WO2022071772A1 - Protein kinase inhibitor and use thereof - Google Patents

Protein kinase inhibitor and use thereof Download PDF

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Publication number
WO2022071772A1
WO2022071772A1 PCT/KR2021/013380 KR2021013380W WO2022071772A1 WO 2022071772 A1 WO2022071772 A1 WO 2022071772A1 KR 2021013380 W KR2021013380 W KR 2021013380W WO 2022071772 A1 WO2022071772 A1 WO 2022071772A1
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amino
thiazol
pyridin
tetrazol
piperidin
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French (fr)
Korean (ko)
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방극찬
서행수
신미선
안지윤
이현진
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(주)메디톡스
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present disclosure relates to compounds of formula (1) having activity of inhibiting protein kinases and uses thereof.
  • Protein kinases are enzymes that catalyze the phosphorylation of hydroxyl groups located at tyrosine, serine, and threonine residues of proteins, and play an important role in growth factor signal transduction leading to cell growth, differentiation and proliferation. Mutation or overexpression of specific protein kinases can cause various diseases by disrupting normal intracellular signal transduction systems.
  • ibrutinib is known as a BTK inhibitor, but there is a need for an alternative BTK inhibitor.
  • One aspect is to provide a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • Another aspect is to provide a pharmaceutical composition for use in treating a disease mediated by a protein kinase comprising a compound of formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. .
  • Another aspect is to provide a pharmaceutical composition for use in inhibiting the activity of a protein kinase comprising a compound of Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another aspect is to provide a method for treating a disease mediated by protein kinase in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof. .
  • Another aspect is to provide a method for inhibiting the activity of a protein kinase, comprising contacting a compound of Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof, with the protein kinase.
  • One aspect provides a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • Cy is C 3-12 aryl, C 3-12 cycloalkyl or C 3-10 heteroaryl, said C 3-12 aryl, C 3-12 cycloalkyl or C 3-10 heteroaryl is C 1-6 alkyl, may be substituted with one or more substituents selected from the group consisting of C 1-6 alkoxy and halo;
  • A is a 5-membered ring having 2 or more N atoms
  • Y is NH or O when X is CH and CH when X is S;
  • Z 1 is N is absent, when Z 1 is C, m is an integer of 0 to 3, and R 1 may be substituted with one or more substituents selected from the group consisting of C 1-6 alkyl and C 1-6 alkylcarbonyl. is C 3-10 heterocycloalkyl, which may be substituted with one or more C 1-6 alkyl, amino, hydrogen, C 1-6 alkoxy, or halo;
  • R 2 is or (wherein R 3 and R 4 are independently of each other hydrogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl);
  • L 1 and L 2 are each independently NH, O, or S;
  • n is an integer from 0 to 3.
  • Cy may be phenyl or pyrazolyl.
  • A may have 2 to 4 N atoms, or may have 2 or 3 N atoms and 1 O atom.
  • A may be imidazolyl, triazolyl, tetrazolyl or oxadiazolyl.
  • A may be tetrazolyl or oxadiazolyl.
  • m may be 0 or 1.
  • R 1 is C 4-6 heterocycloalkyl, which may be substituted with one or more substituents selected from the group consisting of C 1-6 alkyl and C 1-6 alkylcarbonyl; amino which may be substituted with one or more C 1-6 alkyl; Hydrogen; Alternatively, it may be C 1-6 alkoxy.
  • R 1 is morpholinyl which may be substituted with one or more C 1-6 alkyl; Hydrogen; Alternatively, it may be C 1-6 alkoxy.
  • n can be 1 or 2.
  • the compound of Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof may be the following compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • the compound of Formula 1 may be substituted with a detectable label.
  • the detectable label may be an optical label, an electrical label, a magnetic label, or an indirect label.
  • the optical label is a material that generates a detectable optical signal, and may be a radioactive material or a chromogenic material such as a fluorescent material.
  • Indirect label refers to a substance capable of generating a detectable label as a result of binding to a specific substance, such as an enzyme that converts a substrate into a chromogenic substance or its substrate, antibody or antigen.
  • the optical label may be an isotope of an element constituting the compound of Formula 1.
  • alkyl refers to a straight-chain or branched saturated hydrocarbon group.
  • the alkyl may contain 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl.
  • alkenyl means an alkyl having at least one carbon-carbon double bond. wherein alkyl is as defined above. Alkenyl can be, for example, ethenyl or propenyl.
  • alkynyl means an alkyl having at least one carbon-carbon triple bond. wherein alkyl is as defined above. Alkynyl can be, for example, ethynyl or 2-propynyl.
  • alkoxy refers to an (alkyl)O- group. wherein alkyl is as defined above.
  • aryl denotes an aromatic ring in which each atom forming the ring is a carbon atom.
  • the ring may be monocyclic or polycyclic.
  • the polycyclic ring may include one having a fused ring (eg, naphthalene) or one having an unfused ring (eg, biphenyl).
  • the polycyclic ring may have, for example, 2, 3 or 4 rings.
  • the aryl group is, for example, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 5 to 20, 5 to 15, 5 to 12, 5 to 10 , or 6 to 10 carbon ring atoms.
  • Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norcanyl, and adamantyl.
  • Another aspect provides a pharmaceutical composition for use in treating a disease mediated by a protein kinase comprising a compound of Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the disease may be caused by an increase in the protein kinase activity.
  • cSRC is a prototypical member of the SRC family of tyrosine kinases including Lyn, Fyn, Lck, Hck, Fgr, Blk, Syk, Yrk and Yes.
  • Bruton's Tyrosine Kinase is a member of the Tec family of tyrosine kinases and is a key regulator of early B cell development, mature B cell activation, signaling and survival.
  • B cell signaling through the B cell receptor (BCR) results in a wide range of biological outputs.
  • Abnormal BCR-mediated signaling can lead to deregulated B cell proliferation and/or the formation of etiological autoantibodies leading to multiple autoimmune and/or inflammatory diseases.
  • Mutations in BTK in humans can cause X-linked agammaglobulinaemia (XLA). The disease is associated with impaired maturation of B cells, decreased immunoglobulin production, T cell independent immune responses, and marked attenuation of sustained calcium signaling in response to BCR stimulation.
  • XLA X-linked agammaglobulinaemia
  • treatment means treating a disease or medical condition, eg, a BTK-associated disease, in a subject, eg, a mammal, including a human, including: (a) a disease or medical condition alleviation of, ie, the elimination or recovery of, a disease or medical condition in a patient; (b) inhibiting the disease or medical condition, ie, slowing or arresting the progression of the disease or medical condition in a subject; or (c) alleviating the disease or medical condition in the subject.
  • a disease or medical condition alleviation of, ie, the elimination or recovery of, a disease or medical condition in a patient
  • inhibiting the disease or medical condition ie, slowing or arresting the progression of the disease or medical condition in a subject
  • alleviating the disease or medical condition in the subject including: (a) a disease or medical condition alleviation of, ie, the elimination or recovery of, a disease or medical condition in a patient.
  • the compound of Formula 1 as defined in the present disclosure may exhibit an effect of inhibiting protein kinase activity.
  • inhibiting includes reducing the kinase activity of a protein kinase.
  • the protein kinase may be BTK.
  • Another aspect provides the use of a compound of formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof, as defined above, for the manufacture of a medicament for the treatment of a disease associated with protein kinase.
  • the administration route may be appropriately selected by a person skilled in the art according to the condition of the patient.
  • the administration may be oral, parenteral, or topical administration.
  • the subject may be a mammal, such as a human, cow, pig, horse, or cat.
  • a compound of Formula 1-VIb may be prepared by reacting a compound of Formula 1-VIa with a compound of Formula 1-VII.
  • This reaction is an amide reaction with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, hydroxybenzotriazole, (1-[bis(dimethylamino)methylene]-1H-1,2,3) -triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, in the presence of 1,1'-carbonyldiimidazole in an organic solvent such as N,N-dimethylformamide, dichloromethane can be performed.
  • a compound of Formula 1-IIb in which the halogen group of the compound of Formula 1-IIa is substituted with an amino group can be prepared.
  • This reaction can be carried out in an organic solvent, for example, a glycol solvent, especially ethylene glycol, in the presence of potassium carbonate, copper peroxide, N,N'-dimethylethylenediamine, and aqueous ammonia.
  • step (1-5) the compound of formula 1-Ia can be prepared by reacting the compound of formula 1-IIb obtained in step (1-4) with the compound of formula III. This reaction can be carried out using the same reagents or solvents as in step (1-3).
  • step (1-6) the compound of formula 1-Ia obtained in step (1-5) in the presence of a strong acid, for example hydrochloric acid, in particular 4N hydrochloric acid, in an organic solvent, for example a C 1 -C 4 alcohol, especially methanol
  • a strong acid for example hydrochloric acid, in particular 4N hydrochloric acid
  • an organic solvent for example a C 1 -C 4 alcohol, especially methanol
  • a compound of Formula 1-Ib may be prepared by removing the protecting group from
  • step (2-4) the compound of formula 2-Ia obtained in step (2-3) in the presence of a strong acid, for example hydrochloric acid, in particular 4N hydrochloric acid, in an organic solvent, for example a C 1 -C 4 alcohol, especially methanol
  • a strong acid for example hydrochloric acid, in particular 4N hydrochloric acid
  • an organic solvent for example a C 1 -C 4 alcohol, especially methanol
  • a compound of Formula 2-VIa can be prepared by reacting Formula 3-IVa with Compound 3-VII.
  • This reaction is carried out in the presence of a base such as diisopropylethylamine, triethylamine, pyridine, sodium hydride, sodium-t-butoxide, potassium carbonate, cesium carbonate, sodium hydrogen carbonate and a polar aprotic organic solvent such as, For example, it can be carried out in tetrahydrofuran, ethyl acetate, acetone, N,N-dimethylformamide, acetonitrile, N,N-dimethylsulfoxide.
  • a base such as diisopropylethylamine, triethylamine, pyridine, sodium hydride, sodium-t-butoxide, potassium carbonate, cesium carbonate, sodium hydrogen carbonate and a polar aprotic organic solvent such as, For example, it can be carried out in tetrahydrofuran, ethy
  • step (3-7) the compound of formula 3-I obtained in step (3-6) is prepared in the presence of a strong acid, such as trifluoroacetic acid, hydrochloric acid, in particular 4N hydrochloric acid, in an organic solvent, such as a C1-C4 alcohol, especially Compounds of formula (I) can be prepared by removing the protecting group in methanol and introducing an acyl group.
  • This reaction can be carried out by reacting with an acryloyl compound, for example acryloyl halide, especially acryloyl chloride, in the presence of sodium hydrogen carbonate in an organic solvent, for example tetrahydrofuran and water.
  • the reaction solution was cooled to 0 °C, the pH was adjusted to about 8 with a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and washed with water. The obtained organic layer was dried over magnesium sulfate, and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (750 mg, 70%).
  • Step 2 tert-Butyl (S)-3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole- Synthesis of 2-yl)amino)pyridin-2-yl)amino)piperidine-1-carboxylate
  • the target compound (25 mg, 40%) was obtained by reacting in the same manner except that crotonoyl chloride (cis-, trans- mixture) was used instead of acryloyl chloride in step 9) of Example 1).
  • step 5 of Example 1 2,6-dibromo-4-methylpyridine (500 mg, 1.99 mmol) was used instead of 4-((2,6-dibromopyridin-4-yl)methyl)morpholine. Except for the use, the target compound (570 mg, 77%) was obtained in the same manner.
  • Example 16 1-((S)-3-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3) Synthesis of ,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
  • Step 7) 1-((S)-3-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3, Synthesis of 4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one

Abstract

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

Description

단백질 키나제 저해제 및 그의 용도Protein kinase inhibitors and uses thereof
본 개시는 단백질 키나제를 저해하는 활성을 갖는 화학식 1의 화합물 및 그의 용도에 관한 것이다.The present disclosure relates to compounds of formula (1) having activity of inhibiting protein kinases and uses thereof.
단백질 키나제는 단백질의 티로신, 세린 및 트레오닌 잔기에 위치하는 히드록시 그룹의 인산화를 촉매하는 효소로서, 세포의 성장, 분화 및 증식을 유발하는 성장 인자 신호 전달에 중요한 역할을 담당하고 있다. 특정 단백질 키나제의 돌연변이나 과발현은 정상적인 세포 내 신호 전달체계를 붕괴시켜서 다양한 질병을 유발할 수 있다.Protein kinases are enzymes that catalyze the phosphorylation of hydroxyl groups located at tyrosine, serine, and threonine residues of proteins, and play an important role in growth factor signal transduction leading to cell growth, differentiation and proliferation. Mutation or overexpression of specific protein kinases can cause various diseases by disrupting normal intracellular signal transduction systems.
상기 단백질 키나제는 브루톤스 티로신 키나제(BTK)를 포함한다. BTK는 사람에서 BTK 유전자에 의하여 코딩되는 효소이다. BTK는 B 세포 발생에 중요한 역할을 하는 키나제이다. BTK는 고친화성 IgE 수용체를 통한 마스트 세포 활성화뿐만 아니라 B 세포 성숙화에 중요한 역할을 한다. BTK는 포스파티딜이노시톨(3,4,5)-트리포스페이트(PIP3)에 결합하는 PH 도메인을 포함한다. PIP3가 BTK에 결합하면, BTK가 포스포리파제 C를 인산화하도록 유도한다. 인산화된 포스포리파제 C는 PIP2와 포스파티딜이노시톨을 가수분해하여 2개의 2차 메신저, 이노시톨트리포스페이트(IP3)와 디아실글리세롤(DAG)을 생성한다. 이들 2차 메신저는 B 세포 신호전달 동안 하류 단백질의 활성을 조절한다.The protein kinase includes Bruton's tyrosine kinase (BTK). BTK is an enzyme encoded by the BTK gene in humans. BTK is a kinase that plays an important role in B cell development. BTK plays an important role in B cell maturation as well as mast cell activation through the high-affinity IgE receptor. BTK contains a PH domain that binds to phosphatidylinositol (3,4,5)-triphosphate (PIP3). When PIP3 binds to BTK, it induces BTK to phosphorylate phospholipase C. Phosphorylated phospholipase C hydrolyzes PIP2 and phosphatidylinositol to produce two secondary messengers, inositol triphosphate (IP3) and diacylglycerol (DAG). These second messengers regulate the activity of downstream proteins during B cell signaling.
종래 BTK 저해제로 이브루티닙(ibrutinib)이 알려져 있으나, 대안적 BTK 저해제가 요구되고 있다.Conventionally, ibrutinib is known as a BTK inhibitor, but there is a need for an alternative BTK inhibitor.
일 양상은 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염을 제공하는 것이다.One aspect is to provide a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
다른 양상은 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염, 및 약제학적으로 허용가능한 담체를 포함하는 단백질 키나제에 의하여 매개되는 질환을 치료하는데 사용하기 위한 약제학적 조성물을 제공하는 것이다.Another aspect is to provide a pharmaceutical composition for use in treating a disease mediated by a protein kinase comprising a compound of formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. .
다른 양상은 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염, 및 약제학적으로 허용가능한 담체를 포함하는 단백질 키나제의 활성을 저해하는데 사용하기 위한 약제학적 조성물을 제공하는 것이다.Another aspect is to provide a pharmaceutical composition for use in inhibiting the activity of a protein kinase comprising a compound of Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
다른 양상은 치료학적 유효량의 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염을 개체에 투여하는 단계를 포함하는, 개체에서 단백질 키나제에 의하여 매개되는 질환을 치료하는 방법을 제공하는 것이다.Another aspect is to provide a method for treating a disease mediated by protein kinase in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof. .
다른 양상은 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염을 단백질 키나제와 접촉시키는 단계를 포함하는 단백질 키나제의 활성을 저해하는 방법을 제공하는 것이다. Another aspect is to provide a method for inhibiting the activity of a protein kinase, comprising contacting a compound of Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof, with the protein kinase.
일 양상은 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염을 제공한다.One aspect provides a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
Figure PCTKR2021013380-appb-C000001
Figure PCTKR2021013380-appb-C000001
상기 화학식 1에서,In Formula 1,
Cy는 C3-12아릴, C3-12사이클로알킬 또는 C3-10헤테로아릴이고, 상기 C3-12아릴, C3-12사이클로알킬 또는 C3-10헤테로아릴은 C1-6알킬, C1-6알콕시 및 할로로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있고;Cy is C 3-12 aryl, C 3-12 cycloalkyl or C 3-10 heteroaryl, said C 3-12 aryl, C 3-12 cycloalkyl or C 3-10 heteroaryl is C 1-6 alkyl, may be substituted with one or more substituents selected from the group consisting of C 1-6 alkoxy and halo;
A는 2개 이상의 N 원자를 갖는 5-원 환이며;A is a 5-membered ring having 2 or more N atoms;
X는 CH 또는 S이고;X is CH or S;
Y는 X가 CH인 경우 NH 또는 O이고, X가 S인 경우 CH이며;Y is NH or O when X is CH and CH when X is S;
Z1은 C 또는 N이고;Z 1 is C or N;
Z1이 N인 경우
Figure PCTKR2021013380-appb-I000001
은 부재하고, Z1이 C인 경우, m은 0~3의 정수이고, R1은 C1-6알킬 및 C1-6알킬카보닐로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있는 C3-10헤테로사이클로알킬, 1개 이상의 C1-6알킬로 치환될 수 있는 아미노, 수소, C1-6알콕시, 또는 할로이고;If Z 1 is N
Figure PCTKR2021013380-appb-I000001
is absent, when Z 1 is C, m is an integer of 0 to 3, and R 1 may be substituted with one or more substituents selected from the group consisting of C 1-6 alkyl and C 1-6 alkylcarbonyl. is C 3-10 heterocycloalkyl, which may be substituted with one or more C 1-6 alkyl, amino, hydrogen, C 1-6 alkoxy, or halo;
Z2는 CH 또는 N이며;Z 2 is CH or N;
R2는
Figure PCTKR2021013380-appb-I000002
또는
Figure PCTKR2021013380-appb-I000003
(여기에서, R3 및 R4는 서로 독립적으로 수소, C1-6알킬, C2-6알케닐 또는 C2-6알키닐이다)이고;R 2 is
Figure PCTKR2021013380-appb-I000002
or
Figure PCTKR2021013380-appb-I000003
(wherein R 3 and R 4 are independently of each other hydrogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl);
L1 및 L2는 서로 독립적으로 NH, O, 또는 S이며;L 1 and L 2 are each independently NH, O, or S;
n은 0 내지 3의 정수이다.n is an integer from 0 to 3.
구체예에서, Cy는 C5-12아릴, C5-12사이클로알킬 또는 C3-6헤테로아릴일 수 있다.In embodiments, Cy can be C 5-12 aryl, C 5-12 cycloalkyl or C 3-6 heteroaryl.
특정 예에서, Cy는 페닐, 사이클로헥실, 피라졸릴 또는 피리딜일 수 있다.In certain instances, Cy can be phenyl, cyclohexyl, pyrazolyl or pyridyl.
특히, Cy는 페닐 또는 피라졸릴일 수 있다.In particular, Cy may be phenyl or pyrazolyl.
구체예에서, A는 2개 내지 4개의 N 원자를 갖거나, 2개 또는 3개의 N 원자와 1개의 O 원자를 갖는 것일 수 있다.In embodiments, A may have 2 to 4 N atoms, or may have 2 or 3 N atoms and 1 O atom.
특정 예에서, A는 이미다졸릴, 피라졸릴, 트리아졸릴, 테트라졸릴 또는 옥사디아졸릴일 수 있다.In certain instances, A can be imidazolyl, pyrazolyl, triazolyl, tetrazolyl or oxadiazolyl.
특히, A는 이미다졸릴, 트리아졸릴, 테트라졸릴 또는 옥사디아졸릴일 수 있다.In particular, A may be imidazolyl, triazolyl, tetrazolyl or oxadiazolyl.
보다 특히, A는 테트라졸릴 또는 옥사디아졸릴일 수 있다.More particularly, A may be tetrazolyl or oxadiazolyl.
구체예에서, m은 0 또는 1일 수 있다.In embodiments, m may be 0 or 1.
구체예에서, R1은 C1-6알킬 및 C1-6알킬카보닐로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있는 C4-6헤테로사이클로알킬; 1개 이상의 C1-6알킬로 치환될 수 있는 아미노; 수소; 또는, C1-6알콕시일 수 있다.In embodiments, R 1 is C 4-6 heterocycloalkyl, which may be substituted with one or more substituents selected from the group consisting of C 1-6 alkyl and C 1-6 alkylcarbonyl; amino which may be substituted with one or more C 1-6 alkyl; Hydrogen; Alternatively, it may be C 1-6 alkoxy.
특정 예에서, R1은 C1-6알킬 및 C1-6알킬카보닐로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있는 몰포리닐, 피페라지닐, 피페리디닐 또는 피롤리디닐; 1개 이상의 C1-6알킬로 치환될 수 있는 아미노; 수소; 또는, C1-6알콕시일 수 있다.In certain instances, R 1 is morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl, which may be substituted with one or more substituents selected from the group consisting of C 1-6 alkyl and C 1-6 alkylcarbonyl. ; amino which may be substituted with one or more C 1-6 alkyl; Hydrogen; Alternatively, it may be C 1-6 alkoxy.
특히, R1은 1개 이상의 C1-6알킬로 치환될 수 있는 몰포리닐; 수소; 또는, C1-6알콕시일 수 있다.In particular, R 1 is morpholinyl which may be substituted with one or more C 1-6 alkyl; Hydrogen; Alternatively, it may be C 1-6 alkoxy.
구체예에서, R3 및 R4는 서로 독립적으로 수소 또는 C1-6알킬일 수 있다.In embodiments, R 3 and R 4 may independently of each other be hydrogen or C 1-6 alkyl.
구체예에서, L1 및 L2는 서로 독립적으로 NH 또는 O일 수 있다.In embodiments, L 1 and L 2 may be each independently NH or O.
구체예에서, n은 1 또는 2일 수 있다.In embodiments, n can be 1 or 2.
예를 들어, 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염은 하기 화합물, 그의 입체이성질체 또는 그의 약제학으로 허용가능한 염일 수 있다:For example, the compound of Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof may be the following compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin- 2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin- 2-yl)oxy)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(2-(2-클로로-6-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-(2-chloro-6-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4 -(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(2-(2-메톡시페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-(2-methoxyphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4-( morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl) )amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(2-(5-클로로-2-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-(5-chloro-2-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4 -(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(2-(2-클로로-6-플루오로페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-(2-chloro-6-fluorophenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino) -4-(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(2-(1-메틸-1H-피라졸-4-일)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-(1-methyl-1H-pyrazol-4-yl)-2H-tetrazol-5-yl)thiazol-2-yl) )amino)-4-(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(2-(4-브로모페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-(4-bromophenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4-( morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)부트-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin- 2-yl)amino)piperidin-1-yl)but-2-en-1-one;
(S)-1-(3-((4-메톡시-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-methoxy-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin-2-yl )amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-메틸-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-methyl-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin-2-yl) amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-메틸-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-methyl-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine -2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-인-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin- 2-yl)amino)piperidin-1-yl)prop-2-yn-1-one;
(S)-1-(3-((6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피라진-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyrazin-2-yl)amino)piperi din-1-yl)prop-2-en-1-one;
1-((S)-3-((4-(((2S,6R)-2,6-디메틸몰포리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;1-((S)-3-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxa) diazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)piperi din-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl )amino)piperidin-1-yl)prop-2-en-1-one;
1-((S)-3-((4-(((2S,6R)-2,6-디메틸몰포리노)메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;1-((S)-3-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(2-phenyl-2H-tetrazole-5-) yl)thiazol-2-yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-((4-메틸피페라진-1-일)메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-((4-methylpiperazin-1-yl)methyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazole -2-yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-((4-메틸피페라진-1-일)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-((4-methylpiperazin-1-yl)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2) -yl)thiazol-2-yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-((4-아세틸피페라진-1-일)메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-((4-acetylpiperazin-1-yl)methyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazole -2-yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-((4-아세틸피페라진-1-일)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-((4-acetylpiperazin-1-yl)methyl)-6-((5-(5-phenyl-1,3,4-oxadiazole-2) -yl)thiazol-2-yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피라진-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyrazin-2-yl )amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(디메틸아미노)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(dimethylamino)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin-2 -yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(디메틸아미노)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(dimethylamino)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl) amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(피롤리딘-1-일)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4-(pyrrolidin-1- yl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)-4-(피롤리딘-1-일)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)-4-(p rollidin-1-yl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(5-(피리딘-2-일)-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl) thiazol-2-yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-(피리딘-2-일)-2H-테트라졸-5-일)-1H-피라졸-3-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-(pyridin-2-yl)-2H-tetrazol-5-yl)-1H-pyrazole) -3-yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(5-(피리딘-2-일)-1,3,4-옥사디아졸-2-일)-1H-피라졸-3-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl) -1H-pyrazol-3-yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(5-(피리딘-2-일)-1,3,4-옥사디아졸-2-일)이소옥사졸-3-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl) isoxazol-3-yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-(피리딘-2-일)-2H-테트라졸-5-일)이소옥사졸-3-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-(pyridin-2-yl)-2H-tetrazol-5-yl)isoxazole-3 -yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-(피리딘-2-일)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-(pyridin-2-yl)-2H-tetrazol-5-yl)thiazole-2- yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(2-사이클로헥실-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-cyclohexyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4-(morpholinomethyl)pyridine -2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(1-페닐-1H-1,2,3-트리아졸-4-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(1-phenyl-1H-1,2,3-triazol-4-yl)thiazole-2- yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(피페리딘-1-일메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4-(piperidin-1- ylmethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-((디메틸아미노)메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-((dimethylamino)methyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino) pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(피롤리딘-1-일메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4-(pyrrolidin-1- ylmethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피롤리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin- 2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyrimidine -2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(5-페닐-1,2,4-옥사디아졸-3-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,2,4-oxadiazol-3-yl)thiazol-2-yl) )amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-1H-이미다졸-4-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-1H-imidazol-4-yl)thiazol-2-yl)amino)pyridine- 2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin- 2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin- 2-yl)oxy)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(2-(2-클로로-6-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-(2-chloro-6-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4 -(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(2-(2-메톡시페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-(2-methoxyphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4-( morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl) )amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(2-(5-클로로-2-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-(5-chloro-2-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4 -(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(2-(2-클로로-6-플루오로페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-(2-chloro-6-fluorophenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino) -4-(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(2-(1-메틸-1H-피라졸-4-일)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-(1-methyl-1H-pyrazol-4-yl)-2H-tetrazol-5-yl)thiazol-2-yl) )amino)-4-(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((6-((5-(2-(4-브로모페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-(4-bromophenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4-( morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)부트-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin- 2-yl)amino)piperidin-1-yl)but-2-en-1-one;
(S)-1-(3-((4-메톡시-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-methoxy-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin-2-yl )amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-메틸-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-methyl-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin-2-yl) amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-메틸-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-methyl-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine -2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-인-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin- 2-yl)amino)piperidin-1-yl)prop-2-yn-1-one;
(S)-1-(3-((6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피라진-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온(S)-1-(3-((6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyrazin-2-yl)amino)piperi Din-1-yl) prop-2-en-1-one
1-((S)-3-((4-(((2S,6R)-2,6-디메틸몰포리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온; 및,1-((S)-3-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxa) diazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one; and,
(S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온.(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyrimidine -2-yl)amino)piperidin-1-yl)prop-2-en-1-one.
화학식 1의 화합물은 검출가능한 표지로 치환된 것일 수 있다. 상기 검출가능한 표지는 광학적 표지, 전기적 표지, 자기적 표지, 또는 간접 표지일 수 있다. 광학적 표지는 검출가능한 광학적 신호를 발생시키는 물질로서, 방사성 물질, 또는 형광 물질과 같은 발색 물질일 수 있다. 간접 표지는 기질을 발색 물질로 전환시키는 효소 또는 그 기질, 항체 또는 항원과 같이 특정 물질과 결합한 결과, 검출가능한 표지를 발생시킬 수 있는 물질을 나타낸다. 상기 광학적 표지는 화학식 1의 화합물을 구성하는 원소의 동위원소일 수 있다. 따라서, 화학식 1의 화합물은 그를 구성하는 원소 중 하나 이상이 그의 동위원소, 예를 들면 방사성 동위원소로 치환된 것일 수 있다. 상기 동위원소의 예는 2H(중수소를 의미하는 D로 나타낼 수 있음),　3H(삼중수소를 의미하는 T로 나타낼 수 있음), 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36Cl, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I, 131I 등을 포함한다. The compound of Formula 1 may be substituted with a detectable label. The detectable label may be an optical label, an electrical label, a magnetic label, or an indirect label. The optical label is a material that generates a detectable optical signal, and may be a radioactive material or a chromogenic material such as a fluorescent material. Indirect label refers to a substance capable of generating a detectable label as a result of binding to a specific substance, such as an enzyme that converts a substrate into a chromogenic substance or its substrate, antibody or antigen. The optical label may be an isotope of an element constituting the compound of Formula 1. Accordingly, in the compound of Formula 1, one or more of the elements constituting the compound may be substituted with an isotope thereof, for example, a radioactive isotope. Examples of the isotopes include 2 H (which may be represented by D for deuterium), 3 H (which may be represented as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, 131 I, and the like.
본 개시의 화합물은 그의 약제학적으로 허용가능한 염의 형태일 수 있다. 상기 염은 제약 분야에서 사용되는 통상의 산 부가염, 예를 들면 염산, 브롬산, 황산, 설팜산, 인산 또는 질산과 같은 무기산으로부터 유도된 염 및 아세트산, 프로피온산, 숙신산, 글리콜산, 스테아르산, 시트르산, 말레산, 말론산, 메탄술폰산, 타르타르산, 말산, 페닐아세트산, 글루탐산, 벤조산, 살리실산, 2-아세톡시벤조산, 푸마르산, 톨루엔술폰산, 옥살산 또는 트리플루오로아세트산과 같은 유기산으로부터 유도된 염을 포함한다. 또한, 상기 염은 통상의 금속 염 형태, 예를 들면 리튬, 소듐, 칼륨, 마그네슘, 또는 칼슘과 같은 금속으로부터 유도된 염을 포함한다. 상기 산 부가염 또는 금속염은 통상의 방법에 따라 제조될 수 있다. A compound of the present disclosure may be in the form of a pharmaceutically acceptable salt thereof. These salts include the customary acid addition salts used in the pharmaceutical field, for example salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid or nitric acid and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, including salts derived from organic acids such as citric acid, maleic acid, malonic acid, methanesulfonic acid, tartaric acid, malic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, oxalic acid or trifluoroacetic acid do. The salts also include conventional metal salt forms, for example salts derived from metals such as lithium, sodium, potassium, magnesium, or calcium. The acid addition salt or metal salt may be prepared according to a conventional method.
본 개시의 화합물은 또한 그의 용매화물(solvate)의 형태일 수 있다. "용매화물"이란 하나 이상의 용질 분자, 즉 화학식 1의 화합물, 또는 그의 입체이성질체 또는 약제학적으로 허용가능한 염, 및 하나 이상의 용매 분자에 의해 형성되는 복합체 또는 집합체를 의미한다. 용매화물은 예를 들면 물, 메탄올, 에탄올, 이소프로판올, 아세트산, 또는 디메틸술폭시드(DMSO)와 형성된 복합체 또는 집합체일 수 있다.The compounds of the present disclosure may also be in the form of their solvates. "Solvate" means a complex or aggregate formed by one or more solute molecules, ie a compound of Formula 1, or a stereoisomer or pharmaceutically acceptable salt thereof, and one or more solvent molecules. The solvate may be, for example, a complex or aggregate formed with water, methanol, ethanol, isopropanol, acetic acid, or dimethylsulfoxide (DMSO).
본 개시의 화합물은 또한 그의 입체이성질체의 형태일 수 있다. 상기 입체이성질체는 거울상 이성질체(enantiomer) 및 부분입체이성질체(diastereomer)와 같은 모든 입체이성질체를 포함한다. 상기 화합물은 입체이성질체의 순수 형태(stereoisomerically pure form) 또는 하나 이상의 입체이성질체의 혼합물, 예를 들면 라세미 혼합물일 수 있다. 특정 입체이성질체의 분리는 당해 분야에 공지된 통상의 방법 중 하나에 의해 수행될 수 있다. 본 개시의 화합물의 일부 예는 그 라세미 혼합물에 비하여 특정 입체이성질체의 BTK 억제 효과가 더 큰 것일 수 있다. 이 경우, 특정 입체이성질체를 사용함으로써, 투여량을 줄일 수 있다.The compounds of the present disclosure may also be in the form of their stereoisomers. The stereoisomer includes all stereoisomers such as enantiomers and diastereomers. The compound may be in a stereoisomerically pure form or a mixture of one or more stereoisomers, for example a racemic mixture. Separation of specific stereoisomers can be carried out by one of the conventional methods known in the art. Some examples of the compounds of the present disclosure may have a greater BTK inhibitory effect of a specific stereoisomer than that of the racemic mixture. In this case, the dosage can be reduced by using a specific stereoisomer.
본 개시의 화합물, 조성물 및 방법과 관련하여, 달리 나타내지 않는다면 하기의 용어는 하기의 의미를 갖는다. With respect to the compounds, compositions and methods of the present disclosure, unless otherwise indicated, the following terms have the following meanings.
용어 "알킬(alkyl)"은 직쇄상 또는 분지상의 포화 탄화수소기를 의미한다. 상기 알킬은 1 내지 10개, 1 내지 8개, 1 내지 6개, 1 내지 4개, 또는 1 내지 3개의 탄소 원자를 포함할 수 있다. 알킬은 예를 들면, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, t-부틸, n-펜틸, 이소펜틸, 네오펜틸, n-헥실, n-헵틸, n-옥틸, n-노닐 또는 n-데실을 포함할 수 있다. The term “alkyl” refers to a straight-chain or branched saturated hydrocarbon group. The alkyl may contain 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl.
용어 "알케닐(alkenyl)"은 적어도 하나의 탄소-탄소 이중 결합을 갖는 알킬을 의미한다. 여기서 알킬은 위에서 정의된 바와 같다. 알케닐은 예를 들면, 에테닐 또는 프로페닐일 수 있다.The term “alkenyl” means an alkyl having at least one carbon-carbon double bond. wherein alkyl is as defined above. Alkenyl can be, for example, ethenyl or propenyl.
용어 "알키닐(alkynyl)"은 적어도 하나의 탄소-탄소 삼중 결합을 갖는 알킬을 의미한다. 여기서 알킬은 위에서 정의된 바와 같다. 알키닐은 예를 들면, 에티닐 또는 2-프로피닐일 수 있다.The term “alkynyl” means an alkyl having at least one carbon-carbon triple bond. wherein alkyl is as defined above. Alkynyl can be, for example, ethynyl or 2-propynyl.
용어 "알콕시(alkoxy)"는(알킬)O-기를 나타낸다. 여기서 알킬은 위에서 정의된 바와 같다. The term "alkoxy" refers to an (alkyl)O- group. wherein alkyl is as defined above.
용어 "아릴(aryl)"은 고리를 형성하는 각 원자가 탄소 원자인 방향족 고리를 나타낸다. 상기 고리는 단환 또는 다환일 수 있다. 상기 다환은 융합된 고리(fused ring)를 갖는 것(예; 나프탈렌) 또는 융합되지 않은 고리를 갖는 것(예; 비페닐)을 포함할 수 있다. 상기 다환은 예를 들면, 2개, 3개 또는 4개의 고리를 갖는 것일 수 있다. 상기 아릴기는 예를 들면, 5개 이상, 6개 이상, 7개 이상, 8개 이상, 9개 이상, 10개 이상, 5 내지 20개, 5 내지 15개, 5 내지 12개, 5 내지 10개, 또는 6 내지 10개의 탄소 고리 원자를 가진다. 상기 아릴기는 예를 들면, 페닐, 나프탈레닐(예, 나프탈렌-1-일 및 나프탈렌-2-일), 비페닐, 안트라세닐, 및 페난트레닐을 포함한다. The term "aryl" denotes an aromatic ring in which each atom forming the ring is a carbon atom. The ring may be monocyclic or polycyclic. The polycyclic ring may include one having a fused ring (eg, naphthalene) or one having an unfused ring (eg, biphenyl). The polycyclic ring may have, for example, 2, 3 or 4 rings. The aryl group is, for example, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 5 to 20, 5 to 15, 5 to 12, 5 to 10 , or 6 to 10 carbon ring atoms. Such aryl groups include, for example, phenyl, naphthalenyl (eg, naphthalen-1-yl and naphthalen-2-yl), biphenyl, anthracenyl, and phenanthrenyl.
용어 "사이클로알킬(cycloalkyl)"은 고리를 형성하는 각 원자가 탄소 원자인 비방향성 탄소 고리를 나타낸다. 상기 사이클로알킬은 단환 또는 다환일 수 있다. 상기 다환은 예를 들면, 2개, 3개 또는 4개의 융합된 고리를 갖는 것이다. 상기 사이클로알킬은 방향족 고리에 융합된 것을 포함할 수 있다. 상기 사이클로알킬은 예를 들면, 3개 이상, 4개 이상, 5개 이상, 6개 이상, 7개 이상, 3 내지 10개, 3 내지 7개, 5 내지 7개, 또는 5 내지 6개의 고리 탄소 원자를 포함한다. 사이클로알킬은 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸, 사이클로헥사디에닐, 사이클로헵타트리에닐, 노르보르닐, 노르카닐, 및 아다만틸을 포함한다.The term “cycloalkyl” denotes a non-aromatic carbocyclic ring in which each atom forming the ring is a carbon atom. The cycloalkyl may be monocyclic or polycyclic. The polycyclic ring is one having, for example, 2, 3 or 4 fused rings. The cycloalkyl may include those fused to an aromatic ring. The cycloalkyl is, for example, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 3 to 10, 3 to 7, 5 to 7, or 5 to 6 ring carbons. contains atoms. Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norcanyl, and adamantyl.
용어 "헤테로사이클로알킬(heterocycloalkyl)"은 각각 N, O, 및 S로부터 선택된 1 내지 4개의 고리를 형성하는 헤테로원자를 포함하는 비방향족 탄소 고리를 의미한다. 헤테로사이클로알킬은 2개의 이웃하는 O 또는 S를 갖지 않는 것일 수 있다. 헤테로사이클로알킬은 단환 혹은 다환 구조, 예를 들면, 2개, 3개 또는 4개의 융합된 고리를 갖는 구조를 포함한다. "헤테로사이클로알킬"의 예는 몰포리닐, 티오몰포리닐, 피페라지닐, 테트라히드로푸라닐, 테트라히드로티에닐, 2,3-디히드로벤조푸릴, 1,3-벤조디옥솔, 벤조-1,4-디옥세인, 피페리디닐, 피롤리디닐, 이소옥사졸리디닐, 이소티아졸리디닐, 피라졸리디닐, 옥사졸리디닐, 티아졸리디닐 등을 포함한다. 상기 헤테로사이클로알킬은 예를 들면, 3개 이상, 4개 이상, 5개 이상, 6개 이상, 7개 이상, 3개 내지 10개, 4개 내지 10개, 3개 내지 7개, 5개 내지 7개 또는 5개 내지 6개의 고리를 형성하는 원자를 포함한다.The term “heterocycloalkyl” refers to a non-aromatic carbon ring comprising heteroatoms forming one to four rings each selected from N, O, and S. Heterocycloalkyl may be one that does not have two adjacent O or S. Heterocycloalkyl includes monocyclic or polycyclic structures, for example structures with 2, 3 or 4 fused rings. Examples of "heterocycloalkyl" include morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo- 1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, and the like. The heterocycloalkyl is, for example, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 3 to 10, 4 to 10, 3 to 7, 5 to contains atoms forming 7 or 5 to 6 rings.
용어 "헤테로아릴(heteroaryl)"은 N, O 및 S로부터 선택된 1 내지 4개의 헤테로 원자를 고리 구성원으로 갖는 방향성 탄소 고리를 의미한다. 헤테로아릴은 단환 혹은 다환 구조를 포함한다. 상기 다환은 예를 들면, 2개, 3개 또는 4개의 축합 고리를 갖는 것일 수 있다. 상기 헤테로아릴은 예를 들면, 3 내지 10개, 5 내지 10개, 5 내지 8개, 5 내지 7개, 5개, 6개, 또는 7개의 고리 원자를 포함한다. 상기 헤테로아릴은 1개, 2개 또는 3개의 헤테로원자를 포함하는 것일 수 있다. 헤테로아릴은 예를 들면, 피리딜, N-옥소피리딜, 피리미디닐, 피라지닐, 피리다지닐, 트리아지닐, 푸릴, 퀴놀릴, 이소퀴놀릴, 티에닐, 이미다졸릴, 푸라닐, 티아졸릴, 인돌릴, 피릴, 옥사졸릴, 벤조푸릴, 벤조티에닐, 벤즈티아졸릴, 이소옥사졸릴, 피라졸릴, 트리아졸릴, 테트라졸릴, 인다졸릴, 1,2,4-티아디아졸릴, 이소티아졸릴, 벤조티에닐, 푸리닐, 벤즈이미다졸릴, 또는 인돌리닐을 포함한다. The term "heteroaryl" refers to an aromatic carbon ring having 1 to 4 heteroatoms selected from N, O and S as ring members. Heteroaryl includes monocyclic or polycyclic structures. The polycyclic ring may have, for example, 2, 3 or 4 condensed rings. The heteroaryl contains, for example, 3 to 10, 5 to 10, 5 to 8, 5 to 7, 5, 6, or 7 ring atoms. The heteroaryl may include 1, 2 or 3 heteroatoms. Heteroaryl is, for example, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, furanyl, thia Zolyl, indolyl, pyryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl , benzothienyl, purinyl, benzimidazolyl, or indolinyl.
용어 "할로(halo)" 또는 “할로겐(halogen)”은 플루오로, 클로로, 브로모, 또는 요오도를 나타낸다.The term “halo” or “halogen” refers to fluoro, chloro, bromo, or iodo.
다른 양상은 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염, 및 약제학적으로 허용가능한 담체를 포함하는 단백질 키나제에 의하여 매개되는 질환을 치료하는데 사용하기 위한 약제학적 조성물을 제공한다. 상기 질환은 상기 단백질 키나제 활성의 증가에 의하여 발생하는 것일 수 있다.Another aspect provides a pharmaceutical composition for use in treating a disease mediated by a protein kinase comprising a compound of Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The disease may be caused by an increase in the protein kinase activity.
상기 단백질 키나제는 다른 단백질에 인산기를 부가하는 반응을 촉매하는 것일 수 있다. 상기 단백질 키나제는 세린/트레오닌-특이적 단백질 키나제, 티로신-특이적 단백질 키나제, 또는 세린/트레오닌 및 티로신 단백질 키나제일 수 있다. 상기 단백질 키나제는 수용체 또는 비수용체 단백질 키나제일 수 있다. 수용체 단백질 키나제는 예를 들면, PDGFR 또는 VEGFR을 포함한다. 상기 비수용체 단백질 키나제는 세포내 단백질의 구성원일 수 있다. 상기 비수용체 단백질 키나제는 Syk, SRC, 또는 Tec 패밀리의 구성원일 수 있다.The protein kinase may catalyze a reaction of adding a phosphate group to another protein. The protein kinase may be a serine/threonine-specific protein kinase, a tyrosine-specific protein kinase, or a serine/threonine and tyrosine protein kinase. The protein kinase may be a receptor or a non-receptor protein kinase. Receptor protein kinases include, for example, PDGFR or VEGFR. The non-receptor protein kinase may be a member of an intracellular protein. The non-receptor protein kinase may be a member of the Syk, SRC, or Tec family.
cSRC는 Lyn, Fyn, Lck, Hck, Fgr, Blk, Syk, Yrk 및 Yes를 포함하는 티로신 키나제의 SRC 패밀리의 원형 구성원이다. cSRC is a prototypical member of the SRC family of tyrosine kinases including Lyn, Fyn, Lck, Hck, Fgr, Blk, Syk, Yrk and Yes.
Tec 키나제는 혈액학적 기원의 세포에서 주로 발현되는 비수용체 티로신 키나제일 수 있다. Tec 패밀리는 Tec, Btk, 유도성 T-세포 키나제(Itk), 휴식 림프구 키나제(Rlk/Txk) 및 골수 발현 키나제(Bmx/Etk)를 포함한다.The Tec kinase may be a non-receptor tyrosine kinase expressed primarily in cells of hematological origin. The Tec family includes Tec, Btk, inducible T-cell kinase (Itk), resting lymphocyte kinase (Rlk/Txk) and myeloid expression kinase (Bmx/Etk).
상기 조성물에 있어서, 브루톤스 티로신 키나제(Bruton's Tyrosine Kinase: BTK)는 티로신 키나제의 Tec 패밀리의 일원이고, 초기 B 세포 발생, 성숙한 B 세포 활성화, 신호전달 및 생존의 핵심적 조절자이다. B 세포 수용체(BCR)를 통한 B 세포 신호전달은 넓은 범위의 생물학적 아웃풋을 야기한다. 비정상적 BCR-매개 신호전달은 조절이 해제된 B 세포 증식 및/또는 다중 자가면역 질환 및/또는 염증질환을 야기하는 병인성 자가항체의 형성을 야기할 수 있다. 사람에서 BTK의 돌연변이는 X-연관 무감마글로불린혈증(X-linked agammaglobulinaemia: XLA)을 야기할 수 있다. 이 질병은 B 세포의 손상된 성숙, 감소된 면역글로불린 생산, T 세포 독립적 면역 반응, 및 BCR 자극에 대한 지속된 칼슘 신호의 현저한 약화와 연관된다.In the composition, Bruton's Tyrosine Kinase (BTK) is a member of the Tec family of tyrosine kinases and is a key regulator of early B cell development, mature B cell activation, signaling and survival. B cell signaling through the B cell receptor (BCR) results in a wide range of biological outputs. Abnormal BCR-mediated signaling can lead to deregulated B cell proliferation and/or the formation of etiological autoantibodies leading to multiple autoimmune and/or inflammatory diseases. Mutations in BTK in humans can cause X-linked agammaglobulinaemia (XLA). The disease is associated with impaired maturation of B cells, decreased immunoglobulin production, T cell independent immune responses, and marked attenuation of sustained calcium signaling in response to BCR stimulation.
상기 단백질 키나제는 시스테인-함유 키나제일 수 있다. 상기 단백질 키나제는 키나제의 ATP-결합 부위 근처에 시스테인 잔기를 갖는 것일 수 있다. 상기 시스테인 잔기는 키나제의 ATP-결합 부위 근처에 가까운 공간적 근접(close spatial proximity)에 있는 것일 수 있다. ATP-결합 부위 근처에 시스테인 잔기를 갖는 단백질 키나제는 BTK, BMX, TEC, TXK, ITK, EGFR, ErbB, JAK3, BLK 등일 수 있다.The protein kinase may be a cysteine-containing kinase. The protein kinase may have a cysteine residue near the ATP-binding site of the kinase. The cysteine residue may be in close spatial proximity to the ATP-binding site of the kinase. The protein kinase having a cysteine residue near the ATP-binding site may be BTK, BMX, TEC, TXK, ITK, EGFR, ErbB, JAK3, BLK, and the like.
구체예에서, 상기 단백질 키나제는 ABL, ACK1, ALK, Aurora A, Aurora B, Aurora C, BLK, BMX/ETK, BRSK1, BTK, c-Src, CAMKK, CDK1, CDK2, CDK5, CLK, DDR, DYRK1B, EPHA, EPHB, FAK/PTK2, FER, FES/FPS, FGFR, FGR, FLT3, FLT4/VEGFR3, FMS, FRK/PTK5, FYN, GSK3b, HCK, IGF1R, IR, IRAK1, IRR/INSRR, ITK, JAK2, KHS/MAP4K5, LCK, LYN, PHKg, PLK4/SAK, PYK2, RET, ROS/ROS1, TIE2/TEK, TRK, TXK, TYK, YES/YES1, 또는 이들의 조합일 수 있다.In an embodiment, the protein kinase is ABL, ACK1, ALK, Aurora A, Aurora B, Aurora C, BLK, BMX/ETK, BRSK1, BTK, c-Src, CAMKK, CDK1, CDK2, CDK5, CLK, DDR, DYRK1B , EPHA, EPHB, FAK/PTK2, FER, FES/FPS, FGFR, FGR, FLT3, FLT4/VEGFR3, FMS, FRK/PTK5, FYN, GSK3b, HCK, IGF1R, IR, IRAK1, IRR/INSRR, ITK, JAK2 , KHS/MAP4K5, LCK, LYN, PHKg, PLK4/SAK, PYK2, RET, ROS/ROS1, TIE2/TEK, TRK, TXK, TYK, YES/YES1, or a combination thereof.
단백질 키나제, 예를 들면 BTK 활성의 저해는 하기 자가면역 및/또는 염증 질환을 치료하는데 유용할 수 있다. 더욱이, 단백질 키나제, 예를 들면 BTK는 세포자가사(apoptosis)에 역할을 하는 것으로 보고되었다. 단백질 키나제, 예를 들면 BTK 활성의 저해는 B-세포 증식성 장애 또는 비만세포 증식성 장애를 치료하는데 유용할 수 있다. 단백질 키나제, 예를 들면 BTK 활성의 저해는 B 세포 림프종 및 백혈병(leukemia)과 같은 암을 치료하는데 유용할 수 있다. 상기 조성물에 있어서, 상기 질환은 암, 염증 질환, 또는 자가면역 질환일 수 있다. 상기 암은 고형암 또는 혈액암일 수 있다. 상기 혈액암은 림프종, 백혈병, 다발성 골수종, 형질세포 골수종(plasma cell myeloma) 또는 골수이형성증후군일 수 있다.Inhibition of protein kinases, such as BTK activity, may be useful for treating the following autoimmune and/or inflammatory diseases. Moreover, protein kinases, such as BTK, have been reported to play a role in apoptosis. Inhibition of protein kinase, eg, BTK activity, may be useful for treating a B-cell proliferative disorder or a mast cell proliferative disorder. Inhibition of protein kinases, such as BTK activity, may be useful for treating cancers such as B cell lymphoma and leukemia. In the composition, the disease may be cancer, an inflammatory disease, or an autoimmune disease. The cancer may be a solid cancer or a blood cancer. The hematologic cancer may be lymphoma, leukemia, multiple myeloma, plasma cell myeloma or myelodysplastic syndrome.
상기 림프종은 맨틀세포 림프종(mantle cell lymphoma, MCL) 또는 비호지킨 림프종, 림프형질 림프종(lymphoplasmacytic lymphoma), 변연부B세포림프종(marginal zone lymphoma), 소 림프성 림프종(small lymphocytic lymphoma, SLL), 고위험 소 림프성 림프종(high-risk small lymphocytic lymphoma), 여포성 림프종(follicular lymphoma, FL), 미만성거대 B 세포 림프종(diffuse large B cell lymphoma, DLBCL), 발덴스트롬 거대글로불린혈증(Waldenstrom's macroglobulinemia), 버킷 림프종(Burkitt's lymphoma), 비버킷 고도 B세포 림프종(non-Burkitt high grade B cell lymphoma), 원발 원격동 B세포 림프종(primary mediastinal B-cell lymphoma, PMBL), 면역모세포성 대세포 림프종(immunoblastic large cell lymphoma), 전구 B 림프모구성 림프종(precursor B-lymphoblastic lymphoma), 비장변연부 림프종(splenic marginal zone lymphoma), 형질세포종(plasmacytoma), 종격동 거대 B 세포 림프종(mediastinal(thymic) large B cell lymphoma), 정맥내 거대 B 세포 림프종(intravascular large B cell lymphoma), 일차성 삼출 림프종(primary effusion lymphoma), 또는 림프종양 육아종증(lymphomatoid granulomatosis)일 수 있다. 상기 백혈병은 만성림프성 백혈병(chronic lymphocytic leukemia, CLL), 급성 림프모구성 백혈병(acute lymphoblastic leukemia, ALL), 또는 B 세포 전림프구성 백혈병(B cell prolymphocytic leukemia)일 수 있다.The lymphoma is mantle cell lymphoma (MCL) or non-Hodgkin's lymphoma, lymphoplasmacytic lymphoma, marginal zone lymphoma, small lymphocytic lymphoma (SLL), high-risk cattle High-risk small lymphocytic lymphoma, follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), Waldenstrom's macroglobulinemia, Burkitt's lymphoma ( Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma , precursor B-lymphoblastic lymphoma, splenic marginal zone lymphoma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravenous large It may be intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. The leukemia may be chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or B cell prolymphocytic leukemia.
고형암은 뇌종양, 두경부암, 폐암, 유방암, 흉선종, 중피종, 식도암, 대장암, 간암, 위암, 췌장암, 담도암, 신장암, 방광암, 전립선암, 고환암, 생식세포종, 난소암, 자궁 경부암, 자궁 내막암, 육종, 악성 흑색종 및 피부암을 포함한다.Solid cancers include brain tumor, head and neck cancer, lung cancer, breast cancer, thymoma, mesothelioma, esophageal cancer, colorectal cancer, liver cancer, stomach cancer, pancreatic cancer, biliary tract cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, germ cell tumor, ovarian cancer, cervical cancer, endometrial cancer cancer, sarcoma, malignant melanoma and skin cancer.
상기 염증 질환 및/또는 자가면역 질환은 전신성 홍반성 루푸스(SLE), 류마티스 관절염, 다발혈관염(multiple vasculitis), 특발저혈소판자색반병(idiopathic thrombocytopenic purpura, ITP), 중증근육무력증(myasthenia gravis), 천식, 만성이식편대숙주 질병(chronic graft vs host disease), 다발성 경화증(Multiple Screlosis), 쇼그렌 증후군(Sjogren's syndrome), 크론병(Crohn's disease), 베체트병(Behcet's Disease), 또는 1형 당뇨(Type 1 Diabetes)일 수 있다. 상기 질환은 본 개시의 약제학적 조성물이 적용될 수 있는 구체적인 질환을 예시한 것일 뿐, 본 개시의 범위가 상기 질환들로 제한되는 것은 아니다.The inflammatory disease and/or autoimmune disease is systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple vasculitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, asthma , chronic graft vs host disease, Multiple Screlosis, Sjogren's syndrome, Crohn's disease, Behcet's disease, or Type 1 Diabetes ) can be The above diseases only exemplify specific diseases to which the pharmaceutical composition of the present disclosure can be applied, and the scope of the present disclosure is not limited to the above diseases.
용어 "치료(treatment)"는 개체, 예를 들면 사람을 포함한 포유류에서 질환 또는 의학적 증상, 예를 들면 BTK-연관 질병을 치료함을 의미하고, 이는 다음을 포함한다: (a) 질환 또는 의학적 증상의 완화, 즉, 환자에서 질환 또는 의학적 증상의 제거 또는 회복 야기; (b) 질환 또는 의학적 증상의 억제, 즉, 개체에서 질환 또는 의학적 증상의 진행을 늦춤 또는 정지; 또는 (c) 개체에서 질환 또는 의학적 증상을 경감.The term "treatment" means treating a disease or medical condition, eg, a BTK-associated disease, in a subject, eg, a mammal, including a human, including: (a) a disease or medical condition alleviation of, ie, the elimination or recovery of, a disease or medical condition in a patient; (b) inhibiting the disease or medical condition, ie, slowing or arresting the progression of the disease or medical condition in a subject; or (c) alleviating the disease or medical condition in the subject.
상기한 화학식 1의 화합물 또는 그의 약제학적으로 허용가능한 염의 양은 당업자가 적절하게 선택할 수 있다. 상기 양은 0.01 ㎎ 내지 10,000 ㎎, 0.1 ㎎ 내지 1,000 ㎎, 1 ㎎ 내지 100 ㎎, 0.01 ㎎ 내지 1,000 ㎎, 0.01 ㎎ 내지 100 ㎎, 0.01 ㎎ 내지 10 ㎎, 또는 0.01 ㎎ 내지 1 ㎎일 수 있다.The amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof can be appropriately selected by those skilled in the art. The amount may be 0.01 mg to 10,000 mg, 0.1 mg to 1,000 mg, 1 mg to 100 mg, 0.01 mg to 1,000 mg, 0.01 mg to 100 mg, 0.01 mg to 10 mg, or 0.01 mg to 1 mg.
상기 조성물에 있어서, "약제학적으로 허용가능한 담체"는 활성 성분의 적용을 돕기 위하여 활성 성분과 조합되어 사용되는 물질, 일반적으로 불활성 물질을 나타낸다. 상기 담체는 통상적인 약제학적으로 허용가능한 부형제, 첨가제 또는 희석제를 포함한다. 상기 담체는 예를 들면 충전제(filler), 결합제(binder), 붕해제(disintegrant), 버퍼, 보존제, 항산화제, 활택제, 향미제, 점증제(thickener), 발색제(coloring agent), 유화제, 현탁화제, 안정화제, 및 등장화제로부터 선택된 하나 이상을 포함하는 것일 수 있다.In the above compositions, "pharmaceutically acceptable carrier" refers to a substance used in combination with the active ingredient to aid in application of the active ingredient, usually an inert substance. The carrier includes conventional pharmaceutically acceptable excipients, additives or diluents. The carrier may be, for example, a filler, a binder, a disintegrant, a buffer, a preservative, an antioxidant, a lubricant, a flavoring agent, a thickener, a coloring agent, an emulsifier, a suspending agent. It may include one or more selected from a topical agent, a stabilizer, and an isotonic agent.
본 개시의 조성물은 경구 투여 제형, 또는 정맥내, 복강내, 피하, 직장 및 국소투여를 포함한 비경구 투여 제형일 수 있다. 따라서, 본 개시의 조성물은 정제, 캡슐제, 수성액제 또는 현탁제 등의 다양한 형태로 제제화될 수 있다. 경구용 정제의 경우 락토즈, 옥수수 전분 등의 부형제 및 마그네슘 스테아레이트와 같은 활택제가 통상 가해질 수 있다. 경구투여용 캡슐제의 경우, 락토즈 및/또는 건조 옥수수 전분이 희석제로서 사용될 수 있다. 경구용 수성 현탁제가 필요할 경우, 활성성분을 유화제 및/또는 현탁화제와 결합시킬 수 있다. 필요할 경우, 특정 감미제 및/또는 향미제를 가할 수 있다. 근육내, 복강내, 피하 및 정맥내 투여의 경우, 활성성분의 멸균 용액이 통상 제조되며, 용액의 pH를 적합하게 조절하고 완충시킬 수 있다. 정맥내 투여의 경우, 용질의 총 농도는 제제에 등장성이 부여되도록 조절될 수 있다. 본 개시에 따른 조성물은 생리적 pH의 염수와 같은 약제학적으로 허용되는 담체를 포함하는 수용액제의 형태일 수 있다. 상기 용액은 국소 주사(local bolus injection)로 환자의 근육내 혈류에 도입될 수 있다.The composition of the present disclosure may be an oral dosage form, or a parenteral dosage form including intravenous, intraperitoneal, subcutaneous, rectal and topical administration. Accordingly, the composition of the present disclosure may be formulated in various forms such as tablets, capsules, aqueous solutions or suspensions. In the case of oral tablets, excipients such as lactose and corn starch and lubricants such as magnesium stearate may be usually added. In the case of capsules for oral administration, lactose and/or dry corn starch may be used as a diluent. If an aqueous suspension for oral use is required, the active ingredient may be combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, a sterile solution of the active ingredient is usually prepared, and the pH of the solution can be appropriately adjusted and buffered. For intravenous administration, the total concentration of solutes can be adjusted to render the formulation isotonic. The composition according to the present disclosure may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier, such as saline of physiological pH. The solution may be introduced into the patient's intramuscular bloodstream by local bolus injection.
본 개시에서 정의된 화학식 1의 화합물은 단백질 키나제 활성을 억제하는 효과를 보일 수 있다. 여기서 "억제(inhibition)"는 단백질 키나제의 키나제 활성을 감소시키는 것을 포함한다. 상기 단백질 키나제는 BTK일 수 있다. The compound of Formula 1 as defined in the present disclosure may exhibit an effect of inhibiting protein kinase activity. As used herein, “inhibition” includes reducing the kinase activity of a protein kinase. The protein kinase may be BTK.
약제학적 조성물은 단백질 키나제와 관련된 질환을 치료하기 위한 하나 이상의 다른 치료제와 함께 조합될 수 있다. 다른 치료제는 화학요법제, 항염증제, 면역억제제, 및 항암제를 포함한다. 다른 치료제의 예들은 신생혈관 형성 억제제(anti-angiogenic agent), MALT1, MCL-1 또는 IDH1 저해제, TLR9 저해제, Bcl-2, JAK2, ALK 또는 Hsp90 저해제, CYP3A4 저해제, BET 저해제, 면역 관문 억제제(immune checkpoint inhibitor), 항-CD20 치료제, HDAC 저해제, PIM 저해제, mTOR 저해제를 포함할 수 있다. 병용치료는 상승효과를 발생시킬 수 있다. 병용치료를 위한 약제는 단백질 키나제 억제제와 단회 투여 또는 연속적인 투여 형태로 병용할 수 있거나, 또는 동시에 또는 순차적으로 분리된 투여 형태로서 투여할 수 있다. 상기 단백질 키나제는 BTK일 수 있다.The pharmaceutical composition may be combined with one or more other therapeutic agents to treat a disease associated with a protein kinase. Other therapeutic agents include chemotherapeutic agents, anti-inflammatory agents, immunosuppressive agents, and anti-cancer agents. Examples of other therapeutic agents include anti-angiogenic agents, MALT1, MCL-1 or IDH1 inhibitors, TLR9 inhibitors, Bcl-2, JAK2, ALK or Hsp90 inhibitors, CYP3A4 inhibitors, BET inhibitors, immune checkpoint inhibitors checkpoint inhibitor), anti-CD20 therapeutics, HDAC inhibitors, PIM inhibitors, and mTOR inhibitors. Combination therapy may produce synergistic effects. The agent for combination therapy may be used in combination with the protein kinase inhibitor in a single administration or in a continuous dosage form, or may be administered in separate dosage forms simultaneously or sequentially. The protein kinase may be BTK.
다른 양상은 단백질 키나제와 연관된 질병의 치료에 있어서의 상기에서 정의된 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염의 용도를 제공한다.Another aspect provides the use of a compound of formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof, as defined above, in the treatment of a disease associated with protein kinase.
다른 양상은 단백질 키나제와 연관된 질병을 치료하기 위한 의약을 제조하는데 있어서, 상기에서 정의된 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염의 용도를 제공한다. Another aspect provides the use of a compound of formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof, as defined above, for the manufacture of a medicament for the treatment of a disease associated with protein kinase.
다른 양상은 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염, 및 약제학적으로 허용가능한 담체를 포함하는 단백질 키나제의 활성을 저해하는데 사용하기 위한 약제학적 조성물을 제공한다.Another aspect provides a pharmaceutical composition for use in inhibiting the activity of a protein kinase comprising a compound of Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
다른 양상은 치료학적 유효량의 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염을 개체에 투여하는 단계를 포함하는, 개체에서 단백질 키나제에 의하여 매개되는 질환을 치료하는 방법을 제공한다.Another aspect provides a method of treating a disease mediated by a protein kinase in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof.
상기 방법에 있어서, 투여경로는 환자의 상태에 따라 당업자가 적절하게 선택할 수 있다. 상기 투여는 경구, 비경구, 또는 국부 투여일 수 있다. 상기 개체는 포유동물, 예를 들면, 사람, 소, 돼지, 말, 또는 고양이일 수 있다.In the above method, the administration route may be appropriately selected by a person skilled in the art according to the condition of the patient. The administration may be oral, parenteral, or topical administration. The subject may be a mammal, such as a human, cow, pig, horse, or cat.
상기 방법에 있어서, "치료학적 유효량"은 치료를 필요로 하는 개체에게 투여되는 경우 치료 효과를 나타내기에 충분한 양을 의미한다. 투여량은 전술한 바와 같이 환자의 상태, 투여 경로, 주치의의 판단 등과 같은 다양한 인자들에 따라서 달라질 수 있다. 효과적인 투여량은 체외실험 또는 동물 모델 시험에서 얻어진 용량-반응곡선으로부터 추정할 수 있다. 투여되는 조성물에 존재하는 화합물의 비율 및 농도는 화학적 특성, 투여 경로, 치료적 투여량 등에 따라 결정될 수 있다. 상기 투여량은 개체에게 약 1 ㎍/㎏ 내지 약 1 g/㎏ per day, 또는 약 0.1 ㎎/㎏ 내지 약 500 ㎎/㎏ per day의 유효량으로 투여될 수 있다. 상기 용량은 개체의 나이, 체중, 감수성, 또는 증상에 따라 변경될 수 있다.In the above method, "therapeutically effective amount" means an amount sufficient to exhibit a therapeutic effect when administered to a subject in need of treatment. As described above, the dosage may vary depending on various factors such as the patient's condition, administration route, judgment of the attending physician, and the like. An effective dosage can be estimated from a dose-response curve obtained from an in vitro test or an animal model test. The proportion and concentration of the compound present in the composition to be administered may depend on the chemical nature, route of administration, therapeutic dosage, and the like. The dosage may be administered to an individual in an effective amount of about 1 μg/kg to about 1 g/kg per day, or about 0.1 mg/kg to about 500 mg/kg per day. The dose may be changed according to the age, weight, sensitivity, or symptoms of the individual.
상기 방법에 있어서, 상기 질환은 상기 약제학적 조성물에 대해 기재된 것일 수 있다. 상기 질환은 본 개시의 방법이 적용될 수 있는 구체적인 질환을 예시한 것일 뿐, 본 개시의 범위가 상기 질환들로 제한되는 것은 아니다.In the method, the disease may be the one described for the pharmaceutical composition. The above diseases are merely illustrative of specific diseases to which the method of the present disclosure can be applied, and the scope of the present disclosure is not limited to the above diseases.
또한, 치료학적으로 유효량의 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염은 단백질 키나제, 예를 들면 BTK와 관련된 질환을 치료하기 위한 하나 이상의 다른 치료제와 함께 조합되어 투여될 수 있다. In addition, a therapeutically effective amount of a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be administered in combination with one or more other therapeutic agents for treating a disease associated with a protein kinase, for example, BTK. .
다른 양상은 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염을 단백질 키나제, 예를 들면 브루톤스 티로신 키나제(BTK)와 접촉시키는 단계를 포함하는 브루톤스 티로신 키나제(BTK)의 활성을 저해하는 방법을 제공한다. Another aspect relates to the activity of Bruton's tyrosine kinase (BTK) comprising contacting a compound of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof with a protein kinase, for example Bruton's tyrosine kinase (BTK). provide a way to inhibit it.
상기 접촉시키는 단계는 엑스 비보 또는 인 비트로에서 수행되는 것일 수 있다. 상기 접촉시키는 단계는 화학식 1의 화합물 또는 그의 약제학적으로 허용가능한 염 및 단백질 키나제, 예를 들면 브루톤스 티로신 키나제(BTK)을 포함하는 매질 중에서 인큐베이션하는 단계를 포함할 수 있다. 상기 매질은 액체, 예를 들면, 물, 또는 유기 용매와 같은 액체 매질일 수 있다. 상기 접촉시키는 단계는 상기 화학식 1의 화합물 또는 그의 약제학적으로 허용가능한 염을 개체에게 투여하고, 개체 내에서 단백질 키나제, 예를 들면 브루톤스 티로신 키나제(BTK)와 접촉하도록 하는 것을 포함할 수 있다. The contacting may be performed ex vivo or in vitro. The contacting may include incubating in a medium containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof and a protein kinase, for example, Brutons tyrosine kinase (BTK). The medium may be a liquid, for example water, or a liquid medium such as an organic solvent. The contacting may include administering the compound of Formula 1 or a pharmaceutically acceptable salt thereof to an individual, and allowing the individual to contact with a protein kinase, for example, Bruton's tyrosine kinase (BTK).
구체예에서, 일 양상에 따른 화학식 1의 화합물 중 m이 1인 메틸렌을 포함하는 화합물은 아래와 같은 반응식 1에 따라 제조될 수 있다:In an embodiment, in the compound of Formula 1 according to an aspect, a compound including methylene in which m is 1 may be prepared according to Scheme 1 as follows:
[반응식 1][Scheme 1]
Figure PCTKR2021013380-appb-I000004
Figure PCTKR2021013380-appb-I000004
상기 반응식 1에서, Hal은 할로겐을 나타내고, P는 보호기를 나타낸다. 상기 반응식 1에서, Cy, R1, R2, L1, L2, A, X, Y, Z 및 n은 화학식 1에서 정의된 바와 같다.In Scheme 1, Hal represents halogen and P represents a protecting group. In Scheme 1, Cy, R 1 , R 2 , L 1 , L 2 , A, X, Y, Z and n are as defined in Formula 1.
상기 반응식 1에 있어서, 단계 (1-1)에서는 화학식 1-Ⅵa와 화학식 1-Ⅶ의 화합물을 반응시켜 화학식 1-Ⅵb의 화합물을 제조할 수 있다. 본 반응은 아미드 반응으로 N-(3-디메틸아미노프로필)-N'-에틸카보디이미드 염산염, 히드록시벤조트리아졸, (1-[비스(디메틸아미노)메틸렌]-1H-1,2,3-트리아졸로[4,5-b]피리디늄 3-옥시드 헥사플루오로포스페이트, 1,1'-카보닐디이미다졸 존재 하에 유기용매, 예를 들어. N,N-디메틸포름아미드, 디클로로메탄 중에서 수행될 수 있다. In Scheme 1, in step (1-1), a compound of Formula 1-VIb may be prepared by reacting a compound of Formula 1-VIa with a compound of Formula 1-VII. This reaction is an amide reaction with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, hydroxybenzotriazole, (1-[bis(dimethylamino)methylene]-1H-1,2,3) -triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, in the presence of 1,1'-carbonyldiimidazole in an organic solvent such as N,N-dimethylformamide, dichloromethane can be performed.
단계 (1-2)에서는 단계 (1-1)에서 얻은 화학식 1-Ⅵb의 카보닐 그룹을 환원시켜 화학식 1-Ⅳ의 화합물을 제조할 수 있다. 본 반응은 보란 존재 하에 유기용매, 예를들어 테트라하이드로퓨란 중에서 수행될 수 있다.In step (1-2), the compound of formula 1-IV may be prepared by reducing the carbonyl group of formula 1-VIb obtained in step (1-1). This reaction can be carried out in an organic solvent, for example, tetrahydrofuran in the presence of borane.
단계 (1-3)에서는 화학식 1-Ⅳ의 화합물과 화학식 Ⅴ의 화합물을 반응시켜 화학식 1-Ⅱa의 화합물을 제조할 수 있다. 본 반응은 트리스(디벤질인덴아세톤)디팔라듐, 잔포스, 및 나트륨-t-부톡사이드 존재 하에 극성 유기용매, 예를 들어 디옥산 중에서 수행될 수 있다.In step (1-3), the compound of Formula 1-IIa can be prepared by reacting the compound of Formula 1-IV with the compound of Formula V. This reaction can be carried out in a polar organic solvent such as dioxane in the presence of tris(dibenzylindeneacetone)dipalladium, xanphos, and sodium-t-butoxide.
단계 (1-4)에서는 화학식 1-Ⅱa의 화합물의 할로겐 그룹이 아미노 그룹으로 치환된 화학식 1-Ⅱb의 화합물을 제조할 수 있다. 본 반응은 포타슘카보네이트, 커퍼옥사이드, N,N'-디메틸에틸렌디아민, 및 암모니아수 존재 하에 유기용매, 예를 들어 글리콜 용매, 특히 에틸렌글리콜 중에서 수행될 수 있다In step (1-4), a compound of Formula 1-IIb in which the halogen group of the compound of Formula 1-IIa is substituted with an amino group can be prepared. This reaction can be carried out in an organic solvent, for example, a glycol solvent, especially ethylene glycol, in the presence of potassium carbonate, copper peroxide, N,N'-dimethylethylenediamine, and aqueous ammonia.
단계 (1-5)에서는, 단계 (1-4)에서 얻은 화학식 1-Ⅱb의 화합물과 화학식 Ⅲ의 화합물을 반응시켜 화학식 1-Ⅰa의 화합물을 제조할 수 있다. 본 반응은 단계 (1-3)과 동일한 시약이나 용매를 사용하여 수행될 수 있다.In step (1-5), the compound of formula 1-Ia can be prepared by reacting the compound of formula 1-IIb obtained in step (1-4) with the compound of formula III. This reaction can be carried out using the same reagents or solvents as in step (1-3).
단계 (1-6)에서는, 강산, 예를 들어 염산, 특히 4N 염산 존재 하에 유기용매, 예를 들어 C1-C4 알코올, 특히 메탄올 중에서 단계 (1-5)에서 얻은 화학식 1-Ⅰa의 화합물로부터 보호기를 제거하여 화학식 1-Ⅰb의 화합물을 제조할 수 있다. In step (1-6), the compound of formula 1-Ia obtained in step (1-5) in the presence of a strong acid, for example hydrochloric acid, in particular 4N hydrochloric acid, in an organic solvent, for example a C 1 -C 4 alcohol, especially methanol A compound of Formula 1-Ib may be prepared by removing the protecting group from
단계 (1-7)에서는, 단계 (1-6)에서 얻은 화학식 1-Ⅰb의 화합물에 아실 기를 도입하여 화학식 (Ⅰ)의 화합물을 제조할 수 있다. 본 반응은 유기용매, 예를 들어 테트라하이드로퓨란 및 물 중에서 탄산수소나트륨 존재 하에 아크릴로일 화합물, 예를 들어 아크릴로일 할라이드, 특히 아크릴로일 클로라이드와 반응시켜 수행될 수 있다.In step (1-7), the compound of formula (I) can be prepared by introducing an acyl group into the compound of formula 1-Ib obtained in step (1-6). This reaction can be carried out by reacting with an acryloyl compound such as acryloyl halide, particularly acryloyl chloride in the presence of sodium hydrogen carbonate in an organic solvent such as tetrahydrofuran and water.
구체예에서, 일 양상에 따른 화학식 1의 화합물 중 m이 0인 화합물은 아래와 같은 반응식 2에 따라 제조될 수 있다.In an embodiment, the compound in which m is 0 among the compounds of Formula 1 according to an aspect may be prepared according to Scheme 2 as follows.
[반응식 2][Scheme 2]
Figure PCTKR2021013380-appb-I000005
Figure PCTKR2021013380-appb-I000005
상기 반응식 2에서, Hal은 할로겐을 나타내고, P는 보호기를 나타낸다. 상기 반응식 2에서, Cy, R1, R2, L1, L2, A, X, Y, Z 및 n은 화학식 1에서 정의된 바와 같다.In Scheme 2, Hal represents halogen and P represents a protecting group. In Scheme 2, Cy, R 1 , R 2 , L 1 , L 2 , A, X, Y, Z and n are as defined in Formula 1.
단계 (2-1)에서는 화학식 2-Ⅳ의 화합물과 화학식 Ⅴ의 화합물을 반응시켜 화학식 2-Ⅱa의 화합물을 제조할 수 있다. 본 반응은 트리스(디벤질인덴아세톤)디팔라듐, 잔포스, 및 나트륨-t-부톡사이드 존재 하에 극성 유기용매, 예를 들어 디옥산 중에서 수행될 수 있다.In step (2-1), a compound of Formula 2-IIa may be prepared by reacting a compound of Formula 2-IV with a compound of Formula V. This reaction can be carried out in a polar organic solvent such as dioxane in the presence of tris(dibenzylindeneacetone)dipalladium, xanphos, and sodium-t-butoxide.
단계 (2-2)에서는 화학식 2-Ⅱa의 화합물의 할로겐 그룹이 아미노 그룹으로 치환된 화학식 (2-Ⅱb)의 화합물을 제조할 수 있다. 본 반응은 포타슘카보네이트, 커퍼옥사이드, N,N'-디메틸에틸렌디아민, 및 암모니아수 존재 하에 유기용매, 예를 들어 글리콜 용매, 특히 에틸렌글리콜 중에서 수행될 수 있다.In step (2-2), a compound of formula (2-IIb) in which the halogen group of the compound of formula 2-IIa is substituted with an amino group can be prepared. This reaction may be carried out in an organic solvent, for example, a glycol solvent, particularly ethylene glycol, in the presence of potassium carbonate, copper peroxide, N,N'-dimethylethylenediamine, and aqueous ammonia.
단계 (2-3)에서는, 단계 (2-2)에서 얻은 화학식 2-Ⅱb의 화합물과 화학식 Ⅲ의 화합물을 반응시켜 화학식 2-Ⅰa의 화합물을 제조할 수 있다. 본 반응은 단계 (2-1)과 동일한 시약이나 용매를 사용하여 수행될 수 있다.In step (2-3), the compound of formula 2-Ia can be prepared by reacting the compound of formula 2-IIb obtained in step (2-2) with the compound of formula III. This reaction may be carried out using the same reagents or solvents as in step (2-1).
단계 (2-4)에서는, 강산, 예를 들어 염산, 특히 4N 염산 존재 하에 유기용매, 예를 들어 C1-C4 알코올, 특히 메탄올 중에서 단계 (2-3)에서 얻은 화학식 2-Ⅰa의 화합물로부터 보호기를 제거하여 화학식 2-Ⅰb의 화합물을 제조할 수 있다. In step (2-4), the compound of formula 2-Ia obtained in step (2-3) in the presence of a strong acid, for example hydrochloric acid, in particular 4N hydrochloric acid, in an organic solvent, for example a C 1 -C 4 alcohol, especially methanol By removing the protecting group from the compound of Formula 2-Ib can be prepared.
단계 (2-5)에서는, 단계 (2-4)에서 얻은 화학식 2-Ⅰb의 화합물에 아실 기를 도입하여 화학식 (Ⅰ)의 화합물을 제조할 수 있다. 본 반응은 유기용매, 예를 들어 테트라하이드로퓨란 및 물 중에서 탄산수소나트륨 존재 하에 아크릴로일 화합물, 예를 들어 아크릴로일 할라이드, 특히 아크릴로일 클로라이드와 반응시켜 수행될 수 있다.In step (2-5), the compound of formula (I) can be prepared by introducing an acyl group into the compound of formula 2-Ib obtained in step (2-4). This reaction can be carried out by reacting with an acryloyl compound such as acryloyl halide, particularly acryloyl chloride in the presence of sodium hydrogen carbonate in an organic solvent such as tetrahydrofuran and water.
구체예에서, 일 양상에 따른 화학식 1의 화합물 중 Z2가 N인 화합물은 아래와 같은 반응식3 에 따라 제조될 수 있다.In an embodiment, the compound in which Z 2 is N among the compounds of Formula 1 according to an aspect may be prepared according to Scheme 3 below.
[반응식 3][Scheme 3]
Figure PCTKR2021013380-appb-I000006
Figure PCTKR2021013380-appb-I000006
단계 (3-1) 에서는 화학식 3-IVa와 화합물 3-VII를 반응시켜 화학식 2-VIa의 화합물을 제조할 수 있다. 본 반응은 염기 예를들어 디아이소프로필에틸아민, 트라이에틸아민, 피리딘, 수호화나트륨, 나트륨-t-부톡사이드, 탄산칼륨, 탄산세슘, 탄산수소나트륨 존재하에 극성 비양자성 유기용매 예를들어, 예를 들어 테트라히드로퓨란, 에틸아세테이트, 아세톤, N,N-디메틸포름아미드, 아세토니트릴, N,N-디메틸설폭사이드 중에서 수행될 수 있다.In step (3-1), a compound of Formula 2-VIa can be prepared by reacting Formula 3-IVa with Compound 3-VII. This reaction is carried out in the presence of a base such as diisopropylethylamine, triethylamine, pyridine, sodium hydride, sodium-t-butoxide, potassium carbonate, cesium carbonate, sodium hydrogen carbonate and a polar aprotic organic solvent such as, For example, it can be carried out in tetrahydrofuran, ethyl acetate, acetone, N,N-dimethylformamide, acetonitrile, N,N-dimethylsulfoxide.
단계 (3-2)에서는 화학식 3-VIb 화합물을 3-VIII과 아미드화 반응시켜 화학식 3-VIc의 화합물을 제조할 수 있다. . 본 반응은 아미드 반응으로 1,5,7-트리아자비사이클로[4.4.0]데크-5-엔 (TBD), 1,4,6-트리아자비사이클로[3.3.0]옥트-4-엔 존재 하에 유기용매 예를들어 N,N-디메틸포름아미드, 디클로로메탄, 테트라히드로퓨란 중에서 수행될 수 있다 In step (3-2), the compound of formula 3-VIc may be prepared by amidation reaction of the compound of formula 3-VIb with 3-VIII. . This reaction is an amide reaction in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 1,4,6-triazabicyclo[3.3.0]oct-4-ene It can be carried out in an organic solvent such as N,N-dimethylformamide, dichloromethane, tetrahydrofuran.
단계 (3-3) 에서는 단계 (3-2)에서 얻은 화학식 3-VIc의 카르보닐 그룹을 환원시켜 화학시 3-IVa의 화합물을 제조할 수 있다. 본 반응은 보란 존재 하에 유기용매, 예를들어 테트라히드로퓨란 중에서 수행될 수 있다.In step (3-3), the compound of chemical formula 3-IVa can be prepared by reducing the carbonyl group of formula 3-VIc obtained in step (3-2). This reaction can be carried out in an organic solvent, for example, tetrahydrofuran in the presence of borane.
단계 (3-4) 에서는 단계 (3-3)에서 얻은 화학식 3-Iva에, 강산, 예를 들어 트리플로로아세트산, 염산 존재 하에 유기용매 디클로로메탄 중에서 수행하여 보호기가 제거된 화학식 3-IVb의 화합물을 제조할 수 있다.In step (3-4), the protecting group of Formula 3-IVb obtained in step (3-3) is removed by carrying out in dichloromethane in an organic solvent in the presence of a strong acid such as trifluoroacetic acid or hydrochloric acid to Formula 3-Iva obtained in step (3-3) compounds can be prepared.
단계(3-5)에서는, 단계(3-4)에서 얻은 화학식 3-IVb 화합물과 화학식 3-III의 화합물을 반응시켜 화학식 3-II 화합물을 제조할 수 있다. 본 반응은 단계 (3-1)와 동일한 시약이나 용매를 사용하여 수행될 수 있다.In step (3-5), the compound of formula 3-IVb obtained in step (3-4) and the compound of formula 3-III may be reacted to prepare a compound of formula 3-II. This reaction can be carried out using the same reagent or solvent as in step (3-1).
단계(3-6)에서는, 단계(3-5)에서 얻은 화학식 3-II 화합물을 마이크로웨이브를 이용하여 화학식 V 의 화합물을 반응시켜 화학식 3-I 화합물을 제조할 수 있다. 본 반응에서 유기용매 예를들어 이소프로필알콜, 에탄올 중에서 수행될 수 있다.In step (3-6), the compound of formula 3-II obtained in step (3-5) may be reacted with the compound of formula V using a microwave to prepare a compound of formula 3-I. This reaction may be carried out in an organic solvent such as isopropyl alcohol or ethanol.
단계 (3-7)에서는 단계 (3-6)에서 얻은 화학식 3-I 화합물을 강산, 예를 들어 트리플로로아세트산, 염산, 특히 4N 염산 존재 하에 유기용매, 예를 들어 C1-C4 알코올, 특히 메탄올 중에서 보호기를 제거하고 아실 기를 도입하여 화학식(I)의 화합물을 제조할 수 있다. 본 반응은 유기용매, 예를 들어 테트라히드로푸란 및 물 중에서 탄산수소나트륨 존재 하에 아크릴로일 화합물, 예를 들어 아크릴로일 할라이드, 특히 아크릴로일 클로라이드와 반응시켜 수행될 수 있다.In step (3-7), the compound of formula 3-I obtained in step (3-6) is prepared in the presence of a strong acid, such as trifluoroacetic acid, hydrochloric acid, in particular 4N hydrochloric acid, in an organic solvent, such as a C1-C4 alcohol, especially Compounds of formula (I) can be prepared by removing the protecting group in methanol and introducing an acyl group. This reaction can be carried out by reacting with an acryloyl compound, for example acryloyl halide, especially acryloyl chloride, in the presence of sodium hydrogen carbonate in an organic solvent, for example tetrahydrofuran and water.
일 양상에 따른 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염은 BTK에 의하여 매개되는 질환을 치료하는데 사용될 수 있다.The compound of Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof according to an aspect may be used to treat a disease mediated by BTK.
다른 양상에 따른 약제학적 조성물은 단백질 키나제에 의하여 매개되는 질환을 치료하는데 사용될 수 있다.The pharmaceutical composition according to another aspect may be used to treat a disease mediated by protein kinase.
다른 양상에 따른 단백질 키나제의 활성을 저해하는데 사용하기 위한 약제학적 조성물은 BTK의 활성을 저해하는데 사용될 수 있다.The pharmaceutical composition for use in inhibiting the activity of a protein kinase according to another aspect may be used to inhibit the activity of BTK.
다른 양상에 따른 단백질 키나제에 의하여 매개되는 질환을 치료하는 방법에 의하면, 개체에서 단백질 키나제에 의하여 매개되는 질환을 효율적으로 치료할 수 있다.According to the method for treating a disease mediated by a protein kinase according to another aspect, it is possible to efficiently treat a disease mediated by a protein kinase in an individual.
다른 양상에 따른 단백질 키나제의 활성을 저해하는 방법에 의하면, 단백질 키나제의 활성을 효율적으로 저해할 수 있다.According to the method for inhibiting the activity of a protein kinase according to another aspect, it is possible to efficiently inhibit the activity of a protein kinase.
이하 본 개시를 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 예시적으로 설명하기 위한 것으로 본 개시의 범위가 이들 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present disclosure will be described in more detail through examples. However, these examples are for illustrative purposes only, and the scope of the present disclosure is not limited by these examples.
실시예 1: (S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Example 1: (S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl) Synthesis of amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
단계 1) N'-((5-브로모싸이아졸-2-일)메틸렌)-4-메틸벤젠설폰하이드라자이드의 합성Step 1) Synthesis of N'-((5-bromothiazol-2-yl)methylene)-4-methylbenzenesulfonehydrazide
2-브로모-5-포밀싸이아졸(100 ㎎, 0.52 mmol)과 p-톨루엔설포닐 하이드라자이드(183 ㎎, 0.98 mmol)를 마이크로파 바이알에 첨가한 후 에탄올 용매와 혼합하였다. 이 용액에 1 M의 염산(0.02 ㎖, 0.02 mmol)을 천천히 첨가하고 마이크로파로 80 ℃에서 1 시간 교반하였다. 반응이 완결되면 상온으로 냉각시킨 뒤 3 시간 추가 교반 후 용액을 날려주었다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물(150 ㎎, 80%)을 얻었다.2-Bromo-5-formylthiazole (100 mg, 0.52 mmol) and p-toluenesulfonyl hydrazide (183 mg, 0.98 mmol) were added to a microwave vial and mixed with an ethanol solvent. To this solution, 1 M hydrochloric acid (0.02 ml, 0.02 mmol) was slowly added, followed by stirring in a microwave at 80° C. for 1 hour. When the reaction was completed, the solution was blown off after cooling to room temperature and further stirring for 3 hours. The obtained residue was purified using column chromatography to obtain the target compound (150 mg, 80%).
단계 2) 2-브로모-5-(2-페닐-2H-테트라졸-5-일)싸이아졸의 합성Step 2) Synthesis of 2-bromo-5-(2-phenyl-2H-tetrazol-5-yl)thiazole
단계 1)에서 얻은 N'-((5-브로모싸이아졸-2-일)메틸렌)-4-메틸벤젠설폰하이드라자이드(500 ㎎, 1.39 mmol)와 아닐린(0.13 ㎖, 1.46 mmol)을 테트라하이드로퓨란(2.78 ㎖)과 피리딘(1.39 ㎖) 혼합용매에 녹인 후 상온에서 30분 교반하였다. 이 용액에 아이소아밀 나이트라이트(0.24 ㎖, 1.81 mmol)를 첨가한 후 상온에서 추가 25 시간을 교반하였다. 반응이 종료되면 에틸아세테이트를 이용하여 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물(172 ㎎, 56%)을 얻었다.N'-((5-bromothiazol-2-yl)methylene)-4-methylbenzenesulfonehydrazide (500 mg, 1.39 mmol) obtained in step 1) and aniline (0.13 mL, 1.46 mmol) were mixed with tetra After dissolving in a mixed solvent of hydrofuran (2.78 ml) and pyridine (1.39 ml), the mixture was stirred at room temperature for 30 minutes. After adding isoamyl nitrite (0.24 mL, 1.81 mmol) to this solution, the mixture was stirred at room temperature for an additional 25 hours. Upon completion of the reaction, extraction was performed with ethyl acetate, washed with water, the obtained organic layer was dried over magnesium sulfate, and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (172 mg, 56%).
단계 3) (2,6-디브로모피리딘-4-일)(몰포리노)메타논의 합성Step 3) Synthesis of (2,6-dibromopyridin-4-yl)(morpholino)methanone
2,6-디브로모니코티닉 산(1 g, 3.55 mmol)과 1,1'-카보닐디이미다졸(0.69 g, 4.27 mmol)을 N,N'-디메틸포름아마이드(3.5 ㎖)에 녹인 후 상온에서 5 분간 교반하였다. 이 용액에 몰포린(0.36 ㎖, 4.27 mmol)을 적가한 후 상온에서 2시간 교반하였다. 반응이 종료되면 에틸아세테이트를 이용하여 추출하고, 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물(1.12 g, 90%)을 얻었다.After dissolving 2,6-dibromonicotinic acid (1 g, 3.55 mmol) and 1,1'-carbonyldiimidazole (0.69 g, 4.27 mmol) in N,N'-dimethylformamide (3.5 mL) The mixture was stirred at room temperature for 5 minutes. Morpholine (0.36 mL, 4.27 mmol) was added dropwise to this solution, followed by stirring at room temperature for 2 hours. When the reaction was completed, extraction was performed using ethyl acetate, washed with water, the obtained organic layer was dried over magnesium sulfate, and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (1.12 g, 90%).
단계 4) 4-((2,6-디브로모피리딘-4-일)메틸)몰포린의 합성Step 4) Synthesis of 4-((2,6-dibromopyridin-4-yl)methyl)morpholine
(2,6-디브로모피리딘-4-일)(몰포리노)메타논(1.12 g, 3.22 mmol)을 테트라하이드로퓨란 3.2 ㎖에 녹인 후, 0 ℃로 냉각시켰다. 냉각시킨 반응 액에 1 M 보란-테트라하이드로용액(3.0 eq)을 적가하고 0 ℃에서 1시간 교반하였다. 이후 보란-테트라하이드로용액(3.0 eq)을 추가로 적가한 후 시작물질이 사라질 때까지 0 ℃에서 3시간 교반하였다. 반응액을 1 M 염산 수용액으로 pH 1을 맞춘 뒤, 80 ℃에서 1시간 교반하였다. 반응액을 0 ℃로 냉각한 후, 중탄산나트륨 포화수용액을 사용하여 pH 8 정도로 맞춘 뒤 에틸아세테이트를 이용하여 추출하고, 물로 씻었다. 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물(750 ㎎, 70%)을 얻었다.(2,6-dibromopyridin-4-yl)(morpholino)methanone (1.12 g, 3.22 mmol) was dissolved in 3.2 ml of tetrahydrofuran, and then cooled to 0 °C. To the cooled reaction solution, 1 M borane-tetrahydro solution (3.0 eq) was added dropwise and stirred at 0 °C for 1 hour. Then, borane-tetrahydro solution (3.0 eq) was further added dropwise and stirred at 0° C. for 3 hours until the starting material disappeared. The reaction solution was adjusted to pH 1 with a 1 M aqueous hydrochloric acid solution, followed by stirring at 80° C. for 1 hour. After the reaction solution was cooled to 0 °C, the pH was adjusted to about 8 with a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and washed with water. The obtained organic layer was dried over magnesium sulfate, and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (750 mg, 70%).
단계 5) tert-부틸(3S)-3-((6-브로모-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-카복실레이트의 합성Step 5) Synthesis of tert-butyl (3S)-3-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexane-1-carboxylate
4-((2,6-디브로모피리딘-4-일)메틸)몰포린(200 ㎎. 0.59 mmol), (S)-3-아미노-1-tert-부톡시카보닐피페리딘(0.13 ㎖, 0.71 mmol), 트리스(디벤질인덴아세톤)디팔라듐(27 ㎎, 10 mol%), 잔트포스(17 ㎎, 10 mol%), 나트륨-tert-부톡사이드(85 ㎎, 0.89 mmol)를 무수 1,4-디옥세인 1.5 ㎖에 녹인 후, 상온에서 4 시간 교반하였다. 반응이 완료되면 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류하였다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적 화합물(155 ㎎, 58%)을 얻었다.4-((2,6-dibromopyridin-4-yl)methyl)morpholine (200 mg. 0.59 mmol), (S)-3-amino-1-tert-butoxycarbonylpiperidine (0.13 mL) , 0.71 mmol), tris(dibenzylindeneacetone)dipalladium (27 mg, 10 mol%), xantphos (17 mg, 10 mol%), sodium-tert-butoxide (85 mg, 0.89 mmol) anhydrous After dissolving in 1.5 ml of 1,4-dioxane, the mixture was stirred at room temperature for 4 hours. When the reaction was complete, extraction was performed with ethyl acetate, washed with water, the obtained organic layer was dried over magnesium sulfate, and the solvent was distilled under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (155 mg, 58%).
단계 6) tert-부틸(3S)-3-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-카복실레이트의 합성Step 6) Synthesis of tert-butyl(3S)-3-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexane-1-carboxylate
tert-부틸(3S)-3-((6-브로모-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-카복실레이트(380 ㎎, 0.84 mmol), 쿠프릭 아세틸아세톤(10 mol%), 세슘 카보네이트(551 ㎎, 1.69 mmol)를 슈링크 튜브에 넣고, 질소 환경을 조성하였다. 이후 아세틸아세톤(40 mol%), 암모니아 수용액(0.65 ㎖, 16.91 mmol), 무수 디메틸포름아마이드(4 ㎖)를 차례로 넣고, 90 ℃에서 밤샘 교반하였다. 반응이 완료되면 반응용액을 상온으로 식힌 후 에틸아세테이트로 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압 증류하였다. 얻어진 잔사를 컬럼크로마토그래피로 정제하여 목적 화합물(88 ㎎, 27%)을 얻었다.tert-Butyl (3S)-3-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexane-1-carboxylate (380 mg, 0.84 mmol), cupric acetylacetone (10 mol%), cesium carbonate (551 mg, 1.69 mmol) was placed in a shrink tube, and a nitrogen environment was created. Then, acetylacetone (40 mol%), aqueous ammonia solution (0.65 mL, 16.91 mmol), and anhydrous dimethylformamide (4 mL) were sequentially added, and the mixture was stirred at 90° C. overnight. Upon completion of the reaction, the reaction solution was cooled to room temperature, extracted with ethyl acetate, washed with water, and the resulting organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (88 mg, 27%).
단계 7) tert-부틸(S)-3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 7) tert-Butyl(S)-3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino Synthesis of )pyridin-2-yl)amino)piperidine-1-carboxylate
상기 단계 2)에서 합성된 2-브로모-5-(2-페닐-2H-테트라졸-5-일)싸이아졸(285 ㎎, 0.92 mmol)과 단계 6)에서 합성된 tert-부틸(3S)-3-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-카복실레이트(300 ㎎, 0.77 mmol)를 2 ㎖의 디옥산에 용해시켰다. 이 용액에 트리스(디벤질인덴아세톤)디팔라듐(70 ㎎, 10 mol%), 잔트포스(44 ㎎, 10 mol%) 나트륨-tert-부톡사이드(111 ㎎, 0.89 mmol)를 첨가한 뒤 80 ℃에서 2시간 교반하였다. 반응이 종료되면 에틸아세테이트를 이용하여 추출하고, 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물(360 ㎎, 76%)을 얻었다.2-bromo-5-(2-phenyl-2H-tetrazol-5-yl)thiazole (285 mg, 0.92 mmol) synthesized in step 2) and tert-butyl (3S) synthesized in step 6) -3-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexane-1-carboxylate (300 mg, 0.77 mmol) was dissolved in 2 mL of dioxane. To this solution, tris(dibenzylindenacetone)dipalladium (70 mg, 10 mol%), xantphos (44 mg, 10 mol%) sodium-tert-butoxide (111 mg, 0.89 mmol) was added, and then 80 The mixture was stirred at ℃ for 2 hours. When the reaction was completed, extraction was performed using ethyl acetate, washed with water, the obtained organic layer was dried over magnesium sulfate, and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (360 mg, 76%).
단계 8) (S)-4-(몰포리노메틸)-N2-(5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)-N6-(피페리딘-3-일)피리딘-2,6-디아민의 합성Step 8) (S)-4-(morpholinomethyl)-N2-(5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)-N6-(piperidin-3 -yl) pyridine-2,6-diamine synthesis
상기 단계 7)에서 합성된 tert-부틸(S)-3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-카복실레이트(360 ㎎, 0.58 mmol)를 2.5 ㎖의 디클로로메테인과 2.5 ㎖의 메탄올에 용해시킨 뒤 디옥산에 용해된 4.0 M 염산(1.45 ㎖, 5.82 mmol)을 천천히 첨가하였다. 이 용액을 상온에서 12 시간동안 교반하였다. 반응이 종료되면 디클로로메테인과 메탄올을 이용하여 추출하고, 물로 씻어준 뒤 얻어진 유기층을 황산나트륨으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물(296 ㎎, 98%)을 얻었다.tert-Butyl (S)-3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazole-2 synthesized in step 7) above -yl)amino)pyridin-2-yl)amino)piperidine-1-carboxylate (360 mg, 0.58 mmol) was dissolved in 2.5 ml of dichloromethane and 2.5 ml of methanol, followed by 4.0 dissolved in dioxane M hydrochloric acid (1.45 mL, 5.82 mmol) was added slowly. This solution was stirred at room temperature for 12 hours. When the reaction was completed, extraction was performed using dichloromethane and methanol, washed with water, the obtained organic layer was dried over sodium sulfate, and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (296 mg, 98%).
단계 9) (S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Step 9) (S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino Synthesis of )pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
상기 단계 8)에서 합성된 (S)-4-(몰포리노메틸)-N2-(5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)-N6-(피페리딘-3-일)피리딘-2,6-디아민(296 ㎎, 0.57 mmol)을 4 ㎖ 테트라하이드로퓨란과 2.9 ㎖의 물에 용해시킨 뒤 탄산수소나트륨(192 ㎎, 2.28 mmol)을 첨가하고 0 ℃에서 30 분 교반하였다. 아크릴로일 클로라이드(0.09 ㎖, 1.14 mmol)를 1 ㎖의 테트라하이드로퓨란에 묽힌 뒤 교반중인 용액에 천천히 첨가하고 0 ℃에서 추가 1시간 교반하였다. 용액에 메탄올 한 방울을 첨가하여 반응을 종결시키고 디클로로메테인과 메탄올을 이용하여 추출하고, 물로 씻어준 뒤 얻어진 유기층을 황산나트륨으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물(220 ㎎, 67%)을 얻었다.(S)-4-(morpholinomethyl)-N2-(5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)-N6-(p) synthesized in step 8) above Peridin-3-yl)pyridine-2,6-diamine (296 mg, 0.57 mmol) was dissolved in 4 ml of tetrahydrofuran and 2.9 ml of water, and sodium hydrogen carbonate (192 mg, 2.28 mmol) was added thereto. The mixture was stirred at ℃ for 30 minutes. After diluting acryloyl chloride (0.09 ml, 1.14 mmol) in 1 ml of tetrahydrofuran, it was slowly added to the stirring solution and stirred at 0° C. for an additional 1 hour. The reaction was terminated by adding a drop of methanol to the solution, extraction was performed using dichloromethane and methanol, washed with water, and the obtained organic layer was dried over sodium sulfate, and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (220 mg, 67%).
1H-NMR(400 MHz, CDCl3) δ: 11.08-10.79(m, 1H), 8.32(s, 1H), 8.18(d, 2H, J= 8.0 Hz), 7.60-7.58(m, 2H), 7.51(t, 1H, J= 8.0 Hz), 6.49-6.42(m, 2H), 6.21-6.02(m, 2H), 5.71-5.49(m, 1H), 4.54-4.19(m, 2H), 3.96(d, 1H, J= 12.0 Hz), 3.78(t, 4H, J= 12.0 Hz), 3.61(s, 1H), 3.42(s, 2H), 3.30(s, 1H), 2.51(s, 4H), 2.27(s, 1H), 1.87-1.84(m, 4H), 1.67(s, 1H). 1 H-NMR (400 MHz, CDCl3) δ: 11.08-10.79 (m, 1H), 8.32 (s, 1H), 8.18 (d, 2H, J = 8.0 Hz), 7.60-7.58 (m, 2H), 7.51 (t, 1H, J = 8.0 Hz), 6.49-6.42 (m, 2H), 6.21-6.02 (m, 2H), 5.71-5.49 (m, 1H), 4.54-4.19 (m, 2H), 3.96 (d) , 1H, J = 12.0 Hz), 3.78(t, 4H, J = 12.0 Hz), 3.61(s, 1H), 3.42(s, 2H), 3.30(s, 1H), 2.51(s, 4H), 2.27 (s, 1H), 1.87-1.84 (m, 4H), 1.67 (s, 1H).
실시예 2: (S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)옥시)피페리딘-1-일)프로프-2-엔-1-온의 합성Example 2: (S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl) Synthesis of amino)pyridin-2-yl)oxy)piperidin-1-yl)prop-2-en-1-one
단계 1) tert-부틸(3S)-3-((6-브로모-4-(몰포리노메틸)피리딘-2-일)옥시)사이클로헥산-1-카복실레이트의 합성Step 1) Synthesis of tert-butyl (3S)-3-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylate
(S)-1-Boc-3-하이드록시피페리딘(92 ㎎, 0.46 mmol)을 0 ℃에서 디메틸포름아마이드 용액 1 ㎖에 녹인 후 미네랄 오일에 60% 분산된 수소화 나트륨(30 ㎎, 0.76 mmol)을 첨가하였다. 0 ℃에서 30 분 교반 후 실시예 1의 단계 4)에서 얻은 4-((2,6-디브로모피리딘-4-일)메틸)몰포린(128 ㎎, 0.38 mmol)을 첨가하고, 이후 용액을 90 ℃에서 18시간 교반하였다. 반응이 종결된 후에 디클로로메테인을 이용하여 추출하고, 물로 씻어준 뒤 유기층을 황산나트륨으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물(136 ㎎, 79%)을 얻었다.(S)-1-Boc-3-hydroxypiperidine (92 mg, 0.46 mmol) was dissolved in 1 ml of dimethylformamide solution at 0 ° C. Sodium hydride 60% dispersed in mineral oil (30 mg, 0.76 mmol) ) was added. After stirring at 0° C. for 30 minutes, 4-((2,6-dibromopyridin-4-yl)methyl)morpholine (128 mg, 0.38 mmol) obtained in step 4) of Example 1) was added, and then the solution was stirred at 90 °C for 18 hours. After completion of the reaction, extraction was performed with dichloromethane, washed with water, the organic layer was dried over sodium sulfate, and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (136 mg, 79%).
단계 2) tert-부틸(3S)-3-((6-아미노-4-(몰포리노메틸)피리딘-2-일)옥시)사이클로헥산-1-카복실레이트의 합성Step 2) Synthesis of tert-butyl(3S)-3-((6-amino-4-(morpholinomethyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylate
상기 단계 1)에서 얻은 tert-부틸(3S)-3-((6-브로모-4-(몰포리노메틸)피리딘-2-일)옥시)사이클로헥산-1-카복실레이트(136 ㎎, 0.30 mmol)를 실시예 1의 단계 6)과 같은 방법으로 목적 화합물(39 ㎎, 33%)을 얻었다.tert-Butyl (3S)-3-((6-bromo-4-(morpholinomethyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylate obtained in step 1) (136 mg, 0.30 mmol ) was obtained in the same manner as in step 6) of Example 1 to obtain the target compound (39 mg, 33%).
단계 3) tert-부틸(S)-3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)옥시)피페리딘-1-카복실레이트의 합성Step 3) tert-Butyl(S)-3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino Synthesis of )pyridin-2-yl)oxy)piperidine-1-carboxylate
상기 단계 2)에서 얻은 tert-부틸(3S)-3-((6-아미노-4-(몰포리노메틸)피리딘-2-일)옥시)사이클로헥산-1-카복실레이트(39 ㎎, 0.10 mmol)를 실시예 1의 단계 7)과 같은 방법으로 목적 화합물(43 ㎎, 70%)을 얻었다.tert-Butyl(3S)-3-((6-amino-4-(morpholinomethyl)pyridin-2-yl)oxy)cyclohexane-1-carboxylate obtained in step 2) (39 mg, 0.10 mmol) to obtain the target compound (43 mg, 70%) in the same manner as in step 7) of Example 1.
단계 4) (S)-N-(4-(몰포리노메틸)-6-(피페리딘-3-일옥시)피리딘-2-일)-5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-아민의 합성Step 4) (S)-N-(4-(morpholinomethyl)-6-(piperidin-3-yloxy)pyridin-2-yl)-5-(2-phenyl-2H-tetrazole-5 -yl) thiazol-2-amine synthesis
상기 단계 3)에서 얻은 tert-부틸(S)-3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)옥시)피페리딘-1-카복실레이트(43 ㎎, 0.07 mmol)를 실시예 1의 단계 8)과 같은 방법으로 목적 화합물(34 ㎎, 95%)을 얻었다.tert-Butyl (S)-3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazole-2- yl)amino)pyridin-2-yl)oxy)piperidine-1-carboxylate (43 mg, 0.07 mmol) was obtained in the same manner as in Example 1 step 8) to obtain the target compound (34 mg, 95%). .
단계 5) (S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)옥시)피페리딘-1-일)프로프-2-엔-1-온의 합성Step 5) (S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino Synthesis of )pyridin-2-yl)oxy)piperidin-1-yl)prop-2-en-1-one
상기 단계 4)에서 얻은 (S)-N-(4-(몰포리노메틸)-6-(피페리딘-3-일옥시)피리딘-2-일)-5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-아민(34 ㎎, 0.07 mmol)을 실시예 1의 단계 9)와 같은 방법으로 목적 화합물(21 ㎎, 57%)을 얻었다.(S)-N-(4-(morpholinomethyl)-6-(piperidin-3-yloxy)pyridin-2-yl)-5-(2-phenyl-2H-tetra obtained in step 4) above Zol-5-yl)thiazol-2-amine (34 mg, 0.07 mmol) was obtained in the same manner as in Example 1 step 9) to obtain the target compound (21 mg, 57%).
1H-NMR(400 MHz, CDCl3) δ: 10.30(s, 1H), 8.330-8.26(m, 1H), 8.20-8.16(m, 2H), 7.64-7.50(m, 3H), 6.66-6.43(m, 2H), 6.36(s, 1H), 6.20-6.16(m, 1H), 5.61-5.49(m, 2H), 3.89-3.86(m, 2H), 3.78(t, 4H, J= 8.0 Hz), 3.67-3.65(m, 1H), 3.47(s, 2H), 2.51(s, 4H), 2.30-2.29(m, 1H), 2.20-1.99(m, 2H), 1.85(s, 1H). 1 H-NMR (400 MHz, CDCl 3 ) δ: 10.30(s, 1H), 8.330-8.26(m, 1H), 8.20-8.16(m, 2H), 7.64-7.50(m, 3H), 6.66-6.43 (m, 2H), 6.36(s, 1H), 6.20-6.16(m, 1H), 5.61-5.49(m, 2H), 3.89-3.86(m, 2H), 3.78(t, 4H, J = 8.0 Hz ), 3.67-3.65 (m, 1H), 3.47 (s, 2H), 2.51 (s, 4H), 2.30-2.29 (m, 1H), 2.20-1.99 (m, 2H), 1.85 (s, 1H).
실시예 3: (S)-1-(3-((6-((5-(2-(2-클로로-6-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Example 3: (S)-1-(3-((6-((5-(2-(2-chloro-6-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl) Synthesis of amino)-4-(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
단계 1) 2-브로모-5-(2-(2-클로로-6-메틸페닐)-2H-테트라졸-5-일)싸이아졸의 합성Step 1) Synthesis of 2-bromo-5-(2-(2-chloro-6-methylphenyl)-2H-tetrazol-5-yl)thiazole
실시예 1의 단계 1)에서 얻어진 N'-((5-브로모싸이아졸-2-일)메틸렌)-4-메틸벤젠설폰하이드라자이드(500 ㎎, 1.39 mmol)와 2-클로로-6-메틸아닐린(0.18 ㎖, 1.46 mmol)을 실시예 1의 단계 2)와 같은 방법으로 목적 화합물(310 ㎎, 62%)을 얻었다.N'-((5-bromothiazol-2-yl)methylene)-4-methylbenzenesulfonehydrazide (500 mg, 1.39 mmol) obtained in step 1) of Example 1 and 2-chloro-6- Methylaniline (0.18 mL, 1.46 mmol) was used in the same manner as in step 2) of Example 1 to obtain the target compound (310 mg, 62%).
단계 2) tert-부틸(S)-3-((6-((5-(2-(2-클로로-6-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 2) tert-Butyl (S)-3-((6-((5-(2-(2-chloro-6-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino Synthesis of )-4-(morpholinomethyl)pyridin-2-yl)amino)piperidine-1-carboxylate
상기 단계 1)에서 얻은 2-브로모-5-(2-(2-클로로-6-메틸페닐)-2H-테트라졸-5-일)싸이아졸(164 ㎎, 0.46 mmol)과 실시예 1의 단계 6)에서 얻은 tert-부틸(3S)-3-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-카복실레이트(150 ㎎, 0.38 mmol)를 실시예 1의 단계 7)과 같은 방법으로 목적 화합물(149 ㎎, 58%)을 얻었다.2-bromo-5-(2-(2-chloro-6-methylphenyl)-2H-tetrazol-5-yl)thiazole (164 mg, 0.46 mmol) obtained in step 1) and the step of Example 1 tert-Butyl (3S)-3-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexane-1-carboxylate (150 mg, 0.38 mmol) obtained in 6) was carried out In the same manner as in step 7) of Example 1), the target compound (149 mg, 58%) was obtained.
단계 3) (S)-N2-(5-(2-(2-클로로-6-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)-4-(몰포리노메틸)-N6-(피페리딘-3-일)피리딘-2,6-디아민의 합성Step 3) (S)-N2-(5-(2-(2-chloro-6-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)-4-(morpholinomethyl)- Synthesis of N6-(piperidin-3-yl)pyridine-2,6-diamine
상기 단계 2)에서 얻은 tert-부틸(S)-3-((6-((5-(2-(2-클로로-6-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-카복실레이트(147 ㎎, 0.22 mmol)를 실시예 1의 단계 8)과 같은 방법으로 목적 화합물(73 ㎎, 58%)을 얻었다.tert-Butyl (S)-3-((6-((5-(2-(2-chloro-6-methylphenyl)-2H-tetrazol-5-yl)thiazole-2- yl)amino)-4-(morpholinomethyl)pyridin-2-yl)amino)piperidine-1-carboxylate (147 mg, 0.22 mmol) was prepared in the same manner as in step 8) of Example 1 to the target compound ( 73 mg, 58%) was obtained.
단계 4) (S)-1-(3-((6-((5-(2-(2-클로로-6-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Step 4) (S)-1-(3-((6-((5-(2-(2-chloro-6-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino Synthesis of )-4-(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
상기 단계 3)에서 얻은 (S)-N2-(5-(2-(2-클로로-6-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)-4-(몰포리노메틸)-N6-(피페리딘-3-일)피리딘-2,6-디아민(70 ㎎, 0.12 mmol)을 실시예 1의 단계 9)와 같은 방법으로 목적 화합물(20 ㎎, 26%)을 얻었다.(S)-N2-(5-(2-(2-chloro-6-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)-4-(morpholino obtained in step 3) above Methyl)-N6-(piperidin-3-yl)pyridine-2,6-diamine (70 mg, 0.12 mmol) was prepared in the same manner as in Example 1 step 9) to prepare the target compound (20 mg, 26%). got it
1H-NMR(400 MHz, DMSO-d6): 11.36(s, 1H), 8.12(s, 1H), 7.70-7.68(m, 2H), 7.58(s, 1H), 6.76(d, 1H, J= 7.6 Hz), 6.54-6.32(m, 1H), 6.23(s, 1H), 6.12-6.09(m, 1H), 5.89-5.82(m, 1H), 5.34(t, 1H, J= 14.8 Hz), 4.41-4.10(m, 2H), 3.89-3.72(m, 1H), 3.60(s, 5H), 3.30(s, 2H), 3.13-3.06(m, 1H), 2.72(t, 1H, J= 6.4 Hz), 2.37(s, 4H), 2.05(s, 4H), 1.72(s, 2H), 1.55(s, 1H). 1 H-NMR (400 MHz, DMSO-d 6 ): 11.36 (s, 1H), 8.12 (s, 1H), 7.70-7.68 (m, 2H), 7.58 (s, 1H), 6.76 (d, 1H, J = 7.6 Hz), 6.54-6.32 (m, 1H), 6.23 (s, 1H), 6.12-6.09 (m, 1H), 5.89-5.82 (m, 1H), 5.34 (t, 1H, J = 14.8 Hz) ), 4.41-4.10(m, 2H), 3.89-3.72(m, 1H), 3.60(s, 5H), 3.30(s, 2H), 3.13-3.06(m, 1H), 2.72(t, 1H, J ) = 6.4 Hz), 2.37(s, 4H), 2.05(s, 4H), 1.72(s, 2H), 1.55(s, 1H).
실시예 4: (S)-1-(3-((6-((5-(2-(2-메톡시페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Example 4: (S)-1-(3-((6-((5-(2-(2-methoxyphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino) Synthesis of -4-(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
단계 1) 2-브로모-5-(2-(2-메톡시페닐)-2H-테트라졸-5-일)싸이아졸의 합성Step 1) Synthesis of 2-bromo-5-(2-(2-methoxyphenyl)-2H-tetrazol-5-yl)thiazole
실시예 1의 단계 1)에서 얻은 N'-((5-브로모싸이아졸-2-일)메틸렌)-4-메틸벤젠설폰하이드라자이드(500 ㎎, 1.39 mmol)와 o-아니시딘(180 ㎎, 1.46 mmol)을 실시예 1의 단계 2)와 같은 방법으로 반응시켜 목적 화합물(350 ㎎, 74%)을 얻었다.N'-((5-bromothiazol-2-yl)methylene)-4-methylbenzenesulfonehydrazide (500 mg, 1.39 mmol) obtained in step 1) of Example 1 and o -anisidine (180 mg, 1.46 mmol) was reacted in the same manner as in step 2) of Example 1 to obtain the target compound (350 mg, 74%).
단계 2) tert-부틸(S)-3-((6-((5-(2-(2-메톡시페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 2) tert-Butyl(S)-3-((6-((5-(2-(2-methoxyphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)- Synthesis of 4-(morpholinomethyl)pyridin-2-yl)amino)piperidine-1-carboxylate
실시예 1의 단계 6)에서 얻은 tert-부틸(3S)-3-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-카복실레이트(100 ㎎, 0.26 mmol)와 상기 단계 1)에서 얻은 2-브로모-5-(2-(2-메톡시페닐)-2H-테트라졸-5-일)싸이아졸을 실시예 1의 단계 7)과 같은 방법으로 목적 화합물(115 ㎎, 70%)을 얻었다.tert-butyl(3S)-3-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexane-1-carboxylate obtained in step 6) of Example 1 (100 mg, 0.26 mmol) and 2-bromo-5-(2-(2-methoxyphenyl)-2H-tetrazol-5-yl)thiazole obtained in step 1) in the same manner as in step 7) of Example 1. to obtain the target compound (115 mg, 70%).
단계 3) (S)-N2-(5-(2-(2-메톡시페닐)-2H-테트라졸-5-일)싸이아졸-2-일)-4-(몰포리노메틸)-N6-(피페리딘-3-일)피리딘-2,6-디아민의 합성Step 3) (S)-N2-(5-(2-(2-methoxyphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)-4-(morpholinomethyl)-N6- Synthesis of (piperidin-3-yl)pyridine-2,6-diamine
상기 단계 2)에서 얻은 tert-부틸(S)-3-((6-((5-(2-(2-메톡시페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-카복실레이트(112 ㎎, 0.17 mmol)를 실시예 1 단계 8)과 같은 방법으로 목적 화합물(68 ㎎, 72%)을 얻었다.tert-Butyl (S)-3-((6-((5-(2-(2-methoxyphenyl)-2H-tetrazol-5-yl)thiazol-2-yl) obtained in step 2) above Amino)-4-(morpholinomethyl)pyridin-2-yl)amino)piperidine-1-carboxylate (112 mg, 0.17 mmol) was prepared by preparing the target compound (68 mg, 72%) was obtained.
단계 4) (S)-1-(3-((6-((5-(2-(2-메톡시페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Step 4) (S)-1-(3-((6-((5-(2-(2-methoxyphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)- Synthesis of 4-(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
상기 단계 3)에서 얻은 (S)-N2-(5-(2-(2-메톡시페닐)-2H-테트라졸-5-일)싸이아졸-2-일)-4-(몰포리노메틸)-N6-(피페리딘-3-일)피리딘-2,6-디아민(66 ㎎, 0.12 mmol)을 실시예 1의 단계 9)와 같은 방법으로 목적 화합물(4 ㎎, 6%)을 얻었다.(S)-N2-(5-(2-(2-methoxyphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)-4-(morpholinomethyl) obtained in step 3) above -N6-(piperidin-3-yl)pyridine-2,6-diamine (66 mg, 0.12 mmol) was obtained in the same manner as in Example 1 step 9) to obtain the target compound (4 mg, 6%).
1H-NMR(400 MHz, DMSO-d6) δ: 11.31(s, 1H), 8.06(s, 1H), 7.72-7.62(m, 3H), 7.40(t, 1H, J= 8.4 Hz), 7.22(s, 1H), 6.74(d, 1H, J= 8.0 Hz), 6.55-6.34(m, 1H), 6.22(s, 1H), 6.09(d, 1H, J= 2.0 Hz), 5.83(dd, 1H, J= 16.8, 2.4 Hz), 5.39-5.33(m, 1H), 4.37-4.12(m, 2H), 3.84(s, 4H), 3.61-3.58(m, 4H), 3.29(s, 2H), 3.16-3.06(m, 2H), 2.37(s, 4H), 2.24(s, 1H), 2.12-2.09(m, 1H), 1.76(s, 2H), 1.56(s, 1H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.31 (s, 1H), 8.06 (s, 1H), 7.72-7.62 (m, 3H), 7.40 (t, 1H, J = 8.4 Hz), 7.22 (s, 1H), 6.74 (d, 1H, J = 8.0 Hz), 6.55-6.34 (m, 1H), 6.22 (s, 1H), 6.09 (d, 1H, J = 2.0 Hz), 5.83 (dd) , 1H, J = 16.8, 2.4 Hz), 5.39-5.33 (m, 1H), 4.37-4.12 (m, 2H), 3.84 (s, 4H), 3.61-3.58 (m, 4H), 3.29 (s, 2H) ), 3.16-3.06(m, 2H), 2.37(s, 4H), 2.24(s, 1H), 2.12-2.09(m, 1H), 1.76(s, 2H), 1.56(s, 1H).
실시예 5: (S)-1-(3-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Example 5: (S)-1-(3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole) Synthesis of -2-yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
단계 1) 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸의 합성Step 1) Synthesis of 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole
2-브로모-5-포밀싸이아졸(0.50 g, 2.60 mmol)과 벤즈하이드라자이드(0.35 g, 2.60 mmol)를 26 ㎖의 에탄올에 용해시킨 뒤 1시간 가열 환류하였다. 반응이 종료되면 용매를 감압증류하였다. 얻어진 잔사를 13 ㎖의 디메틸 설폭사이드로 용해시킨 뒤 탄산 칼륨(1.08 g, 7.80 mmol)과 아이오딘(0.79 g, 3.12 mmol)을 첨가하였다. 이 용액을 100 ℃에서 1시간 교반하였다. 반응이 종료되면 에틸아세테이트를 이용하여 추출하고 물로 씻어준 뒤 얻어진 유기층을 황산마그네슘으로 건조하고 용매를 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물(0.72 g, 90%)을 얻었다.2-Bromo-5-formylthiazole (0.50 g, 2.60 mmol) and benzhydrazide (0.35 g, 2.60 mmol) were dissolved in 26 ml of ethanol, and then heated to reflux for 1 hour. When the reaction was completed, the solvent was distilled under reduced pressure. The obtained residue was dissolved with 13 ml of dimethyl sulfoxide, and potassium carbonate (1.08 g, 7.80 mmol) and iodine (0.79 g, 3.12 mmol) were added thereto. This solution was stirred at 100 °C for 1 hour. Upon completion of the reaction, extraction was performed with ethyl acetate, washed with water, the obtained organic layer was dried over magnesium sulfate, and the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (0.72 g, 90%).
단계 2) tert-부틸(S)-3-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 2) tert-Butyl (S)-3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole- Synthesis of 2-yl)amino)pyridin-2-yl)amino)piperidine-1-carboxylate
상기 단계 1)에서 얻은 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸(142 ㎎, 0.46 mmol)과 실시예 1의 단계 6)에서 얻은 tert-부틸(3S)-3-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-카복실레이트(150 ㎎, 0.38 mmol)를 실시예 1의 단계 7)과 같은 방법으로 반응시켜 목적 화합물(160 ㎎, 68%)을 얻었다.2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (142 mg, 0.46 mmol) obtained in step 1) and step 6) of Example 1 The obtained tert-butyl (3S)-3-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexane-1-carboxylate (150 mg, 0.38 mmol) was synthesized from Example 1 The reaction was carried out in the same manner as in step 7) to obtain the target compound (160 mg, 68%).
단계 3) (S)-4-(몰포리노메틸)-N2-(5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)-N6-(피페리딘-3-일)피리딘-2,6-디아민의 합성Step 3) (S)-4-(morpholinomethyl)-N2-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-N6-( Synthesis of piperidin-3-yl)pyridin-2,6-diamine
상기 단계 2)에서 얻은 tert-부틸(S)-3-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-카복실레이트(157 ㎎, 0.25 mmol)를 실시예 1의 단계 8)과 같은 방법으로 반응시켜 목적 화합물(92 ㎎, 70%)을 얻었다.tert-Butyl (S)-3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl) obtained in step 2) above Thiazol-2-yl)amino)pyridin-2-yl)amino)piperidine-1-carboxylate (157 mg, 0.25 mmol) was reacted in the same manner as in Example 1 step 8) to react the target compound (92) mg, 70%) was obtained.
단계 4) (S)-1-(3-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Step 4) (S)-1-(3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole- Synthesis of 2-yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
상기 단계 3)에서 얻은 (S)-4-(몰포리노메틸)-N2-(5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)-N6-(피페리딘-3-일)피리딘-2,6-디아민(56 ㎎, 0.11 mmol)을 실시예 1의 단계 9)와 같은 방법으로 반응시켜 목적 화합물(5 ㎎, 8%)을 얻었다.(S)-4-(morpholinomethyl)-N2-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)- N6-(piperidin-3-yl)pyridine-2,6-diamine (56 mg, 0.11 mmol) was reacted in the same manner as in Example 1 step 9) to obtain the target compound (5 mg, 8%). .
1H-NMR(400 MHz, DMSO-d6) δ: 11.56(s, 1H), 8.19(s, 1H), 8.06-8.03(m, 2H), 7.65-7.61(m, 3H), 6.86-6.56(m, 2H), 6.25(s, 1H), 6.21(d, 1H, J= 11.2 Hz), 5.90(t, 1H, J= 13.6 Hz), 5.45(dd, 1H, J= 30.8, 10.4 Hz), 4.18-3.87(m, 2H), 3.60(t, 4H, J= 4.4 Hz), 3.34(s, 6H), 3.30(s, 2H), 3.17(d, 2H, J= 5.2 Hz), 2.37(s, 4H), 2.21(s, 1H), 1.91-1.86(m, 1H), 1.76-1.55(m, 2H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.56 (s, 1H), 8.19 (s, 1H), 8.06-8.03 (m, 2H), 7.65-7.61 (m, 3H), 6.86-6.56 (m, 2H), 6.25 (s, 1H), 6.21 (d, 1H, J = 11.2 Hz), 5.90 (t, 1H, J = 13.6 Hz), 5.45 (dd, 1H, J = 30.8, 10.4 Hz) , 4.18-3.87 (m, 2H), 3.60 (t, 4H, J = 4.4 Hz), 3.34 (s, 6H), 3.30 (s, 2H), 3.17 (d, 2H, J = 5.2 Hz), 2.37 ( s, 4H), 2.21 (s, 1H), 1.91-1.86 (m, 1H), 1.76-1.55 (m, 2H).
실시예 6: (S)-1-(3-((6-((5-(2-(5-클로로-2-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Example 6: (S)-1-(3-((6-((5-(2-(5-chloro-2-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl) Synthesis of amino)-4-(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
단계 1) 2-브로모-5-(2-(5-클로로-2-메틸페닐)-2H-테트라졸-5-일)싸이아졸의 합성Step 1) Synthesis of 2-bromo-5-(2-(5-chloro-2-methylphenyl)-2H-tetrazol-5-yl)thiazole
실시예 1의 단계 1)에서 얻은 N'-((5-브로모싸이아졸-2-일)메틸렌)-4-메틸벤젠설폰하이드라자이드(500 ㎎, 1.39 mmol)과 5-클로로-2-메틸아닐린(207 ㎎, 1.46 mmol)을 실시예 1의 단계 2)와 같이 반응시켜 목적 화합물(320 ㎎, 64%)을 얻었다.N'-((5-bromothiazol-2-yl)methylene)-4-methylbenzenesulfonehydrazide (500 mg, 1.39 mmol) obtained in step 1) of Example 1 and 5-chloro-2- Methylaniline (207 mg, 1.46 mmol) was reacted as in Example 1, step 2) to obtain the target compound (320 mg, 64%).
단계 2) tert-부틸(S)-3-((6-((5-(2-(5-클로로-2-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 2) tert-Butyl (S)-3-((6-((5-(2-(5-chloro-2-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino Synthesis of )-4-(morpholinomethyl)pyridin-2-yl)amino)piperidine-1-carboxylate
상기 단계 1)에서 얻은 2-브로모-5-(2-(5-클로로-2-메틸페닐)-2H-테트라졸-5-일)싸이아졸(164 ㎎, 0.46 mmol)과 실시예 1의 단계 6)에서 얻은 tert-부틸(3S)-3-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-카복실레이트(150 ㎎, 0.38 mmol)를 실시예 1의 단계 7)과 같이 반응시켜 목적 화합물(175 ㎎, 68%)을 얻었다.2-bromo-5-(2-(5-chloro-2-methylphenyl)-2H-tetrazol-5-yl)thiazole (164 mg, 0.46 mmol) obtained in step 1) and the step of Example 1 tert-Butyl (3S)-3-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexane-1-carboxylate (150 mg, 0.38 mmol) obtained in 6) was carried out Step 7 of Example 1) was reacted to obtain the target compound (175 mg, 68%).
단계 3) (S)-N2-(5-(2-(5-클로로-2-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)-4-(몰포리노메틸)-N6-(피페리딘-3-일)피리딘-2,6-디아민의 합성Step 3) (S)-N2-(5-(2-(5-chloro-2-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)-4-(morpholinomethyl)- Synthesis of N6-(piperidin-3-yl)pyridine-2,6-diamine
상기 단계 2)에서 얻은 tert-부틸(S)-3-((6-((5-(2-(5-클로로-2-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-카복실레이트(172 ㎎, 0.26 mmol)를 실시예 1의 단계 8)과 같이 반응시켜 목적 화합물(118 ㎎, 81%)을 얻었다.tert-Butyl (S)-3-((6-((5-(2-(5-chloro-2-methylphenyl)-2H-tetrazol-5-yl)thiazol-2- yl)amino)-4-(morpholinomethyl)pyridin-2-yl)amino)piperidine-1-carboxylate (172 mg, 0.26 mmol) was reacted as in Example 1 step 8) to obtain the target compound ( 118 mg, 81%) was obtained.
단계 4) (S)-1-(3-((6-((5-(2-(5-클로로-2-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Step 4) (S)-1-(3-((6-((5-(2-(5-chloro-2-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino Synthesis of )-4-(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
상기 단계 3)에서 얻은 (S)-N2-(5-(2-(5-클로로-2-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)-4-(몰포리노메틸)-N6-(피페리딘-3-일)피리딘-2,6-디아민(60 ㎎, 0.11 mmol)을 실시예 1의 단계 9)와 같이 반응시켜 목적 화합물(13 ㎎, 20%)을 얻었다.(S)-N2-(5-(2-(5-chloro-2-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)-4-(morpholino obtained in step 3) above Methyl)-N6-(piperidin-3-yl)pyridine-2,6-diamine (60 mg, 0.11 mmol) was reacted as in Example 1 step 9) to obtain the target compound (13 mg, 20%) got it
1H-NMR(400 MHz, DMSO-d6) δ: 11.35(s, 1H), 8.11(d, 1H, J= 3.2 Hz), 7.90(d, 1H, J= 51.2 Hz), 7.70-7.58(m, 2H), 6.81-6.39(m, 2H), 6.22(s, 1H), 6.12(d, 1H, t= 12.4 Hz), 5.78(dd, 1H, J= 42.4, 16.4 Hz), 5.32-5.29(m, 1H), 4.40-3.97(m, 3H), 3.59(t, 5H, J= 4.0 Hz), 3.29(s, 2H), 3.20-3.03(m, 2H), 2.81-2.67(m, 1H), 2.36(s, 4H), 2.32(s, 3H), 1.96(d, 1H, J= 14.0 Hz), 1.79-1.42(m, 3H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.35 (s, 1H), 8.11 (d, 1H, J = 3.2 Hz), 7.90 (d, 1H, J = 51.2 Hz), 7.70-7.58 ( m, 2H), 6.81-6.39 (m, 2H), 6.22 (s, 1H), 6.12 (d, 1H, t = 12.4 Hz), 5.78 (dd, 1H, J = 42.4, 16.4 Hz), 5.32-5.29 (m, 1H), 4.40-3.97 (m, 3H), 3.59 (t, 5H, J = 4.0 Hz), 3.29 (s, 2H), 3.20-3.03 (m, 2H), 2.81-2.67 (m, 1H) ), 2.36 (s, 4H), 2.32 (s, 3H), 1.96 (d, 1H, J = 14.0 Hz), 1.79-1.42 (m, 3H).
실시예 7: (S)-1-(3-((6-((5-(2-(2-클로로-6-플루오로페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Example 7: (S)-1-(3-((6-((5-(2-(2-chloro-6-fluorophenyl)-2H-tetrazol-5-yl)thiazole-2- Synthesis of yl)amino)-4-(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
단계 1) 2-브로모-5-(2-(2-클로로-6-플루오로페닐)-2H-테트라졸-5-일)싸이아졸의 합성Step 1) Synthesis of 2-bromo-5-(2-(2-chloro-6-fluorophenyl)-2H-tetrazol-5-yl)thiazole
실시예 1의 단계 1)에서 얻은 N'-((5-브로모싸이아졸-2-일)메틸렌)-4-메틸벤젠설폰하이드라자이드(500 ㎎, 1.39 mmol)와 2-클로로-5-플루오로아닐린(213 ㎎, 1.46 mmol)을 실시예 1의 단계 2)와 같이 반응시켜 목적 화합물(105 ㎎, 21%)을 얻었다.N'-((5-bromothiazol-2-yl)methylene)-4-methylbenzenesulfonehydrazide (500 mg, 1.39 mmol) obtained in step 1) of Example 1 and 2-chloro-5- Fluoroaniline (213 mg, 1.46 mmol) was reacted as in Example 1, step 2) to obtain the target compound (105 mg, 21%).
단계 2) tert-부틸(S)-3-((6-((5-(2-(2-클로로-6-플루오로페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노페닐)피리딘-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 2) tert-Butyl (S)-3-((6-((5-(2-(2-chloro-6-fluorophenyl)-2H-tetrazol-5-yl)thiazol-2-yl) Synthesis of )amino)-4-(morpholinophenyl)pyridin-2-yl)amino)piperidine-1-carboxylate
실시예 1의 단계 6)에서 얻은 tert-부틸(3S)-3-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-카복실레이트(150 ㎎, 0.38 mmol)와 상기 단계 1)에서 얻은 2-브로모-5-(2-(2-클로로-6-플루오로페닐)-2H-테트라졸-5-일)싸이아졸(166 ㎎, 0.46 mmol)을 실시예 1의 단계 7)과 같이 반응시켜 목적 화합물(150 ㎎, 58%)을 얻었다.tert-butyl(3S)-3-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexane-1-carboxylate obtained in step 6) of Example 1 (150 mg, 0.38 mmol) and 2-bromo-5-(2-(2-chloro-6-fluorophenyl)-2H-tetrazol-5-yl)thiazole obtained in step 1) (166 mg, 0.46 mmol) was reacted as in step 7) of Example 1) to obtain the target compound (150 mg, 58%).
단계 3) (S)-N2-(5-(2-(2-클로로-6-플루오로페닐)-2H-테트라졸-5-일)싸이아졸-2-일)-4-(몰포리노메틸)-N6-(피페리딘-3-일)피리딘-2,6-디아민의 합성Step 3) (S)-N2-(5-(2-(2-chloro-6-fluorophenyl)-2H-tetrazol-5-yl)thiazol-2-yl)-4-(morpholinomethyl Synthesis of )-N6-(piperidin-3-yl)pyridine-2,6-diamine
상기 단계 2)에서 얻은 tert-부틸(S)-3-((6-((5-(2-(2-클로로-6-플루오로페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노페닐)피리딘-2-일)아미노)피페리딘-1-카복실레이트(150 ㎎, 0.22 mmol)를 실시예 1의 단계 8)과 같이 반응시켜 목적 화합물(84 ㎎, 66%)을 얻었다.tert-Butyl (S)-3-((6-((5-(2-(2-chloro-6-fluorophenyl)-2H-tetrazol-5-yl)thiazole- 2-yl)amino)-4-(morpholinophenyl)pyridin-2-yl)amino)piperidine-1-carboxylate (150 mg, 0.22 mmol) was reacted as in Example 1 step 8) to the desired The compound (84 mg, 66%) was obtained.
단계 4) (S)-1-(3-((6-((5-(2-(2-클로로-6-플루오로페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Step 4) (S)-1-(3-((6-((5-(2-(2-chloro-6-fluorophenyl)-2H-tetrazol-5-yl)thiazol-2-yl) Synthesis of )amino)-4-(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
상기 단계 3)에서 얻은 (S)-N2-(5-(2-(2-클로로-6-플루오로페닐)-2H-테트라졸-5-일)싸이아졸-2-일)-4-(몰포리노메틸)-N6-(피페리딘-3-일)피리딘-2,6-디아민(43 ㎎, 0.08 mmol)을 실시예 1의 단계 9)와 같이 반응시켜 목적 화합물(8 ㎎, 17%)을 얻었다.(S)-N2-(5-(2-(2-chloro-6-fluorophenyl)-2H-tetrazol-5-yl)thiazol-2-yl)-4-( Morpholinomethyl)-N6-(piperidin-3-yl)pyridine-2,6-diamine (43 mg, 0.08 mmol) was reacted as in Example 1 step 9) to obtain the target compound (8 mg, 17%) ) was obtained.
1H-NMR(400 MHz, DMSO-d6) δ: 11.38(s, 1H), 8.24(s, 1H), 7.91-7.71(m, 3H), 6.59-6.14(m, 3H), 5.91-5.84(m, 1H), 5.34(s, 1H), 4.61-4.57(m, 1H), 4.43(s, 1H), 4.20-4.06(m, 2H), 3.63-3.69(4H), 3.30(s, 2H), 3.03(s, 1H), 2.95(t, 1H, J= 6.8 Hz), 2.79(t, 1H, J= 7.6 Hz), 2.67-2.61(m, 1H), 2.38(d, 4H, J= 13.2 Hz), 1.71-1.54(m, 3H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.38 (s, 1H), 8.24 (s, 1H), 7.91-7.71 (m, 3H), 6.59-6.14 (m, 3H), 5.91-5.84 (m, 1H), 5.34(s, 1H), 4.61-4.57(m, 1H), 4.43(s, 1H), 4.20-4.06(m, 2H), 3.63-3.69(4H), 3.30(s, 2H) ), 3.03 (s, 1H), 2.95 (t, 1H, J = 6.8 Hz), 2.79 (t, 1H, J = 7.6 Hz), 2.67-2.61 (m, 1H), 2.38 (d, 4H, J = 13.2 Hz), 1.71-1.54 (m, 3H).
실시예 8: (S)-1-(3-((6-((5-(2-(1-메틸-1H-피라졸-4-일)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Example 8: (S)-1-(3-((6-((5-(2-(1-methyl-1H-pyrazol-4-yl)-2H-tetrazol-5-yl)thiazole) Synthesis of -2-yl)amino)-4-(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
단계 1) 2-브로모-5-(2-(1-메틸-1H-피라졸-4-일)-2H-테트라졸-5-일)싸이아졸의 합성Step 1) Synthesis of 2-bromo-5-(2-(1-methyl-1H-pyrazol-4-yl)-2H-tetrazol-5-yl)thiazole
실시예 1의 단계 1)에서 얻은 N'-((5-브로모싸이아졸-2-일)메틸렌)-4-메틸벤젠설폰하이드라자이드(500 ㎎, 1.39 mmol)를 1-메틸-1H-피라졸-4-아민(0.10 ㎖, 1.46 mmol)과 실시예 1의 단계 2)와 같이 반응시켜 목적 화합물(153 ㎎, 35%)을 얻었다.N'-((5-bromothiazol-2-yl)methylene)-4-methylbenzenesulfonehydrazide (500 mg, 1.39 mmol) obtained in step 1) of Example 1 was mixed with 1-methyl-1H- The target compound (153 mg, 35%) was obtained by reacting with pyrazol-4-amine (0.10 mL, 1.46 mmol) in the same manner as in Example 1, step 2).
단계 2) tert-부틸(S)-3-((6-((5-(2-(1-메틸-1H-피라졸-4-일)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 2) tert-Butyl (S)-3-((6-((5-(2-(1-methyl-1H-pyrazol-4-yl)-2H-tetrazol-5-yl)thiazole- Synthesis of 2-yl)amino)-4-(morpholinomethyl)pyridin-2-yl)amino)piperidine-1-carboxylate
상기 단계 1)에서 얻은 2-브로모-5-(2-(1-메틸-1H-피라졸-4-일)-2H-테트라졸-5-일)싸이아졸(144 ㎎, 0.46 mol)과 실시예 1의 단계 6)에서 얻은 tert-부틸(3S)-3-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-카복실레이트(150 ㎎, 0.38 mmol)를 실시예 1의 단계 7)과 같이 반응시켜 목적 화합물(107 ㎎, 45%)을 얻었다.2-bromo-5-(2-(1-methyl-1H-pyrazol-4-yl)-2H-tetrazol-5-yl)thiazole obtained in step 1) (144 mg, 0.46 mol) and tert-butyl(3S)-3-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexane-1-carboxylate obtained in step 6) of Example 1 (150 mg, 0.38 mmol) was reacted as in Example 1 step 7) to obtain the target compound (107 mg, 45%).
단계 3) (S)-N2-(5-(2-(1-메틸-1H-피라졸-4-일)-2H-테트라졸-5-일)싸이아졸-2-일)-4-(몰포리노메틸)-N6-(피페리딘-3-일)피리딘-2,6-디아민의 합성Step 3) (S)-N2-(5-(2-(1-methyl-1H-pyrazol-4-yl)-2H-tetrazol-5-yl)thiazol-2-yl)-4-( Synthesis of morpholinomethyl)-N6-(piperidin-3-yl)pyridine-2,6-diamine
상기 단계 2)에서 얻은 tert-부틸(S)-3-((6-((5-(2-(1-메틸-1H-피라졸-4-일)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-카복실레이트(100 ㎎, 0.16 mmol)를 실시예 1의 단계 8)과 같이 반응시켜 목적 화합물(60 ㎎, 72%)을 얻었다.tert-Butyl (S)-3-((6-((5-(2-(1-methyl-1H-pyrazol-4-yl)-2H-tetrazol-5-yl) obtained in step 2) above Thiazol-2-yl)amino)-4-(morpholinomethyl)pyridin-2-yl)amino)piperidine-1-carboxylate (100 mg, 0.16 mmol) was prepared as in Example 1 step 8). The reaction was carried out to obtain the target compound (60 mg, 72%).
단계 4) (S)-1-(3-((6-((5-(2-(1-메틸-1H-피라졸-4-일)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Step 4) (S)-1-(3-((6-((5-(2-(1-methyl-1H-pyrazol-4-yl)-2H-tetrazol-5-yl)thiazole- Synthesis of 2-yl)amino)-4-(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
상기 단계 3)에서 얻은 (S)-N2-(5-(2-(1-메틸-1H-피라졸-4-일)-2H-테트라졸-5-일)싸이아졸-2-일)-4-(몰포리노메틸)-N6-(피페리딘-3-일)피리딘-2,6-디아민(90 ㎎, 0.17 mmol)을 실시예 1의 단계 9)와 같은 방법으로 반응시켜 목적 화합물(5 ㎎, 5%)을 얻었다.(S)-N2-(5-(2-(1-methyl-1H-pyrazol-4-yl)-2H-tetrazol-5-yl)thiazol-2-yl)- 4-(morpholinomethyl)-N6-(piperidin-3-yl)pyridine-2,6-diamine (90 mg, 0.17 mmol) was reacted in the same manner as in Example 1 step 9) to react the target compound ( 5 mg, 5%) was obtained.
1H-NMR(400 MHz, DMSO-d6) δ: 11.29(s, 1H), 8.13-8.05(m, 3H), 7.71(t, 2H, J= 7.2 Hz), 7.63(d, 1H, J= 6.8 Hz), 6.76-6.62(m, 2H), 5.88-5.85(m, 2H), 5.73(s, 1H), 5.46-5.38(m, 1H), 4.23-3.93(m, 3H), 3.72(s, 3H), 3.20-3.14(m, 1H), 2.99-2.95(m, 1H), 2.78-2.67(m, 1H), 2.24-2.22(m, 1H), 1.85-1.74(m, 2H), 1.51-1.48(m, 1H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.29 (s, 1H), 8.13-8.05 (m, 3H), 7.71 (t, 2H, J = 7.2 Hz), 7.63 (d, 1H, J ) = 6.8 Hz), 6.76-6.62 (m, 2H), 5.88-5.85 (m, 2H), 5.73 (s, 1H), 5.46-5.38 (m, 1H), 4.23-3.93 (m, 3H), 3.72 ( s, 3H), 3.20-3.14 (m, 1H), 2.99-2.95 (m, 1H), 2.78-2.67 (m, 1H), 2.24-2.22 (m, 1H), 1.85-1.74 (m, 2H), 1.51-1.48 (m, 1H).
실시예 9: (S)-1-(3-((6-((5-(2-(4-브로모페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Example 9: (S)-1-(3-((6-((5-(2-(4-bromophenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino) Synthesis of -4-(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
단계 1) 2-브로모-5-(2-(4-브로모페닐)-2H-테트라졸-5-일)싸이아졸의 합성Step 1) Synthesis of 2-bromo-5-(2-(4-bromophenyl)-2H-tetrazol-5-yl)thiazole
실시예 1의 단계 1)에서 얻은 N'-((5-브로모싸이아졸-2-일)메틸렌)-4-메틸벤젠설폰하이드라자이드(500 ㎎, 1.39 mmol)와 4-브로모아닐린(251 ㎎, 1.46 mmol)을 실시예 1의 단계 2)와 같은 방법으로 반응시켜 목적 화합물(193 ㎎, 36%)을 얻었다.N'-((5-bromothiazol-2-yl)methylene)-4-methylbenzenesulfonehydrazide (500 mg, 1.39 mmol) obtained in step 1) of Example 1 and 4-bromoaniline ( 251 mg, 1.46 mmol) was reacted in the same manner as in step 2) of Example 1 to obtain the target compound (193 mg, 36%).
단계 2) tert-부틸(S)-3-((6-((5-(2-(4-브로모페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 2) tert-Butyl (S)-3-((6-((5-(2-(4-bromophenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)- Synthesis of 4-(morpholinomethyl)pyridin-2-yl)amino)piperidine-1-carboxylate
실시예 1의 단계 6)에서 얻은 tert-부틸(3S)-3-((6-아미노-4-(몰포리노메틸)피리딘-2-일)아미노)사이클로헥산-1-카복실레이트(150 ㎎, 0.38 mmol)와 상기 단계 1)에서 얻은 2-브로모-5-(2-(4-브로모페닐)-2H-테트라졸-5-일)싸이아졸(178 ㎎, 0.46 mmol)을 실시예 1의 단계 7)과 같은 방법으로 반응시켜 목적 화합물(137 ㎎, 51%)을 얻었다.tert-butyl(3S)-3-((6-amino-4-(morpholinomethyl)pyridin-2-yl)amino)cyclohexane-1-carboxylate obtained in step 6) of Example 1 (150 mg, 0.38 mmol) and 2-bromo-5-(2-(4-bromophenyl)-2H-tetrazol-5-yl)thiazole (178 mg, 0.46 mmol) obtained in step 1) were prepared in Example 1 Step 7) was reacted in the same way to obtain the target compound (137 mg, 51%).
단계 3) (S)-N2-(5-(2-(4-브로모페닐)-2H-테트라졸-5-일)싸이아졸-2-일)-4-(몰포리노메틸)-N6-(피페리딘-3-일)피리딘-2,6-디아민의 합성Step 3) (S)-N2-(5-(2-(4-bromophenyl)-2H-tetrazol-5-yl)thiazol-2-yl)-4-(morpholinomethyl)-N6- Synthesis of (piperidin-3-yl)pyridine-2,6-diamine
상기 단계 2)에서 얻은 tert-부틸(S)-3-((6-((5-(2-(4-브로모페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-카복실레이트(130 ㎎, 0.19 mmol)를 실시예 1의 단계 8)과 같은 방법으로 반응시켜 목적 화합물(90 ㎎, 81%)을 얻었다.tert-Butyl (S)-3-((6-((5-(2-(4-bromophenyl)-2H-tetrazol-5-yl)thiazol-2-yl) obtained in step 2) above Amino)-4-(morpholinomethyl)pyridin-2-yl)amino)piperidine-1-carboxylate (130 mg, 0.19 mmol) was reacted in the same manner as in Example 1 step 8) to react with the target compound ( 90 mg, 81%) was obtained.
단계 4) (S)-1-(3-((6-((5-(2-(4-브로모페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Step 4) (S)-1-(3-((6-((5-(2-(4-bromophenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)- Synthesis of 4-(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
상기 단계 3)에서 얻은 (S)-N2-(5-(2-(4-브로모페닐)-2H-테트라졸-5-일)싸이아졸-2-일)-4-(몰포리노메틸)-N6-(피페리딘-3-일)피리딘-2,6-디아민(60 ㎎, 0.10 mmol)을 실시예 1의 단계 9)와 같은 방법으로 반응시켜 목적 화합물(9 ㎎, 14%)을 얻었다.(S)-N2-(5-(2-(4-bromophenyl)-2H-tetrazol-5-yl)thiazol-2-yl)-4-(morpholinomethyl) obtained in step 3) above -N6-(piperidin-3-yl)pyridine-2,6-diamine (60 mg, 0.10 mmol) was reacted in the same manner as in Example 1 step 9) to obtain the target compound (9 mg, 14%) got it
1H-NMR(400 MHz, DMSO-d6) δ: 11.39(s, 1H), 8.08-7.86(m, 5H), 6.84-6.77(m, 1H), 6.69-6.62(m, 1H), 6.22(s, 1H), 6.13(s, 1H), 5.85(d, 1H, J= 16.0 Hz), 5.44-5.36(m, 1H), 4.80-4.78(m, 1H), 4.24-3.96(m, 2H), 3.60(t, 4H, J= 4.0 Hz), 2.30(s, 3H), 3.19-3.13(m, 1H), 2.94-2.86(m, 1H), 2.37(s, 4H), 2.26(s, 1H), 1.82-1.71(m, 2H), 1.50-1.45(m, 2H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.39 (s, 1H), 8.08-7.86 (m, 5H), 6.84-6.77 (m, 1H), 6.69-6.62 (m, 1H), 6.22 (s, 1H), 6.13 (s, 1H), 5.85 (d, 1H, J = 16.0 Hz), 5.44-5.36 (m, 1H), 4.80-4.78 (m, 1H), 4.24-3.96 (m, 2H) ), 3.60(t, 4H, J = 4.0 Hz), 2.30(s, 3H), 3.19-3.13(m, 1H), 2.94-2.86(m, 1H), 2.37(s, 4H), 2.26(s, 1H), 1.82-1.71 (m, 2H), 1.50-1.45 (m, 2H).
실시예 10: (S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)부트-2-엔-1-온의 합성Example 10: (S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl) Synthesis of amino)pyridin-2-yl)amino)piperidin-1-yl)but-2-en-1-one
실시예 1의 단계 9)에서 아크릴로일클로라이드 대신 크로토노일클로라이드(시스-, 트랜스- 혼합물)를 사용한 것을 제외하고, 동일한 방법으로 반응시켜 목적 화합물(25 ㎎, 40%)을 얻었다.The target compound (25 mg, 40%) was obtained by reacting in the same manner except that crotonoyl chloride (cis-, trans- mixture) was used instead of acryloyl chloride in step 9) of Example 1).
1H-NMR(400 MHz, DMSO-d6): 11.36(s, 1H), 8.14-8.10(m, 3H), 7.72-7.70(m, 2H), 7.64-7.62(m, 1H), 6.83-6.79(m, 1H), 6.43-6.35(m, 2H), 6.23(s, 1H), 6.12(s, 1H), 3.61-3.60(m, 4H), 3.60-3.59(m, 4H), 3.30(s, 2H), 3.10-2.63(m, 2H), 2.37-2.36(m, 4H), 2.28-2.27(m, 1H), 1.91-1.74(m, 2H), 1.60-1.47(m, 5H), 1.18-1.14(m, 1H). 1 H-NMR (400 MHz, DMSO-d 6 ): 11.36 (s, 1H), 8.14-8.10 (m, 3H), 7.72-7.70 (m, 2H), 7.64-7.62 (m, 1H), 6.83 6.79(m, 1H), 6.43-6.35(m, 2H), 6.23(s, 1H), 6.12(s, 1H), 3.61-3.60(m, 4H), 3.60-3.59(m, 4H), 3.30( s, 2H), 3.10-2.63 (m, 2H), 2.37-2.36 (m, 4H), 2.28-2.27 (m, 1H), 1.91-1.74 (m, 2H), 1.60-1.47 (m, 5H), 1.18-1.14 (m, 1H).
실시예 11: (S)-1-(3-((4-메톡시-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Example 11: (S)-1-(3-((4-methoxy-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridine Synthesis of -2-yl)amino)piperidin-1-yl)prop-2-en-1-one
단계 1) tert-부틸(S)-3-((6-브로모-4-메톡시피리딘-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 1) Synthesis of tert-butyl (S)-3-((6-bromo-4-methoxypyridin-2-yl)amino)piperidine-1-carboxylate
실시예 1의 단계 5)에서 4-((2,6-디브로모피리딘-4-일)메틸)몰포린 대신 2,6-디브로모-4-메톡시피리딘(2.0 g, 7.49 mmol)을 사용한 것을 제외하고, 동일한 방법으로 목적 화합물(1.8 g, 62%)을 얻었다.2,6-dibromo-4-methoxypyridine (2.0 g, 7.49 mmol) instead of 4-((2,6-dibromopyridin-4-yl)methyl)morpholine in step 5) of Example 1 Except for using , the target compound (1.8 g, 62%) was obtained in the same manner.
단계 2) tert-부틸(S)-3-((6-아미노-4-메틸옥시피리딘-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 2) Synthesis of tert-butyl(S)-3-((6-amino-4-methyloxypyridin-2-yl)amino)piperidine-1-carboxylate
단계 1)에서 얻은 tert-부틸(S)-3-((6-브로모-4-메톡시피리딘-2-일)아미노)피페리딘-1-카복실레이트(500 ㎎, 1.29 mmol)를 실시예 1의 단계 6)과 같은 방법으로 반응시켜 목적 화합물(200 ㎎, 48%)을 얻었다.Carry out tert-butyl (S)-3-((6-bromo-4-methoxypyridin-2-yl)amino)piperidine-1-carboxylate (500 mg, 1.29 mmol) obtained in step 1) The target compound (200 mg, 48%) was obtained by reacting in the same manner as in step 6) of Example 1.
단계 3) tert-부틸(S)-3-((4-메톡시-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 3) tert-Butyl(S)-3-((4-methoxy-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin- Synthesis of 2-yl)amino)piperidine-1-carboxylate
단계 2)에서 얻은 tert-부틸(S)-3-((6-아미노-4-메틸옥시피리딘-2-일)아미노)피페리딘-1-카복실레이트(200 ㎎, 0.62 mmol)와 실시예 1의 단계 2)에서 얻은 2-브로모-5-(2-페닐-2H-테트라졸-5-일)싸이아졸(228 ㎎, 0.74 mmol)을 실시예 1의 단계 7)과 같은 방법으로 반응시켜 목적 화합물(200 ㎎, 59%)을 얻었다.tert-Butyl (S)-3-((6-amino-4-methyloxypyridin-2-yl)amino)piperidine-1-carboxylate (200 mg, 0.62 mmol) obtained in step 2) and the Examples 2-bromo-5-(2-phenyl-2H-tetrazol-5-yl)thiazole (228 mg, 0.74 mmol) obtained in step 2) of 1 was reacted in the same manner as in step 7) of Example 1. to obtain the target compound (200 mg, 59%).
단계 4) (S)-4-메톡시-N2-(5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)-N6-(피페리딘-3-일)피리딘-2,6-디아민의 합성Step 4) (S)-4-Methoxy-N2-(5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)-N6-(piperidin-3-yl) Synthesis of pyridine-2,6-diamine
단계 3)에서 얻은 tert-부틸(S)-3-((4-메톡시-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-카복실레이트(50 ㎎, 0.09 mmol)를 실시예 1의 단계 8)과 같은 방법으로 목적 화합물(38 ㎎, 94%)을 얻었다.tert-Butyl (S)-3-((4-methoxy-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino) obtained in step 3) Pyridin-2-yl)amino)piperidine-1-carboxylate (50 mg, 0.09 mmol) was obtained in the same manner as in Example 1 step 8) to obtain the target compound (38 mg, 94%).
단계 5) (S)-1-(3-((4-메톡시-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Step 5) (S)-1-(3-((4-methoxy-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin- Synthesis of 2-yl)amino)piperidin-1-yl)prop-2-en-1-one
단계 4)에서 얻은 (S)-4-메톡시-N2-(5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)-N6-(피페리딘-3-일)피리딘-2,6-디아민(40 ㎎, 0.09 mmol)을 실시예 1의 단계 9)와 같은 방법으로 반응시켜 목적 화합물(9 ㎎, 20%)을 얻었다.(S)-4-Methoxy-N2-(5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)-N6-(piperidin-3- Day) Pyridine-2,6-diamine (40 mg, 0.09 mmol) was reacted in the same manner as in Example 1 step 9) to obtain the target compound (9 mg, 20%).
1H-NMR(400 MHz, CDCl3) δ: 10.47(s, 1H), 8.21-8.15(m, 3H), 7.59(s, 2H), 7.50(t, 1H, J= 7.2 Hz), 6.52-6.18(m, 2H), 7.85-5.54(m, 3H), 4.72-4.26(m, 2H), 3.98-3.87(m, 1H), 3.81(s, 3H), 3.54-3.49(m, 1H), 3.42-3.38(m, 1H), 2.26(s, 1H), 1.87(s, 3H), 0.94-0.92(m, 1H). 1 H-NMR (400 MHz, CDCl 3 ) δ: 10.47 (s, 1H), 8.21-8.15 (m, 3H), 7.59 (s, 2H), 7.50 (t, 1H, J = 7.2 Hz), 6.52 6.18 (m, 2H), 7.85-5.54 (m, 3H), 4.72-4.26 (m, 2H), 3.98-3.87 (m, 1H), 3.81 (s, 3H), 3.54-3.49 (m, 1H), 3.42-3.38 (m, 1H), 2.26 (s, 1H), 1.87 (s, 3H), 0.94-0.92 (m, 1H).
실시예 12: (S)-1-(3-((4-메틸-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Example 12: (S)-1-(3-((4-methyl-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin- Synthesis of 2-yl)amino)piperidin-1-yl)prop-2-en-1-one
단계 1) tert-부틸(S)-3-((6-브로모-4-메틸피리딘-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 1) Synthesis of tert-butyl (S)-3-((6-bromo-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate
실시예 1의 단계 5)에서 4-((2,6-디브로모피리딘-4-일)메틸)몰포린 대신 2,6-디브로모-4-메틸피리딘(500 ㎎, 1.99 mmol)을 사용한 것을 제외하고, 동일한 방법으로 목적 화합물(570 ㎎, 77%)을 얻었다.In step 5) of Example 1, 2,6-dibromo-4-methylpyridine (500 mg, 1.99 mmol) was used instead of 4-((2,6-dibromopyridin-4-yl)methyl)morpholine. Except for the use, the target compound (570 mg, 77%) was obtained in the same manner.
단계 2) tert-부틸(S)-3-((6-아미노-4-메틸피리딘-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 2) Synthesis of tert-butyl (S)-3-((6-amino-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate
단계 1)에서 얻은 tert-부틸(S)-3-((6-브로모-4-메틸피리딘-2-일)아미노)피페리딘-1-카복실레이트(570 ㎎, 1.54 mmol)를 실시예 1의 단계 6)과 같은 방법으로 반응시켜 목적 화합물(240 ㎎, 51%)을 얻었다.tert-Butyl (S)-3-((6-bromo-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate (570 mg, 1.54 mmol) obtained in step 1) was prepared in Example The target compound (240 mg, 51%) was obtained by reacting in the same manner as in step 6) of 1).
단계 3) tert-부틸(S)-3-((4-메틸-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 3) tert-Butyl(S)-3-((4-methyl-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin-2 Synthesis of -yl)amino)piperidine-1-carboxylate
단계 2)에서 얻은 tert-부틸(S)-3-((6-아미노-4-메틸피리딘-2-일)아미노)피페리딘-1-카복실레이트(120 ㎎, 0.39 mmol)와 실시예 1의 단계 2)에서 얻은 2-브로모-5-(2-페닐-2H-테트라졸-5-일)싸이아졸(145 ㎎, 0.47 mmol)을 실시예 1의 단계 7)과 같은 방법으로 반응시켜 목적 화합물(150 ㎎, 72%)을 얻었다.tert-Butyl (S)-3-((6-amino-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate (120 mg, 0.39 mmol) obtained in step 2) and Example 1 2-bromo-5-(2-phenyl-2H-tetrazol-5-yl)thiazole (145 mg, 0.47 mmol) obtained in step 2) of step 2) was reacted in the same manner as in step 7) of Example 1. The target compound (150 mg, 72%) was obtained.
단계 4) (S)-4-메틸-N2-(5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)-N6-(피페리딘-3-일)피리딘-2,6-디아민의 합성Step 4) (S)-4-Methyl-N2-(5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)-N6-(piperidin-3-yl)pyridine Synthesis of -2,6-diamine
단계 3)에서 얻은 tert-부틸(S)-3-((4-메틸-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-카복실레이트(150 ㎎, 0.28 mmol)를 실시예 1의 단계 8)과 같은 방법으로 반응시켜 목적 화합물(120 ㎎, 98%)을 얻었다.tert-Butyl(S)-3-((4-methyl-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridine obtained in step 3) -2-yl)amino)piperidine-1-carboxylate (150 mg, 0.28 mmol) was reacted in the same manner as in Example 1 step 8) to obtain the target compound (120 mg, 98%).
단계 5) (S)-1-(3-((4-메틸-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Step 5) (S)-1-(3-((4-methyl-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin-2 Synthesis of -yl)amino)piperidin-1-yl)prop-2-en-1-one
단계 4)에서 얻은 (S)-4-메틸-N2-(5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)-N6-(피페리딘-3-일)피리딘-2,6-디아민(120 ㎎, 0.28 mmol)을 실시예 1의 단계 9)와 같은 방법으로 반응시켜 목적 화합물(49 ㎎, 36%)을 얻었다.(S)-4-methyl-N2-(5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)-N6-(piperidin-3-yl from step 4) ) Pyridine-2,6-diamine (120 mg, 0.28 mmol) was reacted in the same manner as in step 9) of Example 1 to obtain the target compound (49 mg, 36%).
1H-NMR(400 MHz, CDCl3) δ: 10.55(s, 1H), 9.11-8.80(m, 1H), 8.18-8.16(m, 2H), 6.53-6.21(m, 2H), 6.16-5.99(m, 1H), 5.70(dd, 1H, J= 132.0, 90.4 Hz), 4.65-4.40(m, 2H), 4.30-3.70(m, 1H), 3.53-3.39(m, 2H), 2.24(s, 3H), 1.84-1.89(3H), 0.85-0.79(m, 1H). 1 H-NMR (400 MHz, CDCl 3 ) δ: 10.55(s, 1H), 9.11-8.80(m, 1H), 8.18-8.16(m, 2H), 6.53-6.21(m, 2H), 6.16-5.99 (m, 1H), 5.70 (dd, 1H, J = 132.0, 90.4 Hz), 4.65-4.40 (m, 2H), 4.30-3.70 (m, 1H), 3.53-3.39 (m, 2H), 2.24 (s) , 3H), 1.84-1.89 (3H), 0.85-0.79 (m, 1H).
실시예 13: (S)-1-(3-((4-메틸-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Example 13: (S)-1-(3-((4-methyl-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl) Synthesis of )amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
단계 1) tert-부틸(S)-3-((4-메틸-6-((5-(5-페닐-1,3,4-옥시디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 1) tert-Butyl(S)-3-((4-methyl-6-((5-(5-phenyl-1,3,4-oxydiazol-2-yl)thiazol-2-yl) Synthesis of amino)pyridin-2-yl)amino)piperidine-1-carboxylate
실시예 12의 단계 2)에서 얻은 tert-부틸(S)-3-((6-아미노-4-메틸피리딘-2-일)아미노)피페리딘-1-카복실레이트(120 ㎎, 0.39 mmol)와 실시예 5의 단계 1)에서 얻은 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸(145 ㎎, 0.47 mmol)을 실시예 1의 단계 7)과 같은 방법으로 반응시켜 목적 화합물(130 ㎎, 62%)을 얻었다.tert-Butyl (S)-3-((6-amino-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate obtained in step 2) of Example 12 (120 mg, 0.39 mmol) and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadiazole (145 mg, 0.47 mmol) obtained in step 1) of Example 5 The reaction was carried out in the same manner as in step 7) to obtain the target compound (130 mg, 62%).
단계 2) (S)-4-메틸-N2-(5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)-N6-(피페리딘-3-일)피리딘-2,6-디아민의 합성Step 2) (S)-4-methyl-N2-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-N6-(piperidin- 3-yl) pyridine-2,6-diamine synthesis
상기 단계 1)에서 얻은 tert-부틸(S)-3-((4-메틸-6-((5-(5-페닐-1,3,4-옥시디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-카복실레이트(130 ㎎, 0.24 mmol)를 실시예 1의 단계 8)과 같은 방법으로 반응시켜 목적 화합물(100 ㎎, 94%)을 얻었다.tert-Butyl (S)-3-((4-methyl-6-((5-(5-phenyl-1,3,4-oxydiazol-2-yl)thiazole-2 obtained in step 1) -yl)amino)pyridin-2-yl)amino)piperidine-1-carboxylate (130 mg, 0.24 mmol) was reacted in the same manner as in Example 1 step 8) to obtain the target compound (100 mg, 94%) ) was obtained.
단계 3) (S)-1-(3-((4-메틸-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Step 3) (S)-1-(3-((4-methyl-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl) Synthesis of amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
상기 단계 2)에서 얻은 (S)-4-메틸-N2-(5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)-N6-(피페리딘-3-일)피리딘-2,6-디아민(100 ㎎, 0.23 mmol)을 실시예 1의 단계 9)와 같은 방법으로 반응시켜 목적 화합물(39 ㎎, 35%)을 얻었다.(S)-4-methyl-N2-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-N6-(p Peridin-3-yl)pyridine-2,6-diamine (100 mg, 0.23 mmol) was reacted in the same manner as in Example 1 step 9) to obtain the target compound (39 mg, 35%).
1H-NMR(400 MHz, CDCl3) δ: 10.52(s, 1H), 9.07(d, 1H, J= 25.2 Hz), 8.12-8.06(m, 3H), 7.06(s, 3H), 7.55-6.42(m, 1H), 6.32-6.21(m, 1H), 6.02-5.89(m, 1H), 5.62(dd, 1H, J= 58.4, 10.0 Hz), 4.15(d, 1H, J= 56.8 Hz), 3.87-3.65(m, 3H), 3.34(d, 1H, J= 54.4 Hz), 3.24(s, 3H), 1.86-1.74(m, 3H), 0.88-0.81(m, 1H). 1 H-NMR (400 MHz, CDCl 3 ) δ: 10.52 (s, 1H), 9.07 (d, 1H, J = 25.2 Hz), 8.12-8.06 (m, 3H), 7.06 (s, 3H), 7.55- 6.42 (m, 1H), 6.32-6.21 (m, 1H), 6.02-5.89 (m, 1H), 5.62 (dd, 1H, J = 58.4, 10.0 Hz), 4.15 (d, 1H, J = 56.8 Hz) , 3.87-3.65 (m, 3H), 3.34 (d, 1H, J = 54.4 Hz), 3.24 (s, 3H), 1.86-1.74 (m, 3H), 0.88-0.81 (m, 1H).
실시예 14: (S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-인-1-온의 합성Example 14: (S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl) Synthesis of amino) pyridin-2-yl) amino) piperidin-1-yl) prop-2-yn-1-one
실시예 1의 단계 8)에서 얻은 (S)-4-(몰포리노메틸)-N2-(5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)-N6-(피페리딘-3-일)피리딘-2,6-디아민(50 ㎎, 0.10 mmol)과 1,5,7-트리아자바이사이클로[4,4,0]덱-5-엔(30 mol%)을 테트라하이드로퓨란(3 ㎖)에 녹인 후, 메틸프로피올레이트(9 ㎎, 0.11 mmol)를 적가하여 상온에서 밤샘 교반하였다. 반응이 완료되면 에틸아세테이트로 추출한 후 유기층을 황산나트륨으로 건조하고 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물(14 ㎎, 26%)을 얻었다.(S)-4-(morpholinomethyl)-N2-(5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)-N6- obtained in step 8) of Example 1 (piperidin-3-yl)pyridin-2,6-diamine (50 mg, 0.10 mmol) and 1,5,7-triazabicyclo[4,4,0]dec-5-ene (30 mol%) was dissolved in tetrahydrofuran (3 ml), methyl propiolate (9 mg, 0.11 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. Upon completion of the reaction, the mixture was extracted with ethyl acetate, the organic layer was dried over sodium sulfate, and distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (14 mg, 26%).
1H-NMR(400 MHz, DMSO-d6): 11.34(s, 1H), 8.10(s, 1H), 8.08-8.06(m, 2H), 7.72-7.69(m, 2H), 7.63-7.59(m, 1H), 6.77(m, 1H), 6.23(s, 1H), 6.11(s, 1H), 4.27-4.23(m, 1H), 3.80-3.77(m ,1H), 3.60-6.58(m, 4H), 3.49-3.44(m, 1H), 3.30(s, 1H), 3.23(s, 2H), 3.04-2.28(m, 2H), 2.38-2.36(m, 4H), 2.20-2.09(m, 1H), 1.97-1.79(m, 2H), 1.55-1.47(m, 1H), 1.24-1.23(m, 1H). 1 H-NMR (400 MHz, DMSO-d 6 ): 11.34 (s, 1H), 8.10 (s, 1H), 8.08-8.06 (m, 2H), 7.72-7.69 (m, 2H), 7.63-7.59 ( m, 1H), 6.77(m, 1H), 6.23(s, 1H), 6.11(s, 1H), 4.27-4.23(m, 1H), 3.80-3.77(m,1H), 3.60-6.58(m, 4H), 3.49-3.44(m, 1H), 3.30(s, 1H), 3.23(s, 2H), 3.04-2.28(m, 2H), 2.38-2.36(m, 4H), 2.20-2.09(m, 1H), 1.97-1.79 (m, 2H), 1.55-1.47 (m, 1H), 1.24-1.23 (m, 1H).
실시예 15: (S)-1-(3-((6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피라진-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Example 15: (S)-1-(3-((6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyrazin-2-yl) Synthesis of amino) piperidin-1-yl) prop-2-en-1-one
단계 1) tert-부틸(S)-3-((6-브로모피라진-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 1) Synthesis of tert-butyl (S)-3-((6-bromopyrazin-2-yl)amino)piperidine-1-carboxylate
실시예 1의 단계 5)에서 4-((2,6-디브로모피리딘-4-일)메틸)몰포린 대신 2,6-디브로모피라진(100 ㎎, 0.42 mmol)을 사용한 것을 제외하고, 동일한 방법으로 목적 화합물(66 ㎎, 43%)을 얻었다.Except for using 2,6-dibromopyrazine (100 mg, 0.42 mmol) instead of 4-((2,6-dibromopyridin-4-yl)methyl)morpholine in step 5) of Example 1 , to obtain the target compound (66 mg, 43%) in the same manner.
단계 2) tert-부틸(S)-3-((6-아미노피라진-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 2) Synthesis of tert-butyl (S)-3-((6-aminopyrazin-2-yl)amino)piperidine-1-carboxylate
상기 단계 1)에서 얻은 tert-부틸(S)-3-((6-브로모피라진-2-일)아미노)피페리딘-1-카복실레이트(66 ㎎, 0.18 mmol)를 실시예 1의 단계 6)과 같은 방법으로 반응시켜 목적 화합물(26 ㎎, 50%)을 얻었다.tert-Butyl (S)-3-((6-bromopyrazin-2-yl)amino)piperidine-1-carboxylate (66 mg, 0.18 mmol) obtained in step 1) was prepared from the step of Example 1 6) was reacted in the same manner to obtain the target compound (26 mg, 50%).
단계 3) tert-부틸(S)-3-((6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피라진-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 3) tert-Butyl(S)-3-((6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyrazin-2-yl)amino ) Synthesis of piperidine-1-carboxylate
상기 단계 2)에서 얻은 tert-부틸(S)-3-((6-아미노피라진-2-일)아미노)피페리딘-1-카복실레이트(26 ㎎, 0.09 mmol)와 실시예 1의 단계 2)에서 얻은 2-브로모-5-(2-페닐-2H-테트라졸-5-일)싸이아졸(34 ㎎, 0.11 mmol)을 실시예 1의 단계 7)과 같은 방법으로 반응시켜 목적 화합물(27 ㎎, 56%)을 얻었다.tert-Butyl (S)-3-((6-aminopyrazin-2-yl)amino)piperidine-1-carboxylate (26 mg, 0.09 mmol) obtained in step 2) above and step 2 of Example 1 ) and 2-bromo-5-(2-phenyl-2H-tetrazol-5-yl)thiazole (34 mg, 0.11 mmol) obtained from 27 mg, 56%) was obtained.
단계 4) (S)-N2-(5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)-N6-(피페리딘-3-일)피라진-2,6-디아민의 합성Step 4) (S)-N2-(5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)-N6-(piperidin-3-yl)pyrazine-2,6 -Synthesis of diamines
상기 단계 3)에서 얻은 tert-부틸(S)-3-((6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피라진-2-일)아미노)피페리딘-1-카복실레이트(27 ㎎, 0.05 mmol)를 실시예 1의 단계 8)과 같은 방법으로 반응시켜 목적 화합물(20 ㎎, 95%)을 얻었다.tert-Butyl (S)-3-((6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyrazine-2- yl)amino)piperidine-1-carboxylate (27 mg, 0.05 mmol) was reacted in the same manner as in step 8) of Example 1 to obtain the target compound (20 mg, 95%).
단계 5) (S)-1-(3-((6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피라진-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Step 5) (S)-1-(3-((6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyrazin-2-yl)amino Synthesis of )piperidin-1-yl)prop-2-en-1-one
상기 단계 4)에서 얻은 (S)-N2-(5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)-N6-(피페리딘-3-일)피라진-2,6-디아민(20 ㎎, 0.05 mmol)을 실시예 1의 단계 9)와 같은 방법으로 반응시켜 목적 화합물(8 ㎎, 35%)을 얻었다.(S)-N2-(5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)-N6-(piperidin-3-yl)pyrazine- 2,6-diamine (20 mg, 0.05 mmol) was reacted in the same manner as in Example 1, step 9) to obtain the target compound (8 mg, 35%).
1H-NMR(400 MHz, MeOD) δ: 8.18-8.10(m, 3H), 7.68-7.64(m, 2H), 7.59-7.57(m, 1H), 7.49-7.46(m, 2H), 6.64-6.57(m, 1H), 5.92(d, 1H, J= 16.0 Hz), 5.44(d, 1H, J= 4.0 Hz), 4.58(s, 1H), 4.39-4.36(m, 1H), 4.24-4.16(m, 1H), 3.99(d, 1H, J= 16.0 Hz), 2.36-2.1(m, 1H), 1.90-1.85(m, 4H), 1.69-1.53(m, 2H). 1 H-NMR (400 MHz, MeOD) δ: 8.18-8.10 (m, 3H), 7.68-7.64 (m, 2H), 7.59-7.57 (m, 1H), 7.49-7.46 (m, 2H), 6.64 6.57 (m, 1H), 5.92 (d, 1H, J = 16.0 Hz), 5.44 (d, 1H, J = 4.0 Hz), 4.58 (s, 1H), 4.39-4.36 (m, 1H), 4.24-4.16 (m, 1H), 3.99 (d, 1H, J = 16.0 Hz), 2.36-2.1 (m, 1H), 1.90-1.85 (m, 4H), 1.69-1.53 (m, 2H).
실시예 16: 1-((S)-3-((4-(((2S,6R)-2,6-디메틸몰포리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Example 16: 1-((S)-3-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3) Synthesis of ,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
단계 1) (2,6-디브로모피리딘-4-일)((2S,6R)-2,6-디메틸몰포리노)메타논의 합성Step 1) Synthesis of (2,6-dibromopyridin-4-yl)((2S,6R)-2,6-dimethylmorpholino)methanone
실시예 1의 단계 3)에서 몰포린 대신 시스-2,6-디메틸몰포린을 사용한 것을 제외하고, 동일한 방법으로 목적 화합물(1.01 g, 75%)을 얻었다.The target compound (1.01 g, 75%) was obtained in the same manner as in Example 1, except that cis-2,6-dimethylmorpholine was used instead of morpholine in step 3).
단계 2) (2S,6R)-4-((2,6-디브로포피리딘-4-일)메틸)-2,6-디메틸몰포린의 합성Step 2) Synthesis of (2S,6R)-4-((2,6-dibropopyridin-4-yl)methyl)-2,6-dimethylmorpholine
상기 단계 1)에서 얻은 (2,6-디브로모피리딘-4-일)((2S,6R)-2,6-디메틸몰포리노)메타논(700 ㎎, 1.85 mmol)을 실시예 1의 단계 4)와 같은 방법으로 목적 화합물(220 ㎎, 33%)을 얻었다.(2,6-dibromopyridin-4-yl)((2S,6R)-2,6-dimethylmorpholino)methanone (700 mg, 1.85 mmol) obtained in step 1) was prepared in the step of Example 1 4) to obtain the target compound (220 mg, 33%).
단계 3) tert-부틸(3S)-3-((6-브로모-4-(((2S,6R)-2,6-디메틸몰포리노)메틸)피리딘-2-일)아미노)사이클로헥산-1-카복실레이트의 합성Step 3) tert-Butyl (3S)-3-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclohexane- Synthesis of 1-carboxylate
상기 단계 2)에서 얻은 (2S,6R)-4-((2,6-디브로모피리딘-4-일)메틸)-2,6-디메틸몰포린(450 ㎎, 1.24 mmol)을 실시예 1의 단계 5)와 같은 방법으로 반응시켜 목적 화합물(240 ㎎, 40%)을 얻었다.(2S,6R)-4-((2,6-dibromopyridin-4-yl)methyl)-2,6-dimethylmorpholine (450 mg, 1.24 mmol) obtained in step 2) was prepared in Example 1 The target compound (240 mg, 40%) was obtained by reacting in the same manner as in step 5).
단계 4) tert-부틸(3S)-3-((6-아미노-4-(((2S,6R)-2,6-디메틸몰포리노)메틸)피리딘-2-일)아미노)사이클로헥산-1-카복실레이트의 합성Step 4) tert-Butyl(3S)-3-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclohexane-1 -Synthesis of carboxylates
상기 단계 3)에서 얻은 tert-부틸(3S)-3-((6-브로모-4-(((2S,6R)-2,6-디메틸몰포리노)메틸)피리딘-2-일)아미노)사이클로헥산-1-카복실레이트(240 ㎎, 0.50 mmol)를 실시예 1의 단계 6)과 같은 방법으로 반응시켜 목적 화합물(80 ㎎, 38%)을 얻었다.tert-Butyl (3S)-3-((6-bromo-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino) obtained in step 3) above Cyclohexane-1-carboxylate (240 mg, 0.50 mmol) was reacted in the same manner as in Example 1 step 6) to obtain the target compound (80 mg, 38%).
단계 5) tert-부틸(S)-3-((4-(((2S,6R)-2,6-디메틸몰포리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-카복실레이트의 합성Step 5) tert-Butyl(S)-3-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3, Synthesis of 4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)piperidine-1-carboxylate
상기 단계 4)에서 얻은 tert-부틸(3S)-3-((6-아미노-4-(((2S,6R)-2,6-디메틸몰포리노)메틸)피리딘-2-일)아미노)사이클로헥산-1-카복실레이트(80 ㎎, 0.19 mmol)와 실시예 5의 단계 1)에서 얻은 2-(2-브로모싸이아졸-5-일)-5-페닐-1,3,4-옥사디아졸(70 ㎎, 0.23 mmol)을 실시예 1의 단계 7)과 같이 반응시켜 목적 화합물(71 ㎎, 57%)을 얻었다.tert-Butyl(3S)-3-((6-amino-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)pyridin-2-yl)amino)cyclo obtained in step 4) above. Hexane-1-carboxylate (80 mg, 0.19 mmol) and 2-(2-bromothiazol-5-yl)-5-phenyl-1,3,4-oxadia obtained in step 1) of Example 5 The sol (70 mg, 0.23 mmol) was reacted as in Example 1 step 7) to obtain the target compound (71 mg, 57%).
단계 6) 4-(((2S,6R)-2,6-디메틸몰포리노)메틸)-N2-(5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)-N6-((S)-피페리딘-3-일)피리딘-2,6-디아민의 합성Step 6) 4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-N2-(5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazole Synthesis of -2-yl)-N6-((S)-piperidin-3-yl)pyridin-2,6-diamine
상기 단계 5)에서 얻은 tert-부틸(S)-3-((4-(((2S,6R)-2,6-디메틸몰포리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-카복실레이트(71 ㎎, 0.11 mmol)를 실시예 1의 단계 8)과 같이 반응시켜 목적 화합물(60 ㎎, 100%)을 얻었다.tert-Butyl (S)-3-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1) obtained in step 5) above ,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)piperidine-1-carboxylate (71 mg, 0.11 mmol) of Example 1 The reaction was carried out as in step 8) to obtain the target compound (60 mg, 100%).
단계 7) 1-((S)-3-((4-(((2S,6R)-2,6-디메틸몰포리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Step 7) 1-((S)-3-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3, Synthesis of 4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
상기 단계 6)에서 얻은 4-(((2S,6R)-2,6-디메틸몰포리노)메틸)-N2-(5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)-N6-((S)-피페리딘-3-일)피리딘-2,6-디아민(60 ㎎, 0.11 mmol)을 실시예 1의 단계 9)와 같이 반응시켜 목적 화합물(15 ㎎, 23%)을 얻었다.4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-N2-(5-(5-phenyl-1,3,4-oxadiazol-2-yl obtained in step 6) above ) Thiazol-2-yl)-N6-((S)-piperidin-3-yl)pyridine-2,6-diamine (60 mg, 0.11 mmol) was reacted as in Example 1 step 9) The target compound (15 mg, 23%) was obtained.
1H-NMR(400 MHz, DMSO-d6) δ: 11.56(s, 1H), 8.19(d, 1H, J= 6.4 Hz), 8.05-8.02(m, 2H), 7.65-7.63(m, 3H), 6.86-6.80(m, 1H), 6.70-6.53(m, 1H), 6.23(s, 1H), 6.16-6.14(m, 1H), 5.93-5.87(m, 1H), 5.50-5.40(m, 1H), 4.35-3.90(m, 3H), 3.62-3.56(m, 3H), 3.28(s, 2H), 3.21-3.16(m, 1H), 2.73-2.68(m, 2H), 2.20-2.18(m, 1H), 1.94-1.73(m, 2H), 1.52-1.48(m, 1H), 1.23-1.16(m, 2H), 1.05-1.03(m, 6H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.56 (s, 1H), 8.19 (d, 1H, J = 6.4 Hz), 8.05-8.02 (m, 2H), 7.65-7.63 (m, 3H) ), 6.86-6.80(m, 1H), 6.70-6.53(m, 1H), 6.23(s, 1H), 6.16-6.14(m, 1H), 5.93-5.87(m, 1H), 5.50-5.40(m) , 1H), 4.35-3.90(m, 3H), 3.62-3.56(m, 3H), 3.28(s, 2H), 3.21-3.16(m, 1H), 2.73-2.68(m, 2H), 2.20-2.18 (m, 1H), 1.94-1.73 (m, 2H), 1.52-1.48 (m, 1H), 1.23-1.16 (m, 2H), 1.05-1.03 (m, 6H).
실시예 17. (S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Example 17. (S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl) Synthesis of amino)pyrimidin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
단계 1) 메틸 2-클로로-6-((2,4,4-트리메틸펜탄-2-일)아미노)피리미딘-4-카르보실레이트의 합성Step 1) Synthesis of methyl 2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carbohydrate
상온에서 메틸 2,6-디클로로피리미딘-4-카르복실레이트 (1.4 g, 10.14 mmol), tert-옥틸아민 (1.31 g, 1.5 eq.) 과 DIPEA (1.77 mL, 1.5 eq.)를 테트리히드로퓨란 (2 mL) 용매하에 68시간 교반한 뒤 용매를 감압 제거하고 디클로로메탄으로 추출하고 탄산수소나트륨 수용액으로 씻어준뒤 감압증류 하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물 (1.44 g, 71%)을 얻었다.Methyl 2,6-dichloropyrimidine-4-carboxylate (1.4 g, 10.14 mmol), tert-octylamine (1.31 g, 1.5 eq.) and DIPEA (1.77 mL, 1.5 eq.) were mixed with tetrahydro at room temperature After stirring in a furan (2 mL) solvent for 68 hours, the solvent was removed under reduced pressure, extracted with dichloromethane, washed with an aqueous sodium hydrogen carbonate solution, and distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (1.44 g, 71%).
단계 2) (2-클로로-6-((2,4,4-트리메틸펜탄-2-일)아미노)피리미딘-4-일)(몰포리노)메탄온의 합성Step 2) Synthesis of (2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(morpholino)methanone
상기 단계 1에서 얻은 메틸 2-클로로-6-((2,4,4-트리메틸펜탄-2-일)아미노)피리미딘-4-카르보실레이트 (1.2 g, 4 mmol), 1,5,7-트리아자비사이클로[4.4.0]데크-5-엔 (167 mg , 0.3 eq.) 과 몰포린 (0.35 mL, 1 eq.) 을 테트라히드로퓨란 (6 mL)용매에서 3시간 상온에서 교반하였다. 반응용액을 디클로로메탄으로 추출하고 탄산나트륨 수용액으로 씻어준 뒤 감압증류 하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물 (1.16 g, 82%)을 얻었다.Methyl 2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carbohydrate (1.2 g, 4 mmol) obtained in step 1 above, 1,5,7 -Triazabicyclo[4.4.0]dec-5-ene (167 mg, 0.3 eq.) and morpholine (0.35 mL, 1 eq.) were stirred in a tetrahydrofuran (6 mL) solvent at room temperature for 3 hours. The reaction solution was extracted with dichloromethane, washed with aqueous sodium carbonate solution, and distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (1.16 g, 82%).
단계 3) 2-클로로-6-(몰포리노메틸)-N-(2,4,4-트리메틸펜탄-2-일)피리미틴-4-아민의 합성Step 3) Synthesis of 2-chloro-6-(morpholinomethyl)-N-(2,4,4-trimethylpentan-2-yl)pyrimitin-4-amine
상기 단계 2)에서 얻은 (2-클로로-6-((2,4,4-트리메틸펜탄-2-일)아미노)피리미딘-4-일)(몰포리노)메탄온 (200 mg, 0.56 mmol)를 실시예 1의 단계 4)와 같은 방법으로 목적 화합물(70 mg, 36%)을 얻었다(2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(morpholino)methanone (200 mg, 0.56 mmol) obtained in step 2) above to obtain the target compound (70 mg, 36%) in the same manner as in step 4) of Example 1
단계 4) 2-클로로-6-(몰포리노메틸)피리미딘-4-아민의 합성Step 4) Synthesis of 2-chloro-6-(morpholinomethyl)pyrimidin-4-amine
상기 단계 3)에서 얻은 2-클로로-6-(몰포리노메틸)-N-(2,4,4-트리메틸펜탄-2-일)피리미틴-4-아민 (120 mg, 0.35 mmol)을 디클로로메탄 용매에 녹이 후 이 용액에 트리플로로아세트산 (1.08 mL, 40 eq.)을 첨가하고 50 °C에서 16시간 교반 후 온도를 상온으로 낮춘 후 밤새 교반하였다. 반응이 완료되면 감압증류하고 디클로로메탄으로 추출하고 탄산나트륨 수용액으로 씻어준 후 용액을 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물 (52.4 mg, 65%)을 얻었다.2-chloro-6-(morpholinomethyl)-N-(2,4,4-trimethylpentan-2-yl)pyrimitin-4-amine (120 mg, 0.35 mmol) obtained in step 3) above was dissolved in dichloromethane After dissolving in a solvent, trifluoroacetic acid (1.08 mL, 40 eq.) was added to this solution, and after stirring at 50 °C for 16 hours, the temperature was lowered to room temperature, followed by stirring overnight. Upon completion of the reaction, the mixture was distilled under reduced pressure, extracted with dichloromethane, washed with an aqueous sodium carbonate solution, and the solution was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (52.4 mg, 65%).
단계 5) N-(2-클로로-6-(몰포리노메틸)피리미딘-4-일)-5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-아민의 합성Step 5) Synthesis of N-(2-chloro-6-(morpholinomethyl)pyrimidin-4-yl)-5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-amine
질소환경하에서 상기 단계 4)에서 얻어진 2-클로로-6-(몰포리노메틸)피리미딘-4-아민 (465 mg, 2.03 mmol)과 실시예 1을 단계 2에서 얻어진 2-브로모-5-(2-페닐-2H-테트라졸-5-일)싸이아졸 (689 mg ,1.1 eq.)을 N,N-디메틸포름아미드 용매에 녹인 후 온도를 0 °C로 내리고 수소화나트륨 (60% w/w in mineral oil, 163 mg , 2 eq.)을 5분간 천천히 첨가한 뒤 1시간 교반하고 상온에서 1시간 더 교반하였다. 반응용액에 탄산나트륨 수용액을 첨가하여 pH9로 맞추고 이 용액을 디클로로메탄으로 추출한 뒤 감압증류하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물 (500 mg, 54%)을 얻었다.In a nitrogen environment, 2-chloro-6-(morpholinomethyl)pyrimidin-4-amine (465 mg, 2.03 mmol) obtained in step 4) and Example 1 were prepared by preparing 2-bromo-5-( After dissolving 2-phenyl-2H-tetrazol-5-yl)thiazole (689 mg ,1.1 eq.) in N,N-dimethylformamide solvent, lower the temperature to 0 °C and sodium hydride (60% w/w in mineral oil, 163 mg , 2 eq.) was slowly added for 5 minutes, stirred for 1 hour, and stirred at room temperature for 1 hour more. An aqueous sodium carbonate solution was added to the reaction solution to adjust the pH to 9, and the solution was extracted with dichloromethane and distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (500 mg, 54%).
단계 6) tert-부틸 (S)-3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리미딘-2-일)아미노)피페리딘-1-카르복실레이트의 합성Step 6) tert-Butyl (S)-3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino Synthesis of )pyrimidin-2-yl)amino)piperidine-1-carboxylate
마이크로웨이브 반응기에서 상기 단계 5)에서 얻은 N-(2-클로로-6-(몰포리노메틸)피리미딘-4-일)-5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-아민 (45 mg, 0.1 mmol) 과 tert-부틸 (S)-3- 아미노피페리딘-1-카르복실레이트 (24 mg, 1.2 eq.)를 이소프로판올 용매섞은 후 160 °C에서 30 분간 반응시킨 후 용매를 감압증류 하였다. 얻어진 잔사를 컬럼크로마토그래피를 이용하여 정제하여 목적 화합물 (6 mg, 10%)을 얻었다.N-(2-chloro-6-(morpholinomethyl)pyrimidin-4-yl)-5-(2-phenyl-2H-tetrazol-5-yl)thiazole obtained in step 5) in the microwave reactor After mixing -2-amine (45 mg, 0.1 mmol) and tert-butyl (S)-3-aminopiperidine-1-carboxylate (24 mg, 1.2 eq.) in isopropanol solvent, at 160 °C for 30 minutes After the reaction, the solvent was distilled under reduced pressure. The obtained residue was purified using column chromatography to obtain the target compound (6 mg, 10%).
단계 7) (S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온의 합성Step 7) (S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino Synthesis of )pyrimidin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one
상기 단계 6)에서 얻은 tert-부틸 (S)-3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리미딘-2-일)아미노)피페리딘-1-카르복실레이트 (70 mg, 0.11 mmol)를 실시예 1의 단계 8)과 같이 반응시켰다. 얻어진 잔사를 실시예 1의 단계 9)와 같이 반응시켜 목적 화합물(27 mg, 42%)을 얻었다.tert-Butyl (S)-3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2- yl)amino)pyrimidin-2-yl)amino)piperidine-1-carboxylate (70 mg, 0.11 mmol) was reacted as in Example 1 step 8). The obtained residue was reacted as in step 9) of Example 1 to obtain the target compound (27 mg, 42%).
1H-NMR(400 MHz, DMSO-d6) δ: 12.14(bs, 1H), 8.35-8.10 (m, 3H), 7.59-7.49 (m, 3H), 6.59-6.55 (m, 2H), 6.22-6.15 (m, 1H), 5.70-5.60 (m, 1H), 4.41 (bs, 1H), 3.92-3.45 (m, 10H), 2.58 (m, 4H), 2.31 (m, 1H), 1.90-1.76 (m, 4H).1H-NMR (400 MHz, DMSO-d6) δ: 12.14 (bs, 1H), 8.35-8.10 (m, 3H), 7.59-7.49 (m, 3H), 6.59-6.55 (m, 2H), 6.22-6.15 (m, 1H), 5.70-5.60 (m, 1H), 4.41 (bs, 1H), 3.92-3.45 (m, 10H), 2.58 (m, 4H), 2.31 (m, 1H), 1.90-1.76 (m) , 4H).
실험예: 화합물의 세포내 p-BTK IC50 평가Experimental Example: Intracellular p-BTK IC50 of the compound evaluation
세포 내 BTK에 대한 BTK 저해제의 IC50를 측정하기 위하여 웨스턴 블랏 분석법을 수행하여 평가하였다. 소 태아 혈청(Fetal bovine serum)이 첨가되지 않은 배양배지에 세포(Ramos cells)를 넣고 BTK 저해제를 연속 희석하여 37 ℃의 인큐베이터에서 4 시간 동안 반응시켰다. 이후 항-인간 IgM(SouthernBiotech 2020-01) 15 ㎍/㎖을 세포에 처리하고 2~8 ℃의 저온에서 10분간 자극하였다. 저온의 DPBS(Dulbecco's Phosphate-Buffered Saline)로 세포에 남아있는 배양배지를 제거하고 프로테아제와 포스파타제 저해제(Thermo 78442)가 포함된 RIPA 완충용액(Radioimmunoprecipitation assay buffer, Thermo 89901)으로 저온에서 30 분 동안 세포막을 용해시켰다.Western blot analysis was performed to measure the IC 50 of the BTK inhibitor against intracellular BTK. The cells (Ramos cells) were placed in a culture medium without fetal bovine serum, serially diluted with a BTK inhibitor, and reacted in an incubator at 37°C for 4 hours. Then, 15 μg/ml of anti-human IgM (SouthernBiotech 2020-01) was applied to the cells and stimulated at a low temperature of 2 to 8° C. for 10 minutes. Remove the culture medium remaining in the cells with low-temperature DPBS (Dulbecco's Phosphate-Buffered Saline) and RIPA buffer (Radioimmunoprecipitation assay buffer, Thermo 89901) containing protease and phosphatase inhibitor (Thermo 78442) at low temperature for 30 minutes at low temperature. dissolved.
고속원심분리기로 단백질을 추출하여 BCA(bicinchoninic acid) 용액(Thermo 23225)으로 정량하고 4× 샘플 완충 용액(Invitrogen NP0007)을 넣어 샘플을 제작하였다. 각 샘플의 단백질은 전기영동시킨 다음 니트로셀룰로스로 구성된 막(Invitrogen IB23001)으로 옮겼다. 단백질이 없는 부분을 블로킹하기 위하여 TBS-T(TBS-Tween, Thermo 28360)에 5%의 소혈청알부민(BSA)(GenDEPOT A0100-010)이 포함된 용액을 만들어 30 분간 상온에서 처리하였다. 1차 항체를 희석하여 단백질이 붙은 막에 넣고 저온의 쉐이커 위에서 16~20 시간(또는 상온에서 1 시간) 동안 반응시켰다. TBS-T를 넣고 10 분간 상온의 쉐이커 위에서 막에 붙지 않은 1차 항체를 제거하였으며 이 과정을 3회 반복하였다. HRP가 붙은 2차 항체를 희석하여 막에 넣고 45 분간 반응시켰다. TBS-T를 넣어 10 분간 상온의 쉐이커 위에 두어 1차 항체와 붙지 않은 2차 항체를 제거하는 과정을 3회 반복하였다. 인핸스드 케미루미네슨트(Enhanced chemiluminescent)(ECL) 용액(Thermo 34095)을 이용하여 HRP(horseradish peroxidase) 효소를 반응시키고 막의 단백질 수치를 확인하였다. 음성 대조군 및 양성 대조군의 단백질을 기준으로 하고 산출된 값을 통해 IC50를 계산하였다.Proteins were extracted with a high-speed centrifuge, quantified with a bicinchoninic acid (BCA) solution (Thermo 23225), and 4× sample buffer solution (Invitrogen NP0007) was added to prepare a sample. Proteins in each sample were electrophoresed and transferred to a membrane made of nitrocellulose (Invitrogen IB23001). To block the protein-free portion, a solution containing 5% bovine serum albumin (BSA) (GenDEPOT A0100-010) in TBS-T (TBS-Tween, Thermo 28360) was prepared and treated at room temperature for 30 minutes. The primary antibody was diluted and put into a protein-attached membrane and reacted for 16-20 hours (or 1 hour at room temperature) on a low-temperature shaker. TBS-T was added and the primary antibody not attached to the membrane was removed on a shaker at room temperature for 10 minutes, and this process was repeated 3 times. The HRP-attached secondary antibody was diluted and put into a membrane and reacted for 45 minutes. TBS-T was put on a shaker at room temperature for 10 minutes, and the process of removing the primary antibody and the non-attached secondary antibody was repeated 3 times. Horseradish peroxidase (HRP) enzyme was reacted using an enhanced chemiluminescent (ECL) solution (Thermo 34095), and the protein level of the membrane was checked. The IC 50 was calculated based on the protein of the negative control and the positive control and through the calculated values.
화합물compound IC50(nM)IC 50 (nM)
실시예 1Example 1 1.11.1
실시예 2Example 2 1.01.0
실시예 3Example 3 8.08.0
실시예 4Example 4 10.510.5
실시예 5Example 5 0.30.3
실시예 6Example 6 7.27.2
실시예 7Example 7 13.013.0
실시예 8Example 8 7.77.7
실시예 9Example 9 1.41.4
실시예 11Example 11 0.70.7
실시예 12Example 12 1.11.1
실시예 13Example 13 0.10.1
실시예 17Example 17 9.39.3

Claims (14)

  1. 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염:A compound of Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2021013380-appb-I000007
    Figure PCTKR2021013380-appb-I000007
    상기 화학식 1에서,In Formula 1,
    Cy는 C3-12아릴, C3-12사이클로알킬 또는 C3-10헤테로아릴이고, 상기 C3-12아릴, C3-12사이클로알킬 또는 C3-10헤테로아릴은 C1-6알킬, C1-6알콕시 및 할로로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있고;Cy is C 3-12 aryl, C 3-12 cycloalkyl or C 3-10 heteroaryl, said C 3-12 aryl, C 3-12 cycloalkyl or C 3-10 heteroaryl is C 1-6 alkyl, may be substituted with one or more substituents selected from the group consisting of C 1-6 alkoxy and halo;
    A는 2개 이상의 N 원자를 갖는 5-원 환이며;A is a 5-membered ring having 2 or more N atoms;
    X는 CH 또는 S이고;X is CH or S;
    Y는 X가 CH인 경우 NH 또는 O이고, X가 S인 경우 CH이며;Y is NH or O when X is CH and CH when X is S;
    Z1은 C 또는 N이고;Z 1 is C or N;
    Z1이 N인 경우
    Figure PCTKR2021013380-appb-I000008
    은 부재하고, Z1이 C인 경우, m은 0~3의 정수이고, R1은 C1-6알킬 및 C1-6알킬카보닐로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있는 C3-10헤테로사이클로알킬, 1개 이상의 C1-6알킬로 치환될 수 있는 아미노, 수소, C1-6알콕시, 또는 할로이고;    If Z 1 is N
    Figure PCTKR2021013380-appb-I000008
    is absent, when Z 1 is C, m is an integer of 0 to 3, and R 1 may be substituted with one or more substituents selected from the group consisting of C 1-6 alkyl and C 1-6 alkylcarbonyl. is C 3-10 heterocycloalkyl, which may be substituted with one or more C 1-6 alkyl, amino, hydrogen, C 1-6 alkoxy, or halo;
    Z2는 CH 또는 N이고;Z 2 is CH or N;
    R2는
    Figure PCTKR2021013380-appb-I000009
    , 또는
    Figure PCTKR2021013380-appb-I000010
    (여기에서, R3는 및 R4는 서로 독립적으로 수소, C1-6알킬, C2-6알케닐 또는 C2-6알키닐이다)이고;    R 2 is
    Figure PCTKR2021013380-appb-I000009
    , or
    Figure PCTKR2021013380-appb-I000010
    (wherein R 3 and R 4 are independently of each other hydrogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl);
    L1 및 L2는 서로 독립적으로 NH, O, 또는 S이며;L 1 and L 2 are each independently NH, O, or S;
    n은 0 내지 3의 정수이다.n is an integer from 0 to 3.
  2. 제1항에 있어서, Cy는 C5-12아릴, C5-12사이클로알킬 또는 C3-6헤테로아릴인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.The compound of Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein Cy is C 5-12 aryl, C 5-12 cycloalkyl or C 3-6 heteroaryl.
  3. 제2항에 있어서, Cy는 페닐, 사이클로헥실, 피라졸릴 또는 피리딜인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.The compound of Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 2, wherein Cy is phenyl, cyclohexyl, pyrazolyl or pyridyl.
  4. 제1항에 있어서, A는 2개 내지 4개의 N 원자를 갖거나, 2개 또는 3개의 N 원자와 1개의 O 원자를 갖는 것인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.The compound of formula (1) according to claim 1, wherein A has 2 to 4 N atoms, or 2 or 3 N atoms and 1 O atom, a stereoisomer thereof, or a pharmaceutically acceptable compound thereof. salt.
  5. 제4항에 있어서, A는 이미다졸릴, 피라졸릴, 트리아졸릴, 테트라졸릴, 또는 옥사디아졸릴인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.The compound of Formula 1, a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 4, wherein A is imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or oxadiazolyl.
  6. 제1항에 있어서, m은 0 또는 1인 화학식 1의 화합물, 그의 입체이성질체, 또는 그의 약제학적으로 허용가능한 염.The compound of formula (1) according to claim 1, wherein m is 0 or 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  7. 제1항에 있어서, R1은 C1-6알킬 및 C1-6알킬카보닐로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있는 C4-6헤테로사이클로알킬; 1개 이상의 C1-6알킬로 치환될 수 있는 아미노; 수소; 또는, C1-6알콕시인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.The method according to claim 1, wherein R 1 is C 4-6 heterocycloalkyl which may be substituted with one or more substituents selected from the group consisting of C 1-6 alkyl and C 1-6 alkylcarbonyl; amino which may be substituted with one or more C 1-6 alkyl; Hydrogen; Or, a compound of Formula 1 which is C 1-6 alkoxy, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  8. 제7항에 있어서, R1은 C1-6알킬 및 C1-6알킬카보닐로 이루어진 군으로부터 선택되는 1개 이상의 치환기로 치환될 수 있는 몰포리닐, 피페라지닐, 피페리디닐 또는 피롤리디닐; 1개 이상의 C1-6알킬로 치환될 수 있는 아미노; 수소; 또는, C1-6알콕시인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.8. The method of claim 7, wherein R 1 is morpholinyl, piperazinyl, piperidinyl or pipe which may be substituted with one or more substituents selected from the group consisting of C 1-6 alkyl and C 1-6 alkylcarbonyl. rollidinyl; amino which may be substituted with one or more C 1-6 alkyl; Hydrogen; Or, a compound of Formula 1 which is C 1-6 alkoxy, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  9. 제1항에 있어서, R3 및 R4는 서로 독립적으로 수소 또는 C1-6알킬인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.The compound of Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 and R 4 are each independently hydrogen or C 1-6 alkyl.
  10. 제1항에 있어서, L1 및 L2는 서로 독립적으로 NH 또는 O인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.The compound of Formula 1, a stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 1 and L 2 are each independently NH or O.
  11. 제1항에 있어서, n은 1 또는 2인 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염.The compound of formula (1) according to claim 1, wherein n is 1 or 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  12. 제1항에 있어서, 하기 화합물, 그의 입체이성질체 또는 그의 약제학으로 허용가능한 염:[Claim 2] The compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    (S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin- 2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
    (S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)옥시)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin- 2-yl)oxy)piperidin-1-yl)prop-2-en-1-one;
    (S)-1-(3-((6-((5-(2-(2-클로로-6-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-(2-chloro-6-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4 -(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
    (S)-1-(3-((6-((5-(2-(2-메톡시페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-(2-methoxyphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4-( morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
    (S)-1-(3-((4-(몰포리노메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl) )amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
    (S)-1-(3-((6-((5-(2-(5-클로로-2-메틸페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-(5-chloro-2-methylphenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4 -(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
    (S)-1-(3-((6-((5-(2-(2-클로로-6-플루오로페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-(2-chloro-6-fluorophenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino) -4-(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
    (S)-1-(3-((6-((5-(2-(1-메틸-1H-피라졸-4-일)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-(1-methyl-1H-pyrazol-4-yl)-2H-tetrazol-5-yl)thiazol-2-yl) )amino)-4-(morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
    (S)-1-(3-((6-((5-(2-(4-브로모페닐)-2H-테트라졸-5-일)싸이아졸-2-일)아미노)-4-(몰포리노메틸)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((6-((5-(2-(4-bromophenyl)-2H-tetrazol-5-yl)thiazol-2-yl)amino)-4-( morpholinomethyl)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
    (S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)부트-2-엔-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin- 2-yl)amino)piperidin-1-yl)but-2-en-1-one;
    (S)-1-(3-((4-메톡시-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-methoxy-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin-2-yl )amino)piperidin-1-yl)prop-2-en-1-one;
    (S)-1-(3-((4-메틸-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-methyl-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin-2-yl) amino)piperidin-1-yl)prop-2-en-1-one;
    (S)-1-(3-((4-메틸-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온;(S)-1-(3-((4-methyl-6-((5-(5-phenyl-1,3,4-oxadiazol-2-yl)thiazol-2-yl)amino)pyridine -2-yl)amino)piperidin-1-yl)prop-2-en-1-one;
    (S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-인-1-온;(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyridin- 2-yl)amino)piperidin-1-yl)prop-2-yn-1-one;
    (S)-1-(3-((6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피라진-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온; (S)-1-(3-((6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyrazin-2-yl)amino)piperi din-1-yl)prop-2-en-1-one;
    1-((S)-3-((4-(((2S,6R)-2,6-디메틸몰포리노)메틸)-6-((5-(5-페닐-1,3,4-옥사디아졸-2-일)싸이아졸-2-일)아미노)피리딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온; 및,1-((S)-3-((4-(((2S,6R)-2,6-dimethylmorpholino)methyl)-6-((5-(5-phenyl-1,3,4-oxa) diazol-2-yl)thiazol-2-yl)amino)pyridin-2-yl)amino)piperidin-1-yl)prop-2-en-1-one; and,
    (S)-1-(3-((4-(몰포리노메틸)-6-((5-(2-페닐-2H-테트라졸-5-일)싸이아졸-2-일)아미노)피리미딘-2-일)아미노)피페리딘-1-일)프로프-2-엔-1-온.(S)-1-(3-((4-(morpholinomethyl)-6-((5-(2-phenyl-2H-tetrazol-5-yl)thiazol-2-yl)amino)pyrimidine -2-yl)amino)piperidin-1-yl)prop-2-en-1-one.
  13. 제1항 내지 제12항 중 어느 한 항의 화학식 1의 화합물, 그의 입체이성질체 또는 그의 약제학적으로 허용가능한 염, 및 약제학적으로 허용가능한 담체를 포함하는 단백질 키나제에 의하여 매개되는 질환을 치료하는데 사용하기 위한 약제학적 조성물.13. Use for treating a disease mediated by a protein kinase comprising a compound of formula 1 according to any one of claims 1 to 12, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. pharmaceutical composition for
  14. 제13항에 있어서, 상기 질환은 암, 염증 질환, 또는 자가면역 질환인 것인 조성물.The composition of claim 13, wherein the disease is cancer, an inflammatory disease, or an autoimmune disease.
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