WO2024099242A1 - Dérivé d'aminopyridine deutéré et composition pharmaceutique comprenant ledit composé - Google Patents

Dérivé d'aminopyridine deutéré et composition pharmaceutique comprenant ledit composé Download PDF

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Publication number
WO2024099242A1
WO2024099242A1 PCT/CN2023/129826 CN2023129826W WO2024099242A1 WO 2024099242 A1 WO2024099242 A1 WO 2024099242A1 CN 2023129826 W CN2023129826 W CN 2023129826W WO 2024099242 A1 WO2024099242 A1 WO 2024099242A1
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compound
cancer
synthesis
btk
deuterated
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PCT/CN2023/129826
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English (en)
Chinese (zh)
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鲍荣肖
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天津征程医药科技有限公司
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Publication of WO2024099242A1 publication Critical patent/WO2024099242A1/fr

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  • the invention belongs to the field of biomedicine, and in particular relates to deuterated aminopyridine derivatives and a pharmaceutical composition containing the compound.
  • B cell signal transduction via the B cell receptor (BCR) can produce a wide range of biological output signals, and abnormal BCR-mediated signal transduction can cause dysregulated B cell activation and/or the formation of pathogenic autoantibodies that lead to a variety of autoimmune diseases and/or inflammatory diseases.
  • Mutations in BTK in humans lead to X-linked agammaglobulinemia (XLA) (Conley et al., Annu. Rev. Immunol. 27: 199-227, 2009). This disease is associated with impaired B cell maturation, reduced immunoglobulin production, impaired immune responses that are independent of T cells, and significant reductions in sustained calcium signals during BCR stimulation.
  • XLA X-linked agammaglobulinemia
  • BTK inhibitors can be used as inhibitors of B cell-mediated pathogenic activities (such as the production of autoantibodies). BTK is also expressed in osteoclasts, mast cells and monocytes and has been shown to be important for the function of these cells.
  • inhibition of BTK activity can be used to treat allergic diseases and/or autoimmune diseases and/or inflammatory diseases, such as rheumatoid arthritis, polyangiitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis and asthma (Di Paolo et al. (2011) Nature Chem. Biol. 7(1):41-50; Liu et al. (2011) Jour. of Pharm. and Exper. Ther. 338(1):154-163).
  • allergic diseases and/or autoimmune diseases and/or inflammatory diseases such as rheumatoid arthritis, polyangiitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis and asthma (Di Paolo et al. (2011) Nature Chem. Biol. 7(1):41-50; Liu et al. (2011) Jour. of Pharm. and Exper. Ther. 338(1):154-163).
  • BTK hematological malignancies
  • BTK plays a central role as a mediator in multiple signal transduction pathways
  • inhibiting BTK activity can be anti-inflammatory and/or anti-cancer, and can be used for cancer and the treatment of B-cell lymphoma, leukemia and other hematological malignancies (Mohamed et al., Immunol. Rev. 228:58-73, 2009; Pan, Drug News perspective 21:357-362, 2008; Rokosz et al., Expert Opin. Ther.
  • BTK inhibition of BTK activity may be useful in treating bone diseases, such as osteoporosis. Therefore, compounds having BTK inhibitory activity may be useful in treating diseases associated with B cells and/or mast cells, such as allergies. It is useful for the treatment of reactive diseases, autoimmune diseases, inflammatory diseases, thromboembolic diseases, cancer, etc. (Uckun et al. (2007) Anticancer Agents in Medicinal Chemistry. 7(6):624-632).
  • Tolebrutinib (SAR442168, PRN2246) is a potent, selective, orally active and blood-brain barrier-permeable Bruton's tyrosine kinase (BTK) inhibitor. It is an investigational brain-penetrating Bruton's tyrosine kinase (BTK) inhibitor and the first drug to complete a proof-of-concept study of BTK inhibitors for the treatment of multiple sclerosis (MS). It can produce the cerebrospinal fluid (CSF) concentrations required to target microglia and B lymphocytes. It is undergoing Phase III clinical trials for multiple sclerosis (MS) and myasthenia gravis (MG).
  • BTK Bruton's tyrosine kinase
  • Tolebrutinib has a short half-life and is eliminated very quickly, which also indicates to a certain extent that Tolebrutinib may be metabolized faster, and the metabolites produced may also increase the risk of toxicity.
  • the poor absorption, distribution, metabolism and/or excretion (ADME) performance of some current drugs has hindered their wider use or limited their use in specific indications.
  • ADME absorption, distribution, metabolism and/or excretion
  • the solution often used is to administer drugs frequently or in high doses to obtain sufficiently high plasma levels of drugs.
  • this introduces a large number of potential treatment problems, such as patient compliance with medication intervals, and higher doses, which will cause more severe side effects and increase treatment costs. Rapidly metabolized drugs may also expose patients to undesirable toxic or reactive metabolites.
  • ADME limitation affecting drugs is the formation of toxic or biologically reactive metabolites. Therefore, some patients receiving the drug may experience toxicity, or the safe dose of such a drug may be limited so that the patient receives a suboptimal amount of treatment. In some cases, changing the dosing interval or formulation method can help reduce clinical adverse reactions, but the frequent formation of such undesirable metabolites is inherent to compound metabolism.
  • a potential attractive strategy for improving drug metabolism performance is deuterium modification (modification).
  • deuterium modification modification
  • people attempt to slow down the metabolism of the drug, or by replacing one or more hydrogen atoms with deuterium atoms to reduce the formation of undesirable metabolites.
  • Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared with hydrogen, deuterium forms a stronger chemical bond with carbon. In selected cases, the bond strength of the increase given by deuterium can positively affect the ADME performance of the drug, with the potential for improving drug effect, safety, and/or tolerability.
  • due to the size and shape of deuterium being substantially equivalent to hydrogen, compared with the original chemical entity that only comprises hydrogen, it is expected that replacing hydrogen with deuterium will not affect the biochemical efficacy and selectivity of the drug.
  • deuteration slows their metabolic clearance in the body and increases their half-life; for other compounds, deuteration does not cause metabolic changes; for still other compounds, deuteration speeds up their metabolic clearance and shortens their half-life (Blake, MI et al, J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res 1985, 14:1-40 ("Foster”); Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Dev 2006, 9:101-09 (“Fisher”)).
  • deuterium substitution at certain sites of the compound not only fails to increase the half-life, but may shorten it (Scott L. Harbeson, Roger D. Tung. Deuterium in Drug Discovery and Development, P405-406), and deteriorate its pharmacokinetic properties.
  • hydrogen at certain positions on the drug molecule is not easily substituted by deuterium due to steric hindrance and other reasons.
  • deuterium modification deuterium modification
  • the effect of deuterium modification (deuterium modification) on the metabolism of drugs is not predictable. Only by actually preparing and testing deuterated drugs can it be determined whether and how the rate of metabolism will differ from the corresponding chemical entity of the non-deuterated. Many drugs have multiple sites that may be metabolized. The position (site) where deuterium substitution is required and the degree of deuteration necessary to find an effect on metabolism, if any, will be different for each drug (Fukuto et al. J. Med. Chem. 1991, 34, 2871-76).
  • metabolic switching indicates that when a drug is encapsulated by a phase I metabolizing enzyme, it can briefly bind and rebind with the phase I metabolizing enzyme in various conformations before a chemical reaction (such as an oxidation reaction). Therefore, metabolic switching can potentially lead to different proportions of known metabolites and new metabolites. This new metabolic property can cause more or less toxicity. And lead to faster or slower drug clearance, thereby reducing or increasing the drug's in vivo exposure. Such changes caused by metabolic switching are unpredictable, and so far no adequate a priori prediction has been made for any drug.
  • Tolebrutinib and its metabolites in vivo have the disadvantage of hepatotoxicity risk, and clinical trials of Tolebrutinib have also shown hepatotoxicity, causing great clinical concerns. Hepatotoxicity is not only related to the chemical structure, but also closely related to the clinical dosage.
  • the purpose of the present invention is to provide a new type of compound having BTK inhibitory activity and better pharmacodynamic properties and its use.
  • a deuterated aminopyridine derivative represented by formula I represented by formula I, its optical isomers or mixtures thereof, its crystal forms, its salts, its hydrates or solvates.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 or R 19 are each independently selected from hydrogen (H) or deuterium (D), provided that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 or R 19 is deuterium.
  • the compound is a preferred compound selected from the following group:
  • the compound is a preferred compound selected from the following group:
  • a method for preparing a pharmaceutical composition comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound described in the first aspect of the present invention, its optical isomer or a mixture thereof, its crystal form, its salt, its hydrate or solvate, thereby forming a pharmaceutical composition.
  • a pharmaceutical composition which contains a pharmaceutically acceptable carrier and the compound described in the first aspect of the present invention, its optical isomer or mixture thereof, its crystal form, its salt, its hydrate or solvate.
  • the pharmaceutical composition is a capsule, tablet, injection, pill, powder or granule.
  • the pharmaceutical composition is used to prevent and/or treat diseases related to BTK.
  • the pharmaceutical composition is used to prevent and/or treat allergic diseases, autoimmune diseases, inflammatory diseases, thromboembolic diseases or cancer.
  • the pharmaceutical composition is used to treat autoimmune diseases, including multiple sclerosis (MS), myasthenia gravis (MG), chronic spontaneous urticaria, neuromyelitis optica, systemic lupus erythematosus (SLE), or rheumatoid arthritis (RA).
  • MS multiple sclerosis
  • MG myasthenia gravis
  • SLE systemic lupus erythematosus
  • RA rheumatoid arthritis
  • the pharmaceutical composition is used to treat cancers including (but not limited to): lymphoma, leukemia, non-small cell lung cancer, uterine cancer, colorectal cancer, brain cancer, head cancer, neck cancer, bladder cancer, prostate cancer, breast cancer, kidney cancer, Liver cancer, stomach cancer, or pancreatic cancer.
  • cancers including (but not limited to): lymphoma, leukemia, non-small cell lung cancer, uterine cancer, colorectal cancer, brain cancer, head cancer, neck cancer, bladder cancer, prostate cancer, breast cancer, kidney cancer, Liver cancer, stomach cancer, or pancreatic cancer.
  • a treatment method which comprises the steps of administering the compound described in the first aspect of the present invention, its optical isomer or mixture thereof, its crystalline form, its salt, hydrate or solvate thereof, or administering the pharmaceutical composition described in the third aspect of the present invention to a subject in need of treatment, thereby inhibiting BTK.
  • deuterated refers to a compound or group in which one or more hydrogen atoms are replaced by deuterium. Deuterated can be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • the deuterium isotope content of deuterium at the deuterium substitution position is greater than the natural deuterium isotope content (0.015%), preferably greater than 50%, more preferably greater than 85%, more preferably greater than 95%, more preferably greater than 99%, and more preferably greater than 99.5%.
  • the compound of formula I contains at least 1 or 3 deuterium atoms, more preferably 5 or 8 deuterium atoms.
  • the term "compound of the present invention” refers to a compound represented by Formula I.
  • the term also includes optical isomers of the compound of Formula I or mixtures thereof, crystal forms, salts thereof, hydrates thereof or solvates thereof.
  • the term "pharmaceutically acceptable salt” refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts is a salt formed by a compound of the present invention and an acid.
  • Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid, and acidic amino acids such as aspartic acid and glutamic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric
  • the compounds of the present invention have good selective BTK inhibitory effects and can be effectively used for treating diseases associated with BTK.
  • the compound of the present invention has good selectivity in inhibiting B cell activation and is effectively used as a B cell activation inhibitor.
  • the deuterated aminopyridine derivatives of the present invention have low hepatotoxicity, good pharmacokinetic properties, reduced dosage and/or reduced toxic and side effects, and better drugability.
  • the following is a more specific description of the preparation method of the compound of formula I of the present invention, but these specific methods do not constitute the present invention.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such a combination can be easily performed by a person skilled in the art to which the present invention belongs.
  • the preparation methods of the non-deuterated pyrimidine derivatives and their physiologically compatible salts used in the present invention are known.
  • the corresponding deuterated pyrimidine derivatives can be synthesized using the corresponding deuterated starting compounds as raw materials and in the same way.
  • Phenol-d 5 (Compound T030) (9.4 g) was dissolved in anhydrous tetrahydrofuran (100 ml), stirred, sodium hydride (9.6 g) was slowly added in batches, and then 1-bromo-4-iodobenzene (Compound T031) (31.1 g) was added in batches, reacted at room temperature for 15 hours, the reactant was filtered, the filtrate was spin-dried, dichloromethane was added to dissolve, and passed through a column, eluted with petroleum ether: ethyl acetate (1:5), to obtain Compound T032.
  • Example 16 The synthesis of compound T203 was carried out according to "Example 16: Synthesis of compound T008", except that in step 8, compound T030 was replaced by compound T035, and the remaining steps were carried out in the same manner as “Example 16: Synthesis of compound T008" to obtain compound T203.
  • Example 16 The synthesis of compound T206 was carried out according to "Example 16: Synthesis of compound T008", except that in step 8, compound T030 was replaced by compound T036, and the remaining steps were carried out in the same manner as “Example 16: Synthesis of compound T008" to obtain compound T206.
  • Example 16 The synthesis of compound T207 was carried out according to "Example 16: Synthesis of compound T008", except that in step 8, compound T030 was replaced by compound T037, and the remaining steps were carried out in the same manner as “Example 16: Synthesis of compound T008" to obtain compound T207.
  • Rats were fed with standard feed and fasted 12 hours before administration.
  • the administration solution was prepared with 0.5% sodium carboxymethylcellulose (CMC-Na).
  • Blood was collected from the orbital venous plexus at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 24 hours after administration.
  • the blood sample After the blood sample is collected, it is placed in a centrifuge tube coated with sodium heparin solution. Immediately and gently invert the tube at least 5 times to ensure sufficient mixing and then place it on ice. The blood sample is centrifuged at 5000 rpm for 5 minutes at 4°C to separate the plasma from the red blood cells. Use a pipette to aspirate 100 ⁇ L of plasma into a clean plastic centrifuge tube, mark the sample number and blood collection time point. The plasma is stored in a -80°C refrigerator before LC-MS/MS analysis.
  • test results show that compared with Tolebrutinib, the elimination half-life T 1/2 and/or the area under the curve AUC and/or the maximum blood drug concentration C max of compound T101 increased by more than 40%; compared with Tolebrutinib, the elimination half-life T 1/2 and/or the area under the curve AUC and/or the maximum blood drug concentration C max of compound T104 increased by more than 40%; compared with Tolebrutinib, the elimination half-life T 1/2 and/or the area under the curve AUC and/or the maximum blood drug concentration C max of compound T105 increased by more than 50%; compared with Tolebrutinib, the elimination half-life T 1/2 and/or the area under the curve AUC and/or the maximum blood drug concentration C max of compound T106 increased by more than 50%; compared with Tolebrutinib, the elimination half-life T 1/2 and/or the area under the curve AUC and/or the maximum blood drug concentration C max of compound T107 increased by more than 50%; compared with Tolebrutinib
  • the elimination half-life T 1/2 and/or the area under the curve AUC and/or the maximum blood drug concentration C max of compound T109 increased by more than 50%; compared with Tolebrutinib, the elimination half-life T 1/2 and/or the area under the curve AUC and/or the maximum blood drug concentration C max of compound T112 increased by more than 40%.
  • compound T101, compound T104, compound T105, compound T106, compound T107, compound T109 and compound T112 of the present invention have better pharmacokinetic properties in animals, indicating better pharmacodynamics and therapeutic effects.
  • the ADP-Glo TM kit was used to determine the effect of the compounds of the present invention on the activity of BTK.
  • the experimental method is as follows:
  • ADP is the product of the kinase reaction, and the activity of the kinase can usually be detected by detecting the amount of ADP generated.
  • the ADP-Glo TM kit developed by Promega measures the in vitro activity of BTK by detecting the level of ADP produced in the kinase reaction.
  • the kinase consumes ATP to phosphorylate the substrate and produces ADP.
  • the ADP-Glo reagent is added to terminate the kinase reaction and completely consume the remaining ATP.
  • the kinase detection reagent is added to convert the generated ADP into new ATP.
  • the luciferase in the detection reagent can catalyze luciferin with the participation of ATP and O2 to generate a light signal, thereby converting the chemical signal into a light signal.
  • the intensity of the light signal is positively correlated with the amount of ADP produced in the kinase reaction, thereby being able to quantitatively detect the activity of the kinase BTK.
  • the detection buffer included 40mM Tris-HCl (pH7.5), 10mM MgCl 2 (Sigma), 2mM MnCl 2 (Sigma), 0.05mM DTT (Sigma) and 0.01% BSA (Sigma); the kinase BTK was prepared into a kinase reaction solution with a concentration of 1.3ng/ ⁇ L using the detection buffer; the substrate reaction solution included 0.25mg/mL peptide substrate and 60 ⁇ M ATP.
  • the compound of the present invention was diluted with DMSO to a 0.5 mM solution, and then three-fold gradient dilution was performed with DMSO to a minimum concentration of 0.025 ⁇ M.
  • 50 nL of compound solutions of serial concentrations and 2.5 ⁇ L of kinase reaction solution were first added to a 384-well plate using Echo555, mixed evenly, and incubated at room temperature in the dark for 30 minutes; then 2.5 ⁇ L of substrate reaction solution was added, and the total reaction volume was 5.05 ⁇ L, and the reaction mixture was reacted at room temperature in the dark for 60 minutes; then 5 ⁇ L of ADP-Glo TM reagent was added to terminate the reaction, mixed evenly, and left at room temperature for 40 minutes; finally, 10 ⁇ L of kinase detection reagent was added, left at room temperature in the dark for 30 minutes, and then the value was read on Envision.
  • the inhibition percentage was calculated according to the following formula:
  • Inhibition % [1 - (RLU compound - RLU min ) / (RLU max - RLU min )] ⁇ 100
  • RLU compound is the reading at a given concentration of the compound of the present invention
  • RLU min is the reading without the addition of kinase BTK
  • RLU max is the reading without the addition of the compound of the present invention.
  • the IC 50 value of the compound was calculated by using the XLfit program in Excel.
  • Example 25 Comparative study of liver toxicity in mice
  • mice Thirty-two adult male ICR mice with a body weight of (25 ⁇ 2 g) were selected, and all mice were allowed to freely access water and feed, and maintained under a day-night cycle at a temperature of 25 ⁇ 2° C. and a relative humidity of 50 ⁇ 10%.
  • mice 32 male ICR mice were divided into four groups, 8 mice in each group, namely normal control group, model group, model + example compound group and model + Tolebrutinib group.
  • the model + example compound group was intragastrically administered with the example compound once a day at a dose (50 mg/kg);
  • the model + Tolebrutinib group was intragastrically administered with Tolebrutinib once a day at a dose (50 mg/kg), respectively, for 8-16 weeks
  • the normal control group and the model group were intragastrically administered with an equal volume of purified water. Food was cut off after the last administration.
  • mice in the model group, the model + example compound group and the model + Tolebrutinib group were intraperitoneally injected with 250 mg/kg of APAP saline solution.
  • blood was collected from the eyeballs of the mice in each group in turn, and the serum was separated by centrifugation at 3000r/min for 10 minutes, and stored at 4°C for later use; the liver and spleen were quickly dissected.
  • the filter paper was blotted dry, and the weight was weighed. Part of the liver was fixed in 10% formaldehyde solution for slicing, and the remaining liver was stored in a -80°C low-temperature refrigerator.
  • the experimental data were expressed as mean ⁇ standard deviation ( ⁇ s) and analyzed using SPSS 22.0 statistical software. One-way analysis of variance was used to compare the differences between the groups. P ⁇ 0.05 was considered a significant difference.
  • the MDA content in the liver tissue homogenate of the mice in the model group increased significantly, and the GSH level decreased significantly (P ⁇ 0.05), which caused the accumulation of lipid peroxidation products in the mice and reduced the antioxidant metabolism level; compared with the model group, the MDA content and GSH level of the model + example compound group did not change significantly (P>0.05); compared with the model group, the MDA content of the model + Tolebrutinib group increased significantly (P ⁇ 0.05), and the GSH level decreased significantly (P ⁇ 0.05), indicating that the example compound (50 mg/kg) of the present application had no significant effect on lipid peroxidation caused by APAP, while Tolebrutinib (50 mg/kg) had an effect on lipid peroxidation caused by APAP, suggesting that the liver toxicity of the example compound of the present application was less than that of Tolebrutinib in mice.
  • the results are shown in Table 2.
  • the compound of the present application (50 mg/kg) has no significant effect on lipid peroxidation induced by APAP, while Tolebrutinib (50 mg/kg) has an effect on lipid peroxidation induced by APAP, indicating that the compound of the present application is less toxic to the mouse liver than Tolebrutinib.

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Abstract

L'invention concerne un dérivé d'aminopyridine deutéré tel que représenté par la formule I, un isomère optique ou un mélange de ceux-ci, un polymorphe de celui-ci, un sel de celui-ci, ou un hydrate ou un solvate de celui-ci ; l'invention concerne en outre une composition pharmaceutique comprenant un véhicule pharmaceutiquement acceptable et le dérivé d'aminopyridine deutéré, l'isomère optique ou un mélange de ceux-ci, le polymorphe de celui-ci, le sel de celui-ci, ou l'hydrate ou le solvate de celui-ci. Le composé représenté par la formule générale I sert d'inhibiteur de BTK, est un agent prophylactique et/ou thérapeutique pour des maladies associées à BTK, a une faible toxicité hépatique, et a un bon effet thérapeutique sur des maladies allergiques, des maladies auto-immunes, des maladies inflammatoires, des maladies thromboemboliques ou des cancers.
PCT/CN2023/129826 2022-11-07 2023-11-04 Dérivé d'aminopyridine deutéré et composition pharmaceutique comprenant ledit composé WO2024099242A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202211366535.1 2022-11-07
CN202211366535.1A CN118027022A (zh) 2022-11-07 2022-11-07 氘代的氨基吡啶衍生物以及包含该化合物的药物组合物
CN202311446410 2023-11-02
CN202311446410.4 2023-11-02

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105753863A (zh) * 2015-09-11 2016-07-13 东莞市真兴贝特医药技术有限公司 氧代二氢咪唑并吡啶类化合物及其应用
CN106459049A (zh) * 2015-06-03 2017-02-22 普林斯匹亚生物制药公司 酪氨酸激酶抑制剂
CN110563733A (zh) * 2019-09-12 2019-12-13 安帝康（无锡）生物科技有限公司 作为选择性btk抑制剂的咪唑并吡嗪类化合物
WO2022171140A1 (fr) * 2021-02-09 2022-08-18 明慧医药（杭州）有限公司 Composé de promédicament, son procédé de préparation et son utilisation
WO2022218430A1 (fr) * 2021-04-16 2022-10-20 南京明德新药研发有限公司 Composés d'imidazopyridine et leur utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106459049A (zh) * 2015-06-03 2017-02-22 普林斯匹亚生物制药公司 酪氨酸激酶抑制剂
CN105753863A (zh) * 2015-09-11 2016-07-13 东莞市真兴贝特医药技术有限公司 氧代二氢咪唑并吡啶类化合物及其应用
CN110563733A (zh) * 2019-09-12 2019-12-13 安帝康（无锡）生物科技有限公司 作为选择性btk抑制剂的咪唑并吡嗪类化合物
WO2022171140A1 (fr) * 2021-02-09 2022-08-18 明慧医药（杭州）有限公司 Composé de promédicament, son procédé de préparation et son utilisation
WO2022218430A1 (fr) * 2021-04-16 2022-10-20 南京明德新药研发有限公司 Composés d'imidazopyridine et leur utilisation

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