WO2024109789A1 - 作为btk抑制剂的吡啶酰胺类化合物 - Google Patents

作为btk抑制剂的吡啶酰胺类化合物 Download PDF

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WO2024109789A1
WO2024109789A1 PCT/CN2023/133130 CN2023133130W WO2024109789A1 WO 2024109789 A1 WO2024109789 A1 WO 2024109789A1 CN 2023133130 W CN2023133130 W CN 2023133130W WO 2024109789 A1 WO2024109789 A1 WO 2024109789A1
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compound
disease
synthesis
btk
chronic
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路玉娜
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天津瑞程健达医药科技有限公司
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    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention belongs to the field of biomedicine, and specifically relates to a pyridine amide compound used as a BTK inhibitor.
  • 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.
  • XLA X-linked agammaglobulinemia
  • 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 perspect 21:357-362, 2008; Rokosz et al., Expert Opin. Ther.
  • 2-(4-phenoxyphenyl)-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide (Orelabrutinib, ICP-022) is a Bruton's tyrosine kinase (BTK) inhibitor used to treat lymphoma, leukemia and autoimmune diseases. Its elimination half-life in rats is 8.25 hours (Ya-nan Liu et al. (2022), Frontiers in Pharmacology.10.3389/fphar.2022.991281), and the effects of orelabrutinib drug metabolism and kinetics on efficacy and/or toxicity are still not very clear, and there is the possibility of improvement.
  • BTK Bruton's tyrosine kinase
  • 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 increased bond strength given by deuterium can improve the drug metabolism and kinetic properties of drugs, with the possibility of improving drug efficacy, safety, and/or tolerance.
  • the size and shape of deuterium are substantially equivalent to hydrogen, compared with the original chemical entity containing only hydrogen, it is expected that replacing hydrogen with deuterium will not affect the biochemical efficacy and selectivity of drugs.
  • 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).
  • Obtunib and its metabolites in vivo have the defect of hepatotoxicity risk, and clinical trials of Obtunib 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 novel pyridine amide compound having BTK inhibitory activity and use thereof.
  • R1 , R2 , R3 , R4 , R5 , R6 , R7, R8 , R9 , R10 , R11 , R12 , R13 , R14 , R15 , R16 , R17 , R18 or R19 are each independently selected from hydrogen (H) or deuterium (D), provided that at least one of R1 , R2 , R3 , R4 , R5 , R6 , R7 , R8 , R9 , R10 , R11 , R12 , R13 , R14 , R15 , R16 , R17 , R18 or R19 is deuterium .
  • the compound is the compound according to claim 1, which is the following compound P001, compound P002, compound P003, compound P004 and compound P005.
  • the compound is the compound according to claim 1, which is the following compound P006, compound P007, compound P008, compound P009, compound P010, compound P011, compound P012, compound P013, compound P014 and compound P015.
  • 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 tautomer, its crystalline form, its salt, its hydrate or solvate, to form 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 tautomer, its crystal form, its salt, its hydrate or solvate.
  • the pharmaceutical composition is used to prevent and/or treat diseases related to BTK.
  • the pharmaceutical composition is used to prevent and/or treat a BTK-related disease, such as an allergic disorder, an autoimmune disease, an inflammatory disease, a thromboembolic disease or a cancer.
  • a BTK-related disease such as an allergic disorder, an autoimmune disease, an inflammatory disease, a thromboembolic disease or a cancer.
  • the pharmaceutical composition is used to treat rheumatoid arthritis, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, teratogenic arthritis, osteoarthritis, traumatic arthritis, gouty arthritis, Reiter's syndrome, polychondritis, acute synovitis, spondylitis, glomerulonephritis with nephrotic syndrome, glomerulonephritis without nephrotic syndrome, autoimmune blood system disorders, hemolytic anemia, aplastic anemia, idiopathic thrombocytopenia, neutropenia, autoimmune gastritis, autoimmune Inflammatory bowel disease, ulcerative colitis, Crohn's disease, host-versus-graft disease, allograft rejection, chronic thyroiditis, Graves' disease, scleroderma, type I diabetes, type II diabetes, acute active hepatitis, chronic active hepatitis, pancreatitis, primary biliary cirrhosis, myasthenia gravis
  • the pharmaceutical composition is used to treat chronic lymphocytic lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma and chronic lymphocytic leukemia.
  • 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 tautomers of the compound of Formula I, crystal forms thereof, 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 or pharmaceutically acceptable derivatives thereof may also be administered at the same time, before or after administering one or more other therapeutic agents.
  • This combination therapy includes administering a single pharmaceutical administration preparation containing the compounds of the present invention and one or more other active agents, as well as administering a separate pharmaceutical administration preparation of the compounds of the present invention and each active agent.
  • the compounds of the present invention and another active agent can be administered to the patient together with a single oral administration composition (e.g., tablets or capsules), or each agent is administered with a separate oral administration preparation.
  • the compounds of the present invention and one or more additional active agents can be administered substantially at the same time (i.e., simultaneously) or at a separate staggered time (i.e., successively); combination therapy should be understood to include all of these schemes.
  • the dosage of the pharmaceutical combination of the present invention may be adjusted according to the disease state, route of administration, age or weight of the patient.
  • the dosage is usually 0.2-35 mg/kg/day, preferably 0.8-20 mg/kg/day.
  • the dosage needs to be set considering the patient's age, weight, condition, route of administration, etc.
  • Oral administration is usually 0.1-35 mg/kg/day, preferably in the range of 0.5-15 mg/kg/day.
  • 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.
  • deuterated pyridine amide compounds and pharmaceutically acceptable salts thereof of the present invention have low hepatotoxicity, good pharmacokinetic properties, reduced dosage and/or reduced toxic side effects, and better drugability. Compared with orelabrutinib, they have significantly better pharmacokinetic and/or pharmacodynamic properties and/or safety properties, and are more suitable for the preparation and treatment of diseases related to BTK.
  • the preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to 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 carried out by a technician in the field to which the present invention belongs.
  • the preparation methods of the non-deuterated pyridine amide compounds and their physiologically compatible salts used in the present invention are known.
  • the corresponding deuterated pyridine amide compounds can be synthesized using the corresponding deuterated starting compounds as raw materials and the same route.
  • Rats were fasted 12 hours before administration.
  • the administration solution was prepared with 0.5% sodium carboxymethylcellulose (CMC-Na).
  • CBD-Na sodium carboxymethylcellulose
  • 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, 12 hours, 16 hours and 24 hours after administration. After plasma was separated from the blood sample, the plasma was stored in a -80°C refrigerator for future use. An LC-MS/MS analysis method was established to measure the plasma samples.
  • test results show that compared with orelabrutinib, the elimination half-life T 1/2 and/or the area under the curve AUC and/or the maximum blood concentration C max of compound P001, compound P002, compound P005 and compound P009 increased by more than 50%.
  • Rats were fasted 12 hours before administration.
  • the administration solution was prepared with 0.5% sodium carboxymethylcellulose (CMC-Na).
  • CBD-Na sodium carboxymethylcellulose
  • 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, 12 hours, 16 hours and 24 hours after administration. After plasma was separated from the blood sample, the plasma was stored in a -80°C refrigerator for future use. An LC-MS/MS analysis method was established to measure the plasma samples.
  • test results show that compared with orelabrutinib, the elimination half-life T 1/2 and/or the area under the curve AUC and/or the maximum blood concentration C max of compound P006, compound P007 and compound P012 increased by more than 40%.
  • 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 is to measure the in vitro activity of BTK by detecting the level of ADP generated in the kinase reaction.
  • the kinase consumes ATP to phosphorylate the substrate and produces ADP at the same time.
  • 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, and the intensity of the light signal is positively correlated with the amount of ADP generated in the kinase reaction, so that the activity of the kinase BTK can be quantitatively detected.
  • the detection buffer included 40mM Tris-HCl (pH 7.5), 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 diluted three-fold with DMSO to The lowest concentration was 0.025 ⁇ M.
  • 50 nL of compound solution with a series of concentrations and 2.5 ⁇ L of kinase reaction solution were first added to a 384-well plate using Echo555. After mixing well, the plate was incubated at room temperature in the dark for 30 minutes. Subsequently, 2.5 ⁇ L of substrate reaction solution was added, and the total reaction volume was 5.05 ⁇ L. The reaction mixture was reacted at room temperature in the dark for 60 minutes. Subsequently, 5 ⁇ L of ADP-Glo TM reagent was added to terminate the reaction. After mixing well, the plate was placed at room temperature for 40 minutes. Finally, 10 ⁇ L of kinase detection reagent was added, and the plate was placed at room temperature in the dark for 30 minutes before the values were read on Envision.
  • 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 26 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 + Orelabrutinib group.
  • the model + example compound group was intragastrically administered with the example compound once a day at a dose (50 mg/kg); the model + Orelabrutinib group was intragastrically administered with Orelabrutinib once a day at a dose (50 mg/kg), for 8-16 weeks respectively.
  • 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, model + example compound group and model + Orelabrutinib group were intraperitoneally injected with 250 mg/kg of acetaminophen (APAP) saline solution.
  • APAP acetaminophen
  • blood was collected from the eyeballs of mice in each group in turn, and the rotation speed was 3000r/min Centrifuge for 10 minutes to separate serum and store at 4°C for later use; quickly dissect and remove liver and spleen. Rinse with 4°C saline, dry with filter paper, weigh, fix part of liver in 10% formaldehyde solution, wait for slices, and store the remaining liver 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 + Orelabrutinib 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 Orelabrutinib (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 Orelabrutinib in mice.
  • the results are shown in Table 2.
  • A+ is 2.4-3.5; A- is 1.5-2.2; A++ is 3.8-5.2; B+ is 28-39; B- is 42-52; B++ is 16-27.
  • the compound of the present invention (50 mg/kg) has no significant effect on lipid peroxidation induced by APAP, while Orelabrutinib (50 mg/kg) has an effect on lipid peroxidation induced by APAP, indicating that the compound of the present invention is less toxic to the mouse liver than Orelabrutinib.

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Abstract

本发明涉及作为布鲁顿酪氨酸激酶(BTK)抑制剂的吡啶酰胺类化合物。具体而言，本发明公开了2-(4-苯氧基苯基)-6-[1-(丙-2-烯酰)哌啶-4-基]吡啶-3-甲酰胺和/或其互变异构体的氘代化合物，其晶型、其盐、其水合物或溶剂合物的药物组合物，以及它们作为BTK相关的疾病的预防和/或治疗剂。

Description

作为BTK抑制剂的吡啶酰胺类化合物 技术领域
本发明属于生物医药领域，具体涉及一种作为BTK抑制剂的吡啶酰胺类化合物。
背景技术
经B细胞受体(BCR)的B细胞信号转导能产生广泛的生物学输出信号，异常的BCR介导的信号转导能造成失调的B细胞活化和/或形成导致多种自身免疫疾病和/或炎性疾病的致病性自身抗体。人体内BTK的突变导致X连锁无Y球蛋白血症(XLA)(Conley等人，Annu.Rev.Immunol.27:199-227,2009)。这种疾病与B细胞成熟受损、免疫球蛋白产生减少、不依赖T细胞的免疫应答受损以及在BCR刺激时持续的钙信号的显著减弱有关。
抑制BTK活性可以用于治疗变态反应性疾病和/或自身免疫疾病和/或炎性疾病，例如：类风湿性关节炎、多血管炎、特发性血小板减少性紫殿(ITP)、重症肌无力、变应性鼻炎和哮喘(Di Paolo等人(2011)Nature Chem.Biol.7(1):41-50；Liu等人(2011)Jour.of Pharm.and Exper.Ther.338(1):154-163)。
此外，BTK的异常活化在B细胞淋巴瘤的发病机制中起着重要的作用，这意味着在血液恶性肿瘤的治疗中抑制BTK是有很有用的(Davis等人，Nature 463:88-92,2010)。由于BTK作为介体在多个信号转导通路中起着核心作用，因此，抑制BTK活性可抗炎和/或抗癌，用于癌症及治疗B细胞淋巴瘤、白血病和其它血液恶性肿瘤(Mohamed等人，Immunol.Rev.228:58-73，2009；Pan，Drug News perspect 21:357-362,2008；Rokosz等人，Expert Opin.Ther.Targets 12:883-903，2008；Uckun等人，Anti-cancer Agents Med.Chem.7:624-632,2007；Lou等人，J.Med.Chem.55(10):4539-4550，2012)。
2-(4-苯氧基苯基)-6-[1-(丙-2-烯酰)哌啶-4-基]吡啶-3-甲酰胺(奥布替尼，Orelabrutinib,ICP-022)，是布鲁顿酪氨酸激酶(BTK)抑制剂，用于治疗淋巴瘤、白血病及自身免疫性疾病。其在大鼠体内的消除半衰期为8.25小时(Ya-nan Liu等人(2022)，Frontiers in Pharmacology.10.3389/fphar.2022.991281)，而奥布替尼药物代谢和动力学对药效和/或毒性的影响仍不是十分清楚，存在改进的可能性。
目前一些药物的不太好的药物代谢和动力学性能，如：吸收、分布、代谢和/或排泄，妨碍了它们更广泛的使用或限制了它们在特定适应症中的应用。例如，由于药物在体内的较快清除，常采用的解决办法是频繁地给药或给予高剂量的药物以获得足够高的药物血浆水平。 然而，这引入了大量潜在的治疗问题，如患者对于服药间隔的顺应性，以及较高的剂量给药，副作用会更加严重，并且增加了治疗成本。
人们尝试通过氘修饰(改性)减缓药物的代谢，或通过用氘原子取代一个或多个氢原子以减少不期望的代谢物的形成等，从而改善药物的药物代谢和动力学性能。氘是氢的一种安全、稳定、非放射性的同位素。与氢相比，氘与碳形成更强的化学键。在选定的情况下，由氘赋予的增加的键强度可以改善药物的药物代谢和动力学性能，具有改进药效、安全性、和/或耐受性的可能性。同时，由于氘的大小和形状基本上等同于氢，与仅包含氢的原始化学实体相比，预期用氘取代氢将不影响药物的生物化学效能和选择性。
但是，由于生物系统的代谢过程复杂，药物在生物体内的药代动力学性质受到多方面因素影响，也表现出相应的复杂性。与相应的非氘代药物相比，氘代药物药代动力学性质的变化表现出极大的偶然性和不可预测性。对于一些化合物，氘代减慢了其在体内的代谢清除、半衰期增长；对于其它化合物，氘代没有引起代谢改变；对于另一些其它化合物，氘代加快了代谢清除，半衰期缩短(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 De ve l,2006,9:101-09("Fisher"))。
故化合物某些位点的氘代非但不能增长半衰期，反而可能会使其缩短(Scott L.Harbeson,Roger D.Tung.Deuterium in Drug Discovery and Developme nt,P405-406)，劣化其药代动力学性质；另一方面，药物分子上某些位置的氢因为空间位阻等原因也不易被氘代。
甚至当将氘原子并入已知代谢位点时，氘修饰(氘改性)对药物的代谢的影响也不是可预测的。只有通过实际制备和测试氘代的药物，才能确定代谢的速率将是否和怎样不同于非氘代的对应的化学实体。许多药物具有可能代谢的多个部位。需要氘取代的位置(部位)和发现影响代谢所必需的氘化程度，如果有，对于每种药物将是不同的(Fukuto et al.J.Med.Chem.1991,34,2871-76)。
如前所述，氘修饰(氘改性)对药物的代谢的影响是不可预测的。奥布替尼及其体内代谢产物具有肝毒性风险的缺陷，且奥布替尼的临床实验也显示了肝毒性，引起很大的临床担忧。肝毒性不仅与化学结构有关，且与临床给药剂量也密切相关。
因此，针对现有技术的不足，我们设计新化合物，提高新化合物在体内的暴露量，减小用药剂量和/或频率，减小肝毒性；和/或通过结构改造，降低其原形或代谢物的肝毒性，或减少其毒性代谢物的生成，从而达到减毒增效的目的。
发明内容
本发明的目的是提供一类新型的具有BTK抑制活性的吡啶酰胺类化合物及其用途。
在本发明的第一方面，提供了一种式Ⅰ的吡啶酰胺类化合物、其互变异构体、其晶型、其盐、其水合物或溶剂合物
其中：
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18或R19各自独立的选自氢(H)或氘(D)，条件是R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18或R19中至少一个是氘。
在一优选例中，所述化合物为权利要求1所述的化合物，为下列的化合物P001、化合物P002、化合物P003、化合物P004和化合物P005。
在另一优选例中，所述化合物为权利要求1所述的化合物，为下列的化合物P006、化合物P007、化合物P008、化合物P009、化合物P010、化合物P011、化合物P012、化合物P013、化合物P014和化合物P015。
在本发明的第二方面，提供了一种制备药物组合物的方法，包括步骤：将药学上可接受的载体与本发明中第一方面所述的化合物，其互变异构体、其晶型、其盐、其水合物或溶剂合物进行混合，从而形成药物组合物。
在本发明的第三方面，提供了一种药物组合物，它含有药学上可接受的载体与本发明中第一方面所述的化合物，其互变异构体、其晶型、其盐、其水合物或溶剂合物。
在本发明的第四方面，提供了本发明第一方面中所述的化合物，其互变异构体、其晶型、其盐、其水合物或溶剂合物的用途，它们被用于制备抑制BTK的药物组合物。
在另一优选例中，所述的药物组合物用于预防和/或治疗与BTK相关的疾病。
在另一优选例中，所述的药物组合物用于预防和/或治疗与BTK相关的疾病为变态反应性病症、自身免疫性疾病、炎性疾病、血栓栓塞性疾病或癌症。
在另一优选例中，所述的药物组合物用于治疗类风湿性关节炎、银屑病性关节炎、感染性关节炎、进行性慢性关节炎、致畸性关节炎、骨关节炎、创伤性关节炎、痛风性关节炎、Reiter氏综合症、多软骨炎、急性滑膜炎、脊椎炎、有肾病综合症的肾小球肾炎、没有肾病综合症的肾小球肾炎、自身免疫性血液系统病症、溶血性贫血、再生障碍性贫血、特发性血小板减少症、嗜中性白血球减少症、自身免疫性胃炎、自身免疫性炎性肠病、溃病性结肠炎、Crohn氏病、宿主抗移植物病、同种异体移植物排斥、慢性甲状腺炎、格雷夫斯氏病、硬皮病、I型糖尿病、II型糖尿病、急性活动性肝炎、慢性活动性肝炎、胰腺炎、原发性胆汁性肝硬化、重症肌无力、多发性硬化症、系统性红斑狼疮、银屑病、特应性皮炎、接触性皮炎、湿痒、皮肤晒伤、血管炎、Behcet氏病、慢性肾功能不全、Stevens-Johnson综合症、炎性痛、 特发性脂肪泻、恶病质、结节病、Guillain-Barré综合症、葡萄膜炎、结膜炎、角膜结膜炎、中耳炎、牙周病、肺间质性纤维化、哮喘、支气管炎、鼻炎、窦炎、尘肺病、肺功能不全综合症、肺气肿、肺纤维化、砂肺、慢性炎性肺病、慢性阻塞性肺病、增生性疾病、非霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、套细胞淋巴瘤(MCL)、B细胞慢性淋巴细胞性白血病、急性成淋巴细胞性白血病、具有成熟B细胞的急性成淋巴细胞性白血病、由慢性活动型B细胞受体信号传导引起的B细胞淋巴瘤和与多发性骨髓瘤相关的骨病。
在另一优选例中，所述的药物组合物用于治疗慢性淋巴细胞性淋巴瘤、非霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤、滤泡性淋巴瘤和慢性淋巴细胞白血病。
如本文所用，“氘代”指化合物或基团中的一个或多个氢被氘所取代。氘代可以是一取代、二取代、多取代或全取代。
在另一优选例中，氘在氘取代位置的氘同位素含量是大于天然氘同位素含量(0.015％),更佳地大于50％,更佳地大于85％,更佳地大于95％,更佳地大于99％,更佳地大于99.5％。
在另一优选例中，式I化合物至少含有1或3个氘原子，更佳地5或8个氘原子。
如本文所用，术语“本发明化合物”指式I所示的化合物。该术语还包括式I化合物的互变异构体、其晶型、其盐、其水合物或溶剂合物。
如本文所用，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、拧檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。
本发明化合物或其药学上可接受的衍生物也可在投予一种或多种其它治疗剂的同时、之前或之后投予。此组合疗法包括投予含有本发明化合物和一种或多种其它活性剂的单一药学给药制剂，以及投予本发明化合物与各活性剂自己的单独药学给药制剂。例如，本发明化合物与另一活性剂可以单一口服给药组合物(例如片剂或胶囊)一起投予患者，或各药剂以单独口服给药制剂投予。在使用单独给药制剂的情况下，本发明化合物与一种或多种额外活性剂可基本上在同一时间(即同时)或在单独错开的时间(即相继)投予；组合疗法应理解为包括所有这些方案。
本发明的药用组合根据疾病状态、给药途径、患者年龄或者体重的不同，给药剂量会做调整。对于成人口服给药，通常为0.2-35mg/kg/天，较佳为0.8-20mg/kg/天。本发明适宜的给 药剂量需要考虑患者的年龄、体重、病情、给药途径等进行设定，口服给药通常为0.1-35mg/kg/天，较佳为0.5-15mg/kg/天范围内。
本发明的积极进步效果在于：
(1)本发明化合物具有良好的选择性BTK抑制作用，能有效用作与BTK相关的疾病。
(2)本发明化合物具有良好的选择性抑制B细胞活化作用，是一种有效用作B细胞活化抑制剂。
(3)本发明氘代的吡啶酰胺类化合物及其药学上可接受的盐肝毒性小，药代动力学性质良好、降低使用剂量和/或降低毒副作用，成药性更好。与奥布替尼相比，具有明显更优异的药物动力学和/或药效学性能和/或安全性性能，更适用制备治疗与BTK相关的疾病。
具体的实施方法
下面更具体地描述本发明式I结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。
本发明使用的未氘代的吡啶酰胺类化合物及其生理上相容的盐的制备方法是已知的。对应氘代的吡啶酰胺类化合物可以用相应的氘代起始化合物为原料，用相同的路线合成。
以化合物P001为例，一种优选的制备流程如下：
其具体合成方法在实施例1中说明。
下面结合具体实施例，进一步阐述本发明。这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。
实施例1：化合物P001的合成
合成路线
步骤1：化合物P102的合成
在浓硫酸(10ml)和水(2ml)的混合溶液中，加入2,6-二氯尼古丁腈(化合物P101)(10mmol)，加热到90℃,搅拌l小时。冷却至室温后，将反应混合物置于冰水浴中，用氨水调节PH值至8。过滤，滤饼用水洗涤，干燥后得到化合物P102。
步骤2：化合物P104的合成
在1,4-二氧六环(60ml)和水(12ml)混合溶液中，加入化合物P102(3.0mmol)、4-苯氧基苯基硼酸-d5(化合物P103)(3.0mmol)、三(二亚苄基丙酮)二钯(0.55mmol)、碳酸铯(6.0mmol)后，加热到120℃,回流搅拌16小时。减压浓缩，残余物用硅胶柱纯化，洗脱剂为二氯甲烷/甲醇(150/1)，去除溶剂，得化合物P104。
步骤3：化合物P106的合成
在乙二醇二甲醚(l0ml)和水(2ml)的混合溶液中，加入化合物P104(0.50mmol)、(1-(叔丁氧基羰基)-1，2，3，6-四氢吡啶-4-基)硼酸(化合物P105)(0.75mmol)、四(三苯基膦)钯(0.lmmol)和碳酸钾(l.5mmol)，加热到90℃,搅拌5小时。冷却至室温，减压浓缩，残余物用硅胶柱纯化，洗脱剂为二氯甲烷/甲醇(700/1),去除溶剂，得化合物P106。
步骤4：化合物P107的合成
在乙酸乙酯(10ml)中，加入化合物P106(0.45mmol)和钯碳(10mg)，在除去氧的氢气气氛下室温搅拌16小时。减压浓缩，残余物用硅胶柱纯化，洗脱剂为二氯甲烷/甲醇(70/1),去除溶剂,得化合物P107。
步骤5：化合物P108的合成
在二氯甲烷(5ml)中，加入化合物P107和三氟乙酸(2ml)，室温下搅拌l小时。减压浓缩，残余物溶解于二氯甲烷，用饱和碳酸氢钠溶液洗涤。有机相用无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，残余物用硅胶柱纯化，洗脱剂为二氯甲烷/甲醇(70/1到5/1)，合并目标产物馏分，去除溶剂，得化合物P108。
步骤6：化合物P001的合成
在二氯甲烷(6ml)中，加入化合物P108(0.40mmol)、烯丙酰氯-d3(化合物P109)(0.56mmol)和三乙胺(0.85mmol)，在0℃下搅拌l小时。反应用水(10ml)淬灭，用乙酸乙酯(30ml)稀释，依次用水(20ml×2)和饱和食盐水(20ml×2)洗涤。将有机相用无水硫酸钠干燥，过滤除去干燥剂，减压浓缩，残余物用硅胶柱纯化。洗脱剂为二氯甲烷/甲醇(20/1)，去除溶剂，得化合物P001。化合物P001的核磁共振氢谱为：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.2-6.9(3H),5.8(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H)。
实施例2：化合物P002的合成
化合物P002的合成，将“实施例1：化合物P001的合成”中步骤2的化合物P103改为化合物P202。其余步骤同“实施例1：化合物P001的合成”操作，得化合物P002。化合物P002的核磁共振氢谱为：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.5-7.3(2H),7.2-6.9(5H),5.8(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H)。
实施例3：化合物P003的合成
化合物P003的合成，将“实施例1：化合物P001的合成”中步骤2的化合物P103改为化合物P203。其余步骤同“实施例1：化合物P001的合成”操作，得化合物P003。化合物P003的核磁共振氢谱为：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.5-7.3(2H),7.2-6.9(3H),5.8(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H)。
实施例4：化合物P004的合成
化合物P004的合成，将“实施例1：化合物P001的合成”中步骤2的化合物P103改为化合物P204。其余步骤同“实施例1：化合物P001的合成”操作，得化合物P004。化合物P004的核磁共振氢谱为：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.2-6.9(5H),5.8(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H)。
实施例5：化合物P005的合成
化合物P005的合成，将“实施例1：化合物P001的合成”中步骤2的化合物P103改为化合物P205。其余步骤同“实施例1：化合物P001的合成”操作，得化合物P005。化合物P005的核磁共振氢谱为：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.5-7.3(2H),7.2-6.9(6H),5.8(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H)。
实施例6：化合物P006的合成
化合物P006的合成，将“实施例1：化合物P001的合成”中步骤6的化合物P109改为化合物P206。其余步骤同“实施例1：化合物P001的合成”操作，得化合物P006。化合物P006的核磁共振氢谱为：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.2-6.9(3H),6.6(1H),6.3(1H), 5.8(1H),5.7(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H)。
实施例7：化合物P007的合成
化合物P007的合成，将“实施例6：化合物P006的合成”中步骤2的化合物P103改为化合物P202。其余步骤同“实施例6：化合物P006的合成”操作，得化合物P007。化合物P007的核磁共振氢谱为：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.5-7.3(2H),7.2-6.9(5H),6.6(1H),6.3(1H),5.8(1H),5.7(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H)。
实施例8：化合物P008的合成
化合物P008的合成，将“实施例6：化合物P006的合成”中步骤2的化合物P103改为化合物P203。其余步骤同“实施例6：化合物P006的合成”操作，得化合物P008。化合物P008的核磁共振氢谱为：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.5-7.3(2H),7.2-6.9(3H),6.6(1H),6.3(1H),5.8(1H),5.7(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H)。
实施例9：化合物P009的合成
化合物P009的合成，将“实施例6：化合物P006的合成”中步骤2的化合物P103改为化合物P204。其余步骤同“实施例6：化合物P006的合成”操作，得化合物P009。化合物P009的核磁共振氢谱为：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.2-6.9(5H),6.6(1H),6.3(1H),5.8(1H),5.7(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H)。
实施例10：化合物P010的合成
化合物P010的合成，将“实施例1：化合物P001的合成”中步骤2的化合物P103改为化合物P207。其余步骤同“实施例1：化合物P001的合成”操作，得化合物P010。化合物P010的核磁共振氢谱为：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.2-6.9(4H),5.8(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H)。
实施例11：化合物P011的合成
化合物P011的合成，将“实施例1：化合物P001的合成”中步骤2的化合物P103改为化合物P208。其余步骤同“实施例1：化合物P001的合成”操作，得化合物P011。化合物P011的核磁共振氢谱为：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.5-7.3(2H),7.2-6.9(4H),5.8(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H)。
实施例12：化合物P012的合成
化合物P012的合成，将“实施例1：化合物P001的合成”中步骤2的化合物P103改为化合物P209。其余步骤同“实施例1：化合物P001的合成”操作，得化合物P012。化合物P012的核磁共振氢谱为：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.2-6.9(6H),5.8(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H)。
实施例13：化合物P013的合成
化合物P013的合成，将“实施例6：化合物P006的合成”中步骤2的化合物P103改为化合物P207。其余步骤同“实施例6：化合物P006的合成”操作，得化合物P013。化合物P013的核磁共振氢谱为：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.2-6.9(4H),6.6(1H),6.3(1H),5.8(1H),5.7(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H)。
实施例14：化合物P014的合成
化合物P014的合成，将“实施例6：化合物P006的合成”中步骤2的化合物P103改为化合物P208。其余步骤同“实施例6：化合物P006的合成”操作，得化合物P014。化合物P014的核磁共振氢谱为：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.5-7.3(2H),7.2-6.9(4H),6.6 (1H),6.3(1H),5.8(1H),5.7(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H)。
实施例15：化合物P015的合成
化合物P015的合成，将“实施例6：化合物P006的合成”中步骤2的化合物P103改为化合物P209。其余步骤同“实施例6：化合物P006的合成”操作，得化合物P015。化合物P015的核磁共振氢谱为：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.2-6.9(6H),6.6(1H),6.3(1H),5.8(1H),5.7(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H)。
实施例16：化合物P103的合成
步骤7:化合物P403的合成
取化合物P401(11.8g),溶于无水四氢呋喃(120ml)中，搅拌，分批次缓慢加入氢化钠(12.1g)，再分批次加入1-溴-4-碘苯(化合物P402)(39.1g)，室温反应15hr，将反应物过滤，滤液旋干，加入二氯甲烷溶解。过硅胶柱，用石油醚：乙酸乙酯(1:5)洗脱，得化合物P403(12.7g)
步骤8:化合物P103的合成
将化合物P403(5.2g)溶解于干燥的THF(100ml)，N2保护下在-78℃反应30mi n,缓慢滴加正丁基锂(1.9g),滴加结束后保持-78℃反应3h,再缓慢滴加硼酸三异丙酯(4.3g),滴加结束后保持在-78℃反应2h,缓慢升至室温，反应15hr左右，TLC监测反应结束后，用水缓慢 淬灭反应液，萃取浓缩，得化合物P103(3.0g)。
实施例17：化合物P203的合成
化合物P203的合成，按“实施例16：化合物P103的合成”进行，只在步骤7中，化合物P401改为化合物P402，其余步骤同“实施例16：化合物P103的合成”操作，得化合物P203。
实施例18：化合物P204的合成
化合物P204的合成，按“实施例16：化合物P103的合成”进行，只在步骤7中，化合物P401改为化合物P403，其余步骤同“实施例16：化合物P103的合成”操作，得化合物P204。
实施例19：化合物P202的合成
化合物P202的合成，按“实施例16：化合物P103的合成”进行，只在步骤7中，化合物P401改为化合物P404，其余步骤同“实施例16：化合物P103的合成”操作，得化合物P202。
实施例20：化合物P207的合成
化合物P207的合成，按“实施例16：化合物P103的合成”进行，只在步骤7中，化合物P401改为化合物P405，其余步骤同“实施例16：化合物P103的合成”操作，得化合物P207。
实施例21：化合物P208的合成
化合物P208的合成，按“实施例16：化合物P103的合成”进行，只在步骤7中，化合物P401改为化合物P406，其余步骤同“实施例16：化合物P103的合成”操作，得化合物P208。
实施例22：化合物P209的合成
化合物P209的合成，按“实施例16：化合物P103的合成”进行，只在步骤7中，化合物P401改为化合物P407，其余步骤同“实施例16：化合物P103的合成”操作，得化合物P209。
实施例23：大鼠药代动力学
30只雄性Sprague-Dawley大鼠，6-9周龄，体重约220g，分成5组(奥布替尼组、化合物P001组、化合物P002组、化合物P005组和化合物P009组)，每组6只。按照分组分别单次灌胃给予10mg/kg剂量的奥布替尼、化合物P001、化合物P002、化合物P005和化合物P009，比较其药代动力学差异。
大鼠给药前12小时开始禁食。用0.5％羧甲基纤维素钠(CMC-Na)配制给药溶液。眼眶静脉丛采血，采血时间点为给药后0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、12小时、16小时和24小时。血样分离出血浆后，将血浆保存在-80℃冰箱中备用。建立LC-MS/MS分析方法对血浆样品进行测定。
由试验结果可知，与奥布替尼相比，化合物P001、化合物P002、化合物P005和化合物P009的消除半衰期T1/2和/或曲线下面积AUC和/或最大血药浓度Cmax增加50％以上。
由本结果可知，与奥布替尼相比，本发明化合物P001、化合物P002、化合物P005和/或化合物P009在大鼠体内具有更好的药代动力学性质，预示具有更好的药效学和治疗效果。
实施例24：大鼠药代动力学
24只雄性Sprague-Dawley大鼠，6-9周龄，体重约220g，分成4组(奥布替尼组、化合物P006组、化合物P007组、化合物P012组)，每组6只。按照分组分别单次灌胃给予10mg/kg剂量的奥布替尼、化合物P006、化合物P007和化合物P012，比较其药代动力学差异。
大鼠给药前12小时开始禁食。用0.5％羧甲基纤维素钠(CMC-Na)配制给药溶液。眼眶静脉丛采血，采血时间点为给药后0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、12小时、16小时和24小时。血样分离出血浆后，将血浆保存在-80℃冰箱中备用。建立LC-MS/MS分析方法对血浆样品进行测定。
由试验结果可知，与奥布替尼相比，化合物P006、化合物P007和化合物P012的消除半衰期T1/2和/或曲线下面积AUC和/或最大血药浓度Cmax增加40％以上。
由本结果可知，与奥布替尼相比，本发明化合物P006、化合物P007和/或化合物P012在大鼠体内具有更好的药代动力学性质，预示具有更好的药效学和治疗效果。
实施例25：BTK的抑制活性测定
使用ADP-GloTM试剂盒测定本发明的化合物对BTK的活性影响。实验方法如下：
ADP是激酶反应的产物，通常可以通过检测ADP的生成量来检测激酶活性。Promega公司开发的ADP-GloTM试剂盒即是通过检测激酶反应中所产生的ADP水平来测定BTK的体外活性。在激酶检测实验中，激酶消耗ATP将底物磷酸化，同时产生ADP。然后加入ADP-Glo试剂终止激酶反应并且将剩余的ATP完全消耗。再加入激酶检测试剂，将产生的ADP转化为新的ATP，检测试剂中的萤光素酶在ATP和O2参与下能够催化荧光素，产生光信号，从而将化学信号转为光信号，且光信号的强度与激酶反应中ADP产生的量呈正相关，从而能够定量检测激酶BTK的活性。
所有检测实验均在23℃恒室温进行，使用Corning 3674白色384孔检测板，激酶BTK(Invitrogen公司)，激酶底物为多肽(4:l Glu,Tyr)(Signal Chem)和ATP(Sigma),使用酶标仪EnVision(Perkin Elmer)读取光信号。检测缓冲液包括40mM Tris-HCl(pH 7.5)、10mM MgCl2(Sigma)、2mM MnCl2(Sigma)、0.05mM DTT(Sigma)和0.01％BSA(Sigma)；将激酶BTK使用检测缓冲液配制为1.3ng/μL浓度的激酶反应溶液；底物反应溶液包括0.25mg/mL多肽底物和60μM ATP。
将本发明的化合物用DMSO稀释成0.5mM的溶液，然后用DMSO进行三倍梯度稀释至 最低浓度为0.025μM，用Echo555向384孔板中先添加50nL系列浓度的化合物溶液和2.5μL激酶反应溶液,混合均匀后室温避光孵育30分钟；随后加入2.5μL底物反应溶液,反应总体积为5.05μL,将反应混合物在室温避光反应60分钟；随后加入5μL ADP-GloTM试剂终止反应，混合均匀后室温放置40分钟；最后加入10μL激酶检测试剂，室温避光放置30分钟，然后在Envision上读取数值。
抑制百分率按以下公式计算：
抑制％＝[1-(RLU化合物-RLUmin)/(RLUmax-RLUmin)]×100
其中RLU化合物为本发明化合物的给定浓度下的读数，RLUmin为不加入激酶BTK的情况下的读数，RLUmax为不加入本发明化合物的情况下的读数。通过使用Excel中XLfit程序计算化合物的IC50值。
表1：本发明化合物的IC50值
由本结果可知，本发明化合物对BTK具有明显的抑制效应。
实施例26：小鼠肝毒性对比研究
(1)实验动物
选择成年雄性ICR小鼠32只，体重(25±2g)，所有小鼠允许自由进食水和维持饲料，25±2℃的温度，50±10％的相对湿度下昼夜交替循环。
(2)动物分组与给药
32只雄性ICR小鼠分为四组，每组8只，分别为正常对照组、模型组、模型+实施例化合物组和模型+Orelabrutinib组。模型+实施例化合物组按剂量(50mg/kg)每天灌胃给药一次实施例化合物；模型+Orelabrutinib组按剂量(50mg/kg)每天灌胃给药一次Orelabrutinib，分别持续8-16周，正常对照组和模型组分别灌胃等体积纯净水。末次给药后开始断粮，1h后对模型组、模型+实施例化合物组和模型+Orelabrutinib组小鼠分别一次性腹腔注射250mg/kg的对乙酰氨基酚(APAP)生理盐水溶液，造模24h后依次对各组小鼠进行眼球取血，3000r/min 离心10min分离血清，4℃保存备用；迅速解剖取肝脏及脾脏。经4℃生理盐水冲洗，滤纸吸干，称重，取部分肝脏于10％的甲醛溶液中固定，待切片，剩余肝脏-80℃低温冰箱中保存。
(3)肝脏中生化指标的测定：
取部分肝脏称重，加入9倍体积的冰生理盐水，用组织匀浆机制得10％的肝组织匀浆，离心取上清液。按照试剂盒方法点板，在450nm处测定OD值，根据公式计算肝脏中MDA的含量和GSH的活性。
(4)数据处理
实验数据均用均数±标准差(±s)表示，用SPSS 22.0统计软件进行分析，组间采用单因素方差分析比较差异。P<0.05位明显差异。
(5)本申请实施例化合物对APAP肝损伤小鼠肝组织脂质过氧化影响
与正常对照组相比，模型组小鼠肝组织匀浆中MDA含量明显的上升，GSH水平显著下降(P<0.05)，使小鼠体内脂质过氧化产物累积，抗氧化代谢水平降低；与模型组相比，模型+实施例化合物组的MDA含量和GSH水平均无明显变化(P>0.05)；与模型组相比，模型+Orelabrutinib组的MDA含量明显的上升(P<0.05)，GSH水平显著下降(P<0.05)，表明本申请实施例化合物(50mg/kg)对APAP引起的脂质过氧化没有明显影响，而Orelabrutinib(50mg/kg)对APAP引起的脂质过氧化有影响，提示本申请实施例化合物的小鼠肝脏毒性小于Orelabrutinib。结果如表2所示。
表2.对APAP肝损伤小鼠肝组织脂质过氧化影响
标注(等级)：A+为2.4-3.5；A-为1.5-2.2；A++为3.8-5.2；B+为28-39；B-为42-52；B++为16-27。
结论：本申请实施例化合物(50mg/kg)对APAP引起的脂质过氧化没有明显影响，而Orelabrutinib(50mg/kg)对APAP引起的脂质过氧化有影响，提示本申请实施例化合物的小鼠肝脏毒性小于Orelabrutinib。
最后有必要说明的是，以上对本发明的具体实施例进行了详细描述，但其只作为范例，本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言，任何对本发明进行的等同修改和替代也都在本发明的范畴之中。因此，在不脱离本发明的精神和范围下所作的均等变换和修改，都应涵盖在本发明的范围内。

Claims (8)

  1. 本发明提供一种式Ⅰ的吡啶酰胺类化合物、其互变异构体、其晶型、其盐、其水合物或溶剂合物
    其中：
    R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18或R19各自独立的选自氢或氘，条件是R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18或R19中至少一个是氘。
  2. 权利要求1所述的化合物，其互变异构体、其晶型、其盐、其水合物或溶剂合物，其特征在于所述化合物选自以下结构：

  3. 一种药物组合物，其包含药学上可接受的载体与权利要求1-2中任一所述的化合物，其互变异构体、其晶型、其盐、其水合物或溶剂合物。
  4. 权利要求1-2中任一项的吡啶酰胺类化合物，其互变异构体、其晶型、其盐、其水合物或溶剂合物在制备BTK抑制剂上的应用。
  5. 权利要求3所述的药物组合物在制备治疗和/或预防与BTK相关的疾病的药物上的应用。
  6. 权利要求5所述的药物组合物，其中，与BTK相关的疾病为变态反应性病症、自身免疫性疾病、炎性疾病、血栓栓塞性疾病或癌症。
  7. 权利要求1-2中任一项的化合物，其互变异构体、其晶型、其盐、其水合物或溶剂合物用于制备用于治疗BTK介导的病症的药物的用途，其中所述BTK介导的病症选自：类风湿性关节炎、银屑病性关节炎、感染性关节炎、进行性慢性关节炎、致畸性关节炎、骨关节炎、创伤性关节炎、痛风性关节炎、Reiter氏综合症、多软骨炎、急性滑膜炎、脊椎炎、有肾病综合症的肾小球肾炎、没有肾病综合症的肾小球肾炎、自身免疫性血液系统病症、溶血性贫血、再生障碍性贫血、特发性血小板减少症、嗜中性白血球减少症、自身免疫性胃炎、自身免疫性炎性肠病、溃病性结肠炎、Crohn氏病、宿主抗移植物病、同种异体移植物排斥、慢性甲状腺炎、格雷夫斯氏病、硬皮病、I型糖尿病、II型糖尿病、急性活动性肝炎、慢性活动性肝炎、胰腺炎、原发性胆汁性肝硬化、重症肌无力、多发性硬化症、系统性红斑狼疮、银屑病、特应性皮炎、接触性皮炎、湿痒、皮肤晒伤、血管炎、Behcet氏病、慢性肾功能不全、Stevens-Johnson综合症、炎性痛、特发性脂肪泻、恶病质、结节病、Guillain-Barré综合症、葡萄膜炎、结膜炎、角膜结膜炎、中耳炎、牙周病、肺间质性纤维化、哮喘、支气管炎、鼻炎、窦炎、尘肺病、肺功能不全综合症、肺气肿、肺纤维化、砂肺、慢性炎性肺病、慢性阻塞性肺病、增生性疾病、非霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤、B细胞慢性淋巴细胞性白血病、急性成淋巴细胞性白血病、具有成熟B细胞的急性成淋巴细胞性白血病、由慢性活动型B细胞受体信号传导引起的B细胞淋巴瘤和与多发性骨髓瘤相关的骨病。
  8. 根据权利要求7的用途，其中所述BTK介导的病症是B细胞增殖性疾病，选自慢性淋巴细胞性淋巴瘤、非霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤、滤泡性淋巴瘤和慢性淋巴细胞白血病。
PCT/CN2023/133130 2022-11-23 2023-11-22 作为btk抑制剂的吡啶酰胺类化合物 WO2024109789A1 (zh)

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CN104507946A (zh) * 2012-07-30 2015-04-08 康塞特医药品有限公司 氘代依鲁替尼
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CN104507946A (zh) * 2012-07-30 2015-04-08 康塞特医药品有限公司 氘代依鲁替尼
US20160237075A1 (en) * 2013-09-30 2016-08-18 Beijing Synercare Pharma Tech Co., Ltd. Substituted nicotinimide inhibitors of btk and their preparation and use in the treatment of cancer, inflammation and autoimmune disease

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