1 g, 3.55 mmol)과 1,1'-카보닐디이미다졸(0.69 g, 4.27 mmol)을 N,N'-디메틸포름아마이드(3.5 ㎖)에 녹인 후 상온에서 5 분간 교반하였다. 이 용액에 몰포린(0.36 ㎖, 4.27 mmol)을 적가한 후 상온에서 2시간 교반하였다. 반응이 종료되면 에틸아세테이트를 이용하여 추출하고, 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물(1.12 g, 90%)을 얻었다.After dissolving 2,6-dibromonicotinic acid (1 g, 3.55 mmol) and 1,1'-carbonyldiimidazole (0.69 g, 4.27 mmol) in N,N'-dimethylformamide (3.5 mL) The mixture was stirred at room temperature for 5 minutes. Morpholine (0.36 mL, 4.27 mmol) was added dropwise to this solution, followed by stirring at room temperature for 2 hours. When the reaction was completed, extraction was performed using ethyl acetate, 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 (1.12 g, 90%).
단계 4) 4-((2,6-디브로모피리딘-4-일)메틸)몰포린의 합성Step 4) Synthesis of 4-((2,6-dibromopyridin-4-yl)methyl)morpholine
(2,6-디브로모피리딘-4-일)(몰포리노)메탄온(1.12 g, 3.22 mmol)을 테트라하이드로퓨란 3.2 ㎖에 녹인 후, 0 ℃로 냉각시켰다. 냉각시킨 반응액에 1 M 보란-테트라하이드로용액(3.0 eq)을 적가하고 0 ℃에서 1시간 교반하였다. 이후 보란-테트라하이드로용액(3.0 eq)을 추가로 적가한 후 시작물질이 사라질 때까지 0 ℃에서 3 시간 교반하였다. 반응액을 1 M 염산 수용액으로 pH 1을 맞춘 뒤, 80 ℃에서 1 시간 교반하였다. 반응액을 0 ℃로 냉각한 후, 중탄산나트륨 포화수용액을 사용하여 pH 8 정도로 맞춘 뒤 에틸아세테이트를 이용하여 추출하고, 물로 씻었다. 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적화합물(750 ㎎, 70%)을 얻었다.(2,6-dibromopyridin-4-yl)(morpholino)methanone (1.12 g, 3.22 mmol) was dissolved in 3.2 ml of tetrahydrofuran, and then cooled to 0 °C. To the cooled reaction solution, 1 M borane-tetrahydro solution (3.0 eq) was added dropwise and stirred at 0° C. for 1 hour. Then, borane-tetrahydro solution (3.0 eq) was further added dropwise and stirred at 0° C. for 3 hours until the starting material disappeared. The reaction solution was adjusted to pH 1 with a 1 M aqueous hydrochloric acid solution, followed by stirring at 80 °C for 1 hour. After 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%).
단계 5) (1R,4R)-4-((6-브로모-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Step 5) Synthesis of (1R,4R)-4-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol
4-((2,6-디브로모피리딘-4-일)메틸)몰포린(200 ㎎. 0.59 mmol), 트랜스-4-아미노사이클로헥산올(81 ㎎, 0.71 mmol), 트리스(디벤질리덴아세톤)디팔라듐(27 ㎎, 10 mol%), 잔트포스(17 ㎎, 10 mol%), 나트륨-터트-부톡사이드(85 ㎎, 0.89 mmol)를 무수 1,4-디옥세인 1.5 ㎖에 녹인 후, 상온에서 4 시간 교반하였다. 반응이 완료되면 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적 화합물(126 ㎎, 58%)을 얻었다.4-((2,6-dibromopyridin-4-yl)methyl)morpholine (200 mg. 0.59 mmol), trans-4-aminocyclohexanol (81 mg, 0.71 mmol), tris(dibenzylidene) Acetone) dipalladium (27 mg, 10 mol%), xantphos (17 mg, 10 mol%), sodium-tert-butoxide (85 mg, 0.89 mmol) was dissolved in 1.5 ml of anhydrous 1,4-dioxane , and stirred at room temperature for 4 hours. Upon completion of the reaction, extraction was performed with ethyl acetate, 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 by column chromatography to obtain the target compound (126 mg, 58%).
단계 6) (1R,4R)-4-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Step 6) Synthesis of (1R,4R)-4-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol
(1R,4R)-4-((6-브로모-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올(311 ㎎, 0.84 mmol), 쿠프릭 아세틸아세톤(10 mol%), 세슘 카보네이트(551 ㎎, 1.69 mmol)를 슈링크튜브에 넣고, 질소 환경을 조성하였다. 이후 아세틸아세톤(40 mol%), 암모니아 수용액(0.65 ㎖, 16.91 mmol), 무수 디메틸포름아마이드(4 ㎖)를 차례로 넣고, 90 ℃에서 밤샘 교반하였다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적 화합물(69 ㎎, 27%)을 얻었다.(1R,4R)-4-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol (311 mg, 0.84 mmol), cupric acetylacetone (10 mol%) and cesium carbonate (551 mg, 1.69 mmol) were put 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 the mixture was stirred at 90° C. overnight. When the reaction was completed, 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%).
단계 7) (1R,4R)-4-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Step 7) (1R,4R)-4-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino) Synthesis of pyridin-2-yl)amino)cyclohexan-1-ol
상기 단계 2)에서 합성된 2-브로모-5-(2-페닐-2H-테트라졸-5-일)싸이아졸 (285 ㎎, 0.92 mmol)과 단계 6)에서 합성된 (1R,4R)-4-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올(236 ㎎, 0.77 mmol)을 2 ㎖의 다이옥산에 용해시켰다. 이 용액에 트리스(디벤질리덴아세톤)디팔라듐(70 ㎎, 10 mol%), 잔트포스(44 ㎎, 10 mol%), 나트륨-터트-부톡사이드(111 ㎎, 0.89 mmol)를 첨가한 뒤 80 ℃에서 2 시간 교반하였다. 반응이 종료되면 에틸아세테이트를 이용하여 추출하고, 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물(312 ㎎, 76%)을 얻었다.2-bromo-5-(2-phenyl-2H-tetrazol-5-yl)thiazole (285 mg, 0.92 mmol) synthesized in step 2) and (1R,4R)- synthesized in step 6) 4-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol (236 mg, 0.77 mmol) was dissolved in 2 mL of dioxane. To this solution, tris(dibenzylideneacetone)dipalladium (70 mg, 10 mol%), xanthos (44 mg, 10 mol%), sodium-tert-butoxide (111 mg, 0.89 mmol) was added, and then 80 The mixture was stirred at ℃ for 2 hours. When the reaction was completed, extraction was performed using ethyl acetate, 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 (312 mg, 76%).
1H-NMR(400 MHz, DMSO-d6) δ: 11.32(s, 1H), 8.27-8.25(m, 2H), 8.17(s, 1H), 7.67-7.58(m, 3H), 6.6(d, 1H, J=4 MHz), 6.16(s, 1H), 6.06(s, 1H), 4.80(d, 1H, J=4 MHz), 4.06-4.03(m, 1H), 3.61-3.54(m, 5H), 3.27(s, 2H), 2.37-2.36(m, 4H), 2.12-2.09(m, 2H), 1.96-1.93(m, 2H), 1.64-1.60(m, 2H), 1.29-1.26(m, 2H) 1 H-NMR (400 MHz, DMSO-d6) δ: 11.32 (s, 1H), 8.27-8.25 (m, 2H), 8.17 (s, 1H), 7.67-7.58 (m, 3H), 6.6 (d, 1H, J=4 MHz), 6.16(s, 1H), 6.06(s, 1H), 4.80(d, 1H, J=4 MHz), 4.06-4.03(m, 1H), 3.61-3.54(m, 5H) ), 3.27(s, 2H), 2.37-2.36(m, 4H), 2.12-2.09(m, 2H), 1.96-1.93(m, 2H), 1.64-1.60(m, 2H), 1.29-1.26(m) , 2H)
실시예 2: (1R,4R)-4-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Example 2: (1R,4R)-4-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole- Synthesis of 2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol
단계 1) 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸의 합성Step 1) Synthesis of 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole
2-브로모-5-포밀싸이아졸(0.50 g, 2.60 mmol)과 벤즈하이드라자이드(0.35 g, 2.60 mmol)를 26 ㎖의 에탄올에 용해시킨 뒤 1 시간 가열 환류하였다. 반응이 종료되면 용매를 감압증류하였다. 얻어진 잔사를 13 ㎖의 디메틸 설폭사이드로 용해시킨 뒤 탄산칼륨(1.08 g, 7.80 mmol)과 아이오딘(0.79 g, 3.12 mmol)을 첨가하였다. 이 용액을 100 ℃에서 1 시간 교반하였다. 반응이 종료되면 에틸아세테이트를 이용하여 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물(0.72 g, 90%)을 얻었다.2-Bromo-5-formylthiazole (0.50 g, 2.60 mmol) and benzhydrazide (0.35 g, 2.60 mmol) were dissolved in 26 ml of ethanol, and then heated to reflux for 1 hour. When the reaction was completed, the solvent was distilled under reduced pressure. The obtained residue was dissolved with 13 ml of dimethyl sulfoxide, and potassium carbonate (1.08 g, 7.80 mmol) and iodine (0.79 g, 3.12 mmol) were added thereto. This solution was stirred at 100 DEG C for 1 hour. Upon completion of the reaction, extraction was performed with ethyl acetate, 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 (0.72 g, 90%).
단계 2) (1R,4R)-4-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Step 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
상기 단계 1)에서 얻은 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸(142 ㎎, 0.46 mmol)과 실시예 1의 단계 6)에서 얻은 (1R,4R)-4-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올(118 ㎎, 0.38 mmol)을 실시예 1의 단계 7)과 같은 방법으로 반응시켜 목적 화합물(137 ㎎, 68%)을 얻었다.2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (142 mg, 0.46 mmol) obtained in step 1) and step 6) of Example 1 The obtained (1R,4R)-4-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol (118 mg, 0.38 mmol) was prepared in step 7 of Example 1 ) was reacted in the same way to obtain the target compound (137 mg, 68%).
1H-NMR(400 MHz, DMSO-d6) δ: 11.49(s, 1H), 8.21(s, 1H), 8.11-8.08(m, 2H), 7.63-7.61(m, 3H), 6.59(d, 1H, J=8 MHz), 6.18(s, 1H), 6.08(s, 1H), 4.66(d, 1H, J=3.2 MHz), 3.95-3.94(m, 1H), 3.59-3.57(m, 5H), 3.27(s, 2H), 2.37-2.36(m, 4H), 2.09-2.07(m, 2H), 1.97-1.89(m, 2H), 1.53-1.45(m, 2H), 1.17-1.13(m, 2H) 1 H-NMR (400 MHz, DMSO-d6) δ: 11.49 (s, 1H), 8.21 (s, 1H), 8.11-8.08 (m, 2H), 7.63-7.61 (m, 3H), 6.59 (d, 1H, J=8 MHz), 6.18(s, 1H), 6.08(s, 1H), 4.66(d, 1H, J=3.2 MHz), 3.95-3.94(m, 1H), 3.59-3.57(m, 5H) ), 3.27(s, 2H), 2.37-2.36(m, 4H), 2.09-2.07(m, 2H), 1.97-1.89(m, 2H), 1.53-1.45(m, 2H), 1.17-1.13(m) , 2H)
실시예 3: (1R,4R)-4-((4-(((2S,6R)-2,6-디메틸몰포리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Example 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)cyclohexan-1-ol
단계 1) (2,6-디브로모피리딘-4-일)((2S,6R)-2,6-디메틸몰포리노)메탄온의 합성Step 1) Synthesis of (2,6-dibromopyridin-4-yl)((2S,6R)-2,6-dimethylmorpholino)methanone
실시예 1의 단계 3)에서 몰포린 대신 시스-2,6-디메틸몰포린을 사용한 것을 제외하고, 동일한 방법으로 목적 화합물(1.01 g, 75%)을 얻었다.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).
단계 2) (2S,6R)-4-((2,6-디브로모피리딘-4-일)메틸)-2,6-디메틸몰포린의 합성Step 2) Synthesis of (2S,6R)-4-((2,6-dibromopyridin-4-yl)methyl)-2,6-dimethylmorpholine
상기 단계 1)에서 얻은 (2,6-디브로모피리딘-4-일)((2S,6R)-2,6-디메틸몰포리노)메탄온(700 ㎎, 1.85 mmol)을 실시예 1의 단계 4)와 같은 방법으로 목적 화합물(220 ㎎, 33%)을 얻었다.(2,6-dibromopyridin-4-yl)((2S,6R)-2,6-dimethylmorpholino)methanone (700 mg, 1.85 mmol) obtained in step 1) above was mixed with the step of Example 1 4) to obtain the target compound (220 mg, 33%).
단계 3) (1R,4R)-4-((6-브로모-4-(((2S,6R)-2,6-디메틸몰포리노)메틸)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Step 3) (1R,4R)-4-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclohexane-1 -Synthesis of ol
상기 단계 2)에서 얻은 (2S,6R)-4-((2,6-디브로모피리딘-4-일)메틸)-2,6-디메틸몰포린(300 ㎎, 0.82 mmol)을 실시예 1의 단계 5)와 같은 방법으로 반응시켜 목적 화합물(135 ㎎, 41%)을 얻었다.(2S,6R)-4-((2,6-dibromopyridin-4-yl)methyl)-2,6-dimethylmorpholine (300 mg, 0.82 mmol) obtained in step 2) was prepared in Example 1 The target compound (135 mg, 41%) was obtained by reacting in the same manner as in step 5).
단계 4) (1R,4R)-4-((6-아미노-4-(((2S,6R)-2,6-디메틸몰포리노)메틸)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Step 4) (1R,4R)-4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclohexane-1- synthesis of ol
상기 단계 3)에서 얻은 (1R,4R)-4-((6-브로모-4-(((2S,6R)-2,6-디메틸몰포리노)메틸)피리딘-2-일)아미노)사이클로헥산-1-올(135 ㎎, 0.34 mmol)을 실시예 1의 단계 6)과 같은 방법으로 반응시켜 목적 화합물(47 ㎎, 41%)을 얻었다.(1R,4R)-4-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclo obtained in step 3) above Hexan-1-ol (135 mg, 0.34 mmol) was reacted in the same manner as in Example 1 step 6) to obtain the target compound (47 mg, 41%).
단계 5) (1R,4R)-4-((4-(((2S,6R)-2,6-디메틸몰포리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Step 5) (1R,4R)-4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4) Synthesis of -oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol
상기 단계 4)에서 얻은 (1R,4R)-4-((6-아미노-4-(((2S,6R)-2,6-디메틸몰포리노)메틸)피리딘-2-일)아미노)사이클로헥산-1-올(47 ㎎, 0.11 mmol)과 실시예 2의 단계 1)에서 얻은 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸(41 ㎎, 0.13 mmol)을 실시예 1의 단계 7)과 같은 방법으로 반응시켜 목적 화합물(22 ㎎, 35%)을 얻었다.(1R,4R)-4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclohexane obtained in step 4) above -1-ol (47 mg, 0.11 mmol) and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole obtained in step 1) of Example 2 ( 41 mg, 0.13 mmol) was reacted in the same manner as in Example 1 step 7) to obtain the target compound (22 mg, 35%).
실시예 4: (1R,4R)-4-((6-((5-(2-(4-브로모페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Example 4: (1R,4R)-4-((6-((5-(2-(4-bromophenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)- Synthesis of 4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol
단계 1) 2-브로모-5-(2-(4-브로모페닐)-2H-테트라졸-5-일)싸이아졸의 합성Step 1) Synthesis of 2-bromo-5-(2-(4-bromophenyl)-2H-tetrazol-5-yl)thiazole
실시예 1의 단계 1)에서 얻은 N'-((5-브로모싸이아졸-2-일)메틸렌)-4-메틸벤젠설폰하이드라자이드(500 ㎎, 1.39 mmol)와 4-브로모아닐린(251 ㎎, 1.46 mmol)을 실시예 1의 단계 2)와 같은 방법으로 반응시켜 목적 화합물(193 ㎎, 36%)을 얻었다.N'-((5-bromothiazol-2-yl)methylene)-4-methylbenzenesulfonehydrazide (500 mg, 1.39 mmol) obtained in step 1) of Example 1 and 4-bromoaniline ( 251 mg, 1.46 mmol) was reacted in the same manner as in step 2) of Example 1 to obtain the target compound (193 mg, 36%).
단계 2) (1R,4R)-4-((6-((5-(2-(4-브로모페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Step 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
상기 단계 1)에서 얻은 2-브로모-5-(2-(4-브로모페닐)-2H-테트라졸-5-일)싸이아졸(59 ㎎, 0.16 mmol)과 실시예 1의 단계 6)에서 얻은 (1R,4R)-4-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올(40 ㎎, 0.13 mmol)을 실시예 1의 단계 7)과 같은 방법으로 반응시켜 목적 화합물(36 ㎎, 45%)을 얻었다.2-bromo-5-(2-(4-bromophenyl)-2H-tetrazol-5-yl)thiazole (59 mg, 0.16 mmol) obtained in step 1) and step 6 of Example 1) (1R,4R)-4-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol (40 mg, 0.13 mmol) obtained from the step of Example 1 7) was reacted in the same manner to obtain the target compound (36 mg, 45%).
1H-NMR(400 MHz, DMSO-d6) δ: 8.22(d, 2H, J= 8.8 Hz), 8.17(s, 1H), 7.81(d, 2H, J= 8.8 Hz), 6.59(d, 1H, J= 8.0 Hz), 6.16(s, 1H), 6.05(s, 1H), 4.88(d, 1H, J= 2.8 Hz), 4.05-4.02(m, 1H), 3.59(t, 6H, 4.4 Hz), 3.26(s, 2H), 2.36(s, 4H), 2.10(d, 2H, J= 10.8 Hz), 1.94(d, 2H, J= 10.8 Hz), 1.66-1.57(m, 2H), 1.32-1.18(m, 2H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8.22 (d, 2H, J = 8.8 Hz), 8.17 (s, 1H), 7.81 (d, 2H, J = 8.8 Hz), 6.59 (d, 1H, J = 8.0 Hz), 6.16 (s, 1H), 6.05 (s, 1H), 4.88 (d, 1H, J = 2.8 Hz), 4.05-4.02 (m, 1H), 3.59 (t, 6H, 4.4) Hz), 3.26 (s, 2H), 2.36 (s, 4H), 2.10 (d, 2H, J = 10.8 Hz), 1.94 (d, 2H, J = 10.8 Hz), 1.66-1.57 (m, 2H), 1.32-1.18 (m, 2H).
실시예 5: (1R,4R)-4-((6-((5-(2-(2-클로로-6-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노사이클로헥산-1-올의 합성Example 5: (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
단계 1) 2-브로모-5-(2-(2-클로로-6-메틸페닐)-2H-테트라졸-5-일)싸이아졸의 합성Step 1) Synthesis of 2-bromo-5-(2-(2-chloro-6-methylphenyl)-2H-tetrazol-5-yl)thiazole
실시예 1의 단계 1)에서 얻어진 N'-((5-브로모싸이아졸-2-일)메틸렌)-4-메틸벤젠설폰하이드라자이드(500 ㎎, 1.39 mmol)와 2-클로로-6-메틸아닐린(0.18 ㎖, 1.46 mmol)을 실시예 1의 단계 2)와 같은 방법으로 목적 화합물(310 ㎎, 62%)을 얻었다.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%).
단계 2) (1R,4R)-4-((6-((5-(2-(2-클로로-6-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노사이클로헥산-1-올의 합성Step 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
상기 단계 1)에서 얻은 2-브로모-5-(2-(2-클로로-6-메틸페닐)-2H-테트라졸-5-일)싸이아졸(56 ㎎, 0.16 mmol)과 실시예 1의 단계 6)에서 얻은 (1R,4R)-4-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올(40 ㎎, 55%)을 실시예 1의 단계 7)와 같은 방법으로 반응시켜 목적 화합물(42 ㎎, 55%)을 얻었다.2-bromo-5-(2-(2-chloro-6-methylphenyl)-2H-tetrazol-5-yl)thiazole (56 mg, 0.16 mmol) obtained in step 1) and the step of Example 1 6) (1R,4R)-4-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol (40 mg, 55%) obtained in Example 1 Step 7) of the reaction was followed to obtain the target compound (42 mg, 55%).
1H-NMR(400 MHz, CDCl3) δ: 10.01(s, 1H), 8.27(s, 1H), 7.46-7.43(m, 2H), 7.34-7.33(m, 1H), 6.25(s, 1H), 5.98(s, 1H), 4.36(d, 1H, J= 8.4 Hz), 3.99(s, 1H), 3.74-3.63(m, 5H), 3.62-3.59(m, 1H), 3.38(s, 2H), 2.47(s, 5H), 2.24(d, 2H, J= 12.0 Hz), 2.11-2.02(m, 5H), 1.65-1.57(m, 2H), 1.33-1.24(m, 2H) 1 H-NMR (400 MHz, CDCl 3 ) δ: 10.01(s, 1H), 8.27(s, 1H), 7.46-7.43(m, 2H), 7.34-7.33(m, 1H), 6.25(s, 1H) ), 5.98(s, 1H), 4.36(d, 1H, J= 8.4 Hz), 3.99(s, 1H), 3.74-3.63(m, 5H), 3.62-3.59(m, 1H), 3.38(s, 2H), 2.47 (s, 5H), 2.24 (d, 2H, J = 12.0 Hz), 2.11-2.02 (m, 5H), 1.65-1.57 (m, 2H), 1.33-1.24 (m, 2H)
실시예 6: 2-((6-(((1R,4R)-4-하이드록시사이클로헥실)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)-N-페닐싸이아졸-5-카복스아미드의 합성Example 6: 2-((6-(((1R,4R)-4-hydroxycyclohexyl)amino)-4-(morpholinomethyl)pyridin-2-yl)amino)-N-phenylthiazole- Synthesis of 5-carboxamide
단계 1) 에틸 2-((tert-부톡시카보닐)아미노)싸이아졸-5-카복실레이트의 합성Step 1) Synthesis of ethyl 2-((tert-butoxycarbonyl)amino)thiazole-5-carboxylate
에틸 2-아미노싸이아졸-5-카복실레이트(3.6 g, 20.93 mmol)와 디-tert-부틸 디카보네이트(13.7 g, 62.79 mmol)를 이소프로판올 용매와 혼합한 후 50 ℃에서 24 시간 교반하였다. 반응이 완결되면 용매를 감압농축하여 목적 화합물(5.3 g, 93 %)을 얻었다.Ethyl 2-aminothiazole-5-carboxylate (3.6 g, 20.93 mmol) and di-tert-butyl dicarbonate (13.7 g, 62.79 mmol) were mixed with an isopropanol solvent, followed by stirring at 50° C. for 24 hours. Upon completion of the reaction, the solvent was concentrated under reduced pressure to obtain the target compound (5.3 g, 93%).
단계 2) 2-((tert-부톡시카보닐)아미노)싸이아졸-5-카복실산의 합성Step 2) Synthesis of 2-((tert-butoxycarbonyl)amino)thiazole-5-carboxylic acid
단계 1)에서 얻은 에틸 2-((tert-부톡시카보닐)아미노)싸이아졸-5-카복실레이트(4.5 g, 16.52 mmol)와 수산화나트륨(62.78 ㎎, 62.78 mmol)을 THF와 물 혼합용매에서 혼합한 후 12시간 가열 환류하였다. 반응이 종료되면 1 N 염산용액을 가하여 결정화하고 생성된 결정을 여과하여 목적 화합물(2.9 g, 99 %)을 얻었다.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 %).
단계 3) tert-부틸(5-(페닐카바모일)싸이아졸-2-일)카바메이트의 합성Step 3) Synthesis of tert-butyl (5- (phenylcarbamoyl) thiazol-2-yl) carbamate
단계 2)에서 얻은 2-((tert-부톡시카보닐)아미노)싸이아졸-5-카복실산(234 ㎎, 1 mmol)을 용매 테트라히드로퓨란에 녹인 뒤 2 M의 옥살릴 클로리드 디클로로메탄 용액(1 ㎖, 2 mmol)을 천천히 첨가하였다. 이 용액에 N,N-디메틸포름아미드 3 방울을 첨가하고 상온에서 4시간 교반하였다. 이 용액을 감압 증류하고 얻어진 잔사에 디클로로메탄을 넣은 후 온도를 0 ℃로 낮춘 후 아닐린(140 ㎎, 1.5 mmol)과 디이소프로필에틸아민(0.70 ㎖, 4 mmol)을 천천히 첨가한 후 온도를 상온으로 올려 24 시간 교반하였다. 반응이 종료되면 디클로로메탄을 이용하여 추출하고 2 N 염산 수용액과 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물(140 ㎎, 40 %)을 얻었다.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. This solution was distilled under reduced pressure, dichloromethane was added to the obtained residue, the temperature was lowered to 0 °C, aniline (140 mg, 1.5 mmol) and diisopropylethylamine (0.70 mL, 4 mmol) were slowly added, and the temperature was brought to room temperature. and stirred for 24 hours. When the reaction was completed, extraction was performed with dichloromethane, washed with 2 N aqueous hydrochloric acid solution and 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 (140 mg, 40%).
단계 4) 2-아미노-N-페닐싸이아졸-5-카복스아미드의 합성Step 4) Synthesis of 2-amino-N-phenylthiazole-5-carboxamide
단계 3)에서 얻어진 tert-부틸(5-(페닐카바모일)싸이아졸-2-일)카바메이트(61 ㎎, 0.19 mmol)와 디클로로메탄 용액을 0 ℃로 온도를 낮추고 트리플로로아세트산(1 ㎖, 2.47 mmol)을 첨가하였다. 이 용액을 2 시간 교반하고 용매를 감압증류하였다. 얻어진 잔사에 탄산수소나트륨 수용액을 이용하여 중화하고 디클로로메탄을 이용하여 추출하였다. 유기용매를 황산마그네슘을 이용하여 건조하고 감압여과하여 목적 화합물(25 ㎎, 60 %)을 얻었다.A solution of tert-butyl(5-(phenylcarbamoyl)thiazol-2-yl)carbamate (61 mg, 0.19 mmol) and dichloromethane obtained in step 3) was lowered to 0 ° C., and trifluoroacetic acid (1 mL) , 2.47 mmol) was added. The solution was stirred for 2 hours, and the solvent was distilled under reduced pressure. The obtained residue was neutralized with an aqueous sodium hydrogen carbonate solution and extracted using dichloromethane. The organic solvent was dried over magnesium sulfate and filtered under reduced pressure to obtain the target compound (25 mg, 60%).
단계 5) 2-브로모-N-페닐싸이아졸-5-카복스아미드의 합성Step 5) Synthesis of 2-bromo-N-phenylthiazole-5-carboxamide
질소하에서 브롬화제이구리(134 ㎎, 0.6 mmol)를 아세토니트릴 용매에 넣고 온도를 0 ℃로 낮추었다. 이 용액에 tert-부틸 나이트리트(89 ㎕, 0.75 mmol)와 아세토니트릴에 녹인 단계 4)에서 얻어진 2-아미노-N-페닐싸이아졸-5-카복스아미드(109 ㎎, 0.5 mmol)를 넣고 상온으로 온도를 올린 후 4시간 교반하였다. 반응이 완료되면 용매를 감압증류하고 에틸아세테이트로 추출하고 포화 탄산수소나트륨 수용액으로 씻어주었다. 유기층을 황산나트륨으로 건조하고 여과한 뒤 용매를 감압증류하고 잔사를 컬럼크로마토그래피로 정제하여 목적 화합물(89 ㎎, 63%)을 얻었다.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 μl, 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. Upon completion of the reaction, 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%).
단계 6) 2-((6-(((1R,4R)-4-하이드록시사이클로헥실)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)-N-페닐싸이아졸-5-카복스아미드의 합성Step 6) 2-((6-(((1R,4R)-4-hydroxycyclohexyl)amino)-4-(morpholinomethyl)pyridin-2-yl)amino)-N-phenylthiazole-5 -Synthesis of carboxamides
상기 단계 5)에서 얻은 2-브로모-N-페닐싸이아졸-5-카복스아미드(111 ㎎, 0.39 mmol)와 실시예 1의 단계 6)에서 얻은 (1R,4R)-4-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올(100 ㎎, 0.33 mmol)을 실시예 1의 단계 7)과 같은 방법으로 반응시켜 목적 화합물(88 ㎎, 53%)을 얻었다.2-bromo-N-phenylthiazole-5-carboxamide (111 mg, 0.39 mmol) obtained in step 5) and (1R,4R)-4-((6) obtained in step 6) of Example 1 -Amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol (100 mg, 0.33 mmol) was reacted in the same manner as in Example 1 step 7) to react the target compound (88 mg) , 53%) was obtained.
1H-NMR(400 MHz, DMSO-d6) δ: 11.16(s, 1H), 9.76(s, 1H), 8.2(s, 1H), 7.69(d, 2H, J= 1.6 Hz), 7.38-7.22(m, 3H), 6.44(d, 1H, J= 4.0 Hz), 6.13(s, 1H), 6.03(s, 1H), 4.46(d, 1H, J= 3.6 Hz), 3.87-3.85(m, 1H), 3.58(t, 5H, J= 4.4 Hz), 3.42-3.33(m, 1H), 3.25(s, 2H), 2.35(s, 4H), 2.01(d, 2H, J= 14.4 Hz), 1.77(d, 2H, J= 10 Hz), 1.42-1.34(m, 2H), 1.24-1.17(m, 2H) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.16 (s, 1H), 9.76 (s, 1H), 8.2 (s, 1H), 7.69 (d, 2H, J=1.6 Hz), 7.38- 7.22 (m, 3H), 6.44 (d, 1H, J = 4.0 Hz), 6.13 (s, 1H), 6.03 (s, 1H), 4.46 (d, 1H, J = 3.6 Hz), 3.87-3.85 (m) , 1H), 3.58 (t, 5H, J = 4.4 Hz), 3.42-3.33 (m, 1H), 3.25 (s, 2H), 2.35 (s, 4H), 2.01 (d, 2H, J = 14.4 Hz) , 1.77 (d, 2H, J = 10 Hz), 1.42-1.34 (m, 2H), 1.24-1.17 (m, 2H)
실시예 7: (1R,4R)-4-((4-(몰포리노메틸)-6-((5-(3-페닐-1,2,4-옥사디아졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Example 7: (1R,4R)-4-((4-(morpholinomethyl)-6-((5-(3-phenyl-1,2,4-oxadiazol-5-yl)thiazole- Synthesis of 2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol
단계 1) 5-(2-브로모싸이아졸-5-일)-3-페닐-1,2,4-옥사디아졸의 합성Step 1) Synthesis of 5-(2-bromothiazol-5-yl)-3-phenyl-1,2,4-oxadiazole
벤즈아미독심(79 ㎎, 0.58 mmol), 2-브로모싸이아졸-5-카르복실산(100 ㎎, 0.48 mmol), EDCI(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide)(138 ㎎, 0.72 mmol)과 HOBt(Hydroxybenzotriazole)(98 ㎎, 0.72 mmol)를 마이크로파 바이알에 첨가한 후 디메틸포름아미드 2.5 ㎖와 혼합하였다. 혼합한 용액을 마이크로파로 80 ℃에서 30 분 교반하였다. 반응이 완결되면 상온으로 냉각시킨 뒤 에틸아세테이트를 이용하여 추출하고, 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물(100 ㎎, 67%)을 얻었다.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. Upon completion of the reaction, 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%).
단계 2) (1R,4R)-4-((4-(몰포리노메틸)-6-((5-(3-페닐-1,2,4-옥사디아졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Step 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
상기 단계 1)에서 얻은 5-(2-브로모싸이아졸-5-일)-3-페닐-1,2,4-옥사디아졸(120 ㎎, 0.39 mmol)과 실시예 1의 단계 6)에서 얻은 (1R,4R)-4-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올(100 ㎎, 0.33 mmol)을 실시예 1의 단계 7)과 같은 방법으로 반응시켜 목적 화합물(75 ㎎, 43%)을 얻었다.5-(2-bromothiazol-5-yl)-3-phenyl-1,2,4-oxadiazole (120 mg, 0.39 mmol) obtained in step 1) above and in step 6) of Example 1 The obtained (1R,4R)-4-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol (100 mg, 0.33 mmol) was prepared in step 7 of Example 1 ) was reacted in the same way to obtain the target compound (75 mg, 43%).
1H-NMR(400 MHz, DMSO-d6) δ: 11.65(s, 1H), 8.32(s, 1H), 8.19(d, 2H, J= 6.4 Hz), 7.60-7.51(m, 3H), 6.67(d, 1H, J= 7.6 Hz), 6.20(s, 1H), 6.10(s, 1H), 4.75(d, 1H, J= 3.2 Hz), 4.06-4.00(m, 1H), 3.59(t, 5H, J= 4.4 Hz), 3.53-3.51(m, 1H), 3.28(s, 2H), 2.36(s, 4H), 2.10(d, 2H, J= 12.4 Hz), 1.94(d, 2H, J= 9.6 Hz), 1.68-1.60(m, 2H), 1.32-1.23(m, 2H) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.65 (s, 1H), 8.32 (s, 1H), 8.19 (d, 2H, J=6.4 Hz), 7.60-7.51 (m, 3H), 6.67 (d, 1H, J = 7.6 Hz), 6.20 (s, 1H), 6.10 (s, 1H), 4.75 (d, 1H, J = 3.2 Hz), 4.06-4.00 (m, 1H), 3.59 (t) , 5H, J = 4.4 Hz), 3.53-3.51 (m, 1H), 3.28 (s, 2H), 2.36 (s, 4H), 2.10 (d, 2H, J = 12.4 Hz), 1.94 (d, 2H, J = 9.6 Hz), 1.68-1.60 (m, 2H), 1.32-1.23 (m, 2H)
실시예 8: (1R,3R)-3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로부탄-1-올의 합성Example 8: (1R,3R)-3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino Synthesis of )pyridin-2-yl)amino)cyclobutan-1-ol
단계 1) (1R,3R)-3-((6-브로모-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로부탄-1-올의 합성Step 1) Synthesis of (1R,3R)-3-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)amino)cyclobutan-1-ol
4-((2,6-디브로모피리딘-4-일)메틸)몰포린(200 ㎎. 0.59 mmol), 트랜스-4-아미노사이클로부탄올(61 ㎎, 0.71 mmol), 트리스(디벤질리덴아세톤)디팔라듐(27 ㎎, 10 mol%), 잔트포스(17 ㎎, 10 mol%), 나트륨-터트-부톡사이드(85 ㎎, 0.89 mmol)를 무수 1,4-디옥세인 1.5 ㎖에 녹인 후, 상온에서 4시간 교반하였다. 반응이 완료되면 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적 화합물(99 ㎎, 49%)을 얻었다.4-((2,6-dibromopyridin-4-yl)methyl)morpholine (200 mg. 0.59 mmol), trans-4-aminocyclobutanol (61 mg, 0.71 mmol), tris(dibenzylideneacetone) ) Dipalladium (27 mg, 10 mol%), xantphos (17 mg, 10 mol%), sodium-tert-butoxide (85 mg, 0.89 mmol) was dissolved in 1.5 ml of anhydrous 1,4-dioxane, The mixture was stirred at room temperature for 4 hours. Upon completion of the reaction, extraction was performed with ethyl acetate, 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 by column chromatography to obtain the target compound (99 mg, 49%).
단계 2) (1R,3R)-3-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로부탄-1-올의 합성Step 2) Synthesis of (1R,3R)-3-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclobutan-1-ol
(1R,3R)-3-((6-브로모-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로부탄-1-올(287 ㎎, 0.84 mmol), 쿠프릭 아세틸아세톤(10 mol%), 세슘 카보네이트(551 ㎎, 1.69 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성하였다. 이 후 아세틸아세톤(40 mol%), 암모니아 수용액(0.65 ㎖, 16.91 mmol), 무수 디메틸포름아마이드(4㎖)를 차례로 넣고, 90 ℃에서 밤샘 교반하였다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적 화합물(53 ㎎, 23%)을 얻었다.(1R,3R)-3-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)amino)cyclobutan-1-ol (287 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. After that, acetylacetone (40 mol%), aqueous ammonia solution (0.65 mL, 16.91 mmol), and anhydrous dimethylformamide (4 mL) were sequentially added, and the mixture was stirred at 90° C. overnight. When the reaction was completed, 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%).
단계 3) (1R,3R)-3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로부탄-1-올의 합성Step 3) (1R,3R)-3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino) Synthesis of pyridin-2-yl)amino)cyclobutan-1-ol
상기 단계 2)에서 합성된 (1R,3R)-3-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로부탄-1-올(92 ㎎, 0.33 mmol)과 실시예 1의 단계 2)에서 합성된 2-브로모-5-(2-페닐-2H-테트라졸-5-일)싸이아졸(123 ㎎, 0.39 mmol)을 실시예 1의 단계 7)과 같은 방법으로 반응시켜 목적 화합물(30 ㎎, 18%)을 얻었다.(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%).
1H-NMR(400 MHz, DMSO-d6) δ: 11.28(s, 1H), 8.18-8.16(m, 2H), 8.11(s, 1H), 7.70-7.59(m, 3H), 6.95(d, 1H, J=6 MHz), 6.19(s, 1H), 6.05(s, 1H), 5.08(d, 1H, J=5.2 MHz), 4.45-4.42(m, 1H), 4.40-4.37(m, 1H), 3.60-3.59(m, 4H), 3.29(s, 2H), 2.38-2.36(m, 6H), 2.29-2.23(m, 2H) 1 H-NMR (400 MHz, DMSO-d6) δ: 11.28 (s, 1H), 8.18-8.16 (m, 2H), 8.11 (s, 1H), 7.70-7.59 (m, 3H), 6.95 (d, 1H, J=6 MHz), 6.19(s, 1H), 6.05(s, 1H), 5.08(d, 1H, J=5.2 MHz), 4.45-4.42(m, 1H), 4.40-4.37(m, 1H) ), 3.60-3.59(m, 4H), 3.29(s, 2H), 2.38-2.36(m, 6H), 2.29-2.23(m, 2H)
실시예 9: 6-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)스피로[3.3]헵탄-2-올의 합성Example 9: 6-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin-2-yl ) Synthesis of amino) spiro [3.3] heptan-2-ol
단계 1) 6-((6-브로모-4-(몰포리노메틸)피리딘-2-일)아미노)스피로[3.3]헵탄-2-올의 합성Step 1) Synthesis of 6-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)amino)spiro[3.3]heptan-2-ol
4-((2,6-디브로모피리딘-4-일)메틸)몰포린(1 g, 2.97 mmol), 6-아미노스피로[3,3]헵탄-2-올 하이드로클로라이드(584 ㎎, 3.57 mmol), 트리스(디벤질리덴아세톤)디팔라듐(136 ㎎, 10 mol%), 잔트포스(172 ㎎, 10 mol%), 나트륨-터트-부톡사이드(712 ㎎, 7.41 mmol)를 무수 1,4-디옥세인 15 ㎖에 녹인 후, 상온에서 4 시간 교반하였다. 반응이 완료되면 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적 화합물(400 ㎎, 35%)을 얻었다.4-((2,6-dibromopyridin-4-yl)methyl)morpholine (1 g, 2.97 mmol), 6-aminospiro[3,3]heptan-2-ol hydrochloride (584 mg, 3.57) mmol), tris(dibenzylideneacetone)dipalladium (136 mg, 10 mol%), xantphos (172 mg, 10 mol%), sodium-tert-butoxide (712 mg, 7.41 mmol) anhydrous 1,4 After dissolving in 15 ml of dioxane, the mixture was stirred at room temperature for 4 hours. Upon completion of the reaction, extraction was performed with ethyl acetate, 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 by column chromatography to obtain the target compound (400 mg, 35%).
단계 2) 6-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)스피로[3.3]헵탄-2-올의 합성Step 2) Synthesis of 6-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)spiro[3.3]heptan-2-ol
6-((6-브로모-4-(몰포리노메틸)피리딘-2-일)아미노)스피로[3.3]헵탄-2-올(400 ㎎, 1.04 mmol), 쿠프릭 아세틸아세톤(10 mol%), 세슘 카보네이트(681 ㎎, 2.09 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성하였다. 이 후 아세틸아세톤(40 mol%), 암모니아 수용액(0.81 ㎖, 20.92 mmol), 무수 디메틸포름아마이드(5㎖)를 차례로 넣고, 90 ℃에서 밤샘 교반하였다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적 화합물(136㎎, 41%)을 얻었다.6-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)amino)spiro[3.3]heptan-2-ol (400 mg, 1.04 mmol), cupric acetylacetone (10 mol%) , cesium carbonate (681 mg, 2.09 mmol) was placed in a shrink tube, and a nitrogen environment was created. After that, acetylacetone (40 mol%), aqueous ammonia solution (0.81 mL, 20.92 mmol), and anhydrous dimethylformamide (5 mL) were sequentially added, followed by stirring at 90° C. overnight. When the reaction was completed, 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%).
단계 3) 6-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)스피로[3.3]헵탄-2-올의 합성Step 3) 6-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin-2-yl) Synthesis of amino) spiro [3.3] heptan-2-ol
상기 단계 2)에서 합성된 6-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)스피로[3.3]헵탄-2-올(80 ㎎, 0.25 mmol)과 실시예 1의 단계 2)에서 합성된 2-브로모-5-(2-페닐-2H-테트라졸-5-일)싸이아졸(92 ㎎, 0.30 mmol)을 실시예 1의 단계 7)과 같은 방법으로 반응시켜 목적 화합물(30 ㎎, 22%)을 얻었다.6-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)spiro[3.3]heptan-2-ol (80 mg, 0.25 mmol) synthesized in step 2) and Example 1 2-bromo-5-(2-phenyl-2H-tetrazol-5-yl)thiazole (92 mg, 0.30 mmol) synthesized in step 2) of step 2) was reacted in the same manner as in step 7) of Example 1. to obtain the target compound (30 mg, 22%).
1H-NMR(400 MHz, DMSO-d6) δ: 11.31(s, 1H), 8.15(s, 1H), 8.13-8.11(m, 2H), 7.70-7.67(m, 2H), 7.62-7.58(m, 1H), 6.91(d, 1H, J=7.6 MHz), 6.18(s, 1H), 6.02(s, 1H), 4.93(d, 1H, J=7.2 MHz), 4.61-4.55(m, 1H), 4.05-4.00(m, 1H), 3.59-3.57(m, 4H), 3.27(s, 2H), 2.72-2.66(m, 1H), 2.35-2.32(m, 5H), 2.22-2.16(m, 1H), 2.05-1.93(m, 5H) 1 H-NMR (400 MHz, DMSO-d6) δ: 11.31 (s, 1H), 8.15 (s, 1H), 8.13-8.11 (m, 2H), 7.70-7.67 (m, 2H), 7.62-7.58 ( m, 1H), 6.91 (d, 1H, J=7.6 MHz), 6.18 (s, 1H), 6.02 (s, 1H), 4.93 (d, 1H, J=7.2 MHz), 4.61-4.55 (m, 1H) ), 4.05-4.00 (m, 1H), 3.59-3.57 (m, 4H), 3.27 (s, 2H), 2.72-2.66 (m, 1H), 2.35-2.32 (m, 5H), 2.22-2.16 (m) , 1H), 2.05-1.93 (m, 5H)
실시예 10: 6-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)스피로[3.3]헵탄-2-올의 합성Example 10: 6-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) Synthesis of pyridin-2-yl)amino)spiro[3.3]heptan-2-ol
단계 1) 6-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)스피로[3.3]헵탄-2-올의 합성Step 1) 6-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine Synthesis of -2-yl)amino)spiro[3.3]heptan-2-ol
실시예 9의 단계 2)에서 합성된 6-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)스피로[3.3]헵탄-2-올(136 ㎎, 0.42 mmol)과 실시예 2의 단계 1)에서 합성된 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸(157 ㎎, 0.51 mmol)을 실시예 2의 단계 2)와 같은 방법으로 반응시켜 목적 화합물(70 ㎎, 30%)을 얻었다.6-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)spiro[3.3]heptan-2-ol (136 mg, 0.42 mmol) synthesized in step 2) of Example 9 and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (157 mg, 0.51 mmol) synthesized in step 1) of Example 2 was mixed with the The reaction was carried out in the same manner as in step 2) to obtain the target compound (70 mg, 30%).
1H-NMR(400 MHz, DMSO-d6) δ: 11.50(s, 1H), 8.20(s, 1H), 8.10-8.07(m, 2H), 7.64-7.61(m, 3H), 6.95(d, 1H, J=7.6 MHz), 6.20(s, 1H), 6.05(s, 1H), 4.94(d, 1H, J=6.8 MHz), 4.55-4.48(m, 1H), 4.03-3.95(m, 1H), 3.59-3.57(m, 4H), 3.28(s, 2H), 2.63-2.57(m, 1H), 2.50-2.49(m, 1H), 2.40-2.35(m, 5H), 2.21-2.15(m, 1H), 1.98-1.89(m, 4H) 1 H-NMR (400 MHz, DMSO-d6) δ: 11.50 (s, 1H), 8.20 (s, 1H), 8.10-8.07 (m, 2H), 7.64-7.61 (m, 3H), 6.95 (d, 1H, J=7.6 MHz), 6.20(s, 1H), 6.05(s, 1H), 4.94(d, 1H, J=6.8 MHz), 4.55-4.48(m, 1H), 4.03-3.95(m, 1H) ), 3.59-3.57(m, 4H), 3.28(s, 2H), 2.63-2.57(m, 1H), 2.50-2.49(m, 1H), 2.40-2.35(m, 5H), 2.21-2.15(m) , 1H), 1.98-1.89 (m, 4H)
실시예 11: 2-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)에탄-1-설폰아미드의 합성Example 11: 2-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) Synthesis of pyridin-2-yl)amino)ethane-1-sulfonamide
단계 1) 2-((6-브로모-4-(몰포리노메틸)피리딘-2-일)아미노)에탄-1-설폰아미드의 합성Step 1) Synthesis of 2-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)amino)ethane-1-sulfonamide
4-((2,6-디브로모피리딘-4-일)메틸)몰포린(780 ㎎. 2.32 mmol), 2-아미노에틸메틸설폰 하이드로클로라이드(444 ㎎, 2.78 mmol), 트리스(디벤질리덴아세톤)디팔라듐(106 ㎎, 10 mol%), 잔트포스(134 ㎎, 10 mol%), 나트륨-터트-부톡사이드(602 ㎎, 6.26 mmol)를 무수 1,4-디옥세인 11 ㎖에 녹인 후, 상온에서 4 시간 교반하였다. 반응이 완료되면 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적 화합물(250 ㎎, 28%)을 얻었다.4-((2,6-dibromopyridin-4-yl)methyl)morpholine (780 mg. 2.32 mmol), 2-aminoethylmethylsulfone hydrochloride (444 mg, 2.78 mmol), tris(dibenzylidene) Acetone) dipalladium (106 mg, 10 mol%), xantphos (134 mg, 10 mol%), sodium-tert-butoxide (602 mg, 6.26 mmol) was dissolved in 11 ml of anhydrous 1,4-dioxane , and stirred at room temperature for 4 hours. Upon completion of the reaction, extraction was performed with ethyl acetate, 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 by column chromatography to obtain the target compound (250 mg, 28%).
단계 2) 2-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)에탄-1-설폰아미드의 합성Step 2) Synthesis of 2-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)ethane-1-sulfonamide
2-((6-브로모-4-(몰포리노메틸)피리딘-2-일)아미노)에탄-1-설폰아미드(398 ㎎, 1.05 mmol), 쿠프릭 아세틸아세톤(10 mol%), 세슘 카보네이트(685 ㎎, 2.10 mmol)를 슈링크튜브에 넣고, 질소 환경을 조성하였다. 이후 아세틸아세톤(40 mol%), 암모니아 수용액(0.81 ㎖, 21.041 mmol), 무수 디메틸포름아마이드(5 ㎖)를 차례로 넣고, 90 ℃에서 밤샘 교반하였다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적 화합물(127 ㎎, 38%)을 얻었다.2-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)amino)ethane-1-sulfonamide (398 mg, 1.05 mmol), cupric acetylacetone (10 mol%), cesium carbonate (685 mg, 2.10 mmol) was placed in a shrink tube, and a nitrogen environment was created. Then, acetylacetone (40 mol%), aqueous ammonia solution (0.81 mL, 21.041 mmol), and anhydrous dimethylformamide (5 mL) were sequentially added, followed by stirring at 90° C. overnight. When the reaction was completed, 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%).
단계 3) 2-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)에탄-1-설폰아미드의 합성Step 3) 2-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine Synthesis of -2-yl)amino)ethane-1-sulfonamide
상기 단계 2)에서 합성된 2-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)에탄-1-설폰아미드(127 ㎎, 0.40 mmol)와 실시예 2의 단계 1)에서 합성된 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸(149 ㎎, 0.48 mmol)을 실시예 2의 단계 2)와 같은 방법으로 반응시켜 목적 화합물(34 ㎎, 15%)을 얻었다.2-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)ethane-1-sulfonamide (127 mg, 0.40 mmol) synthesized in step 2) above and step 1 of Example 2 ) of 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (149 mg, 0.48 mmol) synthesized in the same method as in Example 2 step 2). to give the target compound (34 mg, 15%).
1H-NMR(400 MHz, DMSO-d6) δ: 11.60(s, 1H), 8.22(s, 1H), 8.11-8.08(m, 2H), 7.66-7.59(m, 3H), 7.01-6.99(m, 1H), 6.31(s, 1H), 6.16(s, 1H), 3.93-3.90(m, 2H), 3.60-3.58(m, 4H), 3.46-3.43(m, 2H), 3.33-3.32 (m, 4H), 3.07 (s, 3H) 1 H-NMR (400 MHz, DMSO-d6) δ: 11.60 (s, 1H), 8.22 (s, 1H), 8.11-8.08 (m, 2H), 7.66-7.59 (m, 3H), 7.01-6.99 ( m, 1H), 6.31(s, 1H), 6.16(s, 1H), 3.93-3.90(m, 2H), 3.60-3.58(m, 4H), 3.46-3.43(m, 2H), 3.33-3.32 ( m, 4H), 3.07 (s, 3H)
실시예 12: 3-(4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)페놀의 합성Example 12: 3-(4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine Synthesis of -2-yl)phenol
단계 1) 6-브로모-4-(몰포리노메틸)피리딘-2-아민의 합성Step 1) Synthesis of 6-bromo-4-(morpholinomethyl)pyridin-2-amine
마이크로파 바이알에 4-((2,6-디브로모피리딘-4-일)메틸)몰포린(2.27 g, 6.76 mmol)을 아이소프로필알코올(1.3 ㎖)에 녹인 후 암모니아 수용액(2 ㎖)을 적가하였다. 반응 용액을 마이크로파로 160 ℃에서 15 시간 교반하였다. 반응이 완결되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적 화합물(1.1g, 90%)을 얻었다.In a microwave vial, 4-((2,6-dibromopyridin-4-yl)methyl)morpholine (2.27 g, 6.76 mmol) was dissolved in isopropyl alcohol (1.3 mL), and then aqueous ammonia (2 mL) was added dropwise. did The reaction solution was stirred in a microwave at 160° C. for 15 hours. Upon completion of the reaction, 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 (1.1 g, 90%).
단계 2) 3-(6-아미노-4-(몰포리노메틸)피리딘-2-일)페놀의 합성Step 2) Synthesis of 3-(6-amino-4-(morpholinomethyl)pyridin-2-yl)phenol
마이크로파 바이알에 상기 단계 1)에서 합성된 6-브로모-4-(몰포리노메틸)피리딘-2-아민(50 ㎎, 0.18 mmol)과 3-하이드록시페닐보로닉 애시드(28 ㎎, 0.20 mmol), 탄산나트륨(39 ㎎, 0.36 mmol), [1,1'-비스(디페닐포스피노)페로센]디클로로팔라듐(Ⅱ) 디클로로메탄 착물(30 ㎎, 0.036 mmol)을 1,4-디옥세인:물(1:1 용액, 2㎖)에 녹여준 후 반응 용액을 마이크로파로 120 ℃에서 1시간 교반하였다. 반응이 완결되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적 화합물(51 ㎎, 98%)을 얻었다.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. Upon completion of the reaction, 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%).
단계 3) 3-(4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)페놀의 합성Step 3) 3-(4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin- 2-yl) phenol synthesis
상기 단계 2)에서 합성된 3-(6-아미노-4-(몰포리노메틸)피리딘-2-일)페놀 (50 ㎎, 0.17 mmol)과 실시예 2의 단계 1)에서 합성된 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸(65 ㎎, 0.21 mmol)을 실시예 2의 단계 2)와 같은 방법으로 반응시켜 목적 화합물(60 ㎎, 67%)을 얻었다.3-(6-amino-4-(morpholinomethyl)pyridin-2-yl)phenol (50 mg, 0.17 mmol) synthesized in step 2) and 2-(2) synthesized in step 1) of Example 2 -Bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (65 mg, 0.21 mmol) was reacted in the same manner as in step 2) of Example 2) to react the target compound (60 mg) , 67%) was obtained.
1H-NMR(400 MHz, DMSO-d6) δ: 12.02(s, 1H), 9.66(s, 1H), 8.30(s, 1H), 8.16-8.09(m, 2H), 7.66-7.59(m, 5H), 7.44(s, 1H), 7.36(t, 1H, J= 7.68 MHz), 7.12(s, 1H), 6.93-6.91(m, 1H), 3.64-3.61(m, 4H), 3.57(s, 2H), 2.45-2.44(m, 4H) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.02(s, 1H), 9.66(s, 1H), 8.30(s, 1H), 8.16-8.09(m, 2H), 7.66-7.59(m) , 5H), 7.44 (s, 1H), 7.36 (t, 1H, J = 7.68 MHz), 7.12 (s, 1H), 6.93-6.91 (m, 1H), 3.64-3.61 (m, 4H), 3.57 ( s, 2H), 2.45-2.44 (m, 4H)
실시예 13. (1R,4R)-4-((4-(모르폴리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)티아졸-2-일)아미노)피리미딘-2-일)아미노 )시클로헥산-1-올의 합성Example 13. (1R,4R)-4-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl) Synthesis of amino) pyrimidin-2-yl) amino) cyclohexan-1-ol
단계 1) 메틸 2-클로로-6-((2,4,4-트리메틸펜탄-2-일)아미노)피리미딘-4-카르보실레이트의 합성Step 1) Synthesis of methyl 2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carbohydrate
상온에서 메틸 2,6-디클로로피리미딘-4-카르복실레이트 (1.4 g, 10.14 mmol), tert-옥틸아민 (1.31 g, 1.5 eq.) 과 DIPEA (1.77 mL, 1.5 eq.)를 테트리히드로퓨란 (2 mL) 용매하에 68시간 교반한 뒤 용매를 감압 제거하고 디클로로메탄으로 추출하고 탄산수소나트륨 수용액으로 씻어준뒤 감압증류 하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물 (1.44 g, 71%)을 얻었다.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%).
단계 2) (2-클로로-6-((2,4,4-트리메틸펜탄-2-일)아미노)피리미딘-4-일)(몰포리노)메탄온의 합성Step 2) Synthesis of (2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(morpholino)methanone
상기 단계 1에서 얻은 메틸 2-클로로-6-((2,4,4-트리메틸펜탄-2-일)아미노)피리미딘-4-카르보실레이트 (1.2 g, 4 mmol), 1,5,7-트리아자비사이클로[4.4.0]데크-5-엔 (167 mg, 0.3 eq.) 과 몰포린 (0.35 mL, 1 eq.) 을 테트라히드로퓨란 (6 mL)용매에서 3시간 상온에서 교반하였다. 반응용액을 디클로로메탄으로 추출하고 탄산나트륨 수용액으로 씻어준 뒤 감압증류 하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물 (1.16 g, 82%)을 얻었다.Methyl 2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carbohydrate (1.2 g, 4 mmol) obtained in step 1 above, 1,5,7 -Triazabicyclo[4.4.0]dec-5-ene (167 mg, 0.3 eq.) and morpholine (0.35 mL, 1 eq.) were stirred in a tetrahydrofuran (6 mL) solvent at room temperature for 3 hours. The reaction solution was extracted with dichloromethane, washed with aqueous sodium carbonate solution, and distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (1.16 g, 82%).
단계 3) 2-클로로-6-(몰포리노메틸)-N-(2,4,4-트리메틸펜탄-2-일)피리미틴-4-아민의 합성Step 3) Synthesis of 2-chloro-6-(morpholinomethyl)-N-(2,4,4-trimethylpentan-2-yl)pyrimitin-4-amine
상기 단계 2)에서 얻은 (2-클로로-6-((2,4,4-트리메틸펜탄-2-일)아미노)피리미딘-4-일)(몰포리노)메탄온 (200 mg, 0.56 mmol)를 실시예 1의 단계 4)와 같은 방법으로 목적 화합물(70 mg, 36%)을 얻었다.(2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(morpholino)methanone (200 mg, 0.56 mmol) obtained in step 2) above to obtain the target compound (70 mg, 36%) in the same manner as in step 4) of Example 1.
단계 4) 2-클로로-6-(몰포리노메틸)피리미딘-4-아민의 합성Step 4) Synthesis of 2-chloro-6-(morpholinomethyl)pyrimidin-4-amine
상기 단계 3)에서 얻은 2-클로로-6-(몰포리노메틸)-N-(2,4,4-트리메틸펜탄-2-일)피리미틴-4-아민 (120 mg, 0.35 mmol)을 디클로로메탄 용매에 녹이 후 이 용액에 트리플로로아세트산 (1.08 mL, 40 eq.)을 첨가하고 50 °C에서 16시간 교반 후 온도를 상온으로 낮춘 후 밤새 교반하였다. 반응이 완료되면 감압증류하고 디클로로메탄으로 추출하고 탄산나트륨 수용액으로 씻어준 후 용액을 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물 (52.4 mg, 65%)을 얻었다.2-chloro-6-(morpholinomethyl)-N-(2,4,4-trimethylpentan-2-yl)pyrimitin-4-amine (120 mg, 0.35 mmol) obtained in step 3) above was dissolved in dichloromethane After dissolving in a solvent, trifluoroacetic acid (1.08 mL, 40 eq.) was added to this solution, and after stirring at 50 °C for 16 hours, the temperature was lowered to room temperature, followed by stirring overnight. Upon completion of the reaction, the mixture was distilled under reduced pressure, extracted with dichloromethane, washed with an aqueous sodium carbonate solution, and the solution was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (52.4 mg, 65%).
단계 5) N-(2-클로로-6-(몰포리노메틸)피리미딘-4-일)-5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-아민의 합성Step 5) Synthesis of N-(2-chloro-6-(morpholinomethyl)pyrimidin-4-yl)-5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-amine
질소환경하에서 상기 단계 4)에서 얻어진 2-클로로-6-(몰포리노메틸)피리미딘-4-아민 (465 mg, 2.03 mmol)과 실시예 1을 단계 2에서 얻어진 2-브로모-5-(2-페닐-2H-테트라졸-5-일)싸이아졸 (689 mg ,1.1 eq.)을 N,N-디메틸포름아미드 용매에 녹인 후 온도를 0 °C로 내리고 수소화나트륨 (60% w/w in mineral oil, 163 mg , 2 eq.)을 5분간 천천히 첨가한 뒤 1시간 교반하고 상온에서 1시간 더 교반하였다. 반응용액에 탄산나트륨 수용액을 첨가하여 pH9로 맞추고 이 용액을 디클로로메탄으로 추출한 뒤 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물 (500 mg, 54%)을 얻었다.In a nitrogen environment, 2-chloro-6-(morpholinomethyl)pyrimidin-4-amine (465 mg, 2.03 mmol) obtained in step 4) and Example 1 were prepared by preparing 2-bromo-5-( After dissolving 2-phenyl-2H-tetrazol-5-yl)thiazole (689 mg ,1.1 eq.) in N,N-dimethylformamide solvent, lower the temperature to 0 °C and sodium hydride (60% w/w in mineral oil, 163 mg , 2 eq.) was slowly added for 5 minutes, stirred for 1 hour, and stirred at room temperature for 1 hour more. An aqueous sodium carbonate solution was added to the reaction solution to adjust the pH to 9, and the solution was extracted with dichloromethane and distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (500 mg, 54%).
단계6) (1R,4R)-4-((4-(모르폴리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)티아졸-2-일)아미노)피리미딘-2-일)아미노 )시클로헥산-1-올의 합성Step 6) (1R,4R)-4-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino Synthesis of ) pyrimidin-2-yl) amino ) cyclohexan-1-ol
상기 단계5에서 얻어진 N-(2-클로로-6-(몰포리노메틸)피리미딘-4-일)-5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-아민과 (30 mg, 0.66 mmol) (1R,4R)-4-아미노시클로헥산1-올 (24 mg, 1.2 eq.)을 이소프로판올 (1 mL) 용매하에서 160 °C 마이크로웨티브에서 30분간 반응하였다. 반응용액을 감압증류 한 후 컬럼크로마토그래피를 이용하여 목적화합물 (9 mg, 25%)을 얻었다.N-(2-chloro-6-(morpholinomethyl)pyrimidin-4-yl)-5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-amine obtained in step 5 and (30 mg, 0.66 mmol) (1R,4R)-4-aminocyclohexan1-ol (24 mg, 1.2 eq.) was reacted in a solvent of isopropanol (1 mL) at 160 °C in a microwave for 30 minutes. After the reaction solution was distilled under reduced pressure, the target compound (9 mg, 25%) was obtained by column chromatography.
1H-NMR (400 MHz, DMSO-d6) δ: 11.72 (bs, 1H), 8.26-8.24 (m, 3H), 7.64-7.59 (m, 3H), 7.23-7.21 (m, 1H), 6.38 (s, 1H), 4.82 (s, 1H), 3.99-3.85 (m, 1H), 3.62-3.60 (m, 4H), 3.57-6.50 (m, 1H), 3.27 (s, 2H), 2.42-2.33 (m, 4H), 2.07-2.04 (m, 2H), 1.97-1.93 (m, 2H), 1.60-1.57 (m, 2H), 1.37-1.34 (m, 2H) 1 H-NMR (400 MHz, DMSO-d6) δ: 11.72 (bs, 1H), 8.26-8.24 (m, 3H), 7.64-7.59 (m, 3H), 7.23-7.21 (m, 1H), 6.38 ( s, 1H), 4.82 (s, 1H), 3.99-3.85 (m, 1H), 3.62-3.60 (m, 4H), 3.57-6.50 (m, 1H), 3.27 (s, 2H), 2.42-2.33 ( m, 4H), 2.07-2.04 (m, 2H), 1.97-1.93 (m, 2H), 1.60-1.57 (m, 2H), 1.37-1.34 (m, 2H)
실시예 14. 4-(4-(모르폴리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)페놀의 합성Example 14. 4-(4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) Synthesis of pyridin-2-yl)phenol
단계1) 4-(6-아미노-4-(모르폴리노메틸)피리딘-2-일)페놀의 합성Step 1) Synthesis of 4-(6-amino-4-(morpholinomethyl)pyridin-2-yl)phenol
마이크로파 바이알에 실시예 12의 단계 1에서 합성된 6-브로모-4-(몰포리노메틸)피리딘-2-아민 (100 mg, 0.36 mmol)과 4-하이드록시페닐보로닉 애시드 (56 mg, 0.40 mmol), 탄산나트륨 (80 mg, 0.73 mmol), [1,1’-비스(디페닐포스피노)페로센]다이클로로팔라듐(Ⅱ) 다이클로로메탄 착물 (60 mg, 0.073 mmol)을 1,4-디옥세인:물(1:1 용액, 4mL)에 녹여준 후 반응 용액을 마이크로파로 120℃에서 1시간 교반한다. 반응이 완결되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (97 mg, 93%)을 얻었다.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. When the reaction is complete, 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%).
단계2) 4-(4-(모르폴리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)페놀의 합성Step 2) 4-(4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine Synthesis of -2-yl)phenol
상기 단계 1)에서 합성된 4-(6-아미노-4-(모르폴리노메틸)피리딘-2-일)페놀 (50 mg, 0.17 mmol)과 실시예 2의 단계1에서 합성된 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (65 mg, 0.21 mmol)를 실시예 2의 단계 2와 같은 방법으로 반응하여 목적화합물 (45 mg, 50%)을 얻었다.4-(6-amino-4-(morpholinomethyl)pyridin-2-yl)phenol (50 mg, 0.17 mmol) synthesized in step 1) and 2-(2 synthesized in step 1 of Example 2) -Bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (65 mg, 0.21 mmol) was reacted in the same manner as in step 2 of Example 2 to react the target compound (45 mg, 50%) was obtained.
1H-NMR (400 MHz, DMSO-d6) δ: 11.97 (s, 1H), 9.87 (s, 1H), 8.29 (s, 1H), 8.10-8.08 (m, 3H), 8.06 (s, 1H), 7.66-7.41 (m, 3H), 7.41 (s, 1H), 7.04 (s, 1H), 6.94 (d, 2H, J=8MHz), 3.63-3.61 (m, 4H), 3.55 (s, 2H), 2.49-2.48 (m, 4H) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.97 (s, 1H), 9.87 (s, 1H), 8.29 (s, 1H), 8.10-8.08 (m, 3H), 8.06 (s, 1H) ), 7.66-7.41 (m, 3H), 7.41 (s, 1H), 7.04 (s, 1H), 6.94 (d, 2H, J=8 MHz), 3.63-3.61 (m, 4H), 3.55 (s, 2H) ), 2.49-2.48 (m, 4H)
실시예 15. (1R,4R)-4-((6-((5-(5-(4-플루오로페닐)-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)-4-(모르폴리노메틸)피리딘-2-일)아미노)시클로헥산-1-올 의 합성Example 15. (1R,4R)-4-((6-((5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thiazole-2- Synthesis of yl)amino)-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol
단계1) 4-플루오로벤조히드라지드의 합성Step 1) Synthesis of 4-fluorobenzohydrazide
메틸 4-플루오로벤조산나트륨 (0.5 g, 3.24 mmol)과 하이드라진 일수화물 (1.73 ml, 16.2 mmol)을 메탄올 6.5 ml에 용해한 뒤 70°에서 3시간 교반한다. 반응이 완결되면 상온으로 냉각시킨 뒤, 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적화합물 (0.5 g, 100%)을 얻었다.Sodium methyl 4-fluorobenzoate (0.5 g, 3.24 mmol) and hydrazine monohydrate (1.73 ml, 16.2 mmol) were dissolved in 6.5 ml of methanol and stirred at 70° for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and the obtained residue was purified using column chromatography to obtain the target compound (0.5 g, 100%).
단계2) 2-(2-브로모티아졸-5-일)-5-(4-플루오로페닐)-1,3,4-옥사디아졸의 합성Step 2) Synthesis of 2-(2-bromothiazol-5-yl)-5-(4-fluorophenyl)-1,3,4-oxadiazole
상기 단계1에서 얻어진 4-플루오로벤조히드라지드 (0.5 g, 3.24 mmol)을 실시예2의 단계1과 같은 방법으로 목적화합물 (0.32 g, 30%)을 얻었다.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.
단계3) (1R,4R)-4-((6-((5-(5-(4-플루오로페닐)-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)-4-(모르폴리노메틸 )피리딘-2-일)아미노)시클로헥산-1-올의 합성Step 3) (1R,4R)-4-((6-((5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl) Synthesis of )amino)-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol
상기 단계2에서 얻어진 2-(2-브로모티아졸-5-일)-5-(4-플루오로페닐)-1,3,4-옥사디아졸 (0.13 g, 0.40 mmol)과 실시예1의 단계6에서 얻어진 (1R,4R)-4-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올 (0.14 g, 0.33 mmol)을 실시예1의 단계7과 같은 방법으로 목적화합물 (0.02 g, 8%)을 얻었다.2-(2-bromothiazol-5-yl)-5-(4-fluorophenyl)-1,3,4-oxadiazole (0.13 g, 0.40 mmol) obtained in step 2 and the (1R,4R)-4-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol (0.14 g, 0.33 mmol) obtained in step 6 was prepared in Example 1 The target compound (0.02 g, 8%) was obtained in the same manner as in step 7.
1H-NMR (400 MHz, DMSO-d6) δ: 11.48 (s, 1H), 8.21 (s, 1H), 8.17-8.14 (m, 2H), 7.46 (t, 2H, J= 8.8 Hz), 6.59 (d, 1H, J= 8.0 Hz), 6.18 (s, 1H), 6.09 (s, 1H), 4.70 (d, 1H, J= 3.2 Hz), 4.02-3.92 (m, 1H), 3.59 (t, 4H, J= 4.4 Hz), 3.27 (s, 2H), 2.36 (s, 4H), 2.08 (d, 2H, J= 11.6 Hz), 1.92 (d, 2H, J= 7.2 Hz), 1.53-1.45 (m, 2H), 1.31-1.23 (m, 3H) 1 H-NMR (400 MHz, DMSO-d6) δ: 11.48 (s, 1H), 8.21 (s, 1H), 8.17-8.14 (m, 2H), 7.46 (t, 2H, J=8.8 Hz), 6.59 (d, 1H, J = 8.0 Hz), 6.18 (s, 1H), 6.09 (s, 1H), 4.70 (d, 1H, J= 3.2 Hz), 4.02-3.92 (m, 1H), 3.59 (t, 4H, J= 4.4 Hz), 3.27 (s, 2H), 2.36 (s, 4H), 2.08 (d, 2H, J= 11.6 Hz), 1.92 (d, 2H, J= 7.2 Hz), 1.53-1.45 ( m, 2H), 1.31-1.23 (m, 3H)
실시예 16. (1S,4S)-4-((4-(모르폴리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2 -일)아미노)사이클로헥산-1-올의 합성Example 16. (1S,4S)-4-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole Synthesis of -2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol
단계1) (1S,4S)-4-((6-브로모-4-(모르폴리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Step 1) Synthesis of (1S,4S)-4-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol
4-((2,6-디브로모피리딘-4-일)메틸)몰포린 (2 g, 5.95 mmol), 시스-4-아미노사이클로헥산올 하이드로클로라이드 (1.08 g, 7.14 mmol), 트리스(디벤질인덴아세톤)디팔라듐 (10 mol%), 잔트포스 (10 mol%) 나트륨-터트-부톡사이트 (1.43 g, 14.88 mmol)을 무수 1,4-디옥세인 (0.2M)에 녹인 후, 상온에서 4시간 교반한다. 반응이 완료되면 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (1 g, 45%)을 얻었다.4-((2,6-dibromopyridin-4-yl)methyl)morpholine (2 g, 5.95 mmol), cis-4-aminocyclohexanol hydrochloride (1.08 g, 7.14 mmol), tris(di Benzylindenacetone)dipalladium (10 mol%), xanthos (10 mol%) sodium-tert-butoxide (1.43 g, 14.88 mmol) was dissolved in anhydrous 1,4-dioxane (0.2M), and then at room temperature stirred for 4 hours. When the reaction is complete, extraction is performed 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 (1 g, 45%).
단계2) (1S,4S)-4-((6-아미노-4-(모르폴리노메틸)피리딘-2-일)아미노)시클로헥산-1-올의 합성Step 2) Synthesis of (1S,4S)-4-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol
(1S,4S)-4-((6-브로모-4-(모르폴리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올 (764 mg, 2.06 mmol), 쿠프릭 아세틸아세톤 (10 mol%), 세슘 카보네이트 (551 mg, 1.69 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성한다, 이후 아세틸아세톤 (40 mol%), 암모니아 수용액 (4.82 mL, 41.31 mmol), 무수 다이메틸포름아마이드 (0.2M)를 차례로 넣고, 90 ℃에서 밤샘교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (417 mg, 66%)을 얻었다.(1S,4S)-4-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol (764 mg, 2.06 mmol), cupric acetylacetone ( 10 mol%), cesium carbonate (551 mg, 1.69 mmol) is placed in a shrink tube, and a nitrogen environment is created, then acetylacetone (40 mol%), ammonia aqueous solution (4.82 mL, 41.31 mmol), anhydrous dimethylform Add amide (0.2M) one after another, and stir overnight at 90°C. When the reaction is complete, 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%).
단계3) (1S,4S)-4-((4-(모르폴리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2 -일)아미노)사이클로헥산-1-올의 합성Step 3) (1S,4S)-4-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole- Synthesis of 2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol
상기 단계2에서 합성된 (1S,4S)-4-((6-아미노-4-(모르폴리노메틸)피리딘-2-일)아미노)시클로헥산-1-올 (150 mg, 0.48 mmol)과 실시예 2의 단계1에서 합성된 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (181 mg, 0.58 mmol)를 실시예 2의 단계 2과 같은 방법으로 반응하여 목적화합물 (10 mg, 4%)을 얻었다.(1S,4S)-4-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol (150 mg, 0.48 mmol) synthesized in step 2 above and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (181 mg, 0.58 mmol) synthesized in step 1 of Example 2 was prepared in the step of Example 2 The reaction was carried out in the same manner as in 2 to obtain the target compound (10 mg, 4%).
1H-NMR (400 MHz, DMSO-d6) δ11.47 (s, 1H), 8.19 (s, 1H), 8.06-8.03 (m, 2H),　7.65-7.60 (m, 3H), 6.68 (d, 1H, J=8MHz), 6.17　(s, 1H), 6.12 (s, 1H),　4.38　(d, 1H, J=2.8MHz), 4.08-4.04 (m, 1H), 3.84-3.82 (m, 1H), 3.60-3.58 (m, 4H), 3.27 (s, 2H), 2.39-2.36 (m, 4H), 1.78-1.65 (m, 8H) 1 H-NMR (400 MHz, DMSO-d6) δ11.47 (s, 1H), 8.19 (s, 1H), 8.06-8.03 (m, 2H), 7.65-7.60 (m, 3H), 6.68 (d, 1H, J=8MHz), 6.17 (s, 1H), 6.12 (s, 1H), 4.38 (d, 1H, J=2.8MHz), 4.08-4.04 (m, 1H), 3.84-3.82 (m, 1H) , 3.60-3.58 (m, 4H), 3.27 (s, 2H), 2.39-2.36 (m, 4H), 1.78-1.65 (m, 8H)
실시예 17. 4-(모르폴리노메틸)-N2-(5-(2-페닐-2H-테트라졸-5-일)티아졸-2-일)-N6-((1R,4R)-4-(트리플루오로메틸)시클로헥실)피리딘-2 ,6-디아민의 합성Example 17. 4-(morpholinomethyl)-N2-(5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)-N6-((1R,4R)-4 Synthesis of -(trifluoromethyl)cyclohexyl)pyridine-2,6-diamine
단계1) 6-브로모-4-(모르폴리노메틸)-N-((1R,4R)-4-(트리플루오로메틸)시클로헥실)피리딘-2-아민의 합성Step 1) Synthesis of 6-bromo-4-(morpholinomethyl)-N-((1R,4R)-4-(trifluoromethyl)cyclohexyl)pyridin-2-amine
4-((2,6-디브로모피리딘-4-일)메틸)몰포린 (1.99 g, 5.92 mmol), 트랜스-4-(트리플루오로메틸)사이클로헥산아민 (0.9 g, 5.38 mmol), 트리스(디벤질인덴아세톤)디팔라듐 (10 mol%), 잔트포스 (10 mol%) 나트륨-터트-부톡사이트 (712 mg, 7.41 mmol)을 무수 1,4-디옥세인 (0.2M)에 녹인 후, 상온에서 4시간 교반한다. 반응이 완료되면 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (687 mg, 27%)을 얻었다.4-((2,6-dibromopyridin-4-yl)methyl)morpholine (1.99 g, 5.92 mmol), trans-4-(trifluoromethyl)cyclohexanamine (0.9 g, 5.38 mmol), Tris(dibenzylindenacetone)dipalladium (10 mol%), xantphos (10 mol%) sodium-tert-butoxide (712 mg, 7.41 mmol) was dissolved in anhydrous 1,4-dioxane (0.2M) Then, the mixture was stirred at room temperature for 4 hours. When the reaction is complete, extraction is performed 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 (687 mg, 27%).
단계2) 4-(모르폴리노메틸)-N2-((1R,4R)-4-(트리플루오로메틸)시클로헥실)피리딘-2,6-디아민의 합성Step 2) Synthesis of 4-(morpholinomethyl)-N2-((1R,4R)-4-(trifluoromethyl)cyclohexyl)pyridine-2,6-diamine
6-브로모-4-(모르폴리노메틸)-N-((1R,4R)-4-(트리플루오로메틸)시클로헥실)피리딘-2-아민 (687 mg, 1.62 mmol), 쿠프릭 아세틸아세톤 (10 mol%), 세슘 카보네이트 (1.06 mg, 3.25 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성한다, 이후 아세틸아세톤 (40 mol%), 암모니아 수용액 (3.8 mL, 32.53 mmol), 무수 다이메틸포름아마이드 (0.2M)를 차례로 넣고, 90 ℃에서 밤샘교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (333 mg, 57%)을 얻었다.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. When the reaction is complete, 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%).
단계3) 4-(모르폴리노메틸)-N2-(5-(2-페닐-2H-테트라졸-5-일)티아졸-2-일)-N6-((1R,4R)-4-(트리플루오로메틸)시클로헥실)피리딘-2 ,6-디아민 합성Step 3) 4-(morpholinomethyl)-N2-(5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)-N6-((1R,4R)-4- (trifluoromethyl)cyclohexyl)pyridine-2,6-diamine synthesis
상기 단계2에서 합성된 4-(모르폴리노메틸)-N2-((1R,4R)-4-(트리플루오로메틸)시클로헥실)피리딘-2,6-디아민 (150 mg, 0.40 mmol)과 실시예 1의 단계 2에서 합성된 2-브로모-5-(2-페닐-2H-테트라졸-5-일)사이아졸 (150 mg, 0.48 mmol)를 실시예 1의 단계 7과 같은 방법으로 반응하여 목적화합물 (144 mg, 60%)을 얻었다.4-(morpholinomethyl)-N2-((1R,4R)-4-(trifluoromethyl)cyclohexyl)pyridine-2,6-diamine (150 mg, 0.40 mmol) synthesized in step 2 and 2-bromo-5-(2-phenyl-2H-tetrazol-5-yl)cyazole (150 mg, 0.48 mmol) synthesized in Step 2 of Example 1 was prepared in the same manner as in Step 7 of Example 1. The reaction gave the target compound (144 mg, 60%).
1H-NMR (400 MHz, DMSO-d6) δ: 11.30 (s, 1H), 8.14 (s, 1H),　8.07-8.05 (m, 2H),　7.65-7.58 (m, 3H),　6.67 (d, 1H, J=7.2 MHz), 6.18　(s, 1H), 6.08 (s, 1H),　4.04-4.00　(m, 1H),　3.60-3.58 (m, 4H), 3.27 (s, 2H), 2.37-2.36 (m, 4H), 2.32-2.30 (m, 1H), 2.23-2.20 (m, 2H), 1.99-1.96 (m, 2H), 1.66-1.57 (m, 2H), 1.34-1.26 (m, 2H) 1 H-NMR (400 MHz, DMSO-d6) δ: 11.30 (s, 1H), 8.14 (s, 1H), 8.07-8.05 (m, 2H), 7.65-7.58 (m, 3H), 6.67 (d, 1H, J=7.2 MHz), 6.18 (s, 1H), 6.08 (s, 1H), 4.04-4.00 (m, 1H), 3.60-3.58 (m, 4H), 3.27 (s, 2H), 2.37-2.36 (m, 4H), 2.32-2.30 (m, 1H), 2.23-2.20 (m, 2H), 1.99-1.96 (m, 2H), 1.66-1.57 (m, 2H), 1.34-1.26 (m, 2H)
실시예 18. 4-(모르폴리노메틸)-N2-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)-N6-((1R,4R)-4-(트리플루오로메틸)시클로헥실 )피리딘-2,6-디아민의 합성Example 18. 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
단계 1) 4-(모르폴리노메틸)-N2-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)-N6-((1R,4R)-4-(트리플루오로메틸)시클로헥실 )피리딘-2,6-디아민의 합성Step 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
상기 실시예 17 단계 2에서 합성된 4-(모르폴리노메틸)-N2-((1R,4R)-4-(트리플루오로메틸)시클로헥실)피리딘-2,6-디아민 (183 mg, 0.51 mmol)과 실시예 2의 단계1에서 합성된 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (188 mg, 0.61 mmol)를 실시예 2의 단계 2와 같은 방법으로 반응하여 목적화합물 (114 mg, 38%)을 얻었다.4-(morpholinomethyl)-N2-((1R,4R)-4-(trifluoromethyl)cyclohexyl)pyridine-2,6-diamine synthesized in Example 17 step 2 (183 mg, 0.51 mmol) and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (188 mg, 0.61 mmol) synthesized in step 1 of Example 2 The target compound (114 mg, 38%) was obtained by reacting in the same manner as in step 2 of 2.
1H-NMR (400 MHz, DMSO-d6) δ: 11.49 (s, 1H), 8.19 (s, 1H),　8.07-8.05 (m, 2H),　7.64-7.59 (m, 3H),　6.71 (d, 1H, J=7.6 MHz), 6.20　(s, 1H), 6.10 (s, 1H),　4.01-3.99　(m, 1H),　3.60-3.58 (m, 4H), 3.26 (s, 2H), 2.37-2.36 (m, 4H), 2.33-2.32 (m, 1H), 2.20-2.19 (m, 2H), 1.97-1.94 (m, 2H), 1.67-1.58 (m, 2H), 1.34-1.23 (m, 2H) 1 H-NMR (400 MHz, DMSO-d6) δ: 11.49 (s, 1H), 8.19 (s, 1H), 8.07-8.05 (m, 2H), 7.64-7.59 (m, 3H), 6.71 (d, 1H, J=7.6 MHz), 6.20 (s, 1H), 6.10 (s, 1H), 4.01-3.99 (m, 1H), 3.60-3.58 (m, 4H), 3.26 (s, 2H), 2.37-2.36 (m, 4H), 2.33-2.32 (m, 1H), 2.20-2.19 (m, 2H), 1.97-1.94 (m, 2H), 1.67-1.58 (m, 2H), 1.34-1.23 (m, 2H)
실시예 19. N2-((1R,4R)-4-메톡시시클로헥실)-4-(모르폴리노메틸)-N6-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)피리딘- 2,6-디아민의 합성Example 19. N2-((1R,4R)-4-methoxycyclohexyl)-4-(morpholinomethyl)-N6-(5-(5-phenyl-1,3,4-oxadiazole- Synthesis of 2-yl)thiazol-2-yl)pyridin-2,6-diamine
단계1) 6-브로모-N-((1R,4R)-4-메톡시시클로헥실)-4-(모르폴리노메틸)피리딘-2-아민 합성Step 1) Synthesis of 6-bromo-N-((1R,4R)-4-methoxycyclohexyl)-4-(morpholinomethyl)pyridin-2-amine
4-((2,6-디브로모피리딘-4-일)메틸)몰포린 (1.15 g. 4.46 mmol), 4-메톡시사이클로헥산아민 하이드로클로라이드 (739 mg, 4.46 mmol), 트리스(디벤질인덴아세톤)디팔라듐 (10 mol%), 잔트포스 (10 mol%) 나트륨-터트-부톡사이트 (1.07 mg, 11.16 mmol)을 무수 1,4-디옥세인 (0.2M)에 녹인 후, 상온에서 4시간 교반한다. 반응이 완료되면 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (445 mg, 26%)을 얻었다.4-((2,6-dibromopyridin-4-yl)methyl)morpholine (1.15 g. 4.46 mmol), 4-methoxycyclohexanamine hydrochloride (739 mg, 4.46 mmol), tris(dibenzyl) Indeneacetone)dipalladium (10 mol%), xanthos (10 mol%) sodium-tert-butoxide (1.07 mg, 11.16 mmol) was dissolved in anhydrous 1,4-dioxane (0.2M), and then at room temperature Stir for 4 hours. When the reaction is complete, extraction is performed 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 (445 mg, 26%).
단계2) N2-((1R,4R)-4-메톡시시클로헥실)-4-(모르폴리노메틸)피리딘-2,6-디아민 합성Step 2) Synthesis of N2-((1R,4R)-4-methoxycyclohexyl)-4-(morpholinomethyl)pyridine-2,6-diamine
6-브로모-N-((1R,4R)-4-메톡시시클로헥실)-4-(모르폴리노메틸)피리딘-2-아민 (466 mg, 1.21 mmol), 쿠프릭 아세틸아세톤 (10 mol%), 세슘 카보네이트 (790 mg, 2.42 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성한다, 이후 아세틸아세톤 (40 mol%), 암모니아 수용액 (2.83 mL, 24.24 mmol), 무수 다이메틸포름아마이드 (0.2 M)를 차례로 넣고, 90 ℃에서 밤샘교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (132 mg, 34%)을 얻었다.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. When the reaction is complete, 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%).
단계3) N2-((1R,4R)-4-메톡시시클로헥실)-4-(모르폴리노메틸)-N6-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)피리딘- 2,6-디아민의 합성Step 3) N2-((1R,4R)-4-methoxycyclohexyl)-4-(morpholinomethyl)-N6-(5-(5-phenyl-1,3,4-oxadiazole-2 Synthesis of -yl)thiazol-2-yl)pyridin-2,6-diamine
상기 단계2에서 합성된 N2-((1R,4R)-4-메톡시시클로헥실)-4-(모르폴리노메틸)피리딘-2,6-디아민 (130 mg, 0.40 mmol)과 실시예 2의 단계1에서 합성된 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (150 mg, 0.48 mmol)를 실시예 2의 단계 2과 같은 방법으로 반응하여 목적화합물 (88 mg, 39%)을 얻었다.N2-((1R,4R)-4-methoxycyclohexyl)-4-(morpholinomethyl)pyridine-2,6-diamine (130 mg, 0.40 mmol) synthesized in step 2 and the 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (150 mg, 0.48 mmol) synthesized in step 1 was prepared in the same manner as in step 2 of Example 2 to obtain the target compound (88 mg, 39%).
1H-NMR (400 MHz, DMSO-d6) δ: 11.49 (s, 1H), 8.20 (s, 1H),　8.08-8.06 (m, 2H),　7.66-7.58 (m, 3H),　6.64 (d, 1H, J=8 MHz), 6.18　(s, 1H), 6.09 (s, 1H),　4.01-3.98　(m, 1H),　3.60-3.57 (m, 4H), 3.27 (s, 2H),　3.26 (s, 3H), 3.19-3.16 (m, 1H), 3.46-3.44 (m, 4H), 2.15-2.06 (m, 4H), 1.50-1.42 (m, 2H), 1.31-1.23 (m, 1H) 1 H-NMR (400 MHz, DMSO-d6) δ: 11.49 (s, 1H), 8.20 (s, 1H), 8.08-8.06 (m, 2H), 7.66-7.58 (m, 3H), 6.64 (d, 1H, J=8 MHz), 6.18 (s, 1H), 6.09 (s, 1H), 4.01-3.98 (m, 1H), 3.60-3.57 (m, 4H), 3.27 (s, 2H), 3.26 (s) , 3H), 3.19-3.16 (m, 1H), 3.46-3.44 (m, 4H), 2.15-2.06 (m, 4H), 1.50-1.42 (m, 2H), 1.31-1.23 (m, 1H)
실시예 20. N2-시클로헥실-4-(모르폴리노메틸)-N6-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)피리딘-2,6-디아민의 합성Example 20. N2-Cyclohexyl-4-(morpholinomethyl)-N6-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)pyridine Synthesis of -2,6-diamine
단계1) 6-브로모-N-사이클로헥실-4-(모르폴리노메틸)피리딘-2-아민 합성Step 1) Synthesis of 6-bromo-N-cyclohexyl-4- (morpholinomethyl) pyridin-2-amine
4-((2,6-디브로모피리딘-4-일)메틸)몰포린 (1 mg. 2.97 mmol), 사이클로헥실아민 (354 mg, 3.57 mmol), 트리스(디벤질인덴아세톤)디팔라듐 (10 mol%), 잔트포스 (mol%) 나트륨-터트-부톡사이트 (429 mg, 04.46mmol)을 무수 1,4-디옥세인 (0.2M)에 녹인 후, 상온에서 4시간 교반한다. 반응이 완료되면 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (487 mg, 46%)을 얻었다.4-((2,6-dibromopyridin-4-yl)methyl)morpholine (1 mg. 2.97 mmol), cyclohexylamine (354 mg, 3.57 mmol), tris(dibenzylindeneacetone)dipalladium (10 mol%), xanthoth (mol%) sodium-tert-butoxide (429 mg, 04.46mmol) was dissolved in anhydrous 1,4-dioxane (0.2M), followed by stirring at room temperature for 4 hours. When the reaction is complete, extraction is performed 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 (487 mg, 46%).
단계2) N2-시클로헥실-4-(모르폴리노메틸)피리딘-2,6-디아민 합성Step 2) Synthesis of N2-cyclohexyl-4-(morpholinomethyl)pyridine-2,6-diamine
6-브로모-N-사이클로헥실-4-(모르폴리노메틸)피리딘-2-아민 (487 mg, 1.37 mmol), 쿠프릭 아세틸아세톤 (10 mol%), 세슘 카보네이트 (895 mg, 2.74 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성한다, 이후 아세틸아세톤 (40 mol%), 암모니아 수용액 (3.21 mL, 27.49 mmol), 무수 다이메틸포름아마이드 (0.2M)를 차례로 넣고, 90 ℃에서 밤샘교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (259 mg, 64%)을 얻었다.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) Put into a shrink tube, create a nitrogen environment, then 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. When the reaction is complete, 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%).
단계3) N2-시클로헥실-4-(모르폴리노메틸)-N6-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)피리딘-2,6-디아민의 합성Step 3) N2-Cyclohexyl-4-(morpholinomethyl)-N6-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)pyridin- Synthesis of 2,6-diamine
상기 단계2에서 합성된 N2-시클로헥실-4-(모르폴리노메틸)피리딘-2,6-디아민 (147 mg, 0.50 mmol)과 실시예 2의 단계1에서 합성된 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (188 mg, 0.61 mmol)를 실시예 2의 단계 2과 같은 방법으로 반응하여 목적화합물 (90 mg, 34%)을 얻었다.N2-cyclohexyl-4-(morpholinomethyl)pyridine-2,6-diamine (147 mg, 0.50 mmol) synthesized in step 2 and 2-(2-bromo) synthesized in step 1 of Example 2 Thiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (188 mg, 0.61 mmol) was reacted in the same manner as in step 2 of Example 2 to obtain the target compound (90 mg, 34%) got
1H-NMR (400 MHz, DMSO-d6) δ: 11.48 (s, 1H), 8.20 (s, 1H),　8.06-8.04 (m, 2H),　7.66-7.59 (m, 3H),　6.66 (d, 1H, J=8 MHz), 6.17　(s, 1H), 6.08 (s, 1H),　4.04-4.00　(m, 1H),　3.60-3.57 (m, 4H), 3.27 (s, 2H), 2.36-2.33 (m, 4H),　2.10-2.07 (m, 2H),　1.81-1.77 (m, 2H), 1.68-1.66 (m, 1H), 1.59-1.52 (m, 2H), 1.22-1.15 (m, 4H) 1 H-NMR (400 MHz, DMSO-d6) δ: 11.48 (s, 1H), 8.20 (s, 1H), 8.06-8.04 (m, 2H), 7.66-7.59 (m, 3H), 6.66 (d, 1H, J=8 MHz), 6.17 (s, 1H), 6.08 (s, 1H), 4.04-4.00 (m, 1H), 3.60-3.57 (m, 4H), 3.27 (s, 2H), 2.36-2.33 (m, 4H), 2.10-2.07 (m, 2H), 1.81-1.77 (m, 2H), 1.68-1.66 (m, 1H), 1.59-1.52 (m, 2H), 1.22-1.15 (m, 4H)
실시예 21. N2-((1R,4R)-4-플루오로시클로헥실)-4-(모르폴리노메틸)-N6-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)피리딘- 2,6-디아민의 합성Example 21. N2-((1R,4R)-4-fluorocyclohexyl)-4-(morpholinomethyl)-N6-(5-(5-phenyl-1,3,4-oxadiazole- Synthesis of 2-yl)thiazol-2-yl)pyridin-2,6-diamine
단계1) 6-브로모-N-((1R,4R)-4-플루오로시클로헥실)-4-(모르폴리노메틸)피리딘-2-아민 합성Step 1) Synthesis of 6-bromo-N-((1R,4R)-4-fluorocyclohexyl)-4-(morpholinomethyl)pyridin-2-amine
4-((2,6-디브로모피리딘-4-일)메틸)몰포린 (1 g. 2.97 mmol), 트랜스-4-플루오고사이클로헥세인-1-아민 하이드로클로라이드 (457 mg, 2.97 mmol), 트리스(디벤질인덴아세톤)디팔라듐 (10 mol%), 잔트포스 (10 mol%) 나트륨-터트-부톡사이트 (715 mg, 7.43 mmol)을 무수 1,4-디옥세인 (0.2M)에 녹인 후, 상온에서 4시간 교반한다. 반응이 완료되면 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (426 mg, 38%)을 얻었다.4-((2,6-dibromopyridin-4-yl)methyl)morpholine (1 g. 2.97 mmol), trans-4-fluorogocyclohexane-1-amine hydrochloride (457 mg, 2.97 mmol) ), tris(dibenzylindeneacetone)dipalladium (10 mol%), xantphos (10 mol%) sodium-tert-butoxide (715 mg, 7.43 mmol) with anhydrous 1,4-dioxane (0.2M) After dissolving in, stirred at room temperature for 4 hours. When the reaction is complete, extraction is performed 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 (426 mg, 38%).
단계2) N2-((1R,4R)-4-플루오로시클로헥실)-4-(모르폴리노메틸)피리딘-2,6-디아민 합성Step 2) Synthesis of N2-((1R,4R)-4-fluorocyclohexyl)-4-(morpholinomethyl)pyridine-2,6-diamine
6-브로모-N-((1R,4R)-4-플루오로시클로헥실)-4-(모르폴리노메틸)피리딘-2-아민 (426 mg, 1.14 mmol), 쿠프릭 아세틸아세톤 (10 mol%), 세슘 카보네이트 (745 mg, 2.28 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성한다, 이후 아세틸아세톤 (40 mol%), 암모니아 수용액 (2.67 mL, 22.88 mmol), 무수 다이메틸포름아마이드 (0.2M)를 차례로 넣고, 90 ℃에서 밤샘교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (217 mg, 61%)을 얻었다.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. When the reaction is complete, 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%).
단계3) N2-((1R,4R)-4-플루오로시클로헥실)-4-(모르폴리노메틸)-N6-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)피리딘- 2,6-디아민의 합성Step 3) N2-((1R,4R)-4-fluorocyclohexyl)-4-(morpholinomethyl)-N6-(5-(5-phenyl-1,3,4-oxadiazole-2 Synthesis of -yl)thiazol-2-yl)pyridin-2,6-diamine
상기 단계2에서 합성된 N2-((1R,4R)-4-플루오로시클로헥실)-4-(모르폴리노메틸)피리딘-2,6-디아민 (107 mg, 0.34 mmol)과 실시예 2의 단계1에서 합성된 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (130 mg, 0.41 mmol)를 실시예 2의 단계 2과 같은 방법으로 반응하여 목적화합물 (33 mg, 17%)을 얻었다.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%).
1H-NMR (400 MHz, DMSO-d6) δ: 11.52 (s, 1H), 8.21 (s, 1H),　8.07-8.06 (m, 2H),　7.65-7.58 (m, 3H),　6.70 (d, 1H, J=7.6 MHz), 6.20　(s, 1H), 6.10 (s, 1H), 4.72-4.59 (m, 1H), 4.01-4.04 (m, 1H), 3.60-3.59 (m, 4H), 3.28 (s, 2H), 2.36-2.35 (m, 4H), 2.13-2.12 (m, 4H), 1.81-1.76 (m, 2H)m 1.39-1.33 (m, 2H) 1 H-NMR (400 MHz, DMSO-d6) δ: 11.52 (s, 1H), 8.21 (s, 1H), 8.07-8.06 (m, 2H), 7.65-7.58 (m, 3H), 6.70 (d, 1H, J=7.6 MHz), 6.20 (s, 1H), 6.10 (s, 1H), 4.72-4.59 (m, 1H), 4.01-4.04 (m, 1H), 3.60-3.59 (m, 4H), 3.28 (s, 2H), 2.36-2.35 (m, 4H), 2.13-2.12 (m, 4H), 1.81-1.76 (m, 2H)m 1.39-1.33 (m, 2H)
실시예 22. (1R,4R)-4-((4-((4-메틸피페리딘-1-일)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸- 2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Example 22. (1R,4R)-4-((4-((4-methylpiperidin-1-yl)methyl)-6-((5-(5-phenyl-1,3,4-oxa) Synthesis of diazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol
단계1) (2,6-디브로모피리딘-4-일)(4-메틸피페리딘-1-일)메탄온의 합성Step 1) Synthesis of (2,6-dibromopyridin-4-yl)(4-methylpiperidin-1-yl)methanone
실시예1의 단계3에서 몰폴린 대신 4-메틸피페리딘을 사용한 것을 제외하고, 2,6-다이브로모니코티닉 산 (1.00 g, 3.55 mmol)과 동일한 방법으로 반응하여 목적화합물 (1.00 g, 80%)을 얻었다.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.
단계2) 2,6-디브로모-4-((4-메틸피페리딘-1-일)메틸)피리딘의 합성Step 2) Synthesis of 2,6-dibromo-4-((4-methylpiperidin-1-yl)methyl)pyridine
상기 단계1에서 합성된 (2,6-디브로모피리딘-4-일)(4-메틸피페리딘-1-일)메탄온 (1.00 g, 2.87 mmol)을 실시예1의 단계4와 같은 방법으로 목적화합물 (0.21 g, 49%)을 얻었다.(2,6-dibromopyridin-4-yl)(4-methylpiperidin-1-yl)methanone (1.00 g, 2.87 mmol) synthesized in step 1 above was prepared in the same manner as in step 4 of Example 1. By this method, the target compound (0.21 g, 49%) was obtained.
단계3) (1R,4R)-4-((6-브로모-4-((4-메틸피페리딘-1-일)메틸)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Step 3) of (1R,4R)-4-((6-bromo-4-((4-methylpiperidin-1-yl)methyl)pyridin-2-yl)amino)cyclohexan-1-ol synthesis
상기 단계2에서 합성된 2,6-디브로모-4-((4-메틸피페리딘-1-일)메틸)피리딘 (0.49 g, 1.41 mmol)을 실시예1의 단계5와 같은 방법으로 목적화합물 (0.21 g, 39%)을 얻었다.2,6-dibromo-4-((4-methylpiperidin-1-yl)methyl)pyridine (0.49 g, 1.41 mmol) synthesized in step 2 was prepared in the same manner as in step 5 of Example 1. The target compound (0.21 g, 39%) was obtained.
단계4) (1R,4R)-4-((6-아미노-4-((4-메틸피페리딘-1-일)메틸)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Step 4) Synthesis of (1R,4R)-4-((6-amino-4-((4-methylpiperidin-1-yl)methyl)pyridin-2-yl)amino)cyclohexan-1-ol
상기 단계3에서 합성된 (1R,4R)-4-((6-브로모-4-((4-메틸피페리딘-1-일)메틸)피리딘-2-일)아미노)사이클로헥산-1-올 (0.21 g, 0.55 mmol)을 실시예1의 단계 6과 같은 방법으로 목적화합물 (0.11 g, 61%)을 얻었다.(1R,4R)-4-((6-bromo-4-((4-methylpiperidin-1-yl)methyl)pyridin-2-yl)amino)cyclohexane-1 synthesized in step 3 -ol (0.21 g, 0.55 mmol) was used in the same manner as in step 6 of Example 1 to obtain the target compound (0.11 g, 61%).
단계5) (1R,4R)-4-((4-((4-메틸피페리딘-1-일)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸- 2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Step 5) (1R,4R)-4-((4-((4-methylpiperidin-1-yl)methyl)-6-((5-(5-phenyl-1,3,4-oxadia) Synthesis of zol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol
상기 단계4에서 합성된 (1R,4R)-4-((6-아미노-4-((4-메틸피페리딘-1-일)메틸)피리딘-2-일)아미노)사이클로헥산-1-올 (0.11 g, 0.34 mmol)과 실시예1의 단계2에서 합성된 2-브로모-5-(2-페닐-2H-테트라졸-5-일)사이아졸 (0.13 g, 0.41 mmol)을 실시예1의 단계7과 같은 방법으로 목적화합물 (0.02 g, 10%)을 얻었다.(1R,4R)-4-((6-amino-4-((4-methylpiperidin-1-yl)methyl)pyridin-2-yl)amino)cyclohexane-1-synthesized in step 4 above ol (0.11 g, 0.34 mmol) and 2-bromo-5-(2-phenyl-2H-tetrazol-5-yl)cyazole synthesized in step 2 of Example 1 (0.13 g, 0.41 mmol) The target compound (0.02 g, 10%) was obtained in the same manner as in step 7 of Example 1.
1H-NMR (400 MHz, DMSO-d6) δ: 11.47 (s, 1H), 8.22 (s, 1H), 8.11-8.09 (m, 2H), 7.63-7.61 (m, 3H), 6.17 (s, 1H), 6.08 (s, 1H), 4.67 (1H, d, J= 2.8 Hz), 3.98 (s, 1H), 3.52-3.47 (m, 1H), 3.24 (s, 2H), 2.76 (s, 1H), 2.10-2.08 (m, 2H), 1.92-1.89 (m, 4H), 1.60-1.51 (m, 2H), 1.48-1.46 (m, 2H), 1.31-1.23 (m, 3H), 1.15-1.14 (m, 2H), 0.90 (d, 3H, J= 6.4 Hz). 1 H-NMR (400 MHz, DMSO-d6) δ: 11.47 (s, 1H), 8.22 (s, 1H), 8.11-8.09 (m, 2H), 7.63-7.61 (m, 3H), 6.17 (s, 1H), 6.08 (s, 1H), 4.67 (1H, d, J= 2.8 Hz), 3.98 (s, 1H), 3.52-3.47 (m, 1H), 3.24 (s, 2H), 2.76 (s, 1H) ), 2.10-2.08 (m, 2H), 1.92-1.89 (m, 4H), 1.60-1.51 (m, 2H), 1.48-1.46 (m, 2H), 1.31-1.23 (m, 3H), 1.15-1.14 (m, 2H), 0.90 (d, 3H, J = 6.4 Hz).
실시예 23. 4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-N2-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)-N6- (테트라히드로-2H-피란-4-일)피리딘-2,6-디아민의 합성Example 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
단계1) 6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-N-(테트라히드로-2H-피란-4-일)피리딘-2-아민의 합성Step 1) of 6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine synthesis
상기 실시예 3 단계 2에서 얻은 (2S,6R)-4-((2,6-디브로포피리딘-4-일)메틸)-2,6-디메틸몰포린 (800 mg, 2.19 mmol), 4-아미노테트라하이드로피란 (266 mg, 2.63 mmol), 트리스(디벤질인덴아세톤)디팔라듐 (10 mol%), 잔트포스 (10 mol%) 나트륨-터트-부톡사이트 (317 mg, 3.29 mmol)을 무수 1,4-디옥세인 (0.2M)에 녹인 후, 상온에서 4시간 교반한다. 반응이 완료되면 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (528 mg, 62%)을 얻었다.(2S,6R)-4-((2,6-dibropopyridin-4-yl)methyl)-2,6-dimethylmorpholine (800 mg, 2.19 mmol), 4 -Aminotetrahydropyran (266 mg, 2.63 mmol), tris(dibenzylindenacetone)dipalladium (10 mol%), xanthos (10 mol%) sodium-tert-butoxide (317 mg, 3.29 mmol) After dissolving in anhydrous 1,4-dioxane (0.2M), the mixture was stirred at room temperature for 4 hours. When the reaction is complete, extraction is performed 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 (528 mg, 62%).
단계2) 4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-N2-(테트라히드로-2H-피란-4-일)피리딘-2,6-디아민 합성Step 2) Synthesis of 4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-N2-(tetrahydro-2H-pyran-4-yl)pyridine-2,6-diamine
상기 단계 1에서 얻은 6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-N-(테트라히드로-2H-피란-4-일)피리딘-2-아민 (528 mg, 1.37 mmol), 쿠프릭 아세틸아세톤 (10 mol%), 세슘 카보네이트 (896 mg, 2.75 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성한다, 이후 아세틸아세톤 (40 mol%), 암모니아 수용액 (3.21 mL, 27.50 mmol), 무수 다이메틸포름아마이드 (0.2M)를 차례로 넣고, 90 ℃에서 밤샘교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (308 mg, 70%)을 얻었다.6-Bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-N-(tetrahydro-2H-pyran-4-yl)pyridin-2- obtained in step 1 above Amine (528 mg, 1.37 mmol), cupric acetylacetone (10 mol%), cesium carbonate (896 mg, 2.75 mmol) are placed in a shrink tube, and a nitrogen environment is prepared, then acetylacetone (40 mol%), Aqueous ammonia solution (3.21 mL, 27.50 mmol) and anhydrous dimethylformamide (0.2M) are sequentially added, and the mixture is stirred at 90°C overnight. When the reaction is complete, 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%).
단계3) 4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-N2-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)-N6-(테트라히드로-2H-피란-4-일)피리딘-2,6-디아민의 합성Step 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
상기 단계 2에서 얻은 4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-N2-(테트라히드로-2H-피란-4-일)피리딘-2,6-디아민 (94 mg, 0.29 mmol)과 실시예 2의 단계 1에서 얻은 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (109 mg, 0.35 mmol)을 실시예 1의 단계 7와 같은 방법으로 반응하여 목적화합물 (30 mg, 18%)을 얻었다.4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-N2-(tetrahydro-2H-pyran-4-yl)pyridine-2,6-diamine (94 mg, 0.29 mmol) and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (109 mg, 0.35 mmol) obtained in step 1 of Example 2 The target compound (30 mg, 18%) was obtained by reacting in the same manner as in step 7 of Example 1.
1H-NMR (400 MHz, DMSO-d6) δ11.53 (s, 1H), 8.20 (s, 1H),　8.07-8.05 (m, 2H),　7.66-7.62 (m, 3H),　6.81 (d, 1H, J=8 MHz), 6.19　(s, 1H), 6.09 (s, 1H),　4.27-4.25　(m, 1H),　3.97-3.95 (m, 2H), 3.60-3.57 (m, 4H), 3.26 (s, 2H), 2.70-2.67 (m, 2H),　2.00-1.98 (m, 2H),　1.53-1.44 (m, 2H), 1.03 (d, 6H, J=6 MHz) 1 H-NMR (400 MHz, DMSO-d 6 ) δ11.53 (s, 1H), 8.20 (s, 1H), 8.07-8.05 (m, 2H), 7.66-7.62 (m, 3H), 6.81 (d , 1H, J=8 MHz), 6.19 (s, 1H), 6.09 (s, 1H), 4.27-4.25 (m, 1H), 3.97-3.95 (m, 2H), 3.60-3.57 (m, 4H), 3.26 (s, 2H), 2.70-2.67 (m, 2H), 2.00-1.98 (m, 2H), 1.53-1.44 (m, 2H), 1.03 (d, 6H, J=6 MHz)
실시예 24. 3-((4-(모르폴리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로헥산 -1-올의 합성Example 24. 3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino Synthesis of )pyridin-2-yl)amino)cyclohexan-1-ol
단계1) 3-((6-브로모-4-(모르폴리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올 합성Step 1) Synthesis of 3-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol
4-((2,6-디브로모피리딘-4-일)메틸)몰포린 (1 g. 2.97 mmol), 3-아미노사이클로헥산올 (377 mg, 3.27 mmol), 트리스(디벤질인덴아세톤)디팔라듐 (10 mol%), 잔트포스 (10 mol%) 나트륨-터트-부톡사이트 (428 mg, 4.46 mmol)을 무수 1,4-디옥세인 (0.2M)에 녹인 후, 상온에서 4시간 교반한다. 반응이 완료되면 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (646 mg, 58%)을 얻었다.4-((2,6-dibromopyridin-4-yl)methyl)morpholine (1 g. 2.97 mmol), 3-aminocyclohexanol (377 mg, 3.27 mmol), tris(dibenzylindeneacetone) ) Dipalladium (10 mol%), xanthos (10 mol%) sodium-tert-butoxide (428 mg, 4.46 mmol) was dissolved in anhydrous 1,4-dioxane (0.2M), followed by stirring at room temperature for 4 hours do. When the reaction is complete, extraction is performed 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 (646 mg, 58%).
단계2) 3-((6-아미노-4-(모르폴리노메틸)피리딘-2-일)아미노)시클로헥산-1-올 합성Step 2) Synthesis of 3-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol
상기 단계 1에서 얻은 3-((6-브로모-4-(모르폴리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올 (646 mg, 1.74 mmol), 쿠프릭 아세틸아세톤 (10 mol%), 세슘 카보네이트 (1.13 g, 3.48 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성한다, 이후 아세틸아세톤 (40 mol%), 암모니아 수용액 (4.07 mL, 34.89 mmol), 무수 다이메틸포름아마이드 (0.2M)를 차례로 넣고, 90 ℃에서 밤샘교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (328 mg, 61%)을 얻었다.3-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol (646 mg, 1.74 mmol) obtained in step 1 above, cupric acetylacetone (10 mol%), cesium carbonate (1.13 g, 3.48 mmol) is placed in a shrink tube, and a nitrogen environment is created, then acetylacetone (40 mol%), aqueous ammonia solution (4.07 mL, 34.89 mmol), anhydrous dimethylformamide (0.2M) was added sequentially and stirred overnight at 90 °C. When the reaction is complete, 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%).
단계3) 3-((4-(모르폴리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로헥산 -1-올 합성Step 3) 3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) Synthesis of pyridin-2-yl)amino)cyclohexan-1-ol
상기 단계2에서 합성된 3-((6-아미노-4-(모르폴리노메틸)피리딘-2-일)아미노)시클로헥산-1-올 (328 mg, 1.07 mmol)과 실시예 2의 단계 1에서 합성된 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (396 mg, 01.28 mmol)를 실시예 2의 단계 2과 같은 방법으로 반응하여 목적화합물 (171 mg, 30%)을 얻었다.3-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol (328 mg, 1.07 mmol) synthesized in step 2 above and step 1 of Example 2 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (396 mg, 01.28 mmol) synthesized in to obtain the target compound (171 mg, 30%).
1H-NMR (400 MHz, DMSO-d6) δ11.51 (s, 1H), 11.47 (s, 0.3H), 8.21 (s, 1.3H),　8.13-8.12 (m, 0.6H), 8.07- 8.06 (m, 2H), 7.65-7.63 (m, 4H), 6.72　(m, 1H), 6.59-6.57 (m, 0.3H), 6.18 (s, 1.3H), 6.13 (s, 0.6H), 6.08 (s, 1H),　4.67-4.65 (m, 1H), 4.48-4.41 (m, 0.6H), 4.07-4.01 (m, 1.3H), 3.70-3.67 (m, 1.3H), 3.60-3.59 (m, 5.2H), 3.28 (s, 2.6H), 1.37-2.36 (m, 5.2H), 2.25-2.23 (m, 1.3H), 2.07-2.04 (m, 1.3H), 1.90-1.87 (m, 1.3H), 1.76-1.66 (m, 1.3H), 1.55-1.54 (m, 1.3H), 1.16-1.02 (m, 3.9H) 1 H-NMR (400 MHz, DMSO-d6) δ11.51 (s, 1H), 11.47 (s, 0.3H), 8.21 (s, 1.3H), 8.13-8.12 (m, 0.6H), 8.07-8.06 (m, 2H), 7.65-7.63 (m, 4H), 6.72 (m, 1H), 6.59-6.57 (m, 0.3H), 6.18 (s, 1.3H), 6.13 (s, 0.6H), 6.08 ( s, 1H), 4.67-4.65 (m, 1H), 4.48-4.41 (m, 0.6H), 4.07-4.01 (m, 1.3H), 3.70-3.67 (m, 1.3H), 3.60-3.59 (m, 5.2H), 3.28 (s, 2.6H), 1.37-2.36 (m, 5.2H), 2.25-2.23 (m, 1.3H), 2.07-2.04 (m, 1.3H), 1.90-1.87 (m, 1.3H) ), 1.76-1.66 (m, 1.3H), 1.55-1.54 (m, 1.3H), 1.16-1.02 (m, 3.9H)
실시예 25. (1R,4R)-4-((4-((디메틸아미노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노) 피리딘-2-일)아미노)시클로헥산-1-올의 합성Example 25. (1R,4R)-4-((4-((dimethylamino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thia Synthesis of zol-2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol
단계1) 2,6-디브로모-N,N-디메틸이소니코틴아미드의 합성Step 1) Synthesis of 2,6-dibromo-N,N-dimethylisonicotinamide
실시예1의 단계3에서 몰폴린 대신 다이메틸아민을 사용한 것을 제외하고, 2,6-다이브로모니코티닉 산 (3.00 g, 10.68 mmol)과 동일한 방법으로 반응하여 목적화합물 (2.86 g, 87%)을 얻었다.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.
단계2) 1-(2,6-디브로모피리딘-4-일)-N,N-디메틸메탄아민의 합성Step 2) Synthesis of 1-(2,6-dibromopyridin-4-yl)-N,N-dimethylmethanamine
상기 단계1에서 합성된 2,6-디브로모-N,N-디메틸이소니코틴아미드 (2.86 g, 9.29 mmol)을 실시예 1의 단계4와 같은 방법으로 목적화합물 (1.70 g, 59%)을 얻었다.2,6-dibromo-N,N-dimethylisonicotinamide (2.86 g, 9.29 mmol) synthesized in step 1 was prepared in the same manner as in step 4 of Example 1 to prepare the target compound (1.70 g, 59%). got it
단계3) (1R,4R)-4-((6-브로모-4-((디메틸아미노)메틸)피리딘-2-일)아미노)시클로헥산-1-올의 합성Step 3) Synthesis of (1R,4R)-4-((6-bromo-4-((dimethylamino)methyl)pyridin-2-yl)amino)cyclohexan-1-ol
상기 단계1에서 합성된 1-(2,6-디브로모피리딘-4-일)-N,N-디메틸메탄아민 (0.98 g, 3.33 mmol)을 실시예 1의 단계4와 같은 방법으로 목적화합물 (0.67 g, 61%)을 얻었다.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.
단계3) (1R,4R)-4-((6-아미노-4-((디메틸아미노)메틸)피리딘-2-일)아미노)시클로헥산-1-올의 합성Step 3) Synthesis of (1R,4R)-4-((6-amino-4-((dimethylamino)methyl)pyridin-2-yl)amino)cyclohexan-1-ol
상기 단계3에서 합성된 (1R,4R)-4-((6-브로모-4-((디메틸아미노)메틸)피리딘-2-일)아미노)시클로헥산-1-올 (0.67 g, 2.04 mmol)을 실시예1의 단계6과 같은 방법으로 목적화합물 (0.3 g, 56%)을 얻었다.(1R,4R)-4-((6-bromo-4-((dimethylamino)methyl)pyridin-2-yl)amino)cyclohexan-1-ol synthesized in step 3 (0.67 g, 2.04 mmol ) was obtained in the same manner as in step 6 of Example 1 to obtain the target compound (0.3 g, 56%).
단계4) (1R,4R)-4-((4-((디메틸아미노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노) 피리딘-2-일)아미노)시클로헥산-1-올의 합성Step 4) (1R,4R)-4-((4-((dimethylamino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole Synthesis of -2-yl)amino) pyridin-2-yl)amino)cyclohexan-1-ol
상기 단계4에서 합성된 (1R,4R)-4-((6-아미노-4-((디메틸아미노)메틸)피리딘-2-일)아미노)시클로헥산-1-올 (0.05 g, 0.19 mmol)과 실시예1의 단계2에서 합성된 2-브로모-5-(2-페닐-2H-테트라졸-5-일)사이아졸 (0.7 g, 0.23 mmol)을 실시예1의 단계7과 같은 방법으로 목적화합물 (2.0 mg, 2%)을 얻었다.(1R,4R)-4-((6-amino-4-((dimethylamino)methyl)pyridin-2-yl)amino)cyclohexan-1-ol (0.05 g, 0.19 mmol) synthesized in step 4 above and 2-bromo-5-(2-phenyl-2H-tetrazol-5-yl)cyazole (0.7 g, 0.23 mmol) synthesized in step 2 of Example 1 in the same manner as in step 7 of Example 1. to obtain the target compound (2.0 mg, 2%).
1H-NMR (400 MHz, DMSO-d6) δ: 11.50 (s, 1H), 8.11 (s, 1H), 8.10-8.07 (m, 2H), 7.67-7.61 (m, 3H), 5.94 (d, 1H, J= 2.0 Hz), 5.66 (s, 1H), 5.62 (s, 1H), 5.50 (s, 2H), 5.09-4.97 (m, 1H), 3.68-3.66 (m, 1H), 3.57 (s, 2H), 2.40 (s, 6H), 2.24-2.23 (m, 4H), 2.00 (d, 2H, J= 4.0 Hz), 1.68-1.59 (m, 2H), 1.41-1.33 (m, 2H). 1 H-NMR (400 MHz, DMSO-d6) δ: 11.50 (s, 1H), 8.11 (s, 1H), 8.10-8.07 (m, 2H), 7.67-7.61 (m, 3H), 5.94 (d, 1H, J= 2.0 Hz), 5.66 (s, 1H), 5.62 (s, 1H), 5.50 (s, 2H), 5.09-4.97 (m, 1H), 3.68-3.66 (m, 1H), 3.57 (s) , 2H), 2.40 (s, 6H), 2.24-2.23 (m, 4H), 2.00 (d, 2H, J=4.0 Hz), 1.68-1.59 (m, 2H), 1.41-1.33 (m, 2H).
실시예 26. (1R,4R)-4-((6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)-4-(피페라진-1-일메틸 )피리딘-2-일)아미노)시클로헥산-1-올의 합성Example 26. (1R,4R)-4-((6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-4 Synthesis of -(piperazin-1-ylmethyl)pyridin-2-yl)amino)cyclohexan-1-ol
단계1) tert-부틸 4-(2,6-디브로모이소니코티노일)피페라진-1-카르복실레이트의 합성Step 1) Synthesis of tert-butyl 4-(2,6-dibromoisonicotinoyl)piperazine-1-carboxylate
실시예1의 단계3에서 몰폴린 대신 tert-부틸 피페라진-1-카르복실 산을 사용한 것을 제외하고, 2,6-다이브로모니코티닉 산 (6.0 g, 21.36 mmol)과 동일한 방법으로 반응하여 목적화합물 (7.7 g, 80%)을 얻었다.Except for using tert -butyl piperazine-1-carboxylic acid instead of morpholine in step 3 of Example 1, it was reacted in the same manner as 2,6-dibromonicotinic acid (6.0 g, 21.36 mmol) The target compound (7.7 g, 80%) was obtained.
단계2) tert-부틸 4-((2,6-디브로모피리딘-4-일)메틸)피페라진-1-카르복실레이트의 합성Step 2) Synthesis of tert-butyl 4-((2,6-dibromopyridin-4-yl)methyl)piperazine-1-carboxylate
상기 단계1에서 합성된 tert-부틸 4-(2,6-디브로모이소니코티노일)피페라진-1-카르복실레이트 (7.7 g, 17.14 mmol)을 실시예 1의 단계4와 같은 방법으로 목적화합물 (6.1 g, 82%)을 얻었다.tert-Butyl 4-(2,6-dibromoisonicotinoyl)piperazine-1-carboxylate (7.7 g, 17.14 mmol) synthesized in step 1 was prepared in the same manner as in step 4 of Example 1. The compound (6.1 g, 82%) was obtained.
단계3) tert-부틸 4-((2-브로모-6-(((1R,4R)-4-히드록시시클로헥실)아미노)피리딘-4-일)메틸)피페라진-1-카르복실레이트 의 합성Step 3) tert-Butyl 4-((2-bromo-6-(((1R,4R)-4-hydroxycyclohexyl)amino)pyridin-4-yl)methyl)piperazine-1-carboxylate synthesis of
상기 단계2에서 합성된 tert-부틸 4-((2,6-디브로모피리딘-4-일)메틸)피페라진-1-카르복실레이트 (6.1 g, 14.1 mmol)을 실시예1의 단계5와 같은 방법으로 목적화합물 (2.7 g, 41%)을 얻었다.tert-Butyl 4-((2,6-dibromopyridin-4-yl)methyl)piperazine-1-carboxylate (6.1 g, 14.1 mmol) synthesized in step 2 was prepared in step 5 of Example 1 The target compound (2.7 g, 41%) was obtained in the same manner as described above.
단계4) tert-부틸 4-((2-아미노-6-(((1R,4R)-4-히드록시시클로헥실)아미노)피리딘-4-일)메틸)피페라진-1-카르복실레이트 의 합성Step 4) of tert-butyl 4-((2-amino-6-(((1R,4R)-4-hydroxycyclohexyl)amino)pyridin-4-yl)methyl)piperazine-1-carboxylate synthesis
상기 단계3에서 합성된 tert-부틸 4-((2-브로모-6-(((1R,4R)-4-히드록시시클로헥실)아미노)피리딘-4-일)메틸)피페라진-1-카르복실레이트 (2.7 g, 5.75 mmol)을 실시예1의 단계6과 같은 방법으로 목적화합물 (1.59 g, 68%)을 얻었다.tert-Butyl 4-((2-bromo-6-(((1R,4R)-4-hydroxycyclohexyl)amino)pyridin-4-yl)methyl)piperazine-1-synthesized in step 3 Carboxylate (2.7 g, 5.75 mmol) was obtained in the same manner as in step 6 of Example 1 to obtain the target compound (1.59 g, 68%).
단계5) tert-부틸 4-((2-(((1R,4R)-4-히드록시시클로헥실)아미노)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2 -일)아미노)피리딘-4-일)메틸)피페라진-1-카르복실레이트 의 합성Step 5) tert-Butyl 4-((2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-oxadiazole) Synthesis of -2-yl)thiazol-2-yl)amino)pyridin-4-yl)methyl)piperazine-1-carboxylate
상기 단계4에서 합성된 tert-부틸 4-((2-아미노-6-(((1R,4R)-4-히드록시시클로헥실)아미노)피리딘-4-일)메틸)피페라진-1-카르복실레이트 (1.59 g, 3.92 mmol)과 실시예1의 단계2에서 합성된 2-브로모-5-(2-페닐-2H-테트라졸-5-일)사이아졸 (1.45 g, 4.70 mmol)을 실시예1의 단계7과 같은 방법으로 목적화합물 (0.55 g, 22%)을 얻었다.tert-Butyl 4-((2-amino-6-(((1R,4R)-4-hydroxycyclohexyl)amino)pyridin-4-yl)methyl)piperazin-1-carrine synthesized in step 4 above carboxylate (1.59 g, 3.92 mmol) and 2-bromo-5-(2-phenyl-2H-tetrazol-5-yl)cyazole (1.45 g, 4.70 mmol) synthesized in step 2 of Example 1 The target compound (0.55 g, 22%) was obtained in the same manner as in step 7 of Example 1.
단계6) (1R,4R)-4-((6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)-4-(피페라진-1-일메틸 )피리딘-2-일)아미노)시클로헥산-1-올 의 합성Step 6) (1R,4R)-4-((6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-4- Synthesis of (piperazin-1-ylmethyl)pyridin-2-yl)amino)cyclohexan-1-ol
상기 단계 5에서 합성된 tert-부틸 4-((2-(((1R,4R)-4-히드록시시클로헥실)아미노)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2 -일)아미노)피리딘-4-일)메틸)피페라진-1-카르복실레이트 (0.45 g, 0.71 mmol)와 트리플루오로아세트산 (1.09 ml, 14.22 mmol)을 다이클로로메테인 1.5 ml에 용해하여 상온에서 16시간 교반한다. 반응이 종료되면 탄산수소나트륨 수용액으로 중화시켜준 뒤, 다이클로로메테인을 이용하여 추출한다. 얻어진 유기층을 황산나트륨으로 건조하고 용매를 감압증류한다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적화합물 (0.37 g, 98%)을 얻었다.tert-Butyl 4-((2-(((1R,4R)-4-hydroxycyclohexyl)amino)-6-((5-(5-phenyl-1,3,4-) synthesized in step 5 above Oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-4-yl)methyl)piperazine-1-carboxylate (0.45 g, 0.71 mmol) with trifluoroacetic acid (1.09 ml, 14.22) mmol) was dissolved in 1.5 ml of dichloromethane and stirred at room temperature for 16 hours. When the reaction is completed, it is neutralized with an aqueous sodium hydrogen carbonate solution, and then extracted using dichloromethane. The obtained 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 (0.37 g, 98%).
1H-NMR (400 MHz, DMSO-d6) δ: 11.50 (s, 1H), 8.21 (s, 1H), 8.11-8.09 (m, 2H), 7.63-7.62 (m, 4H), 6.17 (s, 1H), 6.07 (s, 1H), 4.66 (d, 1H, J= 3.2 Hz), 3.96-3.93 (m, 1H), 3.49-3.48 (m, 1H), 3.23 (s, 2H), 2.70 (s, 5H), 2.33-2.29 (m, 4H), 2.10-2.07 (m, 2H), 1.92-1.89 (m, 2H), 1.54-1.45 (m, 2H), 1.31-1.23 (m, 2H). 1 H-NMR (400 MHz, DMSO-d6) δ: 11.50 (s, 1H), 8.21 (s, 1H), 8.11-8.09 (m, 2H), 7.63-7.62 (m, 4H), 6.17 (s, 1H), 6.07 (s, 1H), 4.66 (d, 1H, J= 3.2 Hz), 3.96-3.93 (m, 1H), 3.49-3.48 (m, 1H), 3.23 (s, 2H), 2.70 (s) , 5H), 2.33-2.29 (m, 4H), 2.10-2.07 (m, 2H), 1.92-1.89 (m, 2H), 1.54-1.45 (m, 2H), 1.31-1.23 (m, 2H).
실시예 27. 4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-N2-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)-N6- ((테트라히드로-2H-피란-4-일)메틸)피리딘-2,6-디아민의 합성Example 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
단계1) 6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-N-((테트라히드로-2H-피란-4-일)메틸)피리딘-2-아민의 합성Step 1) 6-Bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2 -Synthesis of amines
상기 실시예 3 단계 2에서 얻은 (2S,6R)-4-((2,6-디브로포피리딘-4-일)메틸)-2,6-디메틸몰포린 (970 mg, 2.67 mmol), 4-아미노메틸테트라하이드로피란 (369 mg, 3.21 mmol), 트리스(디벤질인덴아세톤)디팔라듐 (10 mol%), 잔트포스 (10 mol%) 나트륨-터트-부톡사이트 (308mg, 3.21 mmol)을 무수 1,4-디옥세인 (0.2M)에 녹인 후, 상온에서 4시간 교반한다. 반응이 완료되면 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (624 mg, 58%)을 얻었다.(2S,6R)-4-((2,6-dibropopyridin-4-yl)methyl)-2,6-dimethylmorpholine (970 mg, 2.67 mmol), 4 -Aminomethyltetrahydropyran (369 mg, 3.21 mmol), tris(dibenzylindeneacetone)dipalladium (10 mol%), xanthos (10 mol%) sodium-tert-butoxide (308mg, 3.21 mmol) After dissolving in anhydrous 1,4-dioxane (0.2M), the mixture was stirred at room temperature for 4 hours. When the reaction is complete, extraction is performed 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 (624 mg, 58%).
단계2) 4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-N2-((테트라히드로-2H-피란-4-일)메틸)피리딘-2,6-디아민 합성Step 2) Synthesis of 4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-N2-((tetrahydro-2H-pyran-4-yl)methyl)pyridine-2,6-diamine
상기 단계 1에서 얻은 6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-N-((테트라히드로-2H-피란-4-일)메틸)피리딘-2-아민 (624 mg, 1.56 mmol), 쿠프릭 아세틸아세톤 (10 mol%), 세슘 카보네이트 (1.02 g, 3.13 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성한다, 이후 아세틸아세톤 (40 mol%), 암모니아 수용액 (3.6 mL, 31.32 mmol), 무수 다이메틸포름아마이드 (0.2M)를 차례로 넣고, 90 ℃에서 밤샘교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (393 mg, 75%)을 얻었다.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. When the reaction is complete, 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%).
단계3) 4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-N2-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)-N6- ((테트라히드로-2H-피란-4-일)메틸)피리딘-2,6-디아민의 합성Step 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
상기 단계 2에서 얻은 4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-N2-((테트라히드로-2H-피란-4-일)메틸)피리딘-2,6-디아민 (393 mg, 1.17 mmol)과 실시예 2의 단계 1에서 얻은 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (434 mg, 1.41 mmol)을 실시예 1의 단계 7와 같은 방법으로 반응하여 목적화합물 (231 mg, 35%)을 얻었다. 4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-N2-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2,6- obtained in step 2 above Diamine (393 mg, 1.17 mmol) and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole obtained in step 1 of Example 2 (434 mg, 1.41) mmol) was reacted in the same manner as in step 7 of Example 1 to obtain the target compound (231 mg, 35%).
1H-NMR (400 MHz, DMSO-d6) δ: 11.50 (s, 1H), 8.20 (s, 1H),　8.07-8.04 (m, 2H),　7.67-7.59 (m, 3H),　6.94 (t, 1H, J=6 MHz), 6.18　(s, 1H), 6.10 (s, 1H),　3.87-3.83 (m, 2H),　3.59-3.55 (m, 2H), 3.41-3.37 (m, 2H), 3.30-3.23(m, 4H), 2.70-2.66 (m, 2H),　2.00-1.93 (m, 1H), 1.84-1.80 (m, 2H), 1.66-1.64 (m, 2H), 1.32-1.19 (m, 2H), 1.03 (d, 6H, J=6.4　MHz) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.50 (s, 1H), 8.20 (s, 1H), 8.07-8.04 (m, 2H), 7.67-7.59 (m, 3H), 6.94 (t) , 1H, J=6 MHz), 6.18 (s, 1H), 6.10 (s, 1H), 3.87-3.83 (m, 2H), 3.59-3.55 (m, 2H), 3.41-3.37 (m, 2H), 3.30-3.23 (m, 4H), 2.70-2.66 (m, 2H), 2.00-1.93 (m, 1H), 1.84-1.80 (m, 2H), 1.66-1.64 (m, 2H), 1.32-1.19 (m) , 2H), 1.03 (d, 6H, J=6.4 MHz)
실시예 28. (1R,4R)-4-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-(4-플루오로페닐)-1,3,4- 옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로헥산-1-올의 합성Example 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
단계1) (1R,4R)-4-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-(4-플루오로페닐)-1,3,4- 옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로헥산-1-올의 합성Step 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
실시예15의 단계2에서 얻어진 2-(2-브로모티아졸-5-일)-5-(4-플루오로페닐)-1,3,4-옥사디아졸 (0.09 g, 0.29 mmol)와 실시예3의 단계4에서 얻어진 (1R,4R)-4-((6-아미노-4-(((2S,6R)-2,6-디메틸몰포리노)메틸)피리딘-2-일)아미노)사이클로헥산-1-올 (0.1 g, 0.24 mmol)을 실시예1의 단계7과 같은 방법으로 목적화합물 (0.02 g, 13%)을 얻었다.Example 15 with 2-(2-bromothiazol-5-yl)-5-(4-fluorophenyl)-1,3,4-oxadiazole (0.09 g, 0.29 mmol) obtained in step 2 of Example 15 (1R,4R)-4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclo obtained in step 4 of Example 3 Hexan-1-ol (0.1 g, 0.24 mmol) was used in the same manner as in step 7 of Example 1 to obtain the target compound (0.02 g, 13%).
1H-NMR (400 MHz, DMSO-d6) δ: 11.49 (s, 1H), 8.22 (s, 1H), 8.17-8.14 (m, 2H), 7.46 (t, 2H, J= 8.8 Hz), 6.60 (d, 1H, J= 8.0 Hz), 6.17 (s, 1H), 6.07 (s, 1H), (4.72 (d, 1H, J= 2.8 Hz), 4.00-3.94 (m, 1H), 3.59-3.50 (m, 3H), 3.24 (s, 2H), 2.69 (d, 2H, J= 10.8 Hz), 2.09 (d, 2H, J= 10.0 Hz), 1.91 (d, 2H, J= 10.4 Hz), 1.63 (t, 2H, J= 10.8 Hz), 1.53-1.45 (m, 2H), 1.31-1.22 (m, 2H), 1.04 (s, 3H), 1.03 (s, 3H). 1 H-NMR (400 MHz, DMSO-d6) δ: 11.49 (s, 1H), 8.22 (s, 1H), 8.17-8.14 (m, 2H), 7.46 (t, 2H, J= 8.8 Hz), 6.60 (d, 1H, J= 8.0 Hz), 6.17 (s, 1H), 6.07 (s, 1H), (4.72 (d, 1H, J= 2.8 Hz), 4.00-3.94 (m, 1H), 3.59-3.50 (m, 3H), 3.24 (s, 2H), 2.69 (d, 2H, J= 10.8 Hz), 2.09 (d, 2H, J= 10.0 Hz), 1.91 (d, 2H, J= 10.4 Hz), 1.63 (t, 2H, J = 10.8 Hz), 1.53-1.45 (m, 2H), 1.31-1.22 (m, 2H), 1.04 (s, 3H), 1.03 (s, 3H).
실시예 29. ((1R,4R)-4-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2)-일)티아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥실)메탄올의 합성Example 29. ((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)cyclohexyl)methanol
단계1) ((1R,4R)-4-((6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로헥실)메탄올의 합성Step 1) ((1R,4R)-4-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclohexyl ) synthesis of methanol
상기 실시예 3 단계 2에서 얻은 (2S,6R)-4-((2,6-디브로포피리딘-4-일)메틸)-2,6-디메틸몰포린 (109 mg, 0.3 mmol) 와 (트랜스-4-아미노사이클로헥실)메탄올 (193 mg, 1.5 mmol) 을 아세토나이트릴 (0.3M)에 녹이어 마이크로웨이브 이니시에이터에서 160℃에서 5시간 교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (123 mg, 100%)을 얻었다.(2S,6R)-4-((2,6-dibropopyridin-4-yl)methyl)-2,6-dimethylmorpholine (109 mg, 0.3 mmol) obtained in Example 3 step 2 above and ( Trans-4-aminocyclohexyl)methanol (193 mg, 1.5 mmol) was dissolved in acetonitrile (0.3M) and stirred in a microwave initiator at 160° C. for 5 hours. When the reaction is complete, 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 (123 mg, 100%).
단계2) ((1R,4R)-4-((6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로헥실)메탄올 합성Step 2) ((1R,4R)-4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclohexyl) methanol synthesis
상기 단계 1에서 얻은 ((1R,4R)-4-((6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로헥실)메탄올 (690 mg, 1.67 mmol), 쿠프릭 아세틸아세톤 (10 mol%), 세슘 카보네이트 (1.09 g, 3.34 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성한다, 이후 아세틸아세톤 (40 mol%), 암모니아 수용액 (3.9 mL, 33.46 mmol), 무수 다이메틸포름아마이드 (0.2M)를 차례로 넣고, 90 ℃에서 밤샘교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (400 mg, 68%)을 얻었다.((1R,4R)-4-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino) obtained in step 1 above Cyclohexyl) methanol (690 mg, 1.67 mmol), cupric acetylacetone (10 mol%), and cesium carbonate (1.09 g, 3.34 mmol) are placed in a shrink tube, and a nitrogen environment is created, then acetylacetone (40 mol) %), aqueous ammonia solution (3.9 mL, 33.46 mmol), and anhydrous dimethylformamide (0.2M) were sequentially added, followed by stirring at 90 °C overnight. When the reaction is complete, 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%).
단계3) ((1R,4R)-4-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2) -일)티아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥실)메탄올의 합성Step 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
상기 단계 2에서 얻은 ((1R,4R)-4-((6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로헥실)메탄올 (290 mg, 0.83 mmol)과 실시예 2의 단계 1에서 얻은 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (307 mg, 0.99 mmol)을 실시예 1의 단계 7와 같은 방법으로 반응하여 목적화합물 (124 mg, 25%)을 얻었다.((1R,4R)-4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclo obtained in step 2 above Hexyl)methanol (290 mg, 0.83 mmol) and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole obtained in step 1 of Example 2 (307 mg , 0.99 mmol) was reacted in the same manner as in step 7 of Example 1 to obtain the target compound (124 mg, 25%).
1H-NMR (400 MHz, DMSO-d6) δ: 11.48 (s, 1H), 8.19 (s, 1H),　8.08-8.05 (m, 2H),　7.66-7.60 (m, 3H),　6.04 (d, 1H, J=8 MHz), 6.16　(s, 1H), 6.06 (s, 1H),　4.38 (t, 1H, J=5.2 MHz), 4.05-3.95 (m. 1H),　3.59-3.55 (m, 2H), 3.30 (s, 2H),　 3.26-3.23 (m, 3H), 2.70-2.67 (m, 2H),　2.10-2.08 (m, 2H), 1.86-1.84 (m, 2H),　1.66-1.60 (m, 2H), 1.39-1.38 (m, 1H), 1.25-1.14 (m, 4H), 1.03 (d, 6H, J=6.4 MHz) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.48 (s, 1H), 8.19 (s, 1H), 8.08-8.05 (m, 2H), 7.66-7.60 (m, 3H), 6.04 (d , 1H, J=8 MHz), 6.16 (s, 1H), 6.06 (s, 1H), 4.38 (t, 1H, J=5.2 MHz), 4.05-3.95 (m. 1H), 3.59-3.55 (m, 2H), 3.30 (s, 2H), 3.26-3.23 (m, 3H), 2.70-2.67 (m, 2H), 2.10-2.08 (m, 2H), 1.86-1.84 (m, 2H), 1.66-1.60 ( m, 2H), 1.39-1.38 (m, 1H), 1.25-1.14 (m, 4H), 1.03 (d, 6H, J=6.4 MHz)
실시예 30. (1R,4R)-4-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-(2-플루오로페닐)-1,3,4- 옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로헥산-1-올의 합성Example 30. (1R,4R)-4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-(2-fluoro) Synthesis of phenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol
단계1) 2-플루오로벤조히드라지드의 합성Step 1) Synthesis of 2-fluorobenzohydrazide
실시예 15의 단계 1에서 메틸 4-플루오로벤조산나트륨대신 메틸 2-플루오로 벤조산나트륨 (2.00 g, 12.96 mmol)을 사용한 것을 제외하고, 같은 방법으로 목적화합물 (1.83 g, 92%)을 얻었다.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.
단계2) 2-(2-브로모티아졸-5-일)-5-(2-플루오로페닐)-1,3,4-옥사디아졸의 합성Step 2) Synthesis of 2-(2-bromothiazol-5-yl)-5-(2-fluorophenyl)-1,3,4-oxadiazole
상기 단계1에서 얻어진 2-플루오로벤조히드라지드 (1.00 g, 0.80 mmol)을 실시예2의 단계1과 같은 방법으로 목적화합물 (0.12 g, 7%)을 얻었다.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.
단계3) (1R,4R)-4-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-(2-플루오로페닐)-1,3,4- 옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로헥산-1-올의 합성Step 3) (1R,4R)-4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-(2-fluorophenyl) Synthesis of )-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol
상기 단계2에서 얻어진 2-(2-브로모티아졸-5-일)-5-(2-플루오로페닐)-1,3,4-옥사디아졸 (0.10 g, 0.30 mmol)와 실시예3의 단계4에서 얻어진 (1R,4R)-4-((6-아미노-4-(((2S,6R)-2,6-디메틸몰포리노)메틸)피리딘-2-일)아미노)사이클로헥산-1-올 (0.12 g, 0.36 mmol)을 실시예1의 단계7과 같은 방법으로 목적화합물 (0.03 g, 17%)을 얻었다.2-(2-bromothiazol-5-yl)-5-(2-fluorophenyl)-1,3,4-oxadiazole (0.10 g, 0.30 mmol) obtained in step 2 and the (1R,4R)-4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclohexane-1 obtained in step 4 -ol (0.12 g, 0.36 mmol) was used in the same manner as in step 7 of Example 1 to obtain the target compound (0.03 g, 17%).
1H-NMR (400 MHz, DMSO-d6) δ: 11.50 (s, 1H), 8.18 (s, 1H), 8.11 (t, 1H, J= 6.8 Hz), 7.70-7.68 (m, 1H), 7.52-7.44 (m, 2H), 6.59 (d, 1H, J= 5.6 Hz), 6.17 (s, 1H), 6.07 (s, 1H), 4.60 (s, 1H), 3.93 (s, 2H), 3.57 (m, 3H), 3.24 (s, 2H), 2.69 (d, 2H, J= 11.2 Hz), 2.08 (d, 2H, J= 11.6 Hz), 1.88 (d, 2H, J= 11.2 Hz), 1.63 (t, 2H, J= 10.8 Hz), 1.52-1.46 (m, 2H), 1.30-1.24 (m, 2H), 1.04 (s, 3H), 1.03 (s, 3H) 1 H-NMR (400 MHz, DMSO-d6) δ: 11.50 (s, 1H), 8.18 (s, 1H), 8.11 (t, 1H, J=6.8 Hz), 7.70-7.68 (m, 1H), 7.52 -7.44 (m, 2H), 6.59 (d, 1H, J= 5.6 Hz), 6.17 (s, 1H), 6.07 (s, 1H), 4.60 (s, 1H), 3.93 (s, 2H), 3.57 ( m, 3H), 3.24 (s, 2H), 2.69 (d, 2H, J= 11.2 Hz), 2.08 (d, 2H, J= 11.6 Hz), 1.88 (d, 2H, J= 11.2 Hz), 1.63 ( t, 2H, J = 10.8 Hz), 1.52-1.46 (m, 2H), 1.30-1.24 (m, 2H), 1.04 (s, 3H), 1.03 (s, 3H)
실시예 31. (1R,4R)-4-(((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2) -일)티아졸-2-일)아미노)피리딘-2-일)아미노)메틸)사이클로헥산-1-올의 합성Example 31. (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)cyclohexan-1-ol
단계1) (1R,4R)-4-(((6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)메틸)시클로헥산-1-올의 합성Step 1) (1R,4R)-4-(((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)methyl) Synthesis of cyclohexan-1-ol
상기 실시예 3 단계 2에서 얻은 (2S,6R)-4-((2,6-디브로포피리딘-4-일)메틸)-2,6-디메틸몰포린 (760 mg, 2.08 mmol) 와 트랜스-4-(아미노메틸)사이클로헥산-1-올 (270 mg, 2.08 mmol) 을 아세토나이트릴 (0.3M)에 녹이어 마이크로웨이브 이니시에이터에서 160℃에서 5시간 교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (175 mg, 24%)을 얻었다.(2S,6R)-4-((2,6-dibropopyridin-4-yl)methyl)-2,6-dimethylmorpholine (760 mg, 2.08 mmol) obtained in Example 3 step 2 above with trans -4-(aminomethyl)cyclohexan-1-ol (270 mg, 2.08 mmol) was dissolved in acetonitrile (0.3M) and stirred in a microwave initiator at 160° C. for 5 hours. When the reaction is complete, 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 (175 mg, 24%).
단계2) (1R,4R)-4-(((6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)메틸)시클로헥산-1-올 합성Step 2) (1R,4R)-4-(((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)methyl)cyclo Hexan-1-ol synthesis
상기 단계 1에서 얻은 (1R,4R)-4-(((6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)메틸)시클로헥산-1-올 (175 mg, 0.05 mmol), 쿠프릭 아세틸아세톤 (10 mol%), 세슘 카보네이트 (33 g, 0.10 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성한다, 이후 아세틸아세톤 (40 mol%), 암모니아 수용액 (0.1 mL, 1.00 mmol), 무수 다이메틸포름아마이드 (0.2M)를 차례로 넣고, 90 ℃에서 밤샘교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (40 mg, 25%)을 얻었다.(1R,4R)-4-(((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino) obtained in step 1 above Methyl)cyclohexan-1-ol (175 mg, 0.05 mmol), cupric acetylacetone (10 mol%), and cesium carbonate (33 g, 0.10 mmol) are placed in a shrink tube, and a nitrogen environment is established, then acetyl Acetone (40 mol%), aqueous ammonia solution (0.1 mL, 1.00 mmol), and anhydrous dimethylformamide (0.2M) are sequentially added, and the mixture is stirred at 90° C. overnight. When the reaction is complete, 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%).
단계3) (1R,4R)-4-(((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2) -일)티아졸-2-일)아미노)피리딘-2-일)아미노)메틸)사이클로헥산-1-올의 합성Step 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)methyl)cyclohexan-1-ol
상기 단계 2에서 얻은 (1R,4R)-4-(((6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)메틸)시클로헥산-1-올 (40 mg, 0.10 mmol)과 실시예 2의 단계 1에서 얻은 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (40 mg, 0.12 mmol)을 실시예 1의 단계 7와 같은 방법으로 반응하여 목적화합물 (31 mg, 50%)을 얻었다.(1R,4R)-4-(((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)methyl obtained in step 2 above ) Cyclohexan-1-ol (40 mg, 0.10 mmol) and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadia obtained in step 1 of Example 2 The sol (40 mg, 0.12 mmol) was reacted in the same manner as in step 7 of Example 1 to obtain the target compound (31 mg, 50%).
1H-NMR (400 MHz, DMSO-d6) δ: 11.48 (s, 1H), 8.20 (s, 1H), 8.06-8.05 (m, 2H), 7.66-7.61 (m, 3H), 6.87 (t, 1H, J=5.6 MHz), 6.17 (s, 1H), 6.09 (s, 1H), 4.43 (d, 1H, J=4.2 MHz), 3.59-3.56 (m, 2H), 3.33-3.30 (m, 1H), 3.18 (s, 2H), 2.69 (d, 2H, J=10.5 MHz), 1.95-1.93 (m, 2H), 1.83-1.82 (m, 2H), 1.65-1.59 (m, 3H), 1.09-0.99 (m, 12H) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.48 (s, 1H), 8.20 (s, 1H), 8.06-8.05 (m, 2H), 7.66-7.61 (m, 3H), 6.87 (t) , 1H, J=5.6 MHz), 6.17 (s, 1H), 6.09 (s, 1H), 4.43 (d, 1H, J=4.2 MHz), 3.59-3.56 (m, 2H), 3.33-3.30 (m, 1H), 3.18 (s, 2H), 2.69 (d, 2H, J=10.5 MHz), 1.95-1.93 (m, 2H), 1.83-1.82 (m, 2H), 1.65-1.59 (m, 3H), 1.09 -0.99 (m, 12H)
실시예 32. ((1R,4R)-4-(((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸- 2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)메틸)사이클로헥실)메탄올의 합성Example 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
단계1) ((1R,4R)-4-(((6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)메틸)시클로헥실)메탄올의 합성Step 1) ((1R,4R)-4-(((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)methyl ) Synthesis of cyclohexyl) methanol
상기 실시예 3 단계 2에서 얻은 (2S,6R)-4-((2,6-디브로포피리딘-4-일)메틸)-2,6-디메틸몰포린 (700 mg, 1.92 mmol) 와 (트랜스-4-(아미노메틸)사이클로헥실)메탄올 (520 mg, 3.63 mmol) 을 아세토나이트릴 (0.3M)에 녹이어 마이크로웨이브 이니시에이터에서 160℃에서 5시간 교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (522 mg, 63%)을 얻었다.(2S,6R)-4-((2,6-dibropopyridin-4-yl)methyl)-2,6-dimethylmorpholine (700 mg, 1.92 mmol) obtained in Example 3 step 2 above and ( Trans-4-(aminomethyl)cyclohexyl)methanol (520 mg, 3.63 mmol) was dissolved in acetonitrile (0.3M) and stirred in a microwave initiator at 160° C. for 5 hours. When the reaction is complete, 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 (522 mg, 63%).
단계2) ((1R,4R)-4-(((6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)메틸)시클로헥실)메탄올 합성Step 2) ((1R,4R)-4-(((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)methyl) Cyclohexyl) methanol synthesis
상기 단계 1에서 얻은 ((1R,4R)-4-(((6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)메틸)시클로헥실)메탄올 (540 mg, 1.26 mmol), 쿠프릭 아세틸아세톤 (10 mol%), 세슘 카보네이트 (825 g, 2.53 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성한다, 이후 아세틸아세톤 (40 mol%), 암모니아 수용액 (2.9 mL, 25.32mmol), 무수 다이메틸포름아마이드 (0.2M)를 차례로 넣고, 90 ℃에서 밤샘교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (40 mg, 8%)을 얻었다.((1R,4R)-4-(((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino obtained in step 1 above )methyl)cyclohexyl)methanol (540 mg, 1.26 mmol), cupric acetylacetone (10 mol%), and cesium carbonate (825 g, 2.53 mmol) are placed in a shrink tube, and a nitrogen environment is created, then acetylacetone (40 mol%), aqueous ammonia solution (2.9 mL, 25.32 mmol), and anhydrous dimethylformamide (0.2M) were sequentially added, followed by stirring at 90 °C overnight. When the reaction is complete, 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%).
단계3) ((1R,4R)-4-(((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸- 2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)메틸)사이클로헥실)메탄올의 합성Step 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
상기 단계 2에서 얻은 ((1R,4R)-4-(((6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)메틸)시클로헥실)메탄올 (40 mg, 0.11 mmol)과 실시예 2의 단계 1에서 얻은 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (40 mg, 0.13 mmol)을 실시예 1의 단계 7와 같은 방법으로 반응하여 목적화합물 (22 mg, 35%)을 얻었다.((1R,4R)-4-(((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino) obtained in step 2 above Methyl)cyclohexyl)methanol (40 mg, 0.11 mmol) and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole obtained in step 1 of Example 2 (40 mg, 0.13 mmol) was reacted in the same manner as in step 7 of Example 1 to obtain the target compound (22 mg, 35%).
1H-NMR (400 MHz, DMSO-d6) δ: 11.48 (s, 1H), 8.19 (s, 1H), 8.06-8.05 (m, 2H), 7.64-7.61 (m, 3H), 6.88-6.87 (m, 1H), 6.17 (s, 1H), 6.09 (s, 1H), 4.31 (t, 1H, J= 5.25 Hz), 3.59-3.56 (m, 2H), 3.25 (s, 2H), 3.18-3.16 (m, 2H), 2.70-2.68 (m, 2H), 2.00-1.98 (m, 2H), 1.75-1.74 (m, 2H), 1.65-1.62 (m, 4H), 1.33-1.30 (m, 1H), 1.24-1.23 (m, 1H), 1.03 (d, 6H, J=6.3 MHz), 1.02-0.96 (m, 2H), 0.87-0.83 (3, 2H) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.48 (s, 1H), 8.19 (s, 1H), 8.06-8.05 (m, 2H), 7.64-7.61 (m, 3H), 6.88-6.87 (m, 1H), 6.17 (s, 1H), 6.09 (s, 1H), 4.31 (t, 1H, J= 5.25 Hz), 3.59-3.56 (m, 2H), 3.25 (s, 2H), 3.18- 3.16 (m, 2H), 2.70-2.68 (m, 2H), 2.00-1.98 (m, 2H), 1.75-1.74 (m, 2H), 1.65-1.62 (m, 4H), 1.33-1.30 (m, 1H) ), 1.24-1.23 (m, 1H), 1.03 (d, 6H, J=6.3 MHz), 1.02-0.96 (m, 2H), 0.87-0.83 (3, 2H)
실시예 33. (1R,4R)-4-((4-(((2S,6R)-2,6-디메틸몰포리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Example 33. (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)cyclohexan-1-ol
단계1) (1R,4R)-4-((6-브로모피리딘-2-일)아미노)사이클로헥산-1-터트뷰틸 카바메이트의 합성Step 1) Synthesis of (1R,4R)-4-((6-bromopyridin-2-yl)amino)cyclohexane-1-tertbutyl carbamate
실시예 1의 단계 5에서 4-((2,6-디브로모피리딘-4-일)메틸)몰포린 대신 2,6-디브로모피리딘 (0.5g, 2.11mmol)을 사용하고 트랜스-4-아미노사이클로헥사놀 대신 1-N-Boc-트랜스-1,4-사이클로헥실아민 (0.45g, 2.11mmol)을 사용한 것을 제외하고 동일한 방법으로 반응하여 목적화합물 (0.23g, 29.6%)를 얻었다. In 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.
단계2) (1R,4R)-4-((6-아미노피리딘-2-일)아미노)사이클로헥산-1-터트뷰틸 카바메이트의 합성Step 2) Synthesis of (1R,4R)-4-((6-aminopyridin-2-yl)amino)cyclohexane-1-tertbutyl carbamate
상기 단계 1에서 얻은 (1R,4R)-4-((6-브로모피리딘-2-일)아미노)사이클로헥산-1-터트뷰틸 카바메이트 (230 mg, 0.62 mmol)을 실시예 1의 단계 6와 같은 방법으로 목적화합물 (116 mg, 61.0%)을 얻었다.(1R,4R)-4-((6-bromopyridin-2-yl)amino)cyclohexane-1-tertbutyl carbamate (230 mg, 0.62 mmol) obtained in step 1 above was prepared in step 6 of Example 1 The target compound (116 mg, 61.0%) was obtained in the same manner as described above.
단계 3) (1R,4R)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-터트뷰틸 카바메이트의 합성Step 3) (1R,4R)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino ) Synthesis of cyclohexane-1-tertbutyl carbamate
실시예 2의 단계 2에서 (1R,4R)-4-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올 대신 상기 단계 2에서 얻은 (1R,4R)-4-((6-아미노피리딘-2-일)아미노)사이클로헥산-1-터트뷰틸 카바메이트 (110 mg, 0.36 mmol)을 사용한 것을 제외하고 동일한 방법으로 반응하여 목적화합물 (20 mg, 10.5%)을 얻었다.In 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.
단계 4) (1R,4R)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)-4-아미노사이클로헥산의 합성Step 4) (1R,4R)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino ) Synthesis of -4-aminocyclohexane
상기 단계 3에서 얻은 ((1R,4R)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-터트뷰틸 카바메이트 (17 mg, 0.31 mmol)을 MC에 녹여 교반하며 상온에서 트리플로로아세틱 액시드 (240ul, 0.312mmol)넣고 약 1시간 교반한다. 반응이 완료되면 반응용액을 물로 씻어준뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (5 mg, 37.2%)을 얻었다.((1R,4R)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2- yl)amino)cyclohexane-1-tertbutyl carbamate (17 mg, 0.31 mmol) was dissolved in MC and stirred at room temperature to add trifluoroacetic acid (240ul, 0.312mmol) and stirred for about 1 hour. When the reaction is complete, the reaction solution is 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 (5 mg, 37.2%).
1H-NMR (400 MHz, DMSO-d6) δ: 8.24 (s, 1H), 8.13-8.05 (m, 3H), 7.96-7.89 (m, 3H), 7.35 (t, 1H, J = 2Hz), 6.21 (d, 1H, J = 2Hz), 6.12 (d, 1H, J = 2.2Hz), 4.04 (brs, 1H), 3.88 (brs, 1H), 3.01 (s, 1H), 2.90 (s, 1H), 2.73 (s, 1H), 1.37-1.18 (m, 8H) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8.24 (s, 1H), 8.13-8.05 (m, 3H), 7.96-7.89 (m, 3H), 7.35 (t, 1H, J = 2Hz) , 6.21 (d, 1H, J = 2 Hz), 6.12 (d, 1H, J = 2.2 Hz), 4.04 (brs, 1H), 3.88 (brs, 1H), 3.01 (s, 1H), 2.90 (s, 1H) ), 2.73 (s, 1H), 1.37-1.18 (m, 8H)
실시예 34. (2-(4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2- 일)아미노)피리딘-2-일)페닐)메탄올의 합성Example 34. (2-(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
단계1) 6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-아민의 합성Step 1) Synthesis of 6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-amine
마이크로파 바이알에 (2S,6R)-4-((2,6-디브로포피리딘-4-일)메틸)-2,6-디메틸몰포린 (2g, 5.49mmol)을 아이소프로필알코올 (3mL)에 녹인 후 암모니아 수용액 (4mL)를 적가한다. 반응 용액을 마이크로파로 160℃에서 15시간 교반한다. 반응이 완결되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (1.31g, 80%)을 얻었다.(2S,6R)-4-((2,6-dibropopyridin-4-yl)methyl)-2,6-dimethylmorpholine (2g, 5.49mmol) in isopropyl alcohol (3mL) in a microwave vial After dissolving, aqueous ammonia solution (4 mL) is added dropwise. The reaction solution is stirred in a microwave at 160° C. for 15 hours. When the reaction is complete, 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 (1.31 g, 80%).
단계2) (2-(6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)페닐)메탄올 합성Step 2) Synthesis of (2-(6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)phenyl)methanol
마이크로파 바이알에 상기 단계 1에서 합성된 6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-아민 (150 mg, 0.49 mmol)과 2-(하이드록시메틸)페닐보로닉 애시드 (83 mg, 0.54 mmol), 탄산나트륨 (105 mg, 0.99mmol), [1,1’-비스(디페닐포스피노)페로센]다이클로로팔라듐(Ⅱ) 다이클로로메탄 착물 (81 mg, 0.099 mmol) 을 1,4-디옥세인:물 (1:1 용액, 4mL)에 녹이어준 후 반응 용액을 마이크로파로 120℃에서 1시간 교반한다. 반응이 완결되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (123 mg, 75%)을 얻었다.6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-amine (150 mg, 0.49 mmol) synthesized in step 1 and 2- (hydroxymethyl)phenylboronic acid (83 mg, 0.54 mmol), sodium carbonate (105 mg, 0.99mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloro After dissolving the methane complex (81 mg, 0.099 mmol) in 1,4-dioxane:water (1:1 solution, 4mL), the reaction solution was stirred at 120° C. in a microwave for 1 hour. When the reaction is complete, 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%).
단계3) (2-(4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2- 일)아미노)피리딘-2-일)페닐)메탄올 합성Step 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
상기 단계 2에서 합성된 (2-(6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)페닐)메탄올 (65 mg, 0.19 mmol)과 실시예 2의 단계1에서 합성된 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (73 mg, 0.23 mmol)를 실시예 2의 단계 2과 같은 방법으로 반응하여 목적화합물 (30 mg, 27%)을 얻었다.(2-(6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)phenyl)methanol (65 mg, 0.19 mmol) synthesized in step 2 above ) and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (73 mg, 0.23 mmol) synthesized in step 1 of Example 2 in Example 2 The target compound (30 mg, 27%) was obtained by reacting in the same manner as in step 2.
1H-NMR (400 MHz, DMSO-d6) δ: 12.01 (s, 1H),　8.25 (s, 1H),　8.06-8.04 (m, 2H), 7.70-7.68 (m, 1H), 7.63-7.61 (m, 4H), 7.53-7.49 (m, 1H), 7.45-7.42 (m, 1H), 7.15 (s, 1H), 7.13 (s, 1H),　5.10　(t, 1H, J=5.38MHz), 4.64 (d, 2H, J=5.24MHz), 3.64-3.60 (m, 2H), 3.55 (s, 2H), 2.75 (d, 2H, J=10.64 MHz), 1.73 (t, 2H, J=10.56MHz), 1.06 (d, 6H, J=6.32 MHz) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.01 (s, 1H), 8.25 (s, 1H), 8.06-8.04 (m, 2H), 7.70-7.68 (m, 1H), 7.63-7.61 (m, 4H), 7.53-7.49 (m, 1H), 7.45-7.42 (m, 1H), 7.15 (s, 1H), 7.13 (s, 1H), 5.10 (t, 1H, J=5.38 MHz), 4.64 (d, 2H, J=5.24 MHz), 3.64-3.60 (m, 2H), 3.55 (s, 2H), 2.75 (d, 2H, J=10.64 MHz), 1.73 (t, 2H, J=10.56 MHz) ), 1.06 (d, 6H, J=6.32 MHz)
실시예 35. (3-(4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2- 일)아미노)피리딘-2-일)페닐)메탄올의 합성Example 35. (3-(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
단계1) (3-(6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)페닐)메탄올의 합성Step 1) Synthesis of (3-(6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)phenyl)methanol
마이크로파 바이알에 상기 실시예 34 단계 1에서 합성된 6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-아민 (150 mg, 0.49 mmol)과 3-(하이드록시메틸)페닐보로닉 애시드 (83 mg, 0.54 mmol), 탄산나트륨 (105 mg, 0.99mmol), [1,1’-비스(디페닐포스피노)페로센]다이클로로팔라듐(Ⅱ) 다이클로로메탄 착물 (81 mg, 0.099 mmol) 을 1,4-디옥세인:물 (1:1 용액, 4mL)에 녹이어준 후 반응 용액을 마이크로파로 120℃에서 1시간 교반한다. 반응이 완결되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (160 mg, 100%)을 얻었다.6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-amine (150 mg, 0.49 mmol) synthesized in Example 34 step 1 above in a microwave vial and 3-(hydroxymethyl)phenylboronic acid (83 mg, 0.54 mmol), sodium carbonate (105 mg, 0.99mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) ) dichloromethane complex (81 mg, 0.099 mmol) was dissolved in 1,4-dioxane:water (1:1 solution, 4mL), and the reaction solution was stirred at 120°C in a microwave for 1 hour. When the reaction is complete, 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%).
단계3) (3-(4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2- 일)아미노)피리딘-2-일)페닐)메탄올 합성Step 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
상기 단계 2에서 합성된 (3-(6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)페닐)메탄올 (74 mg, 0.22 mmol)과 실시예 2의 단계1에서 합성된 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (83 mg, 0.27 mmol)를 실시예 2의 단계 2과 같은 방법으로 반응하여 목적화합물 (40 mg, 32%)을 얻었다.(3-(6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)phenyl)methanol (74 mg, 0.22 mmol) synthesized in step 2 above ) and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (83 mg, 0.27 mmol) synthesized in step 1 of Example 2 in Example 2 The target compound (40 mg, 32%) was obtained by reacting in the same manner as in step 2.
1H-NMR (400 MHz, DMSO-d6) δ: 12.04 (s, 1H),　8.30 (s, 1H), 8.20 (s, 1H),　8.11-8.08 (m, 3H), 7.65-7.62 (m, 3H), 7.57-7.48 (m, 3H), 7.13 (s, 1H), 5.36　(t, 1H, J=5.82MHz), 4.68 (d, 2H, J=5.76MHz), 3.65-3.59 (m, 2H), 3.56 (s, 2H), 2.75 (d, 2H, J=10.48 MHz), 1.73 (t, 2H, J=10.64MHz), 1.05 (d, 6H, J=6.24 MHz) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.04 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 8.11-8.08 (m, 3H), 7.65-7.62 (m) , 3H), 7.57-7.48 (m, 3H), 7.13 (s, 1H), 5.36 (t, 1H, J=5.82 MHz), 4.68 (d, 2H, J=5.76 MHz), 3.65-3.59 (m, 2H), 3.56 (s, 2H), 2.75 (d, 2H, J=10.48 MHz), 1.73 (t, 2H, J=10.64 MHz), 1.05 (d, 6H, J=6.24 MHz)
실시예 36. (4-(4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2- 일)아미노)피리딘-2-일)페닐)메탄올의 합성Example 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
단계1) (4-(6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)페닐)메탄올의 합성Step 1) Synthesis of (4-(6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)phenyl)methanol
마이크로파 바이알에 상기 실시예 34 단계 1에서 합성된 6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-아민 (150 mg, 0.49 mmol)과 4-(하이드록시메틸)페닐보로닉 애시드 (83 mg, 0.54 mmol), 탄산나트륨 (105 mg, 0.99mmol), [1,1’-비스(디페닐포스피노)페로센]다이클로로팔라듐(Ⅱ) 다이클로로메탄 착물 (81 mg, 0.099 mmol) 을 1,4-디옥세인:물 (1:1 용액, 4mL)에 녹이어준 후 반응 용액을 마이크로파로 120℃에서 1시간 교반한다. 반응이 완결되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (160 mg, 100%)을 얻었다.6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-amine (150 mg, 0.49 mmol) synthesized in Example 34 step 1 above in a microwave vial and 4- (hydroxymethyl) phenylboronic acid (83 mg, 0.54 mmol), sodium carbonate (105 mg, 0.99 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II ) dichloromethane complex (81 mg, 0.099 mmol) was dissolved in 1,4-dioxane:water (1:1 solution, 4mL), and the reaction solution was stirred at 120°C in a microwave for 1 hour. When the reaction is complete, 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%).
단계3) (4-(4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2- 일)아미노)피리딘-2-일)페닐)메탄올 합성Step 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
상기 단계 2에서 합성된 (4-(6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)페닐)메탄올 (91 mg, 0.27 mmol)과 실시예 2의 단계1에서 합성된 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (102 mg, 0.33 mmol)를 실시예 2의 단계 2과 같은 방법으로 반응하여 목적화합물 (60 mg, 38%)을 얻었다.(4-(6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)phenyl)methanol (91 mg, 0.27 mmol) synthesized in step 2 above ) and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (102 mg, 0.33 mmol) synthesized in step 1 of Example 2 in Example 2 The target compound (60 mg, 38%) was obtained by reacting in the same manner as in step 2.
1H-NMR (400 MHz, DMSO-d6) δ: 12.03 (s, 1H),　8.29 (s, 1H), 8.19-8.17 (m, 2H), 8.10-8.08(m, 2H), 7.66-7.64 (m, 3H), 7.54-7.51 (m, 3H), 7.12 (s, 1H), 5.33　(t, 1H, J=5.7MHz), 4.62 (d, 2H, J=5.6MHz), 3.65-3.61 (m, 2H), 3.55 (s, 2H), 2.59 (d, 2H, J=10.6 MHz), 1.73 (t, 2H, J=10.6MHz), 1.05 (d, 6H, J=6.2 MHz) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12.03 (s, 1H), 8.29 (s, 1H), 8.19-8.17 (m, 2H), 8.10-8.08 (m, 2H), 7.66-7.64 (m, 3H), 7.54-7.51 (m, 3H), 7.12 (s, 1H), 5.33 (t, 1H, J=5.7 MHz), 4.62 (d, 2H, J=5.6 MHz), 3.65-3.61 ( m, 2H), 3.55 (s, 2H), 2.59 (d, 2H, J=10.6 MHz), 1.73 (t, 2H, J=10.6 MHz), 1.05 (d, 6H, J=6.2 MHz)
실시예 37. 5-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2- 일)아미노)피리딘-2-일)아미노)시클로옥탄-1-올의 합성Example 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
단계1) 5-((6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로옥탄-1-올의 합성Step 1) Synthesis of 5-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclooctan-1-ol
상기 실시예 3 단계 2에서 얻은 (2S,6R)-4-((2,6-디브로포피리딘-4-일)메틸)-2,6-디메틸몰포린 (700 mg, 1.92 mmol), 5-아미노사이클로옥탄올 하이드로클로라이드 (380 mg, 2.11 mmol), 트리스(디벤질인덴아세톤)디팔라듐 (10 mol%), 잔트포스 (10 mol%) 나트륨-터트-부톡사이트 (480 mg, 4.99 mmol)을 무수 1,4-디옥세인 (0.2M)에 녹인 후, 상온에서 4시간 교반한다. 반응이 완료되면 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (516 mg, 63%)을 얻었다.(2S,6R)-4-((2,6-dibropopyridin-4-yl)methyl)-2,6-dimethylmorpholine (700 mg, 1.92 mmol) obtained in Example 3 step 2 above, 5 -aminocyclooctanol hydrochloride (380 mg, 2.11 mmol), tris(dibenzylindeneacetone)dipalladium (10 mol%), xanthos (10 mol%) sodium-tert-butoxide (480 mg, 4.99 mmol) ) was dissolved in anhydrous 1,4-dioxane (0.2M), followed by stirring at room temperature for 4 hours. When the reaction is complete, extraction is performed 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 (516 mg, 63%).
단계2) 5-((6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로옥탄-1-올 합성Step 2) Synthesis of 5-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclooctan-1-ol
상기 단계 1에서 얻은 5-((6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로옥탄-1-올 (519 mg, 1.21 mmol), 쿠프릭 아세틸아세톤 (10 mol%), 세슘 카보네이트 (7.64 g, 2.42 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성한다, 이후 아세틸아세톤 (40 mol%), 암모니아 수용액 (2.82 mL, 24.20 mmol), 무수 다이메틸포름아마이드 (0.2M)를 차례로 넣고, 90 ℃에서 밤샘교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (340 mg, 77%)을 얻었다.5-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclooctan-1-ol obtained in step 1 above ( 519 mg, 1.21 mmol), cupric acetylacetone (10 mol%), and cesium carbonate (7.64 g, 2.42 mmol) are placed in a shrink tube, and a nitrogen environment is created, then acetylacetone (40 mol%), aqueous ammonia solution (2.82 mL, 24.20 mmol) and anhydrous dimethylformamide (0.2M) were sequentially added, followed by stirring at 90 °C overnight. When the reaction is complete, 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%).
단계3) 5-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2- 일)아미노)피리딘-2-일)아미노)시클로옥탄-1-올의 합성Step 3) 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
상기 단계 2에서 얻은 5-((6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로옥탄-1-올 (340 mg, 0.93 mmol)과 실시예 2의 단계 1에서 얻은 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (346 mg, 1.12 mmol)을 실시예 1의 단계 7와 같은 방법으로 반응하여 목적화합물 (193 mg, 35%)을 얻었다.5-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclooctan-1-ol (340 mg, 0.93 mmol) and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (346 mg, 1.12 mmol) obtained in step 1 of Example 2 The target compound (193 mg, 35%) was obtained by reacting in the same manner as in step 7 of Example 1.
1H-NMR (400 MHz, DMSO-d6) δ: 11.48 (s, 1H), 8.21 (s, 1H), 8.07-8.06 (m, 2H), 7.65-7.64 (m, 3H), 6.40-6.39 (m, 1H), 6.16 (s, 1H), 6.07 (s, 1H), 4.33-4.18 (m, 2H), 3.80-3.71 (m, 1H), 3.58-3.56 (m, 2H), 3.24 (s, 2H), 2.70-2.67 (m, 2H), 1.98-1.93 (m, 3H), 1.81-1.74 (m, 3H), 1.66-1.55 (m, 8H), 1.03 (d, 6H, J=6.24 MHz)　 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.48 (s, 1H), 8.21 (s, 1H), 8.07-8.06 (m, 2H), 7.65-7.64 (m, 3H), 6.40-6.39 (m, 1H), 6.16 (s, 1H), 6.07 (s, 1H), 4.33-4.18 (m, 2H), 3.80-3.71 (m, 1H), 3.58-3.56 (m, 2H), 3.24 (s) , 2H), 2.70-2.67 (m, 2H), 1.98-1.93 (m, 3H), 1.81-1.74 (m, 3H), 1.66 1.55 (m, 8H), 1.03 (d, 6H, J=6.24 MHz) )
실시예 38. d(1R,3R)-3-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2- 일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로펜탄-1-올의 합성Example 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
단계1) (1R,3R)-3-((6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로펜탄-1-올의 합성Step 1) (1R,3R)-3-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclopentane- 1-ol synthesis
상기 실시예 3 단계 2에서 얻은 (2S,6R)-4-((2,6-디브로포피리딘-4-일)메틸)-2,6-디메틸몰포린 (800 mg, 2.19 mmol), 트랜스-3-아미노사이클로펜탄올 하이드로클로라이드 (362 mg, 2.63 mmol), 탄산수소나트륨 (221 mg, 2.63 mmol) 을 아세토나이트릴 (0.3M)에 녹이어 마이크로웨이브 이니시에이터에서 160℃에서 5시간 교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (233 mg, 27%)을 얻었다.(2S,6R)-4-((2,6-dibropopyridin-4-yl)methyl)-2,6-dimethylmorpholine (800 mg, 2.19 mmol) obtained in Example 3 step 2 above, trans -3-Aminocyclopentanol hydrochloride (362 mg, 2.63 mmol) and sodium hydrogen carbonate (221 mg, 2.63 mmol) were dissolved in acetonitrile (0.3M) and stirred in a microwave initiator at 160° C. for 5 hours. When the reaction is complete, 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 (233 mg, 27%).
단계2) (1R,3R)-3-((6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로펜탄-1-올 합성Step 2) (1R,3R)-3-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclopentane-1 -All synthesis
상기 단계 1에서 얻은 (1R,3R)-3-((6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로펜탄-1-올 (233 mg, 0.60 mmol), 쿠프릭 아세틸아세톤 (10 mol%), 세슘 카보네이트 (3.82 g, 1.21 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성한다, 이후 아세틸아세톤 (40 mol%), 암모니아 수용액 (1.41 mL, 12.12 mmol), 무수 다이메틸포름아마이드 (0.2M)를 차례로 넣고, 90 ℃에서 밤샘교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (150 mg, 77%)을 얻었다.(1R,3R)-3-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclo obtained in step 1 above Pentan-1-ol (233 mg, 0.60 mmol), cupric acetylacetone (10 mol%), and cesium carbonate (3.82 g, 1.21 mmol) are placed in a shrink tube, and a nitrogen environment is created, then acetylacetone (40 mol%), aqueous ammonia solution (1.41 mL, 12.12 mmol), and anhydrous dimethylformamide (0.2M) are sequentially added, and the mixture is stirred at 90 °C overnight. When the reaction is complete, 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%).
단계3) (1R,3R)-3-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2- 일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로펜탄-1-올의 합성Step 3) (1R,3R)-3-((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)cyclopentan-1-ol
상기 단계 2에서 얻은 (1R,3R)-3-((6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로펜탄-1-올 (90 mg, 0.28 mmol)과 실시예 2의 단계 1에서 얻은 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (103 mg, 0.33 mmol)을 실시예 1의 단계 7와 같은 방법으로 반응하여 목적화합물 (53 mg, 35%)을 얻었다.(1R,3R)-3-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclopentane obtained in step 2 above -1-ol (90 mg, 0.28 mmol) and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole obtained in step 1 of Example 2 (103 mg, 0.33 mmol) was reacted in the same manner as in step 7 of Example 1 to obtain the target compound (53 mg, 35%).
1H-NMR (400 MHz, DMSO-d6) δ: 11.48 (s, 1H), 8.20 (s, 1H),　8.10-8.08 (m, 2H),　7.64-7.59 (m, 3H),　6.71(d, 1H, J=7.24 MHz), 6.18　(s, 1H), 6.07 (s, 1H),　4.61-4.56 (m, 2H), 4.31-4.25 (m, 1H), 3.59-3.55 (m, 2H), 3.25 (s, 2H), 2.70-2.68 (m, 2H),　2.32-2.24 (m, 1H), 2.01-1.90 (m, 2H),　1.81-1.75 (m, 1H),　1.66-1.50 (m, 3H), 1.48-1.04 (m, 1H), 1.03 (d, 6H, J=6.24 MHz)　 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.48 (s, 1H), 8.20 (s, 1H), 8.10-8.08 (m, 2H), 7.64-7.59 (m, 3H), 6.71 (d) , 1H, J=7.24 MHz), 6.18 (s, 1H), 6.07 (s, 1H), 4.61-4.56 (m, 2H), 4.31-4.25 (m, 1H), 3.59-3.55 (m, 2H), 3.25 (s, 2H), 2.70-2.68 (m, 2H), 2.32-2.24 (m, 1H), 2.01-1.90 (m, 2H), 1.81-1.75 (m, 1H), 1.66-1.50 (m, 3H) ), 1.48-1.04 (m, 1H), 1.03 (d, 6H, J=6.24 MHz)
실시예 39. (1S,3S)-3-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2- 일)티아졸-2-일)아미노)피리딘-2-일)아미노)사이클로펜탄-1-올의 합성Example 39. (1S,3S)-3-((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)cyclopentan-1-ol
단계1) (1S,3S)-3-((6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로펜탄-1-올의 합성Step 1) (1S,3S)-3-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclopentane- 1-ol synthesis
상기 실시예 3 단계 2에서 얻은 (2S,6R)-4-((2,6-디브로포피리딘-4-일)메틸)-2,6-디메틸몰포린 (800 mg, 2.19 mmol), (1S,3S)-3-아미노사이클로펜탄올 하이드로클로라이드 (362 mg, 2.63 mmol), 탄산수소나트륨 (221 mg, 2.63 mmol) 을 아세토나이트릴 (0.3M)에 녹이어 마이크로웨이브 이니시에이터에서 160℃에서 5시간 교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (468 mg, 55%)을 얻었다.(2S,6R)-4-((2,6-dibropopyridin-4-yl)methyl)-2,6-dimethylmorpholine (800 mg, 2.19 mmol) obtained in Example 3 step 2 above, ( 1S,3S)-3-aminocyclopentanol hydrochloride (362 mg, 2.63 mmol) and sodium hydrogen carbonate (221 mg, 2.63 mmol) were dissolved in acetonitrile (0.3M) in a microwave initiator at 160°C for 5 time to stir. When the reaction is complete, 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 (468 mg, 55%).
단계2) (1S,3S)-3-((6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로펜탄-1-올 합성Step 2) (1S,3S)-3-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclopentane-1 -All synthesis
상기 단계 1에서 얻은 (1S,3S)-3-((6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로펜탄-1-올 (468 mg, 1.21 mmol), 쿠프릭 아세틸아세톤 (10 mol%), 세슘 카보네이트 (770 mg, 2.43 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성한다, 이후 아세틸아세톤 (40 mol%), 암모니아 수용액 (2.84 mL, 24.392 mmol), 무수 다이메틸포름아마이드 (0.2M)를 차례로 넣고, 90 ℃에서 밤샘교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (270 mg, 70%)을 얻었다.(1S,3S)-3-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclo obtained in step 1 above Pentan-1-ol (468 mg, 1.21 mmol), cupric acetylacetone (10 mol%), and cesium carbonate (770 mg, 2.43 mmol) are placed in a shrink tube, and a nitrogen environment is created, then acetylacetone (40 mol%), aqueous ammonia solution (2.84 mL, 24.392 mmol), and anhydrous dimethylformamide (0.2M) were sequentially added, followed by stirring at 90 °C overnight. When the reaction is complete, 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%).
단계3) (1S,3S)-3-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2- 일)티아졸-2-일)아미노)피리딘-2-일)아미노)사이클로펜탄-1-올의 합성Step 3) (1S,3S)-3-((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)cyclopentan-1-ol
상기 단계 2에서 얻은 (1S,3S)-3-((6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로펜탄-1-올 (148 mg, 0.46 mmol)과 실시예 2의 단계 1에서 얻은 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (170 mg, 0.55 mmol)을 실시예 1의 단계 7와 같은 방법으로 반응하여 목적화합물 (88 mg, 35%)을 얻었다.(1S,3S)-3-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclopentane obtained in step 2 above -1-ol (148 mg, 0.46 mmol) and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole obtained in step 1 of Example 2 (170 mg, 0.55 mmol) was reacted in the same manner as in step 7 of Example 1 to obtain the target compound (88 mg, 35%).
1H-NMR (400 MHz, DMSO-d6) δ: 11.49 (s, 1H), 8.20 (s, 1H),　8.10-8.08 (m, 2H),　7.64-7.59 (m, 3H),　6.71(d, 1H, J=7.2 MHz), 6.18　(s, 1H), 6.06 (s, 1H),　4.61-4.57 (m, 2H), 4.29-4.28 (m, 1H),　3.60-3.54 (m, 2H), 3.25 (s, 2H), 2.70-2.68 (m, 2H),　2.32-2.24 (m, 1H), 2.02-1.91 (m, 2H),　1.81-1.75 (m, 1H),　1.66-1.54 (m, 3H), 1.50-1.42 (m, 1H), 1.03 (d, 6H, J=6.24 MHz) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.49 (s, 1H), 8.20 (s, 1H), 8.10-8.08 (m, 2H), 7.64-7.59 (m, 3H), 6.71 (d) , 1H, J=7.2 MHz), 6.18 (s, 1H), 6.06 (s, 1H), 4.61-4.57 (m, 2H), 4.29-4.28 (m, 1H), 3.60-3.54 (m, 2H), 3.25 (s, 2H), 2.70-2.68 (m, 2H), 2.32-2.24 (m, 1H), 2.02-1.91 (m, 2H), 1.81-1.75 (m, 1H), 1.66-1.54 (m, 3H) ), 1.50-1.42 (m, 1H), 1.03 (d, 6H, J=6.24 MHz)
실시예 40. (1R,4R)-4-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-카보니트릴 의 합성Example 40. (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)cyclohexane-1-carbonitrile
단계1) (1R,4R)-4-((6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로헥산-1-카르보니트릴의 합성Step 1) (1R,4R)-4-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclohexane- Synthesis of 1-carbonitrile
상기 실시예 3 단계 2에서 얻은 (2S,6R)-4-((2,6-디브로포피리딘-4-일)메틸)-2,6-디메틸몰포린 (700 mg, 1.92 mmol),트랜스-4-아미노사이클로헥세인카보나이드릴 하이드로클로라이드 (339 mg, 2.12 mmol), 트리스(디벤질인덴아세톤)디팔라듐 (10 mol%), 잔트포스 (10 mol%) 나트륨-터트-부톡사이트 (463 mg, 4.82 mmol)을 무수 1,4-디옥세인 (0.2M)에 녹인 후, 상온에서 4시간 교반한다. 반응이 완료되면 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (608 mg, 77%)을 얻었다.(2S,6R)-4-((2,6-dibropopyridin-4-yl)methyl)-2,6-dimethylmorpholine (700 mg, 1.92 mmol), trans -4-aminocyclohexanecarbonidyl hydrochloride (339 mg, 2.12 mmol), tris(dibenzylindeneacetone)dipalladium (10 mol%), xanthos (10 mol%) sodium-tert-butoxide ( 463 mg, 4.82 mmol) was dissolved in anhydrous 1,4-dioxane (0.2M), followed by stirring at room temperature for 4 hours. When the reaction is complete, extraction is performed 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 (608 mg, 77%).
단계2) (1R,4R)-4-((6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로헥산-1-카르보니트릴 합성Step 2) (1R,4R)-4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclohexane-1 - Synthesis of carbonitrile
상기 단계 1에서 얻은 (1R,4R)-4-((6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로헥산-1-카르보니트릴 (608 mg, 1.49 mmol), 쿠프릭 아세틸아세톤 (10 mol%), 세슘 카보네이트 (942 mg, 2.98 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성한다, 이후 아세틸아세톤 (40 mol%), 암모니아 수용액 (3.48 mL, 29.85 mmol), 무수 다이메틸포름아마이드 (0.2M)를 차례로 넣고, 90 ℃에서 밤샘교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (323 mg, 63%)을 얻었다.(1R,4R)-4-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclo obtained in step 1 above Hexane-1-carbonitrile (608 mg, 1.49 mmol), cupric acetylacetone (10 mol%), and cesium carbonate (942 mg, 2.98 mmol) are placed in a shrink tube, and a nitrogen environment is created, then acetylacetone ( 40 mol%), aqueous ammonia solution (3.48 mL, 29.85 mmol), and anhydrous dimethylformamide (0.2M) were sequentially added, followed by stirring at 90 °C overnight. When the reaction is complete, 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%).
단계3) (1R,4R)-4-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2- 일)티아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-카보니트릴의 합성Step 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)cyclohexane-1-carbonitrile
상기 단계 2에서 얻은 (1R,4R)-4-((6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)시클로헥산-1-카르보니트릴 (140 mg, 0.41 mmol)과 실시예 2의 단계 1에서 얻은 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (152 mg, 0.49 mmol)을 실시예 1의 단계 7와 같은 방법으로 반응하여 목적화합물 (82 mg, 35%)을 얻었다.(1R,4R)-4-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclohexane obtained in step 2 above -1-carbonitrile (140 mg, 0.41 mmol) and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole obtained in step 1 of Example 2 ( 152 mg, 0.49 mmol) was reacted in the same manner as in step 7 of Example 1 to obtain the target compound (82 mg, 35%).
1H-NMR (400 MHz, DMSO-d6) δ: 11.51 (s, 1H), 8.21 (s, 1H),　8.09-8.06 (m, 2H),　7.64-7.61 (m, 3H),　6.70 (d, 1H, J=7.64 MHz), 6.19　(s, 1H), 6.09 (s, 1H),　4.05-4.00 (m, 1H), 3.59-3.55 (m, 2H),　3.25 (s, 2H), 2.81-2.75 (m, 1H),　2.70-2.67 (m, 2H), 2.14-2.11 (m, 4H),　1.83-1.74 (m, 2H),　1.66-1.60 (m, 2H), 1.38-1.30 (m, 2H), 1.03 (d, 6H, J=6.24 MHz) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.51 (s, 1H), 8.21 (s, 1H), 8.09-8.06 (m, 2H), 7.64-7.61 (m, 3H), 6.70 (d) , 1H, J=7.64 MHz), 6.19 (s, 1H), 6.09 (s, 1H), 4.05-4.00 (m, 1H), 3.59-3.55 (m, 2H), 3.25 (s, 2H), 2.81 2.75 (m, 1H), 2.70-2.67 (m, 2H), 2.14-2.11 (m, 4H), 1.83-1.74 (m, 2H), 1.66-1.60 (m, 2H), 1.38-1.30 (m, 2H) ), 1.03 (d, 6H, J=6.24 MHz)
실시예 41. ((2S,5R)-5-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2) -일)티아졸-2-일)아미노)피리딘-2-일)아미노)테트라하이드로-2H-피란-2-일)메탄올 의 합성Example 41. ((2S,5R)-5-((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)tetrahydro-2H-pyran-2-yl)methanol
단계1) ((2S,5R)-5-((6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)테트라히드로-2H-피란-2-일 )메탄올의 합성Step 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
상기 실시예 3 단계 2에서 얻은 (2S,6R)-4-((2,6-디브로포피리딘-4-일)메틸)-2,6-디메틸몰포린 (800 mg, 2.19 mmol), ((2S,5R)-5-아미노테트라하이드로-2H-피란-2-일)메탄올 하이드로클로라이드 (440 mg, 2.63 mmol), 탄산수소나트륨 (221 mg, 2.63 mmol) 을 아세토나이트릴 (0.3M)에 녹이어 마이크로웨이브 이니시에이터에서 160℃에서 5시간 교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (447 mg, 60%)을 얻었다.(2S,6R)-4-((2,6-dibropopyridin-4-yl)methyl)-2,6-dimethylmorpholine (800 mg, 2.19 mmol) obtained in Example 3 step 2 above, ( (2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol hydrochloride (440 mg, 2.63 mmol), sodium hydrogen carbonate (221 mg, 2.63 mmol) in acetonitrile (0.3M) Dissolve and stir in a microwave initiator at 160° C. for 5 hours. When the reaction is complete, 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%).
단계2) ((2S,5R)-5-((6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)테트라히드로-2H-피란-2-일 )메탄올 합성Step 2) ((2S,5R)-5-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)tetrahydro- 2H-pyran-2-yl) methanol synthesis
상기 단계 1에서 얻은 ((2S,5R)-5-((6-브로모-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)테트라히드로-2H-피란-2-일 )메탄올 (447 mg, 1.08 mmol), 쿠프릭 아세틸아세톤 (10 mol%), 세슘 카보네이트 (704 mg, 2.98 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성한다, 이후 아세틸아세톤 (40 mol%), 암모니아 수용액 (2.52 mL, 21.6 mmol), 무수 다이메틸포름아마이드 (0.2M)를 차례로 넣고, 90 ℃에서 밤샘교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (323 mg, 63%)을 얻었다.((2S,5R)-5-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino) obtained in step 1 above Tetrahydro-2H-pyran-2-yl)methanol (447 mg, 1.08 mmol), cupric acetylacetone (10 mol%), and cesium carbonate (704 mg, 2.98 mmol) were placed in a shrink tube, and a nitrogen environment was created After that, acetylacetone (40 mol%), aqueous ammonia solution (2.52 mL, 21.6 mmol), and anhydrous dimethylformamide (0.2M) are sequentially added, and the mixture is stirred at 90 °C overnight. When the reaction is complete, 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%).
단계3) ((2S,5R)-5-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2) -일)티아졸-2-일)아미노)피리딘-2-일)아미노)테트라하이드로-2H-피란-2-일)메탄올의 합성Step 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
상기 단계 2에서 얻은 ((2S,5R)-5-((6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)아미노)테트라히드로-2H-피란-2-일 )메탄올 (47 mg, 0.11 mmol)과 실시예 2의 단계 1에서 얻은 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (41 mg, 0.13 mmol)을 실시예 1의 단계 7와 같은 방법으로 반응하여 목적화합물 (22 mg, 35%)을 얻었다.((2S,5R)-5-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)tetra obtained in step 2 above Hydro-2H-pyran-2-yl)methanol (47 mg, 0.11 mmol) and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3 obtained in step 1 of Example 2, 4-oxadiazole (41 mg, 0.13 mmol) was reacted in the same manner as in step 7 of Example 1 to obtain the target compound (22 mg, 35%).
1H-NMR (400 MHz, DMSO-d6) δ: 11.51 (s, 1H), 8.21 (s, 1H),　8.09-8.04 (m, 2H),　7.68-7.57 (m, 3H),　6.70 (d, 1H, J=8.08 MHz), 6.23　(s, 1H), 6.10 (s, 1H),　4.58-4.54 (m, 1H), 4.45-4.43 (m, 1H), 4.29-4.25 (m, 1H), 4.11-4.07 (m, 1H), 3.83-3.78 (m, 2H), 3.59-3.56 (m, 2H),　3.27 -3.20 (m, 4H), 2.70-2.68 (m, 2H),　2.35-2.32 (m, 1H), 1.87-1.73 (m, 2H),　1.66-1.61 (m, 2H), 1.53-1.45 (m, 1H), 1.04 (d, 6H, J=6.24 MHz) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.51 (s, 1H), 8.21 (s, 1H), 8.09-8.04 (m, 2H), 7.68-7.57 (m, 3H), 6.70 (d , 1H, J=8.08 MHz), 6.23 (s, 1H), 6.10 (s, 1H), 4.58-4.54 (m, 1H), 4.45-4.43 (m, 1H), 4.29-4.25 (m, 1H), 4.11-4.07 (m, 1H), 3.83-3.78 (m, 2H), 3.59-3.56 (m, 2H), 3.27 -3.20 (m, 4H), 2.70-2.68 (m, 2H), 2.35-2.32 (m) , 1H), 1.87-1.73 (m, 2H), 1.66-1.61 (m, 2H), 1.53-1.45 (m, 1H), 1.04 (d, 6H, J=6.24 MHz)
실시예 42. 4-(4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)페놀 의 합성Example 42. 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)phenol
단계1) 4-(6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)페놀의 합성Step 1) Synthesis of 4-(6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)phenol
마이크로파 바이알에 상기 실시예 34 단계 1에서 합성된 6-브로모-4-(몰포리노메틸)피리딘-2-아민 (50 mg, 0.18 mmol)과 3-하이드록시페닐보로닉 애시드(28 mg, 0.20 mmol), 탄산나트륨 (39 mg, 0.36 mmol), [1,1’-비스(디페닐포스피노)페로센]다이클로로팔라듐(Ⅱ) 다이클로로메탄 착물 (30 mg, 0.036 mmol) 을 1,4-디옥세인:물(1:1 용액, 4mL)에 녹이어준 후 반응 용액을 마이크로파로 120℃에서 1시간 교반한다. 반응이 완결되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (51 mg, 98%)을 얻었다.6-bromo-4-(morpholinomethyl)pyridin-2-amine (50 mg, 0.18 mmol) and 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) was prepared 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. When the reaction is complete, 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%).
단계2) 4-(4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일 )아미노)피리딘-2-일)페놀 합성Step 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
상기 단계 2에서 합성된 4-(6-아미노-4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)피리딘-2-일)페놀 (50 mg, 0.17 mmol)과 실시예 2의 단계1에서 합성된 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸 (65 mg, 0.21 mmol)를 실시예 2의 단계 2과 같은 방법으로 반응하여 목적화합물 (60 mg, 67%)을 얻었다.Conducted with 4-(6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)phenol (50 mg, 0.17 mmol) synthesized in step 2 above 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (65 mg, 0.21 mmol) synthesized in Step 1 of Example 2 was prepared in Step 2 of Example 2 The target compound (60 mg, 67%) was obtained by reacting in the same manner as described above.
1H-NMR (400 MHz, DMSO-d6) δ: 11.51 (s, 1H), 8.21 (s, 1H),　8.09-8.04 (m, 2H),　7.68-7.57 (m, 3H),　6.70 (d, 1H, J=8.08 MHz), 6.23　(s, 1H), 6.10 (s, 1H),　4.58-4.54 (m, 1H), 4.45-4.43 (m, 1H), 4.29-4.25 (m, 1H), 4.11-4.07 (m, 1H), 3.83-3.78 (m, 2H), 3.59-3.56 (m, 2H),　3.27 -3.20 (m, 4H), 2.70-2.68 (m, 2H),　2.35-2.32 (m, 1H), 1.87-1.73 (m, 2H),　1.66-1.61 (m, 2H), 1.53-1.45 (m, 1H), 1.04 (d, 6H, J=6.24 MHz) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.51 (s, 1H), 8.21 (s, 1H), 8.09-8.04 (m, 2H), 7.68-7.57 (m, 3H), 6.70 (d , 1H, J=8.08 MHz), 6.23 (s, 1H), 6.10 (s, 1H), 4.58-4.54 (m, 1H), 4.45-4.43 (m, 1H), 4.29-4.25 (m, 1H), 4.11-4.07 (m, 1H), 3.83-3.78 (m, 2H), 3.59-3.56 (m, 2H), 3.27 -3.20 (m, 4H), 2.70-2.68 (m, 2H), 2.35-2.32 (m) , 1H), 1.87-1.73 (m, 2H), 1.66-1.61 (m, 2H), 1.53-1.45 (m, 1H), 1.04 (d, 6H, J=6.24 MHz)
실시예 43. (1R,4R)-4-((6-((5-(5-(2-클로로-6-메틸페닐)-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)- 4-(모르폴리노메틸)피리딘-2-일)아미노)시클로헥산-1-올의 합성Example 43. (1R,4R)-4-((6-((5-(5-(2-chloro-6-methylphenyl)-1,3,4-oxadiazol-2-yl)thiazole- Synthesis of 2-yl)amino)-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol
단계1) 2-클로로-6-메틸벤조히드라지드의 합성Step 1) Synthesis of 2-chloro-6-methylbenzohydrazide
2-클로로-6-메틸벤조산 (2.0 g, 11.72 mmol), HOBt (1.90 g, 14.06 mmol)과 EDCI (2.18 g, 14.06 mmol)을 아세토나이트릴 23 ml에 용해한 뒤 상온에서 12시간 교반하였다. 이후 하이드라진 일수화물 (1.25 ml, 23.44 mmol)을 첨가한 뒤 상온에서 추가 12시간 교반하였다. 반응이 완결되어 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적화합물 (1.24 g, 57%)을 얻었다.2-Chloro-6-methylbenzoic acid (2.0 g, 11.72 mmol), HOBt (1.90 g, 14.06 mmol) and EDCI (2.18 g, 14.06 mmol) were dissolved in 23 ml of acetonitrile and stirred at room temperature for 12 hours. Thereafter, hydrazine monohydrate (1.25 ml, 23.44 mmol) was added, followed by stirring at room temperature for an additional 12 hours. After the reaction was completed, the residue obtained was purified using column chromatography to obtain the target compound (1.24 g, 57%).
단계2) 2-(2-브로모티아졸-5-일)-5-(2-클로로-6-메틸페닐)-1,3,4-옥사디아졸의 합성Step 2) Synthesis of 2-(2-bromothiazol-5-yl)-5-(2-chloro-6-methylphenyl)-1,3,4-oxadiazole
상기 단계1에서 얻어진 2-클로로-6-메틸벤조히드라지드 (0.20 g, 1.08 mmol)을 실시예2의 단계1과 같은 방법으로 목적화합물 (0.05 g, 15%)을 얻었다.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.
단계3) Step 3)
(1R,4R)-4-((6-((5-(5-(2-클로로-6-메틸페닐)-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)- 4-(모르폴리노메틸)피리딘-2-일)아미노)시클로헥산-1-올의 합성(1R,4R)-4-((6-((5-(5-(2-chloro-6-methylphenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl) Synthesis of amino)-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol
상기 단계2에서 얻어진 2-(2-브로모티아졸-5-일)-5-(2-클로로-6-메틸페닐)-1,3,4-옥사디아졸 (0.06 g, 0.20 mmol)와 실시예1의 단계6에서 얻어진 (1R,4R)-4-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올 (0.05 g, 0.18 mmol)을 실시예1의 단계7과 같은 방법으로 목적화합물 (0.04 g, 38%)을 얻었다.2-(2-bromothiazol-5-yl)-5-(2-chloro-6-methylphenyl)-1,3,4-oxadiazole (0.06 g, 0.20 mmol) obtained in step 2 and Examples Perform (1R,4R)-4-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol (0.05 g, 0.18 mmol) obtained in step 6 of 1 The target compound (0.04 g, 38%) was obtained in the same manner as in step 7 of Example 1.
1H-NMR (400 MHz, DMSO-d6) δ: 11.56 (s, 1H), 8.12 (s, 1H), 7.60-7.54 (m, 2H), 7.46-7.44 (m, 1H), 6.58 (d, 1H, J= 8.0 Hz), 6.18 (s, 1H), 6.09 (s, 1H), 4.52 (d, 1H, J= 4.0 Hz), 3.96-3.88 (m, 1H), 3.66 (m, 4H), 3.53 (m, 1H), 3.27 (s, 2H), 2.36 (s, 4H), 2.30 (s, 3H), 2.06 (d, 2H, J= 20.0 Hz), 1.84 (d, 2H, J= 12.0 Hz), 1.49-1.40 (m, 2H), 1.29-1.21 (m, 2H) 1 H-NMR (400 MHz, DMSO-d6) δ: 11.56 (s, 1H), 8.12 (s, 1H), 7.60-7.54 (m, 2H), 7.46-7.44 (m, 1H), 6.58 (d, 1H, J= 8.0 Hz), 6.18 (s, 1H), 6.09 (s, 1H), 4.52 (d, 1H, J= 4.0 Hz), 3.96-3.88 (m, 1H), 3.66 (m, 4H), 3.53 (m, 1H), 3.27 (s, 2H), 2.36 (s, 4H), 2.30 (s, 3H), 2.06 (d, 2H, J= 20.0 Hz), 1.84 (d, 2H, J= 12.0 Hz) ), 1.49-1.40 (m, 2H), 1.29-1.21 (m, 2H)
실시예 44. N2-((1R,4R)-4-메틸시클로헥실)-N6-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)피리딘-2,6-디아민의 합성Example 44. N2-((1R,4R)-4-methylcyclohexyl)-N6-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl ) Synthesis of pyridine-2,6-diamine
단계1) 6-브로모-N-((1R,4R)-4-메틸시클로헥실)피리딘-2-아민 합성Step 1) Synthesis of 6-bromo-N-((1R,4R)-4-methylcyclohexyl)pyridin-2-amine
2,6-다이브로모피리딘 (700 mg, 2.95 mmol), 트랜스-4-메틸사이클로헥실아민 (0.46 ml, 3.54 mmol), 트리스(디벤질인덴아세톤)디팔라듐 (10 mol%), 잔트포스 (10 mol%) 나트륨-터트-부톡사이트 (425 mg, 4.43 mmol)을 무수 1,4-디옥세인 (0.2M)에 녹인 후, 상온에서 4시간 교반한다. 반응이 완료되면 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (716 mg, 90%)을 얻었다.2,6-dibromopyridine (700 mg, 2.95 mmol), trans-4-methylcyclohexylamine (0.46 ml, 3.54 mmol), tris(dibenzylindeneacetone)dipalladium (10 mol%), xantphos ( 10 mol%) sodium-tert-butoxide (425 mg, 4.43 mmol) was dissolved in anhydrous 1,4-dioxane (0.2M), followed by stirring at room temperature for 4 hours. When the reaction is complete, extraction is performed 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 (716 mg, 90%).
단계2) N2-((1R,4R)-4-메틸시클로헥실)피리딘-2,6-디아민 합성Step 2) Synthesis of N2-((1R,4R)-4-methylcyclohexyl)pyridine-2,6-diamine
상기 단계 1에서 얻은 6-브로모-N-((1R,4R)-4-메틸시클로헥실)피리딘-2-아민 (716 mg, 2.66 mmol), 쿠프릭 아세틸아세톤 (10 mol%), 세슘 카보네이트 (1.7 g, 5.32 mmol)을 슈링크튜브에 넣고, 질소 환경을 조성한다, 이후 아세틸아세톤 (40 mol%), 암모니아 수용액 (2.6 mL, 53.26 mmol), 무수 다이메틸포름아마이드 (0.2M)를 차례로 넣고, 90 ℃에서 밤샘교반한다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적화합물 (450 mg, 82%)을 얻었다.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. When the reaction is complete, 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%).
단계 3) N2-((1R,4R)-4-메틸시클로헥실)-N6-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)피리딘-2,6-디아민 합성Step 3) N2-((1R,4R)-4-methylcyclohexyl)-N6-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl) Synthesis of pyridine-2,6-diamine
상기 단계 2에서 얻어진 N2-((1R,4R)-4-메틸시클로헥실)피리딘-2,6-디아민 (450 mg, 2.19 mmol)와 실시예1의 단계6에서 얻어진 (1R,4R)-4-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올 (743 mg, 2.41 mmol)을 실시예1의 단계7과 같은 방법으로 목적화합물 ( 470 mg, 50%)을 얻었다.N2-((1R,4R)-4-methylcyclohexyl)pyridine-2,6-diamine (450 mg, 2.19 mmol) obtained in step 2 above and (1R,4R)-4 obtained in step 6 of Example 1 -((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol (743 mg, 2.41 mmol) was prepared in the same manner as in step 7 of Example 1 to prepare the target compound (470 mg, 50%) was obtained.
1H-NMR (400 MHz, DMSO-d6) δ: 11.51 (s, 1H), 8.20 (s, 1H), 8.08-8.06 (m, 2H), 7.66-7.60 (m, 3H), 7.30 (t, 1H, J=7.84 MHz), 6.62 (d, 1H, J=8 MHz), 6.16 (d, 1H, J=7.6 MHz), 6.07 (d, 1H, J= 8 MHz), 4.02-4.00 (m, 1H), 2.08-2.06 (m, 2H), 1.74-1.71 (m, 2H), 1.35-1.19 (m, 5H), 0.87 (d, 3H, J=13.24 MHz) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.51 (s, 1H), 8.20 (s, 1H), 8.08-8.06 (m, 2H), 7.66-7.60 (m, 3H), 7.30 (t) , 1H, J=7.84 MHz), 6.62 (d, 1H, J=8 MHz), 6.16 (d, 1H, J=7.6 MHz), 6.07 (d, 1H, J= 8 MHz), 4.02-4.00 (m , 1H), 2.08-2.06 (m, 2H), 1.74-1.71 (m, 2H), 1.35-1.19 (m, 5H), 0.87 (d, 3H, J=13.24 MHz)
실시예 45. (1R,4R)-4-((6-((5-(2-(2-메톡시페닐)-2H-테트라졸-5-일)티아졸-2-일)아미노)-4-(모르폴리노메틸)피리딘-2 -일)아미노)사이클로헥산-1-올의 합성Example 45. (1R,4R)-4-((6-((5-(2-(2-methoxyphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)- Synthesis of 4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol
단계1) 2-브로모-5-(2-(2-메톡시페닐)-2H-테트라졸-5-일)티아졸의 합성Step 1) Synthesis of 2-bromo-5-(2-(2-methoxyphenyl)-2H-tetrazol-5-yl)thiazole
실시예1의 단계2에서 아닐린 대신 2-메톡시아닐린을 사용한 것을 제외하고 같은 방법으로 반응하여 목적화합물 (0.30 g, 64%)을 얻었다.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.
단계2) (1R,4R)-4-((6-((5-(2-(2-메톡시페닐)-2H-테트라졸-5-일)티아졸-2-일)아미노)-4-(모르폴리노메틸)피리딘-2 -일)아미노)사이클로헥산-1-올의 합성Step 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
상기 단계2에서 얻어진 2-브로모-5-(2-(2-메톡시페닐)-2H-테트라졸-5-일)티아졸 (0.10 g, 0.30 mmol)와 실시예1의 단계6에서 얻어진 (1R,4R)-4-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올 (0.08 g, 0.27 mmol)을 실시예1의 단계7과 같은 방법으로 목적화합물 (0.04 g, 26%)을 얻었다.2-bromo-5-(2-(2-methoxyphenyl)-2H-tetrazol-5-yl)thiazole (0.10 g, 0.30 mmol) obtained in step 2 above and step 6 of Example 1 (1R,4R)-4-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol (0.08 g, 0.27 mmol) was mixed with step 7 of Example 1 In the same way, the target compound (0.04 g, 26%) was obtained.
1H-NMR (400 MHz, DMSO-d6) δ: 11.24 (s, 1H), 8.06 (s, 1H), 7.73 (d, 1H, J= 8.0 Hz), 7.64 (t, 1H, J= 8.0 Hz), 7.37 (d, 1H, J= 8.0 Hz), 7.17 (t, 1H, J= 8.0 Hz), 6.49 (d, 1H, J= 8.0 Hz), 6.16 (s, 1H), 6.05 (s, 1H), 4.47 (d, 1H, J= 4.0 Hz), 4.10-4.00 (m, 1H), 3.86 (s, 3H), 3.58 (s, 4H), 3.48-3.42 (m, 1H), 3.27 (s, 2H), 2.36 (s, 4H), 2.05 (d, 2H, J= 12.0 Hz), 1.99 (s, 1H), 1.83 (d, 2H, J= 8.0 Hz), 1.50-1.41 (m, 2H), 1.28-1.16 (m, 2H) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.24 (s, 1H), 8.06 (s, 1H), 7.73 (d, 1H, J= 8.0 Hz), 7.64 (t, 1H, J= 8.0 Hz), 7.37 (d, 1H, J= 8.0 Hz), 7.17 (t, 1H, J= 8.0 Hz), 6.49 (d, 1H, J= 8.0 Hz), 6.16 (s, 1H), 6.05 (s, 1H), 4.47 (d, 1H, J= 4.0 Hz), 4.10-4.00 (m, 1H), 3.86 (s, 3H), 3.58 (s, 4H), 3.48-3.42 (m, 1H), 3.27 (s) , 2H), 2.36 (s, 4H), 2.05 (d, 2H, J= 12.0 Hz), 1.99 (s, 1H), 1.83 (d, 2H, J= 8.0 Hz), 1.50-1.41 (m, 2H) , 1.28-1.16 (m, 2H)
실시예 46. (1R,4R)-4-((6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)-4-(피롤리딘-1-일메틸 )피리딘-2-일)아미노)시클로헥산-1-올의 합성Example 46. (1R,4R)-4-((6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-4 Synthesis of -(pyrrolidin-1-ylmethyl)pyridin-2-yl)amino)cyclohexan-1-ol
단계1) (2,6-디브로모피리딘-4-일)(피롤리딘-1-일)메탄온의 합성Step 1) Synthesis of (2,6-dibromopyridin-4-yl)(pyrrolidin-1-yl)methanone
실시예1의 단계3에서 몰폴린 대신 피롤리딘을 사용한 것을 제외하고, 2,6-다이브로모니코티닉 산 (10.00 g, 35.60 mmol)과 동일한 방법으로 반응하여 목적화합물 (11.2 g, 94%)을 얻었다.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.
단계2) 2,6-디브로모-4-(피롤리딘-1-일메틸)피리딘의 합성Step 2) Synthesis of 2,6-dibromo-4-(pyrrolidin-1-ylmethyl)pyridine
상기 단계1에서 합성된 (2,6-디브로모피리딘-4-일)(피롤리딘-1-일)메탄온 (11.20 g, 33.83 mmol)을 실시예 1의 단계4와 같은 방법으로 목적화합물 (4.70 g, 43%)을 얻었다.(2,6-dibromopyridin-4-yl)(pyrrolidin-1-yl)methanone (11.20 g, 33.83 mmol) synthesized in step 1 was prepared in the same manner as in step 4 of Example 1 The compound (4.70 g, 43%) was obtained.
단계3) (1R,4R)-4-((6-브로모-4-(피롤리딘-1-일메틸)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Step 3) Synthesis of (1R,4R)-4-((6-bromo-4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)amino)cyclohexan-1-ol
상기 단계2에서 합성된 2,6-디브로모-4-(피롤리딘-1-일메틸)피리딘 (4.70 g, 14.69 mmol)을 실시예1의 단계5와 같은 방법으로 목적화합물 (2.17 g, 42%)을 얻었다.2,6-dibromo-4-(pyrrolidin-1-ylmethyl)pyridine (4.70 g, 14.69 mmol) synthesized in step 2 above was synthesized in the same manner as in step 5 of Example 1, with the target compound (2.17 g) , 42%) was obtained.
단계4) (1R,4R)-4-((6-아미노-4-(피롤리딘-1-일메틸)피리딘-2-일)아미노)사이클로헥산-1-올의 합성Step 4) Synthesis of (1R,4R)-4-((6-amino-4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)amino)cyclohexan-1-ol
상기 단계3에서 합성된 (1R,4R)-4-((6-브로모-4-(피롤리딘-1-일메틸)피리딘-2-일)아미노)사이클로헥산-1-올 (2.00 g, 5.64 mmol)을 실시예1의 단계6과 같은 방법으로 목적화합물 (0.66 g, 40%)을 얻었다.(1R,4R)-4-((6-bromo-4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)amino)cyclohexan-1-ol synthesized in step 3 (2.00 g , 5.64 mmol) was obtained in the same manner as in step 6 of Example 1 to obtain the target compound (0.66 g, 40%).
단계5) (1R,4R)-4-((6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)-4-(피롤리딘-1-일메틸 )피리딘-2-일)아미노)시클로헥산-1-올의 합성Step 5) (1R,4R)-4-((6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-4- Synthesis of (pyrrolidin-1-ylmethyl)pyridin-2-yl)amino)cyclohexan-1-ol
상기 단계4에서 합성된 (1R,4R)-4-((6-아미노-4-(피롤리딘-1-일메틸)피리딘-2-일)아미노)사이클로헥산-1-올 (0.20 g, 0.69 mmol)과 실시예1의 단계2에서 합성된 2-브로모-5-(2-페닐-2H-테트라졸-5-일)사이아졸 (0.23 g, 0.76 mmol)을 실시예1의 단계7과 같은 방법으로 목적화합물 (0.04 g, 11%)을 얻었다.(1R,4R)-4-((6-amino-4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)amino)cyclohexan-1-ol (0.20 g, 0.69 mmol) and 2-bromo-5-(2-phenyl-2H-tetrazol-5-yl)cyazole (0.23 g, 0.76 mmol) synthesized in step 2 of Example 1 were prepared in step 7 of Example 1. The target compound (0.04 g, 11%) was obtained in the same manner as described above.
1H-NMR (400 MHz, DMSO-d6) δ: 11.74 (s, 1H), 8.25 (s, 1H), 8.11-8.09 (m, 2H), 7.63-7.62 (m, 3H), 6.84 (s, 1H), 6.23 (s, 1H), 6.15 (s, 1H), 4.67 (d, 1H, J= 4.0 Hz), 4.10-3.98 (m, 3H), 3.51-3.50 (m, 1H), 3.06 (s, 2H), 2.09-2.07 (m, 2H), 1.93-1.91 (m, 7H), 1.54-1.46 (m, 2H), 1.36-1.27 (m, 2H) 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.74 (s, 1H), 8.25 (s, 1H), 8.11-8.09 (m, 2H), 7.63-7.62 (m, 3H), 6.84 (s) , 1H), 6.23 (s, 1H), 6.15 (s, 1H), 4.67 (d, 1H, J= 4.0 Hz), 4.10-3.98 (m, 3H), 3.51-3.50 (m, 1H), 3.06 ( s, 2H), 2.09-2.07 (m, 2H), 1.93-1.91 (m, 7H), 1.54-1.46 (m, 2H), 1.36-1.27 (m, 2H)
실험예 1: 화합물의 세포내 p-BTK IC50 평가Experimental Example 1: Evaluation of intracellular p -BTK IC 50 of the compound
세포 내 BTK에 대한 BTK 저해제의 IC50를 측정하기 위하여 웨스턴 블랏 분석법을 수행하여 평가하였다. 소 태아 혈청(Fetal bovine serum)이 첨가되지 않은 배양배지에 세포(Ramos cells)를 넣고 BTK 저해제를 연속 희석하여 37 ℃의 인큐베이터에서 4 시간 동안 반응시켰다. 이후 항-인간 IgM(SouthernBiotech 2020-01) 15 ㎍/㎖을 세포에 처리하고 2~8 ℃의 저온에서 10분간 자극하였다. 저온의 DPBS(Dulbecco's Phosphate-Buffered Saline)로 세포에 남아있는 배양배지를 제거하고 프로테아제와 포스파타제 저해제(Thermo 78442)가 포함된 RIPA 완충용액(Radioimmunoprecipitation assay buffer, Thermo 89901)으로 저온에서 30 분 동안 세포막을 용해시켰다.Western blot analysis was performed to measure the IC 50 of the BTK inhibitor against intracellular BTK. The cells (Ramos cells) were placed in a culture medium without fetal bovine serum, serially diluted with a BTK inhibitor, and reacted in an incubator at 37°C for 4 hours. Then, 15 μg/ml of anti-human IgM (SouthernBiotech 2020-01) was applied to the cells and stimulated at a low temperature of 2 to 8° C. for 10 minutes. Remove the culture medium remaining in the cells with low-temperature DPBS (Dulbecco's Phosphate-Buffered Saline) and RIPA buffer (Radioimmunoprecipitation assay buffer, Thermo 89901) containing protease and phosphatase inhibitor (Thermo 78442) at low temperature for 30 minutes at low temperature. dissolved.
고속원심분리기로 단백질을 추출하여 BCA(bicinchoninic acid) 용액(Thermo 23225)으로 정량하고 4× 샘플 완충 용액(Invitrogen NP0007)을 넣어 샘플을 제작하였다. 각 샘플의 단백질은 전기영동시킨 다음 니트로셀룰로스로 구성된 막(Invitrogen IB23001)으로 옮겼다. 단백질이 없는 부분을 블로킹하기 위하여 TBS-T(TBS-Tween, Thermo 28360)에 5%의 소혈청알부민(BSA)(GenDEPOT A0100-010)이 포함된 용액을 만들어 30 분간 상온에서 처리하였다. 1차 항체를 희석하여 단백질이 붙은 막에 넣고 저온의 쉐이커 위에서 16~20 시간(또는 상온에서 1 시간) 동안 반응시켰다. TBS-T를 넣고 10 분간 상온의 쉐이커 위에서 막에 붙지 않은 1차 항체를 제거하였으며 이 과정을 3회 반복하였다. HRP(horseradish peroxidase)가 붙은 2차 항체를 희석하여 막에 넣고 45 분간 반응시켰다. TBS-T를 넣어 10 분간 상온의 쉐이커 위에 두어 1차 항체와 붙지 않은 2차 항체를 제거하는 과정을 3회 반복하였다. 인핸스드 케미루미네슨트(Enhanced chemiluminescent)(ECL) 용액(Thermo 34095)을 이용하여 HRP 효소를 반응시키고 막의 단백질 수치를 확인하였다. 음성 대조군 및 양성 대조군의 단백질을 기준으로 하고 산출된 값을 통해 IC50를 계산하였다. 그 결과를 아래 표 1에 나타내었다.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. 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. The HRP enzyme was reacted using an Enhanced chemiluminescent (ECL) solution (Thermo 34095), and the protein level of the membrane was checked. 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.
실험예 2: 화합물의 BTK WT(wild-type), C481S IC50 효소 분석Experimental Example 2: BTK WT (wild-type) of the compound, C481S IC 50 enzyme analysis
BTK 효소에 대한 BTK 저해제의 IC50을 측정하기 위하여 BTK WT/C481S 키나제 효소 시스템(Promega V9071, VA7033)을 이용하여 평가하였다. BTK 저해제는 연속 희석하여 1 ㎕씩 준비하고 BTK 키나제 2 ㎕와 상온에서 10 분동안 반응시켰다. 40 mM Tris(pH 7.5), 20 mM MgCl2, 0.1㎎/㎖ 소혈청알부민(BSA), 2 mM MnCl2, 및 50 μM DTT(dithiothreitol)로 구성된 BTK 키나제 버퍼를 이용하여 기질/ATP 믹스(ATP 최종농도: 50 μM)를 제조하고 2 ㎕씩 첨가하여 상온에서 60분동안 인큐베이션하였다. ADP Glo™ 시약 5 ㎕를 첨가하여 상온에서 40 분동안 반응시키고 키나제 검출 시약 첨가 30분 후 발광(luminescence)(Integration time 0.5 second)을 측정하였다. 평가는 중복(duplicate) 실험에 대하여 수행되었고, 음성 대조군 및 양성 대조군을 산출하여, 그 값을 기준으로 IC50을 계산하였다. 그 결과를 아래 표 1에 나타내었다.To measure the IC 50 of the BTK inhibitor against the BTK enzyme, the BTK WT/C481S kinase enzyme system (Promega V9071, VA7033) was used. 1 μl of the BTK inhibitor was serially diluted and reacted with 2 μl 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 μM dithiothreitol (DTT). Final concentration: 50 μM) was prepared and 2 μl was added and incubated at room temperature for 60 minutes. 5 μl of ADP Glo™ reagent was added and reacted at room temperature for 40 minutes, and luminescence (integration time 0.5 second) was measured 30 minutes after the addition of the kinase detection reagent. Evaluation was performed for duplicate experiments, and negative and positive controls were calculated, and IC 50 was calculated based on the values. The results are shown in Table 1 below.
실시예Example p-BTK IC50, nMp-BTK IC 50 , nM BTK WT IC50, nMBTK WT IC 50 , nM BTK C481S IC50, nMBTK C481S IC 50 , nM
1One 10.110.1 51.051.0 37.037.0
22 8.98.9 2.72.7 2.02.0
33 2.32.3 -- --
44 12.712.7 -- --
55 20.620.6 -- --
66 2.12.1 -- --
77 43.643.6 -- --
88 240240 -- --
99 24.124.1 -- --
1010 2.32.3 5.25.2 6.06.0
1111 301301 -- --
1212 >1000>1000 -- --
1313 63.463.4 -- --
1414 > 1000> 1000 -- --
1515 0.30.3 -- --
1616 37.837.8 -- --
1717 > 1000> 1000 -- --
1818 > 1000> 1000 -- --
1919 14.414.4 -- --
2020 > 1000> 1000 -- --
2121 > 1000> 1000 -- --
2222 26.226.2 -- --
2323 40.940.9 -- --
2424 11.411.4 -- --
2525 > 1000> 1000 -- --
2626 29.229.2 -- --
2727 > 1000> 1000 -- --
2828 8.78.7 -- --
2929 > 1000> 1000 -- --
3030 8.18.1 -- --
3131 > 1000> 1000 -- --
3232 > 1000> 1000 -- --
3333 17.317.3 -- --
3434 > 1000> 1000 -- --
3535 > 1000> 1000 -- --
3636 > 1000> 1000 -- --
3737 > 100> 100 -- --
3838 10.310.3 -- --
3939 4.64.6 -- --
4040 9.69.6 -- --
4141 > 1000> 1000 -- --
4242 > 1000> 1000 -- --
4343 10.510.5 -- --
4444 > 1000> 1000 -- --
4545 18.418.4 -- --
4646 9.69.6 -- --

Claims (15)

  1. 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염:A compound of Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2021014942-appb-I000026
    Figure PCTKR2021014942-appb-I000026
    상기 화학식 1에서,In Formula 1,
    Cy는 C3-12아릴, C3-12사이클로알킬 또는 C3-10헤테로아릴이고, 상기 C3-12아릴, C3-12사이클로알킬 또는 C3-10헤테로아릴은 C1-6알킬, C1-6알콕시, 할로, 시아노, 및 하이드록시로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있고;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;
    A는 2개 이상의 N 원자를 갖는 5-원 환 또는 -CONH-이며;A is a 5-membered ring having 2 or more N atoms or -CONH-;
    X는 CH 또는 S이고;X is CH or S;
    Y는 X가 CH인 경우 NH 또는 O이고, X가 S인 경우 CH이며;Y is NH or O when X is CH and CH when X is S;
    Z1은 C 또는 N이고;Z 1 is C or N;
    Z1이 N인 경우
    Figure PCTKR2021014942-appb-I000027
    은 부재하고, Z1이 C인 경우, m은 0~3의 정수이고, R1은 C1-6알킬 및 C1-6알킬카보닐로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있는 C3-10헤테로사이클로알킬, 1개 이상의 C1-6알킬로 치환될 수 있는 아미노, 수소, C1-6알콕시, 또는 할로이며;    If Z 1 is N
    Figure PCTKR2021014942-appb-I000027
    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;
    Z2는 CH 또는 N이고;Z 2 is CH or N;
    R2는 C3-12사이클로알킬, C1-6알킬, C2-6알케닐, C2-6알키닐, C3-10헤테로사이클로알킬, C3-10헤테로아릴, 또는 C3-12아릴이고, 상기 C3-12사이클로알킬, C1-6알킬, C2-6알케닐, C2-6알키닐, C3-10헤테로사이클로알킬, C3-10헤테로아릴, 또는 C3-12아릴은 하이드록시, C1-6알콕시, -NR3R4(여기에서 R3 및 R4는 각각 독립적으로 수소, C1-6알킬, 또는 C1-6알킬카보닐이다), 시아노, 할로, C1-6알킬(여기에서 C1-6알킬은 1개 이상의 할로 또는 하이드록시로 치환될 수 있다), C1-6알킬설포닐, C1-6알킬포스포닐, 아미노설포닐, 또는 C3-12사이클로알킬(여기에서 C3-12사이클로알킬은 하이드록시 또는 하이드록시C1-6알킬로 치환될 수 있다)로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있으며;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 are each independently 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 the group consisting of , or C 3-12 cycloalkyl, wherein C 3-12 cycloalkyl may be substituted with hydroxy or hydroxyC 1-6 alkyl;
    L1 및 L2는 서로 독립적으로 NH, O, 또는 S이며;L 1 and L 2 are each independently NH, O, or S;
    n은 0 또는 1의 정수이다.n is an integer of 0 or 1.
  2. 제1항에 있어서, Cy는 C5-12아릴, C5-12사이클로알킬 또는 C3-6헤테로아릴인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.The compound of Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein Cy is C 5-12 aryl, C 5-12 cycloalkyl or C 3-6 heteroaryl.
  3. 제2항에 있어서, Cy는 페닐, 사이클로헥실, 피라졸릴 또는 피리딜인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.The compound of Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 2, wherein Cy is phenyl, cyclohexyl, pyrazolyl or pyridyl.
  4. 제1항에 있어서, A는 2개 내지 4개의 N 원자를 갖거나, 2개 또는 3개의 N 원자와 1개의 O 원자를 갖는 5-원 환, 또는 -CONH-인 것인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.The compound of formula (1) according to claim 1, wherein A is a 5-membered ring having 2 to 4 N atoms, 2 or 3 N atoms and 1 O atom, or -CONH-; A stereoisomer thereof or a pharmaceutically acceptable salt thereof.
  5. 제4항에 있어서, A는 이미다졸릴, 피라졸릴, 트리아졸릴, 테트라졸릴, 옥사디아졸릴, 또는 -CONH-인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.5. The compound of Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 4, wherein A is imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, or -CONH-.
  6. 제1항에 있어서, m은 0 또는 1인 화학식 1의 화합물, 그의 입체이성질체, 또는 그의 약제학적으로 허용가능한 염.The compound of formula (1) according to claim 1, wherein m is 0 or 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  7. 제1항에 있어서, R1은 C1-6알킬 및 C1-6알킬카보닐로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있는 C4-6헤테로사이클로알킬; 1개 이상의 C1-6알킬로 치환될 수 있는 아미노; 수소; 또는, C1-6알콕시인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.The method according to claim 1, wherein 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; Or, a compound of Formula 1 which is C 1-6 alkoxy, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  8. 제7항에 있어서, R1은 C1-6알킬 및 C1-6알킬카보닐로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있는 몰포리닐, 피페라지닐, 피페리디닐 또는 피롤리디닐; 1개 이상의 C1-6알킬로 치환될 수 있는 아미노; 수소; 또는, C1-6알콕시인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.8. The method of claim 7, wherein R 1 is morpholinyl, piperazinyl, piperidinyl or pipe which may be substituted with one or more substituents selected from the group consisting of C 1-6 alkyl and C 1-6 alkylcarbonyl. rollidinyl; amino which may be substituted with one or more C 1-6 alkyl; Hydrogen; Or, a compound of Formula 1 which is C 1-6 alkoxy, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  9. 제1항에 있어서, R2는 C3-12사이클로알킬, C1-6알킬, 또는 C3-12아릴인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.The compound of Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is C 3-12 cycloalkyl, C 1-6 alkyl, or C 3-12 aryl.
  10. 제9항에 있어서, R2는 C4-7사이클로알킬, C1-6알킬, 또는 C5-12아릴인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.10. The compound of Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 9, wherein R 2 is C 4-7 cycloalkyl, C 1-6 alkyl, or C 5-12 aryl.
  11. 제10항에 있어서, R2는 C4-7사이클로알킬, C1-6알킬, 또는 C5-12아릴이고, 상기 C4-7사이클로알킬, C1-6알킬, 또는 C5-12아릴은 하이드록시 또는 아미노설포닐로 치환될 수 있는 것인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.11. The method of claim 10, wherein R 2 is C 4-7 cycloalkyl, C 1-6 alkyl, or C 5-12 aryl, said C 4-7 cycloalkyl, C 1-6 alkyl, or C 5-12 aryl A compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein silver may be substituted with hydroxy or aminosulfonyl.
  12. 제1항에 있어서, L1 및 L2는 서로 독립적으로 NH 또는 O인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.The compound of Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 1 and L 2 are each independently NH or O.
  13. 제1항에 있어서, 하기 화합물, 그의 입체이성질체 또는 그의 약제학으로 허용가능한 염:[Claim 2] The compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    (1R,4R)-4-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올;(1R,4R)-4-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin-2 -yl)amino)cyclohexan-1-ol;
    (1R,4R)-4-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올;(1R,4R)-4-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl) amino)pyridin-2-yl)amino)cyclohexan-1-ol;
    (1R,4R)-4-((4-(((2S,6R)-2,6-디메틸몰포리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올;(1R,4R)-4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadia) zol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol;
    (1R,4R)-4-((6-((5-(2-(4-브로모페닐)-2H-테트라놀-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-올;(1R,4R)-4-((6-((5-(2-(4-bromophenyl)-2H-tetranol-5-yl)thiazol-2-yl)amino)-4-(morpho rinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol;
    (1R,4R)-4-((6-((5-(2-(2-클로로-6-메틸펜닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노사이클로헥산-올;(1R,4R)-4-((6-((5-(2-(2-chloro-6-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4 -(morpholinomethyl)pyridin-2-yl)aminocyclohexan-ol;
    2-((6-(((1R,4R)-4-히드록시사이클로헥실)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)-N-페닐싸이아졸-5-카복스아미드;2-((6-(((1R,4R)-4-hydroxycyclohexyl)amino)-4-(morpholinomethyl)pyridin-2-yl)amino)-N-phenylthiazole-5-carbox amides;
    (1R,4R)-4-((4-(몰포리노메틸)-6-((5-(3-페닐-1,2,4-옥사디아졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올;(1R,4R)-4-((4-(morpholinomethyl)-6-((5-(3-phenyl-1,2,4-oxadiazol-5-yl)thiazol-2-yl) amino)pyridin-2-yl)amino)cyclohexan-1-ol;
    (1r,3r)-3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로부탄-1-올;(1r,3r)-3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin-2 -yl)amino)cyclobutan-1-ol;
    6-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)스피로[3.3]헵탄-2-올;6-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)spiro [3.3]heptan-2-ol;
    6-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)스피로[3.3]헵탄-2-올;6-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2- yl)amino)spiro[3.3]heptan-2-ol;
    2-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)에탄-1-설폰아미드;2-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2- yl)amino)ethane-1-sulfonamide;
    3-(4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)페놀;3-(4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl )phenol;
    (1R,4R)-4-((4-(모르폴리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)티아졸-2-일)아미노)피리미딘-2-일)아미노)시클로헥산-1-올;(1R,4R)-4-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyrimidine -2-yl)amino)cyclohexan-1-ol;
    4-(4-(모르폴리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)페놀;4-(4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2- 1) phenol;
    (1R,4R)-4-((6-((5-(5-(4-플루오로페닐)-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)-4-(모르폴리노메틸)피리딘-2-일)아미노)시클로헥산-1-올;(1R,4R)-4-((6-((5-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino) -4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol;
    (1s,4s)-4-((4-(모르폴리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2 -일)아미노)사이클로헥산-1-올;(1s,4s)-4-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl )amino)pyridin-2-yl)amino)cyclohexan-1-ol;
    4-(모르폴리노메틸)-N2-(5-(2-페닐-2H-테트라졸-5-일)티아졸-2-일)-N6-((1R,4R)-4-(트리플루오로메틸)시클로헥실)피리딘-2,6-디아민;4-(morpholinomethyl)-N2-(5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)-N6-((1R,4R)-4-(trifluoro romethyl)cyclohexyl)pyridine-2,6-diamine;
    4-(모르폴리노메틸)-N2-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)-N6-((1R,4R)-4-(트리플루오로메틸)시클로헥실)피리딘-2,6-디아민;4-(morpholinomethyl)-N2-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-N6-((1R,4R)- 4-(trifluoromethyl)cyclohexyl)pyridine-2,6-diamine;
    N2-((1R,4R)-4-메톡시시클로헥실)-4-(모르폴리노메틸)-N6-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)피리딘-2,6-디아민;N2-((1R,4R)-4-methoxycyclohexyl)-4-(morpholinomethyl)-N6-(5-(5-phenyl-1,3,4-oxadiazol-2-yl) thiazol-2-yl)pyridin-2,6-diamine;
    N2-시클로헥실-4-(모르폴리노메틸)-N6-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)피리딘-2,6-디아민;N2-Cyclohexyl-4-(morpholinomethyl)-N6-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)pyridin-2,6 -diamine;
    N2-((1R,4R)-4-플루오로시클로헥실)-4-(모르폴리노메틸)-N6-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)피리딘- 2,6-디아민;N2-((1R,4R)-4-fluorocyclohexyl)-4-(morpholinomethyl)-N6-(5-(5-phenyl-1,3,4-oxadiazol-2-yl) thiazol-2-yl)pyridin-2,6-diamine;
    (1R,4R)-4-((4-((4-메틸피페리딘-1-일)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올;(1R,4R)-4-((4-((4-methylpiperidin-1-yl)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2) -yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol;
    4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-N2-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)-N6- (테트라히드로-2H-피란-4-일)피리딘-2,6-디아민;4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-N2-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole-2 -yl)-N6-(tetrahydro-2H-pyran-4-yl)pyridin-2,6-diamine;
    3-((4-(모르폴리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로헥산 -1-올;3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2 -yl)amino)cyclohexan-1-ol;
    (1R,4R)-4-((4-((디메틸아미노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로헥산-1-올;(1R,4R)-4-((4-((dimethylamino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole-2- yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol;
    (1R,4R)-4-((6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)-4-(피페라진-1-일메틸)피리딘-2-일)아미노)시클로헥산-1-올;(1R,4R)-4-((6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-4-(piperazine -1-ylmethyl)pyridin-2-yl)amino)cyclohexan-1-ol;
    4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-N2-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)-N6-((테트라히드로-2H-피란-4-일)메틸)피리딘-2,6-디아민;4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-N2-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole-2 -yl)-N6-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2,6-diamine;
    (1R,4R)-4-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-(4-플루오로페닐)-1,3,4- 옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로헥산-1-올;(1R,4R)-4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-(4-fluorophenyl)-1 ,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol;
    ((1R,4R)-4-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2)-일)티아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥실)메탄올;((1R,4R)-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)cyclohexyl)methanol;
    (1R,4R)-4-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-(2-플루오로페닐)-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로헥산-1-올;(1R,4R)-4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-(2-fluorophenyl)-1 ,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol;
    (1R,4R)-4-(((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2)-일)티아졸-2-일)아미노)피리딘-2-일)아미노)메틸);(1R,4R)-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)methyl);
    ((1R,4R)-4-(((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸- 2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)메틸)사이클로헥실)메탄올;((1R,4R)-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)methyl)cyclohexyl)methanol;
    (1R,4R)-4-((4-(((2S,6R)-2,6-디메틸몰포리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-올;(1R,4R)-4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadia) zol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexan-1-ol;
    (2-(4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)페닐)메탄올;(2-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl) )thiazol-2-yl)amino)pyridin-2-yl)phenyl)methanol;
    (3-(4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)페닐)메탄올;(3-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl) )thiazol-2-yl)amino)pyridin-2-yl)phenyl)methanol;
    (4-(4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)페닐)메탄올;(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)phenyl)methanol;
    5-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로옥탄-1-올;5-((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)cyclooctan-1-ol;
    d(1R,3R)-3-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)시클로펜탄-1-올;d(1R,3R)-3-((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)cyclopentan-1-ol;
    (1S,3S)-3-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)사이클로펜탄-1-올;(1S,3S)-3-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxa) diazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclopentan-1-ol;
    (1R,4R)-4-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)아미노)사이클로헥산-1-카보니트릴;(1R,4R)-4-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxa) diazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)cyclohexane-1-carbonitrile;
    ((2S,5R)-5-((4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2)-일)티아졸-2-일)아미노)피리딘-2-일)아미노)테트라하이드로-2H-피란-2-일)메탄올;((2S,5R)-5-((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)tetrahydro-2H-pyran-2-yl)methanol;
    4-(4-(((2S,6R)-2,6-디메틸모르폴리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)피리딘-2-일)페놀;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)phenol;
    (1R,4R)-4-((6-((5-(5-(2-클로로-6-메틸페닐)-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)-4-(모르폴리노메틸)피리딘-2-일)아미노)시클로헥산-1-올;(1R,4R)-4-((6-((5-(5-(2-chloro-6-methylphenyl)-1,3,4-oxadiazol-2-yl)thiazol-2-yl) amino)-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexan-1-ol;
    N2-((1R,4R)-4-메틸시클로헥실)-N6-(5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)피리딘-2,6-디아민;N2-((1R,4R)-4-methylcyclohexyl)-N6-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)pyridin-2 ,6-diamine;
    (1R,4R)-4-((6-((5-(2-(2-메톡시페닐)-2H-테트라졸-5-일)티아졸-2-일)아미노)-4-(모르폴리노메틸)피리딘-2 -일)아미노)사이클로헥산-1-올; 및,(1R,4R)-4-((6-((5-(2-(2-methoxyphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4-(don't know polynomethyl)pyridin-2-yl)amino)cyclohexan-1-ol; and,
    (1R,4R)-4-((6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)티아졸-2-일)아미노)-4-(피롤리딘-1-일메틸)피리딘-2-일)아미노)시클로헥산-1-올.(1R,4R)-4-((6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-4-(pyrroly Din-1-ylmethyl)pyridin-2-yl)amino)cyclohexan-1-ol.
  14. 제1항 내지 제13항 중 어느 한 항의 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염, 및 약제학적으로 허용가능한 담체를 포함하는 단백질 키나제에 의하여 매개되는 질환을 치료하는데 사용하기 위한 약제학적 조성물.14. Use for treating a disease mediated by a protein kinase comprising a compound of formula 1 according to any one of claims 1 to 13, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. pharmaceutical composition for
  15. 제14항에 있어서, 상기 질환은 암, 염증 질환, 또는 자가면역 질환인 것인 조성물.The composition of claim 14, wherein the disease is cancer, an inflammatory disease, or an autoimmune disease.
PCT/KR2021/014942 2020-10-23 2021-10-22 Protein kinase inhibitor and use thereof WO2022086284A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2020-0138539 2020-10-23
KR1020200138539A KR20220054066A (en) 2020-10-23 2020-10-23 Protein kinase inhibitor and use thereof

Publications (1)

Publication Number Publication Date
WO2022086284A1 true WO2022086284A1 (en) 2022-04-28

Family

ID=81290847

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2021/014942 WO2022086284A1 (en) 2020-10-23 2021-10-22 Protein kinase inhibitor and use thereof

Country Status (2)

Country Link
KR (1) KR20220054066A (en)
WO (1) WO2022086284A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20230149753A (en) * 2022-04-20 2023-10-27 (주)메디톡스 Protein kinase inhibitor and use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106279143A (en) * 2015-05-11 2017-01-04 天津国际生物医药联合研究院 Thiazole heterocycle compounds and its preparation method and application
WO2017168454A2 (en) * 2016-04-02 2017-10-05 Sun Pharma Advanced Research Company Limited Novel compounds as btk inhibitors
US20180016247A1 (en) * 1999-04-15 2018-01-18 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
KR20200140200A (en) * 2019-06-05 2020-12-15 (주)메디톡스 Protein kinase inhibitor and use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180016247A1 (en) * 1999-04-15 2018-01-18 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
CN106279143A (en) * 2015-05-11 2017-01-04 天津国际生物医药联合研究院 Thiazole heterocycle compounds and its preparation method and application
WO2017168454A2 (en) * 2016-04-02 2017-10-05 Sun Pharma Advanced Research Company Limited Novel compounds as btk inhibitors
KR20200140200A (en) * 2019-06-05 2020-12-15 (주)메디톡스 Protein kinase inhibitor and use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LI HUI-YING, HE DING-DI, ZHAO XIU-JUAN, SUN TONG-YAN, ZHANG QUAN, BAI CUI-GAI, CHEN YUE: "Design and synthesis of novel dasatinib derivatives as inhibitors of leukemia stem cells", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 28, no. 4, 1 February 2018 (2018-02-01), AMSTERDAM, NL , pages 700 - 706, XP055923165, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2018.01.011 *

Also Published As

Publication number Publication date
KR20220054066A (en) 2022-05-02

Similar Documents

Publication Publication Date Title
WO2017204445A2 (en) Pharmaceutical composition inducing decomposition of alk protein, and pharmaceutical composition for cancer prevention or treatment containing same as active component
WO2019190259A1 (en) Novel sulfonamide derivative having inhibitory effect on epidermal growth factor receptor mutation
WO2009126003A9 (en) Novel pyrazole and benzoxazole-substituted pyridine derivatives or pharmaceutically acceptable salts thereof, preparation process for same, and pharmaceutical composition for prevention and treatment of disorders involving aberrant cell proliferation containing same as active ingredients
WO2020171499A1 (en) Novel pyrido[3,4-d]pyrimidin-8-one derivative having protein kinase inhibitory activity, and pharmaceutical composition for preventing, alleviating, or treating cancer, comprising same
WO2020171606A1 (en) Novel heterotricyclic derivative compound and use of same
WO2018208132A1 (en) Pyrazolopyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating cancer, autoimmune disease and brain disease containing the same as an active ingredient
WO2017142325A1 (en) Novel 2,3,5-substituted thiophene compound as protein kinase inhibitor
WO2021145521A1 (en) Pyrido[3,4-d]pyrimidine derivative and therapeutic pharmaceutic composition comprising same
WO2016032209A2 (en) Substituted n-(pyrrolidine-3-yl)-7h-pyrrolo[2,3-d]pyrimidine-4-amine as janus kinase inhibitor
WO2021145520A1 (en) 7-amino-3,4-dihydropyrimidopyrimidin-2-one derivative having inhibitory activity for protein kinases and therapeutic pharmaceutical composition comprising same
WO2020149553A1 (en) Aryl or heteroaryl derivative, and pharmaceutical composition comprising same as active ingredient for treatment of kinase-related disease
AU2017256488B2 (en) Quinazoline derivative or its salt and pharmaceutical composition comprising the same
WO2022086284A1 (en) Protein kinase inhibitor and use thereof
WO2017034245A1 (en) Janus kinase 1 selective inhibitor and pharmaceutical use thereof
WO2016006974A2 (en) Novel triazolopyrimidinone or triazolopyridinone derivatives, and use thereof
WO2022071772A1 (en) Protein kinase inhibitor and use thereof
WO2018021826A1 (en) Novel pyrimidine-2,4-diamine derivative and pharmaceutical composition for prevention or treatment of cancer containing same as active ingredient
WO2023287128A1 (en) Indazole yl benzimidazole derivative or pharmaceutically acceptable salt thereof, and use thereof
WO2022139304A1 (en) Novel quinazoline derivative compound as sos1 inhibitor, and use thereof
WO2021182918A1 (en) Pharmaceutical composition for preventing or treating cancer comprising azole derivatives or pharmaceutically acceptable salt thereof
WO2023204642A1 (en) Protein kinase inhibitor and use thereof
WO2021040422A1 (en) Novel pyrimido[4,5-d]pyrimidine-2-one derivative having protein kinase inhibitory activity
EP3166945A2 (en) Novel triazolopyrimidinone or triazolopyridinone derivatives, and use thereof
WO2020263058A1 (en) Aminocyanopyridine derivative and use thereof
WO2022065894A1 (en) Novel quinazoline derivative having flt3 inhibitory activity, and use thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21883351

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21883351

Country of ref document: EP

Kind code of ref document: A1