[go: up one dir, main page]

WO2025092821A1 - Inhibiteur de ripk2 dérivé de quinazoline et son utilisation - Google Patents

Inhibiteur de ripk2 dérivé de quinazoline et son utilisation Download PDF

Info

Publication number
WO2025092821A1
WO2025092821A1 PCT/CN2024/128515 CN2024128515W WO2025092821A1 WO 2025092821 A1 WO2025092821 A1 WO 2025092821A1 CN 2024128515 W CN2024128515 W CN 2024128515W WO 2025092821 A1 WO2025092821 A1 WO 2025092821A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
substituted
deuterated
independently selected
compound according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/128515
Other languages
English (en)
Chinese (zh)
Inventor
陈俐娟
陈永
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chengdu Zenitar Biomedical Technology Co Ltd
Original Assignee
Chengdu Zenitar Biomedical Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chengdu Zenitar Biomedical Technology Co Ltd filed Critical Chengdu Zenitar Biomedical Technology Co Ltd
Publication of WO2025092821A1 publication Critical patent/WO2025092821A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention belongs to the technical field of chemical medicine, and specifically relates to a quinazoline derivative RIPK2 inhibitor and a use thereof.
  • RIPK2 (RIP2, RICK, CARDIAK, CARD3) is a dual-specificity serine/threonine and tyrosine kinase that regulates proinflammatory signals mediated by NOD1 and NOD2.
  • the nucleotide-binding oligomerization domain (NOD) protein family is an important intracellular pattern recognition receptor, and NOD1 and NOD2 are two representative receptors of this protein family. Nod-like proteins in inflammation and disease (J. Pathol. 2008, 214, 136-148) and Nod-like proteins in immunity, inflammation and disease (Nat. Immunol.
  • RIPK2-dependent signaling disorders have been shown to be associated with autoimmune diseases.
  • Patients with NOD2 gene mutations are prone to Crohn's disease, Blau syndrome, early-onset sarcoidosis, dermatitis, arthritis, etc.
  • NOD1 mutations are closely related to asthma and extraintestinal inflammatory diseases.
  • RIPK2 is amplified in 65% of fatal prostate cancers, and approximately 34,000 American men die from this cancer each year.
  • the amount of RIPK2 protein amplification increases as the cancer progresses, suggesting that the protein may play a very important role in the development of cancer. Therefore, clinical trials targeting RIPK2, either alone or in combination with existing or emerging treatments, are necessary to become personalized anti-metastatic treatments, thereby significantly improving clinical outcomes.
  • the purpose of the present invention is to provide a potent and selective small molecule RIPK2 kinase activity inhibitor that can specifically block RIPK2-dependent pro-inflammatory signaling, thereby providing therapeutic benefits for treating bacterial infections, autoinflammatory and autoimmune diseases, and inhibiting tumor metastasis.
  • the present invention first provides a compound represented by formula I or a pharmaceutically acceptable form thereof, the structure of which is as follows:
  • R1 is selected from C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 deuterated alkyl, C1-C8 alkoxy, C1-C8 haloalkoxy or C1-C8 deuterated alkoxy;
  • R 2 is selected from
  • R 3 , R 4 , R 5 , and R 6 are each independently selected from H, C1-C8 alkyl, 3-8-membered cycloalkyl, or -C(O)-(NH) n -R 11 ;
  • n is selected from 0 or 1;
  • R 11 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 3-8 membered cycloalkyl, C2-C8 alkenyl;
  • the substituents of the substituted C1-C8 alkyl and substituted 3-8-membered cycloalkyl are each independently selected from halogen, deuterium or vinyl;
  • R 7 , R 8 , R 9 , and R 10 are each independently selected from H, C1-C8 alkyl, C1-C8 haloalkyl, or C1-C8 deuterated alkyl;
  • the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites or prodrugs.
  • R 1 is selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 deuterated alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy or C1-C4 deuterated alkoxy.
  • R 1 is selected from C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 deuterated alkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy or C1-C4 deuterated alkoxy.
  • R 1 is selected from methyl, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy or deuterated methoxy.
  • R 1 is selected from -CH 3 , -CF 3 , -CD 3 , -OCH 3 , -OCF 3 or -OCD 3 .
  • R 3 , R 4 , R 5 , and R 6 are each independently selected from H, C1-C4 alkyl, 3-6-membered cycloalkyl, or -C(O)-(NH) n -R 11 .
  • R 11 is selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 3-6-membered cycloalkyl, C2-C4 alkenyl; in R 11 , the substituted C1-C4 alkyl, substituted 3-6-membered cycloalkyl
  • the substituents are each independently selected from halogen, deuterium or vinyl.
  • R 11 is selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, and vinyl; in R 11 , the substituents of the substituted C1-C4 alkyl and substituted 3-6 membered cycloalkyl are each independently selected from fluorine, deuterium or vinyl.
  • R 3 , R 4 , R 5 , and R 6 are each independently selected from H, methyl, ethyl, isopropyl, n-propyl, tert-butyl, n-butyl, cyclopropyl, cyclopentyl, cyclohexyl, or -C(O)-(NH) n -R 11 ;
  • R 11 is selected from methyl, ethyl, isopropyl, n-propyl, tert-butyl, n-butyl, cyclopropyl, cyclopentyl, cyclohexyl, vinyl, or allyl.
  • R 7 , R 8 , R 9 , and R 10 are each independently selected from H, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 deuterated alkyl.
  • R 7 , R 8 , R 9 , and R 10 are each independently selected from H, C1-C4 alkyl, C1-C4 fluoroalkyl, or C1-C4 deuterated alkyl.
  • R 7 , R 8 , R 9 , and R 10 are each independently selected from H, methyl, fluoromethyl, or deuterated methyl.
  • R 7 , R 8 , R 9 , and R 10 are each independently selected from H, -CH 3 , -CF 3 or -CD 3 .
  • R2 is selected from
  • the present invention also provides some specific compounds, which are selected from:
  • the present invention also provides a pharmaceutical composition, which is composed of the above compound or a pharmaceutically acceptable salt thereof as an active ingredient and pharmaceutically acceptable auxiliary ingredients.
  • the present invention also provides use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, and the above-mentioned pharmaceutical composition in the preparation of a RIPK2 inhibitor.
  • the present invention also provides the use of the above compound or its pharmaceutically acceptable salt, and the above pharmaceutical composition in preparing drugs for treating autoimmune diseases.
  • the autoimmune disease is selected from: inflammatory bowel disease, sepsis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, lupus nephritis, scleroderma, asthma, allergic rhinitis, allergic eczema, multiple sclerosis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, reactive arthritis, Crohn's disease, ulcerative colitis, uveitis, etc.
  • the present invention also provides pharmaceutically acceptable salts of the above-mentioned quinazoline derivatives.
  • the acid-salt refers to the reaction of the free base of the parent compound with an inorganic acid or an organic acid.
  • Inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid.
  • Organic acids include acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid or malonic acid.
  • pharmaceutically acceptable means that it is suitable for contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, etc., within the scope of reasonable medical judgment, and can directly or indirectly provide the compound or prodrug of the compound of the present invention when administered to the recipient.
  • the present invention also provides pharmaceutically acceptable solvates of the above-mentioned thienopyrimidine derivatives.
  • solvate refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and the like.
  • the present invention also provides pharmaceutically acceptable hydrates of the above quinazoline derivatives.
  • hydrate refers to a compound that further binds stoichiometric or non-stoichiometric amounts of water through non-covalent intermolecular forces.
  • the present invention also provides pharmaceutically acceptable isomers of the above quinazoline derivatives.
  • the term "isomer” refers to compounds with the same chemical composition but different spatial arrangements of atoms or groups, including diastereomers, enantiomers, regioisomers, structural isomers, rotational isomers, tautomers, etc.
  • the present invention also provides pharmaceutically acceptable polymorphs of the above quinazoline derivatives.
  • polymorph refers to a solid crystalline form of a compound or its complex, which can be characterized by physical methods, such as X-ray powder diffraction patterns or infrared spectroscopy.
  • the present invention also provides a pharmaceutically acceptable pharmaceutical composition of the above quinazoline derivative, which is prepared by adding pharmaceutically acceptable auxiliary ingredients to the quinazoline derivative or its salt or hydrate shown in formula I.
  • the auxiliary ingredients are cyclodextrin, arginine or meglumine.
  • the cyclodextrin is selected from ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, (C 1-4 alkyl)- ⁇ -cyclodextrin, (C 1-4 alkyl)- ⁇ -cyclodextrin, (C 1-4 alkyl)- ⁇ -cyclodextrin, (hydroxy-C 1-4 alkyl)- ⁇ -cyclodextrin, (hydroxy-C 1-4 alkyl)- ⁇ -cyclodextrin, (hydroxy-C 1-4 alkyl)- ⁇ -cyclodextrin, (carboxyl-C 1-4 alkyl)- ⁇ -cyclodextrin, (carboxyl-C 1-4 alkyl)- ⁇ -cyclodextrin, (carboxyl-C 1-4 alkyl)- ⁇ -cyclodextrin, (carboxyl-C 1-4 alkyl)- ⁇ -cyclodextrin, saccharide ethers of
  • the pharmaceutical composition may be in liquid form or solid form.
  • the liquid form may be in the form of an aqueous solution.
  • the solid form may be in the form of a powder, granules, tablets or lyophilized powder.
  • the pharmaceutical composition may also contain water for injection, saline solution, glucose solution, saline for injection/infusion, glucose for injection/infusion, Ringer's solution or Ringer's solution containing lactate.
  • the present invention provides a class of quinazoline derivatives, which can be used to prepare potent and selective small molecule RIPK2 kinase activity inhibitors that specifically block RIPK2-dependent pro-inflammatory signals, thereby providing a new therapeutic approach for treating autoimmune diseases and/or allergic disorders and tumors.
  • FIG1 is a graph showing changes in IL-6 content in the MDP-induced mouse peritonitis model.
  • the intermediate M2 (25.5 g, 100 mmol) from the previous step was dissolved in 100 mL POCl 3 , heated to 100 °C, and then 6-fluoro-5-aminobenzothiazole (20 g, 120 mmol) was added in batches. After the reaction was continued for 4 h, TLC monitoring showed that the reaction was complete. After cooling to room temperature, a large amount of solid precipitated. Filter, rinse the filter cake with 50 mL ether twice, and then slurry it with 100 mL water. After filtering, the filter cake was dried to obtain 32 g of relatively pure M3 intermediate, with a yield of 80%.
  • the intermediate M4 (3.6 g, 7 mmol) from the previous step was dissolved in 20 mL of dichloromethane, and 20 mL of trifluoroacetic acid was added in batches.
  • the reaction was completed after 0.5 hours at room temperature, and the reaction solution was concentrated.
  • the concentrated solution was dispersed in water, and an appropriate amount of potassium hydroxide was added to adjust the pH until pH>9, and a large amount of solid precipitated.
  • the filter cake was filtered and rinsed with ether to obtain a high-purity intermediate M5 (RP1) without further purification.
  • Step f The reaction is further split into two different reaction conditions
  • RIPK2 was incubated in buffer (20 mM MOPS, pH 8.5, 0.2 mM EDTA, 10 mM MnCl 2 ), and 0.33 mg/mL myelin basic protein, 10 mM magnesium acetate and [ ⁇ - 33 P-ATP], as well as different concentrations of compounds, and then Mg/ATP was added to the reaction to start the enzyme reaction process and incubated at room temperature for 120 minutes.
  • RIPK1 was incubated in buffer (8 mM MOPS pH 7.0, 0.2 mM EDTA), and 0.33 mg/mL myelin basic protein, 10 mM magnesium acetate and [ ⁇ - 33 P-ATP], as well as different concentrations of compounds, and then Mg/ATP was added to the reaction to start the enzyme reaction process and incubated at room temperature for 120 minutes. Finally, the reaction was terminated by diluting the solution to 0.5% with phosphate buffer, and 10 ⁇ l of the reaction solution was titrated onto the P30 membrane, washed four times with 0.425% phosphate solution for 5 minutes each time, and then washed once with methanol. Finally, the P30 membrane was dried and scintillation counted.
  • the scintillation count value reflects the degree of substrate phosphorylation, which can characterize the inhibition of kinase activity.
  • the IC 50 value was fitted according to the inhibition rate of 9 concentrations, and the test was repeated. IC 50 value, A: 1-10nM; B: 10-100nM.
  • the logarithmic phase THP-1 cells were centrifuged, collected, resuspended and counted, and then inoculated into a 96-well plate at 2.5 ⁇ 10 5 /mL and incubated overnight. After adding the test compound for 30 minutes, the cells were induced with 10 ⁇ g/mL MDP for 6 hours, and the cell supernatant was collected and the IL-1 ⁇ content was detected using an ELISA kit.
  • mice were divided into a normal group, a model group, a positive control group and a test compound group.
  • the normal group was not treated with any treatment. All compounds were administered by oral gavage at a dose of 3 mg/kg.
  • MDP 100 ⁇ g/mouse was intraperitoneally injected. Four hours later, blood was collected from the eyeballs of the mice, and the IL-6 content in the serum was detected by Elisa.
  • the experimental results are shown in Figure 1.
  • the results showed that compared with the normal group, the IL-6 level (106.67pg/mL) was significantly increased after MDP modeling, indicating that the downstream inflammatory pathway was activated and the model was successfully induced.
  • the IL-6 level in each drug-treated group declined to varying degrees compared with the model group, among which the compounds RP32 (38.81pg/mL) and RP74 (57.63pg/mL) declined more significantly than the positive control GSK2983559 (97.43pg/mL) at the same dosage, indicating that these two compounds more effectively inhibited the activity of RIPK2 kinase, blocked the activation of downstream inflammatory signals, and thus affected the synthesis and release of cytokine IL-6.
  • mice The pharmacokinetic experiment was conducted on 2 male and 2 female BALB/c mice. The mice were fasted the night before administration and were orally administered at 5 mg/kg (p.o). 70-80 ⁇ L of blood was collected from the eye socket at 0 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 10 h and 24 h after administration. The collected blood was centrifuged at 3500 rpm for 15 min, and the serum was collected and frozen at -80 ° C. The collected samples were analyzed by LC/MS/MS and data were collected. The experimental results are shown in Table 10.
  • the experimental results show that the compound of the present invention has excellent plasma exposure in mice.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un inhibiteur de RIPK2 dérivé de quinazoline et son utilisation, se rapportant au domaine technique des produits pharmaceutiques chimiques. L'invention concerne un dérivé de quinazoline représenté par la formule I, qui peut être utilisé pour préparer un inhibiteur puissant et sélectif à petites molécules de l'activité kinase RIPK2 pouvant bloquer de manière spécifique la signalisation pro-inflammatoire dépendante de RIPK2, et fournit une nouvelle voie thérapeutique pour le traitement de maladies immunitaires autologues et/ou de troubles allergiques et de tumeurs.
PCT/CN2024/128515 2023-11-01 2024-10-30 Inhibiteur de ripk2 dérivé de quinazoline et son utilisation Pending WO2025092821A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202311452515 2023-11-01
CN202311452515.0 2023-11-01

Publications (1)

Publication Number Publication Date
WO2025092821A1 true WO2025092821A1 (fr) 2025-05-08

Family

ID=95582404

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/128515 Pending WO2025092821A1 (fr) 2023-11-01 2024-10-30 Inhibiteur de ripk2 dérivé de quinazoline et son utilisation

Country Status (1)

Country Link
WO (1) WO2025092821A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103874495A (zh) * 2011-08-18 2014-06-18 葛兰素史密斯克莱知识产权发展有限公司 作为激酶抑制剂的氨基喹唑啉
CN104619327A (zh) * 2012-09-13 2015-05-13 葛兰素史密斯克莱知识产权发展有限公司 作为激酶抑制剂的氨基喹唑啉的前药
CN105143208A (zh) * 2013-02-21 2015-12-09 葛兰素史密斯克莱知识产权发展有限公司 作为激酶抑制剂的喹唑啉
WO2017046036A1 (fr) * 2015-09-14 2017-03-23 Glaxosmithkline Intellectual Property Development Limited Composés pour la modulation de l'activité de la kinase rip2
CN107709305A (zh) * 2015-04-22 2018-02-16 葛兰素史克知识产权开发有限公司 新型化合物
CN109311867A (zh) * 2016-04-20 2019-02-05 葛兰素史克知识产权开发有限公司 包含ripk2抑制剂的共轭物
WO2020043122A1 (fr) * 2018-08-28 2020-03-05 南京明德新药研发有限公司 Dérivés de quinazoline servant d'inhibiteur de kinase rip2

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103874495A (zh) * 2011-08-18 2014-06-18 葛兰素史密斯克莱知识产权发展有限公司 作为激酶抑制剂的氨基喹唑啉
CN104619327A (zh) * 2012-09-13 2015-05-13 葛兰素史密斯克莱知识产权发展有限公司 作为激酶抑制剂的氨基喹唑啉的前药
CN105143208A (zh) * 2013-02-21 2015-12-09 葛兰素史密斯克莱知识产权发展有限公司 作为激酶抑制剂的喹唑啉
CN107709305A (zh) * 2015-04-22 2018-02-16 葛兰素史克知识产权开发有限公司 新型化合物
WO2017046036A1 (fr) * 2015-09-14 2017-03-23 Glaxosmithkline Intellectual Property Development Limited Composés pour la modulation de l'activité de la kinase rip2
CN109311867A (zh) * 2016-04-20 2019-02-05 葛兰素史克知识产权开发有限公司 包含ripk2抑制剂的共轭物
WO2020043122A1 (fr) * 2018-08-28 2020-03-05 南京明德新药研发有限公司 Dérivés de quinazoline servant d'inhibiteur de kinase rip2

Similar Documents

Publication Publication Date Title
CN111646995B (zh) 4-氨基-嘧啶并氮杂环-苯基脲类衍生物及其制备方法和用途
JP7050093B2 (ja) 置換５員および６員複素環式化合物、その調製方法、薬剤の組み合わせおよびその使用
WO2021238827A1 (fr) Inhibiteur d'egfr, son procédé de préparation et son utilisation
CN112707905B (zh) 一种三并杂环化合物及其制备方法和用途
EP4339194A1 (fr) Sel d'addition d'acide d'un inhibiteur de rock, et forme cristalline, composition et utilisation pharmaceutique associée
TW202327593A (zh) Kras抑制劑的多晶型物及其製備方法和用途
JP2019512459A (ja) ７員環化合物、その調製方法、その医薬組成物、およびその使用
CN111763215A (zh) 一种具有含氮杂环结构的化合物及其制备方法和用途
CN113416181B (zh) 喹唑啉类衍生物及其用途
CN117820239A (zh) 新型csf1r抑制剂及其制备方法和用途
KR102874188B1 (ko) 융합된 아자 헤테로 시클릭 아미드계 화합물 및 이의 용도
CN116390728A (zh) 喹唑啉衍生物及其制备方法和用途
JP2023527204A (ja) ３，４－ジヒドロイソキノリン系化合物及びその使用
CN115724844A (zh) 一种具有抗肿瘤活性的杂环化合物及其用途
WO2025092821A1 (fr) Inhibiteur de ripk2 dérivé de quinazoline et son utilisation
JP2019514906A (ja) 置換された縮合ピリミジノン化合物
TW202321220A (zh) 含吡啶基的化合物
CN118355000A (zh) 二甲基亚磺酰亚胺衍生物的盐型及晶型
EP3632912B1 (fr) Inhibiteurs de protéine kinase
TW202227444A (zh) 四環類化合物及其醫藥用途
WO2022063229A1 (fr) Sel d'un composé contenant de l'arylaminoquinazoline, procédé de préparation associé et utilisation associée
CN116514726B (zh) 嘧啶类衍生物及其用途
WO2021249324A1 (fr) Composé d'alcényle pyrimidine, procédé de préparation associé et son application
RU2811975C1 (ru) Конденсированное аза-гетероциклическое амидное соединение и его применение
RU2811975C9 (ru) Конденсированное аза-гетероциклическое амидное соединение и его применение

Legal Events

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

Ref document number: 24884821

Country of ref document: EP

Kind code of ref document: A1