WO2024099242A1 - Deuterated aminopyridine derivative and pharmaceutical composition comprising said compound - Google Patents
Deuterated aminopyridine derivative and pharmaceutical composition comprising said compound Download PDFInfo
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- 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
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Classifications
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- 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
Provided are a deuterated aminopyridine derivative as represented by formula I, an optical isomer or mixture thereof, a polymorph thereof, a salt thereof, or a hydrate or solvate thereof; further provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the deuterated aminopyridine derivative, the optical isomer or mixture thereof, the polymorph thereof, the salt thereof, or the hydrate or solvate thereof. The compound represented by general formula I serves as a BTK inhibitor, is a prophylactic and/or therapeutic agent for BTK-related diseases, has low hepatic toxicity, and has a good therapeutic effect on allergic diseases, autoimmune diseases, inflammatory diseases, thromboembolic diseases, or cancers.
Description
本发明属于生物医药领域，具体涉及氘代的氨基吡啶衍生物以及包含该化合物的药物组合物。The invention belongs to the field of biomedicine, and in particular relates to deuterated aminopyridine derivatives and a pharmaceutical composition containing the compound.
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。BTK在***反应性疾病和/或自身免疫疾病和/或炎性疾病中起作用的证据已经在BTK缺陷小鼠模型中得到确定。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. Evidence that BTK plays a role in allergic diseases and/or autoimmune diseases and/or inflammatory diseases has been determined in BTK-deficient mouse models.
由于BTK在B细胞活化中的作用，BTK抑制剂可以被用作B细胞介导的致病性活动(例如产生自身抗体)的抑制剂。BTK也在破骨细胞、肥大细胞和单核细胞中表达，并且显示其对于这些细胞的功能很重要。Due to the role of BTK in B cell activation, 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.
因此，抑制BTK活性可以用于治疗***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)。Therefore, 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).
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.Targets12:883-903，2008；Uckun等人，Anti-cancer Agents Med.Chem.7:624-632,2007；Lou等人，J.Med.Chem.55(10):4539-4550，2012)。In addition, aberrant activation of BTK plays an important role in the pathogenesis of B-cell lymphoma, which means that inhibition of BTK is useful in the treatment of hematological malignancies (Davis et al., Nature 463:88-92, 2010). Since 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. Targets 12:883-903, 2008; Uckun et al., Anti-cancer Agents Med. Chem. 7:624-632, 2007; Lou et al., J. Med. Chem. 55(10):4539-4550, 2012).
而且，考虑到BTK在破骨细胞功能方面的作用，抑制BTK活性可用于治疗骨病，例如，骨质疏松。因此，具有BTK抑制活性的化合物对与B细胞和/或肥大细胞有关的疾病，例如，***
反应性疾病、自身免疫疾病和、炎性疾病、血栓栓塞性疾病、癌症等的治疗是有用的(Uckun等人(2007)Anticancer Agents in Medicinal Chemistry.7(6):624-632)。Furthermore, considering the role of BTK in osteoclast function, 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)是一种有效的，选择性，具有口服活性和可透过血脑屏障的布鲁顿氏酪氨酸激酶(BTK)抑制剂，是一种研究性脑渗透性布鲁顿酪氨酸激酶(BTK)抑制剂，是首个完成BTK抑制剂治疗多发性硬化症(MS)概念性验证研究的药物，可产生靶向小胶质细胞和B淋巴细胞所需的脑脊液(CSF)浓度，正在针对多发性硬化症(MS)和重症肌无力(MG)进行临床III期试验。但Tolebrutinib在患者中出现了药物性肝损伤病例，美国FDA暂停了其部分临床试验。改善Tolebrutinib的药物代谢动力学行为，如Tolebrutinib的吸收和/或分布和/或代谢和/或***，可能是减小Tolebrutinib的毒性的一种有效方式。Tolebrutinib的人体消除半衰期T1/2在1.39-2.18小时之间，消除很快(Owens TD等人.ClinTransl Sci.2022；15:442–450)。提示需要较大的剂量才能维持较好的治疗效果，但这也不可避免地带来了更大的毒性风险。另外，Tolebrutinib的半衰期短，消除很快，也在一定程度上预示了Tolebrutinib的代谢可能较快，而产生的这些代谢物可能也增加了毒性风险。目前一些药物的不太好的吸收、分布、代谢和/或***(ADME)性能，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。快速代谢的药物也可能使患者暴露于不期望的毒性或反应性代谢物中。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). However, cases of drug-induced liver injury have occurred in patients with Tolebrutinib, and the US FDA has suspended some of its clinical trials. Improving the pharmacokinetic behavior of Tolebrutinib, such as the absorption and/or distribution and/or metabolism and/or excretion of Tolebrutinib, may be an effective way to reduce the toxicity of Tolebrutinib. The human elimination half-life T 1/2 of Tolebrutinib is between 1.39-2.18 hours, and it is eliminated very quickly (Owens TD et al. Clin Transl Sci. 2022; 15: 442–450). This suggests that a larger dose is needed to maintain a better therapeutic effect, but this also inevitably brings a greater risk of toxicity. In addition, 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. For example, due to the short elimination half-life of drugs in the body and rapid clearance, the solution often used is to administer drugs frequently or in high doses to obtain sufficiently high plasma levels of drugs. However, 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.
影响药物的另外的ADME限制是毒性或生物学反应性代谢物的形成。因此，接受药物的一些患者可能经历毒性，或者可以限制这样的药物的安全剂量使得患者接受并非最佳量(最适度以下的，suboptimal)的治疗。在某些情况下，改变服药间隔或制剂方法可以有助于减少临床不良反应，但是经常形成这样的不期望的代谢物是化合物代谢所固有的。Another 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.
用于改进药物代谢性能的一种潜在的具有吸引力的策略是氘修饰(改性)。在这种方法中，人们尝试减缓药物的代谢，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。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正面地影响药物的ADME性能，具有改进药效、安全性、和/或耐受性的潜力。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。
A potential attractive strategy for improving drug metabolism performance is deuterium modification (modification). In this method, 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. Meanwhile, 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.
但是，由于生物***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"))。However, due to the complex metabolic process of biological systems, the pharmacokinetic properties of drugs in vivo are affected by many factors and also show corresponding complexity. Compared with the corresponding non-deuterated drugs, the changes in the pharmacokinetic properties of deuterated drugs show great randomness and unpredictability. For some compounds, 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")).
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。Therefore, 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. On the other hand, hydrogen at certain positions on the drug molecule is not easily substituted by deuterium due to steric hindrance and other reasons.
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)。Even when deuterium atoms are incorporated into known metabolic sites, 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).
另外，氘代可导致代谢转换(metabolic switching)，代谢转换的概念表明，当药物被I相代谢酶包裹时，其可在化学反应(例如氧化反应)之前短暂地以各种构象与I相代谢酶结合与重新结合。故代谢转换可潜在地导致不同比例的已知代谢物以及新的代谢物。这种新的代谢性质可引起更多或更少的毒性。并导致更快或更慢的药物清除率，从而减少或增加药物的体内暴露量。代谢转换导致的这种改变是不可预测的，并且迄今还没有对任何药物做到充分的先验性预测。In addition, deuteration can lead to metabolic switching. The concept of 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.
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。Tolebrutinib及其体内代谢产物具有肝毒性风险的缺陷，且Tolebrutinib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。As mentioned above, the effect of deuterium modification on drug metabolism is unpredictable. 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.
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，或减少毒性代谢物的生成，从而达到减毒增效的目的。Therefore, in response to the shortcomings of existing technologies, we design new compounds to increase the exposure of new compounds in the body, reduce the dosage and/or frequency of administration, and reduce liver toxicity; and/or through structural modification, reduce the liver toxicity of its prototype or metabolites, or reduce the generation of toxic metabolites, so as to achieve the purpose of reducing toxicity and increasing efficacy.
发明内容
Summary of the invention
本发明的目的是提供一类新型的具有BTK抑制活性和更好药效学性能的化合物及其用途。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.
在本发明的第一方面，提供了一种式Ⅰ所示的氘代的氨基吡啶衍生物、其光学异构体或其混合物、其晶型、其盐、其水合物或溶剂合物。
In the first aspect of the present invention, there is provided a deuterated aminopyridine derivative represented by formula I, its optical isomers or mixtures thereof, its crystal forms, its salts, its hydrates or solvates.
In the first aspect of the present invention, there is provided a deuterated aminopyridine derivative represented by formula I, its optical isomers or mixtures thereof, its crystal forms, its salts, its hydrates or solvates.
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。wherein: 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.
在一个优选例中，所述化合物是选自下组的优选化合物：
In a preferred embodiment, the compound is a preferred compound selected from the following group:
In a preferred embodiment, the compound is a preferred compound selected from the following group:
在另一个优选例中，所述化合物是选自下组的优选化合物：
In another preferred embodiment, the compound is a preferred compound selected from the following group:
In another preferred embodiment, the compound is a preferred compound selected from the following group:
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，其光学异构体或其混合物、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。In the second aspect of the present invention, a method for preparing a pharmaceutical composition is provided, 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.
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，其光学异构体或其混合物、其晶型、其盐、其水合物或溶剂合物。在另一优选例中，所述的药物组合物为胶囊剂、片剂、注射剂、丸剂、散剂或颗粒剂。In the third aspect of the present invention, a pharmaceutical composition is provided, 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. In another preferred embodiment, the pharmaceutical composition is a capsule, tablet, injection, pill, powder or granule.
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，其光学异构体或其混合物、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。In the fourth aspect of the present invention, there is provided the use of 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, which is used to prepare a pharmaceutical composition for inhibiting BTK. In another preferred embodiment, the pharmaceutical composition is used to prevent and/or treat diseases related to BTK.
在另一优选例中，所述的药物组合物用于预防和/或治疗***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。In another preferred embodiment, the pharmaceutical composition is used to prevent and/or treat allergic diseases, autoimmune diseases, inflammatory diseases, thromboembolic diseases or cancer.
在另一优选例中，所述的药物组合物用于治疗自身免疫性疾病，包括多发性硬化症(MS)、重症肌无力(MG)、慢性自发性荨麻疹、视神经脊髓炎、***性红斑狼疮(SLE)、或类风湿性关节炎(RA)。In another preferred embodiment, 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).
在另一优选例中，所述的药物组合物用于治疗癌症包括(但并不限于)：淋巴瘤、白血病、非小型细胞肺癌、子宫癌、直肠癌、脑癌、头癌、颈癌、膀胱癌、***癌、乳腺癌、肾癌、
肝癌、胃癌、或胰腺癌。In another preferred embodiment, 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.
在本发明的第五方面，提供了一种治疗方法，它包括步骤：给需要治疗的对象施用本发明第一方面中所述的化合物，其光学异构体或其混合物、其晶型、其盐、其水合物或溶剂合物，或施用本发明第三方面中所述的药物组合物，从而抑制BTK。In the fifth aspect of the present invention, a treatment method is provided, 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.
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。As used herein, "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.
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％。In another preferred embodiment, 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%.
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。In another preferred embodiment, the compound of formula I contains at least 1 or 3 deuterium atoms, more preferably 5 or 8 deuterium atoms.
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化合物的光学异构体或其混合物、晶型、其盐、其水合物或溶剂合物。As used herein, 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.
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。As used herein, 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.
本发明的积极进步效果在于：The positive and progressive effects of the present invention are:
(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。(1) The compounds of the present invention have good selective BTK inhibitory effects and can be effectively used for treating diseases associated with BTK.
(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。(2) The compound of the present invention has good selectivity in inhibiting B cell activation and is effectively used as a B cell activation inhibitor.
(3)本发明氘代的氨基吡啶衍生物肝毒性小，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。(3) 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.
具体的实施方法Specific implementation methods
下面结合具体实施例，进一步阐述本发明。应理解，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。The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer.
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。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.
本发明使用的未氘代的嘧啶衍生物及其生理上相容的盐的制备方法是已知的。对应氘代的嘧啶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。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.
实施例1：化合物T109的合成Example 1: Synthesis of Compound T109
合成路线
synthetic route
synthetic route
步骤1：化合物T003的合成
Step 1: Synthesis of compound T003
Step 1: Synthesis of compound T003
向N,N-二甲基甲酰胺(50ml)中加入2,4-二氯-3-硝基吡啶(41.5mmol)、叔丁基(R)-3-氨基哌啶-1-羧酸酯(41.4mmo1)和TEA(62.2mmol)，将所得反应混合物在25℃下搅拌过夜。用水稀释反应混合物，用乙酸乙酯萃取，并合并有机层，用饱和氯化钠洗涤，并用无水硫酸钠进行干燥并浓缩。用硅胶柱纯化，洗脱液为乙酸乙酯/石油醚(1:1)，去除溶剂，得到黄色油状的化合物T003。2,4-dichloro-3-nitropyridine (41.5mmol), tert-butyl (R)-3-aminopiperidine-1-carboxylate (41.4mmol) and TEA (62.2mmol) were added to N,N-dimethylformamide (50ml), and the resulting reaction mixture was stirred overnight at 25°C. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic layers were combined, washed with saturated sodium chloride, dried with anhydrous sodium sulfate and concentrated. Purification was performed on a silica gel column with ethyl acetate/petroleum ether (1:1) as the eluent, and the solvent was removed to obtain compound T003 as a yellow oil.
步骤2：化合物T005的合成
Step 2: Synthesis of compound T005
Step 2: Synthesis of compound T005
向异丙醇(100ml)中加入化合物T003(22.4mmol)、双[(4-甲氧苯基)甲基]胺(化合物T004)(22.4mmol)和TEA(29.5mmol)，将所得反应混合物在95℃下搅拌过夜，冷却并真空浓缩，得黄色油状的化合物T005。Compound T003 (22.4 mmol), bis[(4-methoxyphenyl)methyl]amine (compound T004) (22.4 mmol) and TEA (29.5 mmol) were added to isopropanol (100 ml), and the resulting reaction mixture was stirred at 95° C. overnight, cooled and concentrated in vacuo to obtain compound T005 as a yellow oil.
步骤3：化合物T006的合成
Step 3: Synthesis of compound T006
Step 3: Synthesis of compound T006
向AcOH/MeOH(1:1,100mL)的溶液中，加入化合物T005(17.3mmol)和Fe(173.1mmol)，将反应混合物在25℃下搅拌过夜，并随后真空浓缩，用碳酸氢钠将残留溶液的pH值调节到8.0-9.0。用二氯甲烷萃取所得溶液，并用碳酸氢钠洗涤有机层，用无水硫酸钠干燥，真空浓缩，得黄色油状的化合物T006。Compound T005 (17.3 mmol) and Fe (173.1 mmol) were added to a solution of AcOH/MeOH (1:1, 100 mL), the reaction mixture was stirred overnight at 25°C, and then concentrated in vacuo, and the pH value of the residual solution was adjusted to 8.0-9.0 with sodium bicarbonate. The resulting solution was extracted with dichloromethane, and the organic layer was washed with sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain compound T006 as a yellow oil.
步骤4：化合物T007的合成
Step 4: Synthesis of compound T007
Step 4: Synthesis of compound T007
向CH3CN(100ml)中，加入化合物T006(20.2mmol)和CDI(30.1mmol)，将反应混合物在80℃下搅拌过夜。冷却并浓缩反应混合物。用硅胶柱纯化，洗脱液为乙酸乙酯/石油醚(1:5)，去
除溶剂，得化合物T007。Compound T006 (20.2 mmol) and CDI (30.1 mmol) were added to CH 3 CN (100 ml), and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was cooled and concentrated. Purification was performed on a silica gel column with ethyl acetate/petroleum ether (1:5) as the eluent to remove The solvent was removed to obtain compound T007.
步骤5：化合物T009的合成
Step 5: Synthesis of compound T009
Step 5: Synthesis of compound T009
向二氯甲烷(100ml)中，加入化合物T007(17.5mmol)、五氘代(4-苯氧苯基)硼酸(化合物T008)(35.1mmol)、TEMPO(19.5mmol)和TEA(69.5mmol)、Cu(OAc)2(8.9mmol)。在氧气氛围环境压力下将反应混合物在25℃下搅拌过夜。再添加五氘代(4-苯氧苯基)硼酸(化合物T008)(35.1mmol)，并使反应混合物在25℃下反应过夜。用硅胶柱纯化，洗脱液为乙酸乙酯/石油醚(1:3)，去除溶剂，得化合物T009。Compound T007 (17.5 mmol), penta-deuterated (4-phenoxyphenyl) boronic acid (compound T008) (35.1 mmol), TEMPO (19.5 mmol) and TEA (69.5 mmol), Cu(OAc) 2 (8.9 mmol) were added to dichloromethane (100 ml). The reaction mixture was stirred at 25° C. overnight under an oxygen atmosphere. Penta-deuterated (4-phenoxyphenyl) boronic acid (compound T008) (35.1 mmol) was added, and the reaction mixture was reacted at 25° C. overnight. The mixture was purified by silica gel column with ethyl acetate/petroleum ether (1:3) as the eluent, and the solvent was removed to obtain compound T009.
步骤6：化合物T010的合成
Step 6: Synthesis of compound T010
Step 6: Synthesis of compound T010
向二氯甲烷(80ml)中，加入化合物T009(6.1mmol)和三氟乙酸(80ml)。将所得反应混合物在50℃下搅拌5小时，真空浓缩，用碳酸氢钠将残留溶液的pH值调节到9，用二氯甲烷萃取所得溶液，并合并有机层，用无水硫酸钠干燥。用硅胶柱纯化，洗脱液为二氯甲烷/甲醇(30:1)，去除溶剂，得化合物T010。Compound T009 (6.1 mmol) and trifluoroacetic acid (80 ml) were added to dichloromethane (80 ml). The resulting reaction mixture was stirred at 50°C for 5 hours, concentrated in vacuo, and the pH value of the residual solution was adjusted to 9 with sodium bicarbonate. The resulting solution was extracted with dichloromethane, and the organic layers were combined and dried over anhydrous sodium sulfate. The mixture was purified by silica gel column with dichloromethane/methanol (30:1) as the eluent, and the solvent was removed to obtain compound T010.
步骤7：化合物T109的合成
Step 7: Synthesis of compound T109
Step 7: Synthesis of compound T109
向DCM-CH3OH(1:1，6ml)中，加入化合物T010(150mg,0.37mmol,1.00当量)、TEA(113mg,1.12mmol,3.00当量)。然后在0℃下在5分钟内在搅拌下逐滴添加三氘代丙-2-烯酰氯(化合物T011)(40.1mg,0.44mmol,1.20当量)。将所得溶液在0℃下搅拌2小时，真空浓缩。将残留物用硅胶柱纯化，洗脱液二氯甲烷/甲醇(30:1)，去除溶剂，得粗品。粗品用制备性C18色谱柱纯化，流动相为0.05％TFA和ACN，梯度洗脱。得化合物T109。化合物T109的核磁共振氢谱为：1H-NMR(DMSO-d6)δ7.8(1H),7.4-7.5(2H),7.1-7.3(2H),7.0(1H),5.0(2H),4.5(1H),4.2(2H),3.8(0.5H),3.2(1H),2.7(0.5H),2.4(1H),1.9(2H),1.6(1H)。Compound T010 (150 mg, 0.37 mmol, 1.00 equivalent) and TEA (113 mg, 1.12 mmol, 3.00 equivalent) were added to DCM-CH 3 OH (1:1, 6 ml). Trideuterated prop-2-enoyl chloride (compound T011) (40.1 mg, 0.44 mmol, 1.20 equivalent) was then added dropwise at 0°C with stirring within 5 minutes. The resulting solution was stirred at 0°C for 2 hours and concentrated in vacuo. The residue was purified by silica gel column with dichloromethane/methanol (30:1) as eluent, and the solvent was removed to obtain a crude product. The crude product was purified by preparative C 18 column with 0.05% TFA and ACN as mobile phase, gradient elution to obtain compound T109. The hydrogen nuclear magnetic resonance spectrum of compound T109 is: 1 H-NMR (DMSO-d 6 )δ7.8(1H),7.4-7.5(2H),7.1-7.3(2H),7.0(1H),5.0(2H),4.5(1H),4.2(2H),3.8(0.5H),3.2(1H),2.7(0.5H),2.4(1H),1.9(2H),1.6(1H).
实施例2：化合物T108的合成Example 2: Synthesis of Compound T108
化合物T108的合成，将“实施例1：化合物T109的合成”中步骤5的化合物T008改为化合物T201。其余步骤同“实施例1：化合物T109的合成”操作，得化合物T108。化合物T108的核磁共振氢谱为：1H-NMR(DMSO-d6)δ7.8(1H),7.4-7.5(2H),7.1-7.3(4H),7.0(1H),5.0(2H),4.5(1H),4.2(2H),3.8(0.5H),3.2(1H),2.7(0.5H),2.4(1H),1.9(2H),1.6(1H)。
For the synthesis of compound T108, the compound T008 in step 5 of "Example 1: Synthesis of compound T109" was replaced with compound T201. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound T109" to obtain compound T108. The hydrogen nuclear magnetic resonance spectrum of compound T108 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (2H), 7.1-7.3 (4H), 7.0 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
For the synthesis of compound T108, the compound T008 in step 5 of "Example 1: Synthesis of compound T109" was replaced with compound T201. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound T109" to obtain compound T108. The hydrogen nuclear magnetic resonance spectrum of compound T108 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (2H), 7.1-7.3 (4H), 7.0 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
实施例3：化合物T107的合成Example 3: Synthesis of Compound T107
化合物T107的合成，将“实施例1：化合物T109的合成”中步骤5的化合物T008改为化合物T202。其余步骤同“实施例1：化合物T109的合成”操作，得化合物T107。化合物T107的核磁共振氢谱为：1H-NMR(DMSO-d6)δ7.8(1H),7.4-7.5(4H),7.1-7.3(2H),7.0(1H),5.0(2H),4.5(1H),4.2(2H),3.8(0.5H),3.2(1H),2.7(0.5H),2.4(1H),1.9(2H),1.6(1H)。
For the synthesis of compound T107, the compound T008 in step 5 of "Example 1: Synthesis of compound T109" was replaced with compound T202. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound T109" to obtain compound T107. The hydrogen nuclear magnetic resonance spectrum of compound T107 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (4H), 7.1-7.3 (2H), 7.0 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
For the synthesis of compound T107, the compound T008 in step 5 of "Example 1: Synthesis of compound T109" was replaced with compound T202. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound T109" to obtain compound T107. The hydrogen nuclear magnetic resonance spectrum of compound T107 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (4H), 7.1-7.3 (2H), 7.0 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
实施例4：化合物T106的合成Example 4: Synthesis of Compound T106
化合物T106的合成，将“实施例1：化合物T109的合成”中步骤5的化合物T008改为化合物T203。其余步骤同“实施例1：化合物T109的合成”操作，得化合物T106。化合物T106的核磁共振氢谱为：1H-NMR(DMSO-d6)δ7.8(1H),7.4-7.5(4H),7.1-7.3(4H),7.0(1H),5.0(2H),4.5(1H),4.2(2H),3.8(0.5H),3.2(1H),2.7(0.5H),2.4(1H),1.9(2H),1.6(1H)。
For the synthesis of compound T106, the compound T008 in step 5 of "Example 1: Synthesis of compound T109" was replaced with compound T203. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound T109" to obtain compound T106. The hydrogen nuclear magnetic resonance spectrum of compound T106 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (4H), 7.1-7.3 (4H), 7.0 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
For the synthesis of compound T106, the compound T008 in step 5 of "Example 1: Synthesis of compound T109" was replaced with compound T203. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound T109" to obtain compound T106. The hydrogen nuclear magnetic resonance spectrum of compound T106 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (4H), 7.1-7.3 (4H), 7.0 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
实施例5：化合物T105的合成Example 5: Synthesis of Compound T105
化合物T105的合成，将“实施例1：化合物T109的合成”中步骤5的化合物T008改为化合物T204。其余步骤同“实施例1：化合物T109的合成”操作，得化合物T105。化合物T105的核磁共振氢谱为：1H-NMR(DMSO-d6)δ7.8(1H),7.4-7.5(4H),7.1-7.3(5H),7.0(1H),5.0(2H),4.5(1H),4.2(2H),3.8(0.5H),3.2(1H),2.7(0.5H),2.4(1H),1.9(2H),1.6(1H)。
For the synthesis of compound T105, the compound T008 in step 5 of "Example 1: Synthesis of compound T109" was replaced with compound T204. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound T109" to obtain compound T105. The hydrogen nuclear magnetic resonance spectrum of compound T105 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (4H), 7.1-7.3 (5H), 7.0 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
For the synthesis of compound T105, the compound T008 in step 5 of "Example 1: Synthesis of compound T109" was replaced with compound T204. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound T109" to obtain compound T105. The hydrogen nuclear magnetic resonance spectrum of compound T105 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (4H), 7.1-7.3 (5H), 7.0 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
实施例6：化合物T104的合成Example 6: Synthesis of Compound T104
化合物T104的合成，将“实施例1：化合物T109的合成”中步骤7的化合物T011改为化合物T205。其余步骤同“实施例1：化合物T109的合成”操作，得化合物T104。化合物T104的核磁共振氢谱为：1H-NMR(DMSO-d6)δ7.8(1H),7.4-7.5(2H),7.1-7.3(2H),7.0(1H),6.8(1H),6.1(1H),5.7(1H),5.0(2H),4.5(1H),4.2(2H),3.8(0.5H),3.2(1H),2.7(0.5H),2.4(1H),1.9(2H),1.6(1H)。
For the synthesis of compound T104, the compound T011 in step 7 of "Example 1: Synthesis of compound T109" was replaced with compound T205. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound T109" to obtain compound T104. The hydrogen nuclear magnetic resonance spectrum of compound T104 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (2H), 7.1-7.3 (2H), 7.0 (1H), 6.8 (1H), 6.1 (1H), 5.7 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
For the synthesis of compound T104, the compound T011 in step 7 of "Example 1: Synthesis of compound T109" was replaced with compound T205. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound T109" to obtain compound T104. The hydrogen nuclear magnetic resonance spectrum of compound T104 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (2H), 7.1-7.3 (2H), 7.0 (1H), 6.8 (1H), 6.1 (1H), 5.7 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
实施例7：化合物T103的合成Example 7: Synthesis of Compound T103
化合物T103的合成，将“实施例6：化合物T104的合成”中步骤5的化合物T008改为化合物T201。其余步骤同“实施例6：化合物T104的合成”操作，得化合物T103。化合物T103的核磁共振氢谱为：1H-NMR(DMSO-d6)δ7.8(1H),7.4-7.5(2H),7.1-7.3(4H),7.0(1H),6.8(1H),6.1(1H),5.7(1H),5.0(2H),4.5(1H),4.2(2H),3.8(0.5H),3.2(1H),2.7(0.5H),2.4(1H),1.9(2H),1.6(1H)
For the synthesis of compound T103, the compound T008 in step 5 of "Example 6: Synthesis of compound T104" was replaced with compound T201. The remaining steps were performed in the same manner as in "Example 6: Synthesis of compound T104" to obtain compound T103. The hydrogen nuclear magnetic resonance spectrum of compound T103 was: 1 H-NMR (DMSO-d 6 ) δ 7.8 (1H), 7.4-7.5 (2H), 7.1-7.3 (4H), 7.0 (1H), 6.8 (1H), 6.1 (1H), 5.7 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H)
For the synthesis of compound T103, the compound T008 in step 5 of "Example 6: Synthesis of compound T104" was replaced with compound T201. The remaining steps were performed in the same manner as in "Example 6: Synthesis of compound T104" to obtain compound T103. The hydrogen nuclear magnetic resonance spectrum of compound T103 was: 1 H-NMR (DMSO-d 6 ) δ 7.8 (1H), 7.4-7.5 (2H), 7.1-7.3 (4H), 7.0 (1H), 6.8 (1H), 6.1 (1H), 5.7 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H)
实施例8：化合物T102的合成Example 8: Synthesis of Compound T102
化合物T102的合成，将“实施例6：化合物T104的合成”中步骤5的化合物T008改为化合物T202。其余步骤同“实施例6：化合物T104的合成”操作，得化合物T102。化合物T102的核磁共振氢谱为：1H-NMR(DMSO-d6)δ7.8(1H),7.4-7.5(4H),7.1-7.3(2H),7.0(1H),6.8(1H),6.1(1H),5.7(1H),5.0(2H),4.5(1H),4.2(2H),3.8(0.5H),3.2(1H),
2.7(0.5H),2.4(1H),1.9(2H),1.6(1H)。
The synthesis of compound T102, the compound T008 in step 5 of "Example 6: Synthesis of compound T104" was replaced with compound T202. The remaining steps were the same as those in "Example 6: Synthesis of compound T104" to obtain compound T102. The hydrogen nuclear magnetic resonance spectrum of compound T102 is: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (4H), 7.1-7.3 (2H), 7.0 (1H), 6.8 (1H), 6.1 (1H), 5.7 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7(0.5H),2.4(1H),1.9(2H),1.6(1H).
The synthesis of compound T102, the compound T008 in step 5 of "Example 6: Synthesis of compound T104" was replaced with compound T202. The remaining steps were the same as those in "Example 6: Synthesis of compound T104" to obtain compound T102. The hydrogen nuclear magnetic resonance spectrum of compound T102 is: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (4H), 7.1-7.3 (2H), 7.0 (1H), 6.8 (1H), 6.1 (1H), 5.7 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7(0.5H),2.4(1H),1.9(2H),1.6(1H).
实施例9：化合物T101的合成Example 9: Synthesis of Compound T101
化合物T101的合成，将“实施例6：化合物T104的合成”中步骤5的化合物T008改为化合物T203。其余步骤同“实施例6：化合物T104的合成”操作，得化合物T101。化合物T101的核磁共振氢谱为：1H-NMR(DMSO-d6)δ7.8(1H),7.4-7.5(4H),7.1-7.3(4H),7.0(1H),6.8(1H),6.1(1H),5.7(1H),5.0(2H),4.5(1H),4.2(2H),3.8(0.5H),3.2(1H),2.7(0.5H),2.4(1H),1.9(2H),1.6(1H)。
For the synthesis of compound T101, the compound T008 in step 5 of "Example 6: Synthesis of compound T104" was replaced with compound T203. The remaining steps were performed in the same manner as in "Example 6: Synthesis of compound T104" to obtain compound T101. The hydrogen nuclear magnetic resonance spectrum of compound T101 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (4H), 7.1-7.3 (4H), 7.0 (1H), 6.8 (1H), 6.1 (1H), 5.7 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
For the synthesis of compound T101, the compound T008 in step 5 of "Example 6: Synthesis of compound T104" was replaced with compound T203. The remaining steps were performed in the same manner as in "Example 6: Synthesis of compound T104" to obtain compound T101. The hydrogen nuclear magnetic resonance spectrum of compound T101 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (4H), 7.1-7.3 (4H), 7.0 (1H), 6.8 (1H), 6.1 (1H), 5.7 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
实施例10：化合物T113的合成Example 10: Synthesis of Compound T113
化合物T113的合成，将“实施例6：化合物T104的合成”中步骤5的化合物T008改为化合物T206。其余步骤同“实施例6：化合物T104的合成”操作，得化合物T113。化合物T113的核磁共振氢谱为：1H-NMR(DMSO-d6)δ7.8(1H),7.4-7.5(2H),7.1-7.3(3H),7.0(1H),6.8(1H),6.1(1H),5.7(1H),5.0(2H),4.5(1H),4.2(2H),3.8(0.5H),3.2(1H),2.7(0.5H),2.4(1H),1.9(2H),1.6(1H)。
For the synthesis of compound T113, the compound T008 in step 5 of "Example 6: Synthesis of compound T104" was replaced with compound T206. The remaining steps were performed in the same manner as in "Example 6: Synthesis of compound T104" to obtain compound T113. The hydrogen nuclear magnetic resonance spectrum of compound T113 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (2H), 7.1-7.3 (3H), 7.0 (1H), 6.8 (1H), 6.1 (1H), 5.7 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
For the synthesis of compound T113, the compound T008 in step 5 of "Example 6: Synthesis of compound T104" was replaced with compound T206. The remaining steps were performed in the same manner as in "Example 6: Synthesis of compound T104" to obtain compound T113. The hydrogen nuclear magnetic resonance spectrum of compound T113 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (2H), 7.1-7.3 (3H), 7.0 (1H), 6.8 (1H), 6.1 (1H), 5.7 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
实施例11：化合物T114的合成Example 11: Synthesis of Compound T114
化合物T114的合成，将“实施例6：化合物T104的合成”中步骤5的化合物T008改为化合物T207。其余步骤同“实施例6：化合物T104的合成”操作，得化合物T114。化合物T114的核磁共振氢谱为：1H-NMR(DMSO-d6)δ7.8(1H),7.4-7.5(4H),7.1-7.3(3H),7.0(1H),6.8(1H),6.1(1H),5.7(1H),5.0(2H),4.5(1H),4.2(2H),3.8(0.5H),3.2(1H),2.7(0.5H),2.4(1H),1.9(2H),1.6(1H)。
For the synthesis of compound T114, the compound T008 in step 5 of "Example 6: Synthesis of compound T104" was replaced with compound T207. The remaining steps were performed in the same manner as in "Example 6: Synthesis of compound T104" to obtain compound T114. The hydrogen nuclear magnetic resonance spectrum of compound T114 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (4H), 7.1-7.3 (3H), 7.0 (1H), 6.8 (1H), 6.1 (1H), 5.7 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
For the synthesis of compound T114, the compound T008 in step 5 of "Example 6: Synthesis of compound T104" was replaced with compound T207. The remaining steps were performed in the same manner as in "Example 6: Synthesis of compound T104" to obtain compound T114. The hydrogen nuclear magnetic resonance spectrum of compound T114 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (4H), 7.1-7.3 (3H), 7.0 (1H), 6.8 (1H), 6.1 (1H), 5.7 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
实施例12：化合物T115的合成Example 12: Synthesis of Compound T115
化合物T115的合成，将“实施例6：化合物T104的合成”中步骤5的化合物T008改为化合物T208。其余步骤同“实施例6：化合物T104的合成”操作，得化合物T115。化合物T115的核磁共振氢谱为：1H-NMR(DMSO-d6)δ7.8(1H),7.4-7.5(2H),7.1-7.3(5H),7.0(1H),6.8(1H),6.1(1H),5.7(1H),5.0(2H),4.5(1H),4.2(2H),3.8(0.5H),3.2(1H),2.7(0.5H),2.4(1H),1.9(2H),1.6(1H)。
For the synthesis of compound T115, the compound T008 in step 5 of "Example 6: Synthesis of compound T104" was replaced with compound T208. The remaining steps were performed in the same manner as in "Example 6: Synthesis of compound T104" to obtain compound T115. The hydrogen nuclear magnetic resonance spectrum of compound T115 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (2H), 7.1-7.3 (5H), 7.0 (1H), 6.8 (1H), 6.1 (1H), 5.7 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
For the synthesis of compound T115, the compound T008 in step 5 of "Example 6: Synthesis of compound T104" was replaced with compound T208. The remaining steps were performed in the same manner as in "Example 6: Synthesis of compound T104" to obtain compound T115. The hydrogen nuclear magnetic resonance spectrum of compound T115 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (2H), 7.1-7.3 (5H), 7.0 (1H), 6.8 (1H), 6.1 (1H), 5.7 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
实施例13：化合物T112的合成Example 13: Synthesis of Compound T112
化合物T112的合成，将“实施例1：化合物T109的合成”中步骤5的化合物T008改为化合物T208。其余步骤同“实施例1：化合物T109的合成”操作，得化合物T112。化合物T112的核磁共振氢谱为：1H-NMR(DMSO-d6)δ7.8(1H),7.4-7.5(2H),7.1-7.3(5H),7.0(1H),5.0(2H),4.5(1H),4.2(2H),3.8(0.5H),3.2(1H),2.7(0.5H),2.4(1H),1.9(2H),1.6(1H)。
For the synthesis of compound T112, the compound T008 in step 5 of "Example 1: Synthesis of compound T109" was replaced with compound T208. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound T109" to obtain compound T112. The hydrogen nuclear magnetic resonance spectrum of compound T112 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (2H), 7.1-7.3 (5H), 7.0 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
For the synthesis of compound T112, the compound T008 in step 5 of "Example 1: Synthesis of compound T109" was replaced with compound T208. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound T109" to obtain compound T112. The hydrogen nuclear magnetic resonance spectrum of compound T112 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (2H), 7.1-7.3 (5H), 7.0 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
实施例14：化合物T111的合成Example 14: Synthesis of Compound T111
化合物T111的合成，将“实施例1：化合物T109的合成”中步骤5的化合物T008改为化合物T207。其余步骤同“实施例1：化合物T109的合成”操作，得化合物T111。化合物T111的核磁共振氢谱为：1H-NMR(DMSO-d6)δ7.8(1H),7.4-7.5(4H),7.1-7.3(3H),7.0(1H),5.0(2H),4.5(1H),4.2(2H),3.8(0.5H),3.2(1H),2.7(0.5H),2.4(1H),1.9(2H),1.6(1H)。
For the synthesis of compound T111, the compound T008 in step 5 of "Example 1: Synthesis of compound T109" was replaced with compound T207. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound T109" to obtain compound T111. The hydrogen nuclear magnetic resonance spectrum of compound T111 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (4H), 7.1-7.3 (3H), 7.0 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
For the synthesis of compound T111, the compound T008 in step 5 of "Example 1: Synthesis of compound T109" was replaced with compound T207. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound T109" to obtain compound T111. The hydrogen nuclear magnetic resonance spectrum of compound T111 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (4H), 7.1-7.3 (3H), 7.0 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
实施例15：化合物T110的合成Example 15: Synthesis of Compound T110
化合物T110的合成，将“实施例1：化合物T109的合成”中步骤5的化合物T008改为化合物T206。其余步骤同“实施例1：化合物T109的合成”操作，得化合物T110。化合物T110的核磁共振氢谱为：1H-NMR(DMSO-d6)δ7.8(1H),7.4-7.5(2H),7.1-7.3(3H),7.0(1H),5.0(2H),4.5(1H),4.2(2H),3.8(0.5H),3.2(1H),2.7(0.5H),2.4(1H),1.9(2H),1.6(1H)。
For the synthesis of compound T110, the compound T008 in step 5 of "Example 1: Synthesis of compound T109" was replaced with compound T206. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound T109" to obtain compound T110. The hydrogen nuclear magnetic resonance spectrum of compound T110 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (2H), 7.1-7.3 (3H), 7.0 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
For the synthesis of compound T110, the compound T008 in step 5 of "Example 1: Synthesis of compound T109" was replaced with compound T206. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound T109" to obtain compound T110. The hydrogen nuclear magnetic resonance spectrum of compound T110 was: 1 H-NMR (DMSO-d 6 ) δ7.8 (1H), 7.4-7.5 (2H), 7.1-7.3 (3H), 7.0 (1H), 5.0 (2H), 4.5 (1H), 4.2 (2H), 3.8 (0.5H), 3.2 (1H), 2.7 (0.5H), 2.4 (1H), 1.9 (2H), 1.6 (1H).
实施例16：化合物T008的合成
Example 16: Synthesis of Compound T008
Example 16: Synthesis of Compound T008
步骤8:化合物T032的合成Step 8: Synthesis of compound T032
取苯酚-d5(化合物T030)(9.4g),溶于无水四氢呋喃(100ml)中，搅拌，分批次缓慢加入氢化钠(9.6g)，再分批次加入1-溴-4-碘苯(化合物T031)(31.1g)，室温反应15hr，将反应物过滤，滤液旋干，加入二氯甲烷溶解。过柱，用石油醚：乙酸乙酯(1:5)洗脱，得化合物T032。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.
步骤9:化合物T008的合成
Step 9: Synthesis of compound T008
将化合物T032(4.5g)溶解于干燥的THF(100ml)，N2保护下在-78℃反应30min,缓慢滴加正丁基锂(1.7g),滴加结束后保持-78℃反应3h,再缓慢滴加硼酸三异丙酯(3.8g),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T008。Compound T032 (4.5 g) was dissolved in dry THF (100 ml), and the mixture was reacted at -78 °C for 30 min under N2 protection. n-Butyl lithium (1.7 g) was slowly added dropwise, and the mixture was kept at -78 °C for 3 h after the addition was completed. Triisopropyl borate (3.8 g) was then slowly added dropwise, and the mixture was kept at -78 °C for 2 h after the addition was completed. The mixture was slowly warmed to room temperature and reacted for about 15 hr. After the reaction was completed as monitored by TLC, the reaction solution was slowly quenched with water, extracted and concentrated to obtain compound T008.
实施例17：化合物T202的合成Example 17: Synthesis of Compound T202
化合物T202的合成，按“实施例16：化合物T008的合成”进行，只在步骤8中，化合物T030改为化合物T033，其余步骤同“实施例16：化合物T008的合成”操作，得化合物T202。
The synthesis of compound T202 was carried out according to "Example 16: Synthesis of compound T008", except that in step 8, compound T030 was replaced by compound T033, and the remaining steps were carried out in the same manner as "Example 16: Synthesis of compound T008" to obtain compound T202.
The synthesis of compound T202 was carried out according to "Example 16: Synthesis of compound T008", except that in step 8, compound T030 was replaced by compound T033, and the remaining steps were carried out in the same manner as "Example 16: Synthesis of compound T008" to obtain compound T202.
实施例18：化合物T201的合成Example 18: Synthesis of Compound T201
化合物T201的合成，按“实施例16：化合物T008的合成”进行，只在步骤8中，化合物T030改为化合物T034，其余步骤同“实施例16：化合物T008的合成”操作，得化合物T201。
The synthesis of compound T201 was carried out according to "Example 16: Synthesis of compound T008", except that in step 8, compound T030 was replaced by compound T034, and the remaining steps were carried out in the same manner as "Example 16: Synthesis of compound T008" to obtain compound T201.
The synthesis of compound T201 was carried out according to "Example 16: Synthesis of compound T008", except that in step 8, compound T030 was replaced by compound T034, and the remaining steps were carried out in the same manner as "Example 16: Synthesis of compound T008" to obtain compound T201.
实施例19：化合物T203的合成Example 19: Synthesis of Compound T203
化合物T203的合成，按“实施例16：化合物T008的合成”进行，只在步骤8中，化合物T030改为化合物T035，其余步骤同“实施例16：化合物T008的合成”操作，得化合物T203。
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.
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.
实施例20：化合物T206的合成Example 20: Synthesis of Compound T206
化合物T206的合成，按“实施例16：化合物T008的合成”进行，只在步骤8中，化合物T030改为化合物T036，其余步骤同“实施例16：化合物T008的合成”操作，得化合物T206。
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.
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.
实施例21：化合物T207的合成Example 21: Synthesis of Compound T207
化合物T207的合成，按“实施例16：化合物T008的合成”进行，只在步骤8中，化合物T030改为化合物T037，其余步骤同“实施例16：化合物T008的合成”操作，得化合物T207。
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.
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.
实施例22：化合物T208的合成Example 22: Synthesis of Compound T208
化合物T208的合成，按“实施例16：化合物T008的合成”进行，只在步骤8中，化合物T030改为化合物T038，其余步骤同“实施例16：化合物T008的合成”操作，得化合物T208。
The synthesis of compound T208 was carried out according to "Example 16: Synthesis of compound T008", except that in step 8, compound T030 was replaced by compound T038, and the remaining steps were carried out in the same manner as "Example 16: Synthesis of compound T008" to obtain compound T208.
The synthesis of compound T208 was carried out according to "Example 16: Synthesis of compound T008", except that in step 8, compound T030 was replaced by compound T038, and the remaining steps were carried out in the same manner as "Example 16: Synthesis of compound T008" to obtain compound T208.
实施例23：大鼠中的药代动力学评价Example 23: Pharmacokinetic Evaluation in Rats
48只雄性Sprague-Dawley大鼠，7-8周龄，体重约210g，分成8组(Tolebrutinib组、化合物T101组、化合物T104组、化合物T105组、化合物T106组、化合物T107组、化合物T109组和化合物T112组)，每组6只。按照分组分别单次灌胃给予6mg/kg剂量的Tolebrutinib、
化合物T101、化合物T104、化合物T105、化合物T106、化合物T107、化合物T109和化合物T112，比较其药代动力学差异。48 male Sprague-Dawley rats, 7-8 weeks old, weighing about 210 g, were divided into 8 groups (Tolebrutinib group, compound T101 group, compound T104 group, compound T105 group, compound T106 group, compound T107 group, compound T109 group and compound T112 group), 6 rats in each group. According to the group, a single oral gavage of 6 mg/kg dose of Tolebrutinib, The pharmacokinetic differences of compound T101, compound T104, compound T105, compound T106, compound T107, compound T109 and compound T112 were compared.
大鼠采用标准饲料喂养，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、10小时和24小时。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.
血样采集后，置于涂布肝素钠溶液的离心管中，立即温和的颠倒采血管至少5次，保证充分混合后放置于冰上。血样在4℃的温度5000转/分钟离心5分钟，将血浆与红细胞分离。用移液器吸出100μL血浆至干净的塑料离心管中，标明样品编号和采血时间点。血浆在进行LC-MS/MS分析前保存在-80℃冰箱中。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 μL 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.
由试验结果可知，化合物T101与Tolebrutinib相比，化合物T101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；化合物T104与Tolebrutinib相比，化合物T104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；化合物T105与Tolebrutinib相比，化合物T105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；化合物T106与Tolebrutinib相比，化合物T106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；化合物T107与Tolebrutinib相比，化合物T107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；化合物T109与Tolebrutinib相比，化合物T109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；化合物T112与Tolebrutinib相比，化合物T112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。The 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 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%.
由本结果可知，本发明化合物T101、化合物T104、化合物T105、化合物T106、化合物T107、化合物T109和化合物T112在动物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。From the present results, it can be seen that 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.
实施例24：BTK的抑制活性测定Example 24: Determination of BTK inhibitory activity
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：The ADP-Glo ™ 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。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. In the kinase detection experiment, the kinase consumes ATP to phosphorylate the substrate and produces ADP. Then the ADP-Glo reagent is added to terminate the kinase reaction and completely consume the remaining ATP. Then 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.
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。All detection experiments were performed at a constant temperature of 23°C, using Corning 3674 white 384-well detection plates, kinase BTK (Invitrogen), kinase substrates peptide (4:l Glu, Tyr) (Signal Chem) and ATP (Sigma), and light signals were read using an EnVision microplate reader (Perkin Elmer). 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/μL using the detection buffer; the substrate reaction solution included 0.25mg/mL peptide substrate and 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。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 μM. 50 nL of compound solutions of serial concentrations and 2.5 μL 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 μL of substrate reaction solution was added, and the total reaction volume was 5.05 μL, and the reaction mixture was reacted at room temperature in the dark for 60 minutes; then 5 μL of ADP-Glo TM reagent was added to terminate the reaction, mixed evenly, and left at room temperature for 40 minutes; finally, 10 μL of kinase detection reagent was added, left at room temperature in the dark for 30 minutes, and then the value was read on Envision.
抑制百分率按以下公式计算：The inhibition percentage was calculated according to the following formula:
抑制％＝[1-(RLU化合物-RLUmin)/(RLUmax-RLUmin)]×100Inhibition % = [1 - (RLU compound - RLU min ) / (RLU max - RLU min )] × 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。Wherein 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, and 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.
表1：本发明的化合物的IC50值
Table 1: IC50 values of compounds of the present invention
Table 1: IC50 values of compounds of the present invention
由本结果可知，本发明的化合物对BTK具有明显的抑制效应。
It can be seen from the present results that the compounds of the present invention have a significant inhibitory effect on BTK.
实施例25：小鼠肝毒性对比研究Example 25: Comparative study of liver toxicity in mice
(1)实验动物(1) Experimental animals
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。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%.
(2)动物分组与给药(2) Animal grouping and drug administration
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+Tolebrutinib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+Tolebrutinib组按剂量(50mg/kg)每天灌胃给药一次Tolebrutinib，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+Tolebrutinib组小鼠分别一次性腹腔注射250mg/kg的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。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, and 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. One hour later, the 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. After 24 hours of modeling, 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. After being rinsed with 4°C saline, 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.
(3)肝脏中生化指标的测定：(3) Determination of biochemical indicators in the liver:
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。Weigh part of the liver, add 9 times the volume of ice saline, use a tissue homogenizer to make 10% liver tissue homogenate, centrifuge and take the supernatant. Spot the plate according to the kit method, measure the OD value at 450nm, and calculate the MDA content and GSH activity in the liver according to the formula.
(4)数据处理(4) Data processing
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。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.
(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(5) Effects of the compounds in the present examples on lipid peroxidation in liver tissue of mice with APAP liver injury
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+Tolebrutinib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Tolebrutinib(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Tolebrutinib。结果如表2所示。
Compared with the normal control group, 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.
表2.对APAP肝损伤小鼠肝组织脂质过氧化影响
Table 2. Effects on lipid peroxidation in liver tissue of mice with APAP liver injury
Table 2. Effects on lipid peroxidation in liver tissue of mice with APAP liver injury
标注(等级)：A+为2.6-3.7；A-为0.9-2.4；A++为3.9-4.7；B+为29-38；B-为40-57；B++为13-27。Marking (grade): A+ is 2.6-3.7; A- is 0.9-2.4; A++ is 3.9-4.7; B+ is 29-38; B- is 40-57; B++ is 13-27.
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Tolebrutinib(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Tolebrutinib。Conclusion: 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.
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。
Finally, it is necessary to explain that the specific embodiments of the present invention are described in detail above, but they are only examples, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions made to the present invention are also within the scope of the present invention. Therefore, the equalization changes and modifications made without departing from the spirit and scope of the present invention should be included in the scope of the present invention.
Claims (8)
- 一种式Ⅰ所示的氘代的氨基吡啶衍生物、其光学异构体或其混合物、其晶型、其盐、其水合物或溶剂合物：
A deuterated aminopyridine derivative represented by formula I, its optical isomers or mixtures thereof, its crystal forms, its salts, its hydrates or solvates:
其中：in: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。 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 or deuterium, 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 . - 如权利要求1所述的化合物，其特征在于，所述化合物选自下组：
The compound according to claim 1, characterized in that the compound is selected from the group consisting of:
- 药物组合物，其特征在于包含权利要求1或2所述的化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物与药学上可接受的载体或辅料。A pharmaceutical composition characterized by comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof and a pharmaceutically acceptable carrier or excipient.
- 权利要求1或2所述的化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物在制备BTK抑制剂上的应用。Use of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in the preparation of a BTK inhibitor.
- 权利要求1或2所述的化合物或其药学上可接受的盐、异构体、代谢产物、前药、溶剂合物或水合物在制备治疗和/或预防与BTK相关的疾病的药物上的应用。Use of the compound of claim 1 or 2 or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in the preparation of a medicament for treating and/or preventing a disease associated with BTK.
- 根据权利要求5所述的应用，其特征在于，所述与BTK相关的疾病为***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。The use according to claim 5, characterized in that the disease associated with BTK is an allergic disorder, an autoimmune disease, an inflammatory disease, a thromboembolic disease or cancer.
- 根据权利要求6所述的应用，其特征在于，所述自身免疫性疾病选自多发性硬化症、***性红斑狼疮、慢性自发性荨麻疹、视神经脊髓炎或类风湿性关节炎。The use according to claim 6, characterized in that the autoimmune disease is selected from multiple sclerosis, systemic lupus erythematosus, chronic spontaneous urticaria, neuromyelitis optica or rheumatoid arthritis.
- 根据权利要求6所述的应用，其特征在于，所述癌症选自淋巴瘤、白血病、非小型细胞肺癌、子宫癌、直肠癌、脑癌、头癌、颈癌、膀胱癌、***癌、乳腺癌、肾癌、肝癌、胃癌或胰腺癌。 The use according to claim 6 is characterized in that the cancer is selected from 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.
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| CN202211366535.1A CN118027022A (en) | 2022-11-07 | 2022-11-07 | Deuterated aminopyridine derivatives and pharmaceutical compositions containing the same |
| CN202211366535.1 | 2022-11-07 | ||
| CN202311446410 | 2023-11-02 | ||
| CN202311446410.4 | 2023-11-02 |
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| CN106459049A (en) * | 2015-06-03 | 2017-02-22 | 普林斯匹亚生物制药公司 | Tyrosine kinase inhibitors |
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