WO2023124022A1 - Dérivé de thiophène[2,3-d]pyrimidine et son utilisation - Google Patents

Dérivé de thiophène[2,3-d]pyrimidine et son utilisation Download PDF

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WO2023124022A1
WO2023124022A1 PCT/CN2022/106494 CN2022106494W WO2023124022A1 WO 2023124022 A1 WO2023124022 A1 WO 2023124022A1 CN 2022106494 W CN2022106494 W CN 2022106494W WO 2023124022 A1 WO2023124022 A1 WO 2023124022A1
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substituted
unsubstituted
halogen
membered
alkyl
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陈俐娟
陈永
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成都赜灵生物医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A61P37/08—Antiallergic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the field of chemical medicine, and in particular relates to a class of thiophene [2,3-d] pyrimidine derivatives, a preparation method thereof and an application in medicine.
  • RIPK2 (RIP2, RICK, CARDIAK, CARD3) is a dual-specificity serine/threonine and tyrosine kinase that regulates pro-inflammatory signaling mediated by NOD1 and NOD2, and is an emerging therapeutic target for autoimmune and inflammatory diseases .
  • Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract (Science 2005,307,731-734) reported that the nucleotide-binding oligomerization domain (NOD) protein family is an important intracellular pattern recognition receptor, NOD1 and NOD2 is the representative two 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.2006,7,1250-1257) reported that RIPK2 was activated It will bind to NOD1 or NOD2, and mainly function as a molecular scaffold, activate NF- ⁇ B and MAPK signaling pathways, and then recruit downstream kinases such as TAK1, IKK ⁇ , IKK ⁇ , IKK ⁇ , etc., causing IL- ⁇ , IL-6, IL- 12. The increase of immune-related signaling factors such as TNF ⁇ .
  • Dysregulation of RIPK2-dependent signaling has been linked to autoimmune diseases. Patients with NOD2 gene mutations are prone to induce Crohn's disease, Blau syndrome, early-onset sarcoidosis, dermatitis, arthritis, etc. Mutations of NOD1 are closely related to asthma and extraintestinal inflammatory diseases. Therefore, pharmacologically targeting the NOD/RIPK2 signaling pathway, by directly inhibiting the kinase activity of RIPK2, weakening the pro-inflammatory signal through the bacterial sensing pathway stimulated by NOD1 and NOD2, reducing the inflammatory response and the damage caused by inflammation, has become a therapeutic method for autoimmunity. Promising new drug target for sexual and inflammatory diseases.
  • the purpose of the present invention is to provide a potent and selective inhibitor of small molecule RIPK2 kinase activity that can specifically block RIPK2-dependent pro-inflammatory signaling, so as to provide therapeutic benefits for the treatment of autoinflammatory diseases.
  • the present invention firstly provides the compound represented by formula I or its pharmaceutically acceptable salt, solvate, hydrate, isomer, ester, acid, metabolite, or its prodrug, and its structure is as follows:
  • One of X and Y is S and the other is N;
  • R is selected from H, halogen
  • R2 is selected from Wherein, Z and W are independently selected from O, S, CR 13 R 14 ;
  • the substituents of the substituted C1-C8 alkyl are selected from halogen, C2-C6 alkenyl, 3-8 membered cycloalkyl, halogen substituted or unsubstituted 6-10 membered aryl;
  • the substituents of the substituted 3-8 membered cycloalkyl are selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, 3-8 membered cycloalkyl, halogen substituted or unsubstituted 6-10 membered aryl groups;
  • R 15 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted C2-C8 alkenyl;
  • the substituent of the substituted C1-C8 alkyl is selected from halogen, C2-C6 alkenyl, 3-8 membered cycloalkyl, halogen substituted or unsubstituted 6-10 membered aryl;
  • the substituent of the substituted 3-8 membered cycloalkyl is selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, 3-8 membered cycloalkyl, halogen substituted or unsubstituted 6- 10-membered aryl;
  • the substituent of the substituted C2-C8 alkenyl is selected from halogen, 3-8 membered cycloalkyl, halogen substituted or unsubstituted 6-10 membered aryl;
  • R 13 and R 14 are independently selected from halogen, hydroxyl, C1-C8 alkyl, C1-C8 alkoxy, or R 13 and R 14 form a 3-8-membered epoxy group.
  • R is selected from H and F.
  • R 3 to R 12 are independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl; among R 3 to R 12 , the The 3-6 membered cycloalkyl group contains 0-1 heteroatoms, and the heteroatoms are N, S, O; in R3 - R12 , the substituents of the substituted C1-C6 alkyl groups are selected from halogen, C2-C4 Alkenyl, 3-6 membered cycloalkyl, halogen-substituted or unsubstituted 6-10-membered aryl; R 3 -R 12 , the substituents of the substituted 3-6-membered cycloalkyl are selected from halogen, C1 ⁇ C4 alkyl, C2 ⁇ C4 alkenyl, 3 ⁇ 6 membered cycloalkyl, halogen substituted or unsubsti
  • R 3 -R 12 are independently selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 5-6 membered cycloalkyl; among R 3 -R 12 , the The 5-6 membered cycloalkyl group contains 0-1 heteroatoms, and the heteroatoms are N, S, O; in R3 - R12 , the substituents of the substituted C1-C4 alkyl groups are selected from F, C2 alkenes group, cyclopropyl, fluorine-substituted or unsubstituted 6-membered aryl group; in R 3 to R 12 , the substituent of the substituted 5-6 membered cycloalkyl group is selected from F, C1-C4 alkyl, C2 alkenes Base, cyclopropyl, fluorine-substituted or unsubstituted 6-10 membered aryl.
  • R 15 is selected from substituted or unsubstituted C1 ⁇ C6 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C2 ⁇ C6 alkenyl;
  • R 15 the The substituent of the substituted C1 ⁇ C6 alkyl is selected from halogen, C2 ⁇ C4 alkenyl, 3 ⁇ 6 membered cycloalkyl, halogen substituted or unsubstituted 6 ⁇ 10 membered aryl;
  • the substituted The substituents of the 3-6 membered cycloalkyl are selected from halogen, C1-C4 alkyl, C2-C4 alkenyl, 3-6 membered cycloalkyl, halogen substituted or unsubstituted 6-10 membered aryl;
  • R 15 the substituent of the substituted C2-C6 alkenyl is selected from hal
  • R 15 is selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C2-C4 alkenyl;
  • R 15 The substituents of the substituted C1-C4 alkyl are selected from F, C2 alkenyl, 3-6 membered cycloalkyl, fluorine-substituted or unsubstituted 6-membered aryl; in R 15 , the substituted 3-6
  • the substituent of the membered cycloalkyl is selected from F, C1 ⁇ C4 alkyl, C2 alkenyl, 3 ⁇ 6 membered cycloalkyl, fluorine substituted or unsubstituted 6 membered aryl;
  • the substituted C2 ⁇ The substituent of C6 alkenyl is selected from halogen, 3-6 membered cycloalky
  • R 13 and R 14 are independently selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, or R 13 and R 14 form a ring to form a 3-6 membered epoxy group.
  • R 13 and R 14 are independently selected from halogen, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, or R 13 and R 14 form a 5-6-membered epoxy group.
  • R 13 and R 14 are independently selected from F, hydroxyl, methyl, methoxy, or R 13 and R 14 form a ring of 5-membered epoxy group.
  • R 2 is selected from
  • the present invention also provides some specific compounds, and its structural formula is as follows:
  • the present invention also provides a pharmaceutical composition, which is composed of the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable auxiliary ingredient is added.
  • the present invention also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt, and the above-mentioned pharmaceutical composition in the preparation of RIPK2 inhibitors.
  • the present invention also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt and the above-mentioned pharmaceutical composition in the preparation of medicines for treating autoimmune diseases and/or allergic diseases.
  • the autoimmune disease and/or allergic 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 thiophene[2,3-d]pyrimidine derivatives.
  • forming a salt with an acid means that it is obtained by reacting 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, perchloric acid, and the like.
  • Organic acids include acetic, propionic, acrylic, oxalic, (D) or (L) malic, fumaric, maleic, hydroxybenzoic, gamma-hydroxybutyric, methoxybenzoic, phthalic , 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, etc.
  • pharmaceutically acceptable means, within the scope of reasonable medical judgment, suitable for use in contact with tissues of humans and other mammals without undue toxicity, irritation, allergic response, etc. Administration to a recipient can directly or indirectly provide a compound or a prodrug of a compound of the present invention.
  • the present invention also provides pharmaceutically acceptable solvates of the above-mentioned thienopyrimidine derivatives.
  • solvate refers to an association of one or more solvent molecules with a compound of the invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and the like.
  • the present invention also provides pharmaceutically acceptable hydrates of the above-mentioned thien[2,3-d]pyrimidine derivatives.
  • hydrate means a compound that further incorporates stoichiometric or non-stoichiometric amounts of water through non-covalent intermolecular forces.
  • the present invention also provides pharmaceutically acceptable isomers of the above-mentioned thien[2,3-d]pyrimidine derivatives.
  • the term "isomer” refers to compounds having the same chemical composition but differing in the arrangement of atoms or groups in space, including diastereomers, enantiomers, regioisomers, structural isomers, rotational isomers Conformers, tautomers, etc.
  • the present invention also provides pharmaceutically acceptable polymorphs of the above-mentioned thiophene[2,3-d]pyrimidine derivatives.
  • polymorph means a solid crystalline form of a compound or complex thereof 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-mentioned thiophene [2,3-d] pyrimidine derivatives, which is composed of 4-amino-5-aryl-7-ring compound represented by formula I
  • the hexyl-pyrimido nitrogen heterocyclic derivative or its salt or hydrate is prepared by adding pharmaceutically acceptable auxiliary components.
  • 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, (hydroxy-C 1-4 alkyl)- ⁇ -cyclodextrin, (carboxy-C 1-4 alkyl)- ⁇ -cyclodextrin, (carboxy-C 1-4 alkyl)- ⁇ -cyclodextrin, (carboxy-C 1-4 alkyl)- ⁇
  • the auxiliary components also include medically acceptable carriers, adjuvants or vehicles.
  • medically acceptable pharmaceutical compositions are ion exchangers, aluminum oxide, aluminum stearate, lecithin; buffer substances include phosphate, glycine, arginine, sorbic acid and the like.
  • the above-mentioned 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 powder, granule, tablet or lyophilized powder.
  • the pharmaceutical composition also contains water for injection, saline solution, glucose aqueous solution, saline for injection/infusion, glucose for injection/infusion, Guernsey's solution or Guernsey's solution containing lactate.
  • the present invention provides a class of thiophene[2,3-d]pyrimidine derivatives, which can be used to prepare potent and selective small-molecule RIPK2 kinase activity inhibitors that specifically block RIPK2-dependent pro-inflammatory signaling, Provides new therapeutic avenues for the treatment of autoimmune diseases and/or allergic conditions.
  • the intermediate M2 (11.6 g, 25 mmol) from the previous step was dissolved in 100 mL of dichloromethane, and 50 mL of trifluoroacetic acid was added in portions. After reacting at room temperature for 0.5 hours, the reaction was complete, and the reaction solution was concentrated. Disperse the concentrated solution in water, add an appropriate amount of potassium hydroxide to adjust the pH until the pH>9, and a large amount of solid precipitates, filter and rinse the filter cake with ether to obtain a high-purity intermediate M3 (CL-1), without further purification.
  • CL-1 high-purity intermediate M3
  • Step d The reaction continues to split into two different reaction conditions
  • CLJ-24-CLJ-39 is prepared by the same synthetic method, except that N-Boc-1,2,5,6 - Tetrahydropyridine-4-boronic acid pinacol ester replaced by 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5, 6-dihydropyridine-1(2H)-tert-butyl carboxylate, the structural characterization is shown in Table 3:
  • CLJ-40-CLJ-48 is prepared by the same synthetic method, except that N-Boc-1,2,5,6 - Tetrahydropyridine-4-boronic acid pinacol ester replaced by (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ring Hex-3-en-1-yl) tert-butyl carbamate, structural characterization is as shown in table 4:
  • CLJ-49-CLJ-56 is prepared by the same synthetic method, except that N-Boc-1,2,5,6 - Tetrahydropyridine-4-boronic acid pinacol ester is replaced by 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester, and the structural characterization is shown in Table 5:
  • Step b Disperse the intermediate in the previous step in 50 mL of water, and add 10 mL of concentrated hydrochloric acid to deprotect the group. After continuing the reaction for 5 hours, a large amount of solids precipitated out, and the filter cake was obtained by suction filtration. The filter cake was dispersed in 50 mL of water, and the pH was adjusted to above 9. After suction filtration, the filter cake was dried to obtain high-purity CLJ-69.
  • Step c CLJ-69 (378 mg, 1 mmol) was weighed and dissolved in 20 mL of methanol, and sodium borohydride (57 mg, 1.5 mmol) was added. After 5 hours of reaction, the reaction was complete. The sample was mixed with crude silica gel and then separated by Flash column to obtain the final product CLJ-70.
  • Step a Dissolve 2-fluoro-5-nitroaniline (15.6g, 100mmol) in 200mL of acetonitrile, add BzCl (12.8mL, 110mol) in batches, heat up to 50°C for 4h. A large amount of solids precipitated out of the system, and the relatively pure intermediate was obtained by suction filtration and washing the filter cake with acetonitrile.
  • Step c The intermediate (13.8g, 60mmol) and KSCN (8.75g, 90mmol) in the previous step were mixed in 100mL acetic acid, and the acetic acid solution containing Br 2 (4.5mL, 90mmol) was added dropwise into the system. After reacting for 5 hours, a large amount of solids precipitated out, and a relatively pure intermediate was obtained after suction filtration.
  • Step d The intermediate (14.3g, 50mmol) from the previous step was dissolved in 150mL THF and placed in an ice bath. Isoamyl nitrite (10 mL, 75 mmol) was added dropwise. After the dropwise addition, the reaction was carried out at room temperature for 2 hours, a large amount of solids were precipitated, and a relatively pure intermediate was obtained after suction filtration.
  • Step e The intermediate from the previous step (10.9 g, 40 mmol) was dissolved in 70% concentrated sulfuric acid (100 mL), and heated to 100 degrees Celsius. After reacting for 4 hours, TLC was performed to detect that the reaction was complete. After cooling the reaction solution to room temperature, it was slowly diluted into ice water, and the pH was adjusted to above 10 with sodium hydroxide. Then, extraction was performed twice with 500 mL of ethyl acetate, and the organic phases were combined and concentrated. The concentrated crude product was dispersed in 100 mL of ether, and a relatively pure product was obtained after suction filtration.
  • RIPK2 was incubated in buffer (20mM MOPS, pH 8.5, 0.2mM EDTA, 10mM MnCl 2 ), and added 0.33mg/mL myelin basic protein, 10mM magnesium acetate and [ ⁇ - 33P- ATP], and compounds at different concentrations, then Mg/ATP was added to the reaction to initiate the enzymatic reaction process and incubated at room temperature for 120 minutes.
  • RIPK1 was incubated in buffer (8mM MOPS pH 7.0, 0.2mM EDTA), and 0.33mg/mL myelin basic protein, 10mM magnesium acetate and [ ⁇ - 33P -ATP], and different concentrations of compounds were added, and then Mg/ATP was added to the reaction to start the enzymatic process and incubated at room temperature for 120 min. Finally, dilute to 0.5% concentration with phosphate buffer to stop the reaction, and titrate 10 microliters of the reaction solution onto the P30 membrane, wash with 0.425% phosphate solution four times, each time for 5 minutes, and then wash with methanol Once, finally dry the P30 membrane and perform scintillation counting on it.
  • the scintillation counting value reflects the degree of phosphorylation of the substrate, which can characterize the inhibition of kinase activity.
  • the IC 50 values were fitted according to the inhibition rates of the 9 concentrations, and repeated hole tests were performed. A: 1-10 nM; B: 10-100 nM; C: 100-200 nM; D: 200-500 nM.
  • RIPK2 is IC 50 , nM; RIPK1 inhibition rate is 1 ⁇ M, %.
  • the volume of the incubation system is 100 ⁇ L, the system includes 0.1M PBS pH 7.4, NADPH generation system (1mM NADP, 5mM glucose 6-phosphate, 1U/mL glucose 6-phosphate dehydrogenase, 3.3mM MgCl 2 ); Add 1 ⁇ L of K56 solution (concentration 1 ⁇ M/L), pre-incubate in a 37°C water bath for 5 minutes, add 2.5 ⁇ L of liver microsome solution of various species, continue to incubate for 0, 5, 15, 30, 45, 60 minutes, then add 200 ⁇ L containing The internal standard SAHA 20ng/mL glacial acetonitrile terminated the reaction, vortex mixed for 30s, centrifuged at 13000rpm for 10min, took the supernatant, and injected.
  • NADPH generation system 1mM NADP, 5mM glucose 6-phosphate, 1U/mL glucose 6-phosphate dehydrogenase, 3.3mM MgCl 2 .

Abstract

L'invention concerne un dérivé de thiophène[2,3-d]pyrimidine représenté par la formule I ou un sel pharmaceutiquement acceptable de celui-ci, qui peut être utilisé pour préparer un inhibiteur de RIPK2, et représente une nouvelle alternative pour préparer un médicament destiné à traiter une maladie associée provoquée par une activation anormale de RIPK2.
PCT/CN2022/106494 2021-12-31 2022-07-19 Dérivé de thiophène[2,3-d]pyrimidine et son utilisation WO2023124022A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007059905A2 (fr) * 2005-11-25 2007-05-31 Develogen Aktiengesellschaft Nouvelle utilisation de thiénopyrimidines
CN1993129A (zh) * 2004-06-04 2007-07-04 阿斯利康(瑞典)有限公司 用于药物的噻吩并嘧啶和噻唑并嘧啶
CN101273047A (zh) * 2005-09-27 2008-09-24 惠氏公司 作为蛋白激酶抑制剂的噻吩并[2,3-b]吡啶-5-甲腈
US20130317045A1 (en) * 2010-09-01 2013-11-28 Ambit Biosciences Corporation Thienopyridine and thienopyrimidine compounds and methods of use thereof
CN104470931A (zh) * 2012-05-21 2015-03-25 拜耳医药股份有限公司 取代的苯并噻吩并嘧啶
CN107454899A (zh) * 2014-10-27 2017-12-08 大学健康网络 Ripk2抑制剂及用其治疗癌症的方法
WO2020132384A1 (fr) * 2018-12-21 2020-06-25 Celgene Corporation Inhibiteurs thiénopyridine de ripk2

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1993129A (zh) * 2004-06-04 2007-07-04 阿斯利康(瑞典)有限公司 用于药物的噻吩并嘧啶和噻唑并嘧啶
CN101273047A (zh) * 2005-09-27 2008-09-24 惠氏公司 作为蛋白激酶抑制剂的噻吩并[2,3-b]吡啶-5-甲腈
WO2007059905A2 (fr) * 2005-11-25 2007-05-31 Develogen Aktiengesellschaft Nouvelle utilisation de thiénopyrimidines
US20130317045A1 (en) * 2010-09-01 2013-11-28 Ambit Biosciences Corporation Thienopyridine and thienopyrimidine compounds and methods of use thereof
CN104470931A (zh) * 2012-05-21 2015-03-25 拜耳医药股份有限公司 取代的苯并噻吩并嘧啶
CN107454899A (zh) * 2014-10-27 2017-12-08 大学健康网络 Ripk2抑制剂及用其治疗癌症的方法
WO2020132384A1 (fr) * 2018-12-21 2020-06-25 Celgene Corporation Inhibiteurs thiénopyridine de ripk2

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