WO2022071772A1 - Inhibiteur de protéine kinase et son utilisation - Google Patents

Inhibiteur de protéine kinase et son utilisation 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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Prior art keywords
amino
thiazol
pyridin
tetrazol
piperidin
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PCT/KR2021/013380
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English (en)
Korean (ko)
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방극찬
서행수
신미선
안지윤
이현진
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(주)메디톡스
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Publication of WO2022071772A1 publication Critical patent/WO2022071772A1/fr

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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

L'invention concerne : un composé de formule chimique 1 ayant une activité inhibitrice de protéine kinase ; un stéréoisomère associé ou un sel pharmaceutiquement acceptable associé ; et une utilisation associée.
PCT/KR2021/013380 2020-09-29 2021-09-29 Inhibiteur de protéine kinase et son utilisation WO2022071772A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023204642A1 (fr) * 2022-04-20 2023-10-26 (주)메디톡스 Inhibiteur de protéine kinase et son utilisation

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KR20110025224A (ko) * 2008-06-27 2011-03-09 아빌라 테라퓨틱스, 인크. 헤테로아릴 화합물 및 이의 용도
KR20160093675A (ko) * 2013-12-05 2016-08-08 파마싸이클릭스 엘엘씨 브루톤 티로신 키나제의 억제제
KR20180021740A (ko) * 2015-06-02 2018-03-05 파마싸이클릭스 엘엘씨 브루톤 티로신 키나제의 억제제
US10137129B2 (en) * 2014-03-25 2018-11-27 Ono Pharmaceutical Co., Ltd. Prophylactic agent and/or therapeutic agent for diffuse large B-cell lymphoma

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023204642A1 (fr) * 2022-04-20 2023-10-26 (주)메디톡스 Inhibiteur de protéine kinase et son utilisation

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