WO2024104277A1 - 作为btk抑制剂的嘌呤衍生物 - Google Patents

作为btk抑制剂的嘌呤衍生物 Download PDF

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WO2024104277A1
WO2024104277A1 PCT/CN2023/131135 CN2023131135W WO2024104277A1 WO 2024104277 A1 WO2024104277 A1 WO 2024104277A1 CN 2023131135 W CN2023131135 W CN 2023131135W WO 2024104277 A1 WO2024104277 A1 WO 2024104277A1
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compound
disease
synthesis
btk
chronic
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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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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of biomedicine, and specifically relates to a purine derivative 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 perspective 21:357-362, 2008; Rokosz et al., Expert Opin. Ther.
  • Tirabrutinib ONO-4059, GS-4059
  • Tirabrutinib hydrochloride Velexbru
  • Velexbru exerts its therapeutic effect by inhibiting BTK.
  • Tirabrutinib Compared with Lck, Fyn, and LynA, Tirabrutinib has greater selectivity for BTK and only inhibits anti-IgM-induced B cell activation in a concentration-dependent manner, but does not inhibit anti-CD3/CD28-induced activation of human PBMCs into T lymphocytes. Tilabrutinib inhibits cell proliferation in some malignant B cells and induces the classic apoptotic response of TMD8 cells in the nanomolar concentration range (T Yasuhiro, et al. Leuk Lymphoma. 2016, 58(3): 699-707.).
  • tilabrutinib exerts its therapeutic effect by inhibiting the production of inflammatory chemokines and cytokines such as IL-6, IL-8, and TNFalpha in monocytes, accompanied by the regression of cartilage erosion, bone damage, and pannus formation (Akinleye A, et al. J Hematol Oncol. 2013, 6: 59).
  • 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 down their metabolic clearance in the body and increases their half-life; for some 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.
  • the present invention determines chemical entities different from tilarutinib by actually preparing and testing various deuterated tilarutinibs.
  • deuterating tilarutinib a class of deuterated drugs with good pharmacokinetic properties, reduced dosage and reduced toxic side effects are obtained.
  • the purpose of the present invention is to provide a novel class of purine derivatives having BTK inhibitory activity and uses thereof.
  • R1 , R2 , R3 , R4 , R5 , R6 , R7 , R8, R9 , R10 , R11 , R12 , R13 or R14 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 or R14 is deuterium.
  • the compound is the compound according to claim 1.
  • the compound is the following compound C001, compound C002, compound C003, compound C004 and compound C005.
  • the compound is the compound according to claim 1.
  • the compound is the following compound C006, compound C007, compound C008, compound C009, compound C010, compound C011, compound C012, compound C013, compound C014 and compound C015.
  • 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 isomers or mixtures thereof, its salts or N-oxides thereof, 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 isomers or mixtures thereof, its salts or N-oxides thereof.
  • 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 reaction, an autoimmune disease, an inflammatory disease, a thromboembolic disease or a cancer.
  • a BTK-related disease such as an allergic reaction, 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 central nervous system lymphoma, 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 will be adjusted according to the disease state, route of administration, age or weight of the patient. For oral administration in adults, it is usually 0.2-35 mg/kg/day, preferably 0.8-20 mg/kg/day.
  • the suitable dosage of the present invention needs to be set considering the patient's age, weight, condition, route of administration, etc., and 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.
  • the deuterated purine derivatives 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 tilarabrutinib, 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 purine derivatives and their physiologically compatible salts used in the present invention are known.
  • the corresponding deuterated purine derivatives can be synthesized using the corresponding deuterated starting compounds as raw materials and in the same way.
  • Example 24 Pharmacokinetics of Compound C001, Compound C004, Compound C005 and Compound C006 in Rats Mechanics
  • telabrutinib group Thirty male Sprague-Dawley rats, aged 6-9 weeks and weighing about 220 g, were divided into 5 groups (telabrutinib group, compound C001 group, compound C004 group, compound C005 group and compound C006 group), with 6 rats in each group. Telabrutinib, compound C001, compound C004, compound C005 and compound C006 were given a single oral gavage at a dose of 10 mg/kg according to the grouping, and their pharmacokinetic differences were compared.
  • 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 tilarabrutinib, 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 C001, compound C004, compound C005 and compound C006 increased by more than 50%.
  • telabrutinib group 24 male Sprague-Dawley rats, 6-9 weeks old, weighing about 220 g, were divided into 4 groups (telabrutinib group, compound C007 group, compound C009 group, compound C012 group), 6 rats in each group. Telabrutinib, compound C007, compound C009 and compound C012 were given a single oral gavage at a dose of 10 mg/kg according to the grouping, and their pharmacokinetic differences were compared.
  • 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 tilarabrutinib, 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 C007, compound C009 and compound C012 increased by more than 35%.
  • 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 (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.
  • 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 27 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 + tirabrutinib group.
  • the model + example compound group was intragastrically administered with the example compound once a day at a dose (60 mg/kg);
  • the model + tirabrutinib group was intragastrically administered with tirabrutinib once a day at a dose (60 mg/kg), respectively, for 14 consecutive days
  • the normal control group and the model group were intragastrically administered with an equal volume of purified water.
  • mice in the model group, the model + example compound group and the model + tirabrutinib group were intraperitoneally injected with 250 mg/kg of acetaminophen (APAP) saline solution, respectively.
  • APAP acetaminophen
  • blood was collected from the eyeballs of 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 liver was dried with filter paper and 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 + tirabrutinib group increased significantly (P ⁇ 0.05), and the GSH level decreased significantly (P ⁇ 0.05), indicating that the example compound (60 mg/kg) of the present application had no significant effect on lipid peroxidation caused by APAP, while tirabrutinib (60 mg/kg) had an effect on lipid peroxidation caused by APAP, suggesting that the mouse liver toxicity of the example compound of the present application was significantly lower than that of tirabrutinib.
  • Table 2 The results are shown in Table 2.
  • the example compound of the present application (60 mg/kg) has no significant effect on lipid peroxidation induced by APAP, while tirabrutinib (60 mg/kg) has an effect on lipid peroxidation induced by APAP, indicating that the example compound of the present application has significantly less liver toxicity in mice than tirabrutinib.

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Abstract

涉及一种作为布鲁顿酪氨酸激酶(BTK)抑制剂的嘌呤衍生物。具体而言，涉及氘代(R)-6-氨基-9-(1-(丁-2-炔酰基)吡咯烷-3-基)-7-(4-苯氧基苯基)-7H-嘌呤-8(9H)-酮、其光学异构体或它们的混合物、其盐或其N-氧化物，以及它们作为BTK 相关的疾病的预防和/或治疗剂。

Description

作为BTK抑制剂的嘌呤衍生物 技术领域
本发明属于生物医药领域，具体涉及一种作为BTK抑制剂的嘌呤衍生物。
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)。
(R)-6-氨基-9-(1-(丁-2-炔酰基)吡咯烷-3-基)-7-(4-苯氧基苯基)-7H-嘌呤-8(9H)-酮(替拉鲁替尼，Tirabrutinib,ONO-4059，GS-4059)是一种高选择性BTK抑制剂。替拉鲁替尼盐酸盐(Velexbru)是由小野制药开发的口服BTK抑制剂，Velexbru通过抑制BTK发挥治疗作用。相较于Lck、Fyn、LynA，替拉鲁替尼对BTK的选择性更大，并只以浓度依赖性方式抑制anti-IgM诱导的B细胞激活，而不抑制anti-CD3/CD28诱导的人类PBMCs向T淋巴细胞的激活。替拉鲁替尼在一些恶性B细胞中抑制细胞增殖，也在纳摩尔浓度范围内，诱导TMD8细胞的经典凋亡反应(T Yasuhiro,et al.Leuk Lymphoma.2016,58(3):699-707.)。在CIA小鼠模型中，替拉鲁替尼通过抑制炎性趋化因子和单核细胞中细胞因子如IL-6、IL-8、TNFalpha等的产生，发挥疗效，同时伴随软骨侵蚀、骨损伤、血管翳形成的消退(Akinleye A,et al.J Hematol Oncol.2013,6:59)。
替拉鲁替尼的体内代谢复杂。Zhang Hongjian等人研究了替拉鲁替尼在大鼠、犬和人肝微粒体中的代谢物，共鉴别了18个代谢物，其代谢途径复杂(Zhang Hongjian等人Rapid Commun.Mass Spectrom.2022；36:e9240)，其吸收、分布、代谢和/或排泄对药效和/或毒性的影响仍不是十分清楚。
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，由于药物在体内的消除半衰期短，快速清除，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；对于又一些化合物，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 Development,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。
甚至当将氘原子引入已知代谢位点时，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。替拉鲁替尼及其体内代谢产物具有肝毒性风险的缺陷，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。
基于此，本发明通过实际制备和测试各种氘代的替拉鲁替尼，确定不同于替拉鲁替尼的化学实体。通过对替拉鲁替尼进行氘代，得到一类药代动力学性质良好、降低使用剂量和降低毒副作用的氘代药物。
发明内容
本发明的目的是提供一类新型的具有BTK抑制活性的嘌呤衍生物及其用途。
在本发明的第一方面，提供了一种式Ⅰ的嘌呤衍生物、其光学异构体或它们的混合物、其盐或其N-氧化物。
其中：
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13或R14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或R14中至少一个是氘。
在一个优选例中，所述化合物为权利要求1所述的化合物。所述化合物即为下列的化合物C001、化合物C002、化合物C003、化合物C004和化合物C005。
在另一优选例中，所述化合物为权利要求1所述的化合物。所述化合物即为下列的化合物C006、化合物C007、化合物C008、化合物C009、化合物C010、化合物C011、化合物C012、化合物C013、化合物C014和化合物C015。
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，其光学异构体或它们的混合物、其盐或其N-氧化物进行混合，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，其光学异构体或它们的混合物、其盐或其N-氧化物。
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，其光学异构体或它们的混合物、其盐或其N-氧化物的用途，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中枢神经系统淋巴瘤、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)本发明氘代的嘌呤衍生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。与替拉鲁替尼相比，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嘌呤衍生物及其生理上相容的盐的制备方法是已知的。对应氘代的嘌呤衍生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。
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。
实施例1：合成化合物C001
合成路线
第一步：合成化合物C103
在冰浴下，向4,6-二氯-5-硝基嘧啶(化合物C101)(10g)的二氯甲烷(70ml)溶液中滴入在二氯甲烷(32ml)溶液中的二苄胺(化合物C102)(11g)，然后加入三乙胺(15ml)，搅拌1小时。向反应混合物中加入水后，用饱和盐水洗涤有机层，用无水硫酸钠干燥，通过减压浓缩溶剂，得到化合物C103(18.3g)。
第二步：合成化合物C105
将化合物C103(11.1g)和化合物C104(5.0g)溶解在二噁烷(60ml)中，加入三乙胺(8.5mL)后，在50℃下搅拌5小时。将反应混合物恢复到室温后，蒸馏除去溶剂，加入水，用乙酸乙酯萃取。将有机层用饱和盐水洗涤后，用无水硫酸钠干燥，蒸馏除去溶剂。用硅胶柱色谱法纯化残渣，得到化合物C105(9.7g)。
第三步：合成化合物C106
在冰浴下，向锌(24.2g)和3.0M氯化氨水溶液(12.2g)的混合液中滴入在乙酸乙酯(360ml)溶液中的化合物C105(18.3g)，立即升温至室温。搅拌2小时后，用硅藻土过滤反应混合物，蒸馏除去溶剂。用硅胶柱色谱法纯化残渣，得到化合物C106(11.2g)。
第四步：合成化合物C108
将化合物C106(8.7g)和化合物C107(6.1g)溶解在四氢呋喃(120ml)中后，在60℃下搅拌15小时。蒸馏除去反应混合物的溶剂后，加入水，用乙酸乙酯萃取。将有机层用饱和盐水洗涤后，用无水硫酸钠干燥，蒸馏除去溶剂。将残渣用硅胶柱色谱法纯化，得到化合物C108(7.2g)。
第五步：合成化合物C109
将化合物C108(6.2g)溶解在甲醇(200ml)和乙酸乙酯(40ml)中后，加入20％的Pearlman催化剂(Pd(OH)2/C)(6.5g、100wt％)，用氢气置换，在60℃下搅拌7.5小时。用硅藻土过滤反应混合物，通过蒸馏除去溶剂，得到化合物C109(3.8g)。
第六步：合成化合物C111
在室温下，向化合物C109(2.6g)的二氯甲烷(200ml)混悬液中加入化合物C110(2.2g)和乙酸铜(Ⅱ)(1.5g)、分子筛4A(2.6g)、吡啶(0.86ml)，然后搅拌21小时。用硅藻土过滤反应液，将残渣用硅胶柱纯化，得到化合物C111(1.2g)。
第七步：合成化合物C112
在室温下，向化合物C111(1.2g)的甲醇(12ml)混悬液中加入4N盐酸/二噁烷(12ml)，搅拌l小时。通过蒸馏除去溶剂，得到化合物C112的盐酸盐(1.0g)。
第八步：合成化合物C001
向化合物C112的盐酸盐(100mg)的二甲基甲酰胺(3ml)溶液中加入化合物C113(35mg)和1-乙基-3-(3-二甲氨基丙基)碳二亚胺·盐酸盐(EDC·HCl)(80mg)、1-羟基苯并三唑(HOBt)(63mg)、三乙胺(115μL)，然后在室温下搅拌3小时。向反应混合物中加入水，用乙酸乙酯萃取。将有机层用饱和碳酸氢钠水溶液、饱和盐水洗涤后，用无水硫酸钠干燥，蒸馏除去溶剂。将残渣通过薄层色谱(二氯甲烷：甲醇：28％氨水＝90:10:1)纯化，得到化合物C001(68mg)。化合物C001的核磁共振氢谱为：1H-NMR(CD3OD)δ8.4(1H),7.3-7.6(2H),7.0-7.3(2H),5.2-5.4(1H),4.2-4.4(1H),4.0-4.2(1H),3.7-3.9(1H),3.5-3.6(1H),2.6-2.8(1H),2.3-2.5(1H)。
实施例2：合成化合物C002
化合物C002的合成，按“实施例1：合成化合物C001”进行，只在第六步中，用化合物C201替换化合物C110。化合物C002的核磁共振氢谱为：1H-NMR(CD3OD)δ8.4(1H),7.3-7.6(4H),7.0-7.3(2H),5.2-5.4(1H),4.2-4.4(1H),4.0-4.2(1H),3.7-3.9(1H),3.5-3.6(1H),2.6-2.8(1H),2.3-2.5(1H)。
实施例3：合成化合物C003
化合物C003的合成，按“实施例1：合成化合物C001”进行，只在第六步中，用化合物C202替换化合物C110。化合物C003的核磁共振氢谱为：1H-NMR(CD3OD)δ8.4(1H),7.3-7.6(2H),7.0-7.3(4H),5.2-5.4(1H),4.2-4.4(1H),4.0-4.2(1H),3.7-3.9(1H),3.5-3.6(1H),2.6-2.8(1H),2.3-2.5(1H)。
实施例4：合成化合物C004
化合物C004的合成，按“实施例1：合成化合物C001”进行，只在第六步中，用化合物C203替换化合物C110。化合物C004的核磁共振氢谱为：1H-NMR(CD3OD)δ8.4(1H),7.3-7.6(4H),7.0-7.3(4H),5.2-5.4(1H),4.2-4.4(1H),4.0-4.2(1H),3.7-3.9(1H),3.5-3.6(1H),2.6-2.8(1H),2.3-2.5(1H)。
实施例5：合成化合物C005
化合物C005的合成，按“实施例1：合成化合物C001”进行，只在第六步中，用化合物C204替换化合物C110。化合物C005的核磁共振氢谱为：1H-NMR(CD3OD)δ8.4(1H),7.3-7.6(4H),7.0-7.3(5H),5.2-5.4(1H),4.2-4.4(1H),4.0-4.2(1H),3.7-3.9(1H),3.5-3.6(1H),2.6-2.8(1H),2.3-2.5(1H)。
实施例6：合成化合物C006
化合物C006的合成，按“实施例1：合成化合物C001”进行，只在第八步中，用化合物C205替换化合物C113。化合物C006的核磁共振氢谱为：1H-NMR(CD3OD)δ8.4(1H),7.3-7.6(2H),7.0-7.3(2H),5.2-5.4(1H),4.2-4.4(1H),4.0-4.2(1H),3.7-3.9(1H),3.5-3.6(1H),2.6-2.8(1H),2.3-2.5(1H),2.0(3H)。
实施例7：合成化合物C007
化合物C007的合成，按“实施例6：合成化合物C006”进行，只在第六步中，用化合物C201替换化合物C110。化合物C007的核磁共振氢谱为：1H-NMR(CD3OD)δ8.4(1H),7.3-7.6(4H),7.0-7.3(2H),5.2-5.4(1H),4.2-4.4(1H),4.0-4.2(1H),3.7-3.9(1H),3.5-3.6(1H),2.6-2.8(1H),2.3-2.5(1H),2.0(3H)。
实施例8：合成化合物C008
化合物C008的合成，按“实施例6：合成化合物C006”进行，只在第六步中，用化合物C202替换化合物C110。化合物C008的核磁共振氢谱为：1H-NMR(CD3OD)δ8.4(1H),7.3-7.6(2H),7.0-7.3(4H),5.2-5.4(1H),4.2-4.4(1H),4.0-4.2(1H),3.7-3.9(1H),3.5-3.6(1H),2.6-2.8(1H),2.3-2.5(1H),2.0(3H)。
实施例9：合成化合物C009
化合物C009的合成，按“实施例6：合成化合物C006”进行，只在第六步中，用化合物C203替换化合物C110。化合物C009的核磁共振氢谱为：1H-NMR(CD3OD)δ8.4(1H),7.3-7.6(4H),7.0-7.3(4H),5.2-5.4(1H),4.2-4.4(1H),4.0-4.2(1H),3.7-3.9(1H),3.5-3.6(1H),2.6-2.8(1H),2.3-2.5(1H),2.0(3H)。
实施例10：合成化合物C010
化合物C010的合成，按“实施例1：合成化合物C001”进行，只在第六步中，用化合物C206替换化合物C110。化合物C010的核磁共振氢谱为：1H-NMR(CD3OD)δ8.4(1H),7.3-7.6(2H),7.0-7.3(3H),5.2-5.4(1H),4.2-4.4(1H),4.0-4.2(1H),3.7-3.9(1H),3.5-3.6(1H),2.6-2.8(1H),2.3-2.5(1H)。
实施例11：合成化合物C011
化合物C011的合成，按“实施例1：合成化合物C001”进行，只在第六步中，用化合物C207替换化合物C110。化合物C011的核磁共振氢谱为：1H-NMR(CD3OD)δ8.4(1H),7.3-7.6(4H),7.0-7.3(3H),5.2-5.4(1H),4.2-4.4(1H),4.0-4.2(1H),3.7-3.9(1H),3.5-3.6(1H),2.6-2.8(1H),2.3-2.5(1H)。
实施例12：合成化合物C012
化合物C012的合成，按“实施例1：合成化合物C001”进行，只在第六步中，用化合物C208替换化合物C110。化合物C012的核磁共振氢谱为：1H-NMR(CD3OD)δ8.4(1H),7.3-7.6(2H),7.0-7.3(5H),5.2-5.4(1H),4.2-4.4(1H),4.0-4.2(1H),3.7-3.9(1H),3.5-3.6(1H),2.6-2.8(1H),2.3-2.5(1H)。
实施例13：合成化合物C013
化合物C013的合成，按“实施例6：合成化合物C006”进行，只在第六步中，用化合物C206替换化合物C110。化合物C013的核磁共振氢谱为：1H-NMR(CD3OD)δ8.4(1H),7.3-7.6(2H),7.0-7.3(3H),5.2-5.4(1H),4.2-4.4(1H),4.0-4.2(1H),3.7-3.9(1H),3.5-3.6(1H),2.6-2.8(1H),2.3-2.5(1H),2.0(3H)。
实施例14：合成化合物C014
化合物C014的合成，按“实施例6：合成化合物C006”进行，只在第六步中，用化合物C207替换化合物C110。化合物C014的核磁共振氢谱为：1H-NMR(CD3OD)δ8.4(1H),7.3-7.6(4H),7.0-7.3(3H),5.2-5.4(1H),4.2-4.4(1H),4.0-4.2(1H),3.7-3.9(1H),3.5-3.6(1H),2.6-2.8(1H),2.3-2.5(1H),2.0(3H)。
实施例15：合成化合物C015
化合物C015的合成，按“实施例6：合成化合物C006”进行，只在第六步中，用化合物C208替换化合物C110。化合物C015的核磁共振氢谱为：1H-NMR(CD3OD)δ8.4(1H),7.3-7.6(2H),7.0-7.3(5H),5.2-5.4(1H),4.2-4.4(1H),4.0-4.2(1H),3.7-3.9(1H),3.5-3.6(1H),2.6-2.8(1H),2.3-2.5(1H),2.0(3H)。
实施例16：合成化合物C110
第九步:合成化合物C702
取化合物C601(7.7g)，溶于无水四氢呋喃(80ml)中，搅拌，分批次缓慢加入氢化钠(7.9g)，再分批次加入1-溴-4-碘苯(化合物C701)(25.3g)，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C702(8.7g)
第十步:化合物C110的合成
将化合物C603(3.2g)溶解于干燥的THF(75ml)，N2保护下在-78℃反应30min，缓慢滴加正丁基锂(1.2g)，滴加结束后保持-78℃反应3h，再缓慢滴加硼酸三异丙酯(2.6g)，滴加结束后保持在-78℃反应2h，缓慢升至室温，反应15hr左右，用水缓慢淬灭反应液，萃取浓缩，得化合物C110(1.9g)。
实施例17：合成化合物C201
化合物C201的合成，按“实施例16：合成化合物C110”进行，只在第九步中，用化合物C602替换化合物C601。
实施例18：合成化合物C202
化合物C202的合成，按“实施例16：合成化合物C110”进行，只在第九步中，用化合物C603替换化合物C601。
实施例19：合成化合物C203
化合物C203的合成，按“实施例16：合成化合物C110”进行，只在第九步中，用化合物C604替换化合物C601。
实施例20：合成化合物C204
化合物C204的合成，按“实施例16：合成化合物C110”进行，只在第九步中，用化合物C605替换化合物C601。
实施例21：合成化合物C206
化合物C206的合成，按“实施例16：合成化合物C110”进行，只在第九步中，用化合物C606替换化合物C601。
实施例22：合成化合物C207
化合物C207的合成，按“实施例16：合成化合物C110”进行，只在第九步中，用化合物C607替换化合物C601。
实施例23：合成化合物C208
化合物C208的合成，按“实施例16：合成化合物C110”进行，只在第九步中，用化合物C608替换化合物C601。
实施例24：化合物C001、化合物C004、化合物C005和化合物C006在大鼠体内的药代动 力学
30只雄性Sprague-Dawley大鼠，6-9周龄，体重约220g，分成5组(替拉鲁替尼组、化合物C001组、化合物C004组、化合物C005组和化合物C006组)，每组6只。按照分组分别单次灌胃给予10mg/kg剂量的替拉鲁替尼、化合物C001、化合物C004、化合物C005和化合物C006，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，与替拉鲁替尼相比，化合物C001、化合物C004、化合物C005和化合物C006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，与替拉鲁替尼相比，本发明化合物C001、化合物C004、化合物C005和/或化合物C006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：化合物C007、化合物C009和化合物C012在大鼠体内的药代动力学
24只雄性Sprague-Dawley大鼠，6-9周龄，体重约220g，分成4组(替拉鲁替尼组、化合物C007组、化合物C009组、化合物C012组)，每组6只。按照分组分别单次灌胃给予10mg/kg剂量的替拉鲁替尼、化合物C007、化合物C009和化合物C012，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，与替拉鲁替尼相比，化合物C007、化合物C009和化合物C012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35％以上。
由本结果可知，与替拉鲁替尼相比，本发明化合物C007、化合物C009和/或化合物C012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26：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(pH7.5)、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。
本发明的化合物的IC50值见下表：
由本结果可知，本发明的化合物对BTK具有明显的抑制效应。
实施例27：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+替拉鲁替尼组。模型+实施例化合物组按剂量(60mg/kg)每天灌胃给药一次实施例化合物；模型+替拉鲁替尼组按剂量(60mg/kg)每天灌胃给药一次替拉鲁替尼，分别连续14天，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+替拉鲁替尼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+替拉鲁替尼组的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(60mg/kg)对APAP引起的脂质过氧化没有明显影响，而替拉鲁替尼(60mg/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显著小于替拉鲁替尼。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2.5-3.7；A-为1.3-2.4；A++为3.9-5.8；B+为27-39；B-为39-60；B++为14-25。
结论：本申请实施例化合物(60mg/kg)对APAP引起的脂质过氧化没有明显影响，而替拉鲁替尼(60mg/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显著小于替拉鲁替尼。
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. 一种式Ⅰ的嘌呤衍生物、其光学异构体或它们的混合物、其盐或其N-氧化物：
    其中：
    R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13或R14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或R14中至少一个是氘。
  2. [根据细则91更正 13.11.2023]
    如权利要求1所述的嘌呤衍生物、其光学异构体或它们的混合物、其盐或其N-氧化物，其特征在于所述嘌呤衍生物选自以下结构：

  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，其光学异构体或它们的混合物、其盐或其N-氧化物。
  4. 权利要求1-2中任一项的嘌呤衍生物、其光学异构体或它们的混合物、其盐或其N-氧化物在制备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相关的病症的药物的用途，其中所述BTK相关的病症选自：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相关的病症是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/CN2023/131135 2022-11-14 2023-11-11 作为btk抑制剂的嘌呤衍生物 WO2024104277A1 (zh)

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* Cited by examiner, † Cited by third party
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CN102918040A (zh) * 2010-05-31 2013-02-06 小野药品工业株式会社 6-羟基嘌呤衍生物
WO2016087994A1 (en) * 2014-12-05 2016-06-09 Acerta Pharma B.V. Btk inhibitors to treat solid tumors through modulation of the tumor microenvironment
CN113527300A (zh) * 2020-06-04 2021-10-22 广州百霆医药科技有限公司 布鲁顿酪氨酸蛋白激酶抑制剂
US20220000879A1 (en) * 2020-07-06 2022-01-06 Masarykova Univerzita Inhibitors for Treatment of Hematological Malignancies
WO2022212893A1 (en) * 2021-04-02 2022-10-06 Biogen Ma Inc. Combination treatment methods of multiple sclerosis

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102918040A (zh) * 2010-05-31 2013-02-06 小野药品工业株式会社 6-羟基嘌呤衍生物
WO2016087994A1 (en) * 2014-12-05 2016-06-09 Acerta Pharma B.V. Btk inhibitors to treat solid tumors through modulation of the tumor microenvironment
CN113527300A (zh) * 2020-06-04 2021-10-22 广州百霆医药科技有限公司 布鲁顿酪氨酸蛋白激酶抑制剂
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