WO2020045941A1 - Novel heterocyclic amine derivative and pharmaceutical composition comprising same - Google Patents

Novel heterocyclic amine derivative and pharmaceutical composition comprising same Download PDF

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Publication number
WO2020045941A1
WO2020045941A1 PCT/KR2019/010894 KR2019010894W WO2020045941A1 WO 2020045941 A1 WO2020045941 A1 WO 2020045941A1 KR 2019010894 W KR2019010894 W KR 2019010894W WO 2020045941 A1 WO2020045941 A1 WO 2020045941A1
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Prior art keywords
amino
methylthiazol
pyridin
morpholinomethyl
prop
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PCT/KR2019/010894
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French (fr)
Korean (ko)
Inventor
김월영
이연임
윤연정
박준석
엄덕기
방극찬
정재현
Original Assignee
주식회사 대웅제약
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Priority claimed from KR1020190104641A external-priority patent/KR102328682B1/en
Priority to US17/269,325 priority Critical patent/US20220064155A1/en
Priority to JP2021534102A priority patent/JP7162741B2/en
Priority to SG11202101451QA priority patent/SG11202101451QA/en
Priority to BR112021003652-0A priority patent/BR112021003652B1/en
Priority to TNP/2021/000025A priority patent/TN2021000025A1/en
Priority to RU2021107433A priority patent/RU2760184C1/en
Priority to CN201980056437.8A priority patent/CN112638910A/en
Application filed by 주식회사 대웅제약 filed Critical 주식회사 대웅제약
Priority to PE2021000205A priority patent/PE20210417A1/en
Priority to BR122022001938-2A priority patent/BR122022001938B1/en
Priority to MX2021002188A priority patent/MX2021002188A/en
Priority to CA3108856A priority patent/CA3108856C/en
Priority to EP19855534.4A priority patent/EP3845530A4/en
Priority to AU2019331328A priority patent/AU2019331328B2/en
Publication of WO2020045941A1 publication Critical patent/WO2020045941A1/en
Priority to PH12021550329A priority patent/PH12021550329A1/en
Priority to CONC2021/0001849A priority patent/CO2021001849A2/en
Priority to DO2021000030A priority patent/DOP2021000030A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel heterocyclic amines useful as Bruton's Tyrosince Kinase (BTK) inhibitors and pharmaceutical compositions comprising them.
  • BTK Bruton's Tyrosince Kinase
  • Interleukin-2 Tyrosine Kinase ITK
  • BTK Bruton's Tyrosince Kinase
  • TEC hepatocellular carcinoma
  • RTK Resting Lymphocyte Kinase
  • BMX Bone-Marrow tyrosine kinase gene on chromosome X
  • ITK is expressed not only in T cells but also in NK cells and mast cells, and production of important cytokines such as IL-2, IL-4, IL-5, IL-10, IL-13 and IL-17 and T-cell proliferation Play an important role in (Schaeffer et al. Nat. Immune 2001, 2, 1183; Fowell et al. Immunity, 1999, 11, 399).
  • T cells are activated by TCR signaling, and activated T cells activate inflammatory cytokine production, B cells and macrophages, leading to autoimmune diseases such as RA (Sahu N. et al. Curr Top Med Chem. 2009, 9, 690).
  • Th17 / Treg As well as Th1 cells have been reported to be a cause of RA (J Leipe J. et al. Arthritis Rheum. 2010, 62 , 2876).
  • ITK has been previously developed as an immunotherapeutic drug target such as asthma, but has not been developed as a RA therapy (Lo H. Y Expert Opin Ther Pat. 2010, 20, 459).
  • Th17 and Treg cells through ITK-/-mice has been reported to be a potential target for RA treatment (Gomez-Rodriguez J. et al. J. Exp. Med. 2014, 211, 529). ).
  • BTK functions as a regulator of mature B-cell activation, signaling and survival as well as early B-cell development.
  • the B-cells are signaled by a B cell receptor (BCR) that recognizes an antigen attached to the surface of an antigen-presenting cell and activated into mature antibody producing cells.
  • BCR B cell receptor
  • abnormal signal transduction by BCR results in abnormal B-cell proliferation and the formation of pathological autoantibodies, which can lead to cancer, autoimmune and / or inflammatory diseases.
  • signal transduction by BCR may be blocked when BTK is deficient. Accordingly, inhibition of BTK may block the B-cell mediated disease process, so the use of BTK inhibitors may be a useful approach for the treatment of B-cell mediated diseases.
  • BTK can also be expressed by other cells besides B-cells that may be associated with the disease.
  • BTK is an important component of Fc-gamma signaling in bone marrow cells, which is expressed by mast cells.
  • BTK-deficient bone marrow-induced mast cells show impaired antigen-induced degranulation, so that inhibition of BTK activity is known to be useful for treating pathological mast cell responses such as allergy and asthma (Iwaki et al. J. Biol). Chem. 2005 280: 40261).
  • monocytes in XLA patients without BTK activity have been shown to reduce TNF alpha production following stimulation, thereby inhibiting TNF alpha mediated inflammation by BTK inhibitors (Horwood et al. J. Exp. Med. 197: 1603, 2003).
  • WO2008 / 039218 has disclosed 4-aminopyrazolo [3,4-d] pyrimidinylpiperidine derivatives
  • WO2015 / 061247 discloses hetero compounds such as pyridine, pyrimidine, pyrazine and pyridazine compounds
  • WO2014 / 055934 discloses pyrimidinylphenylacrylamide derivatives.
  • WO2005 / 066335 discloses aminobenzimidazoles
  • WO2005 / 056785 discloses pyridones
  • WO2002050071 discloses aminothiazole derivatives
  • WO2014 / 036016 discloses benzimidazole derivatives.
  • the present inventors have completed the present invention by studying a novel compound and confirming that a compound having a chemical structure different from the BTK and ITK inhibitors reported so far has excellent BTK and ITK double activity inhibitory effects.
  • the compounds belonging to the present invention mainly have BTK and ITK inhibitory activity by themselves, but do not exclude the possibility of exhibiting pharmacological action as an agonist by a special body environment or a product of metabolic process after being absorbed into the body.
  • the present invention is to provide a novel heterocyclic amine derivative useful as a BTK inhibitor and a pharmaceutical composition comprising the same.
  • the present invention provides a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof:
  • B is a 5 or 6 membered heterocycle containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, provided that the 5 or 6 membered heterocycle is at least one Including,
  • R 1 is hydrogen, halogen, C 1-4 alkyl, or C 1-4 haloalkyl
  • X 1 and X 2 are each independently N or CR ′,
  • R ' is hydrogen or halogen
  • L is a bond, C 1-4 alkylene, or —O—
  • R 2 is cyano; C 1-4 alkyl; C 6-10 aryl; Pyridinyl; Morpholino; Piperazinyl; Or piperidinyl,
  • piperazinyl and piperidinyl are each independently, unsubstituted or C 1-4 alkyl, a cyano C 1-4 alkyl, C 1-4 substituted with a substituted C 1-4 alkyl, amino Substituted with C 1-4 alkyl substituted with alkoxy, or —CO— (C 1-4 alkyl),
  • Y is a bond, -O-, -NH-, or -N (C 1-4 alkyl)-,
  • A is C 1-4 alkyl, , , , , , or ego,
  • R 3 is C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, or C 2-4 haloalkynyl.
  • B is a thiazole, pyrazole, pyridine, or pyrimidine ring,
  • R 1 is hydrogen, chloro, methyl, or trifluoromethyl.
  • X 1 and X 2 are both CH;
  • One of X 1 and X 2 is CF and the other is CH; or
  • One of X 1 and X 2 is N and the other is CH.
  • X 1 and X 2 are both CH
  • X 1 is CH and X 2 is CF;
  • X 1 is CH and X 2 is N;
  • X 1 is N and X 2 is CH.
  • L is a bond, methylene, or -O-.
  • R 2 is cyano; methyl; Phenyl; Pyridinyl; Morpholino; Piperazinyl substituted with methyl; Piperazinyl substituted with ethyl; Piperazinyl substituted with 2-cyanoethyl; Piperazinyl substituted with 3-aminopropyl; Piperazinyl substituted with 2-methoxyethyl; Piperazinyl substituted with -CO- (methyl); Unsubstituted piperidinyl; Or piperidinyl substituted with methyl.
  • Y is a bond, -O-, -NH-, or -N (methyl)-.
  • Chemical Formula 1-1 the compound represented by Chemical Formula 1-1:
  • R 1 is hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl
  • X 1 and X 2 are each independently N or CR ′,
  • R ' is hydrogen or halogen
  • L is a bond, C 1-4 alkylene, or —O—
  • R 2 is cyano; C 1-4 alkyl; C 6-10 aryl; Pyridinyl; Morpholino; Piperazinyl; Or piperidinyl,
  • piperazinyl and piperidinyl are each independently, unsubstituted or C 1-4 alkyl, a cyano C 1-4 alkyl, C 1-4 substituted with a substituted C 1-4 alkyl, amino Substituted with C 1-4 alkyl substituted with alkoxy, or —CO— (C 1-4 alkyl),
  • Y is a bond, -O-, -NH-, or -N (C 1-4 alkyl)-,
  • A is C 1-4 alkyl, , , , , , or ego,
  • R 3 is C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, or C 2-4 alkynyl.
  • R 1 is C 1-4 alkyl
  • X 1 and X 2 are each independently N or CH,
  • L is a bond, C 1-4 alkylene, or —O—
  • R 2 is cyano; C 1-4 alkyl; C 6-10 aryl; Pyridinyl; Morpholino; Piperazinyl; Or piperidinyl,
  • piperazinyl and piperidinyl are each independently, unsubstituted or C 1-4 alkyl, cyano substituted C 1-4 substituted alkyl, C 1-4 alkoxy C 1-4 alkyl, Or substituted with -CO- (Ci_ 4 alkyl),
  • Y is a bond, -O-, -NH-, or -N (C 1-4 alkyl)-,
  • A is , , , , , or ego
  • R 3 is C 2-4 alkenyl, or C 2-4 alkynyl.
  • Chemical Formula 1 is represented by the following Chemical Formula 1-2:
  • R 1 is hydrogen or halogen
  • X 1 and X 2 are each independently N or CH,
  • L is C 1-4 alkylene
  • R 2 is morpholino
  • Y is -NH-
  • R 3 is C 2-4 alkenyl.
  • Chemical Formula 1 is represented by the following Chemical Formula 1-3:
  • X 1 and X 2 are each independently N or CH,
  • L is C 1-4 alkylene
  • R 2 is morpholino
  • Y is -NH-
  • R 3 is C 2-4 alkenyl.
  • Chemical Formula 1 is represented by the following Chemical Formula 1-4:
  • X 1 and X 2 are each independently N or CH,
  • L is C 1-4 alkylene
  • R 2 is morpholino
  • Y is -NH-
  • R 3 is C 2-4 alkenyl.
  • the compounds of the invention may exist in the form of salts, in particular pharmaceutically acceptable salts.
  • salts conventionally used in the art may be used without limitation, such as acid addition salts formed by pharmaceutically acceptable free acid.
  • pharmaceutically acceptable salt of the present invention is any concentration of the compound which is relatively nontoxic to the patient and has a harmless effective action, in which the side effects caused by the salt do not degrade the beneficial efficacy of the compound represented by the formula (1). Means any organic or inorganic addition salt.
  • Organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid ( maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid ( gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like. It is not limited to these.
  • the salt may be a hydrochloride salt.
  • Bases can also be used to obtain pharmaceutically acceptable metal salts in conventional manner.
  • the compound represented by Chemical Formula 1 may be dissolved in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, the insoluble compound salt is filtered, and the filtrate is evaporated and dried to obtain a pharmaceutically acceptable metal salt.
  • the metal salt it is particularly preferable to prepare sodium salt, potassium salt or calcium salt.
  • the compound represented by Chemical Formula 1 according to the present invention includes not only pharmaceutically acceptable salts thereof, but also solvates such as possible hydrates and all possible stereoisomers which can be prepared therefrom.
  • Solvates and stereoisomers of the compound represented by Formula 1 may be prepared from the compound represented by Formula 1 using methods known in the art.
  • the compound represented by Chemical Formula 1 according to the present invention may be prepared in crystalline form or in amorphous form, and when prepared in crystalline form, may be optionally hydrated or solvated.
  • a compound containing various amounts of water as well as stoichiometric hydrate of the compound represented by Formula 1 may be included.
  • Solvates of the compounds represented by Formula 1 according to the present invention include both stoichiometric and non stoichiometric solvates.
  • Step 1-1 is a step of preparing a compound represented by Chemical Formula 1-3 by reacting the compound represented by Chemical Formula 1-1 with the compound represented by Chemical Formula 1-2.
  • the reaction is an amine substitution reaction, it is preferable to carry out in the presence of a palladium catalyst and a base, and when the reaction is a solvolysis reaction of alkyl chloride according to a secondary alcohol, it is preferable to carry out in the presence of a base.
  • Step 1-2 is a step of preparing a compound represented by Chemical Formula 1-5 by reacting the compound represented by Chemical Formula 1-3 with the compound represented by Chemical Formula 1-4.
  • the reaction is an amine substitution reaction, preferably carried out in the presence of a palladium catalyst and a base.
  • Step 1-3 is a step of preparing a compound represented by the formula (1-6) by removing the protecting group (BOC; tert -butyloxycarbonyl protecting group) from the compound represented by the formula (1-5).
  • the reaction is preferably carried out under acidic conditions capable of removing the protecting group.
  • Step 1-4 is a step of preparing a compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 1-6 with the compound represented by Chemical Formula 1-7.
  • the reaction is an amidation reaction, preferably performed in the presence of a base.
  • Step 2-1 is a step of preparing the compound represented by Chemical Formula 2-2 by reacting the compound represented by Chemical Formula 2-1 with the compound represented by Chemical Formula 1-2.
  • the reaction is an amine substitution reaction, it is preferable to carry out in the presence of a palladium catalyst and a base, and when the reaction is a solvolysis reaction of alkyl chloride according to a secondary alcohol, it is preferable to carry out in the presence of a base.
  • Step 2-2 is a step of preparing the compound represented by Chemical Formula 2-4 by reacting the compound represented by Chemical Formula 2-2 with the compound represented by Chemical Formula 2-3.
  • the reaction is an amidation reaction, preferably carried out in the presence of an amidation reagent.
  • Step 2-3 is a step of preparing a compound represented by Chemical Formula 2-5 by reacting the compound represented by Chemical Formula 2-4 with the compound represented by Chemical Formula 1-4.
  • the reaction is an amine substitution reaction, preferably carried out in the presence of a palladium catalyst and a base.
  • Step 2-4 is a step of preparing a compound represented by Chemical Formula 2-6 by removing the protecting group (BOC) from the compound represented by Chemical Formula 2-5 and reducing the ketone.
  • the reaction is preferably carried out under acidic conditions.
  • Step 2-5 is a step of preparing a compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 2-6 with the compound represented by Chemical Formula 1-7.
  • the reaction is an amidation reaction, preferably performed in the presence of a base.
  • the present invention is a compound in which A is C 1-4 alkyl in the compound represented by Formula 1, in place of the compound represented by Formula 1-2 in step 1-1 of Scheme 1 Except for using the compound represented by the can be prepared using the same method as in step 1-1 and step 1-2 of Scheme 1.
  • the present invention is to prevent the autoimmune disease or cancer disease of which the compound represented by the formula (1), or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof is beneficial ITK and BTK inhibitory action is beneficial or Provided is a therapeutic pharmaceutical composition.
  • the autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, childhood diabetes mellitus, psoriasis, aphthosis, chronic thyroiditis, some acquired regenerative anemia, primary cirrhosis, ulcerative colitis, Beche's disease, Crohn's disease, silicosis, asbestos , Sjogren's syndrome, Gillian-Barre syndrome, dermatitis, multiple myositis, multiple sclerosis, autoimmune hemolytic anemia, autoimmune encephalomyelitis, myasthenia gravis, Grave's hyperthyroidism, nodular polyarteritis, ankylosing spondylitis, fibromyalitis, lateral arthritis , Asthma, or Fanconi syndrome,
  • the cancer is hematologic cancer, extra-nodal margin B-cell lymphoma, glioblastoma, lymphoid cytoplasmic lymphoma, acute myeloid leukemia, macroglobulinemia, B-cell lymphoma, chronic lymphocytic leukemia, vesicular lymphoma, non-Hodgkin's lymphoma, diffuse large B cell lymphoma, hairy cell leukemia, mantle cell lymphoma, glioblastoma, bladder cancer, pancreatic cancer, ovarian cancer, colon cancer, kidney cancer, gastric cancer, transitional epithelial cancer, carcinoid cancer, breast cancer, non-small cell lung cancer, or multiple myeloma.
  • prevention of the present invention means any action that inhibits or delays the occurrence, spread and recurrence of the disease by administration of the composition of the present invention, and “treatment” means the symptoms of the disease by administration of the composition of the present invention. Means any action that improves or beneficially changes;
  • compositions of the invention may be formulated in oral or parenteral dosage forms according to standard pharmaceutical practice. These formulations may contain, in addition to the active ingredient, additives such as pharmaceutically acceptable carriers, adjuvants or diluents.
  • Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oils and isopropyl myristate, and the diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or the like. Or glycine, and the like, but is not limited thereto.
  • the compounds of the present invention may be dissolved in oil, propylene glycol or other solvents commonly used in the preparation of injection solutions.
  • the compounds of the present invention may be formulated into ointments or creams for topical action.
  • Preferred dosages of the compounds of the present invention depend on the condition and weight of the patient, the extent of the disease, the form of the drug, the route and duration of administration, and may be appropriately selected by those skilled in the art. However, for the desired effect, it is preferable to administer the compound of the present invention at 0.0001 to 100 mg / kg body weight, preferably 0.001 to 100 mg / kg body weight. Administration can be administered via oral or parenteral routes once or divided daily.
  • the pharmaceutical composition may contain 0.001 to 99% by weight, preferably 0.01 to 60% by weight of the compound of the present invention.
  • the pharmaceutical composition according to the present invention can be administered to mammals including rats, mice, livestock and humans by various routes. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
  • the compound represented by the formula (1) of the present invention a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof may be usefully used for the prevention or treatment of autoimmune diseases or diseases of cancer.
  • Step 1-1 Preparation of (2,6-dichloropyridin-4-yl) (morpholino) methanone
  • 2,6-dichloroisonicotinic acid (10.0 g, 1.0 eq) was dissolved in dimethylformamide (100.0 mL), and then 1,1-carbonyldiimidazole (1.0 g, 1.2 eq) was added. After stirring for 1 hour at room temperature (25-30 ° C.) under nitrogen gas, morpholine (5.4 mL, 1.2 eq) was added, followed by stirring at the same temperature for 2 hours to complete the reaction. Ethyl acetate (200.0 mL) and water (200.0 mL) were added for extraction, and the water layer was reextracted three times with ethyl acetate (200.0 mL).
  • Step 1-2 Preparation of 4-((2,6-dichloropyridin-4-yl) methyl) morpholine
  • step 1-1 The intermediate (10.0 g, 1.0 eq) obtained in step 1-1 was dissolved in dichloromethane (100.0 mL) and then cooled to 0 to 10 ° C. under nitrogen gas. 1M borane-tetrohydrofuran (115.0 mL, 3.0 eq) was slowly added dropwise. The reaction was completed by stirring at room temperature for 12 hours. After cooling the reaction solution to 0-10 degreeC, 6N hydrochloric acid aqueous solution (256.0 mL, 20.0eq) was slowly added dropwise, and the mixture was stirred at the same temperature for 1 hour. The mixture was adjusted to pH 9 to pH 12 using 10N-sodium hydroxide aqueous solution, and then extracted twice with dichloromethane.
  • Step 1-3 Preparation of tert-butyl 3-((6-chloro-4- (morpholinomethyl) pyridin-2-yl) amino) piperidine-1-carboxylate
  • 1,4-dioxane (10.0 mL) was added to and dissolved in the intermediate (1.0 g, 1.0 eq) obtained in step 1-2, followed by tris (dibenzylideneacetone) dipalladium (0) (465.8 mg, 0.2 eq), Xanthose (1.5 g, 0.4 eq) was added.
  • tert-butyl 3-aminopiperidine-1-carboxylate (780.0 ⁇ l, 1.0 eq) was added, sodium carbonate (1.3 g, 3.0 eq) was added thereto, followed by reflux for 12 hours to complete the reaction. After cooling to 30 ° C.
  • Steps 1-5 Preparation of N 2- (5-methylthiazol-2-yl) -4- (morpholinomethyl) -N 6- (piperidin-3-yl) pyridine-2,6-diamine
  • Steps 1-6 1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidine-1 Preparation of -yl) prop-2-en-1-one
  • Example 1 except that tert-butyl 3-aminopyrrolidine-1-carboxylate was used instead of tert-butyl 3-aminopiperidine-1-carboxylate in Step 1-3 of Example 1 In the same manner the title compound (15.0 mg. Yield 23.0%) was obtained.
  • Example 1 except that tert-butyl 4-aminopiperidine-1-carboxylate was used instead of tert-butyl 3-aminopiperidine-1-carboxylate in Step 1-3 of Example 1 In the same manner the title compound (8.0 mg. Yield 53.0%) was obtained.
  • Example 1 except that tert-butyl (R) 3-aminopyrrolidine-1-carboxylate was used instead of tert-butyl 3-aminopiperidine-1-carboxylate in steps 1-3 of Example 1 In the same manner as in Example 1, the title compound (10.0 mg. Yield 58.0%) was obtained.
  • Example 1 except that tert-butyl (S) 3-aminopyrrolidine-1-carboxylate was used instead of tert-butyl 3-aminopiperidine-1-carboxylate in Step 1-3 of Example 1 In the same manner as in Example 1, the title compound (15.0 mg. Yield 63.0%) was obtained.
  • Example 8 1- (3-((2-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-4-yl) amino) pyrrolidine-1 Preparation of -yl) prop-2-en-1-one
  • Step 8-1 Preparation of methyl 6-((1- (tert-butoxycarbonyl) pyrrolidin-3-yl) amino) -2-chloropyrimidine-4-carboxylate
  • Step 8-2 Preparation of tert-butyl 3-((2-chloro-6- (morpholin-4-carbonyl) pyrimidin-4-yl) amino) pyrrolidine-1-carboxylate
  • Step 8-3 tert-Butyl 3-((2-((5-methylthiazol-2-yl) amino) -6- (morpholin-4-carbonyl) pyrimidin-4-yl) amino) pi
  • Step 8-3 tert-Butyl 3-((2-((5-methylthiazol-2-yl) amino) -6- (morpholin-4-carbonyl) pyrimidin-4-yl) amino) pi
  • Step 8-4 N 2 -(5-methylthiazol-2-yl) -6- (morpholinomethyl) -N 4 Preparation of-(pyrrolidin-3-yl) pyrimidine-2,4-diamine
  • reaction solution was cooled to 0 ° C., adjusted to pH 12 with 12N aqueous sodium hydroxide solution, and extracted with dichloromethane (200.0 mL) and water (200.0 mL). The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the title compound (40.0 mg, yield 20.9%).
  • Step 8-5 1- (3-((2-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-4-yl) amino) pyrrolidine- Preparation of 1-yl) prop-2-en-1-one
  • Step 10-1 Preparation of tert-butyl 3-((6-chloro-4- (morpholinomethyl) pyridin-2-yl) oxy) pyrrolidine-1-carboxylate
  • Step 10-2 (1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) oxy) pyrrolidine- Preparation of 1-yl) prop-2-en-1-one
  • Example 10 except that tert-butyl 4-hydroxypiperidine-1-carboxylate was used instead of tert-butyl 3-hydroxypyrrolidine-1-carboxylate in Step 10-1 of Example 10. In the same manner as the title compound (8.5 mg, yield 65.0%) was obtained.
  • Example 10 except that tert-butyl 3-hydroxypiperidine-1-carboxylate was used instead of tert-butyl 3-hydroxypyrrolidine-1-carboxylate in Step 10-1 of Example 10. In the same manner as the title compound (9.5 mg, yield 63.0%) was obtained.
  • Step 13-1 (R) -N 2 -(5-methylthiazol-2-yl) -4- (morpholinomethyl) -N 6 Preparation of-(piperidin-3-yl) pyridine-2,6-diamine
  • Step 13-2 (R) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pi Preparation of Ferridin-1-yl) but-2-yn-1-one
  • Example 8 except that 3-amino-1-tert-butoxy-carbonylpiperidine was used instead of tert-butyl 3-aminopyrrolidine-1-carboxylate in step 8-1 of Example 8. In the same manner to obtain the title compound (10.0 mg, yield 17.5%).
  • Step 20-1 Preparation of 1-((2,6-dichloropyridin-4-yl) methyl) piperazine
  • Step 20-2 Preparation of 1- (4-((2,6-dichloropyridin-4-yl) methyl) piperazin-1-yl) ethan-1-one
  • Step 20-3 (S) -1- (3-((4-((4-acetylpiperazin-1-yl) methyl) -6-((5-methylthiazol-2-yl) amino) pyridine Preparation of -2-yl) amino) piperidin-1-yl) prop-2-en-1-one
  • Step 20-2 of Example 20 Use the intermediate obtained in Step 20-2 of Example 20 instead of the intermediate obtained in Step 1-2 of Example 1 and tert instead of tert-butyl 3-aminopiperidine-1-carboxylate in Step 1-3.
  • the title compound (50.0 mg. Yield 45.0%) was obtained by the same method as Example 1, except that -butyl (S) -3-aminopiperidine-1-carboxylate was used.
  • Step 21-1 Methyl (S) -6-((1- ( tert Preparation of -butoxycarbonyl) piperidin-3-yl) amino) -2-chloropyrimidine-4-carboxylate
  • Step 21-2 tert-butyl (S) -3-((2-chloro-6- (morpholin-4-carbonyl) pyrimidin-4-yl) amino) piperidine-1-carboxylate Produce
  • Step 21-3 tert-butyl 3-((2-((5-methylthiazol-2-yl) amino) -6- (morpholine-4-carbonyl) pyrimidin-4-yl) amino) pi
  • Step 21-3 tert-butyl 3-((2-((5-methylthiazol-2-yl) amino) -6- (morpholine-4-carbonyl) pyrimidin-4-yl) amino) pi
  • Step 21-4 (S) -N 2 -(5-methylthiazol-2-yl) -6- (morpholinomethyl) -N 4 Preparation of-(piperidin-3-yl) pyrimidine-2,4-diamine
  • reaction solution was cooled to 0 ° C., adjusted to pH 12 with 12N aqueous sodium hydroxide solution, and extracted with dichloromethane (200.0 mL) and water (200.0 mL). The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the title compound (270.0 mg, yield 69.8%).
  • Step 21-5 (S) -1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-2-yl) amino) Preparation of Piperidin-1-yl) prop-2-en-1-one
  • Step 22-1 Preparation of 1-((2,6-dichloropyridin-4-yl) methyl) -4- (2-methoxyethyl) piperazine
  • Step 22-2 (S) -1- (3-((4-((4- (2-methoxyethyl) piperazin-1-yl) methyl) -6-((5-methylthiazole-2 Preparation of -yl) amino) pyridin-2-yl) amino) piperidin-1-yl) prop-2-en-1-one
  • Step 22-1 of Example 22 Use the intermediate obtained in Step 22-1 of Example 22 instead of the intermediate obtained in Step 1-2 of Example 1 and tert instead of tert-butyl 3-aminopiperidine-1-carboxylate in Step 1-3.
  • the title compound (15.0 mg, yield 68.0%) was obtained in the same manner as in Example 1, except that -butyl (S) -3-aminopiperidine-1-carboxylate was used.
  • Example 21 The title compound (25.0 mg, yield 10.7%) was obtained in the same manner as in Example 21, except that boot-2-inoyl chloride was used instead of acryloyl chloride in step 21-5 of Example 21.
  • Step 27-1 Preparation of tert-butyl (1- (6-chloro-4- (morpholinomethyl) pyridin-2-yl) piperidin-4-yl) carbamate
  • Step 27-2 tert-butyl (1- (6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) piperidin-4-yl Preparation of Carbamate
  • Step 27-3 Preparation of N- (6- (4-aminopepyridin-1-yl) -4- (morpholinomethyl) pyridin-2-yl) -5-methylthiazol-2-amine
  • Step 27-4 N- (1- (6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) piperidin-4-yl) Preparation of Acrylamide
  • N- (6- (4-aminopepyridin-1-yl) -4- (morpholinomethyl) pyridin-2-yl) -5-methylthiazol-2-amine obtained in step 27-3 (0.1) g, 0.2 mmol) was dissolved in tetrahydrofuran (6 mL) and water (2 mL), cooled to 0 ° C. and sodium bicarbonate (0.08 g, 1.0 mmol) was added. Acryloyl chloride (0.02 mL, 0.3 mmol) was slowly added to the reaction solution, followed by stirring at 0 ° C. for 10 minutes.
  • Example 29 1- (6- (6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) octahydro-1H-pyrrolo [2 Preparation of, 3-c] pyridin-1-yl) but-2-yn-1-one
  • step 27-1 of Example 27 tert-butyl octahydroxy-1H-pyrrolo [2,3-c] pyridine-1-carboxylate was used instead of tert-butyl piperidin-4-ylcarbamate.
  • the title compound (12 mg, yield 15%) was obtained in the same manner as in Example 27, except that But-2-inoyl chloride was used instead of acryloyl chloride in step 27-4.
  • Example 21 The title compound (0.5 mg, yield 1.1%) was obtained in the same manner as in Example 21, except that 1-ethylpiperazine was used instead of morpholine in step 21-2 of Example 21.
  • Step 33-1 Preparation of tert-butyl 4-((2,6-dichloropyridin-4-yl) oxy) piperidine-1-carboxylate
  • Step 33-2 Preparation of 2,6-dichloro-4- (piperidin-4-yloxy) pyridine
  • Step 33-3 Preparation of 2,6-dichloro-4-((1-methylpiperidin-4-yl) oxy) pyridine
  • Step 33-4 tert-Butyl (S) -3-((6-chloro-4-((1-methylpiperidin-4-yl) oxy) pyridin-2-yl) amino) piperidine-1 Preparation of Carboxylate
  • 2,6-dichloro-4-((1-methylpiperidin-4-yl) oxy) pyridine (2.0 g, 1.0 eq) obtained in step 33-3 was dissolved in 1,4-dioxane (20.0 mL). Later, palladium acetate (0.1 eq), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.2 eq), cesium carbonate (3.0 eq), 2-amino-5-methylthiazole (1.2 eq) was added and reacted in a microwave reactor (150 ° C., 30 min). After the reaction was completed, water (250.0 mL) and dichloromethane (250.0 mL) were added and extracted.
  • Step 33-5 tert-Butyl (S) -3-((4-((1-methylpiperidin-4-yl) oxy) -6-((5-methylthiazol-2-yl) amino) Preparation of Pyridin-2-yl) amino) piperidine-1-carboxylate
  • Step 33-6 (S) -4-((1-methylpiperidin-4-yl) oxy) -N 2 -(5-methylthiazol-2-yl) -N 6 Preparation of-(piperidin-3-yl) pyridine-2,6-diamine
  • Step 33-7 (S) -1- (3-((4-((1-methylpiperidin-4-yl) oxy) -6-((5-methylthiazol-2-yl) amino) Preparation of Pyridin-2-yl) amino) piperidin-1-yl) prop-2-en-1-one
  • Step 34-1 3- (4-((2,6-dichloropyridin-4-yl) methyl) piperazin-1-yl) propanenitrile
  • Step 34-2 t-butyl (S) -3-((4-((4- (2-cyanoethyl) piperazin-1-yl) methyl) -6-((5-methylthiazole-2 Preparation of -yl) amino) pyridin-2-yl) amino) piperidine-1-carboxylate
  • step 34-1 Use the intermediate obtained in step 34-1 instead of the intermediate obtained in steps 1-3 of Example 1 and use t-butyl (S) -3-amino instead of t-butyl 3-aminopiperidine-1-carboxylate.
  • the title compound 400. mg. Yield 76.0%) was obtained by the same method as Steps 1-3 and 1-4 of Example 1, except that piperidine-1-carboxylate was used.
  • Step 34-3 (S) -3- (4-((2-((5-methylthiazol-2-yl) amino) -6- (piperidin-3-ylamino) pyridin-4-yl Preparation of (methyl) piperazin-1-yl) propanenitrile
  • Step 34-4 (S) -3- (4-((2-((1-acryloylpiperidin-3-yl) amino) -6-((5-methylthiazol-2-yl) amino Preparation of Pyridin-4-yl) methyl) piperazin-1-yl) propanenitrile
  • Step 36-1 Preparation of 2,6-dichloro-4- (pyridin-3-ylmethyl) pyridine
  • Step 36-2 Preparation of tert-butyl (S) -3-((6-chloro-4- (pyridin-3-ylmethyl) pyridin-2-yl) amino) piperidine-1-carboxylate
  • 2,6-dichloro-4- (pyridin-3-ylmethyl) pyridine (1.7 g, 7.1 mmol) obtained in step 36-1 was dissolved in 1,4-dioxane (24 mL), followed by tert-butyl (S ) -3-aminopiperidine-1-carboxylate (1.6 g, 7.8 mmol), palladium acetate (0.2 g, 0.7 mmol), xantose (0.8 g, 1.4 mmol), sodium carbonate (2.3 g, 21.3 mmol) It was added sequentially and stirred under reflux at 100 °C for 12 hours. After the reaction was completed, the mixture was filtered through celite, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate 100%) to obtain the title compound (280 mg, yield 15%).
  • Step 36-3 tert-butyl 3-((6-((5-methylthiazol-2-yl) amino) -4- (pyridin-3-ylmethyl) pyridin-2-yl) amino) piperidine Preparation of -1-carboxylate
  • Step 36-4 N 2 -(5-methylthiazol-2-yl) -N 6 Preparation of-(piperidin-3-yl) -4- (pyridin-3-ylmethyl) pyridine-2,6-diamine
  • Step 36-5 (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (pyridin-3-ylmethyl) pyridin-2-yl) amino Preparation of Piperidin-1-yl) prop-2-en-1-one
  • Example 2 Same as Example 1, except that 2,6-dichloroisonicotinonitrile was used instead of 4-((2,6-dichloropyridin-4-yl) methyl) morpholine in steps 1-3 of Example 1
  • the title compound (11 mg, yield 22%) was obtained by the method.
  • Example 1 except that 2,6-dichloro-4-phenylpyridine was used instead of 4-((2,6-dichloropyridin-4-yl) methyl) morpholine in steps 1-3 of Example 1. In the same manner the title compound (10 mg, yield 22%) was obtained.
  • Example 33 The title compound (40.0 mg, yield 34.4%) was obtained by the same method as Example 33, except that boot-2-inoyl chloride was used instead of acryloyl chloride in steps 33-7 of Example 33.
  • Step 44-1 Preparation of 4-((2-chloro-6-methylpyridin-4-yl) methyl) morpholine
  • Step 44-2 Preparation of 5-methyl-N- (6-methyl-4- (morpholinomethyl) pyridin-2-yl) thiazol-2-amine
  • Step 45-1 (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pi Preparation of Hydrochloride of Ferridin-1-yl) prop-2-en-1-one
  • Example 5 Material (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pi After dissolving 10.0 g of ferridin-1-yl) prop-2-en-1-one in 200.0 ml of ethyl acetate, 3 equivalents of 1N hydrochloric acid dissolved in ethyl acetate was added. Stirred at room temperature for 1 hour, filtered, and dried under reduced pressure at room temperature for 12 hours to give (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholino) Hydrochloride (11.6 g. Yield 85%) of methyl) pyridin-2-yl) amino) piperidin-1-yl) prop-2-en-1-one was obtained.
  • Step 45-2 (S) -3-chloro-1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) Preparation of Amino) piperidin-1-yl) propan-1-one
  • step 45-1 The material obtained in step 45-1 was stored at -20 ° C for 7 months.
  • the material produced during the storage was column separated with a 15: 1 mixed solvent of methylene chloride and methanol to obtain the title compound (30.0 mg. Yield 5%).
  • step 45-1 The material obtained in step 45-1 was stored at -20 ° C for 7 months.
  • the material produced during the storage was subjected to column separation with a 15: 1 mixed solvent of methylene chloride and methanol to obtain the title compound (3.0 mg, yield 0.5%).
  • Example (S) -3- (4-((2-((1-acryloylpiperidin-3-yl) amino) -6-((5-methylthiazol-2-yl) amino Pyridin-4-yl) methyl) piperazin-1-yl) propanenitrile (35.0 mg, 1.0 eq) was dissolved in methanol (5.0 mL), followed by addition of 10% palladium / carbon at room temperature and reaction for 5 minutes. I was. Then filtered with methanol using celite. The separated solution was concentrated under reduced pressure and purified by column chromatography to obtain the title compound (4.0 mg, yield 12.1%) as a brown solid.
  • Step 48-1 tert-butyl (S) -3-((6-((1H-pyrazol-3-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperi Preparation of Dean-1 -carboxylate
  • Step 48-2 (S) -4- (morpholinomethyl) -N 2 -(Piperidin-3-yl) -N 6 Preparation of-(1H-pyrazol-3-yl) pyridine-2,6-diamine
  • Step 48-3 (S) -1- (3- (6- (1H-pyrazol-3-ylamino) -4- (morpholinomethyl) pyridin-2-ylamino) piperidine-1- (1) Preparation of prop-2-en-1-one
  • Step 49-1 tert-butyl (S) -3-((4- (morpholinomethyl) -6-((5- (trifluoromethyl) thiazol-2-yl) amino) pyridine-2- I) Preparation of amino) piperidine-1-carboxylate
  • Step 49-2 (S) -4- (morpholinomethyl) -N 2 -(Piperidin-3-yl) -N 6 Preparation of-(5- (trifluoromethyl) thiazol-2-yl) pyridine-2,6-diamine
  • Step 49-3 (S) -1- (3- (4- (morpholinomethyl) -6- (5- (trifluoromethyl) thiazol-2-ylamino) pyridin-2-ylamino) Preparation of Piperidin-1-yl) prop-2-en-1-one
  • Step 52-1 Preparation of (2,6-dichloro-3-fluoropyridin-4-yl) (morpholino) methanone
  • Step 52-2 Preparation of 4-((2,6-dichloro-3-fluoropyridin-4-yl) methyl) morpholine
  • step 52-1 The intermediate (500.0 mg, 1.0 eq) obtained in step 52-1 was dissolved in dichloromethane (20.0 mL) and then stirred at room temperature (25-30 ° C.). 0.9 M borane-tetrohydrofuran (6.0 mL, 3.0 eq) was added slowly dropwise. The reaction was completed by stirring at room temperature for 12 hours. After cooling the reaction solution to 0-10 degreeC, 6N hydrochloric acid aqueous solution (39.0 mL, 20.0eq) was slowly added dropwise, and the mixture was stirred at the same temperature for 1 hour. The mixture was adjusted to pH 9 to pH 12 using 6N aqueous sodium hydroxide solution, and then extracted twice with dichloromethane.
  • Step 52-3 tert-butyl (S) -3-((6-chloro-3-fluoro-4- (morpholinomethyl) pyridin-2-yl) amino) piperidine-1-carboxylate Produce
  • 1,4-dioxane (2.0 mL) was dissolved in the intermediate (100.0 mg, 1.0 eq) obtained in step 52-2, followed by palladium acetate (9.3 mg, 0.1 eq) and xanthose (43.4 mg, 0.2 eq). Input. tert-butyl (S) -3-aminopiperidine-1-carboxylate (75.5 mg, 1.0 eq) was added followed by cesium carbonate (325.8 mg, 3.0 eq). The reaction was performed at 140 ° C. for 30 minutes in a microwave reactor. After cooling to 30 ° C. or less, water (10.0 mL) and ethyl acetate (10.0 mL) were added, and the layers were separated.
  • Step 52-4 tert-Butyl (S) -3-((3-fluoro-6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridine-2- I) Preparation of amino) piperidine-1-carboxylate
  • the intermediate (100.0 mg, 1.0 eq) obtained in step 52-3 was dissolved in 1,4-dioxane (2.0 mL). Palladium acetate (5.1 mg, 0.1 eq), xantose (24.3 mg, 0.2 eq), 5-methylthiano-2-amine (24.0 mg, 1.0 eq), cesium carbonate (205.8 g, 3.0 eq) were added in this order. .
  • the reaction was performed at 150 ° C. for 30 minutes in a microwave reactor. After cooling to 30 ° C. or less, water (10.0 mL) and ethyl acetate (10.0 mL) were added, and the layers were separated.
  • Step 52-5 (S) -3-fluoro-N 6 -(5-methylthiazol-2-yl) -4- (morpholinomethyl) -N 2 Preparation of-(piperidin-3-yl) pyridine-2,6-diamine
  • step 52-4 The intermediate (80.0 mg, 1.0 eq) obtained in step 52-4 was dissolved in ethyl acetate (10.0 mL), and 6N-hydrochloric acid aqueous solution (0.6 mL, 20.0 eq) was slowly added dropwise, followed by stirring for 2 hours. After adjusting to pH 9-12 using 12N-sodium hydroxide aqueous solution, the separated dichloromethane layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Ethyl acetate (10.0 mL) was added to the obtained residue to form crystals for 30 minutes. The crystals were filtered off and dried to afford the title compound (60.5 mg. Yield 99.9%).
  • Step 52-6 (S) -1- (3-fluoro-6- (5-methylthiazol-2-ylamino) -4- (morpholinomethyl) pyridin-2-yl) amino Preparation of Piperidin-1-yl) prop-2-en-1-one
  • ITK Kinase enzyme system' kit 10 ⁇ l of ITK enzyme prepared in a white 96-well plate to a final concentration of 0.4 ng / ⁇ l and final concentration of 1 uM for single concentration evaluation, 1000, 300, 100, 30, 10, 3, 1 for IC 50 evaluation , 0.3, 0.1, 0.03 nM 5 ⁇ l compound was mixed and reacted at room temperature for 15 minutes. 5 ⁇ l of substrate and 5 ⁇ l of ATP prepared to have a final concentration of 25 uM were added to the reaction plate, followed by reaction at 30 ° C. for 1 hour.

Abstract

The present invention relates to a novel heterocyclic amine derivative represented by chemical formula 1 stated below and a pharmaceutical composition comprising same, and a compound according to the present invention may be utilized for prevention or treatment of autoimmune diseases or cancer. [Chemical formula 1] In chemical formula 1, explanations for R1, R2, X1, X2, L, Y, A, and B are as defined in the description.

Description

신규한 헤테로사이클릭아민 유도체 및 이를 포함하는 약학 조성물Novel heterocyclic amine derivatives and pharmaceutical compositions comprising the same
관련 출원(들)과의 상호 인용Cross Citation with Related Application (s)
본 출원은 2018년 8월 27일자 한국 특허 출원 제10-2018-0100359호 및 2019년 8월 26일자 한국 특허 출원 제10-2019-0104641호에 기초한 우선권의 이익을 주장하며, 해당 한국 특허 출원들의 문헌에 개시된 모든 내용은 본 명세서의 일부로서 포함된다.This application claims the benefit of priority based on Korean Patent Application No. 10-2018-0100359 dated August 27, 2018 and Korean Patent Application No. 10-2019-0104641 dated August 26, 2019. All content disclosed in the literature is included as part of this specification.
본 발명은 BTK(Bruton's Tyrosince Kinase) 저해제로서 유용한 신규한 헤테로사이클릭아민 및 이를 포함하는 약학 조성물에 관한 것이다.The present invention relates to novel heterocyclic amines useful as Bruton's Tyrosince Kinase (BTK) inhibitors and pharmaceutical compositions comprising them.
ITK(Interleukin-2 Tyrosine Kinase)와 BTK(Bruton's Tyrosince Kinase)는 Tec(tyrosine kinase expressed in hepatocellular carcinoma), RLK(Resting Lymphocyte Kinase) 및 BMX(Bone-Marrow tyrosine kinase gene on chromosome X)와 함께 TEC 계열의 수용체를 가지지 않는 티로신 키나아제의 일종으로 다양한 면역 반응에 작용한다.Interleukin-2 Tyrosine Kinase (ITK) and Bruton's Tyrosince Kinase (BTK), together with tyrosine kinase expressed in hepatocellular carcinoma (TEC), Resting Lymphocyte Kinase (RLK), and Bone-Marrow tyrosine kinase gene on chromosome X (BMX) It is a type of tyrosine kinase that does not have a receptor and works on various immune responses.
ITK는 T세포뿐만 아니라 NK 세포와 mast세포에서 발현되며, IL-2, IL-4, IL-5, IL-10, IL-13 및 IL-17과 같은 중요한 사이토 카인의 생산 및 T- 세포 증식에 중요한 역할을 한다(Schaeffer et al. Nat. Immune 2001,2, 1183; Fowell et al. Immunity, 1999, 11, 399). T 세포는 TCR 신호전달에 의하여 활성화 되며 활성화된 T세포는 염증성 사이토카인 생성, B 세포 및 마크로파지를 활성화 시켜 RA와 같은 자가면역 질환을 유발한다(Sahu N. et al. Curr Top Med Chem. 2009, 9, 690). 기존에는 T세포가 Th1 세포로 활성화되어 RA 질환이 유발되는 것으로 알려졌으나 최근에 Th1 세포뿐만 아니라 Th17/Treg가 RA의 병인으로 작용된다고 보고되었다(J Leipe J. et al. Arthritis Rheum. 2010, 62, 2876). 또한 ITK는 기존에 천식 등 면역치료 약물 타겟으로 개발된 사례가 있으나 RA 치료제로 개발된 사례는 없다(Lo H. Y Expert Opin Ther Pat. 2010, 20, 459). 하지만 최근 ITK-/- 마우스를 통하여 Th17과 Treg 세포를 발생을 조절하는 것이 보고되어 RA 치료 타겟으로 충분한 가능성을 가지고 있다(Gomez-Rodriguez J. et al. J. Exp. Med. 2014, 211, 529).ITK is expressed not only in T cells but also in NK cells and mast cells, and production of important cytokines such as IL-2, IL-4, IL-5, IL-10, IL-13 and IL-17 and T-cell proliferation Play an important role in (Schaeffer et al. Nat. Immune 2001, 2, 1183; Fowell et al. Immunity, 1999, 11, 399). T cells are activated by TCR signaling, and activated T cells activate inflammatory cytokine production, B cells and macrophages, leading to autoimmune diseases such as RA (Sahu N. et al. Curr Top Med Chem. 2009, 9, 690). Previously, it has been known that T cells are activated as Th1 cells to cause RA disease, but recently, Th17 / Treg as well as Th1 cells have been reported to be a cause of RA (J Leipe J. et al. Arthritis Rheum. 2010, 62 , 2876). In addition, ITK has been previously developed as an immunotherapeutic drug target such as asthma, but has not been developed as a RA therapy (Lo H. Y Expert Opin Ther Pat. 2010, 20, 459). Recently, however, the development of Th17 and Treg cells through ITK-/-mice has been reported to be a potential target for RA treatment (Gomez-Rodriguez J. et al. J. Exp. Med. 2014, 211, 529). ).
ITK 저해제 PRN694을 이용한 연구에서, RA 질환의 대표적 염증성 사이토카인인 TNF-α가 감소하는 연구 등이 보고되어 ITK 저해를 통하여 Th17 발현을 조절하여 RA 치료제로 개발 가능성을 확인할 수 있었다(Zhong Y. ey al. THE JOURNAL OF BIOLOGICAL CHEMISTRY 2015, 290, 5960).In studies using the ITK inhibitor PRN694, a study on the reduction of TNF-α, a representative inflammatory cytokine of RA disease, has been reported, confirming the possibility of developing Th as a therapeutic agent for RA by regulating Th17 expression through ITK inhibition (Zhong Y. ey al. THE JOURNAL OF BIOLOGICAL CHEMISTRY 2015, 290, 5960).
BTK는 초기 B-세포의 발달뿐만 아니라 성숙한 B-세포 활성화, 신호전달 및 생존의 조절제로서 기능한다. 상기 B-세포는 항원제시 세포(antigen-presenting cell)의 표면에 붙어 있는 항원을 인지하는 B 세포 수용체(B cell receptor; BCR)에 의해 신호가 전달되고 성숙한 항체 생성 세포로 활성화된다. 그러나, BCR에 의한 비정상적인 신호 전달은 비정상적인 B-세포 증식 및 병리학적 자가항체의 형성을 야기하게 되고, 이에 따라 암, 자가면역 및/또는 염증성 질환을 유도할 수 있다. 따라서, 비정상적인 B-세포의 증식에서, BTK가 결핍되는 경우 BCR에 의한 신호 전달이 차단될 수 있다. 이에 따라, BTK의 저해는 B-세포 매개 질병 과정을 차단할 수 있어, BTK 저해제의 사용은 B-세포 매개 질병의 치료를 위한 유용한 접근일 수 있다.BTK functions as a regulator of mature B-cell activation, signaling and survival as well as early B-cell development. The B-cells are signaled by a B cell receptor (BCR) that recognizes an antigen attached to the surface of an antigen-presenting cell and activated into mature antibody producing cells. However, abnormal signal transduction by BCR results in abnormal B-cell proliferation and the formation of pathological autoantibodies, which can lead to cancer, autoimmune and / or inflammatory diseases. Thus, in abnormal proliferation of B-cells, signal transduction by BCR may be blocked when BTK is deficient. Accordingly, inhibition of BTK may block the B-cell mediated disease process, so the use of BTK inhibitors may be a useful approach for the treatment of B-cell mediated diseases.
또한, BTK는 B-세포 외에도 질병과 관련될 수 있는 다른 세포들에 의해서도 발현될 수 있다. 일 예로, BTK는 골수 세포에서 Fc-감마 신호전달의 중요 구성 성분으로, 비만 세포(mast cell)에 의해 발현된다. 구체적으로 BTK-결핍 골수 유도된 비만 세포는 손상된 항원 유도된 탈과립을 나타내어, BTK 활성의 저해는 알레르기 및 천식과 같은 병리학적인 비만 세포 반응을 치료하는 데 유용한 것으로 알려져 있다(Iwaki et al. J. Biol. Chem. 2005 280:40261). 또한, BTK 활성이 없는 XLA 환자의 단핵구는 자극에 뒤따르는 TNF 알파 생성이 줄어들어, BTK 저해제에 의해 TNF 알파 매개 염증을 억제할 수 있음이 알려져 있다(Horwood et al. J. Exp. Med. 197:1603, 2003 참조).BTK can also be expressed by other cells besides B-cells that may be associated with the disease. In one example, BTK is an important component of Fc-gamma signaling in bone marrow cells, which is expressed by mast cells. Specifically, BTK-deficient bone marrow-induced mast cells show impaired antigen-induced degranulation, so that inhibition of BTK activity is known to be useful for treating pathological mast cell responses such as allergy and asthma (Iwaki et al. J. Biol). Chem. 2005 280: 40261). In addition, monocytes in XLA patients without BTK activity have been shown to reduce TNF alpha production following stimulation, thereby inhibiting TNF alpha mediated inflammation by BTK inhibitors (Horwood et al. J. Exp. Med. 197: 1603, 2003).
현재 BTK 및 ITK를 이중 저해하는 물질로 개발된 사례는 없으나, BTK 저해제로서, WO2008/039218은 4-아미노피라졸로[3,4-d]피리미디닐피페리딘 유도체를 개시한 바 있으며, WO2015/061247은 피리딘, 피리미딘, 피라진 및 피리다진 화합물과 같은 헤테로 화합물을 개시한 바 있으며, WO2014/055934는 피리미디닐페닐아크릴아미드 유도체를 개시한 바 있다. ITK 저해제로서 WO2005/066335은 아미노벤즈이미다졸, WO2005/056785은 피리돈, WO2002050071은 아미노티아졸 유도체를 개시하였으며, 최근에 WO2014/036016는 벤즈이미다졸 유도체를 개시한 바 있다.Currently, there have been no cases of double-inhibiting BTK and ITK, but as a BTK inhibitor, WO2008 / 039218 has disclosed 4-aminopyrazolo [3,4-d] pyrimidinylpiperidine derivatives, and WO2015 / 061247 discloses hetero compounds such as pyridine, pyrimidine, pyrazine and pyridazine compounds, and WO2014 / 055934 discloses pyrimidinylphenylacrylamide derivatives. As an ITK inhibitor WO2005 / 066335 discloses aminobenzimidazoles, WO2005 / 056785 discloses pyridones, WO2002050071 discloses aminothiazole derivatives, and WO2014 / 036016 discloses benzimidazole derivatives.
이에 본 발명자는, 신규 화합물을 연구한 결과, 현재까지 보고된 BTK, ITK 저해제와는 상이한 화학 구조를 가진 화합물이 우수한 BTK 및 ITK 이중 활성 저해 효과를 가짐을 확인하여 본 발명을 완성하였다. 본 발명에 속하는 화합물들은 주로 그 자체로 BTK 및 ITK 저해 활성을 가지나, 체내에 흡수된 후 특수한 체내 환경에 의해 혹은 대사과정의 산물 등이 효능제로서 약리작용을 나타낼 가능성도 배제하지는 않는다.Accordingly, the present inventors have completed the present invention by studying a novel compound and confirming that a compound having a chemical structure different from the BTK and ITK inhibitors reported so far has excellent BTK and ITK double activity inhibitory effects. The compounds belonging to the present invention mainly have BTK and ITK inhibitory activity by themselves, but do not exclude the possibility of exhibiting pharmacological action as an agonist by a special body environment or a product of metabolic process after being absorbed into the body.
본 발명은 BTK 저해제로서 유용한 신규한 헤테로사이클릭아민 유도체 및 이를 포함하는 약학 조성물을 제공하기 위한 것이다.The present invention is to provide a novel heterocyclic amine derivative useful as a BTK inhibitor and a pharmaceutical composition comprising the same.
상기 과제를 해결하기 위하여, 본 발명은 하기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 제공한다:In order to solve the above problems, the present invention provides a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2019010894-appb-I000001
Figure PCTKR2019010894-appb-I000001
상기 화학식 1에서,In Chemical Formula 1,
B는 N, O 및 S로 구성되는 군으로부터 각각 독립적으로 선택되는 헤테로원자를 1개 내지 3개 포함하는 5원 또는 6원 헤테로고리이고, 단 상기 5원 또는 6원 헤테로고리는 N을 적어도 하나 포함하고,B is a 5 or 6 membered heterocycle containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, provided that the 5 or 6 membered heterocycle is at least one Including,
R1은 수소, 할로겐, C1-4 알킬, 또는 C1-4 할로알킬이고,R 1 is hydrogen, halogen, C 1-4 alkyl, or C 1-4 haloalkyl,
X1 및 X2는 각각 독립적으로, N, 또는 CR'이고,X 1 and X 2 are each independently N or CR ′,
여기서, R'는 수소, 또는 할로겐이고,Where R 'is hydrogen or halogen,
L은 결합, C1-4 알킬렌, 또는 -O-이고,L is a bond, C 1-4 alkylene, or —O—,
R2는 시아노; C1-4 알킬; C6-10 아릴; 피리디닐; 몰폴리노; 피페라지닐; 또는 피페리디닐이고,R 2 is cyano; C 1-4 alkyl; C 6-10 aryl; Pyridinyl; Morpholino; Piperazinyl; Or piperidinyl,
여기서, 상기 피페라지닐 및 피페리디닐은 각각 독립적으로, 비치환되거나, 또는 C1-4 알킬, 시아노로 치환된 C1-4 알킬, 아미노로 치환된 C1-4 알킬, C1-4 알콕시로 치환된 C1-4 알킬, 또는 -CO-(C1-4 알킬)로 치환되고,Wherein said piperazinyl and piperidinyl are each independently, unsubstituted or C 1-4 alkyl, a cyano C 1-4 alkyl, C 1-4 substituted with a substituted C 1-4 alkyl, amino Substituted with C 1-4 alkyl substituted with alkoxy, or —CO— (C 1-4 alkyl),
Y는 결합, -O-, -NH-, 또는 -N(C1-4 알킬)-이고,Y is a bond, -O-, -NH-, or -N (C 1-4 alkyl)-,
A는 C1-4 알킬,
Figure PCTKR2019010894-appb-I000002
,
Figure PCTKR2019010894-appb-I000003
,
Figure PCTKR2019010894-appb-I000004
,
Figure PCTKR2019010894-appb-I000005
,
Figure PCTKR2019010894-appb-I000006
, 또는
Figure PCTKR2019010894-appb-I000007
이고,A is C 1-4 alkyl,
Figure PCTKR2019010894-appb-I000002
,
Figure PCTKR2019010894-appb-I000003
,
Figure PCTKR2019010894-appb-I000004
,
Figure PCTKR2019010894-appb-I000005
,
Figure PCTKR2019010894-appb-I000006
, or
Figure PCTKR2019010894-appb-I000007
ego,
여기서, R3는 C1-4 알킬, C1-4 할로알킬, C2-4 알케닐, C2-4 할로알케닐, C2-4 알키닐, 또는 C2-4 할로알키닐이다.Wherein R 3 is C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, or C 2-4 haloalkynyl.
바람직하게는, B는 티아졸, 피라졸, 피리딘, 또는 피리미딘 고리이고,Preferably, B is a thiazole, pyrazole, pyridine, or pyrimidine ring,
R1은 수소, 클로로, 메틸, 또는 트리플루오로메틸이다.R 1 is hydrogen, chloro, methyl, or trifluoromethyl.
바람직하게는,Preferably,
X1 및 X2는 모두 CH이거나;X 1 and X 2 are both CH;
X1 및 X2 중 하나는 CF이고, 다른 하나는 CH이거나; 또는One of X 1 and X 2 is CF and the other is CH; or
X1 및 X2 중 하나는 N이고, 다른 하나는 CH이다.One of X 1 and X 2 is N and the other is CH.
보다 바람직하게는,More preferably,
X1 및 X2는 모두 CH이거나X 1 and X 2 are both CH
X1은 CH이고, X2는 CF이거나;X 1 is CH and X 2 is CF;
X1은 CH이고, X2는 N이거나; 또는X 1 is CH and X 2 is N; or
X1은 N이고, X2는 CH이다.X 1 is N and X 2 is CH.
바람직하게는, L은 결합, 메틸렌, 또는 -O-이다.Preferably, L is a bond, methylene, or -O-.
바람직하게는, R2는 시아노; 메틸; 페닐; 피리디닐; 몰폴리노; 메틸로 치환된 피페라지닐; 에틸로 치환된 피페라지닐; 2-시아노에틸로 치환된 피페라지닐; 3-아미노프로필로 치환된 피페라지닐; 2-메톡시에틸로 치환된 피페라지닐; -CO-(메틸)로 치환된 피페라지닐; 비치환된 피페리디닐; 또는 메틸로 치환된 피페리디닐이다.Preferably, R 2 is cyano; methyl; Phenyl; Pyridinyl; Morpholino; Piperazinyl substituted with methyl; Piperazinyl substituted with ethyl; Piperazinyl substituted with 2-cyanoethyl; Piperazinyl substituted with 3-aminopropyl; Piperazinyl substituted with 2-methoxyethyl; Piperazinyl substituted with -CO- (methyl); Unsubstituted piperidinyl; Or piperidinyl substituted with methyl.
바람직하게는, Y는 결합, -O-, -NH-, 또는 -N(메틸)-이다.Preferably, Y is a bond, -O-, -NH-, or -N (methyl)-.
바람직하게는, R3는 -CH2CH2Cl, -CH=CH2, -CH=CHCH3, -CH=CHCl, -C≡CH, 또는 -C≡CCH3이다.Preferably, R 3 is -CH 2 CH 2 Cl, -CH = CH 2, -CH = CHCH 3, -CH = CHCl, -C≡CH, or -C≡CCH 3.
바람직하게는, 상기 화학식 1로 표시되는 화합물은 하기 화학식 1-1로 표시된다:Preferably, the compound represented by Chemical Formula 1 is represented by the following Chemical Formula 1-1:
[화학식 1-1][Formula 1-1]
Figure PCTKR2019010894-appb-I000008
Figure PCTKR2019010894-appb-I000008
상기 화학식 1-1에서,In Chemical Formula 1-1,
R1은 수소, C1-4 알킬, 또는 C1-4 할로알킬이고,R 1 is hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl,
X1 및 X2는 각각 독립적으로, N, 또는 CR'이고,X 1 and X 2 are each independently N or CR ′,
여기서, R'는 수소, 또는 할로겐이고,Where R 'is hydrogen or halogen,
L은 결합, C1-4 알킬렌, 또는 -O-이고,L is a bond, C 1-4 alkylene, or —O—,
R2는 시아노; C1-4 알킬; C6-10 아릴; 피리디닐; 몰폴리노; 피페라지닐; 또는 피페리디닐이고,R 2 is cyano; C 1-4 alkyl; C 6-10 aryl; Pyridinyl; Morpholino; Piperazinyl; Or piperidinyl,
여기서, 상기 피페라지닐 및 피페리디닐은 각각 독립적으로, 비치환되거나, 또는 C1-4 알킬, 시아노로 치환된 C1-4 알킬, 아미노로 치환된 C1-4 알킬, C1-4 알콕시로 치환된 C1-4 알킬, 또는 -CO-(C1-4 알킬)로 치환되고,Wherein said piperazinyl and piperidinyl are each independently, unsubstituted or C 1-4 alkyl, a cyano C 1-4 alkyl, C 1-4 substituted with a substituted C 1-4 alkyl, amino Substituted with C 1-4 alkyl substituted with alkoxy, or —CO— (C 1-4 alkyl),
Y는 결합, -O-, -NH-, 또는 -N(C1-4 알킬)-이고,Y is a bond, -O-, -NH-, or -N (C 1-4 alkyl)-,
A는 C1-4 알킬,
Figure PCTKR2019010894-appb-I000009
,
Figure PCTKR2019010894-appb-I000010
,
Figure PCTKR2019010894-appb-I000011
,
Figure PCTKR2019010894-appb-I000012
,
Figure PCTKR2019010894-appb-I000013
, 또는
Figure PCTKR2019010894-appb-I000014
이고,A is C 1-4 alkyl,
Figure PCTKR2019010894-appb-I000009
,
Figure PCTKR2019010894-appb-I000010
,
Figure PCTKR2019010894-appb-I000011
,
Figure PCTKR2019010894-appb-I000012
,
Figure PCTKR2019010894-appb-I000013
, or
Figure PCTKR2019010894-appb-I000014
ego,
여기서, R3는 C1-4 할로알킬, C2-4 알케닐, C2-4 할로알케닐, 또는 C2-4 알키닐이다.Wherein R 3 is C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, or C 2-4 alkynyl.
바람직하게는, 상기 화학식 1-1에서,Preferably, in Chemical Formula 1-1,
R1은 C1-4 알킬이고,R 1 is C 1-4 alkyl,
X1 및 X2는 각각 독립적으로, N 또는 CH이고,X 1 and X 2 are each independently N or CH,
L은 결합, C1-4 알킬렌, 또는 -O-이고,L is a bond, C 1-4 alkylene, or —O—,
R2는 시아노; C1-4 알킬; C6-10 아릴; 피리디닐; 몰폴리노; 피페라지닐; 또는 피페리디닐이고,R 2 is cyano; C 1-4 alkyl; C 6-10 aryl; Pyridinyl; Morpholino; Piperazinyl; Or piperidinyl,
여기서, 상기 피페라지닐 및 피페리디닐은 각각 독립적으로, 비치환되거나, 또는 C1-4 알킬, 시아노로 치환된 C1-4 알킬, C1-4 알콕시로 치환된 C1-4 알킬, 또는 -CO-(C1-4 알킬)로 치환되고,Wherein said piperazinyl and piperidinyl are each independently, unsubstituted or C 1-4 alkyl, cyano substituted C 1-4 substituted alkyl, C 1-4 alkoxy C 1-4 alkyl, Or substituted with -CO- (Ci_ 4 alkyl),
Y는 결합, -O-, -NH-, 또는 -N(C1-4 알킬)-이고,Y is a bond, -O-, -NH-, or -N (C 1-4 alkyl)-,
A는
Figure PCTKR2019010894-appb-I000015
,
Figure PCTKR2019010894-appb-I000016
,
Figure PCTKR2019010894-appb-I000017
,
Figure PCTKR2019010894-appb-I000018
,
Figure PCTKR2019010894-appb-I000019
, 또는
Figure PCTKR2019010894-appb-I000020
이고,A is
Figure PCTKR2019010894-appb-I000015
,
Figure PCTKR2019010894-appb-I000016
,
Figure PCTKR2019010894-appb-I000017
,
Figure PCTKR2019010894-appb-I000018
,
Figure PCTKR2019010894-appb-I000019
, or
Figure PCTKR2019010894-appb-I000020
ego,
여기서, R3는 C2-4 알케닐, 또는 C2-4 알키닐이다.Wherein R 3 is C 2-4 alkenyl, or C 2-4 alkynyl.
또한 바람직하게는, 상기 화학식 1로 표시되는 화합물은 하기 화학식 1-2로 표시된다:Also preferably, the compound represented by Chemical Formula 1 is represented by the following Chemical Formula 1-2:
[화학식 1-2][Formula 1-2]
Figure PCTKR2019010894-appb-I000021
Figure PCTKR2019010894-appb-I000021
상기 화학식 1-2에서,In Chemical Formula 1-2,
R1은 수소, 또는 할로겐이고,R 1 is hydrogen or halogen,
X1 및 X2는 각각 독립적으로, N 또는 CH이고,X 1 and X 2 are each independently N or CH,
L은 C1-4 알킬렌이고,L is C 1-4 alkylene,
R2는 몰폴리노이고,R 2 is morpholino,
Y는 -NH-이고,Y is -NH-,
A는
Figure PCTKR2019010894-appb-I000022
이고,A is
Figure PCTKR2019010894-appb-I000022
ego,
여기서, R3는 C2-4 알케닐이다.Wherein R 3 is C 2-4 alkenyl.
또한 바람직하게는, 상기 화학식 1로 표시되는 화합물은 하기 화학식 1-3으로 표시된다:Also preferably, the compound represented by Chemical Formula 1 is represented by the following Chemical Formula 1-3:
[화학식 1-3][Formula 1-3]
Figure PCTKR2019010894-appb-I000023
Figure PCTKR2019010894-appb-I000023
상기 화학식 1-3에서,In Chemical Formula 1-3,
X1 및 X2는 각각 독립적으로, N 또는 CH이고,X 1 and X 2 are each independently N or CH,
L은 C1-4 알킬렌이고,L is C 1-4 alkylene,
R2는 몰폴리노이고,R 2 is morpholino,
Y는 -NH-이고,Y is -NH-,
A는
Figure PCTKR2019010894-appb-I000024
이고,A is
Figure PCTKR2019010894-appb-I000024
ego,
여기서, R3는 C2-4 알케닐이다.Wherein R 3 is C 2-4 alkenyl.
또한 바람직하게는, 상기 화학식 1로 표시되는 화합물은 하기 화학식 1-4로 표시된다:Also preferably, the compound represented by Chemical Formula 1 is represented by the following Chemical Formula 1-4:
[화학식 1-4][Formula 1-4]
Figure PCTKR2019010894-appb-I000025
Figure PCTKR2019010894-appb-I000025
상기 화학식 1-4에서,In Chemical Formula 1-4,
X1 및 X2는 각각 독립적으로, N 또는 CH이고,X 1 and X 2 are each independently N or CH,
L은 C1-4 알킬렌이고,L is C 1-4 alkylene,
R2는 몰폴리노이고,R 2 is morpholino,
Y는 -NH-이고,Y is -NH-,
A는
Figure PCTKR2019010894-appb-I000026
이고,A is
Figure PCTKR2019010894-appb-I000026
ego,
여기서, R3는 C2-4 알케닐이다.Wherein R 3 is C 2-4 alkenyl.
또한, 본 발명의 화합물은 염, 특히 약학적으로 허용 가능한 염의 형태로 존재할 수 있다. 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산부가염과 같이, 당업계에서 통상적으로 사용되는 염을 제한 없이 사용할 수 있다. 본 발명의 용어 "약학적으로 허용가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 화학식 1로 표시되는 화합물의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기 또는 무기 부가염을 의미한다.In addition, the compounds of the invention may exist in the form of salts, in particular pharmaceutically acceptable salts. As the salt, salts conventionally used in the art may be used without limitation, such as acid addition salts formed by pharmaceutically acceptable free acid. The term "pharmaceutically acceptable salt" of the present invention is any concentration of the compound which is relatively nontoxic to the patient and has a harmless effective action, in which the side effects caused by the salt do not degrade the beneficial efficacy of the compound represented by the formula (1). Means any organic or inorganic addition salt.
상기 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고 유기산으로는 메탄술폰산, p-톨루엔술폰산, 아세트산, 트리플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산(fumaric acid), 만데르산, 프로피온산(propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 요오드화수소산(hydroiodic acid) 등을 사용할 수 있으며, 이들에 제한되지 않는다. 바람직하게는, 상기 염은 염산염일 수 있다.Organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid ( maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid ( gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like. It is not limited to these. Preferably, the salt may be a hydrochloride salt.
또한, 염기를 사용하여 통상적인 방법으로 약학적으로 허용가능한 금속염을 얻을 수 있다. 예를 들어, 상기 화학식 1로 표시되는 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물염을 여과한 후 여액을 증발, 건조시켜 약학적으로 허용가능한 금속염을 얻을 수 있다. 이때 금속염으로서, 특히 나트륨염, 칼륨염 또는 칼슘염을 제조하는 것이 바람직하다.Bases can also be used to obtain pharmaceutically acceptable metal salts in conventional manner. For example, the compound represented by Chemical Formula 1 may be dissolved in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, the insoluble compound salt is filtered, and the filtrate is evaporated and dried to obtain a pharmaceutically acceptable metal salt. . At this time, as the metal salt, it is particularly preferable to prepare sodium salt, potassium salt or calcium salt.
그외 약학적으로 허용가능하지 않은 화학식 1로 표시되는 화합물의 염 또는 용매화물은, 화학식 1로 표시되는 화합물, 이의 약학적으로 허용 가능한 염, 또는 용매화물 제조에서 중간체로 이용할 수 있다.Other salts or solvates of the compound represented by the formula (1), which are not pharmaceutically acceptable, may be used as intermediates in the preparation of the compound represented by the formula (1), pharmaceutically acceptable salts thereof, or solvates.
또한, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은, 이의 약학적으로 허용 가능한 염뿐만 아니라 이로부터 제조될 수 있는 가능한 수화물 등의 용매화물 및 가능한 모든 입체 이성질체를 제한없이 포함한다. 상기 화학식 1로 표시되는 화합물의 용매화물 및 입체 이성질체는 당업계에 공지된 방법을 사용하여 화학식 1로 표시되는 화합물로부터 제조할 수 있다.In addition, the compound represented by Chemical Formula 1 according to the present invention includes not only pharmaceutically acceptable salts thereof, but also solvates such as possible hydrates and all possible stereoisomers which can be prepared therefrom. Solvates and stereoisomers of the compound represented by Formula 1 may be prepared from the compound represented by Formula 1 using methods known in the art.
또한, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 결정 형태 또는 비결정 형태로 제조될 수 있으며, 결정 형태로 제조될 경우 임의로 수화되거나 용매화될 수 있다. 본 발명에서는 상기 화학식 1로 표시되는 화합물의 화학양론적 수화물뿐만 아니라 다양한 양의 물을 함유하는 화합물이 포함될 수 있다. 본 발명에 따른 상기 화학식 1로 표시되는 화합물의 용매화물은 화학양론적 용매화물 및 비화학양론적 용매화물 모두를 포함한다.In addition, the compound represented by Chemical Formula 1 according to the present invention may be prepared in crystalline form or in amorphous form, and when prepared in crystalline form, may be optionally hydrated or solvated. In the present invention, a compound containing various amounts of water as well as stoichiometric hydrate of the compound represented by Formula 1 may be included. Solvates of the compounds represented by Formula 1 according to the present invention include both stoichiometric and non stoichiometric solvates.
상기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염의 대표적인 예는 다음과 같다:Representative examples of the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof are as follows:
1) 1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,1) 1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidin-1-yl) Prop-2-en-1-one,
2) 1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피롤리딘-1-일)프로프-2-엔-1-온,2) 1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pyrrolidin-1-yl) Prop-2-en-1-one,
3) 1-(4-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,3) 1- (4-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidin-1-yl) Prop-2-en-1-one,
4) (R)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,4) (R) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidine- 1-yl) prop-2-en-1-one,
5) (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,5) (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidine- 1-yl) prop-2-en-1-one,
6) (R)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피롤리딘-1-일)프로프-2-엔-1-온,6) (R) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pyrrolidine- 1-yl) prop-2-en-1-one,
7) (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피롤리딘-1-일)프로프-2-엔-1-온,7) (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pyrrolidine- 1-yl) prop-2-en-1-one,
8) 1-(3-((2-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-4-일)아미노)피롤리딘-1-일)프로프-2-엔-1-온,8) 1- (3-((2-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-4-yl) amino) pyrrolidin-1-yl Prop-2-en-1-one,
9) (E)-1-(3-((2-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-4-일)아미노)피롤리딘-1-일)부트-2-엔-1-온,9) (E) -1- (3-((2-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-4-yl) amino) pyrrolidine -1-yl) but-2-en-1-one,
10) 1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥시)피롤리딘-1-일)프로프-2-엔-1-온,10) 1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) oxy) pyrrolidin-1-yl) Prop-2-en-1-one,
11) 1-(4-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥시)피페리딘-1-일)프로프-2-엔-1-온,11) 1- (4-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) oxy) piperidin-1-yl) Prop-2-en-1-one,
12) 1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥시)피페리딘-1-일)프로프-2-엔-1-온,12) 1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) oxy) piperidin-1-yl) Prop-2-en-1-one,
13) (R)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)부트-2-인-1-온,13) (R) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidine- 1-yl) but-2-yn-1-one,
14) 1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피롤리딘-1-일)부트-2-인-1-온,14) 1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pyrrolidin-1-yl) Boot-2-in-1-one,
15) (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥시)피페리딘-1-일)프로프-2-엔-1-온,15) (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) oxy) piperidine- 1-yl) prop-2-en-1-one,
16) (R)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥시)피페리딘-1-일)프로프-2-엔-1-온,16) (R) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) oxy) piperidine- 1-yl) prop-2-en-1-one,
17) 1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,17) 1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-2-yl) amino) piperidin-1-yl Prop-2-en-1-one,
18) (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)부트-2-인-1-온,18) (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidine- 1-yl) but-2-yn-1-one,
19) 1-(4-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)부트-2-인-1-온,19) 1- (4-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidin-1-yl) Boot-2-in-1-one,
20) (S)-1-(3-((4-((4-아세틸피페라진-1-일)메틸)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,20) (S) -1- (3-((4-((4-acetylpiperazin-1-yl) methyl) -6-((5-methylthiazol-2-yl) amino) pyridine-2- One) amino) piperidin-1-yl) prop-2-en-1-one,
21) (S)-1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,21) (S) -1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-2-yl) amino) piperidine -1-yl) prop-2-en-1-one,
22) (S)-1-(3-((4-((4-(2-메톡시에틸)피페라진-1-일)메틸)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,22) (S) -1- (3-((4-((4- (2-methoxyethyl) piperazin-1-yl) methyl) -6-((5-methylthiazol-2-yl) Amino) pyridin-2-yl) amino) piperidin-1-yl) prop-2-en-1-one,
23) (S)-1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-2-일)아미노)피페리딘-1-일)부트-2-인-1-온,23) (S) -1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-2-yl) amino) piperidine -1-yl) but-2-yn-1-one,
24) (S)-1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-2-일)아미노)피롤리딘-1-일)프로프-2-엔-1-온,24) (S) -1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-2-yl) amino) pyrrolidine -1-yl) prop-2-en-1-one,
25) (R)-1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,25) (R) -1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-2-yl) amino) piperidine -1-yl) prop-2-en-1-one,
26) (S)-1-(3-(메틸(6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,26) (S) -1- (3- (methyl (6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidine -1-yl) prop-2-en-1-one,
27) N-(1-(6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)피페리딘-4-일)아크릴아마이드,27) N- (1- (6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) piperidin-4-yl) acrylamide,
28) 1-(6-(6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥타하이드로-1H-피롤로[2,3-c]피리딘-1-일)프로프-2-엔-1-온,28) 1- (6- (6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) octahydro-1H-pyrrolo [2,3 -c] pyridin-1-yl) prop-2-en-1-one,
29) 1-(6-(6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥타하이드로-1H-피롤로[2,3-c]피리딘-1-일)부트-2-인-1-온,29) 1- (6- (6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) octahydro-1H-pyrrolo [2,3 -c] pyridin-1-yl) but-2-yn-1-one,
30) 1-(6-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)-2-아자스피로[3.3]헵탄-2-일)프로프-2-엔-1-온,30) 1- (6-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) -2-azaspiro [3.3] Heptan-2-yl) prop-2-en-1-one,
31) (S)-1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(피페리딘-1-일메틸)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,31) (S) -1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (piperidin-1-ylmethyl) pyrimidin-2-yl) amino ) Piperidin-1-yl) prop-2-en-1-one,
32) (S)-1-(3-((4-((4-에틸피페라진-1-일)메틸)-6-((5-메틸티아졸-2-일)아미노)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,32) (S) -1- (3-((4-((4-ethylpiperazin-1-yl) methyl) -6-((5-methylthiazol-2-yl) amino) pyrimidine-2 -Yl) amino) piperidin-1-yl) prop-2-en-1-one,
33) (S)-1-(3-((4-((1-메틸피페리딘-4-일)옥시)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,33) (S) -1- (3-((4-((1-methylpiperidin-4-yl) oxy) -6-((5-methylthiazol-2-yl) amino) pyridine-2 -Yl) amino) piperidin-1-yl) prop-2-en-1-one,
34) (S)-3-(4-((2-((1-아크릴로일피페리딘-3-일)아미노)-6-((5-메틸티아졸-2-일)아미노)피리딘-4-일)메틸)피페라진-1-일)프로판엔니트릴,34) (S) -3- (4-((2-((1-acryloylpiperidin-3-yl) amino) -6-((5-methylthiazol-2-yl) amino) pyridine- 4-yl) methyl) piperazin-1-yl) propanenitrile,
35) (S)-1-(3-((4-메틸-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,35) (S) -1- (3-((4-methyl-6-((5-methylthiazol-2-yl) amino) pyridin-2-yl) amino) piperidin-1-yl) pro P-2-en-1-one,
36) (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(피리딘-3-일메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,36) (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (pyridin-3-ylmethyl) pyridin-2-yl) amino) piperi Din-1-yl) prop-2-en-1-one,
37) (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(피리딘-2-일메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,37) (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (pyridin-2-ylmethyl) pyridin-2-yl) amino) piperi Din-1-yl) prop-2-en-1-one,
38) (S)-2-((1-아크릴로일피페리딘-3-일)아미노)-6-((5-메틸티아졸-2-일)아미노)아이소니코티노니트릴,38) (S) -2-((1-acryloylpiperidin-3-yl) amino) -6-((5-methylthiazol-2-yl) amino) isonicotinonitrile,
39) (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-페닐피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,39) (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4-phenylpyridin-2-yl) amino) piperidin-1-yl) pro P-2-en-1-one,
40) (S)-1-(3-((4-((1-메틸피페리딘-4-일)옥시)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-인-1-온,40) (S) -1- (3-((4-((1-methylpiperidin-4-yl) oxy) -6-((5-methylthiazol-2-yl) amino) pyridine-2 -Yl) amino) piperidin-1-yl) prop-2-yn-1-one,
41) (S)-1-(3-((4-((1-메틸피페리딘-4-일)옥시)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)부트-2-인-1-온,41) (S) -1- (3-((4-((1-methylpiperidin-4-yl) oxy) -6-((5-methylthiazol-2-yl) amino) pyridine-2 -Yl) amino) piperidin-1-yl) but-2-yn-1-one,
42) (S)-1-(3-((4-((4-에틸피페라진-1-일)메틸)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,42) (S) -1- (3-((4-((4-ethylpiperazin-1-yl) methyl) -6-((5-methylthiazol-2-yl) amino) pyridine-2- One) amino) piperidin-1-yl) prop-2-en-1-one,
43) (S)-1-(3-((4-((4-메틸피페라진-1-일)메틸)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,43) (S) -1- (3-((4-((4-methylpiperazin-1-yl) methyl) -6-((5-methylthiazol-2-yl) amino) pyridine-2- One) amino) piperidin-1-yl) prop-2-en-1-one,
44) 5-메틸-N-(6-메틸-4-(몰폴리노메틸)피리딘-2-일)티아졸-2-아민,44) 5-methyl-N- (6-methyl-4- (morpholinomethyl) pyridin-2-yl) thiazol-2-amine,
45) (S)-3-클로로-1-(3-(6-(5-메틸티아졸-2-일아미노)-4-(몰폴리노메틸)피리딘-2-일아미노)피페리딘-1-일)프로판-1-온,45) (S) -3-chloro-1- (3- (6- (5-methylthiazol-2-ylamino) -4- (morpholinomethyl) pyridin-2-ylamino) piperidine- 1-yl) propan-1-one,
46) (S,E)-3-클로로-1-(3-(6-(5-메틸티아졸-2-일아미노)-4-(몰폴리노메틸)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온,46) (S, E) -3-chloro-1- (3- (6- (5-methylthiazol-2-ylamino) -4- (morpholinomethyl) pyridin-2-ylamino) piperi Din-1-yl) prop-2-en-1-one,
47) (S)-1-(3-(4-((4-(3-아미노프로필)피페라진-1-일)메틸)-6-(5-메틸티아졸-2-일아미노)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온,47) (S) -1- (3- (4-((4- (3-aminopropyl) piperazin-1-yl) methyl) -6- (5-methylthiazol-2-ylamino) pyridine- 2-ylamino) piperidin-1-yl) prop-2-en-1-one,
48) (S)-1-(3-(6-(1H-피라졸-3-일아미노)-4-(몰폴리노메틸)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온,48) (S) -1- (3- (6- (1H-pyrazol-3-ylamino) -4- (morpholinomethyl) pyridin-2-ylamino) piperidin-1-yl) prop P-2-en-1-one,
49) (S)-1-(3-(4-(몰폴리노메틸)-6-(5-(트리플루오로메틸)티아졸-2-일아미노)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온,49) (S) -1- (3- (4- (morpholinomethyl) -6- (5- (trifluoromethyl) thiazol-2-ylamino) pyridin-2-ylamino) piperidine -1-yl) prop-2-en-1-one,
50) (S)-1-(3-(6-(5-클로로-1H-피라졸-3-일아미노)-4-(몰폴리노메틸)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온,50) (S) -1- (3- (6- (5-chloro-1H-pyrazol-3-ylamino) -4- (morpholinomethyl) pyridin-2-ylamino) piperidine-1 -Yl) prop-2-en-1-one,
51) (S)-1-(3-(4-(몰폴리노메틸)-6-(티아졸-2-일아미노)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온,51) (S) -1- (3- (4- (morpholinomethyl) -6- (thiazol-2-ylamino) pyridin-2-ylamino) piperidin-1-yl) prop- 2-en-1-one,
52) (S)-1-(3-(3-플루오로-6-(5-메틸티아졸-2-일아미노)-4-(몰폴리노메틸)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온,52) (S) -1- (3- (3-fluoro-6- (5-methylthiazol-2-ylamino) -4- (morpholinomethyl) pyridin-2-ylamino) piperidine -1-yl) prop-2-en-1-one,
53) (S)-1-(3-(4-(몰폴리노메틸)-6-(피리딘-2-일아미노)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온, 및53) (S) -1- (3- (4- (morpholinomethyl) -6- (pyridin-2-ylamino) pyridin-2-ylamino) piperidin-1-yl) prop-2 -En-1-one, and
54) (S)-1-(3-(4-(몰폴리노메틸)-6-(피리미딘-2-일아미노)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온.54) (S) -1- (3- (4- (morpholinomethyl) -6- (pyrimidin-2-ylamino) pyridin-2-ylamino) piperidin-1-yl) prop- 2-en-1-one.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물은 일례로 A가 C1-4 알킬이 아닌 경우, 하기 반응식 1을 통하여 상기 화학식 1로 표시되는 화합물을 제조할 수 있다.In addition, the present invention, when the compound represented by the formula (1), for example A is not C 1-4 alkyl, it is possible to prepare a compound represented by the formula (1) through the following reaction scheme 1.
[반응식 1]Scheme 1
Figure PCTKR2019010894-appb-I000027
Figure PCTKR2019010894-appb-I000027
상기 반응식 1에서, A'는
Figure PCTKR2019010894-appb-I000028
,
Figure PCTKR2019010894-appb-I000029
,
Figure PCTKR2019010894-appb-I000030
,
Figure PCTKR2019010894-appb-I000031
,
Figure PCTKR2019010894-appb-I000032
, 또는
Figure PCTKR2019010894-appb-I000033
이고, A"는
Figure PCTKR2019010894-appb-I000034
,
Figure PCTKR2019010894-appb-I000035
,
Figure PCTKR2019010894-appb-I000036
,
Figure PCTKR2019010894-appb-I000037
,
Figure PCTKR2019010894-appb-I000038
, 또는
Figure PCTKR2019010894-appb-I000039
이며, 나머지는 앞서 정의한 바와 같다.In Scheme 1, A 'is
Figure PCTKR2019010894-appb-I000028
,
Figure PCTKR2019010894-appb-I000029
,
Figure PCTKR2019010894-appb-I000030
,
Figure PCTKR2019010894-appb-I000031
,
Figure PCTKR2019010894-appb-I000032
, or
Figure PCTKR2019010894-appb-I000033
And A "is
Figure PCTKR2019010894-appb-I000034
,
Figure PCTKR2019010894-appb-I000035
,
Figure PCTKR2019010894-appb-I000036
,
Figure PCTKR2019010894-appb-I000037
,
Figure PCTKR2019010894-appb-I000038
, or
Figure PCTKR2019010894-appb-I000039
The rest is as defined above.
상기 단계 1-1은, 상기 화학식 1-1로 표시되는 화합물과 상기 화학식 1-2로 표시되는 화합물을 반응시켜, 상기 화학식 1-3으로 표시되는 화합물을 제조하는 단계이다. 상기 반응이 아민 치환 반응인 경우 팔라듐 촉매와 염기 존재 하에 수행하는 것이 바람직하고, 상기 반응이 2차 알코올에 따른 알킬 클로라이드의 가용매분해 반응인 경우 염기의 존재 하에서 수행하는 것이 바람직하다.Step 1-1 is a step of preparing a compound represented by Chemical Formula 1-3 by reacting the compound represented by Chemical Formula 1-1 with the compound represented by Chemical Formula 1-2. When the reaction is an amine substitution reaction, it is preferable to carry out in the presence of a palladium catalyst and a base, and when the reaction is a solvolysis reaction of alkyl chloride according to a secondary alcohol, it is preferable to carry out in the presence of a base.
상기 단계 1-2는, 상기 화학식 1-3으로 표시되는 화합물과 상기 화학식 1-4로 표시되는 화합물을 반응시켜, 상기 화학식 1-5로 표시되는 화합물을 제조하는 단계이다. 상기 반응은 아민 치환 반응으로서, 팔라듐 촉매와 염기 존재 하에 수행하는 것이 바람직하다.Step 1-2 is a step of preparing a compound represented by Chemical Formula 1-5 by reacting the compound represented by Chemical Formula 1-3 with the compound represented by Chemical Formula 1-4. The reaction is an amine substitution reaction, preferably carried out in the presence of a palladium catalyst and a base.
상기 단계 1-3은, 상기 화학식 1-5로 표시되는 화합물에서 보호기(BOC; tert-butyloxycarbonyl protecting group)를 제거시켜, 상기 화학식 1-6으로 표시되는 화합물을 제조하는 단계이다. 상기 반응은 보호기를 제거할 수 있는 산 조건하에서 수행하는 것이 바람직하다.Step 1-3 is a step of preparing a compound represented by the formula (1-6) by removing the protecting group (BOC; tert -butyloxycarbonyl protecting group) from the compound represented by the formula (1-5). The reaction is preferably carried out under acidic conditions capable of removing the protecting group.
상기 단계 1-4는, 상기 화학식 1-6으로 표시되는 화합물과 상기 화학식 1-7로 표시되는 화합물을 반응시켜, 상기 화학식 1로 표시되는 화합물을 제조하는 단계이다. 상기 반응은 아미드화 반응으로서, 염기의 존재 하에 수행하는 것이 바람직하다.Step 1-4 is a step of preparing a compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 1-6 with the compound represented by Chemical Formula 1-7. The reaction is an amidation reaction, preferably performed in the presence of a base.
또한, 상기 반응식 1에서, 각 치환기에 따라 보호기로 보호하는 반응과 보호기를 이탈시키는 반응이 추가될 수 있다.In addition, in Scheme 1, a reaction protecting the protecting group and a reaction leaving the protecting group may be added according to each substituent.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 중 L이 메틸렌이고, A가 C1-4 알킬이 아닌 경우, 일례로 하기 반응식 2를 통하여 상기 화학식 1로 표시되는 화합물을 제조할 수 있다.In addition, in the present invention, when L is methylene and A is not C 1-4 alkyl among the compounds represented by Formula 1, the compound represented by Formula 1 may be prepared through, for example, Scheme 2 below.
[반응식 2]Scheme 2
Figure PCTKR2019010894-appb-I000040
Figure PCTKR2019010894-appb-I000040
상기 반응식 2에서, 각 치환기에 대한 설명은 앞서 정의한 바와 같다.In Scheme 2, the description of each substituent is as defined above.
상기 단계 2-1은, 상기 화학식 2-1로 표시되는 화합물과 상기 화학식 1-2로 표시되는 화합물을 반응시켜, 상기 화학식 2-2로 표시되는 화합물을 제조하는 단계이다. 상기 반응이 아민 치환 반응인 경우 팔라듐 촉매와 염기 존재 하에 수행하는 것이 바람직하고, 상기 반응이 2차 알코올에 따른 알킬 클로라이드의 가용매분해 반응인 경우 염기의 존재 하에서 수행하는 것이 바람직하다.Step 2-1 is a step of preparing the compound represented by Chemical Formula 2-2 by reacting the compound represented by Chemical Formula 2-1 with the compound represented by Chemical Formula 1-2. When the reaction is an amine substitution reaction, it is preferable to carry out in the presence of a palladium catalyst and a base, and when the reaction is a solvolysis reaction of alkyl chloride according to a secondary alcohol, it is preferable to carry out in the presence of a base.
상기 단계 2-2는, 상기 화학식 2-2로 표시되는 화합물과 상기 화학식 2-3으로 표시되는 화합물을 반응시켜, 상기 화학식 2-4로 표시되는 화합물을 제조하는 단계이다. 상기 반응은 아미드화 반응으로서, 아미드화 시약 존재 하에서 수행하는 것이 바람직하다.Step 2-2 is a step of preparing the compound represented by Chemical Formula 2-4 by reacting the compound represented by Chemical Formula 2-2 with the compound represented by Chemical Formula 2-3. The reaction is an amidation reaction, preferably carried out in the presence of an amidation reagent.
상기 단계 2-3은, 상기 화학식 2-4로 표시되는 화합물과 상기 화학식 1-4로 표시되는 화합물을 반응시켜, 상기 화학식 2-5로 표시되는 화합물을 제조하는 단계이다. 상기 반응은 아민 치환 반응으로서, 팔라듐 촉매와 염기 존재 하에 수행하는 것이 바람직하다.Step 2-3 is a step of preparing a compound represented by Chemical Formula 2-5 by reacting the compound represented by Chemical Formula 2-4 with the compound represented by Chemical Formula 1-4. The reaction is an amine substitution reaction, preferably carried out in the presence of a palladium catalyst and a base.
상기 단계 2-4는, 상기 화학식 2-5로 표시되는 화합물에서 보호기(BOC)를 제거시키고, 케톤을 환원시켜, 상기 화학식 2-6으로 표시되는 화합물을 제조하는 단계이다. 상기 반응은 산 조건 하에서 수행하는 것이 바람직하다.Step 2-4 is a step of preparing a compound represented by Chemical Formula 2-6 by removing the protecting group (BOC) from the compound represented by Chemical Formula 2-5 and reducing the ketone. The reaction is preferably carried out under acidic conditions.
상기 단계 2-5는, 상기 화학식 2-6으로 표시되는 화합물과 상기 화학식 1-7로 표시되는 화합물을 반응시켜, 상기 화학식 1로 표시되는 화합물을 제조하는 단계이다. 상기 반응은 아미드화 반응으로서, 염기의 존재 하에 수행하는 것이 바람직하다.Step 2-5 is a step of preparing a compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 2-6 with the compound represented by Chemical Formula 1-7. The reaction is an amidation reaction, preferably performed in the presence of a base.
또한, 상기 반응식 2에서, 각 치환기에 따라 보호기로 보호하는 반응과 보호기를 이탈시키는 반응이 추가될 수 있다.In addition, in Scheme 2, a reaction to protect with a protecting group and a reaction to leave the protecting group according to each substituent may be added.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물에서 A가 C1-4 알킬인 화합물은, 상기 반응식 1의 단계 1-1에서 상기 화학식 1-2로 표시되는 화합물 대신
Figure PCTKR2019010894-appb-I000041
로 표시되는 화합물을 사용한 것을 제외하고는 상기 반응식 1의 단계 1-1 및 단계 1-2와 동일한 방법을 사용하여 제조할 수 있다.In addition, the present invention is a compound in which A is C 1-4 alkyl in the compound represented by Formula 1, in place of the compound represented by Formula 1-2 in step 1-1 of Scheme 1
Figure PCTKR2019010894-appb-I000041
Except for using the compound represented by the can be prepared using the same method as in step 1-1 and step 1-2 of Scheme 1.
상술한 각 단계의 제조 방법을 후술할 실시예에서 보다 구체화할 수 있다.The manufacturing method of each step mentioned above can be embodied more in the Example mentioned later.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염, 수화물, 용매화물 또는 이성체를 유효성분으로 하는 ITK 및 BTK 저해 작용이 유익한 자가 면역 질환 또는 암의 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention is to prevent the autoimmune disease or cancer disease of which the compound represented by the formula (1), or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof is beneficial ITK and BTK inhibitory action is beneficial or Provided is a therapeutic pharmaceutical composition.
이때 상기 자가 면역 질환은 류마티스 관절염, 전신 홍반성 낭창, 소아기 당뇨병, 건선, 아프타구내염, 만성 갑상선염, 일부 후천성 재생불량성 빈혈, 일차성 간경변, 궤양성 대장염, 베체씨병, 크론씨병, 실리코시스, 아스베스토시스, 쇼그렌증후군, 길리안-바레증후군, 피부근염, 다발성 근염, 다발성 경화증, 자가면역성 용혈성 빈혈, 자가면역성 뇌척수염, 중증 근무력증, 그레이브씨 갑상선 항진증, 결절성 다발성 동맥염, 강직성 척추염, 섬유조직염, 측두동맥염, 윌슨병, 천식, 또는 판코니증후군이고,At this time, the autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, childhood diabetes mellitus, psoriasis, aphthosis, chronic thyroiditis, some acquired regenerative anemia, primary cirrhosis, ulcerative colitis, Beche's disease, Crohn's disease, silicosis, asbestos , Sjogren's syndrome, Gillian-Barre syndrome, dermatitis, multiple myositis, multiple sclerosis, autoimmune hemolytic anemia, autoimmune encephalomyelitis, myasthenia gravis, Grave's hyperthyroidism, nodular polyarteritis, ankylosing spondylitis, fibromyalitis, lateral arthritis , Asthma, or Fanconi syndrome,
상기 암은 혈액암, 결절외변연부 B-세포림프종, 교모세포종, 림프형질세포성 림프종, 급성골수성 백혈병, 마크로글로불린혈증, B세포림프종, 만성림프구성백혈병, 소포성림프종, 비호치킨스림프종, 미만성 큰B세포림프종, 털세포백혈병, 외투막세포림프종, 교모세포종, 방광암, 췌장암, 난소암, 대장암, 신장암, 위암, 이행상피암, 유암종, 유방암, 비소세포성 폐암, 또는 다발성 골수종일 수 있다.The cancer is hematologic cancer, extra-nodal margin B-cell lymphoma, glioblastoma, lymphoid cytoplasmic lymphoma, acute myeloid leukemia, macroglobulinemia, B-cell lymphoma, chronic lymphocytic leukemia, vesicular lymphoma, non-Hodgkin's lymphoma, diffuse large B cell lymphoma, hairy cell leukemia, mantle cell lymphoma, glioblastoma, bladder cancer, pancreatic cancer, ovarian cancer, colon cancer, kidney cancer, gastric cancer, transitional epithelial cancer, carcinoid cancer, breast cancer, non-small cell lung cancer, or multiple myeloma.
본 발명의 용어 "예방"은 본 발명의 조성물의 투여로 상기 질환의 발생, 확산 및 재발을 억제시키거나 지연시키는 모든 행위를 의미하고, "치료"는 본 발명의 조성물의 투여로 상기 질환의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.The term "prevention" of the present invention means any action that inhibits or delays the occurrence, spread and recurrence of the disease by administration of the composition of the present invention, and "treatment" means the symptoms of the disease by administration of the composition of the present invention. Means any action that improves or beneficially changes;
본 발명의 약학적 조성물은 표준 약학적 실시에 따라 경구 또는 비경구 투여 형태로 제형화할 수 있다. 이들 제형은 유효성분 이외에 약학적으로 허용가능한 담체, 보조제 또는 희석액 등의 첨가물을 함유할 수 있다.The pharmaceutical compositions of the invention may be formulated in oral or parenteral dosage forms according to standard pharmaceutical practice. These formulations may contain, in addition to the active ingredient, additives such as pharmaceutically acceptable carriers, adjuvants or diluents.
적당한 담체로는 예를 들어, 생리식염수, 폴리에틸렌글리콜, 에탄올, 식물성 오일 및 아이소프로필미리스테이트 등이 있고, 희석액으로는 예를 들어 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신 등이 있으나, 이들로 한정되는 것은 아니다. 또한, 본 발명의 화합물들은 주사 용액의 제조에 통상적으로 사용되는 오일, 프로필렌글리콜 또는 다른 용매에 용해시킬 수 있다. 또한, 국소 작용을 위해 본 발명의 화합물을 연고나 크림으로 제형화할 수 있다.Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oils and isopropyl myristate, and the diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or the like. Or glycine, and the like, but is not limited thereto. In addition, the compounds of the present invention may be dissolved in oil, propylene glycol or other solvents commonly used in the preparation of injection solutions. In addition, the compounds of the present invention may be formulated into ointments or creams for topical action.
본 발명의 화합물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물의 형태, 투여 경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 바람직한 효과를 위해서, 본 발명의 화합물을 1일 0.0001 내지 100 mg/kg(체중), 바람직하게는 0.001 내지 100 mg/kg(체중)으로 투여하는 것이 좋다. 투여는 1일 1회 또는 분할하여 경구 또는 비경구적 경로를 통해 투여될 수 있다.Preferred dosages of the compounds of the present invention depend on the condition and weight of the patient, the extent of the disease, the form of the drug, the route and duration of administration, and may be appropriately selected by those skilled in the art. However, for the desired effect, it is preferable to administer the compound of the present invention at 0.0001 to 100 mg / kg body weight, preferably 0.001 to 100 mg / kg body weight. Administration can be administered via oral or parenteral routes once or divided daily.
투여 방법에 따라, 상기 약학적 조성물은 본 발명의 화합물을 0.001 내지 99 중량%, 바람직하게는 0.01 내지 60 중량% 함유할 수 있다.Depending on the method of administration, the pharmaceutical composition may contain 0.001 to 99% by weight, preferably 0.01 to 60% by weight of the compound of the present invention.
본 발명에 따른 약학적 조성물은 쥐, 생쥐, 가축 및 인간 등을 비롯한 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들어, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관(intracerebroventricular) 주사에 의해 투여될 수 있다.The pharmaceutical composition according to the present invention can be administered to mammals including rats, mice, livestock and humans by various routes. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
본 발명의 화학식 1로 표시되는 화합물, 이의 약학적으로 허용 가능한 염, 수화물, 용매화물 또는 이성체는, 자가 면역 질환 또는 암의 질환의 예방 또는 치료에 유용하게 사용될 수 있다.The compound represented by the formula (1) of the present invention, a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof may be usefully used for the prevention or treatment of autoimmune diseases or diseases of cancer.
이하, 하기 실시예에 의하여 본 발명을 더욱 상세하게 설명하고자 한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이들만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.
실시예 1: 1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 1: 1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidine-1- (1) Preparation of prop-2-en-1-one
단계 1-1: (2,6-디클로로피리딘-4-일)(몰폴리노)메탄온의 제조Step 1-1: Preparation of (2,6-dichloropyridin-4-yl) (morpholino) methanone
Figure PCTKR2019010894-appb-I000042
Figure PCTKR2019010894-appb-I000042
2,6-디클로로이소니코틴산(10.0 g, 1.0 eq)를 디메틸포름아미드(100.0 mL)에 용해한 후, 1,1-카보닐디이미다졸(1.0 g, 1.2 eq)을 가하였다. 질소 가스 하에서 1시간 실온(25 ~ 30 ℃)교반한 후, 몰폴린(5.4 mL, 1.2 eq)을 가하고 2시간 동일 온도에서 교반하여 반응을 완결시켰다. 에틸 아세테이트(200.0 mL)와 물(200.0 mL)을 가하여 추출하고 물층을 에틸 아세테이트(200.0 mL)를 이용해서 3회 재추출하였다. 에틸 아세테이트층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:5)로 정제하여 표제 화합물(13.0 g, 93.0 %)를 수득하였다.2,6-dichloroisonicotinic acid (10.0 g, 1.0 eq) was dissolved in dimethylformamide (100.0 mL), and then 1,1-carbonyldiimidazole (1.0 g, 1.2 eq) was added. After stirring for 1 hour at room temperature (25-30 ° C.) under nitrogen gas, morpholine (5.4 mL, 1.2 eq) was added, followed by stirring at the same temperature for 2 hours to complete the reaction. Ethyl acetate (200.0 mL) and water (200.0 mL) were added for extraction, and the water layer was reextracted three times with ethyl acetate (200.0 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1: 5) to obtain the title compound (13.0 g, 93.0%).
단계 1-2: 4-((2,6-디클로로피리딘-4-일)메틸)몰폴린의 제조Step 1-2: Preparation of 4-((2,6-dichloropyridin-4-yl) methyl) morpholine
Figure PCTKR2019010894-appb-I000043
Figure PCTKR2019010894-appb-I000043
단계 1-1에서 수득한 중간체(10.0 g, 1.0 eq)를 디클로로메탄(100.0 mL)에 용해한 후, 질소 가스 하에서 0 내지 10 ℃ 로 냉각하였다. 1M 보란-테트로하이드로퓨란(115.0 mL, 3.0 eq)를 천천히 적가하였다. 실온에서 12 시간 교반하여 반응을 완결시켰다. 반응액을 0 ~ 10 ℃ 로 냉각한 후, 6N-염산 수용액을(256.0 mL, 20.0 eq)천천히 적가한 후, 같은 온도에서 1시간 교반하였다. 10N-수산화나트륨 수용액을 이용하여 pH 9 내지 pH 12 로 조절한 후, 디클로로메탄으로 2회 추출하였다. 디클로로메탄층은 분리하여 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:1)로 정제하여 표제 화합물(8.1 g, 수율 90.0 %)을 수득하였다.The intermediate (10.0 g, 1.0 eq) obtained in step 1-1 was dissolved in dichloromethane (100.0 mL) and then cooled to 0 to 10 ° C. under nitrogen gas. 1M borane-tetrohydrofuran (115.0 mL, 3.0 eq) was slowly added dropwise. The reaction was completed by stirring at room temperature for 12 hours. After cooling the reaction solution to 0-10 degreeC, 6N hydrochloric acid aqueous solution (256.0 mL, 20.0eq) was slowly added dropwise, and the mixture was stirred at the same temperature for 1 hour. The mixture was adjusted to pH 9 to pH 12 using 10N-sodium hydroxide aqueous solution, and then extracted twice with dichloromethane. The dichloromethane layer was separated, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (8.1 g, yield 90.0%).
단계 1-3: tert-부틸 3-((6-클로로-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-카복실레이트의 제조Step 1-3: Preparation of tert-butyl 3-((6-chloro-4- (morpholinomethyl) pyridin-2-yl) amino) piperidine-1-carboxylate
Figure PCTKR2019010894-appb-I000044
Figure PCTKR2019010894-appb-I000044
단계 1-2에서 수득한 중간체(1.0 g, 1.0 eq)에 1,4-다이옥산(10.0 mL)을 가하여 용해한 후, 트리스(디벤질리덴아세톤)디팔라듐(0)(465.8 mg, 0.2 eq), 잔포스(1.5 g, 0.4 eq)를 투입하였다. tert-부틸 3-아미노피페리딘-1-카르복실레이트(780.0 ㎕, 1.0 eq)을 가한 후, 탄산나트륨(1.3 g, 3.0 eq)을 투입한 후, 12시간 환류하여 반응을 완결시켰다. 30℃ 이하로 냉각한 후, 물(20.0 mL)와 에틸아세테이트(20.0 mL)를 가한 후, 층분리하였다. 에틸아세테이트층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:1)로 정제하여 표제 화합물(900.0 mg, 수율 54.1 %)를 수득하였다.1,4-dioxane (10.0 mL) was added to and dissolved in the intermediate (1.0 g, 1.0 eq) obtained in step 1-2, followed by tris (dibenzylideneacetone) dipalladium (0) (465.8 mg, 0.2 eq), Xanthose (1.5 g, 0.4 eq) was added. After tert-butyl 3-aminopiperidine-1-carboxylate (780.0 μl, 1.0 eq) was added, sodium carbonate (1.3 g, 3.0 eq) was added thereto, followed by reflux for 12 hours to complete the reaction. After cooling to 30 ° C. or less, water (20.0 mL) and ethyl acetate (20.0 mL) were added, and the layers were separated. The ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (900.0 mg, yield 54.1%).
단계 1-4: tert-부틸 3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-카복실레이트의 제조Steps 1-4: tert-butyl 3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidine-1 Preparation of Carboxylate
Figure PCTKR2019010894-appb-I000045
Figure PCTKR2019010894-appb-I000045
단계 1-3에서 수득한 중간체 730.0 mg, 1.0 eq)을 1,4-다이옥산(14.0 mL)에 용해하였다. 팔라듐아세테이트(40.0 mg, 0.1 eq), 잔포스(204.7 mg, 0.2 eq), 5-메틸싸이아노-2-아민(203.6 mg, 1.0 eq), 세슘카보네이트(1.7 g, 3.0 eq)를 차례로 가하였다. 마이크로웨이브 반응기에서 150 ℃, 30분 반응시켰다. 에틸아세테이트(10.0 mL), 물(10.0 mL)를 가한 후, 생성된 고체를 여과하여 표제 화합물(424.9 mg, 수율 65.4 %)을 수득하였다. 30℃ 이하로 냉각한 후, 물(15.0 mL)와 에틸아세테이트(15.0 mL)를 가한 후, 층분리하였다. 에틸아세테이트층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(EA 100%)로 정제하여 표제 화합물(564.0 mg, 수율 65.0 %)를 수득하였다.730.0 mg, 1.0 eq) of intermediate obtained in steps 1-3 was dissolved in 1,4-dioxane (14.0 mL). Palladium acetate (40.0 mg, 0.1 eq), xantose (204.7 mg, 0.2 eq), 5-methylthiano-2-amine (203.6 mg, 1.0 eq), cesium carbonate (1.7 g, 3.0 eq) were added in this order. . The reaction was performed at 150 ° C. for 30 minutes in a microwave reactor. Ethyl acetate (10.0 mL) and water (10.0 mL) were added, and then the resulting solid was filtered to give the title compound (424.9 mg, yield 65.4%). After cooling to 30 ° C. or less, water (15.0 mL) and ethyl acetate (15.0 mL) were added, and the layers were separated. The ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (EA 100%) to give the title compound (564.0 mg, 65.0% yield).
단계 1-5: N2 -(5-메틸티아졸-2-일)-4-(몰폴리노메틸)-N6 -(피페리딘-3-일)피리딘-2,6-디아민의 제조 Steps 1-5: Preparation of N 2- (5-methylthiazol-2-yl) -4- (morpholinomethyl) -N 6- (piperidin-3-yl) pyridine-2,6-diamine
Figure PCTKR2019010894-appb-I000046
Figure PCTKR2019010894-appb-I000046
단계 1-4에서 수득한 중간체(500.0 mg, 1.0 eq)을 다이클로로메탄(10.0 mL)에 용해한 후, 0~10 ℃ 로 냉각하였다. 트리플로로아세틱엑시드(1.6 mL, 20.0 eq)을 천천히 적가한 후, 1시간 동안 교반하였다. 12N-수산화나트륨 수용액을 이용하여 pH9~12 로 조절한 후, 분리된 다이클로로메탄층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사에 에틸아테세이트(10.0 mL)를 가하여 30분 동안 결정을 생성시켰다. 결정은 여과한 후, 건조하여 표제 화합물(357.5 mg. 수율 90.0 %)를 수득하였다.The intermediate (500.0 mg, 1.0 eq) obtained in steps 1-4 was dissolved in dichloromethane (10.0 mL) and then cooled to 0-10 ° C. Trifluoroacetic acid (1.6 mL, 20.0 eq) was slowly added dropwise and stirred for 1 hour. After adjusting to pH 9-12 using 12N-sodium hydroxide aqueous solution, the separated dichloromethane layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Ethyl acetate (10.0 mL) was added to the obtained residue to form crystals for 30 minutes. The crystals were filtered off and dried to afford the title compound (357.5 mg. Yield 90.0%).
단계 1-6: 1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Steps 1-6: 1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidine-1 Preparation of -yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000047
Figure PCTKR2019010894-appb-I000047
단계 1-5에서 수득한 중간체(350.0 mg, 1.0 eq)을 테트라하이드로퓨란(7.0 mL)에 용해한 후, 물(7.0 mL)를 가하고 중탄산 나트륨(226.8 mg, 3.0 eq)을 가한 후, 0~10 ℃ 로 냉각하였다. 아크릴로일 클로라이드(73.1 ㎕. 1.0 eq )를 천천히 적가한 후, 30분 동안 교반하여 반응을 완결시켰다. 다이클로로메탄으로 층분리한 후, 무수황산나트륨상에서 건조하고 감압 농축하였다. 얻어진 잔사는 컬럼 크로마토그래피(다이클로로메탄:메탄올 = 15:1)로 정제하여 표제 화합물(318.0 mg, 수율 80.0%)을 수득하였다.After dissolving the intermediate (350.0 mg, 1.0 eq) obtained in the step 1-5 in tetrahydrofuran (7.0 mL), water (7.0 mL) was added and sodium bicarbonate (226.8 mg, 3.0 eq) was added, and then 0-10 Cool to C. Acryloyl chloride (73.1 μL. 1.0 eq) was slowly added dropwise and then stirred for 30 minutes to complete the reaction. The layers were separated with dichloromethane, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 15: 1) to give the title compound (318.0 mg, yield 80.0%).
1H NMR(500 MHz, DMSO): 10.5(s, 1H), 6.94(s, 1H), 6.86-6.80(q, 1H), 6.50-6.49(d, 1H), 6.10-6.07(d, 1H), 6.04(s, 1H), 5.94(s, 1H), 5.66-5.64(d, 1H), 4.38-4.36(m, 1H), 4.18-4.16(m, 1H), 4.08-4.06(m, 1H), 3.55(m, 4H), 3.21(s, 3H), 2.88-2.83(m, 2H), 2.32(m, 4H), 2.28(s, 3H), 2.03(m, 2H), 1.30(m, 2H)1 H NMR (500 MHz, DMSO): 10.5 (s, 1H), 6.94 (s, 1H), 6.86-6.80 (q, 1H), 6.50-6.49 (d, 1H), 6.10-6.07 (d, 1H), 6.04 (s, 1H), 5.94 (s, 1H), 5.66-5.64 (d, 1H), 4.38-4.36 (m, 1H), 4.18-4.16 (m, 1H), 4.08-4.06 (m, 1H), 3.55 (m, 4H), 3.21 (s, 3H), 2.88-2.83 (m, 2H), 2.32 (m, 4H), 2.28 (s, 3H), 2.03 (m, 2H), 1.30 (m, 2H)
실시예 2: 1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피롤리딘-1-일)프로프-2-엔-1-온의 제조Example 2: 1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pyrrolidine-1- (1) Preparation of prop-2-en-1-one
Figure PCTKR2019010894-appb-I000048
Figure PCTKR2019010894-appb-I000048
실시예 1의 단계 1-3에서 tert-부틸 3-아미노피페리딘-1-카르복실레이트 대신 tert-부틸 3-아미노피롤리딘-1-카르복실레이트를 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 표제 화합물(15.0 mg. 수율 23.0%)을 수득하였다.Example 1 except that tert-butyl 3-aminopyrrolidine-1-carboxylate was used instead of tert-butyl 3-aminopiperidine-1-carboxylate in Step 1-3 of Example 1 In the same manner the title compound (15.0 mg. Yield 23.0%) was obtained.
1H NMR(500 MHz, DMSO): 10.58-10.57(m, 1H), 6.94(s, 1H), 6.83-6.75(m, 1H), 6.63-6.48(m, 1H), 6.14-6.10(m, 1H), 6.08(s, 1H), 5.99-5.98(m, 1H), 5.67-5.59(m, 1H), 4.65-4.50(m, 1H), 3.99-3.97(m, 0.5H), 3.70-3.66(m, 1.5H), 3.55(m, 4H), 3.48(m, 1H), 3.35(m, 1H), 3.22(s, 2H), 2.34-2.32(m, 4H), 2.26-2.24(d, 3H), 2.25(m, 1H), 1.95-1.85(m, 1H)1 H NMR (500 MHz, DMSO): 10.58-10.57 (m, 1 H), 6.94 (s, 1 H), 6.83-6.75 (m, 1 H), 6.63-6.48 (m, 1 H), 6.14-6.10 (m, 1 H) ), 6.08 (s, 1H), 5.99-5.98 (m, 1H), 5.67-5.59 (m, 1H), 4.65-4.50 (m, 1H), 3.99-3.97 (m, 0.5H), 3.70-3.66 ( m, 1.5H), 3.55 (m, 4H), 3.48 (m, 1H), 3.35 (m, 1H), 3.22 (s, 2H), 2.34-2.32 (m, 4H), 2.26-2.24 (d, 3H ), 2.25 (m, 1 H), 1.95-1.85 (m, 1 H)
실시예 3: 1-(4-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 3: 1- (4-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidine-1- (1) Preparation of prop-2-en-1-one
Figure PCTKR2019010894-appb-I000049
Figure PCTKR2019010894-appb-I000049
실시예 1의 단계 1-3에서 tert-부틸 3-아미노피페리딘-1-카르복실레이트 대신 tert-부틸 4-아미노피페리딘-1-카르복실레이트를 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 표제 화합물(8.0 mg. 수율 53.0%)을 수득하였다.Example 1 except that tert-butyl 4-aminopiperidine-1-carboxylate was used instead of tert-butyl 3-aminopiperidine-1-carboxylate in Step 1-3 of Example 1 In the same manner the title compound (8.0 mg. Yield 53.0%) was obtained.
1H NMR(500 MHz, DMSO): 10.54(s, 1H), 6.94(s, 1H), 6.93-6.83(m, 1H), 6.51-6.49(d, 1H), 6.10(d, 1H), 6.07(s, 1H), 5.94(s, 1H), 5.66-5.64(d, 1H), 4.38-4.36(m, 1H), 4.16(m, 1H), 4.08-4.02(m, 1H), 3.56(m, 4H), 3.21(s, 2H), 2.85(m, 1H), 2.61(m, 1H), 2.34-2.33(m, 4H), 2.28(s, 3H), 2.0(m, 2H), 1.30-1.21(m, 2H)1 H NMR (500 MHz, DMSO): 10.54 (s, 1H), 6.94 (s, 1H), 6.93-6.83 (m, 1H), 6.51-6.49 (d, 1H), 6.10 (d, 1H), 6.07 ( s, 1H), 5.94 (s, 1H), 5.66-5.64 (d, 1H), 4.38-4.36 (m, 1H), 4.16 (m, 1H), 4.08-4.02 (m, 1H), 3.56 (m, 4H), 3.21 (s, 2H), 2.85 (m, 1H), 2.61 (m, 1H), 2.34-2.33 (m, 4H), 2.28 (s, 3H), 2.0 (m, 2H), 1.30-1.21 (m, 2H)
실시예 4: (R)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 4: (R) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperi Preparation of din-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000050
Figure PCTKR2019010894-appb-I000050
실시예 1의 단계 1-3에서 tert-부틸 3-아미노피페리딘-1-카르복실레이트 대신 tert-부틸 (R)-3-아미노피페리딘-1-카르복실레이트를 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 표제 화합물(10.0 mg. 수율 53.0%)을 수득하였다.Except for using tert-butyl (R) -3-aminopiperidine-1-carboxylate instead of tert-butyl 3-aminopiperidine-1-carboxylate in steps 1-3 of Example 1, In the same manner as in Example 1, the title compound (10.0 mg. Yield 53.0%) was obtained.
1H NMR(500 MHz, DMSO): 10.55-10.50(m, 1H), 6.91-6.90(m, 1H), 6.90-6.78(m, 0.5H), 6.47-6.56(m, 1.5H), 6.06-5.96(m, 3H), 5.65-5.67(m, 0.5H), 5.42-5.40(m, 0.5H), 4.42-4.40(m, 0.5H), 4.10-4.0(m, 1H), 3.90-3.87(m, 1.5H), 3.56(m, 4H), 3.20(s, 2H), 3.14-3.10(m, 1H), 2.68-2.63(m, 0.5H), 2.32(m, 4H), 2.19(s, 3H), 1.90-2.0(m, 1H), 1.80(m, 1H), 1.50-1.40(m, 2.5H)1 H NMR (500 MHz, DMSO): 10.55-10.50 (m, 1H), 6.91-6.90 (m, 1H), 6.90-6.78 (m, 0.5H), 6.47-6.56 (m, 1.5H), 6.06-5.96 (m, 3H), 5.65-5.67 (m, 0.5H), 5.42-5.40 (m, 0.5H), 4.42-4.40 (m, 0.5H), 4.10-4.0 (m, 1H), 3.90-3.87 (m , 1.5H), 3.56 (m, 4H), 3.20 (s, 2H), 3.14-3.10 (m, 1H), 2.68-2.63 (m, 0.5H), 2.32 (m, 4H), 2.19 (s, 3H ), 1.90-2.0 (m, 1H), 1.80 (m, 1H), 1.50-1.40 (m, 2.5H)
실시예 5: (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 5: (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperi Preparation of din-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000051
Figure PCTKR2019010894-appb-I000051
실시예 1의 단계 1-3에서 tert-부틸 3-아미노피페리딘-1-카르복실레이트 대신 tert-부틸 (S)-3-아미노피페리딘-1-카르복실레이트를 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 표제 화합물(13.0 mg. 수율 63.0%)을 수득하였다.Except for using tert-butyl (S) -3-aminopiperidine-1-carboxylate instead of tert-butyl 3-aminopiperidine-1-carboxylate in Step 1-3 of Example 1, In the same manner as in Example 1, the title compound (13.0 mg. Yield 63.0%) was obtained.
1H NMR(500 MHz, DMSO): 10.57(m, 1H), 6.91-6.90(m, 1H), 6.80-6.85(m, 0.5H), 6.70-6.40(m, 1.5H), 6.10-5.96(m, 3H), 5.65-5.63(d, 0.5H), 5.42-5.40(d, 0.5H), 4.42-4.40(m, 0.5H), 4.10-4.0(m, 1H), 3.90-3.87(m, 1.5H), 3.56(m, 4H), 3.20(s, 2H), 3.14-3.10(m, 1H), 2.68-2.63(m, 0.5H), 2.32(m, 4H), 2.19(s, 3H), 1.90-2.0(m, 1H), 1.80(m, 1H), 1.50-1.40(m, 2.5H)1 H NMR (500 MHz, DMSO): 10.57 (m, 1H), 6.91-6.90 (m, 1H), 6.80-6.85 (m, 0.5H), 6.70-6.40 (m, 1.5H), 6.10-5.96 (m , 3H), 5.65-5.63 (d, 0.5H), 5.42-5.40 (d, 0.5H), 4.42-4.40 (m, 0.5H), 4.10-4.0 (m, 1H), 3.90-3.87 (m, 1.5 H), 3.56 (m, 4H), 3.20 (s, 2H), 3.14-3.10 (m, 1H), 2.68-2.63 (m, 0.5H), 2.32 (m, 4H), 2.19 (s, 3H), 1.90-2.0 (m, 1H), 1.80 (m, 1H), 1.50-1.40 (m, 2.5H)
실시예 6: (R)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피롤리딘-1-일)프로프-2-엔-1-온의 제조Example 6: (R) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pyrroli Preparation of din-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000052
Figure PCTKR2019010894-appb-I000052
실시예 1의 단계 1-3에서 tert-부틸 3-아미노피페리딘-1-카르복실레이트 대신 tert-부틸 (R) 3-아미노피롤리딘-1-카르복실레이트를 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 표제 화합물(10.0 mg. 수율 58.0%)을 수득하였다.Example 1 except that tert-butyl (R) 3-aminopyrrolidine-1-carboxylate was used instead of tert-butyl 3-aminopiperidine-1-carboxylate in steps 1-3 of Example 1 In the same manner as in Example 1, the title compound (10.0 mg. Yield 58.0%) was obtained.
1H NMR(500 MHz, DMSO): 10.7(m, 1H), 6.94(s, 1H), 6.83-6.75(m, 1H), 6.63-6.47(m, 1H), 6.14-6.10(m, 2H), 6.09-3.08(m, 1H), 5.67-5.59(m, 1H), 4.67-4.50(1H), 3.97-3.96(m, 0.5H), 3.70(m, 1.5H), 3.55-3.54(m, 4H), 3.40(m, 1H), 3.38(m ,1H), 3.22(s, 2H), 2.32(m, 4H), 2.26-2.24(d, 3H), 2.20(m, 1H), 1.95-1.80(m, 1H)1 H NMR (500 MHz, DMSO): 10.7 (m, 1H), 6.94 (s, 1H), 6.83-6.75 (m, 1H), 6.63-6.47 (m, 1H), 6.14-6.10 (m, 2H), 6.09-3.08 (m, 1H), 5.67-5.59 (m, 1H), 4.67-4.50 (1H), 3.97-3.96 (m, 0.5H), 3.70 (m, 1.5H), 3.55-3.54 (m, 4H ), 3.40 (m, 1H), 3.38 (m, 1H), 3.22 (s, 2H), 2.32 (m, 4H), 2.26-2.24 (d, 3H), 2.20 (m, 1H), 1.95-1.80 ( m, 1H)
실시예 7: (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피롤리딘-1-일)프로프-2-엔-1-온의 제조Example 7: (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pyrroli Preparation of din-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000053
Figure PCTKR2019010894-appb-I000053
실시예 1의 단계 1-3에서 tert-부틸 3-아미노피페리딘-1-카르복실레이트 대신 tert-부틸 (S) 3-아미노피롤리딘-1-카르복실레이트를 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 표제 화합물(15.0 mg. 수율 63.0%)을 수득하였다.Example 1, except that tert-butyl (S) 3-aminopyrrolidine-1-carboxylate was used instead of tert-butyl 3-aminopiperidine-1-carboxylate in Step 1-3 of Example 1 In the same manner as in Example 1, the title compound (15.0 mg. Yield 63.0%) was obtained.
1H NMR(500 MHz, DMSO): 10.7(m, 1H), 6.94(s, 1H), 6.83-6.75(m, 1H), 6.63-6.47(m, 1H), 6.14-6.10(m, 2H), 6.09-3.08(m, 1H), 5.67-5.59(m, 1H), 4.67-4.50(1H), 3.97-3.96(m, 0.5H), 3.70(m, 1.5H), 3.55-3.54(m, 4H), 3.40(m, 1H), 3.38(m ,1H), 3.22(s, 2H), 2.32(m, 4H), 2.26-2.24(d, 3H), 2.20(m, 1H), 1.95-1.80(m, 1H)1 H NMR (500 MHz, DMSO): 10.7 (m, 1H), 6.94 (s, 1H), 6.83-6.75 (m, 1H), 6.63-6.47 (m, 1H), 6.14-6.10 (m, 2H), 6.09-3.08 (m, 1H), 5.67-5.59 (m, 1H), 4.67-4.50 (1H), 3.97-3.96 (m, 0.5H), 3.70 (m, 1.5H), 3.55-3.54 (m, 4H ), 3.40 (m, 1H), 3.38 (m, 1H), 3.22 (s, 2H), 2.32 (m, 4H), 2.26-2.24 (d, 3H), 2.20 (m, 1H), 1.95-1.80 ( m, 1H)
실시예 8: 1-(3-((2-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-4-일)아미노)피롤리딘-1-일)프로프-2-엔-1-온의 제조Example 8: 1- (3-((2-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-4-yl) amino) pyrrolidine-1 Preparation of -yl) prop-2-en-1-one
단계 8-1: 메틸 6-((1-(tert-부톡시카르보닐)피롤리딘-3-일)아미노)-2-클로로피리미딘-4-카복실레이트의 제조Step 8-1: Preparation of methyl 6-((1- (tert-butoxycarbonyl) pyrrolidin-3-yl) amino) -2-chloropyrimidine-4-carboxylate
Figure PCTKR2019010894-appb-I000054
Figure PCTKR2019010894-appb-I000054
메틸 2,4-디클로로피리미딘-6-카복실레이트(500 mg, 1.0 eq)를 테트라하이드로퓨란(10.0 mL)에 녹인 후에, 디이소프로필에틸아민(1.5 eq), tert-부틸 3-아미노피롤리딘-1-카복실레이트(1.5 eq)를 넣고 80℃에서 1시간 교반하였다. 반응이 완결되면 30℃ 이하로 냉각하고 물(100.0 mL)과 디클로로메탄(100.0 mL)을 가한 후 추출하였다. 분리된 유기층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:1)로 정제하여 표제 화합물(640.0 mg, 수율 74.0%)을 수득하였다.Methyl 2,4-dichloropyrimidine-6-carboxylate (500 mg, 1.0 eq) was dissolved in tetrahydrofuran (10.0 mL), followed by diisopropylethylamine (1.5 eq), tert-butyl 3-aminopyrroli Dean-1-carboxylate (1.5 eq) was added and stirred at 80 ° C. for 1 hour. After the reaction was completed, the mixture was cooled to 30 ° C. or lower, and extracted with water (100.0 mL) and dichloromethane (100.0 mL). The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound (640.0 mg, yield 74.0%).
단계 8-2: tert-부틸 3-((2-클로로-6-(몰폴린-4-카르보닐)피리미딘-4-일)아미노)피롤리딘-1-카복실레이트의 제조Step 8-2: Preparation of tert-butyl 3-((2-chloro-6- (morpholin-4-carbonyl) pyrimidin-4-yl) amino) pyrrolidine-1-carboxylate
Figure PCTKR2019010894-appb-I000055
Figure PCTKR2019010894-appb-I000055
단계 8-1에서 수득한 메틸 6-((1-tert-부톡시카르보닐)피롤리딘-3-일)아미노)-2-클로로피리미딘-4-카복실레이트(640.0 mg, 1.0 eq)를 테트라하이드로퓨란(10.0 mL)에 녹인 후에, 1,5,7-트리아자바이사이클로[4,4,0]덱-5-엔(0.3 eq), 몰폴린(1.2 eq)을 넣고 60℃에서 3시간 교반하였다. 반응이 완결되면 물(200.0 mL)과 디클로로메탄(200.0 mL)을 가한 후 추출하였다. 분리된 무유기층은 수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:메탄올 = 9:1)로 정제하여 표제 화합물(470.0 mg, 수율 63.7%)을 수득하였다.Methyl 6-((1-tert-butoxycarbonyl) pyrrolidin-3-yl) amino) -2-chloropyrimidine-4-carboxylate (640.0 mg, 1.0 eq) obtained in step 8-1 was prepared. After dissolving in tetrahydrofuran (10.0 mL), 1,5,7-triazabicyclo [4,4,0] dec-5-ene (0.3 eq) and morpholine (1.2 eq) were added, and 3 hours at 60 ° C. Stirred After the reaction was completed, water (200.0 mL) and dichloromethane (200.0 mL) were added and extracted. The separated organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: methanol = 9: 1) to obtain the title compound (470.0 mg, yield 63.7%).
단계 8-3: tert-부틸 3-((2-((5-메틸티아졸-2-일)아미노)-6-(몰폴린-4-카르보닐)피리미딘-4-일)아미노)피롤리딘-1-카복실레이트의 제조Step 8-3: tert-Butyl 3-((2-((5-methylthiazol-2-yl) amino) -6- (morpholin-4-carbonyl) pyrimidin-4-yl) amino) pi Preparation of Lolidine-1-carboxylate
Figure PCTKR2019010894-appb-I000056
Figure PCTKR2019010894-appb-I000056
단계 8-2에서 수득한 tert-부틸 3-((2-클로로-6-(몰폴린-4-카르보닐)피리미딘-4-일)아미노)피롤리딘-1-카복실레이트(450.0 mg, 1.0 eq)를 1,4-다이옥산(10.0 mL)에 녹인 후에, 팔라듐 아세테이트(0.1 eq), 4,5-비스(디페닐포스피노)-9,9-디메틸잔텐(0.2 eq), 세슘 카보네이트(3.0 eq), 2-아미노-5-메틸티아졸(1.2 eq)을 넣고 마이크로웨이브 반응기에서 반응시켰다(160℃, 30 min). 반응이 완결되면 물(200.0 mL)과 에틸아세테이트(200.0 mL)를 가한 후 추출하였다. 분리된 유기층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:메탄올 = 9:1)로 정제하여 표제 화합물(410.0 mg, 수율 76.6%)을 수득하였다.Tert-butyl 3-((2-chloro-6- (morpholin-4-carbonyl) pyrimidin-4-yl) amino) pyrrolidine-1-carboxylate (450.0 mg, obtained in step 8-2) 1.0 eq) in 1,4-dioxane (10.0 mL), followed by palladium acetate (0.1 eq), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.2 eq), cesium carbonate ( 3.0 eq) and 2-amino-5-methylthiazole (1.2 eq) were added and reacted in a microwave reactor (160 ° C., 30 min). After the reaction was completed, water (200.0 mL) and ethyl acetate (200.0 mL) were added and extracted. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: methanol = 9: 1) to obtain the title compound (410.0 mg, yield 76.6%).
단계 8-4: NStep 8-4: N 22 -(5-메틸티아졸-2-일)-6-(몰폴리노메틸)-N-(5-methylthiazol-2-yl) -6- (morpholinomethyl) -N 44 -(피롤리딘-3-일)피리미딘-2,4-다이아민의 제조Preparation of-(pyrrolidin-3-yl) pyrimidine-2,4-diamine
Figure PCTKR2019010894-appb-I000057
Figure PCTKR2019010894-appb-I000057
단계 8-3에서 수득한 tert-부틸 3-((2-((5-메틸티아졸-2-일)아미노)-6-(몰폴린-4-카르보닐)피리미딘-4-일)아미노)피롤리딘-1-카복실레이트(250.0 mg, 1.0 eq)를 테트라하이드로퓨란(10.0 mL)에 녹인 후에, 0.9M 보란-테트라하이드로용액(5.0 eq)을 넣고 50℃에서 5시간 교반하였다. 반응액을 0℃로 냉각한 다음 6N 염산수용액(5.0 eq)을 넣고 50℃에서 12시간 교반하였다. 다시 반응액을 0℃로 냉각한 다음 12N 수산화나트륨 수용액으로 pH 12를 맞춘 뒤, 디클로로메탄(200.0 mL)과 물(200.0 mL)을 사용하여 추출하였다. 분리된 유기층은 무수황산나트륨상에서 건조한 다음 감압 농축하여 표제화합물(40.0 mg, 수율 20.9%)을 수득하였다.Tert-butyl 3-((2-((5-methylthiazol-2-yl) amino) -6- (morpholine-4-carbonyl) pyrimidin-4-yl) amino obtained in step 8-3 ) Pyrrolidine-1-carboxylate (250.0 mg, 1.0 eq) was dissolved in tetrahydrofuran (10.0 mL), 0.9M borane-tetrahydro solution (5.0 eq) was added thereto, and the mixture was stirred at 50 ° C for 5 hours. The reaction solution was cooled to 0 ° C., added with 6N aqueous hydrochloric acid solution (5.0 eq), and stirred at 50 ° C. for 12 hours. The reaction solution was cooled to 0 ° C., adjusted to pH 12 with 12N aqueous sodium hydroxide solution, and extracted with dichloromethane (200.0 mL) and water (200.0 mL). The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the title compound (40.0 mg, yield 20.9%).
단계 8-5: 1-(3-((2-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-4-일)아미노)피롤리딘-1-일)프로프-2-엔-1-온의 제조Step 8-5: 1- (3-((2-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-4-yl) amino) pyrrolidine- Preparation of 1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000058
Figure PCTKR2019010894-appb-I000058
단계 8-4에서 수득한 N2-(5-메틸티아졸-2-일)-6-(몰폴리노메틸)-N4-(피롤리딘-3-일)피리미딘-2,4-다이아민(50.0 mg, 1.0 eq)을 테트라하이드로퓨란(1.6 mL)과 물(0.4 mL)에 녹인 후에, 중탄산나트륨(3.0 eq), 아크릴로일 클로라이드(1.1 eq)를 넣고 0℃에서 30분 교반하였다. 반응이 완결되면 물(50.0 mL)과 에틸아세테이트(50.0 mL)를 가한 후 추출하였다. 분리된 유기층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:메탄올 = 3:1)로 정제하여 표제 화합물(7.0 mg, 수율 12.2%)을 수득하였다.N 2- (5-methylthiazol-2-yl) -6- (morpholinomethyl) -N 4- (pyrrolidin-3-yl) pyrimidine-2,4- obtained in step 8-4 Diamine (50.0 mg, 1.0 eq) was dissolved in tetrahydrofuran (1.6 mL) and water (0.4 mL), then sodium bicarbonate (3.0 eq) and acryloyl chloride (1.1 eq) were added and stirred at 0 ° C. for 30 minutes. It was. After the reaction was completed, water (50.0 mL) and ethyl acetate (50.0 mL) were added and extracted. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: methanol = 3: 1) to obtain the title compound (7.0 mg, yield 12.2%).
1H NMR(500 MHz, CDCl3): 6.95(s, 1H), 6.40-6.46(m, 3H), 6.18(s, 1H), 5.69-5.74(m, 1H), 3.91-4.10(m, 1H), 3.76(s, 2H), 3.50-3.75(m, 8H), 2.46-2.56(m, 6H), 2.36(s, 3H) 1 H NMR (500 MHz, CDCl 3 ): 6.95 (s, 1 H), 6.40-6.46 (m, 3 H), 6.18 (s, 1 H), 5.69-5.74 (m, 1 H), 3.91-4.10 (m, 1 H) ), 3.76 (s, 2H), 3.50-3.75 (m, 8H), 2.46-2.56 (m, 6H), 2.36 (s, 3H)
실시예 9: (E)-1-(3-((2-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-4-일)아미노)피롤리딘-1-일)부트-2-엔-1-온의 제조Example 9: (E) -1- (3-((2-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-4-yl) amino) pi Preparation of Ralidin-1-yl) but-2-en-1-one
Figure PCTKR2019010894-appb-I000059
Figure PCTKR2019010894-appb-I000059
실시예 8 의 8-5 단계에서 아크릴로일 클로라이드 대신 크로토닐 클로라이드를 사용한 것을 제외하고, 실시예 8과 동일한 방법으로 표제화합물(5.0 mg, 수율 8.5%)을 수득하였다.The title compound (5.0 mg, yield 8.5%) was obtained in the same manner as in Example 8, except that crotonyl chloride was used instead of acryloyl chloride in steps 8-5 of Example 8.
1H NMR(500 MHz, CDCl3): 6.94-7.00(m, 3H), 6.18(s, 1H), 6.13-6.16(m, 2H), 4.3(s, 1H), 3.75(s, 2H), 3.61-3.73(m, 8H), 2.56(s, 4H), 2.29-2.36(m, 5H), 1.86-1.91(m, 3H)1 H NMR (500 MHz, CDCl 3 ): 6.94-7.00 (m, 3H), 6.18 (s, 1H), 6.13-6.16 (m, 2H), 4.3 (s, 1H), 3.75 (s, 2H), 3.61 -3.73 (m, 8H), 2.56 (s, 4H), 2.29-2.36 (m, 5H), 1.86-1.91 (m, 3H)
실시예 10: (1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥시)피롤리딘-1-일)프로프-2-엔-1-온의 제조Example 10: (1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) oxy) pyrrolidine-1 Preparation of -yl) prop-2-en-1-one
단계 10-1: tert-부틸 3-((6-클로로-4-(몰폴리노메틸)피리딘-2-일)옥시)피롤리딘-1-카복실레이트 의 제조Step 10-1: Preparation of tert-butyl 3-((6-chloro-4- (morpholinomethyl) pyridin-2-yl) oxy) pyrrolidine-1-carboxylate
Figure PCTKR2019010894-appb-I000060
Figure PCTKR2019010894-appb-I000060
디메틸포름아미드(10.0 ml)에 tert-부틸 3-히드록시피롤리딘-1-카복실레이트(2.0 g. 1.0 eq)를 용해한 후, t-부톡시칼륨(1.4 g. 1.5 eq)을 가하고 30분 동안 교반하였다. 실시예 1의 단계 1-2에서 수득한 중간체(2.0 g, 1.0 eq)를 가한 후, 60~80 ℃ 에서 4시간 교반하였다. 30℃ 이하로 냉각한 후, 물(40.0 mL)와 에틸아세테이트(40.0 mL)를 가한 후, 층분리하였다. 에틸아세테이트층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:5)로 정제하여 표제 화합물(1.8 g, 수율 55.3 %)를 수득하였다.After dissolving tert-butyl 3-hydroxypyrrolidine-1-carboxylate (2.0 g. 1.0 eq) in dimethylformamide (10.0 ml), t-butoxy potassium (1.4 g. 1.5 eq) was added and 30 minutes Was stirred. After adding the intermediate (2.0 g, 1.0 eq) obtained in the step 1-2 of Example 1, it stirred at 60-80 degreeC for 4 hours. After cooling to 30 ° C. or less, water (40.0 mL) and ethyl acetate (40.0 mL) were added, and the layers were separated. The ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1: 5) to obtain the title compound (1.8 g, yield 55.3%).
단계 10-2: (1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥시)피롤리딘-1-일)프로프-2-엔-1-온의 제조Step 10-2: (1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) oxy) pyrrolidine- Preparation of 1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000061
Figure PCTKR2019010894-appb-I000061
실시예 1의 단계 1-3에서 수득한 중간체 대신 단계 10-1에서 수득한 중간체를 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 표제 화합물(13.2 mg, 수율 65.5 %)을 수득하였다.The title compound (13.2 mg, yield 65.5%) was obtained in the same manner as in Example 1, except that the intermediate obtained in Step 10-1 was used instead of the intermediate obtained in Step 1-3 of Example 1.
1H NMR(500 MHz, DMSO): 10.18(s, 1H), 6.62(m, 1H), 6.53(s, 1H), 6.04(m, 1H), 5.65(s, 1H), 5.58(m, 1H), 5.20(s, 1H), 4.44(s, 2H), 3.99(m, 1H), 3.71(m, 2H), 3.57(m, 4H), 3.50-3.49(m, 2H), 2.42(m, 4H), 2.04(m, 2H)1 H NMR (500 MHz, DMSO): 10.18 (s, 1H), 6.62 (m, 1H), 6.53 (s, 1H), 6.04 (m, 1H), 5.65 (s, 1H), 5.58 (m, 1H) , 5.20 (s, 1H), 4.44 (s, 2H), 3.99 (m, 1H), 3.71 (m, 2H), 3.57 (m, 4H), 3.50-3.49 (m, 2H), 2.42 (m, 4H ), 2.04 (m, 2H)
실시예 11: 1-(4-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 11: 1- (4-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) oxy) piperidine-1- (1) Preparation of prop-2-en-1-one
Figure PCTKR2019010894-appb-I000062
Figure PCTKR2019010894-appb-I000062
실시예 10의 단계 10-1에서 tert-부틸 3-히드록시피롤리딘-1-카복실레이트 대신 tert-부틸 4-히드록시피페리딘-1-카르복실레이트를 사용한 것을 제외하고, 실시예 10과 동일한 방법으로 표제 화합물(8.5 mg, 수율 65.0 %)을 수득하였다.Example 10 except that tert-butyl 4-hydroxypiperidine-1-carboxylate was used instead of tert-butyl 3-hydroxypyrrolidine-1-carboxylate in Step 10-1 of Example 10. In the same manner as the title compound (8.5 mg, yield 65.0%) was obtained.
1H NMR(500 MHz, DMSO): 10.9(s, 1H), 7.00(s, 1H), 6.86-6.80(m, 1H), 6.53(s, 1H), 6.20(s, 1H), 6.11-6.08(d, 1H), 5.68-5.65(d, 1H), 5.36-5.32(m, 1H), 4.03(m, 1.5H), 3.90(m, 1.5H), 3.50(m, 4H), 3.45(m, 2H), 3.40(s, 2H), 2.34(m, 4H), 2.31(s, 3H), 2.08-2.06(m, 2H), 1.61-1.59(m, 2H)1 H NMR (500 MHz, DMSO): 10.9 (s, 1H), 7.00 (s, 1H), 6.86-6.80 (m, 1H), 6.53 (s, 1H), 6.20 (s, 1H), 6.11-6.08 ( d, 1H), 5.68-5.65 (d, 1H), 5.36-5.32 (m, 1H), 4.03 (m, 1.5H), 3.90 (m, 1.5H), 3.50 (m, 4H), 3.45 (m, 2H), 3.40 (s, 2H), 2.34 (m, 4H), 2.31 (s, 3H), 2.08-2.06 (m, 2H), 1.61-1.59 (m, 2H)
실시예 12: 1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 12 1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) oxy) piperidine-1- (1) Preparation of prop-2-en-1-one
Figure PCTKR2019010894-appb-I000063
Figure PCTKR2019010894-appb-I000063
실시예 10의 단계 10-1에서 tert-부틸 3-히드록시피롤리딘-1-카복실레이트 대신 tert-부틸 3-히드록시피페리딘-1-카르복실레이트를 사용한 것을 제외하고, 실시예 10과 동일한 방법으로 표제 화합물(9.5 mg, 수율 63.0 %)을 수득하였다.Example 10, except that tert-butyl 3-hydroxypiperidine-1-carboxylate was used instead of tert-butyl 3-hydroxypyrrolidine-1-carboxylate in Step 10-1 of Example 10. In the same manner as the title compound (9.5 mg, yield 63.0%) was obtained.
1H NMR(500 MHz, DMSO): 10.994-10.92(m, 1H), 7.00-6.99(m, 1H), 6.95-6.85(m, 0.5H), 6.53(s, 1H), 6.60-6.5(m, 0.5H), 6.15-6.13(m, 1H), 6.10-5.96(m, 1H), 5.74(d, 0.5H), 5.43-5.45(d, 0.5H), 5.25-5.15(m, 1H), 4.01-3.95(m, 0.5H), 3.90-3.75(m, 2H), 3.70(m, 0.5H), 3.55(m, 4H), 3.40(s, 2H), 2.34(m, 4H), 2.37-2.20(s, 3H), 2.09-2.04(m, 1.5H), 1.97-1.78(m, 2.5H), 1.50(m, 1H)1 H NMR (500 MHz, DMSO): 10.994-10.92 (m, 1H), 7.00-6.99 (m, 1H), 6.95-6.85 (m, 0.5H), 6.53 (s, 1H), 6.60-6.5 (m, 0.5H), 6.15-6.13 (m, 1H), 6.10-5.96 (m, 1H), 5.74 (d, 0.5H), 5.43-5.45 (d, 0.5H), 5.25-5.15 (m, 1H), 4.01 -3.95 (m, 0.5H), 3.90-3.75 (m, 2H), 3.70 (m, 0.5H), 3.55 (m, 4H), 3.40 (s, 2H), 2.34 (m, 4H), 2.37-2.20 (s, 3H), 2.09-2.04 (m, 1.5H), 1.97-1.78 (m, 2.5H), 1.50 (m, 1H)
실시예 13: (R)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)부트-2-인-1-온의 제조Example 13: (R) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperi Preparation of din-1-yl) but-2-yn-1-one
단계 13-1: (R)-NStep 13-1: (R) -N 22 -(5-메틸티아졸-2-일)-4-(몰폴리노메틸)-N-(5-methylthiazol-2-yl) -4- (morpholinomethyl) -N 66 -(피페리딘-3-일)피리딘-2,6-디아민의 제조Preparation of-(piperidin-3-yl) pyridine-2,6-diamine
Figure PCTKR2019010894-appb-I000064
Figure PCTKR2019010894-appb-I000064
실시예 1의 단계 1-3에서 tert-부틸 3-아미노피페리딘-1-카르복실레이트 대신 tert-부틸 (R)-3-아미노피페리딘-1-카르복실레이트를 사용한 것을 제외하고, 실시예 1의 단계 1-3, 1-4, 1-5와 동일한 방법으로 표제 화합물(150.0 mg. 수율 75.0%)을 수득하였다.Except for using tert-butyl (R) -3-aminopiperidine-1-carboxylate instead of tert-butyl 3-aminopiperidine-1-carboxylate in steps 1-3 of Example 1, The title compound (150.0 mg. Yield 75.0%) was obtained by the same method as Steps 1-3, 1-4, 1-5 of Example 1.
단계 13-2: (R)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)부트-2-인-1-온의 제조Step 13-2: (R) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pi Preparation of Ferridin-1-yl) but-2-yn-1-one
Figure PCTKR2019010894-appb-I000065
Figure PCTKR2019010894-appb-I000065
2-부틴산(21.6 mg. 1.0 eq)을 디메틸아미드(1.0 mL)에 용해한 후, 1-[비스(디메틸아미노)메틸렌]-1H-1,2,3-트리아졸로[4,5-b]피리디늄 3-옥시드헥사플로로포스페이트(97.3 mg. 1.0 eq)을 가하고 30분 동안 교반하였다. 단계 13-1에서 수득한 중간체(100.0 mg. 1.0 eq)을 가하고 트리에틸아민(53.5 ㎕. 1.5 eq)을 가한 후, 1시간 교반하였다. 물(1.0 mL)과 에틸아세테이트(1.0 mL)를 가한 후, 층분리하였다. 에틸아세테이트층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(디클로로메탄:메탄올 = 10:1)로 정제하여 표제 화합물(64.0 mg, 수율 55.0 %)를 얻었다.2-butyric acid (21.6 mg. 1.0 eq) was dissolved in dimethylamide (1.0 mL) and then 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] Pyridinium 3-oxidehexafluorophosphate (97.3 mg. 1.0 eq) was added and stirred for 30 minutes. The intermediate (100.0 mg. 1.0 eq) obtained in step 13-1 was added, triethylamine (53.5 μl. 1.5 eq) was added, followed by stirring for 1 hour. Water (1.0 mL) and ethyl acetate (1.0 mL) were added and the layers separated. The ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to give the title compound (64.0 mg, yield 55.0%).
1H NMR(500 MHz, DMSO): 10.59-10.58(d, 1H), 6.95-6.94(m, 1H), 6.84-6.79(m, 1H), 6.10(m, 1H), 5.99-5.97(m, 1H), 4.57-4.56(m, 1H), 3.85-3.65(m, 2H), 3.55(m, 4H), 3.45-3.35(m, 4H), 3.20(s, 2H), 3.30(m, 4H), 2.26(s, 3H), 2.25-2.15(m, 2H), 2.0(d, 3H)1 H NMR (500 MHz, DMSO): 10.59-10.58 (d, 1 H), 6.95-6.94 (m, 1 H), 6.84-6.79 (m, 1 H), 6.10 (m, 1 H), 5.99-5.97 (m, 1 H) ), 4.57-4.56 (m, 1H), 3.85-3.65 (m, 2H), 3.55 (m, 4H), 3.45-3.35 (m, 4H), 3.20 (s, 2H), 3.30 (m, 4H), 2.26 (s, 3H), 2.25-2.15 (m, 2H), 2.0 (d, 3H)
실시예 14: 1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피롤리딘-1-일)부트-2-인-1-온의 제조Example 14 1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pyrrolidine-1- (1) Preparation of but-2-yn-1-one
Figure PCTKR2019010894-appb-I000066
Figure PCTKR2019010894-appb-I000066
실시예 13의 단계 13-1에서 tert-부틸 (R)-3-아미노피페리딘-1-카르복실레이트 대신 tert-부틸 3-아미노피롤리딘-1-카르복실레이트를 사용한 것을 제외하고, 실시예 13과 동일한 방법으로 표제 화합물(58.6 mg. 수율 50.0%)을 수득하였다Except for using tert-butyl 3-aminopyrrolidine-1-carboxylate instead of tert-butyl (R) -3-aminopiperidine-1-carboxylate in step 13-1 of Example 13, In the same manner as in Example 13, the title compound (58.6 mg. Yield 50.0%) was obtained.
1H NMR(500 MHz, CDCl3): 7.03(s, 1H), 6.11(s, 1H), 5.96(s, 1H), 4.56-4.54(d, 1H), 4.42-4.40(d, 1H), 3.73-3.71(m, 4H), 3.33(s, 2H), 3.30(m, 1H), 2.93(m, 1H), 2.45(m, 4H), 2.38(s, 3H), 1.47-1.40(m, 1H)1 H NMR (500 MHz, CDCl 3): 7.03 (s, 1H), 6.11 (s, 1H), 5.96 (s, 1H), 4.56-4.54 (d, 1H), 4.42-4.40 (d, 1H), 3.73- 3.71 (m, 4H), 3.33 (s, 2H), 3.30 (m, 1H), 2.93 (m, 1H), 2.45 (m, 4H), 2.38 (s, 3H), 1.47-1.40 (m, 1H)
실시예 15: (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 15: (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) oxy) piperi Preparation of din-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000067
Figure PCTKR2019010894-appb-I000067
실시예 10의 단계 10-1에서 tert-부틸 3-히드록시피롤리딘-1-카복실레이트 대신 tert-부틸 (S) 3-히드록시피페리딘-1-카르복실레이트를 사용한 것을 제외하고, 실시예 10과 동일한 방법으로 표제 화합물(496.0 mg. 수율 50.0%)을 수득하였다.Except for using tert-butyl (S) 3-hydroxypiperidine-1-carboxylate instead of tert-butyl 3-hydroxypyrrolidine-1-carboxylate in step 10-1 of Example 10, In the same manner as in Example 10, the title compound (496.0 mg. Yield 50.0%) was obtained.
1H NMR(500 MHz, DMSO): 10.95(m, 1H), 6.99-6.98(m, 1H), 6.75-6.85(m, 0.5H), 6.50(s, 1H), 6.4-6.5(m, 0.5H), 5.74-5.65(d, 1H), 6.45-6.43(d, 1H), 5.24-5.15(m, 1H), 4.02-4.00(m, 0.5H), 3.82-3.81(m, 2H), 3.78(m, 0.5H), 3.55(m, 4H), 3.50(m, 0.5H), 3.15-3.14(d, 2H),, 2.32(m, 4H), 2.27-2.24(d, 3H), 2.06-1.96(m, 1.5H), 1.78-1.72(m, 2.5H), 1.51(m, 1H)1 H NMR (500 MHz, DMSO): 10.95 (m, 1H), 6.99-6.98 (m, 1H), 6.75-6.85 (m, 0.5H), 6.50 (s, 1H), 6.4-6.5 (m, 0.5H ), 5.74-5.65 (d, 1H), 6.45-6.43 (d, 1H), 5.24-5.15 (m, 1H), 4.02-4.00 (m, 0.5H), 3.82-3.81 (m, 2H), 3.78 ( m, 0.5H), 3.55 (m, 4H), 3.50 (m, 0.5H), 3.15-3.14 (d, 2H), 2.32 (m, 4H), 2.27-2.24 (d, 3H), 2.06-1.96 (m, 1.5H), 1.78-1.72 (m, 2.5H), 1.51 (m, 1H)
실시예 16: (R)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 16: (R) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) oxy) piperi Preparation of din-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000068
Figure PCTKR2019010894-appb-I000068
실시예 10의 단계 10-1에서 tert-부틸 3-히드록시피롤리딘-1-카복실레이트 대신 tert-부틸 (R) 3-히드록시피페리딘-1-카르복실레이트를 사용한 것을 제외하고, 실시예 10과 동일한 방법으로 표제 화합물(15.0 mg. 수율 55.0%)을 수득하였다.Except for using tert-butyl (R) 3-hydroxypiperidine-1-carboxylate instead of tert-butyl 3-hydroxypyrrolidine-1-carboxylate in step 10-1 of Example 10, In the same manner as in Example 10, the title compound (15.0 mg. Yield 55.0%) was obtained.
1H NMR(500 MHz, DMSO): 10.95(m, 1H), 6.99-6.98(m, 1H), 6.75-6.85(m, 0.5H), 6.50(s, 1H), 6.4-6.5(m, 0.5H), 5.74-5.65(d, 1H), 6.45-6.43(d, 1H), 5.24-5.15(m, 1H), 4.09-4.00(m, 0.5H), 3.82-3.81(m, 2H), 3.78(m, 0.5H), 3.56(m, 4H), 3.50(m, 0.5H), 3.15-3.14(d, 2H), 2.32(m, 4H), 2.27-2.25(d, 3H), 2.04(m, 1.5H), 1.87-1.72(m, 2.5H), 1.51(m, 1H)1 H NMR (500 MHz, DMSO): 10.95 (m, 1H), 6.99-6.98 (m, 1H), 6.75-6.85 (m, 0.5H), 6.50 (s, 1H), 6.4-6.5 (m, 0.5H ), 5.74-5.65 (d, 1H), 6.45-6.43 (d, 1H), 5.24-5.15 (m, 1H), 4.09-4.00 (m, 0.5H), 3.82-3.81 (m, 2H), 3.78 ( m, 0.5H), 3.56 (m, 4H), 3.50 (m, 0.5H), 3.15-3.14 (d, 2H), 2.32 (m, 4H), 2.27-2.25 (d, 3H), 2.04 (m, 1.5H), 1.87-1.72 (m, 2.5H), 1.51 (m, 1H)
실시예 17: 1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 17 1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-2-yl) amino) piperidine-1 Preparation of -yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000069
Figure PCTKR2019010894-appb-I000069
실시예 8의 8-1 단계에서 tert-부틸 3-아미노피롤리딘-1-카복실레이트 대신 3-아미노-1-tert-부톡시-카르보닐피페리딘을 사용한 것을 제외하고, 실시예 8과 동일한 방법으로 표제화합물(10.0 mg, 수율 17.5%)을 수득하였다.Example 8 except that 3-amino-1-tert-butoxy-carbonylpiperidine was used instead of tert-butyl 3-aminopyrrolidine-1-carboxylate in step 8-1 of Example 8. In the same manner to obtain the title compound (10.0 mg, yield 17.5%).
1H NMR(500 MHz, CDCl3): 7.25(s, 1H), 6.56-6.65(m, 1H), 6.25-6.39(m, 2H), 5.53(s, 0.5H), 5.22(s, 0.5H), 4.26(s, 1H), 4.09(s, 1H), 3.77(s, 4H), 3.72(s, 0.5H), 3.27-3.37(m, 4.5H), 2.54(s, 4H), 2.40(s, 3H), 2.14(s, 1H), 1.85(s, 1H), 1.66-1.67(m, 2H)1 H NMR (500 MHz, CDCl 3 ): 7.25 (s, 1 H), 6.56-6.65 (m, 1 H), 6.25-6.39 (m, 2 H), 5.53 (s, 0.5 H), 5.22 (s, 0.5 H) , 4.26 (s, 1H), 4.09 (s, 1H), 3.77 (s, 4H), 3.72 (s, 0.5H), 3.27-3.37 (m, 4.5H), 2.54 (s, 4H), 2.40 (s , 3H), 2.14 (s, 1H), 1.85 (s, 1H), 1.66-1.67 (m, 2H)
실시예 18: (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)부트-2-인-1-온의 제조Example 18: (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperi Preparation of din-1-yl) but-2-yn-1-one
Figure PCTKR2019010894-appb-I000070
Figure PCTKR2019010894-appb-I000070
실시예 13 의 단계 13-1에서 tert-부틸 (R)-3-아미노피페리딘-1-카르복실레이트 대신 (S)-3-아미노피페리딘-1-카르복실레이트를 사용한 것을 제외하고, 실시예 13과 동일한 방법으로 표제 화합물(12.1 mg. 수율 68.0%)을 수득하였다Except for using (S) -3-aminopiperidine-1-carboxylate instead of tert-butyl (R) -3-aminopiperidine-1-carboxylate in step 13-1 of Example 13 In the same manner as in Example 13, the title compound (12.1 mg. Yield 68.0%) was obtained.
1H NMR(500 MHz, DMSO): 10.18(s, 1H), 6.53(s, 1H), 5.87(s, 1H), 5.85(s, 1H), 4.44(s, 2H), 3.71-3.47(m, 8H), 2.78(m, 1H), 2.42(m, 4H), 2.30(s, 3H), 1.87-1.58(m, 4H), 1.80(s, 3H)1 H NMR (500 MHz, DMSO): 10.18 (s, 1H), 6.53 (s, 1H), 5.87 (s, 1H), 5.85 (s, 1H), 4.44 (s, 2H), 3.71-3.47 (m, 8H), 2.78 (m, 1H), 2.42 (m, 4H), 2.30 (s, 3H), 1.87-1.58 (m, 4H), 1.80 (s, 3H)
실시예 19: 1-(4-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)부트-2-인-1-온의 제조Example 19: 1- (4-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidine-1- (1) Preparation of but-2-yn-1-one
Figure PCTKR2019010894-appb-I000071
Figure PCTKR2019010894-appb-I000071
실시예 13 의 단계 13-1에서 tert-부틸 (R)-3-아미노피페리딘-1-카르복실레이트 대신 tert-부틸 4-아미노피페리딘-1-카르복실레이트를 사용한 것을 제외하고, 실시예 13과 동일한 방법으로 표제 화합물(8.5 mg. 수율 53.0%)을 수득하였다Except for using tert-butyl 4-aminopiperidine-1-carboxylate instead of tert-butyl (R) -3-aminopiperidine-1-carboxylate in step 13-1 of Example 13, In the same manner as in Example 13, the title compound (8.5 mg. Yield 53.0%) was obtained.
1H NMR(500 MHz, DMSO): 10.18(s, 1H), 6.53(s, 1H), 5.87(s, 1H), 5.80(s, 1H), 4.44(s, 2H), 3.59-3.49(m, 8H), 2.68(m, 1H), 2.42(m, 4H), 2.30(s, 3H), 1.97-1.72(m, 4H), 1.80(s, 3H)1 H NMR (500 MHz, DMSO): 10.18 (s, 1H), 6.53 (s, 1H), 5.87 (s, 1H), 5.80 (s, 1H), 4.44 (s, 2H), 3.59-3.49 (m, 8H), 2.68 (m, 1H), 2.42 (m, 4H), 2.30 (s, 3H), 1.97-1.72 (m, 4H), 1.80 (s, 3H)
실시예 20: (S)-1-(3-((4-((4-아세틸피페라진-1-일)메틸)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 20: (S) -1- (3-((4-((4-acetylpiperazin-1-yl) methyl) -6-((5-methylthiazol-2-yl) amino) pyridine- Preparation of 2-yl) amino) piperidin-1-yl) prop-2-en-1-one
단계 20-1: 1-((2,6-디클로로피리딘-4-일)메틸)피페라진의 제조Step 20-1: Preparation of 1-((2,6-dichloropyridin-4-yl) methyl) piperazine
Figure PCTKR2019010894-appb-I000072
Figure PCTKR2019010894-appb-I000072
실시예 1의 단계 1-1에서 몰폴린 대신 tert-부틸 피페라진-1-카르복실레이트를 사용한 것을 제외하고, 실시예 1의 단계 1-1, 1-2 와 동일한 방법으로 표제 화합물(11.0. 수율 86.0%)을 수득하였다.Except for using tert-butyl piperazine-1-carboxylate instead of morpholine in step 1-1 of Example 1, the title compound (11.0. Yield 86.0%) was obtained.
단계 20-2: 1-(4-((2,6-디클로로피리딘-4-일)메틸)피페라진-1-일)에탄-1-온의 제조Step 20-2: Preparation of 1- (4-((2,6-dichloropyridin-4-yl) methyl) piperazin-1-yl) ethan-1-one
Figure PCTKR2019010894-appb-I000073
Figure PCTKR2019010894-appb-I000073
단계 20-1에서 수득한 중간체(1.0 g. 1.0 eq)를 테트라하이드로퓨란(10.0 mL)에 용해한 후, 트리에틸아민(1.1 mL. 2.0 eq)를 가하였다. 아세틸 클로라이드(434.6 ㎕. 1.5 eq)를 가하고 6시간 교반하였다. 농축 후, 에틸아세테이트(10.0 mL), 물(10.0 mL)를 가한 후, 층분리하였다. 에틸아세테이트층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(디클로로메탄:메탄올 = 10:1)로 정제하여 표제 화합물(1.0 g, 수율 85.5 %)를 수득하였다.The intermediate (1.0 g. 1.0 eq) obtained in step 20-1 was dissolved in tetrahydrofuran (10.0 mL) and triethylamine (1.1 mL. 2.0 eq) was added. Acetyl chloride (434.6 μl. 1.5 eq) was added and stirred for 6 hours. After concentration, ethyl acetate (10.0 mL) and water (10.0 mL) were added, and the layers were separated. The ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to give the title compound (1.0 g, yield 85.5%).
단계 20-3: (S)-1-(3-((4-((4-아세틸피페라진-1-일)메틸)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Step 20-3: (S) -1- (3-((4-((4-acetylpiperazin-1-yl) methyl) -6-((5-methylthiazol-2-yl) amino) pyridine Preparation of -2-yl) amino) piperidin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000074
Figure PCTKR2019010894-appb-I000074
실시예 1의 단계 1-2에서 수득한 중간체 대신 실시예 20의 단계 20-2에서 수득한 중간체를 사용하고 단계 1-3에서 tert-부틸 3-아미노피페리딘-1-카르복실레이트 대신 tert-부틸 (S)-3-아미노피페리딘-1-카르복실레이트를 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 표제 화합물(50.0 mg. 수율 45.0%)을 수득하였다.Use the intermediate obtained in Step 20-2 of Example 20 instead of the intermediate obtained in Step 1-2 of Example 1 and tert instead of tert-butyl 3-aminopiperidine-1-carboxylate in Step 1-3. The title compound (50.0 mg. Yield 45.0%) was obtained by the same method as Example 1, except that -butyl (S) -3-aminopiperidine-1-carboxylate was used.
1H NMR(500 MHz, DMSO): 10.55(m, 1H), 6.91-6.90(m, 1H), 6.85-6.75(m, 0.5H), 6.57-6.48(m, 1.5H), 6.06-6.04(m, 1.5H), 5.99-5.96(m, 1.5H), 5.65-5.63(m, 0.5H), 5.43-5.41(m, 0.5H), 4.43-4.40(m, 0.5H), 4.14-4.10(m, 1H), 3.98-3.88(1.5H), 3.40(m, 4H), 3.24(s, 2H), 3.15-3.11(m, 2H), 2.67(m, 0.5H), 2.33-2.27(m, 4H), 2.19(s, 3H), 1.96(d, 3H), 1.79(m, 1H), 1.54-1.44(m, 2.5H)1 H NMR (500 MHz, DMSO): 10.55 (m, 1H), 6.91-6.90 (m, 1H), 6.85-6.75 (m, 0.5H), 6.57-6.48 (m, 1.5H), 6.06-6.04 (m , 1.5H), 5.99-5.96 (m, 1.5H), 5.65-5.63 (m, 0.5H), 5.43-5.41 (m, 0.5H), 4.43-4.40 (m, 0.5H), 4.14-4.10 (m , 1H), 3.98-3.88 (1.5H), 3.40 (m, 4H), 3.24 (s, 2H), 3.15-3.11 (m, 2H), 2.67 (m, 0.5H), 2.33-2.27 (m, 4H ), 2.19 (s, 3H), 1.96 (d, 3H), 1.79 (m, 1H), 1.54-1.44 (m, 2.5H)
실시예 21: (S)-1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 21: (S) -1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-2-yl) amino) pi Preparation of Ferridin-1-yl) prop-2-en-1-one
단계 21-1: 메틸 (S)-6-((1-(Step 21-1: Methyl (S) -6-((1- ( terttert -부톡시카르보닐)피페리딘-3-일)아미노)-2-클로로피리미딘-4-카르복실레이트의 제조Preparation of -butoxycarbonyl) piperidin-3-yl) amino) -2-chloropyrimidine-4-carboxylate
Figure PCTKR2019010894-appb-I000075
Figure PCTKR2019010894-appb-I000075
메틸 2,4-디클로로피리미딘-6-카복실레이트(5.0 g, 1.0 eq)를 테트라하이드로퓨란(100.0 mL)에 녹인 후에, 디이소프로필에틸아민(1.2 eq), tert-부틸 (S)-3-아미노피페리딘-1-카르복실레이트(1.2 eq)를 넣고 80℃에서 1시간 교반하였다. 반응이 완결되면 30℃ 이하로 냉각하고 물(500.0 mL)과 디클로로메탄(500.0 mL)을 가한 후 추출하였다. 분리된 유기층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:3)로 정제하여 표제 화합물(1.7 g, 수율 19.3%)을 수득하였다.Methyl 2,4-dichloropyrimidine-6-carboxylate (5.0 g, 1.0 eq) was dissolved in tetrahydrofuran (100.0 mL), followed by diisopropylethylamine (1.2 eq), tert-butyl (S) -3 -Aminopiperidine-1-carboxylate (1.2 eq) was added and stirred at 80 ° C for 1 hour. When the reaction was completed, the mixture was cooled to 30 ° C. or lower, and extracted with water (500.0 mL) and dichloromethane (500.0 mL). The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1: 3) to obtain the title compound (1.7 g, yield 19.3%).
단계 21-2: tert-부틸 (S)-3-((2-클로로-6-(몰폴린-4-카르보닐)피리미딘-4-일)아미노)피페리딘-1-카르복실레이트의 제조Step 21-2: tert-butyl (S) -3-((2-chloro-6- (morpholin-4-carbonyl) pyrimidin-4-yl) amino) piperidine-1-carboxylate Produce
Figure PCTKR2019010894-appb-I000076
Figure PCTKR2019010894-appb-I000076
단계 21-1에서 수득한 메틸 (S)-6-((1-(tert-부톡시카르보닐)피페리딘-3-일)아미노)-2-클로로피리미딘-4-카르복실레이트(1.7 g, 1.0 eq)를 테트라하이드로퓨란(20.0 mL)에 녹인 후에, 1,5,7-트리아자바이사이클로[4,4,0]덱-5-엔(0.3 eq), 몰폴린(1.2 eq)을 넣고 실온에서 3시간 교반하였다. 반응이 완결되면 물(200.0 mL)과 디클로로메탄(200.0 mL)을 가한 후 추출하였다. 분리된 유기층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:메탄올 = 19:1)로 정제하여 표제 화합물(970.0 mg, 수율 55.7%)을 수득하였다.Methyl (S) -6-((1- (tert-butoxycarbonyl) piperidin-3-yl) amino) -2-chloropyrimidine-4-carboxylate (1.7 obtained in step 21-1 g, 1.0 eq) in tetrahydrofuran (20.0 mL), and then 1,5,7-triazabicyclo [4,4,0] dec-5-ene (0.3 eq) and morpholine (1.2 eq). Put and stirred at room temperature for 3 hours. After the reaction was completed, water (200.0 mL) and dichloromethane (200.0 mL) were added and extracted. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: methanol = 19: 1) to obtain the title compound (970.0 mg, yield 55.7%).
단계 21-3: tert-부틸 3-((2-((5-메틸티아졸-2-일)아미노)-6-(몰폴린-4-카르보닐)피리미딘-4-일)아미노)피페리딘-1-카복실레이트의 제조Step 21-3: tert-butyl 3-((2-((5-methylthiazol-2-yl) amino) -6- (morpholine-4-carbonyl) pyrimidin-4-yl) amino) pi Preparation of Ferridine-1-carboxylate
Figure PCTKR2019010894-appb-I000077
Figure PCTKR2019010894-appb-I000077
단계 21-2에서 수득한 tert-부틸 (S)-3-((2-클로로-6-(몰폴린-4-카르보닐)피리미딘-4-일)아미노)피페리딘-1-카르복실레이트(950.0 mg, 1.0 eq)를 1,4-다이옥산(10.0 mL)에 녹인 후에, 팔라듐 아세테이트(0.1 eq), 4,5-비스(디페닐포스피노)-9,9-디메틸잔텐(0.2 eq), 세슘 카보네이트(3.0 eq), 2-아미노-5-메틸티아졸(1.2 eq)을 넣고 마이크로웨이브 반응기에서 반응시켰다(160℃, 30 min). 반응이 완결되면 물(100.0 mL)과 에틸아세테이트(100.0 mL)를 가한 후 추출하였다. 분리된 유기층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:메탄올 = 19:1)로 정제하여 표제 화합물(900.0 mg, 수율 80.0%)을 수득하였다.Tert-butyl (S) -3-((2-chloro-6- (morpholin-4-carbonyl) pyrimidin-4-yl) amino) piperidine-1-carboxyl obtained in step 21-2 After dissolving the rate (950.0 mg, 1.0 eq) in 1,4-dioxane (10.0 mL), palladium acetate (0.1 eq), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.2 eq ), Cesium carbonate (3.0 eq) and 2-amino-5-methylthiazole (1.2 eq) were added and reacted in a microwave reactor (160 ° C., 30 min). After the reaction was completed, water (100.0 mL) and ethyl acetate (100.0 mL) were added and extracted. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: methanol = 19: 1) to obtain the title compound (900.0 mg, yield 80.0%).
단계 21-4: (S)-NStep 21-4: (S) -N 22 -(5-메틸티아졸-2-일)-6-(몰폴리노메틸)-N-(5-methylthiazol-2-yl) -6- (morpholinomethyl) -N 44 -(피페리딘-3-일)피리미딘-2,4-다이아민의 제조Preparation of-(piperidin-3-yl) pyrimidine-2,4-diamine
Figure PCTKR2019010894-appb-I000078
Figure PCTKR2019010894-appb-I000078
단계 21-3에서 수득한 tert-부틸 3-((2-((5-메틸티아졸-2-일)아미노)-6-(몰폴린-4-카르보닐)피리미딘-4-일)아미노)피페리딘-1-카복실레이트(500.0 mg, 1.0 eq)를 테트라하이드로퓨란(10.0 mL)에 녹인 후에, 0.9M 보란-테트라하이드로퓨란 용액(3.0 eq)을 넣고 50℃에서 5시간 교반하였다. 반응액을 0℃로 냉각한 다음 6N 염산수용액(5.0 eq)을 넣고 50℃에서 12시간 교반하였다. 다시 반응액을 0℃로 냉각한 다음 12N 수산화나트륨 수용액으로 pH 12를 맞춘 뒤, 디클로로메탄(200.0 mL)과 물(200.0 mL)을 사용하여 추출하였다. 분리된 유기층은 무수황산나트륨상에서 건조한 다음 감압 농축하여 표제화합물(270.0 mg, 수율 69.8%)을 수득하였다.Tert-butyl 3-((2-((5-methylthiazol-2-yl) amino) -6- (morpholine-4-carbonyl) pyrimidin-4-yl) amino obtained in step 21-3 ) Piperidine-1-carboxylate (500.0 mg, 1.0 eq) was dissolved in tetrahydrofuran (10.0 mL), 0.9M borane-tetrahydrofuran solution (3.0 eq) was added thereto, and the mixture was stirred at 50 ° C for 5 hours. The reaction solution was cooled to 0 ° C., added with 6N aqueous hydrochloric acid solution (5.0 eq), and stirred at 50 ° C. for 12 hours. The reaction solution was cooled to 0 ° C., adjusted to pH 12 with 12N aqueous sodium hydroxide solution, and extracted with dichloromethane (200.0 mL) and water (200.0 mL). The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the title compound (270.0 mg, yield 69.8%).
단계 21-5: (S)-1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Step 21-5: (S) -1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-2-yl) amino) Preparation of Piperidin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000079
Figure PCTKR2019010894-appb-I000079
단계 21-4에서 수득한 (S)-N2-(5-메틸티아졸-2-일)-6-(몰폴리노메틸)-N4-(피페리딘-3-일)피리미딘-2,4-다이아민(270.0 mg, 1.0 eq)을 테트라하이드로퓨란(4.0 mL)과 물(1.0 mL)에 녹인 후에, 중탄산나트륨(3.0 eq), 아크릴로일 클로라이드(1.2 eq)를 넣고 0℃에서 30분 교반하였다. 반응이 완결되면 물(100.0 mL)과 디클로로메탄(100.0 mL)를 가한 후 추출하였다. 분리된 유기층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:메탄올 = 5:1)로 정제하여 표제 화합물(45.0 mg, 수율 14.6%)을 수득하였다.(S) -N 2- (5-methylthiazol-2-yl) -6- (morpholinomethyl) -N 4- (piperidin-3-yl) pyrimidine- obtained in step 21-4 Dissolve 2,4-diamine (270.0 mg, 1.0 eq) in tetrahydrofuran (4.0 mL) and water (1.0 mL), add sodium bicarbonate (3.0 eq), acryloyl chloride (1.2 eq), and add 0 ° C. Stirred for 30 min. After the reaction was completed, water (100.0 mL) and dichloromethane (100.0 mL) were added and extracted. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: methanol = 5: 1) to obtain the title compound (45.0 mg, yield 14.6%).
1H NMR(500 MHz, CDCl3): 7.17(s, 1H), 6.57-6.61(m, 1H), 6.25-6.42(m, 2H), 5.53(s, 1H), 4.25(s, 1H), 4.10(s, 1H), 3.77(s, 4H), 3.72(s, 0.5H), 3.30-3.37(m, 4.5H), 2.54(s, 4H), 2.40(s, 3H), 2.15(s, 1H), 1.85(s, 1H), 1.66-1.67(m, 2H)1 H NMR (500 MHz, CDCl 3 ): 7.17 (s, 1 H), 6.57-6.61 (m, 1 H), 6.25-6.42 (m, 2 H), 5.53 (s, 1 H), 4.25 (s, 1 H), 4.10 (s, 1H), 3.77 (s, 4H), 3.72 (s, 0.5H), 3.30-3.37 (m, 4.5H), 2.54 (s, 4H), 2.40 (s, 3H), 2.15 (s, 1H ), 1.85 (s, 1 H), 1.66-1.67 (m, 2 H)
실시예 22: (S)-1-(3-((4-((4-(2-메톡시에틸)피페라진-1-일)메틸)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 22: (S) -1- (3-((4-((4- (2-methoxyethyl) piperazin-1-yl) methyl) -6-((5-methylthiazole-2- I) amino) pyridin-2-yl) amino) piperidin-1-yl) prop-2-en-1-one
단계 22-1: 1-((2,6-디클로로피리딘-4-일)메틸)-4-(2-메톡시에틸)피페라진의 제조Step 22-1: Preparation of 1-((2,6-dichloropyridin-4-yl) methyl) -4- (2-methoxyethyl) piperazine
Figure PCTKR2019010894-appb-I000080
Figure PCTKR2019010894-appb-I000080
실시예 20의 단계 20-1에서 수득한 중간체(1.0 g, 1.0 eq)를 테트라하이드로퓨란(10.0 mL)에 용해한 후, 트리에틸아민(1.1 mL, 2.0 eq)를 가하였다. 1-브로모-2-메톡시에탄(572.0 ㎕, 1.5 eq)를 가하고 6시간 교반하였다. 농축 후, 에틸아세테이트(10.0 mL), 물(10.0 mL)를 가한 후, 층분리하였다. 에틸아세테이트층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(디클로로메탄:메탄올 = 10:1)로 정제하여 표제 화합물(711.1 mg, 수율 60.0 %)를 수득하였다.The intermediate (1.0 g, 1.0 eq) obtained in step 20-1 of Example 20 was dissolved in tetrahydrofuran (10.0 mL), and triethylamine (1.1 mL, 2.0 eq) was added. 1-bromo-2-methoxyethane (572.0 μl, 1.5 eq) was added and stirred for 6 hours. After concentration, ethyl acetate (10.0 mL) and water (10.0 mL) were added, and the layers were separated. The ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to give the title compound (711.1 mg, yield 60.0%).
단계 22-2: (S)-1-(3-((4-((4-(2-메톡시에틸)피페라진-1-일)메틸)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Step 22-2: (S) -1- (3-((4-((4- (2-methoxyethyl) piperazin-1-yl) methyl) -6-((5-methylthiazole-2 Preparation of -yl) amino) pyridin-2-yl) amino) piperidin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000081
Figure PCTKR2019010894-appb-I000081
실시예 1의 단계 1-2에서 수득한 중간체 대신 실시예 22의 단계 22-1에서 수득한 중간체를 사용하고 단계 1-3에서 tert-부틸 3-아미노피페리딘-1-카르복실레이트 대신 tert-부틸 (S)-3-아미노피페리딘-1-카르복실레이트를 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 표제 화합물(15.0 mg, 수율 68.0%)을 수득하였다.Use the intermediate obtained in Step 22-1 of Example 22 instead of the intermediate obtained in Step 1-2 of Example 1 and tert instead of tert-butyl 3-aminopiperidine-1-carboxylate in Step 1-3. The title compound (15.0 mg, yield 68.0%) was obtained in the same manner as in Example 1, except that -butyl (S) -3-aminopiperidine-1-carboxylate was used.
1H NMR(500 MHz, CDCl3): 10.50(m, 1H), 7.04-7.02(m, 1.5H), 6.60(m, 0.5H), 6.44-6.49(m, 1H), 6.33-3.18(m, 3H), 5.50-5.48(m, 0.5H), 5.80(m, 0.5H), 4.52-4.05(m, 2H), 4.0-3.70(m, 2H), 3.47(s, 2H), 3.36(s, 3H), 2.74-2.52(m, 13H), 2.35(s, 3H), 2.12-2.01(m, 1H), 1.83(m, 1H), 1.67(m, 2H)1 H NMR (500 MHz, CDCl 3): 10.50 (m, 1H), 7.04-7.02 (m, 1.5H), 6.60 (m, 0.5H), 6.44-6.49 (m, 1H), 6.33-3.18 (m, 3H ), 5.50-5.48 (m, 0.5H), 5.80 (m, 0.5H), 4.52-4.05 (m, 2H), 4.0-3.70 (m, 2H), 3.47 (s, 2H), 3.36 (s, 3H) ), 2.74-2.52 (m, 13H), 2.35 (s, 3H), 2.12-2.01 (m, 1H), 1.83 (m, 1H), 1.67 (m, 2H)
실시예 23: (S)-1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-2-일)아미노)피페리딘-1-일)부트-2-인-1-온Example 23: (S) -1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-2-yl) amino) pi Ferridin-1-yl) but-2-yn-1-one
Figure PCTKR2019010894-appb-I000082
Figure PCTKR2019010894-appb-I000082
실시예 21의 21-5 단계에서 아크릴로일 클로라이드 대신 부트-2-인오일클로라이드를 사용한 것을 제외하고 실시예 21과 동일한 방법으로 표제화합물(25.0 mg, 수율 10.7%)을 수득하였다.The title compound (25.0 mg, yield 10.7%) was obtained in the same manner as in Example 21, except that boot-2-inoyl chloride was used instead of acryloyl chloride in step 21-5 of Example 21.
1H NMR(500 MHz, CDCl3): 7.17(d, 1H), 6.34(d, 1H), 5.30(s, 1H), 4.32-4.36(m, 1H), 4.22(s, 1H), 4.01(s, 1H), 3.78(s, 4H), 3.41-3.45(m, 1H), 3.39(d, 2H), 3.36(s, 1H), 2.54(s, 4H), 2.45(s, 3H), 2.17(s, 1H), 2.04(s, 3H), 1.62-1.72(m, 3H)1 H NMR (500 MHz, CDCl 3 ): 7.17 (d, 1H), 6.34 (d, 1H), 5.30 (s, 1H), 4.32-4.36 (m, 1H), 4.22 (s, 1H), 4.01 (s , 1H), 3.78 (s, 4H), 3.41-3.45 (m, 1H), 3.39 (d, 2H), 3.36 (s, 1H), 2.54 (s, 4H), 2.45 (s, 3H), 2.17 ( s, 1H), 2.04 (s, 3H), 1.62-1.72 (m, 3H)
실시예 24: (S)-1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-2-일)아미노)피롤리딘-1-일)프로프-2-엔-1-온Example 24: (S) -1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-2-yl) amino) pi Ralidin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000083
Figure PCTKR2019010894-appb-I000083
실시예 21의 21-1 단계에서 tert-부틸 (S)-3-아미노피페리딘-1-카르복실레이트 대신 tert-부틸 (S)-3-아미노피롤리딘-1-카르복실레이트를 사용한 것을 제외하고 실시예 21과 동일한 방법으로 표제화합물(15.0 mg, 수율 10.1%)을 수득하였다.Tert-butyl (S) -3-aminopyrrolidine-1-carboxylate was used instead of tert-butyl (S) -3-aminopiperidine-1-carboxylate in step 21-1 of Example 21. Except for the title compound (15.0 mg, yield 10.1%) was obtained in the same manner as in Example 21.
1H NMR(500 MHz, CDCl3): 11.4(s, 1H), 7.21(s, 1H), 6.38-6.47(m, 2H), 5.66-5.72(m, 1H), 5.34(s, 1H), 4.75-4.80(m, 1H), 3.91(d, 0.5H), 3.68-3.77(m, 8H), 3.51(d, 0.5H), 3.38(d, 2H), 2.54(s, 4H), 2.43(d, 3H), 2.17-2.26(m, 1H), 1.96-2.03(m, 1H). 1 H NMR (500 MHz, CDCl 3 ): 11.4 (s, 1H), 7.21 (s, 1H), 6.38-6.47 (m, 2H), 5.66-5.72 (m, 1H), 5.34 (s, 1H), 4.75-4.80 (m, 1H), 3.91 (d, 0.5H), 3.68-3.77 (m, 8H), 3.51 (d, 0.5H), 3.38 (d, 2H), 2.54 (s, 4H), 2.43 ( d, 3H), 2.17-2.26 (m, 1 H), 1.96-2.03 (m, 1 H).
실시예 25: (R)-1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온Example 25: (R) -1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-2-yl) amino) pi Ferridin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000084
Figure PCTKR2019010894-appb-I000084
실시예 21의 21-1 단계에서 tert-부틸 (S)-3-아미노피페리딘-1-카르복실레이트 대신 tert-부틸 (R)-3-아미노피페리딘-1-카르복실레이트를 사용한 것을 제외하고 실시예 21과 동일한 방법으로 표제화합물(7.0 mg, 수율 6.2%)을 수득하였다.Tert-butyl (S) -3-aminopiperidine-1-carboxylate was used instead of tert-butyl (S) -3-aminopiperidine-1-carboxylate in step 21-1 of Example 21. Except for the title compound (7.0 mg, yield 6.2%) was obtained in the same manner as in Example 21.
1H NMR(500 MHz, CDCl3): 7.10(s, 1H), 6.50-6.61(m, 2H), 6.28-6.31(m, 3H), 4.40(s, 1H), 4.20(s, 1H), 4.01(s, 1H), 3.77(s, 4H), 3.30-3.36(m, 4H), 2.53(s, 2H), 2.37(s, 3H), 1.84(s, 2H), 1.70(m, 4H)1 H NMR (500 MHz, CDCl 3 ): 7.10 (s, 1 H), 6.50-6.61 (m, 2 H), 6.28-6.31 (m, 3 H), 4.40 (s, 1 H), 4.20 (s, 1 H), 4.01 (s, 1H), 3.77 (s, 4H), 3.30-3.36 (m, 4H), 2.53 (s, 2H), 2.37 (s, 3H), 1.84 (s, 2H), 1.70 (m, 4H)
실시예 26: (S)-1-(3-(메틸(6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 26: (S) -1- (3- (methyl (6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pi Preparation of Ferridin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000085
Figure PCTKR2019010894-appb-I000085
실시예 1의 단계 1-3에서 tert-부틸 3-아미노피페리딘-1-카르복실레이트 대신 tert-부틸 (S)-3-(메틸아미노)피페리딘-1-카르복실레이트를 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 표제 화합물(145.0 mg. 수율 60.0%)을 수득하였다.Tert-butyl (S) -3- (methylamino) piperidine-1-carboxylate instead of tert-butyl 3-aminopiperidine-1-carboxylate in steps 1-3 of Example 1 Except for the title compound (145.0 mg. Yield 60.0%) in the same manner as in Example 1.
1H NMR(500 MHz, DMSO): 10.62-10.60(m, 1H), 6.92(s, 1H), 6.91-6.81(m, 0.5H), 6.66(m, 0.5H), 6.22(s, 1H), 6.09-5.99(m, 2H), 5.66-5.64(m, 0.5H), 5.50-5.48(m 0.5H), 4.9(m, 0.5H), 4.8(m, 0.5H), 4.49-4.40(m, 1H), 4.08-3.92(m, 1H),, 3.56(m, 4H), 3.30(s, 2H), 3.25-3.22(m, 0.5H), 2.86(s, 3H), 2.99-2.96(m, 0.5H), 2.80-2.77(m, 0.5H), 2.59-2.54(m, 0.5H), 2.34(m, 4H), 2.18(s, 3H), 1.83-1.77(m, 3H), 1.50(m, 1H)1 H NMR (500 MHz, DMSO): 10.62-10.60 (m, 1 H), 6.92 (s, 1 H), 6.91-6.81 (m, 0.5 H), 6.66 (m, 0.5 H), 6.22 (s, 1 H), 6.09-5.99 (m, 2H), 5.66-5.64 (m, 0.5H), 5.50-5.48 (m 0.5H), 4.9 (m, 0.5H), 4.8 (m, 0.5H), 4.49-4.40 (m, 1H), 4.08-3.92 (m, 1H), 3.56 (m, 4H), 3.30 (s, 2H), 3.25-3.22 (m, 0.5H), 2.86 (s, 3H), 2.99-2.96 (m, 0.5H), 2.80-2.77 (m, 0.5H), 2.59-2.54 (m, 0.5H), 2.34 (m, 4H), 2.18 (s, 3H), 1.83-1.77 (m, 3H), 1.50 (m , 1H)
실시예 27: N-(1-(6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)피페리딘-4-일)아크릴아마이드의 제조Example 27 N- (1- (6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) piperidin-4-yl) acrylic Preparation of Amide
단계 27-1: tert-부틸 (1-(6-클로로-4-(몰폴리노메틸)피리딘-2-일)피페리딘-4-일)카바메이트의 제조Step 27-1: Preparation of tert-butyl (1- (6-chloro-4- (morpholinomethyl) pyridin-2-yl) piperidin-4-yl) carbamate
Figure PCTKR2019010894-appb-I000086
Figure PCTKR2019010894-appb-I000086
4-((2,6-디클로로피리딘-4-일)메틸)몰폴린(1.0 g, 3.8 mmol)를 N, N-디메틸포름아마이드(8 mL)에 녹인 후에 tert-부틸 피페리딘-4-일카바메이트(0.9 g, 3.8 mmol)와 세슘카보네이트(1.3 g, 3.8 mmol)를 가한 후 80℃에서 12시간 환류 교반하였다. 반응이 완결되면 에틸 아세테이트로 희석하여 브라인으로 세척하였다. 유기층을 모아 무수황산나트륨으로 건조 여과하고 감압 농축한 후 컬럼 크로마토그래피(헥산/에틸아세테이트= 1/1)로 정제하여 표제 화합물(580 mg, 수율 35%)을 수득하였다.4-((2,6-dichloropyridin-4-yl) methyl) morpholine (1.0 g, 3.8 mmol) was dissolved in N, N-dimethylformamide (8 mL) and then tert-butyl piperidine-4- Ilcarbamate (0.9 g, 3.8 mmol) and cesium carbonate (1.3 g, 3.8 mmol) were added, followed by stirring at reflux for 12 hours at 80 ° C. Upon completion of the reaction, the mixture was diluted with ethyl acetate and washed with brine. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography (hexane / ethyl acetate = 1/1) to obtain the title compound (580 mg, 35% yield).
단계 27-2: tert-부틸 (1-(6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)피페리딘-4-일)카바메이트의 제조Step 27-2: tert-butyl (1- (6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) piperidin-4-yl Preparation of Carbamate
Figure PCTKR2019010894-appb-I000087
Figure PCTKR2019010894-appb-I000087
단계 27-1에서 수득한 tert-부틸 (1-(6-클로로-4-(몰폴리노메틸)피리딘-2-일)피페리딘-4-일)카바메이트(0.5 g, 1.3 mmol)를 1,4-다이옥산(9 mL)에 녹인 후에 5-메틸티아졸-2-아민(0.2 g, 1.4 mmol), 팔라듐 아세테이트(0.06 g, 0.3 mmol), 잔트포스(0.3 g, 0.5 mmol), 세슘카보네이트(1.2 g, 3.8 mmol)를 차례대로 가한 후 마이크로웨이브 기기로 150℃에서 1시간 동안 반응하였다. 반응이 완결되면 셀라이트로 여과하고 감압 농축한 후 컬럼 크로마토그래피(디클로로메탄/메탄올 = 9/1)로 정제하여 표제 화합물(106 mg, 수율 17%)을 수득하였다.Tert-butyl (1- (6-chloro-4- (morpholinomethyl) pyridin-2-yl) piperidin-4-yl) carbamate (0.5 g, 1.3 mmol) obtained in step 27-1 After dissolving in 1,4-dioxane (9 mL), 5-methylthiazol-2-amine (0.2 g, 1.4 mmol), palladium acetate (0.06 g, 0.3 mmol), xantose (0.3 g, 0.5 mmol), cesium Carbonate (1.2 g, 3.8 mmol) was added sequentially, followed by reaction at 150 ° C. for 1 hour using a microwave instrument. After completion of the reaction, the mixture was filtered through celite, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 9/1) to obtain the title compound (106 mg, yield 17%).
단계 27-3: N-(6-(4-아미노페피리딘-1-일)-4-(몰폴리노메틸)피리딘-2-일)-5-메틸티아졸-2-아민의 제조Step 27-3: Preparation of N- (6- (4-aminopepyridin-1-yl) -4- (morpholinomethyl) pyridin-2-yl) -5-methylthiazol-2-amine
Figure PCTKR2019010894-appb-I000088
Figure PCTKR2019010894-appb-I000088
단계 27-2에서 수득한 tert-부틸 (1-(6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)피페리딘-4-일)카바메이트(0.1 g, 0.2 mmol)를 디클로로메탄(11 mL)에 녹인 후에 트리플루오로 아세트산(229 mg, 3.0 mmol)을 가하고 20℃에서 2시간 교반하였다. 반응이 완결되면 1N 수산화나트륨 용액을 가하여 pH 7로 조절하고 에틸아세테이트로 희석하여 브라인으로 세척하였다. 유기층을 모아 무수 황산나트륨으로 건조 여과하고 감압 농축하여 표제화합물(195 mg, 수율 100%)을 수득하였다.Tert-butyl (1- (6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) piperidine-4 obtained in step 27-2 -Yl) carbamate (0.1 g, 0.2 mmol) was dissolved in dichloromethane (11 mL), then trifluoro acetic acid (229 mg, 3.0 mmol) was added and stirred at 20 ° C. for 2 hours. Upon completion of the reaction, 1N sodium hydroxide solution was added to adjust pH to 7, diluted with ethyl acetate, and washed with brine. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (195 mg, yield 100%).
단계 27-4: N-(1-(6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)피페리딘-4-일)아크릴아마이드의 제조Step 27-4: N- (1- (6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) piperidin-4-yl) Preparation of Acrylamide
Figure PCTKR2019010894-appb-I000089
Figure PCTKR2019010894-appb-I000089
단계 27-3에서 수득한 N-(6-(4-아미노페피리딘-1-일)-4-(몰폴리노메틸)피리딘-2-일)-5-메틸티아졸-2-아민(0.1 g, 0.2 mmol)을 테트라하이드로퓨란(6 mL)과 물(2 mL)에 녹인 후에 0 ℃로 냉각하고 중탄산나트륨(0.08 g, 1.0 mmol)를 가하였다. 아크릴로일 클로라이드(0.02 mL, 0.3 mmol)를 반응액에 천천히 가한 후 0℃에서 10분간 교반하였다. 반응이 완결되면 에틸아세테이트로 희석한 후 브라인으로 세척하고 감압 농축하고 컬럼 크로마토그래피(디클로로메탄/메탄올=9/1)로 정제하여 표제 화합물(33 mg, 수율 37%)를 수득하였다.N- (6- (4-aminopepyridin-1-yl) -4- (morpholinomethyl) pyridin-2-yl) -5-methylthiazol-2-amine obtained in step 27-3 (0.1) g, 0.2 mmol) was dissolved in tetrahydrofuran (6 mL) and water (2 mL), cooled to 0 ° C. and sodium bicarbonate (0.08 g, 1.0 mmol) was added. Acryloyl chloride (0.02 mL, 0.3 mmol) was slowly added to the reaction solution, followed by stirring at 0 ° C. for 10 minutes. Upon completion of the reaction, the mixture was diluted with ethyl acetate, washed with brine, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 9/1) to obtain the title compound (33 mg, yield 37%).
1H NMR(500 MHz, CDCl3): 7.02(s, 1H), 6.30-6.32(m, 1H), 6.15-6.20(m, 1H), 6.01-6.10(m, 1H), 5.60-5.62(m, 1H), 5.41-5.45(m, 1H),4.35-4.38(m, 2H), 4.15-4.20(m, 1H),3.78(s, 4H), 3.38(s, 2H), 3.07-3.12(m, 2H), 2.45(s, 4H), 2.37(s, 3H), 2.10-2.12(m, 2H), 1.50-1.60(m, 2H). 1 H NMR (500 MHz, CDCl 3 ): 7.02 (s, 1H), 6.30-6.32 (m, 1H), 6.15-6.20 (m, 1H), 6.01-6.10 (m, 1H), 5.60-5.62 (m , 1H), 5.41-5.45 (m, 1H), 4.35-4.38 (m, 2H), 4.15-4.20 (m, 1H), 3.78 (s, 4H), 3.38 (s, 2H), 3.07-3.12 (m , 2H), 2.45 (s, 4H), 2.37 (s, 3H), 2.10-2.12 (m, 2H), 1.50-1.60 (m, 2H).
실시예 28: 1-(6-(6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥타하이드로-1H-피롤로[2,3-c]피리딘-1-일)프로프-2-엔-1-온의 제조Example 28 1- (6- (6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) octahydro-1H-pyrrolo [2 Preparation of, 3-c] pyridin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000090
Figure PCTKR2019010894-appb-I000090
실시예 27의 27-1 단계에서 tert-부틸 피페리딘-4-일카바메이트 대신 tert-부틸 옥타하이드로-1H-피롤로[2,3-c]피리딘-1-카르복실레이트를 사용한 것을 제외하고, 실시예 27과 동일한 방법으로 표제화합물(7 mg, 수율 19%)을 수득하였다.Except for using tert-butyl octahydro-1H-pyrrolo [2,3-c] pyridine-1-carboxylate instead of tert-butyl piperidin-4-ylcarbamate in step 27-1 of Example 27 In the same manner as in Example 27, the title compound (7 mg, yield 19%) was obtained.
1H NMR(500 MHz, CDCl3): 6.97(s, 1H), 6.40-6.47(m, 2H), 6.07-6.20(m, 2H), 5.67-5.71(m, 1H), 4.32-4.42(m, 2H), 4.05-4.15(m, 2H), 3.70(s, 4H), 3.58-3.62(m, 2H), 3.50(s, 2H), 3.32(s, 2H), 2.95-3.05(m, 2H), 2.50-2.52(m, 1H), 2.47(s, 4H),2.37(s, 3H), 1.85-1.90(m, 1H).1 H NMR (500 MHz, CDCl 3 ): 6.97 (s, 1 H), 6.40-6.47 (m, 2 H), 6.07-6.20 (m, 2 H), 5.67-5.71 (m, 1 H), 4.32-4.42 (m, 2H), 4.05-4.15 (m, 2H), 3.70 (s, 4H), 3.58-3.62 (m, 2H), 3.50 (s, 2H), 3.32 (s, 2H), 2.95-3.05 (m, 2H) , 2.50-2.52 (m, 1H), 2.47 (s, 4H), 2.37 (s, 3H), 1.85-1.90 (m, 1H).
실시예 29: 1-(6-(6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥타하이드로-1H-피롤로[2,3-c]피리딘-1-일)부트-2-인-1-온의 제조Example 29: 1- (6- (6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) octahydro-1H-pyrrolo [2 Preparation of, 3-c] pyridin-1-yl) but-2-yn-1-one
Figure PCTKR2019010894-appb-I000091
Figure PCTKR2019010894-appb-I000091
실시예 27의 27-1 단계에서 tert-부틸 피페리딘-4-일카바메이트 대신 tert-부틸 옥타하이드록-1H-피롤로[2,3-c]피리딘-1-카르복실레이트를 사용하고, 27-4 단계에서 아크릴로일 클로라이드 대신 부트-2-인오일 클로라이드를 사용한 것을 제외하고, 실시예 27과 동일한 방법으로 표제화합물(12 mg, 수율 15%)을 수득하였다.In step 27-1 of Example 27, tert-butyl octahydroxy-1H-pyrrolo [2,3-c] pyridine-1-carboxylate was used instead of tert-butyl piperidin-4-ylcarbamate. The title compound (12 mg, yield 15%) was obtained in the same manner as in Example 27, except that But-2-inoyl chloride was used instead of acryloyl chloride in step 27-4.
1H NMR(500 MHz, CDCl3): 6.98(s, 1H), 6.06-6.10(m, 2H), 4.20-4.25(m, 2H), 3.67(s, 3H), 3.60-3.65(m, 2H), 3.41-3.50(m, 2H), 3.31-3.37(m, 2H), 2.95-3.05(m, 2H), 2.39-2.50(m, 4H), 2.38(s, 3H), 2.27-2.35(m, 2H), 1.87-1.95(m, 4H), 1.75-1.87(m, 2H).1 H NMR (500 MHz, CDCl 3 ): 6.98 (s, 1H), 6.06-6.10 (m, 2H), 4.20-4.25 (m, 2H), 3.67 (s, 3H), 3.60-3.65 (m, 2H) , 3.41-3.50 (m, 2H), 3.31-3.37 (m, 2H), 2.95-3.05 (m, 2H), 2.39-2.50 (m, 4H), 2.38 (s, 3H), 2.27-2.35 (m, 2H), 1.87-1.95 (m, 4H), 1.75-1.87 (m, 2H).
실시예 30: 1-(6-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)-2-아자스피로[3.3]헵탄-2-일)프로프-2-엔-1-온의 제조Example 30 1- (6-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) -2-azaspiro [ 3.3] Preparation of Heptan-2-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000092
Figure PCTKR2019010894-appb-I000092
실시예 1의 1-3 단계에서 tert-부틸 3-아미노피페리딘-1-카르복실레이트 대신 tert-부틸 6-아미노-2-아자스파이로[3.3]헵탄-2-카르복실레이트를 사용한 것을 제외하고, 실시예 1과 동일한 방법으로 표제화합물(5 mg, 수율 11%)을 수득하였다.Using tert-butyl 6-amino-2-azaspiro [3.3] heptan-2-carboxylate instead of tert-butyl 3-aminopiperidine-1-carboxylate in steps 1-3 of Example 1 Except for the title compound, the title compound (5 mg, 11% yield) was obtained in the same manner as in Example 1.
1H NMR(500 MHz, CDCl3): 6.95(s, 1H), 6.40-6.46(m, 2H), 6.25-6.30(m, 1H), 6.18(m, 1H), 5.69-5.74(m, 1H), 3.82(s, 2H), 3.72-3.77(m, 2H), 3.65-3.70(m, 2H), 3.10-3.12(m, 1H), 2.39-2.50(m, 4H), 2.36(s, 3H), 1.87-1.95(m, 4H), 1.85-1.87(m, 2H), 1.60-1.62(m, 2H). 1 H NMR (500 MHz, CDCl 3 ): 6.95 (s, 1H), 6.40-6.46 (m, 2H), 6.25-6.30 (m, 1H), 6.18 (m, 1H), 5.69-5.74 (m, 1H ), 3.82 (s, 2H), 3.72-3.77 (m, 2H), 3.65-3.70 (m, 2H), 3.10-3.12 (m, 1H), 2.39-2.50 (m, 4H), 2.36 (s, 3H) ), 1.87-1.95 (m, 4H), 1.85-1.87 (m, 2H), 1.60-1.62 (m, 2H).
실시예 31: (S)-1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(피페리딘-1-일메틸)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온Example 31: (S) -1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (piperidin-1-ylmethyl) pyrimidin-2-yl ) Amino) piperidin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000093
Figure PCTKR2019010894-appb-I000093
실시예 21의 21-2 단계에서 몰폴린 대신 피페리딘을 사용한 것을 제외하고, 실시예 21과 동일한 방법으로 표제화합물(1.0 mg, 수율 1.5%)을 수득하였다.The title compound (1.0 mg, yield 1.5%) was obtained in the same manner as in Example 21, except that piperidine was used instead of morpholine in step 21-2 of Example 21.
1H NMR(500 MHz, CDCl3): 7.05(s, 1H), 6.50-6.63(m, 2H), 6.21-6.28(m, 2H), 5.70(s, 0.5H), 5.54(s, 0.5H), 4.50-4.70(m, 1H), 4.20-4.40(m, 4H), 3.31(s, 2H), 3.20-3.30(m, 4H), 2.36(s, 3H), 1.33-1.72(m, 10H)1 H NMR (500 MHz, CDCl 3 ): 7.05 (s, 1H), 6.50-6.63 (m, 2H), 6.21-6.28 (m, 2H), 5.70 (s, 0.5H), 5.54 (s, 0.5H) , 4.50-4.70 (m, 1H), 4.20-4.40 (m, 4H), 3.31 (s, 2H), 3.20-3.30 (m, 4H), 2.36 (s, 3H), 1.33-1.72 (m, 10H)
실시예 32: (S)-1-(3-((4-((4-에틸피페라진-1-일)메틸)-6-((5-메틸티아졸-2-일)아미노)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온Example 32: (S) -1- (3-((4-((4-ethylpiperazin-1-yl) methyl) -6-((5-methylthiazol-2-yl) amino) pyrimidine -2-yl) amino) piperidin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000094
Figure PCTKR2019010894-appb-I000094
실시예 21의 21-2 단계에서 몰폴린 대신 1-에틸피페라진을 사용한 것을 제외하고, 실시예 21과 동일한 방법으로 표제화합물(0.5 mg, 수율 1.1%)을 수득하였다.The title compound (0.5 mg, yield 1.1%) was obtained in the same manner as in Example 21, except that 1-ethylpiperazine was used instead of morpholine in step 21-2 of Example 21.
1H NMR(500 MHz, CDCl3): 7.06(s, 1H), 6.50-6.63(m, 1H), 6.19-6.28(m, 2H), 5.71(s, 0.5H), 5.54(s, 0.5H), 4.20-4.44(m, 1H), 3.51-3.60(m, 1H), 3.37(s, 2H), 3.27-3.32(m, 1H), 2.52-2.57(m, 4H), 2.41-2.46(m, 4H), 2.36(s, 3H), 1.66-1.84(m, 8H), 1.08(t, 3H)1 H NMR (500 MHz, CDCl 3 ): 7.06 (s, 1 H), 6.50-6.63 (m, 1 H), 6.19-6.28 (m, 2 H), 5.71 (s, 0.5 H), 5.54 (s, 0.5 H) , 4.20-4.44 (m, 1H), 3.51-3.60 (m, 1H), 3.37 (s, 2H), 3.27-3.32 (m, 1H), 2.52-2.57 (m, 4H), 2.41-2.46 (m, 4H), 2.36 (s, 3H), 1.66-1.84 (m, 8H), 1.08 (t, 3H)
실시예 33: (S)-1-(3-((4-((1-메틸피페리딘-4-일)옥시)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온Example 33: (S) -1- (3-((4-((1-methylpiperidin-4-yl) oxy) -6-((5-methylthiazol-2-yl) amino) pyridine -2-yl) amino) piperidin-1-yl) prop-2-en-1-one
단계 33-1: tert-부틸 4-((2,6-디클로로피리딘-4-일)옥시)피페리딘-1-카르복실레이트의 제조Step 33-1: Preparation of tert-butyl 4-((2,6-dichloropyridin-4-yl) oxy) piperidine-1-carboxylate
Figure PCTKR2019010894-appb-I000095
Figure PCTKR2019010894-appb-I000095
1-(tert-부톡시카르보닐)-4-히드록시피페리딘(5.5 g, 1.0 eq)을 디메틸포름아마이드(50.0 mL)에 녹인 후에, 60% 소듐하이드라이드(3.0 eq)를 넣고 0℃에서 10분 동안 반응시킨 뒤, 2,4,6-트리클로로피리딘(1.0 eq)을 넣고 30분 반응시켰다. 반응이 완결되면 물(500.0 mL)과 에틸아세테이트(500.0 mL)를 가한 후 추출하였다. 분리된 유기층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:5)로 정제하여 표제 화합물(5.1 g, 수율 53.7%)을 수득하였다.Dissolve 1- (tert-butoxycarbonyl) -4-hydroxypiperidine (5.5 g, 1.0 eq) in dimethylformamide (50.0 mL), add 60% sodium hydride (3.0 eq) and add 0 ° C. After reacting for 10 minutes at 2,4,6-trichloropyridine (1.0 eq) was added and reacted for 30 minutes. When the reaction was completed, water (500.0 mL) and ethyl acetate (500.0 mL) were added and extracted. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1: 5) to obtain the title compound (5.1 g, yield 53.7%).
단계 33-2: 2,6-디클로로-4-(피페리딘-4-일옥시)피리딘의 제조Step 33-2: Preparation of 2,6-dichloro-4- (piperidin-4-yloxy) pyridine
Figure PCTKR2019010894-appb-I000096
Figure PCTKR2019010894-appb-I000096
단계 33-1에서 수득한 tert-부틸 4-((2,6-디클로로피리딘-4-일)옥시)피페리딘-1-카르복실레이트(5.0 g, 1.0 eq)에 4M 염산-다이옥산 용액(50.0 mL)을 넣고 실온에서 30분 반응시켰다. 반응이 완결되면 반응액을 0℃에서 냉각시킨 후 12N 수산화나트륨 수용액으로 pH 12를 맞춘 뒤, 물(250 mL)과 에틸아세테이트(500.0 mL)를 가한 후 추출하였다. 분리된 유기층은 무수황산나트륨상에서 건조한 다음, 감압 농축하여 표제 화합물(2.4 g, 수율 68.2%)을 수득하였다.4M hydrochloric acid-dioxane solution in tert-butyl 4-((2,6-dichloropyridin-4-yl) oxy) piperidine-1-carboxylate (5.0 g, 1.0 eq) obtained in step 33-1 ( 50.0 mL) was added and reacted at room temperature for 30 minutes. After the reaction was completed, the reaction solution was cooled at 0 ° C., adjusted to pH 12 with 12N aqueous sodium hydroxide solution, and extracted with water (250 mL) and ethyl acetate (500.0 mL). The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the title compound (2.4 g, yield 68.2%).
단계 33-3: 2,6-디클로로-4-((1-메틸피페리딘-4-일)옥시)피리딘의 제조Step 33-3: Preparation of 2,6-dichloro-4-((1-methylpiperidin-4-yl) oxy) pyridine
Figure PCTKR2019010894-appb-I000097
Figure PCTKR2019010894-appb-I000097
단계 33-2에서 수득한 2,6-디클로로-4-(피페리딘-4-일옥시)피리딘(2.4 g, 1.0 eq)을 메탄올 (50.0 mL)과 디클로로메탄(50.0 mL)에 녹인 후에, 포름알데하이드 용액(1.0 eq), 아세트산(0.1 eq), 소듐트리아세톡시보로하이드라이드(2.0 eq)를 넣고 실온에서 30분 반응시켰다. 반응이 완결되면 물(500.0 mL)과 디클로로메탄(500.0 mL)을 가한 후 추출하였다. 분리된 유기층은 무수황산나트륨상에서 건조한 다음, 감압 농축하여 표제 화합물(5.1 g, 수율 89.8%)을 수득하였다.After dissolving 2,6-dichloro-4- (piperidin-4-yloxy) pyridine (2.4 g, 1.0 eq) obtained in step 33-2 in methanol (50.0 mL) and dichloromethane (50.0 mL), Formaldehyde solution (1.0 eq), acetic acid (0.1 eq) and sodium triacetoxyborohydride (2.0 eq) were added and allowed to react at room temperature for 30 minutes. After the reaction was completed, water (500.0 mL) and dichloromethane (500.0 mL) were added and extracted. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the title compound (5.1 g, 89.8% yield).
단계 33-4: tert-부틸 (S)-3-((6-클로로-4-((1-메틸피페리딘-4-일)옥시)피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step 33-4: tert-Butyl (S) -3-((6-chloro-4-((1-methylpiperidin-4-yl) oxy) pyridin-2-yl) amino) piperidine-1 Preparation of Carboxylate
Figure PCTKR2019010894-appb-I000098
Figure PCTKR2019010894-appb-I000098
단계 33-3에서 수득한 2,6-디클로로-4-((1-메틸피페리딘-4-일)옥시)피리딘(2.0 g, 1.0 eq)을 1,4-다이옥산(20.0 mL)에 녹인 후에, 팔라듐 아세테이트(0.1 eq), 4,5-비스(디페닐포스피노)-9,9-디메틸잔텐(0.2 eq), 세슘 카보네이트(3.0 eq), 2-아미노-5-메틸티아졸(1.2 eq)을 넣고 마이크로웨이브 반응기에서 반응시켰다(150℃, 30 min). 반응이 완결되면 물(250.0 mL)과 디클로로메탄(250.0 mL)을 가한 후 추출하였다. 분리된 유기층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:메탄올 = 1:1)로 정제하여 표제 화합물(900.0 mg, 수율 27.7%)을 수득하였다.2,6-dichloro-4-((1-methylpiperidin-4-yl) oxy) pyridine (2.0 g, 1.0 eq) obtained in step 33-3 was dissolved in 1,4-dioxane (20.0 mL). Later, palladium acetate (0.1 eq), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.2 eq), cesium carbonate (3.0 eq), 2-amino-5-methylthiazole (1.2 eq) was added and reacted in a microwave reactor (150 ° C., 30 min). After the reaction was completed, water (250.0 mL) and dichloromethane (250.0 mL) were added and extracted. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: methanol = 1: 1) to obtain the title compound (900.0 mg, yield 27.7%).
단계 33-5: tert-부틸 (S)-3-((4-((1-메틸피페리딘-4-일)옥시)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step 33-5: tert-Butyl (S) -3-((4-((1-methylpiperidin-4-yl) oxy) -6-((5-methylthiazol-2-yl) amino) Preparation of Pyridin-2-yl) amino) piperidine-1-carboxylate
Figure PCTKR2019010894-appb-I000099
Figure PCTKR2019010894-appb-I000099
단계 33-4에서 수득한 tert-부틸 (S)-3-((6-클로로-4-((1-메틸피페리딘-4-일)옥시)피리딘-2-일)아미노)피페리딘-1-카르복실레이트(900.0 mg, 1.0 eq)를 1,4-다이옥산(20.0 ml)에 녹인 후에, 팔라듐 아세테이트(0.1 eq), 4,5-비스(디페닐포스피노)-9,9-디메틸잔텐(0.2 eq), 세슘 카보네이트(3.0 eq), 2-아미노-5-메틸티아졸(1.1 eq)을 넣고 마이크로웨이브 반응기에서 반응시켰다(160℃, 2hr). 반응이 완결되면 물(250.0 mL)과 에틸아세테이트(250.0 mL)를 가한 후 추출하였다. 분리된 유기층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:메탄올 = 1:1)로 정제하여 표제 화합물(300.0 mg, 수율 28.3%)을 수득하였다.Tert-butyl (S) -3-((6-chloro-4-((1-methylpiperidin-4-yl) oxy) pyridin-2-yl) amino) piperidine obtained in step 33-4 -1-carboxylate (900.0 mg, 1.0 eq) in 1,4-dioxane (20.0 ml), followed by palladium acetate (0.1 eq), 4,5-bis (diphenylphosphino) -9,9- Dimethyl xantene (0.2 eq), cesium carbonate (3.0 eq) and 2-amino-5-methylthiazole (1.1 eq) were added and reacted in a microwave reactor (160 ° C., 2hr). After the reaction was completed, water (250.0 mL) and ethyl acetate (250.0 mL) were added and extracted. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: methanol = 1: 1) to obtain the title compound (300.0 mg, yield 28.3%).
단계 33-6: (S)-4-((1-메틸피페리딘-4-일)옥시)-NStep 33-6: (S) -4-((1-methylpiperidin-4-yl) oxy) -N 22 -(5-메틸티아졸-2-일)-N-(5-methylthiazol-2-yl) -N 66 -(피페리딘-3-일)피리딘-2,6-다이아민의 제조Preparation of-(piperidin-3-yl) pyridine-2,6-diamine
Figure PCTKR2019010894-appb-I000100
Figure PCTKR2019010894-appb-I000100
단계 33-5에서 수득한 tert-부틸 (S)-3-((4-((1-메틸피페리딘-4-일)옥시)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-카르복실레이트(300.0 mg, 1.0 eq)에 1.25M 염산-메탄올 용액(5.0 mL)을 넣고 50℃에서 12시간 반응시켰다. 반응이 완결되면 반응액을 0℃에서 냉각시킨 후, 중탄산나트륨 포화수용액을 사용하여 pH 8 내지 pH 9로 맞춘 뒤 물(100.0 mL)과 에틸아세테이트(100.0 mL)를 가한 후 추출하였다. 분리된 유기층은 무수황산나트륨상에서 건조한 다음, 감압 농축하여 표제화합물(150.0 mg, 수율 62.5%)을 수득하였다.Tert-butyl (S) -3-((4-((1-methylpiperidin-4-yl) oxy) -6-((5-methylthiazol-2-yl) obtained in step 33-5 Amino) pyridin-2-yl) amino) piperidine-1-carboxylate (300.0 mg, 1.0 eq) was added 1.25M hydrochloric acid-methanol solution (5.0 mL) and reacted at 50 ° C. for 12 hours. When the reaction was completed, the reaction solution was cooled to 0 ℃, adjusted to pH 8 to pH 9 with saturated aqueous sodium bicarbonate, and then extracted with water (100.0 mL) and ethyl acetate (100.0 mL). The separated organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give the title compound (150.0 mg, yield 62.5%).
단계 33-7: (S)-1-(3-((4-((1-메틸피페리딘-4-일)옥시)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Step 33-7: (S) -1- (3-((4-((1-methylpiperidin-4-yl) oxy) -6-((5-methylthiazol-2-yl) amino) Preparation of Pyridin-2-yl) amino) piperidin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000101
Figure PCTKR2019010894-appb-I000101
단계 33-6에서 수득한 (S)-4-((1-메틸피페리딘-4-일)옥시)-N2-(5-메틸티아졸-2-일)-N6-(피페리딘-3-일)피리딘-2,6-다이아민(130.0 mg, 1.0 eq)을 테트라하이드로퓨란(2.4 mL)과 물(0.6 mL)에 녹인 후에, 중탄산나트륨(3.0 eq), 아크릴로일 클로라이드(1.2 eq)를 넣고 실온에서 1시간 반응시켰다. 반응이 완결되면 물(100.0 mL)과 디클로로메탄(100.0 mL)을 가한 후 추출하였다. 분리된 유기층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:메탄올 = 1:1)로 정제하여 표제 화합물(1.0 mg, 수율 0.7%)을 수득하였다.(S) -4-((1-methylpiperidin-4-yl) oxy) -N 2- (5-methylthiazol-2-yl) -N 6- (piperi) obtained in step 33-6 Din-3-yl) pyridine-2,6-diamine (130.0 mg, 1.0 eq) was dissolved in tetrahydrofuran (2.4 mL) and water (0.6 mL), followed by sodium bicarbonate (3.0 eq), acryloyl chloride (1.2 eq) was added and reacted at room temperature for 1 hour. After the reaction was completed, water (100.0 mL) and dichloromethane (100.0 mL) were added and extracted. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: methanol = 1: 1) to obtain the title compound (1.0 mg, yield 0.7%).
1H NMR(500 MHz, CDCl3): 6.99(s, 1H), 6.60-6.65(m, 0.5H), 6.46-6.51(m, 0.5H), 6.32(d, 0.5H), 6.24(d, 0.5H), 5.71(s, 1H), 5.53-5.59(m, 1H), 5.40(d, 2H), 4.46(s, 0.5H), 4.31(s, 2H), 4.29(s, 0.5H), 3.93(d, 1H), 3.86(s, 0.5H), 3.71(s, 0.5H), 3.48(s, 1H), 3.37-3.39(m, 1H), 2.69(s, 2H), 2.34(s, 3H), 2.30(s, 5H), 2.11(s, 1H), 2.00(s, 2H), 1.81(s, 3H), 1.65(s, 2H)1 H NMR (500 MHz, CDCl 3 ): 6.99 (s, 1H), 6.60-6.65 (m, 0.5H), 6.46-6.51 (m, 0.5H), 6.32 (d, 0.5H), 6.24 (d, 0.5 H), 5.71 (s, 1H), 5.53-5.59 (m, 1H), 5.40 (d, 2H), 4.46 (s, 0.5H), 4.31 (s, 2H), 4.29 (s, 0.5H), 3.93 (d, 1H), 3.86 (s, 0.5H), 3.71 (s, 0.5H), 3.48 (s, 1H), 3.37-3.39 (m, 1H), 2.69 (s, 2H), 2.34 (s, 3H ), 2.30 (s, 5H), 2.11 (s, 1H), 2.00 (s, 2H), 1.81 (s, 3H), 1.65 (s, 2H)
실시예 34: (S)-3-(4-((2-((1-아크릴로일피페리딘-3-일)아미노)-6-((5-메틸티아졸-2-일)아미노)피리딘-4-일)메틸)피페라진-1-일)프로판엔니트릴Example 34: (S) -3- (4-((2-((1-acryloylpiperidin-3-yl) amino) -6-((5-methylthiazol-2-yl) amino) Pyridin-4-yl) methyl) piperazin-1-yl) propanenitrile
단계 34-1: 3-(4-((2,6-디클로로피리딘- 4-일)메틸)피페라진-1-일)프로판니트릴Step 34-1: 3- (4-((2,6-dichloropyridin-4-yl) methyl) piperazin-1-yl) propanenitrile
Figure PCTKR2019010894-appb-I000102
Figure PCTKR2019010894-appb-I000102
실시예 1의 단계 1-1 에서 몰포린 대신 3-(피페라진-1-일)프로판니트릴을 사용한 것을 제외하고, 실시예 1의 단계 1-1, 1-2 와 동일한 방법으로 표제 화합물(7.1 g. 수율 57.2%)을 수득하였다.The title compound (7.1 was prepared in the same manner as in Step 1-1, 1-2 of Example 1, except that 3- (piperazin-1-yl) propanenitrile was used instead of morpholine in Step 1-1 of Example 1 g. yield 57.2%).
단계 34-2: t-부틸 (S)-3-((4-((4-(2-시아노에틸)피페라진-1-일)메틸)-6-((5-메틸싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-카복실레이트 의 제조Step 34-2: t-butyl (S) -3-((4-((4- (2-cyanoethyl) piperazin-1-yl) methyl) -6-((5-methylthiazole-2 Preparation of -yl) amino) pyridin-2-yl) amino) piperidine-1-carboxylate
Figure PCTKR2019010894-appb-I000103
Figure PCTKR2019010894-appb-I000103
실시예 1의 단계 1-3 에서 수득한 중간체 대신 단계 34-1에서 수득한 중간체를 사용하고 t-부틸 3-아미노피페리딘-1-카르복실레이트 대신 t-부틸 (S)-3-아미노피페리딘-1-카르복실레이트 를 사용한 것을 제외하고, 실시예 1 의 단계 1-3, 1-4 와 동일한 방법으로 표제 화합물(400. mg. 수율 76.0%)을 수득하였다.Use the intermediate obtained in step 34-1 instead of the intermediate obtained in steps 1-3 of Example 1 and use t-butyl (S) -3-amino instead of t-butyl 3-aminopiperidine-1-carboxylate. The title compound (400. mg. Yield 76.0%) was obtained by the same method as Steps 1-3 and 1-4 of Example 1, except that piperidine-1-carboxylate was used.
단계 34-3: (S)-3-(4-((2-((5-메틸티아졸-2-일)아미노)-6-(피페리딘-3-일아미노)피리딘-4-일)메틸)피페라진-1-일)프로판엔니트릴의 제조Step 34-3: (S) -3- (4-((2-((5-methylthiazol-2-yl) amino) -6- (piperidin-3-ylamino) pyridin-4-yl Preparation of (methyl) piperazin-1-yl) propanenitrile
Figure PCTKR2019010894-appb-I000104
Figure PCTKR2019010894-appb-I000104
단계 34-2로 수득한 tert-부틸 (S)-3-((4-((4-(2-시아노에틸)피페라진-1-일)메틸)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-카복실레이트(100.0 mg, 1.0 eq)를 디클로로메탄(10.0 mL)에 녹인 후에, 실온에서 트리플루오로아세트산(141.5 μL, 10.0 eq)를 가하고 반응물을 실온에서 2시간 동안 반응시켜준다. 2.0M 수산화나트륨 수용액을 사용해서 중성화 시켜준 다음 반응물을 디클로로메탄으로 추출하였다. 분리된 유기층을 무수소듐설페이트상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 갈색 고체상태의 표제화합물 65.0 mg(수율 77.6%)을 얻었다.Tert-butyl (S) -3-((4-((4- (2-cyanoethyl) piperazin-1-yl) methyl) -6-((5-methylthiazole) obtained in step 34-2. -2-yl) amino) pyridin-2-yl) amino) piperidine-1-carboxylate (100.0 mg, 1.0 eq) in dichloromethane (10.0 mL), followed by trifluoroacetic acid (141.5 μL) at room temperature , 10.0 eq) is added and the reaction is allowed to react at room temperature for 2 hours. The solution was neutralized with 2.0 M aqueous sodium hydroxide solution and the reaction was extracted with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography to give 65.0 mg (yield 77.6%) of the title compound as a brown solid.
단계 34-4: (S)-3-(4-((2-((1-아크릴로일피페리딘-3-일)아미노)-6-((5-메틸티아졸-2-일)아미노)피리딘-4-일)메틸)피페라진-1-일)프로판엔니트릴의 제조Step 34-4: (S) -3- (4-((2-((1-acryloylpiperidin-3-yl) amino) -6-((5-methylthiazol-2-yl) amino Preparation of Pyridin-4-yl) methyl) piperazin-1-yl) propanenitrile
Figure PCTKR2019010894-appb-I000105
Figure PCTKR2019010894-appb-I000105
단계 34-3으로 수득한 (S)-3-(4-((2-((5-메틸티아졸-2-일)아미노)-6-(피페리딘-3-일아미노)피리딘-4-일)메틸)피페라진-1-일)프로판엔니트릴(65.0 mg, 1.0 eq)을 테트라하이드로퓨란(5.0 mL)과 물(1.0 mL)에 녹인 후에, 실온에서 탄산수소나트륨(24.8 mg, 2.0 eq)를 가하고, 30분 동안 반응 시켰다. 혼합물에 실온에서 아크릴로일클로라이드(24.0 μL, 2.0 eq)를 가하였다. 반응물을 실온에서 10분 동안 반응시켜준 다음 메탄올을 넣어주고, 물과 에틸 아세테이트로 추출하였다. 분리된 유기층을 무수 소튬설페이트상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 갈색 고체상태의 표제화합물 25.0. mg(수율 34.1%)을 얻었다.(S) -3- (4-((2-((5-methylthiazol-2-yl) amino) -6- (piperidin-3-ylamino) pyridine-4 obtained in step 34-3 -Yl) methyl) piperazin-1-yl) propanenitrile (65.0 mg, 1.0 eq) was dissolved in tetrahydrofuran (5.0 mL) and water (1.0 mL), then sodium hydrogencarbonate (24.8 mg, 2.0 at room temperature). eq) was added and reacted for 30 minutes. To the mixture was added acryloyl chloride (24.0 μL, 2.0 eq) at room temperature. The reaction was allowed to react at room temperature for 10 minutes and then methanol was added and extracted with water and ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography to give the title compound as a brown solid 25.0. mg (yield 34.1%) were obtained.
1H NMR(500 MHz, MeOD): 6.89(d, 1H), 6.84-6.79(m, 1H), 6.55-6.50(m, 1H), 6.20-6.03(m, 2H), 5.47(d, 1H), 4.61(d, 1H), 4.38-4.30(m, 1H), 4.29-4.18(m, 1H), 4.09-3.97 (m, 2H), 3.34 (s, 3H), 2.83 (t, 1H), 2.61-4.24 (m, 14H), 2.19-2.11(m, 1H), 1.97-1.88(m, 1H), 1.71-1.55(m, 1H).1 H NMR (500 MHz, MeOD): 6.89 (d, 1H), 6.84-6.79 (m, 1H), 6.55-6.50 (m, 1H), 6.20-6.03 (m, 2H), 5.47 (d, 1H), 4.61 (d, 1H), 4.38-4.30 (m, 1H), 4.29-4.18 (m, 1H), 4.09-3.97 (m, 2H), 3.34 (s, 3H), 2.83 (t, 1H), 2.61- 4.24 (m, 14 H), 2.19-2.11 (m, 1 H), 1.97-1.88 (m, 1 H), 1.71-1.55 (m, 1 H).
실시예 35: (S)-1-(3-((4-메틸-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 35: (S) -1- (3-((4-methyl-6-((5-methylthiazol-2-yl) amino) pyridin-2-yl) amino) piperidin-1-yl Preparation of Prop-2-en-1-one
Figure PCTKR2019010894-appb-I000106
Figure PCTKR2019010894-appb-I000106
실시예 1의 1-3 단계에서 4-((2,6-디클로로피리딘-4-일)메틸)몰폴린 대신 2,6-디클로로-4-메틸피리딘을 사용한 것을 제외하고 실시예 1과 동일한 방법으로 표제화합물(15 mg, 수율 21%)을 수득하였다.The same method as in Example 1, except that 2,6-dichloro-4-methylpyridine was used instead of 4-((2,6-dichloropyridin-4-yl) methyl) morpholine in steps 1-3 of Example 1. The title compound (15 mg, yield 21%) was obtained.
1H NMR(500 MHz, CDCl3): 6.94-6.98(m, 1H), 6.45-6.50(m, 1H), 6.20-6.25(m, 1H), 5.97-6.00(m, 1H), 5.75-5.85(m, 1H), 5.47-5.51(m, 1H), 4.22-4.40(m, 2H), 3.78-3.96(m, 2H), 3.70-3.72(m, 1H), 3.27-3.40(m, 2H), 2.36(s, 3H), 2.21(s, 3H), 1.85-1.90(m, 1H), 1.75-1.80(m, 1H).1 H NMR (500 MHz, CDCl 3 ): 6.94-6.98 (m, 1 H), 6.45-6.50 (m, 1 H), 6.20-6.25 (m, 1 H), 5.97-6.00 (m, 1H), 5.75-5.85 ( m, 1H), 5.47-5.51 (m, 1H), 4.22-4.40 (m, 2H), 3.78-3.96 (m, 2H), 3.70-3.72 (m, 1H), 3.27-3.40 (m, 2H), 2.36 (s, 3H), 2.21 (s, 3H), 1.85-1.90 (m, 1H), 1.75-1.80 (m, 1H).
실시예 36: (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(피리딘-3-일메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 36: (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (pyridin-3-ylmethyl) pyridin-2-yl) amino) Preparation of Piperidin-1-yl) prop-2-en-1-one
단계 36-1: 2,6-디클로로-4-(피리딘-3-일메틸)피리딘의 제조Step 36-1: Preparation of 2,6-dichloro-4- (pyridin-3-ylmethyl) pyridine
Figure PCTKR2019010894-appb-I000107
Figure PCTKR2019010894-appb-I000107
(2,6-디클로로피리딘-4-일)보론산(0.5 g, 2.6 mmol)을 1,4-디옥산(13 mL)과 물(1.6 mL)에 녹인 후에 3-(브로모메틸)피리딘 브롬화수소(0.7 g, 1.6 mmol), 탄산칼륨(1.8 g, 13.0 mmol), [1,1'-비스(디페닐포스피노)페로세네]디클로로팔라듐(II) (0.1 g, 0.2 mmol)을 차례대로 가한 후 110℃에서 2시간 동안 환류 교반 하였다. 반응이 완결되면 감압 농축한 후 컬럼 크로마토그래피(헥산/에틸아세테이트= 1/1)로 정제하여 표제 화합물(420 mg, 수율 67%)을 수득하였다.(2,6-dichloropyridin-4-yl) boronic acid (0.5 g, 2.6 mmol) was dissolved in 1,4-dioxane (13 mL) and water (1.6 mL), and then 3- (bromomethyl) pyridine brominated Hydrogen (0.7 g, 1.6 mmol), potassium carbonate (1.8 g, 13.0 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.1 g, 0.2 mmol) in that order After the addition, the mixture was stirred under reflux at 110 ° C. for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (hexane / ethyl acetate = 1/1) to obtain the title compound (420 mg, yield 67%).
단계 36-2: tert-부틸 (S)-3-((6-클로로-4-(피리딘-3-일메틸)피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step 36-2: Preparation of tert-butyl (S) -3-((6-chloro-4- (pyridin-3-ylmethyl) pyridin-2-yl) amino) piperidine-1-carboxylate
Figure PCTKR2019010894-appb-I000108
Figure PCTKR2019010894-appb-I000108
단계 36-1에서 수득한 2,6-디클로로-4-(피리딘-3-일메틸)피리딘(1.7 g, 7.1 mmol)을 1,4-디옥산(24 mL)에 녹인 후에 tert-부틸 (S)-3-아미노피페리딘-1-카르복실레이트(1.6 g, 7.8 mmol), 팔라듐 아세테이트(0.2 g, 0.7 mmol), 잔트포스(0.8 g, 1.4 mmol), 탄산나트륨(2.3 g, 21.3 mmol)을 차례대로 가한 후 100℃에서 12시간 동안 환류 교반 하였다. 반응이 완결되면 셀라이트로 여과하고 감압 농축한 후 컬럼 크로마토그래피(에틸아세테이트 100%)로 정제하여 표제화합물(280 mg, 수율 15%)을 수득하였다.2,6-dichloro-4- (pyridin-3-ylmethyl) pyridine (1.7 g, 7.1 mmol) obtained in step 36-1 was dissolved in 1,4-dioxane (24 mL), followed by tert-butyl (S ) -3-aminopiperidine-1-carboxylate (1.6 g, 7.8 mmol), palladium acetate (0.2 g, 0.7 mmol), xantose (0.8 g, 1.4 mmol), sodium carbonate (2.3 g, 21.3 mmol) It was added sequentially and stirred under reflux at 100 ℃ for 12 hours. After the reaction was completed, the mixture was filtered through celite, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate 100%) to obtain the title compound (280 mg, yield 15%).
단계 36-3: tert-부틸 3-((6-((5-메틸티아졸-2-일)아미노)-4-(피리딘-3-일메틸)피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step 36-3: tert-butyl 3-((6-((5-methylthiazol-2-yl) amino) -4- (pyridin-3-ylmethyl) pyridin-2-yl) amino) piperidine Preparation of -1-carboxylate
Figure PCTKR2019010894-appb-I000109
Figure PCTKR2019010894-appb-I000109
단계 36-2에서 수득한 tert-부틸 (S)-3-((6-클로로-4-(피리딘-3-일메틸)피리딘-2-일)아미노)피페리딘-1-카르복실레이트(0.4 g, 2.3 mmol)를 1,4-디옥산(6 mL)에 녹인 후에 5-메틸티아졸-2-아민(0.1 g, 2.6 mmol), 팔라듐 아세테이트(0.02 g, 0.2 mmol), 잔트포스(0.1 g, 0.5 mmol), 세슘 카보네이트(0.9 g, 7.0 mmol)를 차례대로 가한 후 마이크로웨이브 기기로 150℃에서 1시간 동안 반응하였다. 반응이 완결되면 셀라이트로 여과하고 감압 농축한 후 컬럼 크로마토그래피(디클로로메탄/메탄올 = 9/1)로 정제하여 표제화합물(360 mg, 수율 84%)을 수득하였다.Tert-butyl (S) -3-((6-chloro-4- (pyridin-3-ylmethyl) pyridin-2-yl) amino) piperidine-1-carboxylate obtained in step 36-2 ( 0.4 g, 2.3 mmol) in 1,4-dioxane (6 mL), followed by 5-methylthiazol-2-amine (0.1 g, 2.6 mmol), palladium acetate (0.02 g, 0.2 mmol), xantphos ( 0.1 g, 0.5 mmol) and cesium carbonate (0.9 g, 7.0 mmol) were added sequentially, followed by reaction at 150 ° C. for 1 hour using a microwave instrument. After the reaction was completed, the mixture was filtered through celite, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 9/1) to obtain the title compound (360 mg, yield 84%).
단계 36-4: NStep 36-4: N 22 -(5-메틸티아졸-2-일)-N-(5-methylthiazol-2-yl) -N 66 -(피페리딘-3-일)-4-(피리딘-3-일메틸)피리딘-2,6-디아민의 제조Preparation of-(piperidin-3-yl) -4- (pyridin-3-ylmethyl) pyridine-2,6-diamine
Figure PCTKR2019010894-appb-I000110
Figure PCTKR2019010894-appb-I000110
단계 36-3에서 수득한 tert-부틸 3-((6-((5-메틸티아졸-2-일)아미노)-4-(피리딘-3-일메틸)피리딘-2-일)아미노)피페리딘-1-카르복실레이트(0.2 g, 0.3 mmol)를 디클로로메탄(2 mL)에 녹인 후에 트리플루오로 아세트산(0.5 mL, 6.6 mmol)을 가하고 20℃에서 2시간 교반하였다. 반응이 완결되면 1N 수산화나트륨 용액을 가하여 pH 7로 조절하고 에틸 아세테이트로 희석하여 브라인으로 세척하였다. 유기층을 모아 무수 황산나트륨으로 건조 여과하고 감압 농축하여 표제화합물(180 mg, 수율 100%)을 수득하였다.Tert-butyl 3-((6-((5-methylthiazol-2-yl) amino) -4- (pyridin-3-ylmethyl) pyridin-2-yl) amino) pi obtained in step 36-3 Ferridine-1-carboxylate (0.2 g, 0.3 mmol) was dissolved in dichloromethane (2 mL), trifluoro acetic acid (0.5 mL, 6.6 mmol) was added, and the mixture was stirred at 20 ° C for 2 hours. Upon completion of the reaction, 1N sodium hydroxide solution was added to adjust pH to 7, diluted with ethyl acetate, and washed with brine. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (180 mg, yield 100%).
단계 36-5: (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(피리딘-3-일메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Step 36-5: (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (pyridin-3-ylmethyl) pyridin-2-yl) amino Preparation of Piperidin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000111
Figure PCTKR2019010894-appb-I000111
단계 36-4에서 수득한 N2-(5-메틸티아졸-2-일)-N6-(피페리딘-3-일)-4-(피리딘-3-일메틸)피리딘-2,6-디아민(0.2 g, 0.4 mmol)를 테트라하이드로퓨란(6 mL)와 물(2 mL)에 녹인 후에 0℃로 냉각하고 중탄산나트륨(0.1 g, 1.1 mmol)을 가하였다. 아크릴로일 클로라이드(0.05 mL, 0.6 mmol)를 반응액에 천천히 가한 후 0℃에서 10분간 교반 하였다. 반응이 완결되면 에틸아세테이트로 희석한 후 브라인으로 세척하고 감압 농축하고 컬럼 크로마토그래피(디클로로메탄/메탄올 = 9/1)로 정제하여 표제화합물(19 mg, 수율 25%)를 수득하였다.N 2- (5-methylthiazol-2-yl) -N 6- (piperidin-3-yl) -4- (pyridin-3-ylmethyl) pyridine-2,6 obtained in step 36-4 Diamine (0.2 g, 0.4 mmol) was dissolved in tetrahydrofuran (6 mL) and water (2 mL), cooled to 0 ° C. and sodium bicarbonate (0.1 g, 1.1 mmol) was added. Acryloyl chloride (0.05 mL, 0.6 mmol) was slowly added to the reaction solution, followed by stirring at 0 ° C. for 10 minutes. Upon completion of the reaction, the mixture was diluted with ethyl acetate, washed with brine, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 9/1) to obtain the title compound (19 mg, yield 25%).
1H NMR(500 MHz, CDCl3): 8.49(m, 2H), 7.45-7.48(m, 1H), 7.20-7.25(m, 1H), 6.78(s, 1H), 6.40-6.59(m, 1H), 6.18-6.30(m, 1H), 5.50-5.85(m, 3H), 4.34-4.48(m, 1H), 4.15-4.30(m, 2H), 4.85-4.89(m, 1H), 3.83(s 2H), 3.31-3.70(m, 3H), 2.32(s, 3H), 2.10-2.15(m, 1H), 1.80-1.85(m, 1H). 1 H NMR (500 MHz, CDCl 3 ): 8.49 (m, 2H), 7.45-7.48 (m, 1H), 7.20-7.25 (m, 1H), 6.78 (s, 1H), 6.40-6.59 (m, 1H ), 6.18-6.30 (m, 1H), 5.50-5.85 (m, 3H), 4.34-4.48 (m, 1H), 4.15-4.30 (m, 2H), 4.85-4.89 (m, 1H), 3.83 (s 2H), 3.31-3.70 (m, 3H), 2.32 (s, 3H), 2.10-2.15 (m, 1H), 1.80-1.85 (m, 1H).
실시예 37: (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(피리딘-2-일메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 37: (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (pyridin-2-ylmethyl) pyridin-2-yl) amino) Preparation of Piperidin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000112
Figure PCTKR2019010894-appb-I000112
실시예 36 의 36-1 단계에서 3-(브로모메틸)피리딘 브롬화수소 대신 2-(브로모메틸)피리딘 브롬화수소를 사용한 것을 제외하고는 실시예 36과 동일한 방법으로 표제화합물(11 mg, 수율 22%)을 수득하였다.The title compound (11 mg, yield) in the same manner as in Example 36, except that 2- (bromomethyl) pyridine hydrogen bromide was used instead of 3- (bromomethyl) pyridine hydrogen bromide in step 36-1 of Example 36 22%) was obtained.
1H NMR(500 MHz, CDCl3): 8.55(m, 1H), 7.59-7.61(m, 1H), 7.27-7.35(m, 2H), 6.90-6.95(s, 1H), 6.45-6.55(m, 1H), 6.20-6.25(m, 1H), 5.95-6.00(m, 1H), 5.85-5.90(m, 1H), 5.42-5.48(m, 1H), 4.18-4.30(m, 2H), 3.92(s, 2H), 3.85-3.90(m, 1H), 3.35-3.40(m, 2H), 2.37(s, 3H), 2.01-2.10(m, 1H), 1.85-1.90(m, 1H). 1 H NMR (500 MHz, CDCl 3 ): 8.55 (m, 1H), 7.59-7.61 (m, 1H), 7.27-7.35 (m, 2H), 6.90-6.95 (s, 1H), 6.45-6.55 (m , 1H), 6.20-6.25 (m, 1H), 5.95-6.00 (m, 1H), 5.85-5.90 (m, 1H), 5.42-5.48 (m, 1H), 4.18-4.30 (m, 2H), 3.92 (s, 2H), 3.85-3.90 (m, 1H), 3.35-3.40 (m, 2H), 2.37 (s, 3H), 2.01-2.10 (m, 1H), 1.85-1.90 (m, 1H).
실시예 38: (S)-2-((1-아크릴로일피페리딘-3-일)아미노)-6-((5-메틸티아졸-2-일)아미노)이소니코티노니트릴의 제조Example 38 Preparation of (S) -2-((1-acryloylpiperidin-3-yl) amino) -6-((5-methylthiazol-2-yl) amino) isonicotinonitrile
Figure PCTKR2019010894-appb-I000113
Figure PCTKR2019010894-appb-I000113
실시예 1의 1-3 단계에서 4-((2,6-디클로로피리딘-4-일)메틸)몰폴린 대신 2,6-디클로로이소니코티노니트릴을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 표제화합물(11 mg, 수율 22%)을 수득하였다.Same as Example 1, except that 2,6-dichloroisonicotinonitrile was used instead of 4-((2,6-dichloropyridin-4-yl) methyl) morpholine in steps 1-3 of Example 1 The title compound (11 mg, yield 22%) was obtained by the method.
1H NMR(500 MHz, CDCl3): 6.95-7.02(m, 1H), 6.20-6.45(m, 3H), 5.50-5.75(m, 1H), 4.95-5.05(m, 1H), 4.17-4.28(m, 1H), 3.80-4.10(m, 1H), 3.50-3.78(m, 3H), 2.37(s, 3H), 2.10-2.15(m, 1H), 1.80-1.87(m, 1H). 1 H NMR (500 MHz, CDCl 3 ): 6.95-7.02 (m, 1 H), 6.20-6.45 (m, 3 H), 5.50-5.75 (m, 1 H), 4.95-5.05 (m, 1 H), 4.17-4.28 (m, 1H), 3.80-4.10 (m, 1H), 3.50-3.78 (m, 3H), 2.37 (s, 3H), 2.10-2.15 (m, 1H), 1.80-1.87 (m, 1H).
실시예 39: (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-페닐피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 39: (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4-phenylpyridin-2-yl) amino) piperidin-1-yl Preparation of Prop-2-en-1-one
Figure PCTKR2019010894-appb-I000114
Figure PCTKR2019010894-appb-I000114
실시예 1의 1-3 단계에서 4-((2,6-디클로로피리딘-4-일)메틸)몰폴린 대신 2,6-디클로로-4-페닐피리딘을 사용한 것을 제외하고는, 실시예 1과 동일한 방법으로 표제화합물(10 mg, 수율 22%)을 수득하였다.Example 1 except that 2,6-dichloro-4-phenylpyridine was used instead of 4-((2,6-dichloropyridin-4-yl) methyl) morpholine in steps 1-3 of Example 1. In the same manner the title compound (10 mg, yield 22%) was obtained.
1H NMR(500 MHz, CDCl3): 7.52-7.60(m, 2H), 7.35-7.50(m, 3H), 6.95-7.02(s,1H), 6.42-6.50(m, 1H), 6.17-6.37(m, 3H), 5.42-5.50(m, 1H), 4.42-4.50(m, 1H), 4.28-4.33(m, 1H), 3.89-3.95(m, 1H), 3.33-3.50(m, 2H), 2.30(s, 3H), 2.05-2.15(m, 2H),1.81-1.90(m, 2H). 1 H NMR (500 MHz, CDCl 3 ): 7.52-7.60 (m, 2H), 7.35-7.50 (m, 3H), 6.95-7.02 (s, 1H), 6.42-6.50 (m, 1H), 6.17-6.37 (m, 3H), 5.42-5.50 (m, 1H), 4.42-4.50 (m, 1H), 4.28-4.33 (m, 1H), 3.89-3.95 (m, 1H), 3.33-3.50 (m, 2H) , 2.30 (s, 3H), 2.05-2.15 (m, 2H), 1.81-1.90 (m, 2H).
실시예 40: (S)-1-(3-((4-((1-메틸피페리딘-4-일)옥시)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-인-1-온Example 40: (S) -1- (3-((4-((1-methylpiperidin-4-yl) oxy) -6-((5-methylthiazol-2-yl) amino) pyridine -2-yl) amino) piperidin-1-yl) prop-2-yn-1-one
Figure PCTKR2019010894-appb-I000115
Figure PCTKR2019010894-appb-I000115
실시예 33의 33-7 단계에서 아크릴로일 클로라이드 대신 프로피올로일클로라이드를 사용한 것을 제외하고, 실시예 33과 동일한 방법으로 표제화합물(10.0 mg, 수율 8.9%)을 수득하였다.The title compound (10.0 mg, yield 8.9%) was obtained by the same method as Example 33, except for using propioloyl chloride instead of acryloyl chloride in steps 33-7 of Example 33.
1H NMR(500 MHz, CDCl3): 7.40(s, 1H), 6.97(s, 1H), 5.74(d, 1H), 5.55(d, 1H), 4.31-4.40(m, 2H), 4.16-4.21(m, 1H), 4.24(d, 1H), 3.82-3.87(m, 1H), 2.67(s, 2H), 2.35(t, 3H), 2.30(s, 6H), 1.94-1.99(m, 3H), 1.83-1.89(m, 4H), 1.65-1.74(m, 3H)1 H NMR (500 MHz, CDCl 3 ): 7.40 (s, 1 H), 6.97 (s, 1 H), 5.74 (d, 1 H), 5.55 (d, 1 H), 4.31-4.40 (m, 2H), 4.16-4.21 (m, 1H), 4.24 (d, 1H), 3.82-3.87 (m, 1H), 2.67 (s, 2H), 2.35 (t, 3H), 2.30 (s, 6H), 1.94-1.99 (m, 3H ), 1.83-1.89 (m, 4H), 1.65-1.74 (m, 3H)
실시예 41: (S)-1-(3-((4-((1-메틸피페리딘-4-일)옥시)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)부트-2-인-1-온Example 41: (S) -1- (3-((4-((1-methylpiperidin-4-yl) oxy) -6-((5-methylthiazol-2-yl) amino) pyridine -2-yl) amino) piperidin-1-yl) but-2-yn-1-one
Figure PCTKR2019010894-appb-I000116
Figure PCTKR2019010894-appb-I000116
실시예 33의 33-7 단계에서 아크릴로일 클로라이드 대신 부트-2-인오일클로라이드를 사용한 것을 제외하고 실시예 33과 동일한 방법으로 표제화합물(40.0 mg, 수율 34.4%)을 수득하였다.The title compound (40.0 mg, yield 34.4%) was obtained by the same method as Example 33, except that boot-2-inoyl chloride was used instead of acryloyl chloride in steps 33-7 of Example 33.
1H NMR(500 MHz, CDCl3): 10.4(s, 1H), 6.99(s, 1H), 5.73(s, 0.5H), 5.71(s, 0.5H), 5.55(d, 0.5H), 5.53(d, 0.5H), 4.35-4.49(m, 1H), 4.28-4.29(m, 1H), 4.24(d, 1H), 3.82-3.86(m, 1H), 3.33-3.47(m, 2H), 2.70(s, 2H), 2.38(d, 3H), 2.30(s, 3H), 2.21-2.26(m, 3H), 2.09-2.13(m, 1H), 2.00(s, 2H), 1.80-1.83(m, 2H), 1.78(s, 3H), 1.61-1.67(m, 2H)1 H NMR (500 MHz, CDCl 3 ): 10.4 (s, 1H), 6.99 (s, 1H), 5.73 (s, 0.5H), 5.71 (s, 0.5H), 5.55 (d, 0.5H), 5.53 ( d, 0.5H), 4.35-4.49 (m, 1H), 4.28-4.29 (m, 1H), 4.24 (d, 1H), 3.82-3.86 (m, 1H), 3.33-3.47 (m, 2H), 2.70 (s, 2H), 2.38 (d, 3H), 2.30 (s, 3H), 2.21-2.26 (m, 3H), 2.09-2.13 (m, 1H), 2.00 (s, 2H), 1.80-1.83 (m , 2H), 1.78 (s, 3H), 1.61-1.67 (m, 2H)
실시예 42: (S)-1-(3-((4-((4-에틸피페라진-1-일)메틸)-6-((5-메틸티아졸l-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 42: (S) -1- (3-((4-((4-ethylpiperazin-1-yl) methyl) -6-((5-methylthiazoll-2-yl) amino) pyridine Preparation of -2-yl) amino) piperidin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000117
Figure PCTKR2019010894-appb-I000117
실시예 22의 단계 22-1에서 1-브로모-2-메톡시에탄 대신 아이오도에탄을 사용한 것을 제외하고, 실시예 22와 동일한 방법으로 표제 화합물(50.0 mg. 수율 25.0%)을 수득하였다.The title compound (50.0 mg. Yield 25.0%) was obtained by the same method as Example 22, except for using iodoethane instead of 1-bromo-2-methoxyethane in Step 22-1 of Example 22.
1H NMR(500 MHz, MeOH): 6.89-6.88(m, 1H), 6.85-6.45(m, 1H), 6.20-6.02(m, 3H), 5.80(m, 0.5H), 5.45(m, 0.5H), 4.60(m, 0.5H), 4.4-4.2(m, 1H), 4.15-4.00(1.5H), 3.40(s, 2H), 2.82-2.80(m, 2H), 2.50(m, 7H), 2.40(m, 2H), 2.27(s, 3H), 2.20-2.10(m, 1H), 1.92-1.80(m, 1H), 1.66-1.59(m, 3H), 1.10-1.07(t, 3H)1 H NMR (500 MHz, MeOH): 6.89-6.88 (m, 1H), 6.85-6.45 (m, 1H), 6.20-6.02 (m, 3H), 5.80 (m, 0.5H), 5.45 (m, 0.5H ), 4.60 (m, 0.5H), 4.4-4.2 (m, 1H), 4.15-4.00 (1.5H), 3.40 (s, 2H), 2.82-2.80 (m, 2H), 2.50 (m, 7H), 2.40 (m, 2H), 2.27 (s, 3H), 2.20-2.10 (m, 1H), 1.92-1.80 (m, 1H), 1.66-1.59 (m, 3H), 1.10-1.07 (t, 3H)
실시예 43: (S)-1-(3-((4-((4-메틸피페라진-1-일)메틸)-6-((5-메틸티아졸l-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 43: (S) -1- (3-((4-((4-methylpiperazin-1-yl) methyl) -6-((5-methylthiazoll-2-yl) amino) pyridine Preparation of -2-yl) amino) piperidin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000118
Figure PCTKR2019010894-appb-I000118
실시예 22의 단계 22-1에서 1-브로모-2-메톡시에탄 대신 아이오도메탄을 사용한 것을 제외하고, 실시예 22와 동일한 방법으로 표제 화합물(61.0 mg. 수율 21.0%)을 수득하였다.The title compound (61.0 mg. Yield 21.0%) was obtained in the same manner as in Example 22, except that iodomethane was used instead of 1-bromo-2-methoxyethane in Step 22-1 of Example 22.
1H NMR(500 MHz, DMSO): 10.53-10.49(m, 1H), 6.91(m, 1H), 6.80-6.70(m, 0.5H), 6.54-6.46(m, 1.5H), 6.07-5.95(m, 3H), 5.65-5.63(m, 0.5H), 5.42-5.40(m, 0.5H), 4.40-4.50(m, 0.5H), 4.20-4.00(m, 1H), 3.90-3.87(m, 1.5H), 3.26(s, 2H), 3.12-3.08(m, 1H), 2.66-2.61(m, 0.5H), 2.41-2.31(m, 4H), 2.19(s, 3H), 2.13(s, 3H), 2.06-1.97(m, 3H), 1.81(m, 1.5H) 1.81(m, 1H), 1.54-1.44(m, 2H)1 H NMR (500 MHz, DMSO): 10.53-10.49 (m, 1H), 6.91 (m, 1H), 6.80-6.70 (m, 0.5H), 6.54-6.46 (m, 1.5H), 6.07-5.95 (m , 3H), 5.65-5.63 (m, 0.5H), 5.42-5.40 (m, 0.5H), 4.40-4.50 (m, 0.5H), 4.20-4.00 (m, 1H), 3.90-3.87 (m, 1.5 H), 3.26 (s, 2H), 3.12-3.08 (m, 1H), 2.66-2.61 (m, 0.5H), 2.41-2.31 (m, 4H), 2.19 (s, 3H), 2.13 (s, 3H ), 2.06-1.97 (m, 3H), 1.81 (m, 1.5H) 1.81 (m, 1H), 1.54-1.44 (m, 2H)
실시예 44: 5-메틸-N-(6-메틸-4-(몰포리노메틸)피리딘-2-일)티아졸-2-아민의 제조Example 44 Preparation of 5-methyl-N- (6-methyl-4- (morpholinomethyl) pyridin-2-yl) thiazol-2-amine
단계 44-1: 4-((2-클로로-6-메틸피리딘-4-일)메틸)몰포린의 제조Step 44-1: Preparation of 4-((2-chloro-6-methylpyridin-4-yl) methyl) morpholine
Figure PCTKR2019010894-appb-I000119
Figure PCTKR2019010894-appb-I000119
실시예 1의 단계 1-1에서 2,6-디클로로이소니코틴산 대신 2-클로로-6-메틸이소니코틴산을 사용한 것을 제외하고 단계 1-1과 동일한 방법으로 표제 화합물(112.0 mg. 수율 46%)을 수득하였다.The title compound (112.0 mg. Yield 46%) was prepared in the same manner as in Step 1-1 except for using 2-chloro-6-methylisonicotinic acid instead of 2,6-dichloroisonicotinic acid in Step 1-1 of Example 1 Obtained.
단계 44-2: 5-메틸-N-(6-메틸-4-(몰포리노메틸)피리딘-2-일)티아졸-2-아민의 제조Step 44-2: Preparation of 5-methyl-N- (6-methyl-4- (morpholinomethyl) pyridin-2-yl) thiazol-2-amine
Figure PCTKR2019010894-appb-I000120
Figure PCTKR2019010894-appb-I000120
단계 44-1에서 얻은 중간체를 이용하여 실시예 1의 단계 1-2와 동일한 방법으로 표제 화합물(55.0 mg. 수율 54%)을 수득하였다.Using the intermediate obtained in step 44-1, the title compound (55.0 mg. Yield 54%) was obtained by the same method as Step 1-2 of Example 1.
1H NMR(500 MHz, CDCl3): 7.10(s, 1H), 6.72(s, 1H), 6.67(s, 1H), 3.74-3.73(m, 4H), 3.43(s, 2H), 2.51(s, 3H), 2.46(m, 4H), 2.41(s, 3H)1 H NMR (500 MHz, CDCl 3 ): 7.10 (s, 1H), 6.72 (s, 1H), 6.67 (s, 1H), 3.74-3.73 (m, 4H), 3.43 (s, 2H), 2.51 (s , 3H), 2.46 (m, 4H), 2.41 (s, 3H)
실시예 45: (S)-3-클로로-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로판-1-온 의 제조Example 45: (S) -3-chloro-1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino Preparation of 1) piperidin-1-yl) propan-1-one
단계 45-1: (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 염산염의 제조Step 45-1: (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pi Preparation of Hydrochloride of Ferridin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000121
Figure PCTKR2019010894-appb-I000121
실시예 5 물질인 (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온 10.0 g을 에틸아세테이트 200.0ml 에 용해한 후, 에틸아세테이트에 용해되어 있는 1N-염산 3당량을 가하였다. 실온에서 1시간 교반하고 여과 후, 실온에서 12시간 감압 건조하여 (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 염산염 (11.6 g. 수율 85%) 을 수득하였다.Example 5 Material (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pi After dissolving 10.0 g of ferridin-1-yl) prop-2-en-1-one in 200.0 ml of ethyl acetate, 3 equivalents of 1N hydrochloric acid dissolved in ethyl acetate was added. Stirred at room temperature for 1 hour, filtered, and dried under reduced pressure at room temperature for 12 hours to give (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholino) Hydrochloride (11.6 g. Yield 85%) of methyl) pyridin-2-yl) amino) piperidin-1-yl) prop-2-en-1-one was obtained.
단계 45-2: (S)-3-클로로-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로판-1-온 의 제조Step 45-2: (S) -3-chloro-1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) Preparation of Amino) piperidin-1-yl) propan-1-one
Figure PCTKR2019010894-appb-I000122
Figure PCTKR2019010894-appb-I000122
단계 45-1 에서 얻은 물질을 -20℃ 에서 7개월 보관하였다. 보관 과정에서 생성된 물질을 메틸렌클로라이드와 메탄올 15:1 혼합용매로 컬럼분리하여 표제 화합물(30.0 mg. 수율 5%)을 수득하였다.The material obtained in step 45-1 was stored at -20 ° C for 7 months. The material produced during the storage was column separated with a 15: 1 mixed solvent of methylene chloride and methanol to obtain the title compound (30.0 mg. Yield 5%).
1H NMR(500 MHz, CDCl3): 7.03-7.0(d, 1H), 6.17-6.12(d, 1H), 5.98(s, 1H), 4.38-4.30(m, 1H), 4.20-4.11(m, 2H), 3.88-3.86(m, 1H), 3.75-3.70(m, 4H), 3.68-3.56(m, 1H), 3.43-3.39(m, 1H), 3.34(s, 2H), 2.91-2.80(m, 1H), 2.80-2.71(m, 1H), 2.62-2.45(m, 1H), 2.37(m, 4H), 2.12(s, 3H), 2.12-2.11(m, 1H), 2.10-2.12(m, 1H), 1.90-1.80(m, 2H)1 H NMR (500 MHz, CDCl 3 ): 7.03-7.0 (d, 1H), 6.17-6.12 (d, 1H), 5.98 (s, 1H), 4.38-4.30 (m, 1H), 4.20-4.11 (m, 2H), 3.88-3.86 (m, 1H), 3.75-3.70 (m, 4H), 3.68-3.56 (m, 1H), 3.43-3.39 (m, 1H), 3.34 (s, 2H), 2.91-2.80 ( m, 1H), 2.80-2.71 (m, 1H), 2.62-2.45 (m, 1H), 2.37 (m, 4H), 2.12 (s, 3H), 2.12-2.11 (m, 1H), 2.10-2.12 ( m, 1H), 1.90-1.80 (m, 2H)
실시예 46: (S,E)-3-클로로-1-(3-(6-(5-메틸티아졸-2-일아미노)-4-(몰폴리노메틸)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온 제조Example 46: (S, E) -3-chloro-1- (3- (6- (5-methylthiazol-2-ylamino) -4- (morpholinomethyl) pyridin-2-ylamino) Preparation of piperidin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000123
Figure PCTKR2019010894-appb-I000123
단계 45-1 에서 얻은 물질을 -20℃ 에서 7개월 보관하였다. 보관 과정에서 생성된 물질을 메틸렌클로라이드와 메탄올 15:1 혼합용매로 컬럼분리하여 표제 화합물(3.0 mg, 수율 0.5%)을 수득하였다.The material obtained in step 45-1 was stored at -20 ° C for 7 months. The material produced during the storage was subjected to column separation with a 15: 1 mixed solvent of methylene chloride and methanol to obtain the title compound (3.0 mg, yield 0.5%).
1H NMR(500 MHz, CDCl3): 6.99(s, 1H), 6.70-6.60(m, 1H), 6.4-6.2(m, 2H), 5.8-5.5(m, 1H), 3.9-3.8(m, 2H), 3.8-3.7(m, 4H), 3.6-3.7(m, 1H), 3.49(s, 2H), 3.39-3.41(m, 2H), 2.52(m, 4H), 2.33(s, 3H), 1.85-1.82(m, 2H), 1.68-1.60(m, 2H)1 H NMR (500 MHz, CDCl 3 ): 6.99 (s, 1 H), 6.70-6.60 (m, 1 H), 6.4-6.2 (m, 2 H), 5.8-5.5 (m, 1 H), 3.9-3.8 (m, 2H), 3.8-3.7 (m, 4H), 3.6-3.7 (m, 1H), 3.49 (s, 2H), 3.39-3.41 (m, 2H), 2.52 (m, 4H), 2.33 (s, 3H) , 1.85-1.82 (m, 2H), 1.68-1.60 (m, 2H)
실시예 47: (S)-1-(3-(4-((4-(3-아미노프로필)피페라진-1-일)메틸)-6-(5-메틸티아졸-2-일아미노)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 47: (S) -1- (3- (4-((4- (3-aminopropyl) piperazin-1-yl) methyl) -6- (5-methylthiazol-2-ylamino) Preparation of Pyridin-2-ylamino) piperidin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000124
Figure PCTKR2019010894-appb-I000124
실시예 34의 물질 (S)-3-(4-((2-((1-아크릴로일피페리딘-3-일)아미노)-6-((5-메틸티아졸-2-일)아미노)피리딘-4-일)메틸)피페라진-1-일)프로판엔니트릴 (35.0 mg, 1.0 eq)을 메탄올(5.0 mL) 에 녹인 후에, 실온에서 팔라듐/카본 10%를 가하고, 5분 동안 반응 시켰다. 이후 셀라이트를 이용하여 메탄올로 필터하였다. 분리된 용액를 감압농축시킨 뒤 컬럼크로마토그래피로 정제하여 갈색 고체상태의 표제화합물(4.0 mg, 수율 12.1%)을 얻었다.Example (S) -3- (4-((2-((1-acryloylpiperidin-3-yl) amino) -6-((5-methylthiazol-2-yl) amino Pyridin-4-yl) methyl) piperazin-1-yl) propanenitrile (35.0 mg, 1.0 eq) was dissolved in methanol (5.0 mL), followed by addition of 10% palladium / carbon at room temperature and reaction for 5 minutes. I was. Then filtered with methanol using celite. The separated solution was concentrated under reduced pressure and purified by column chromatography to obtain the title compound (4.0 mg, yield 12.1%) as a brown solid.
1H NMR(500 MHz, MeOD): 6.57(s, 1H), 6.53-6.50(m, 1.5H), 6.08-5.98(m, 2.5H), 5.67-5.61(m, 0.5H), 5.42-5.38(m, 0.5H), 4.48-4.29(m, 0.5H), 4.20-4.06(m, 1H), 3.98-3.90(m, 1.5H), 3.29(s, 2H), 3.17-3.11(m, 1H), 2.65-2.62(m, 2.5H), 2.40-2.36(m, 6H), 2.23(s, 3H), 2.06-1.99(m, 3H), 1.80-1.79(m, 2.5H), 1,77(m, 2H) 1.54-1.40(m, 2H)1 H NMR (500 MHz, MeOD): 6.57 (s, 1 H), 6.53-6.50 (m, 1.5 H), 6.08-5.98 (m, 2.5 H), 5.67-5.61 (m, 0.5H), 5.42-5.38 ( m, 0.5H), 4.48-4.29 (m, 0.5H), 4.20-4.06 (m, 1H), 3.98-3.90 (m, 1.5H), 3.29 (s, 2H), 3.17-3.11 (m, 1H) , 2.65-2.62 (m, 2.5H), 2.40-2.36 (m, 6H), 2.23 (s, 3H), 2.06-1.99 (m, 3H), 1.80-1.79 (m, 2.5H), 1,77 ( m, 2H) 1.54-1.40 (m, 2H)
실시예 48: (S)-1-(3-(6-(1H-피라졸-3-일아미노)-4-(몰폴리노메틸)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 48: (S) -1- (3- (6- (1H-pyrazol-3-ylamino) -4- (morpholinomethyl) pyridin-2-ylamino) piperidin-1-yl Preparation of Prop-2-en-1-one
단계 48-1: tert-부틸 (S)-3-((6-((1H-피라졸-3-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-카복실레이트의 제조Step 48-1: tert-butyl (S) -3-((6-((1H-pyrazol-3-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperi Preparation of Dean-1 -carboxylate
Figure PCTKR2019010894-appb-I000125
Figure PCTKR2019010894-appb-I000125
(S)-tert-부틸 3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-카복실레이트 (41.0 mg, 1.0 eq)을 1,4-다이옥산(2.0 mL)에 용해한 후, 트리스(디벤질리덴아세톤)디팔라듐(0)(9.2 mg, 0.1 eq), (±)-2,2'비스(디페닐포스피노)-1,1'-비나프탈렌 (12.5 mg, 0.2 eq)를 투입하였다. 1H-피라졸-3-아민 (8.3 mg, 1.0 eq)을 가한 후, 세슘카보네이트(97.7 mg, 3.0 eq)를 차례로 가하였다. 마이크로웨이브 반응기에서 130℃, 30분 반응시켰다 30℃ 이하로 냉각한 후, 물(10.0 mL)와 에틸아세테이트(10.0 mL)를 가한 후, 층분리하였다. 에틸아세테이트층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:1)로 정제하여 표제 화합물(50.2 mg, 수율 99.8 %)를 수득하였다.(S) -tert-butyl 3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidine-1- Carboxylate (41.0 mg, 1.0 eq) was dissolved in 1,4-dioxane (2.0 mL), then tris (dibenzylideneacetone) dipalladium (0) (9.2 mg, 0.1 eq), (±) -2,2 'Bis (diphenylphosphino) -1,1'-binaphthalene (12.5 mg, 0.2 eq) was added. 1H-pyrazol-3-amine (8.3 mg, 1.0 eq) was added followed by cesium carbonate (97.7 mg, 3.0 eq) in turn. The reaction was carried out at 130 ° C. for 30 minutes in a microwave reactor. After cooling to 30 ° C. or less, water (10.0 mL) and ethyl acetate (10.0 mL) were added and the layers were separated. The ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (50.2 mg, yield 99.8%).
단계 48-2: (S)-4-(몰폴리노메틸)-NStep 48-2: (S) -4- (morpholinomethyl) -N 22 -(피페리딘-3-일)-N-(Piperidin-3-yl) -N 66 -(1H-피라졸-3-일)피리딘-2,6-디아민의 제조Preparation of-(1H-pyrazol-3-yl) pyridine-2,6-diamine
Figure PCTKR2019010894-appb-I000126
Figure PCTKR2019010894-appb-I000126
단계 48-1에서 수득한 중간체(50.0 mg, 1.0 eq)을 에틸아세테이트(10.0 mL)에 용해한 후, 6N-염산 수용액(0.4 mL, 20.0 eq)을 천천히 적가한 후, 2시간 동안 교반하였다. 12N-수산화나트륨 수용액을 이용하여 pH9~12 로 조절한 후, 분리된 다이클로로메탄층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(다이클로로메탄:메탄올 = 10:1)로 정제하여 표제 화합물(34.2 mg, 수율 87.9 %)를 수득하였다.The intermediate (50.0 mg, 1.0 eq) obtained in step 48-1 was dissolved in ethyl acetate (10.0 mL), and 6N-hydrochloric acid aqueous solution (0.4 mL, 20.0 eq) was slowly added dropwise, followed by stirring for 2 hours. After adjusting to pH 9-12 using 12N-sodium hydroxide aqueous solution, the separated dichloromethane layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to give the title compound (34.2 mg, yield 87.9%).
단계 48-3: (S)-1-(3-(6-(1H-피라졸-3-일아미노)-4-(몰폴리노메틸)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Step 48-3: (S) -1- (3- (6- (1H-pyrazol-3-ylamino) -4- (morpholinomethyl) pyridin-2-ylamino) piperidine-1- (1) Preparation of prop-2-en-1-one
Figure PCTKR2019010894-appb-I000127
Figure PCTKR2019010894-appb-I000127
단계 48-2에서 수득한 중간체(20.0 mg, 1.0 eq)을 테트라하이드로퓨란(2.0 mL)에 용해한 후, 물(1.0 mL)를 가하고 중탄산 나트륨(14.1 mg, 3.0 eq)을 가한 후, 0~10℃ 로 냉각하였다. 아크릴로일 클로라이드(5.6 ㎕. 1.0 eq )를 천천히 적가한 후, 30분 동안 교반하여 반응을 완결시켰다. 다이클로로메탄으로 층분리한 후, 무수황산나트륨상에서 건조하고 감압 농축하였다. 얻어진 잔사는 컬럼 크로마토그래피(다이클로로메탄:메탄올 = 15:1)로 정제하여 표제 화합물(5.7 mg, 수율 15.4%)을 수득하였다.After dissolving the intermediate (20.0 mg, 1.0 eq) obtained in step 48-2 in tetrahydrofuran (2.0 mL), water (1.0 mL) was added and sodium bicarbonate (14.1 mg, 3.0 eq) was added, followed by 0-10 Cool to C. Acryloyl chloride (5.6 μl. 1.0 eq) was slowly added dropwise and then stirred for 30 minutes to complete the reaction. The layers were separated with dichloromethane, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 15: 1) to give the title compound (5.7 mg, yield 15.4%).
1H NMR(500 MHz, MeOD): 7.76 (d, 1H), 6.54(d, 1H), 6.17-6.13(m, 1H), 6.06(s, 2H), 6.02-5.92(m, 1H), 5.50-5.25(m, 1H), 3.83-3.74(m, 4H), 3.64(s, 2H), 2.65-2.27(m, 4H), 2.12-2.07(m, 1H), 1.73(m, 1H), 1.65-1.48(m, 2H), 1.43-1.20(m, 5H)1 H NMR (500 MHz, MeOD): 7.76 (d, 1H), 6.54 (d, 1H), 6.17-6.13 (m, 1H), 6.06 (s, 2H), 6.02-5.92 (m, 1H), 5.50- 5.25 (m, 1H), 3.83-3.74 (m, 4H), 3.64 (s, 2H), 2.65-2.27 (m, 4H), 2.12-2.07 (m, 1H), 1.73 (m, 1H), 1.65- 1.48 (m, 2H), 1.43-1.20 (m, 5H)
실시예 49: (S)-1-(3-(4-(몰폴리노메틸)-6-(5-(트리플루오로메틸)티아졸-2-일아미노)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 49: (S) -1- (3- (4- (morpholinomethyl) -6- (5- (trifluoromethyl) thiazol-2-ylamino) pyridin-2-ylamino) pi Preparation of Ferridin-1-yl) prop-2-en-1-one
단계 49-1: tert-부틸 (S)-3-((4-(몰폴리노메틸)-6-((5-(트리플루오로메틸)티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-카복실레이트의 제조Step 49-1: tert-butyl (S) -3-((4- (morpholinomethyl) -6-((5- (trifluoromethyl) thiazol-2-yl) amino) pyridine-2- I) Preparation of amino) piperidine-1-carboxylate
Figure PCTKR2019010894-appb-I000128
Figure PCTKR2019010894-appb-I000128
(S)-tert-부틸 3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-카복실레이트 (200.0 mg, 1.0 eq)을 1,4-다이옥산(2.0 mL)에 용해한 후, 팔라듐아세테이트(11.9 mg, 0.1 eq), 잔포스(56.7 mg, 0.2 eq)를 투입하였다. 5-(트리플루오로메틸)티아졸-2-아민(81.8 mg, 1.0 eq)을 가한 후, 세슘카보네이트(476.0 mg, 3.0 eq)를 차례로 가하였다. 마이크로웨이브 반응기에서 150℃, 1시간 반응시켰다 30℃ 이하로 냉각한 후, 물(10.0 mL)와 에틸아세테이트(10.0 mL)를 가한 후, 층분리하였다. 에틸아세테이트층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:1)로 정제하여 표제 화합물(68.2 mg, 수율 25.8 %)를 수득하였다.(S) -tert-butyl 3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidine-1- After carboxylate (200.0 mg, 1.0 eq) was dissolved in 1,4-dioxane (2.0 mL), palladium acetate (11.9 mg, 0.1 eq) and xantose (56.7 mg, 0.2 eq) were added thereto. 5- (trifluoromethyl) thiazol-2-amine (81.8 mg, 1.0 eq) was added followed by cesium carbonate (476.0 mg, 3.0 eq). The reaction was carried out in a microwave reactor at 150 ° C. for 1 hour. After cooling to 30 ° C. or less, water (10.0 mL) and ethyl acetate (10.0 mL) were added, and the layers were separated. The ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound (68.2 mg, yield 25.8%).
단계 49-2: (S)-4-(몰폴리노메틸)-NStep 49-2: (S) -4- (morpholinomethyl) -N 22 -(피페리딘-3-일)-N-(Piperidin-3-yl) -N 66 -(5-(트리플루오로메틸)티아졸-2-일)피리딘-2,6-디아민의 제조Preparation of-(5- (trifluoromethyl) thiazol-2-yl) pyridine-2,6-diamine
Figure PCTKR2019010894-appb-I000129
Figure PCTKR2019010894-appb-I000129
단계 48-1에서 수득한 중간체(50.0 mg, 1.0 eq)을 에틸아세테이트(10.0 mL)에 용해한 후, 6N-염산 수용액(0.4 mL, 20.0 eq)을 천천히 적가한 후, 2시간 동안 교반하였다. 12N-수산화나트륨 수용액을 이용하여 pH9~12 로 조절한 후, 분리된 다이클로로메탄층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(다이클로로메탄:메탄올 = 10:1)로 정제하여 표제 화합물(27.0 mg, 수율 44.3 %)를 수득하였다.The intermediate (50.0 mg, 1.0 eq) obtained in step 48-1 was dissolved in ethyl acetate (10.0 mL), and 6N-hydrochloric acid aqueous solution (0.4 mL, 20.0 eq) was slowly added dropwise, followed by stirring for 2 hours. After adjusting to pH 9-12 using 12N-sodium hydroxide aqueous solution, the separated dichloromethane layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to give the title compound (27.0 mg, yield 44.3%).
단계 49-3: (S)-1-(3-(4-(몰폴리노메틸)-6-(5-(트리플루오로메틸)티아졸-2-일아미노)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Step 49-3: (S) -1- (3- (4- (morpholinomethyl) -6- (5- (trifluoromethyl) thiazol-2-ylamino) pyridin-2-ylamino) Preparation of Piperidin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000130
Figure PCTKR2019010894-appb-I000130
단계 49-2에서 수득한 중간체(20.0 mg, 1.0 eq)을 테트라하이드로퓨란(2.0 mL)에 용해한 후, 물(1.0 mL)를 가하고 중탄산 나트륨(17.2 mg, 3.0 eq)을 가한 후, 0~10℃ 로 냉각하였다. 아크릴로일 클로라이드(4.8 ㎕. 1.0 eq )를 천천히 적가한 후, 30분 동안 교반하여 반응을 완결시켰다. 다이클로로메탄으로 층분리한 후, 무수황산나트륨상에서 건조하고 감압 농축하였다. 얻어진 잔사는 컬럼 크로마토그래피(다이클로로메탄:메탄올 = 15:1)로 정제하여 표제 화합물(3.6 mg, 수율 16.0%)을 수득하였다.After dissolving the intermediate (20.0 mg, 1.0 eq) obtained in step 49-2 in tetrahydrofuran (2.0 mL), water (1.0 mL) was added and sodium bicarbonate (17.2 mg, 3.0 eq) was added, followed by 0-10 Cool to C. Acryloyl chloride (4.8 μl. 1.0 eq) was added slowly dropwise and then stirred for 30 minutes to complete the reaction. The layers were separated with dichloromethane, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 15: 1) to give the title compound (3.6 mg, yield 16.0%).
1H NMR(500 MHz, MeOD): 7.66(d, 1H), 6.83-6.72(m, 0.5H), 6.55-6.44(m, 0.5H), 6.23(d, 1H), 6.16(d, 1H), 6.05(d, 0.5H), 5.73(d, 0.5H), 5.48(d, 0.5H), 4.54(d, 0.5H), 4.43-4.14(m, 1H), 4.03-3.93(m, 1.5H), 3.75-3.62(m, 4H), 3.38(s, 2H), 3.27-3.18(m, 1H), 2.86(t, 0.5H), 2.53-2.38(m, 4H), 2.28-2.12(m, 1H), 1.96-1.83(m, 1H), 1.72-1.49(m, 2.5H), 1.38-1.23(m, 1.5H)1 H NMR (500 MHz, MeOD): 7.66 (d, 1H), 6.83-6.72 (m, 0.5H), 6.55-6.44 (m, 0.5H), 6.23 (d, 1H), 6.16 (d, 1H), 6.05 (d, 0.5H), 5.73 (d, 0.5H), 5.48 (d, 0.5H), 4.54 (d, 0.5H), 4.43-4.14 (m, 1H), 4.03-3.93 (m, 1.5H) , 3.75-3.62 (m, 4H), 3.38 (s, 2H), 3.27-3.18 (m, 1H), 2.86 (t, 0.5H), 2.53-2.38 (m, 4H), 2.28-2.12 (m, 1H ), 1.96-1.83 (m, 1H), 1.72-1.49 (m, 2.5H), 1.38-1.23 (m, 1.5H)
실시예 50: (S)-1-(3-(6-(5-클로로-1H-피라졸-3-일아미노)-4-(몰폴리노메틸)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 50: (S) -1- (3- (6- (5-chloro-1H-pyrazol-3-ylamino) -4- (morpholinomethyl) pyridin-2-ylamino) piperidine Preparation of -1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000131
Figure PCTKR2019010894-appb-I000131
단계 48-1에서 1H-피라졸-3-아민 대신 5-클로로-1H-피라졸-3-아민을 사용한 것을시예 제외하고, 실시예 48와 동일한 방법으로 표제 화합물(14.0 mg, 수율 7.7%)을 수득하였다.In the same manner as in Example 48, except that 5-chloro-1H-pyrazol-3-amine was used instead of 1H-pyrazol-3-amine in Step 48-1, the title compound (14.0 mg, yield 7.7%). ) Was obtained.
1H NMR(500 MHz, MeOD): 6.16-6.14(m, 1H), 6.13-6.11(m, 1H), 6.06(s, 2H), 6.03-6.02(m, 1H), 5.52-5.50(m, 1H), 3.73-3.70(m, 4H), 3.62 (s, 2H), 2.60-2.15(m, 4H), 2.32-2.06(m, 1H), 1.72-1.65(m, 1H), 1.65-1.50(m, 2H), 1.44-1.25(m, 5H)1 H NMR (500 MHz, MeOD): 6.16-6.14 (m, 1H), 6.13-6.11 (m, 1H), 6.06 (s, 2H), 6.03-6.02 (m, 1H), 5.52-5.50 (m, 1H ), 3.73-3.70 (m, 4H), 3.62 (s, 2H), 2.60-2.15 (m, 4H), 2.32-2.06 (m, 1H), 1.72-1.65 (m, 1H), 1.65-1.50 (m) , 2H), 1.44-1.25 (m, 5H)
실시예 51: (S)-1-(3-(4-(몰폴리노메틸)-6-(티아졸-2-일아미노)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 51: (S) -1- (3- (4- (morpholinomethyl) -6- (thiazol-2-ylamino) pyridin-2-ylamino) piperidin-1-yl) prop Production of P-2-en-1-one
Figure PCTKR2019010894-appb-I000132
Figure PCTKR2019010894-appb-I000132
단계 49-1에서 5-(트리플루오로메틸)티아졸-2-아민 대신 티아졸-2-아민을 사용한 것을 제외하고, 실시예 49와 동일한 방법으로 표제 화합물(3.2 mg, 수율 21.1%)을 수득하였다.The title compound (3.2 mg, yield 21.1%) was obtained in the same manner as in Example 49, except that thiazol-2-amine was used instead of 5- (trifluoromethyl) thiazol-2-amine in Step 49-1. Obtained.
1H NMR(500 MHz, MeOD): 6.68-6.53(d, 1H), 6.38-6.30(d, 2H), 6.17-6.05(m, 2H), 5,89-5.83(d, 1H), 5.47-5.43(m, 0.5H), 5.37-5.32(m, 0.5H), 3.94-3.87(m, 1H), 3.80-3.66(m, 2H), 3.63-3.48(m, 2H), 2.58-2.16(m, 4H), 2.08-1.73(m, 4H), 1.65-1.55(m, 2H), 1.41-1.33(m, 4H)1 H NMR (500 MHz, MeOD): 6.68-6.53 (d, 1H), 6.38-6.30 (d, 2H), 6.17-6.05 (m, 2H), 5,89-5.83 (d, 1H), 5.47-5.43 (m, 0.5H), 5.37-5.32 (m, 0.5H), 3.94-3.87 (m, 1H), 3.80-3.66 (m, 2H), 3.63-3.48 (m, 2H), 2.58-2.16 (m, 4H), 2.08-1.73 (m, 4H), 1.65-1.55 (m, 2H), 1.41-1.33 (m, 4H)
실시예 52: (S)-1-(3-(3-플루오로-6-(5-메틸티아졸-2-일아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 52: (S) -1- (3- (3-fluoro-6- (5-methylthiazol-2-ylamino) -4- (morpholinomethyl) pyridin-2-yl) amino) Preparation of Piperidin-1-yl) prop-2-en-1-one
단계 52-1: (2,6-디클로로-3-플루오로피리딘-4-일)(몰폴리노)메타논의 제조Step 52-1: Preparation of (2,6-dichloro-3-fluoropyridin-4-yl) (morpholino) methanone
Figure PCTKR2019010894-appb-I000133
Figure PCTKR2019010894-appb-I000133
2,6-디클로로-3-플루오로니코틴산 (500.0 mg, 1.0 eq)을 테트라하이드로퓨란(15.0 mL)에 용해한 후, 1,1-카보닐디이미다졸(463.3 mg, 1.2 eq)을 가하였다. 질소 가스 하에서 1시간 실온(25 ~ 30℃)교반한 후, 몰폴린(0.2 mL, 1.2 eq)을 가하고 2시간 동일 온도에서 교반하여 반응을 완결시켰다. 에틸 아세테이트(50.0 mL)와 물(50.0 mL)을 가하여 추출하고 물층을 에틸 아세테이트(50.0 mL)를 이용해서 3회 재추출하였다. 에틸 아세테이트층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:5)로 정제하여 표제 화합물(581.0 mg, 87.5 %)을 수득하였다.2,6-dichloro-3-fluoronicotinic acid (500.0 mg, 1.0 eq) was dissolved in tetrahydrofuran (15.0 mL) and then 1,1-carbonyldiimidazole (463.3 mg, 1.2 eq) was added. After stirring for 1 hour at room temperature (25-30 ° C.) under nitrogen gas, morpholine (0.2 mL, 1.2 eq) was added and stirred at the same temperature for 2 hours to complete the reaction. Ethyl acetate (50.0 mL) and water (50.0 mL) were added for extraction, and the water layer was reextracted three times with ethyl acetate (50.0 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1: 5) to give the title compound (581.0 mg, 87.5%).
단계 52-2: 4-((2,6-디클로로-3-플루오로피리딘-4-일)메틸)몰폴린의 제조Step 52-2: Preparation of 4-((2,6-dichloro-3-fluoropyridin-4-yl) methyl) morpholine
Figure PCTKR2019010894-appb-I000134
Figure PCTKR2019010894-appb-I000134
단계 52-1에서 수득한 중간체(500.0 mg, 1.0 eq)를 디클로로메탄(20.0 mL)에 용해한 후, 실온(25 ~ 30℃)교반하였다. 0.9M 보란-테트로하이드로퓨란(6.0 mL, 3.0 eq)를 천천히 적가하였다. 실온에서 12 시간 교반하여 반응을 완결시켰다. 반응액을 0 ~ 10℃ 로 냉각한 후, 6N-염산 수용액을(39.0 mL, 20.0 eq)천천히 적가한 후, 같은 온도에서 1시간 교반하였다. 6N-수산화나트륨 수용액을 이용하여 pH 9 내지 pH 12 로 조절한 후, 디클로로메탄으로 2회 추출하였다. 디클로로메탄층은 분리하여 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:1)로 정제하여 표제 화합물(430.2 mg, 수율 85.9 %)을 수득하였다.The intermediate (500.0 mg, 1.0 eq) obtained in step 52-1 was dissolved in dichloromethane (20.0 mL) and then stirred at room temperature (25-30 ° C.). 0.9 M borane-tetrohydrofuran (6.0 mL, 3.0 eq) was added slowly dropwise. The reaction was completed by stirring at room temperature for 12 hours. After cooling the reaction solution to 0-10 degreeC, 6N hydrochloric acid aqueous solution (39.0 mL, 20.0eq) was slowly added dropwise, and the mixture was stirred at the same temperature for 1 hour. The mixture was adjusted to pH 9 to pH 12 using 6N aqueous sodium hydroxide solution, and then extracted twice with dichloromethane. The dichloromethane layer was separated, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (430.2 mg, yield 85.9%).
단계 52-3: tert-부틸 (S)-3-((6-클로로-3-플루오로-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-카복실레이트의 제조Step 52-3: tert-butyl (S) -3-((6-chloro-3-fluoro-4- (morpholinomethyl) pyridin-2-yl) amino) piperidine-1-carboxylate Produce
Figure PCTKR2019010894-appb-I000135
Figure PCTKR2019010894-appb-I000135
단계 52-2에서 수득한 중간체(100.0 mg, 1.0 eq)에 1,4-다이옥산(2.0 mL)을 가하여 용해한 후, 팔라듐 아세테이트(9.3 mg, 0.1 eq), 잔포스(43.4 mg, 0.2 eq)를 투입하였다. tert-부틸 (S)-3-아미노피페리딘-1-카르복실레이트(75.5 mg, 1.0 eq)을 가한 후, 세슘카보네이트(325.8 mg, 3.0 eq)를 차례로 가하였다. 마이크로웨이브 반응기에서 140℃, 30분 반응시켰다. 30℃ 이하로 냉각한 후, 물(10.0 mL)와 에틸아세테이트(10.0 mL)를 가한 후, 층분리하였다. 에틸아세테이트층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:1)로 정제하여 표제 화합물(144.0 mg, 수율 89.4 %)을 수득하였다.1,4-dioxane (2.0 mL) was dissolved in the intermediate (100.0 mg, 1.0 eq) obtained in step 52-2, followed by palladium acetate (9.3 mg, 0.1 eq) and xanthose (43.4 mg, 0.2 eq). Input. tert-butyl (S) -3-aminopiperidine-1-carboxylate (75.5 mg, 1.0 eq) was added followed by cesium carbonate (325.8 mg, 3.0 eq). The reaction was performed at 140 ° C. for 30 minutes in a microwave reactor. After cooling to 30 ° C. or less, water (10.0 mL) and ethyl acetate (10.0 mL) were added, and the layers were separated. The ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (144.0 mg, yield 89.4%).
단계 52-4: tert-부틸 (S)-3-((3-플루오로-6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-카르복실레이트의 제조Step 52-4: tert-Butyl (S) -3-((3-fluoro-6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridine-2- I) Preparation of amino) piperidine-1-carboxylate
Figure PCTKR2019010894-appb-I000136
Figure PCTKR2019010894-appb-I000136
단계 52-3에서 수득한 중간체(100.0 mg, 1.0 eq)을 1,4-다이옥산(2.0 mL)에 용해하였다. 팔라듐아세테이트(5.1 mg, 0.1 eq), 잔포스(24.3 mg, 0.2 eq), 5-메틸싸이아노-2-아민(24.0 mg, 1.0 eq), 세슘카보네이트(205.8 g, 3.0 eq)를 차례로 가하였다. 마이크로웨이브 반응기에서 150℃, 30분 반응시켰다. 30℃ 이하로 냉각한 후, 물(10.0 mL)와 에틸아세테이트(10.0 mL)를 가한 후, 층분리하였다. 에틸아세테이트층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(에틸아세테이트:헥산 = 1:1)로 정제하여 표제 화합물(86.2 mg, 수율 81.8 %)을 수득하였다.The intermediate (100.0 mg, 1.0 eq) obtained in step 52-3 was dissolved in 1,4-dioxane (2.0 mL). Palladium acetate (5.1 mg, 0.1 eq), xantose (24.3 mg, 0.2 eq), 5-methylthiano-2-amine (24.0 mg, 1.0 eq), cesium carbonate (205.8 g, 3.0 eq) were added in this order. . The reaction was performed at 150 ° C. for 30 minutes in a microwave reactor. After cooling to 30 ° C. or less, water (10.0 mL) and ethyl acetate (10.0 mL) were added, and the layers were separated. The ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (86.2 mg, yield 81.8%).
단계 52-5: (S)-3-플루오로-NStep 52-5: (S) -3-fluoro-N 66 -(5-메틸티아졸-2-일)-4-(몰폴리노메틸)-N-(5-methylthiazol-2-yl) -4- (morpholinomethyl) -N 22 -(피페리딘-3-일)피리딘-2,6-디아민의 제조Preparation of-(piperidin-3-yl) pyridine-2,6-diamine
Figure PCTKR2019010894-appb-I000137
Figure PCTKR2019010894-appb-I000137
단계 52-4에서 수득한 중간체(80.0 mg, 1.0 eq)을 에틸아세테이트(10.0 mL)에 용해한 후, 6N-염산 수용액(0.6 mL, 20.0 eq)을 천천히 적가한 후, 2시간 동안 교반하였다. 12N-수산화나트륨 수용액을 이용하여 pH9~12 로 조절한 후, 분리된 다이클로로메탄층은 무수황산나트륨상에서 건조한 다음, 감압 농축하였다. 얻어진 잔사에 에틸아테세이트(10.0 mL)를 가하여 30분 동안 결정을 생성시켰다. 결정은 여과한 후, 건조하여 표제 화합물(60.5 mg. 수율 99.9 %)를 수득하였다.The intermediate (80.0 mg, 1.0 eq) obtained in step 52-4 was dissolved in ethyl acetate (10.0 mL), and 6N-hydrochloric acid aqueous solution (0.6 mL, 20.0 eq) was slowly added dropwise, followed by stirring for 2 hours. After adjusting to pH 9-12 using 12N-sodium hydroxide aqueous solution, the separated dichloromethane layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Ethyl acetate (10.0 mL) was added to the obtained residue to form crystals for 30 minutes. The crystals were filtered off and dried to afford the title compound (60.5 mg. Yield 99.9%).
단계 52-6: (S)-1-(3-(3-플루오로-6-(5-메틸티아졸-2-일아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Step 52-6: (S) -1- (3- (3-fluoro-6- (5-methylthiazol-2-ylamino) -4- (morpholinomethyl) pyridin-2-yl) amino Preparation of Piperidin-1-yl) prop-2-en-1-one
Figure PCTKR2019010894-appb-I000138
Figure PCTKR2019010894-appb-I000138
단계 52-5에서 수득한 중간체(50.0 mg, 1.0 eq)을 테트라하이드로퓨란(4.0 mL)에 용해한 후, 물(1.0 mL)를 가하고 중탄산 나트륨(31.0 mg, 3.0 eq)을 가한 후, 0~10℃ 로 냉각하였다. 아크릴로일 클로라이드(9.9 ㎕. 1.0 eq )를 천천히 적가한 후, 30분 동안 교반하여 반응을 완결시켰다. 다이클로로메탄으로 층분리한 후, 무수황산나트륨상에서 건조하고 감압 농축하였다. 얻어진 잔사는 컬럼 크로마토그래피(다이클로로메탄:메탄올 = 15:1)로 정제하여 표제 화합물(26.5 mg, 수율 46.8%)을 수득하였다.After dissolving the intermediate (50.0 mg, 1.0 eq) obtained in step 52-5 in tetrahydrofuran (4.0 mL), water (1.0 mL) was added and sodium bicarbonate (31.0 mg, 3.0 eq) was added, followed by 0-10 Cool to C. Acryloyl chloride (9.9 μl. 1.0 eq) was slowly added dropwise and then stirred for 30 minutes to complete the reaction. The layers were separated with dichloromethane, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 15: 1) to give the title compound (26.5 mg, yield 46.8%).
1H NMR(500 MHz, MeOD): 6.88-6.80(m, 1H), 6.65(m, 1H), 6.21-6.15(m, 1 H), 5.68(d, 1H), 5.37-5.28(m, 1H), 3.72-3.65(m, 4H), 3.53-3.48(s, 3H), 2.76-2.69(m, 2H), 2.52-2.42(m, 4H), 2.28-2.14 (m, 3H), 2.12-1.98(m, 2H), 1.66-1.53(m, 4H)1 H NMR (500 MHz, MeOD): 6.88-6.80 (m, 1H), 6.65 (m, 1H), 6.21-6.15 (m, 1H), 5.68 (d, 1H), 5.37-5.28 (m, 1H) , 3.72-3.65 (m, 4H), 3.53-3.48 (s, 3H), 2.76-2.69 (m, 2H), 2.52-2.42 (m, 4H), 2.28-2.14 (m, 3H), 2.12-1.98 ( m, 2H), 1.66-1.53 (m, 4H)
실시예 53: (S)-1-(3-(4-(몰폴리노메틸)-6-(피리딘-2-일아미노)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 53: (S) -1- (3- (4- (morpholinomethyl) -6- (pyridin-2-ylamino) pyridin-2-ylamino) piperidin-1-yl) prop Preparation of 2-en-1-one
Figure PCTKR2019010894-appb-I000139
Figure PCTKR2019010894-appb-I000139
단계 48-1에서 1H-피라졸-3-아민 대신 피리딘-2-아민을 사용한 것을 제외하고, 실시예 48와 동일한 방법으로 표제 화합물(11.0 mg, 수율 31.0%)을 수득하였다.The title compound (11.0 mg, yield 31.0%) was obtained in the same manner as in Example 48, except that pyridin-2-amine was used instead of 1H-pyrazol-3-amine in step 48-1.
1H NMR(500 MHz, MeOD): 8.50-8.45(t, 2H), 7.51(d, 1H), 6.80-6.75(m, 1H), 6.70-6.62(m, 0.5H), 6.24-6.16(m, 1.5H), 6.14-6.08(d, 0.5H), 5.77-5.51(m, 0.5H), 4.03-3.92 (m, 1H), 3.91-3.77(m, 2H), 3.74-3.65(m, 4H), 3.42-3.37(m, 3H), 3.26-3.18(m, 0.5H), 2.81-2.74(m, 0.5H), 2.54-2.40(m, 4H), 2.12-1.98(m, 1H), 1.89-1.81(m, 1H)1 H NMR (500 MHz, MeOD): 8.50-8.45 (t, 2H), 7.51 (d, 1H), 6.80-6.75 (m, 1H), 6.70-6.62 (m, 0.5H), 6.24-6.16 (m, 1.5H), 6.14-6.08 (d, 0.5H), 5.77-5.51 (m, 0.5H), 4.03-3.92 (m, 1H), 3.91-3.77 (m, 2H), 3.74-3.65 (m, 4H) , 3.42-3.37 (m, 3H), 3.26-3.18 (m, 0.5H), 2.81-2.74 (m, 0.5H), 2.54-2.40 (m, 4H), 2.12-1.98 (m, 1H), 1.89- 1.81 (m, 1 H)
실시예 54: (S)-1-(3-(4-(몰폴리노메틸)-6-(피리미딘-2-일아미노)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온의 제조Example 54: (S) -1- (3- (4- (morpholinomethyl) -6- (pyrimidin-2-ylamino) pyridin-2-ylamino) piperidin-1-yl) prop Production of P-2-en-1-one
Figure PCTKR2019010894-appb-I000140
Figure PCTKR2019010894-appb-I000140
단계 48-1에서 1H-피라졸-3-아민 대신 피리미딘-2-아민을 사용한 것을 제외하고, 실시예 1와 동일한 방법으로 표제 화합물(24.2mg, 24.3%)을 수득하였다.The title compound (24.2 mg, 24.3%) was obtained by the same method as Example 1 except for using pyrimidin-2-amine instead of 1H-pyrazol-3-amine in step 48-1.
1H NMR(500 MHz, MeOD): 8.15-8.10(m, 1H), 7.80(d, 1H), 7.62-7.56(m, 1H), 6.86-6.80 (m, 1H), 6.58-6.45(m, 1.5H), 6.24-6.19(m, 0.5H), 6.09(m, 1H), 6.06-6.00(m, 0.5H), 5.79-5.73(m, 0.5H), 4.01-3.80 (m. 4H) 3.73-3.65(m, 4H), 3.36(s, 2H), 2.52-2.41(m, 4H), 2.14-2.304(m, 1H), 1.94-1.86 (m, 2H), 1.73-1.56(m, 2H)1 H NMR (500 MHz, MeOD): 8.15-8.10 (m, 1H), 7.80 (d, 1H), 7.62-7.56 (m, 1H), 6.86-6.80 (m, 1H), 6.58-6.45 (m, 1.5 H), 6.24-6.19 (m, 0.5H), 6.09 (m, 1H), 6.06-6.00 (m, 0.5H), 5.79-5.73 (m, 0.5H), 4.01-3.80 (m. 4H) 3.73- 3.65 (m, 4H), 3.36 (s, 2H), 2.52-2.41 (m, 4H), 2.14-2.304 (m, 1H), 1.94-1.86 (m, 2H), 1.73-1.56 (m, 2H)
실험예: BTK 및 ITK에 대한 저해 활성Experimental Example: Inhibitory Activity against BTK and ITK
상기 실시예에서 제조된 화합물의 BTK 및 ITK에 대한 저해 활성을 다음과 같이 측정하였다.Inhibitory activity of BTK and ITK of the compound prepared in Example was measured as follows.
BTK에 대한 저해활성 평가는 Promega사의 'ADP-GloTM + BTK Kinase enzyme system' kit를 사용하여 평가하였다. White 96-well plate에서 최종농도가 1 ng/㎕이 되도록 준비한 BTK 효소 10 ㎕와 화합물의 단일 농도 평가일 경우 최종농도가 1 uM, IC50 평가일 경우 1000, 300, 100, 30, 10, 3, 1, 0.3, 0.1, 0.03 nM 농도의 화합물 5 ㎕를 섞은 뒤 상온에서 15분 반응시켰다. 반응이 끝난 plate에 substrate 5 ㎕와 최종 농도가 10 uM이 되도록 준비한 ATP 5 ㎕를 넣은 뒤, 30℃에서 1시간 반응시켰다. 반응이 끝난 plate의 모든 well에 ADP-GloTM reagent를 25 ㎕ 처리하여 30℃에서 40분 반응시켰다. 그 뒤, 모든 well에 kinase detection buffer를 50 ㎕ 처리한 뒤, 빛을 차단하여 30℃에서 30분 반응시켰다. 모든 반응이 끝난 plate는 luminescence를 측정하여 결과를 산출하였다. 평가는 duplicate로 진행하였으며, 화합물의 처리 없이 효소의 첨가 여부에 따라 negative control과 positive control을 산출하여, 그 값을 기준으로 IC50을 계산하였다.Evaluation of inhibitory activity against BTK was evaluated using Promega's 'ADP-Glo ™ + BTK Kinase enzyme system' kit. 10 μl of BTK enzyme prepared at a final concentration of 1 ng / μl in a white 96-well plate and a final concentration of 1 uM for compound concentration evaluation, 1000, 300, 100, 30, 10, 3 for an IC 50 assessment , 1, 0.3, 0.1, 0.03 nM 5μl compound was mixed and reacted at room temperature for 15 minutes. 5 μl of substrate and 5 μl of ATP prepared to have a final concentration of 10 uM were added to the reaction plate, followed by reaction at 30 ° C. for 1 hour. 25 μl of ADP-Glo ™ reagent was added to all wells of the reaction plate and reacted at 30 ° C. for 40 minutes. Thereafter, 50 μl of kinase detection buffer was applied to all the wells, and the reaction was blocked at 30 ° C. for 30 minutes. All reaction plates were measured by luminescence and the results were calculated. Evaluation was done in duplicate, and the negative control and positive control were calculated according to the addition of enzyme without treatment of the compound, and IC 50 was calculated based on the value.
ITK에 대한 저해활성 평가는 Promega사의 'ADP-GloTM + ITK Kinase enzyme system' kit를 사용하여 평가하였다. White 96-well plate에서 최종농도가 0.4 ng/㎕가 되도록 준비한 ITK 효소 10 ㎕와 단일 농도 평가일 경우 최종농도가 1 uM, IC50 평가일 경우 1000, 300, 100, 30, 10, 3, 1, 0.3, 0.1, 0.03 nM 농도의 화합물 5 ㎕를 섞은 뒤 상온에서 15분 반응시켰다. 반응이 끝난 plate에 substrate 5 ㎕와 최종 농도가 25 uM이 되도록 준비한 ATP 5 ㎕를 넣은 뒤, 30℃에서 1시간 반응시켰다. 반응이 끝난 plate의 모든 well에 ADP-GloTM reagent를 25 ㎕ 처리하여 30에서 40분 반응시켰다. 그 뒤, 모든 well에 kinase detection buffer를 50 ㎕ 처리한 뒤, 빛을 차단하여 30℃에서 30분 반응시켰다. 모든 반응이 끝난 plate는 luminescence를 측정하여 결과를 산출하였다. 평가는 duplicate로 진행하였으며, 화합물의 처리 없이 효소의 첨가 여부에 따라 negative control과 positive control을 산출하여, 그 값을 기준으로 IC50을 계산하였다. 상기 결과를 하기 표 1에 나타내었다.Evaluation of inhibitory activity against ITK was evaluated using Promega's 'ADP-Glo TM + ITK Kinase enzyme system' kit. 10 μl of ITK enzyme prepared in a white 96-well plate to a final concentration of 0.4 ng / μl and final concentration of 1 uM for single concentration evaluation, 1000, 300, 100, 30, 10, 3, 1 for IC 50 evaluation , 0.3, 0.1, 0.03 nM 5μl compound was mixed and reacted at room temperature for 15 minutes. 5 μl of substrate and 5 μl of ATP prepared to have a final concentration of 25 uM were added to the reaction plate, followed by reaction at 30 ° C. for 1 hour. 25 ㎕ ADP-Glo TM reagent was added to all wells of the reaction plate and reacted for 30 to 40 minutes. Thereafter, 50 μl of kinase detection buffer was applied to all the wells, and the reaction was blocked at 30 ° C. for 30 minutes. All reaction plates were measured by luminescence and the results were calculated. Evaluation was done in duplicate, and the negative control and positive control were calculated according to the addition of enzyme without treatment of the compound, and IC 50 was calculated based on the value. The results are shown in Table 1 below.
Figure PCTKR2019010894-appb-T000001
Figure PCTKR2019010894-appb-T000001

Claims (14)

  1. 하기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염:A compound represented by Formula 1, or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2019010894-appb-I000142
    Figure PCTKR2019010894-appb-I000142
    상기 화학식 1에서,In Chemical Formula 1,
    B는 N, O 및 S로 구성되는 군으로부터 각각 독립적으로 선택되는 헤테로원자를 1개 내지 3개 포함하는 5원 또는 6원 헤테로고리이고, 단 상기 5원 또는 6원 헤테로고리는 N을 적어도 하나 포함하고,B is a 5 or 6 membered heterocycle containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, provided that the 5 or 6 membered heterocycle is at least one Including,
    R1은 수소, 할로겐, C1-4 알킬, 또는 C1-4 할로알킬이고,R 1 is hydrogen, halogen, C 1-4 alkyl, or C 1-4 haloalkyl,
    X1 및 X2는 각각 독립적으로, N, 또는 CR'이고,X 1 and X 2 are each independently N or CR ′,
    여기서, R'는 수소, 또는 할로겐이고,Where R 'is hydrogen or halogen,
    L은 결합, C1-4 알킬렌, 또는 -O-이고,L is a bond, C 1-4 alkylene, or —O—,
    R2는 시아노; C1-4 알킬; C6-10 아릴; 피리디닐; 몰폴리노; 피페라지닐; 또는 피페리디닐이고,R 2 is cyano; C 1-4 alkyl; C 6-10 aryl; Pyridinyl; Morpholino; Piperazinyl; Or piperidinyl,
    여기서, 상기 피페라지닐 및 피페리디닐은 각각 독립적으로, 비치환되거나, 또는 C1-4 알킬, 시아노로 치환된 C1-4 알킬, 아미노로 치환된 C1-4 알킬, C1-4 알콕시로 치환된 C1-4 알킬, 또는 -CO-(C1-4 알킬)로 치환되고,Wherein said piperazinyl and piperidinyl are each independently, unsubstituted or C 1-4 alkyl, a cyano C 1-4 alkyl, C 1-4 substituted with a substituted C 1-4 alkyl, amino Substituted with C 1-4 alkyl substituted with alkoxy, or —CO— (C 1-4 alkyl),
    Y는 결합, -O-, -NH-, 또는 -N(C1-4 알킬)-이고,Y is a bond, -O-, -NH-, or -N (C 1-4 alkyl)-,
    A는 C1-4 알킬,
    Figure PCTKR2019010894-appb-I000143
    ,
    Figure PCTKR2019010894-appb-I000144
    ,
    Figure PCTKR2019010894-appb-I000145
    ,
    Figure PCTKR2019010894-appb-I000146
    ,
    Figure PCTKR2019010894-appb-I000147
    , 또는
    Figure PCTKR2019010894-appb-I000148
    이고,    A is C 1-4 alkyl,
    Figure PCTKR2019010894-appb-I000143
    ,
    Figure PCTKR2019010894-appb-I000144
    ,
    Figure PCTKR2019010894-appb-I000145
    ,
    Figure PCTKR2019010894-appb-I000146
    ,
    Figure PCTKR2019010894-appb-I000147
    , or
    Figure PCTKR2019010894-appb-I000148
    ego,
    여기서, R3는 C1-4 알킬, C1-4 할로알킬, C2-4 알케닐, C2-4 할로알케닐, C2-4 알키닐, 또는 C2-4 할로알키닐이다.Wherein R 3 is C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, or C 2-4 haloalkynyl.
  2. 제1항에 있어서,The method of claim 1,
    B는 티아졸, 피라졸, 피리딘, 또는 피리미딘 고리이고,B is a thiazole, pyrazole, pyridine, or pyrimidine ring,
    R1은 수소, 클로로, 메틸, 또는 트리플루오로메틸인,R 1 is hydrogen, chloro, methyl, or trifluoromethyl,
    화합물, 또는 이의 약학적으로 허용가능한 염.Compound, or a pharmaceutically acceptable salt thereof.
  3. 제1항에 있어서,The method of claim 1,
    X1 및 X2는 모두 CH이거나,X 1 and X 2 are both CH,
    X1 및 X2 중 하나는 CF이고, 다른 하나는 CH이거나, 또는One of X 1 and X 2 is CF and the other is CH, or
    X1 및 X2 중 하나는 N이고, 다른 하나는 CH인,One of X 1 and X 2 is N and the other is CH,
    화합물, 또는 이의 약학적으로 허용가능한 염.Compound, or a pharmaceutically acceptable salt thereof.
  4. 제1항에 있어서,The method of claim 1,
    L은 결합, 메틸렌, 또는 -O-인,L is a bond, methylene, or -O-,
    화합물, 또는 이의 약학적으로 허용가능한 염.Compound, or a pharmaceutically acceptable salt thereof.
  5. 제1항에 있어서,The method of claim 1,
    R2는 시아노; 메틸; 페닐; 피리디닐; 몰폴리노; 메틸로 치환된 피페라지닐; 에틸로 치환된 피페라지닐; 2-시아노에틸로 치환된 피페라지닐; 3-아미노프로필로 치환된 피페라지닐; 2-메톡시에틸로 치환된 피페라지닐; -CO-(메틸)로 치환된 피페라지닐; 비치환된 피페리디닐; 또는 메틸로 치환된 피페리디닐인,R 2 is cyano; methyl; Phenyl; Pyridinyl; Morpholino; Piperazinyl substituted with methyl; Piperazinyl substituted with ethyl; Piperazinyl substituted with 2-cyanoethyl; Piperazinyl substituted with 3-aminopropyl; Piperazinyl substituted with 2-methoxyethyl; Piperazinyl substituted with -CO- (methyl); Unsubstituted piperidinyl; Or piperidinyl substituted with methyl,
    화합물, 또는 이의 약학적으로 허용가능한 염.Compound, or a pharmaceutically acceptable salt thereof.
  6. 제1항에 있어서,The method of claim 1,
    Y는 결합, -O-, -NH-, 또는 -N(메틸)-인,Y is a bond, -O-, -NH-, or -N (methyl)-,
    화합물, 또는 이의 약학적으로 허용가능한 염.Compound, or a pharmaceutically acceptable salt thereof.
  7. 제1항에 있어서,The method of claim 1,
    R3는 -CH2CH2Cl, -CH=CH2, -CH=CHCH3, -CH=CHCl, -C≡CH, 또는 -C≡CCH3인,R 3 is -CH 2 CH 2 Cl, -CH = CH 2, -CH = CHCH 3, -CH = CHCl, -C≡CH, -C≡CCH 3, or phosphorus,
    화합물, 또는 이의 약학적으로 허용가능한 염.Compound, or a pharmaceutically acceptable salt thereof.
  8. 제1항에 있어서,The method of claim 1,
    상기 화학식 1은 하기 화학식 1-1로 표시되는,Formula 1 is represented by the following formula 1-1,
    화합물, 또는 이의 약학적으로 허용가능한 염:Compound, or pharmaceutically acceptable salt thereof:
    [화학식 1-1][Formula 1-1]
    Figure PCTKR2019010894-appb-I000149
    Figure PCTKR2019010894-appb-I000149
    상기 화학식 1-1에서,In Chemical Formula 1-1,
    R1은 수소, C1-4 알킬, 또는 C1-4 할로알킬이고,R 1 is hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl,
    X1 및 X2는 각각 독립적으로, N, 또는 CR'이고,X 1 and X 2 are each independently N or CR ′,
    여기서, R'는 수소, 또는 할로겐이고,Where R 'is hydrogen or halogen,
    L은 결합, C1-4 알킬렌, 또는 -O-이고,L is a bond, C 1-4 alkylene, or —O—,
    R2는 시아노; C1-4 알킬; C6-10 아릴; 피리디닐; 몰폴리노; 피페라지닐; 또는 피페리디닐이고,R 2 is cyano; C 1-4 alkyl; C 6-10 aryl; Pyridinyl; Morpholino; Piperazinyl; Or piperidinyl,
    여기서, 상기 피페라지닐 및 피페리디닐은 각각 독립적으로, 비치환되거나, 또는 C1-4 알킬, 시아노로 치환된 C1-4 알킬, 아미노로 치환된 C1-4 알킬, C1-4 알콕시로 치환된 C1-4 알킬, 또는 -CO-(C1-4 알킬)로 치환되고,Wherein said piperazinyl and piperidinyl are each independently, unsubstituted or C 1-4 alkyl, a cyano C 1-4 alkyl, C 1-4 substituted with a substituted C 1-4 alkyl, amino Substituted with C 1-4 alkyl substituted with alkoxy, or —CO— (C 1-4 alkyl),
    Y는 결합, -O-, -NH-, 또는 -N(C1-4 알킬)-이고,Y is a bond, -O-, -NH-, or -N (C 1-4 alkyl)-,
    A는 C1-4 알킬,
    Figure PCTKR2019010894-appb-I000150
    ,
    Figure PCTKR2019010894-appb-I000151
    ,
    Figure PCTKR2019010894-appb-I000152
    ,
    Figure PCTKR2019010894-appb-I000153
    ,
    Figure PCTKR2019010894-appb-I000154
    , 또는
    Figure PCTKR2019010894-appb-I000155
    이고,    A is C 1-4 alkyl,
    Figure PCTKR2019010894-appb-I000150
    ,
    Figure PCTKR2019010894-appb-I000151
    ,
    Figure PCTKR2019010894-appb-I000152
    ,
    Figure PCTKR2019010894-appb-I000153
    ,
    Figure PCTKR2019010894-appb-I000154
    , or
    Figure PCTKR2019010894-appb-I000155
    ego,
    여기서, R3는 C1-4 할로알킬, C2-4 알케닐, C2-4 할로알케닐, 또는 C2-4 알키닐이다.Wherein R 3 is C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, or C 2-4 alkynyl.
  9. 제8항에 있어서,The method of claim 8,
    R1은 C1-4 알킬이고,R 1 is C 1-4 alkyl,
    X1 및 X2는 각각 독립적으로, N 또는 CH이고,X 1 and X 2 are each independently N or CH,
    L은 결합, C1-4 알킬렌, 또는 -O-이고,L is a bond, C 1-4 alkylene, or —O—,
    R2는 시아노; C1-4 알킬; C6-10 아릴; 피리디닐; 몰폴리노; 피페라지닐; 또는 피페리디닐이고,R 2 is cyano; C 1-4 alkyl; C 6-10 aryl; Pyridinyl; Morpholino; Piperazinyl; Or piperidinyl,
    여기서, 상기 피페라지닐 및 피페리디닐은 각각 독립적으로, 비치환되거나, 또는 C1-4 알킬, 시아노로 치환된 C1-4 알킬, C1-4 알콕시로 치환된 C1-4 알킬, 또는 -CO-(C1-4 알킬)로 치환되고,Wherein said piperazinyl and piperidinyl are each independently, unsubstituted or C 1-4 alkyl, cyano substituted C 1-4 substituted alkyl, C 1-4 alkoxy C 1-4 alkyl, Or substituted with -CO- (Ci_ 4 alkyl),
    Y는 결합, -O-, -NH-, 또는 -N(C1-4 알킬)-이고,Y is a bond, -O-, -NH-, or -N (C 1-4 alkyl)-,
    A는
    Figure PCTKR2019010894-appb-I000156
    ,
    Figure PCTKR2019010894-appb-I000157
    ,
    Figure PCTKR2019010894-appb-I000158
    ,
    Figure PCTKR2019010894-appb-I000159
    ,
    Figure PCTKR2019010894-appb-I000160
    , 또는
    Figure PCTKR2019010894-appb-I000161
    이고,    A is
    Figure PCTKR2019010894-appb-I000156
    ,
    Figure PCTKR2019010894-appb-I000157
    ,
    Figure PCTKR2019010894-appb-I000158
    ,
    Figure PCTKR2019010894-appb-I000159
    ,
    Figure PCTKR2019010894-appb-I000160
    , or
    Figure PCTKR2019010894-appb-I000161
    ego,
    여기서, R3는 C2-4 알케닐, 또는 C2-4 알키닐이다.Wherein R 3 is C 2-4 alkenyl, or C 2-4 alkynyl.
  10. 제1항에 있어서,The method of claim 1,
    상기 화학식 1은 하기 화학식 1-2로 표시되는,Formula 1 is represented by the following formula 1-2,
    화합물, 또는 이의 약학적으로 허용가능한 염:Compound, or pharmaceutically acceptable salt thereof:
    [화학식 1-2][Formula 1-2]
    Figure PCTKR2019010894-appb-I000162
    Figure PCTKR2019010894-appb-I000162
    상기 화학식 1-2에서,In Chemical Formula 1-2,
    R1은 수소, 또는 할로겐이고,R 1 is hydrogen or halogen,
    X1 및 X2는 각각 독립적으로, N 또는 CH이고,X 1 and X 2 are each independently N or CH,
    L은 C1-4 알킬렌이고,L is C 1-4 alkylene,
    R2는 몰폴리노이고,R 2 is morpholino,
    Y는 -NH-이고,Y is -NH-,
    A는
    Figure PCTKR2019010894-appb-I000163
    이고,     A is
    Figure PCTKR2019010894-appb-I000163
    ego,
    여기서, R3는 C2-4 알케닐이다.Wherein R 3 is C 2-4 alkenyl.
  11. 제1항에 있어서,The method of claim 1,
    상기 화학식 1은 하기 화학식 1-3으로 표시되는,Formula 1 is represented by the following formula 1-3,
    화합물, 또는 이의 약학적으로 허용가능한 염:Compound, or pharmaceutically acceptable salt thereof:
    [화학식 1-3][Formula 1-3]
    Figure PCTKR2019010894-appb-I000164
    Figure PCTKR2019010894-appb-I000164
    상기 화학식 1-3에서,In Chemical Formula 1-3,
    X1 및 X2는 각각 독립적으로, N 또는 CH이고,X 1 and X 2 are each independently N or CH,
    L은 C1-4 알킬렌이고,L is C 1-4 alkylene,
    R2는 몰폴리노이고,R 2 is morpholino,
    Y는 -NH-이고,Y is -NH-,
    A는
    Figure PCTKR2019010894-appb-I000165
    이고,    A is
    Figure PCTKR2019010894-appb-I000165
    ego,
    여기서, R3는 C2-4 알케닐이다.Wherein R 3 is C 2-4 alkenyl.
  12. 제1항에 있어서,The method of claim 1,
    상기 화학식 1은 하기 화학식 1-4로 표시되는,Formula 1 is represented by the following formula 1-4,
    화합물, 또는 이의 약학적으로 허용가능한 염:Compound, or pharmaceutically acceptable salt thereof:
    [화학식 1-4][Formula 1-4]
    Figure PCTKR2019010894-appb-I000166
    Figure PCTKR2019010894-appb-I000166
    상기 화학식 1-4에서,In Chemical Formula 1-4,
    X1 및 X2는 각각 독립적으로, N 또는 CH이고,X 1 and X 2 are each independently N or CH,
    L은 C1-4 알킬렌이고,L is C 1-4 alkylene,
    R2는 몰폴리노이고,R 2 is morpholino,
    Y는 -NH-이고,Y is -NH-,
    A는
    Figure PCTKR2019010894-appb-I000167
    이고,    A is
    Figure PCTKR2019010894-appb-I000167
    ego,
    여기서, R3는 C2-4 알케닐이다.Wherein R 3 is C 2-4 alkenyl.
  13. 제1항에 있어서,The method of claim 1,
    상기 화학식 1로 표시되는 화합물은,Compound represented by the formula (1),
    1) 1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,1) 1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidin-1-yl) Prop-2-en-1-one,
    2) 1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피롤리딘-1-일)프로프-2-엔-1-온,2) 1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pyrrolidin-1-yl) Prop-2-en-1-one,
    3) 1-(4-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,3) 1- (4-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidin-1-yl) Prop-2-en-1-one,
    4) (R)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,4) (R) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidine- 1-yl) prop-2-en-1-one,
    5) (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,5) (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidine- 1-yl) prop-2-en-1-one,
    6) (R)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피롤리딘-1-일)프로프-2-엔-1-온,6) (R) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pyrrolidine- 1-yl) prop-2-en-1-one,
    7) (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피롤리딘-1-일)프로프-2-엔-1-온,7) (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pyrrolidine- 1-yl) prop-2-en-1-one,
    8) 1-(3-((2-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-4-일)아미노)피롤리딘-1-일)프로프-2-엔-1-온,8) 1- (3-((2-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-4-yl) amino) pyrrolidin-1-yl Prop-2-en-1-one,
    9) (E)-1-(3-((2-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-4-일)아미노)피롤리딘-1-일)부트-2-엔-1-온,9) (E) -1- (3-((2-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-4-yl) amino) pyrrolidine -1-yl) but-2-en-1-one,
    10) 1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥시)피롤리딘-1-일)프로프-2-엔-1-온,10) 1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) oxy) pyrrolidin-1-yl) Prop-2-en-1-one,
    11) 1-(4-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥시)피페리딘-1-일)프로프-2-엔-1-온,11) 1- (4-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) oxy) piperidin-1-yl) Prop-2-en-1-one,
    12) 1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥시)피페리딘-1-일)프로프-2-엔-1-온,12) 1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) oxy) piperidin-1-yl) Prop-2-en-1-one,
    13) (R)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)부트-2-인-1-온,13) (R) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidine- 1-yl) but-2-yn-1-one,
    14) 1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피롤리딘-1-일)부트-2-인-1-온,14) 1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) pyrrolidin-1-yl) Boot-2-in-1-one,
    15) (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥시)피페리딘-1-일)프로프-2-엔-1-온,15) (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) oxy) piperidine- 1-yl) prop-2-en-1-one,
    16) (R)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥시)피페리딘-1-일)프로프-2-엔-1-온,16) (R) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) oxy) piperidine- 1-yl) prop-2-en-1-one,
    17) 1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,17) 1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-2-yl) amino) piperidin-1-yl Prop-2-en-1-one,
    18) (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)부트-2-인-1-온,18) (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidine- 1-yl) but-2-yn-1-one,
    19) 1-(4-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)부트-2-인-1-온,19) 1- (4-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidin-1-yl) Boot-2-in-1-one,
    20) (S)-1-(3-((4-((4-아세틸피페라진-1-일)메틸)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,20) (S) -1- (3-((4-((4-acetylpiperazin-1-yl) methyl) -6-((5-methylthiazol-2-yl) amino) pyridine-2- One) amino) piperidin-1-yl) prop-2-en-1-one,
    21) (S)-1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,21) (S) -1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-2-yl) amino) piperidine -1-yl) prop-2-en-1-one,
    22) (S)-1-(3-((4-((4-(2-메톡시에틸)피페라진-1-일)메틸)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,22) (S) -1- (3-((4-((4- (2-methoxyethyl) piperazin-1-yl) methyl) -6-((5-methylthiazol-2-yl) Amino) pyridin-2-yl) amino) piperidin-1-yl) prop-2-en-1-one,
    23) (S)-1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-2-일)아미노)피페리딘-1-일)부트-2-인-1-온,23) (S) -1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-2-yl) amino) piperidine -1-yl) but-2-yn-1-one,
    24) (S)-1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-2-일)아미노)피롤리딘-1-일)프로프-2-엔-1-온,24) (S) -1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-2-yl) amino) pyrrolidine -1-yl) prop-2-en-1-one,
    25) (R)-1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(몰폴리노메틸)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,25) (R) -1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (morpholinomethyl) pyrimidin-2-yl) amino) piperidine -1-yl) prop-2-en-1-one,
    26) (S)-1-(3-(메틸(6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,26) (S) -1- (3- (methyl (6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) piperidine -1-yl) prop-2-en-1-one,
    27) N-(1-(6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)피페리딘-4-일)아크릴아마이드,27) N- (1- (6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) piperidin-4-yl) acrylamide,
    28) 1-(6-(6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥타하이드로-1H-피롤로[2,3-c]피리딘-1-일)프로프-2-엔-1-온,28) 1- (6- (6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) octahydro-1H-pyrrolo [2,3 -c] pyridin-1-yl) prop-2-en-1-one,
    29) 1-(6-(6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)옥타하이드로-1H-피롤로[2,3-c]피리딘-1-일)부트-2-인-1-온,29) 1- (6- (6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) octahydro-1H-pyrrolo [2,3 -c] pyridin-1-yl) but-2-yn-1-one,
    30) 1-(6-((6-((5-메틸티아졸-2-일)아미노)-4-(몰폴리노메틸)피리딘-2-일)아미노)-2-아자스피로[3.3]헵탄-2-일)프로프-2-엔-1-온,30) 1- (6-((6-((5-methylthiazol-2-yl) amino) -4- (morpholinomethyl) pyridin-2-yl) amino) -2-azaspiro [3.3] Heptan-2-yl) prop-2-en-1-one,
    31) (S)-1-(3-((4-((5-메틸티아졸-2-일)아미노)-6-(피페리딘-1-일메틸)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,31) (S) -1- (3-((4-((5-methylthiazol-2-yl) amino) -6- (piperidin-1-ylmethyl) pyrimidin-2-yl) amino ) Piperidin-1-yl) prop-2-en-1-one,
    32) (S)-1-(3-((4-((4-에틸피페라진-1-일)메틸)-6-((5-메틸티아졸-2-일)아미노)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,32) (S) -1- (3-((4-((4-ethylpiperazin-1-yl) methyl) -6-((5-methylthiazol-2-yl) amino) pyrimidine-2 -Yl) amino) piperidin-1-yl) prop-2-en-1-one,
    33) (S)-1-(3-((4-((1-메틸피페리딘-4-일)옥시)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,33) (S) -1- (3-((4-((1-methylpiperidin-4-yl) oxy) -6-((5-methylthiazol-2-yl) amino) pyridine-2 -Yl) amino) piperidin-1-yl) prop-2-en-1-one,
    34) (S)-3-(4-((2-((1-아크릴로일피페리딘-3-일)아미노)-6-((5-메틸티아졸-2-일)아미노)피리딘-4-일)메틸)피페라진-1-일)프로판엔니트릴,34) (S) -3- (4-((2-((1-acryloylpiperidin-3-yl) amino) -6-((5-methylthiazol-2-yl) amino) pyridine- 4-yl) methyl) piperazin-1-yl) propanenitrile,
    35) (S)-1-(3-((4-메틸-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,35) (S) -1- (3-((4-methyl-6-((5-methylthiazol-2-yl) amino) pyridin-2-yl) amino) piperidin-1-yl) pro P-2-en-1-one,
    36) (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(피리딘-3-일메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,36) (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (pyridin-3-ylmethyl) pyridin-2-yl) amino) piperi Din-1-yl) prop-2-en-1-one,
    37) (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-(피리딘-2-일메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,37) (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4- (pyridin-2-ylmethyl) pyridin-2-yl) amino) piperi Din-1-yl) prop-2-en-1-one,
    38) (S)-2-((1-아크릴로일피페리딘-3-일)아미노)-6-((5-메틸티아졸-2-일)아미노)아이소니코티노니트릴,38) (S) -2-((1-acryloylpiperidin-3-yl) amino) -6-((5-methylthiazol-2-yl) amino) isonicotinonitrile,
    39) (S)-1-(3-((6-((5-메틸티아졸-2-일)아미노)-4-페닐피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,39) (S) -1- (3-((6-((5-methylthiazol-2-yl) amino) -4-phenylpyridin-2-yl) amino) piperidin-1-yl) pro P-2-en-1-one,
    40) (S)-1-(3-((4-((1-메틸피페리딘-4-일)옥시)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-인-1-온,40) (S) -1- (3-((4-((1-methylpiperidin-4-yl) oxy) -6-((5-methylthiazol-2-yl) amino) pyridine-2 -Yl) amino) piperidin-1-yl) prop-2-yn-1-one,
    41) (S)-1-(3-((4-((1-메틸피페리딘-4-일)옥시)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)부트-2-인-1-온,41) (S) -1- (3-((4-((1-methylpiperidin-4-yl) oxy) -6-((5-methylthiazol-2-yl) amino) pyridine-2 -Yl) amino) piperidin-1-yl) but-2-yn-1-one,
    42) (S)-1-(3-((4-((4-에틸피페라진-1-일)메틸)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,42) (S) -1- (3-((4-((4-ethylpiperazin-1-yl) methyl) -6-((5-methylthiazol-2-yl) amino) pyridine-2- One) amino) piperidin-1-yl) prop-2-en-1-one,
    43) (S)-1-(3-((4-((4-메틸피페라진-1-일)메틸)-6-((5-메틸티아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온,43) (S) -1- (3-((4-((4-methylpiperazin-1-yl) methyl) -6-((5-methylthiazol-2-yl) amino) pyridine-2- One) amino) piperidin-1-yl) prop-2-en-1-one,
    44) 5-메틸-N-(6-메틸-4-(몰폴리노메틸)피리딘-2-일)티아졸-2-아민,44) 5-methyl-N- (6-methyl-4- (morpholinomethyl) pyridin-2-yl) thiazol-2-amine,
    45) (S)-3-클로로-1-(3-(6-(5-메틸티아졸-2-일아미노)-4-(몰폴리노메틸)피리딘-2-일아미노)피페리딘-1-일)프로판-1-온,45) (S) -3-chloro-1- (3- (6- (5-methylthiazol-2-ylamino) -4- (morpholinomethyl) pyridin-2-ylamino) piperidine- 1-yl) propan-1-one,
    46) (S,E)-3-클로로-1-(3-(6-(5-메틸티아졸-2-일아미노)-4-(몰폴리노메틸)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온,46) (S, E) -3-chloro-1- (3- (6- (5-methylthiazol-2-ylamino) -4- (morpholinomethyl) pyridin-2-ylamino) piperi Din-1-yl) prop-2-en-1-one,
    47) (S)-1-(3-(4-((4-(3-아미노프로필)피페라진-1-일)메틸)-6-(5-메틸티아졸-2-일아미노)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온,47) (S) -1- (3- (4-((4- (3-aminopropyl) piperazin-1-yl) methyl) -6- (5-methylthiazol-2-ylamino) pyridine- 2-ylamino) piperidin-1-yl) prop-2-en-1-one,
    48) (S)-1-(3-(6-(1H-피라졸-3-일아미노)-4-(몰폴리노메틸)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온,48) (S) -1- (3- (6- (1H-pyrazol-3-ylamino) -4- (morpholinomethyl) pyridin-2-ylamino) piperidin-1-yl) prop P-2-en-1-one,
    49) (S)-1-(3-(4-(몰폴리노메틸)-6-(5-(트리플루오로메틸)티아졸-2-일아미노)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온,49) (S) -1- (3- (4- (morpholinomethyl) -6- (5- (trifluoromethyl) thiazol-2-ylamino) pyridin-2-ylamino) piperidine -1-yl) prop-2-en-1-one,
    50) (S)-1-(3-(6-(5-클로로-1H-피라졸-3-일아미노)-4-(몰폴리노메틸)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온,50) (S) -1- (3- (6- (5-chloro-1H-pyrazol-3-ylamino) -4- (morpholinomethyl) pyridin-2-ylamino) piperidine-1 -Yl) prop-2-en-1-one,
    51) (S)-1-(3-(4-(몰폴리노메틸)-6-(티아졸-2-일아미노)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온,51) (S) -1- (3- (4- (morpholinomethyl) -6- (thiazol-2-ylamino) pyridin-2-ylamino) piperidin-1-yl) prop- 2-en-1-one,
    52) (S)-1-(3-(3-플루오로-6-(5-메틸티아졸-2-일아미노)-4-(몰폴리노메틸)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온,52) (S) -1- (3- (3-fluoro-6- (5-methylthiazol-2-ylamino) -4- (morpholinomethyl) pyridin-2-ylamino) piperidine -1-yl) prop-2-en-1-one,
    53) (S)-1-(3-(4-(몰폴리노메틸)-6-(피리딘-2-일아미노)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온, 및53) (S) -1- (3- (4- (morpholinomethyl) -6- (pyridin-2-ylamino) pyridin-2-ylamino) piperidin-1-yl) prop-2 -En-1-one, and
    54) (S)-1-(3-(4-(몰폴리노메틸)-6-(피리미딘-2-일아미노)피리딘-2-일아미노)피페리딘-1-일)프로프-2-엔-1-온54) (S) -1- (3- (4- (morpholinomethyl) -6- (pyrimidin-2-ylamino) pyridin-2-ylamino) piperidin-1-yl) prop- 2-en-1-one
    으로 구성되는 군으로부터 선택되는 어느 하나인,Any one selected from the group consisting of,
    화합물, 또는 이의 약학적으로 허용가능한 염.Compound, or a pharmaceutically acceptable salt thereof.
  14. 제1항 내지 제13항 중 어느 한 항의 화합물, 또는 이의 약학적으로 허용가능한 염을 어느 한 항의 화합물, 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 포함하는, 자가 면역 질환 또는 암의 예방 또는 치료용 약학적 조성물.A method for preventing an autoimmune disease or cancer comprising the compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof as an active ingredient, or a compound of any one of the claims, or a pharmaceutically acceptable salt thereof. Therapeutic pharmaceutical composition.
PCT/KR2019/010894 2018-08-27 2019-08-27 Novel heterocyclic amine derivative and pharmaceutical composition comprising same WO2020045941A1 (en)

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PE2021000205A PE20210417A1 (en) 2018-08-27 2019-08-27 NEW DERIVATIVE OF AMINE HETEROCYCLIC AND PHARMACEUTICAL COMPOSITION THAT INCLUDES IT
BR122022001938-2A BR122022001938B1 (en) 2018-08-27 2019-08-27 Heterocyclic amine derivative compound, pharmaceutical composition comprising the same and use of said compound to prevent or treat autoimmune diseases or cancers
JP2021534102A JP7162741B2 (en) 2018-08-27 2019-08-27 Novel heterocyclic amine derivative and pharmaceutical composition containing the same
MX2021002188A MX2021002188A (en) 2018-08-27 2019-08-27 Novel heterocyclic amine derivative and pharmaceutical composition comprising same.
TNP/2021/000025A TN2021000025A1 (en) 2018-08-27 2019-08-27 Novel heterocyclic amine derivative and pharmaceutical composition comprising same
RU2021107433A RU2760184C1 (en) 2018-08-27 2019-08-27 New heterocyclic amine derivative and a pharmaceutical composition containing it
CN201980056437.8A CN112638910A (en) 2018-08-27 2019-08-27 Novel heterocyclic amine derivatives and pharmaceutical compositions comprising the same
US17/269,325 US20220064155A1 (en) 2018-08-27 2019-08-27 Novel heterocyclic amine derivative and pharmaceutical composition comprising same
AU2019331328A AU2019331328B2 (en) 2018-08-27 2019-08-27 Novel heterocyclic amine derivative and pharmaceutical composition comprising same
SG11202101451QA SG11202101451QA (en) 2018-08-27 2019-08-27 Novel heterocyclic amine derivative and pharmaceutical composition comprising same
BR112021003652-0A BR112021003652B1 (en) 2018-08-27 2019-08-27 Heterocyclic amine derivative compound, pharmaceutical composition comprising the same and use of said compound to prevent or treat autoimmune diseases or cancers
CA3108856A CA3108856C (en) 2018-08-27 2019-08-27 Novel heterocyclic amine derivative and pharmaceutical composition comprising same
EP19855534.4A EP3845530A4 (en) 2018-08-27 2019-08-27 Novel heterocyclic amine derivative and pharmaceutical composition comprising same
CONC2021/0001849A CO2021001849A2 (en) 2018-08-27 2021-02-16 New heterocyclic amine derivative and pharmaceutical composition comprising it
PH12021550329A PH12021550329A1 (en) 2018-08-27 2021-02-16 Novel heterocyclic amine derivative and pharmaceutical composition comprising same
DO2021000030A DOP2021000030A (en) 2018-08-27 2021-02-17 NEW HETEROCYCLIC AMINE DERIVATIVE AND COMPOSITION OF THE PHARMACEUTICAL COMPOSITION

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Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002022602A2 (en) * 2000-09-15 2002-03-21 Vertex Pharmaceuticals Incorporated Triazole compounds useful as protein kinase inhibitors
WO2002050071A1 (en) 2000-12-21 2002-06-27 Bristol-Myers Squibb Company Thiazolyl inhibitors of tec family tyrosine kinases
WO2005056785A2 (en) 2003-12-05 2005-06-23 Vertex Pharmaceuticals, Inc. Crystal structure of interleukin-2 tyrosine kinase (itk) and binding pockets thereof
WO2005066335A1 (en) 2003-12-30 2005-07-21 Boehringer Ingelheim Pharmaceuticals, Inc. Crystal structure of the interleukin-2-inducible cell kinase (itk) kinase domain
WO2008039218A2 (en) 2006-09-22 2008-04-03 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
WO2010144359A1 (en) * 2009-06-08 2010-12-16 Abraxis Bioscience, Llc Triazine derivatives and their therapeutical applications
WO2011034907A2 (en) * 2009-09-16 2011-03-24 Avila Therapeutics, Inc. Protein kinase conjugates and inhibitors
WO2014036016A1 (en) 2012-08-31 2014-03-06 Principia Biopharma Inc. Benzimidazole derivatives as itk inhibitors
WO2014048065A1 (en) * 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Triazolyl derivatives as syk inhibitors
WO2014055934A2 (en) 2012-10-04 2014-04-10 University Of Utah Research Foundation Substituted n-(3-(pyrimidin-4-yl)phenyl)acrylamide analogs as tyrosine receptor kinase btk inhibitors
WO2015061247A2 (en) 2013-10-21 2015-04-30 Merck Patent Gmbh Heteroaryl compounds as btk inhibitors and uses thereof
WO2015108861A1 (en) * 2014-01-14 2015-07-23 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002022602A2 (en) * 2000-09-15 2002-03-21 Vertex Pharmaceuticals Incorporated Triazole compounds useful as protein kinase inhibitors
WO2002050071A1 (en) 2000-12-21 2002-06-27 Bristol-Myers Squibb Company Thiazolyl inhibitors of tec family tyrosine kinases
WO2005056785A2 (en) 2003-12-05 2005-06-23 Vertex Pharmaceuticals, Inc. Crystal structure of interleukin-2 tyrosine kinase (itk) and binding pockets thereof
WO2005066335A1 (en) 2003-12-30 2005-07-21 Boehringer Ingelheim Pharmaceuticals, Inc. Crystal structure of the interleukin-2-inducible cell kinase (itk) kinase domain
WO2008039218A2 (en) 2006-09-22 2008-04-03 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
WO2010144359A1 (en) * 2009-06-08 2010-12-16 Abraxis Bioscience, Llc Triazine derivatives and their therapeutical applications
WO2011034907A2 (en) * 2009-09-16 2011-03-24 Avila Therapeutics, Inc. Protein kinase conjugates and inhibitors
WO2014036016A1 (en) 2012-08-31 2014-03-06 Principia Biopharma Inc. Benzimidazole derivatives as itk inhibitors
WO2014048065A1 (en) * 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Triazolyl derivatives as syk inhibitors
WO2014055934A2 (en) 2012-10-04 2014-04-10 University Of Utah Research Foundation Substituted n-(3-(pyrimidin-4-yl)phenyl)acrylamide analogs as tyrosine receptor kinase btk inhibitors
WO2015061247A2 (en) 2013-10-21 2015-04-30 Merck Patent Gmbh Heteroaryl compounds as btk inhibitors and uses thereof
WO2015108861A1 (en) * 2014-01-14 2015-07-23 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
FOWELL ET AL., IMMUNITY, vol. 11, 1999, pages 399
GOMEZ-RODRIGUEZ ET AL., J. EXP. MED., vol. 211, 2014, pages 529
HORWOOD ET AL., J. EXP. MED., vol. 197, 2003, pages 1603
IWAKI ET AL., J. BIOL CHEM., vol. 280, 2005, pages 40261
J LEIPE J. ET AL., ARTHRITIS RHEUM, vol. 62, 2010, pages 2876
LO H. Y, EXPERT OPIN THER PAT, vol. 20, 2010, pages 459
SAHU N. ET AL., CURR TOP MED CHEM, vol. 9, 2009, pages 690
SCHAEFFER ET AL., NAT. IMMUNE, vol. 2, 2001, pages 1183
ZHONG Y ET AL., THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 290, 2015, pages 5960

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