Nothing Special   »   [go: up one dir, main page]

WO2024149150A1 - 氘代吡唑并嘧啶衍生物及其制备方法和药物组合物、结合物及应用 - Google Patents

氘代吡唑并嘧啶衍生物及其制备方法和药物组合物、结合物及应用 Download PDF

Info

Publication number
WO2024149150A1
WO2024149150A1 PCT/CN2024/070622 CN2024070622W WO2024149150A1 WO 2024149150 A1 WO2024149150 A1 WO 2024149150A1 CN 2024070622 W CN2024070622 W CN 2024070622W WO 2024149150 A1 WO2024149150 A1 WO 2024149150A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
deuterium
deuterated
solvent
reaction
Prior art date
Application number
PCT/CN2024/070622
Other languages
English (en)
French (fr)
Inventor
杨诚
汪清民
周红刚
李伟
谷金颖
李志强
高晶晶
崔运遥
王青
马光银
Original Assignee
天津济坤医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 天津济坤医药科技有限公司 filed Critical 天津济坤医药科技有限公司
Publication of WO2024149150A1 publication Critical patent/WO2024149150A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/58—Preparation of carboxylic acid halides
    • C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to the field of medical technology, and in particular to deuterated pyrazolopyrimidine derivatives, preparation methods thereof, and pharmaceutical compositions, conjugates and applications thereof.
  • BTK tyrosine kinase
  • BCR B-cell receptor
  • FcR FcR
  • BTK is activated by upstream Src family kinases. Once activated, BTK in turn phosphorylates PLC ⁇ , thereby affecting the function and survival of B cells (Humphries et al., J. Biol. Chem., 279: 37651, 2004). Therefore, these signaling pathways must be precisely regulated. Mutations in the gene encoding BTK can lead to a hereditary B cell-specific immunodeficiency disease in humans, known as X-linked agammaglobulinemia (XLA) (Conley et al., Annu. Rev. Immunol., 27: 199-227, 2009). Abnormalities in BCR-mediated signals may lead to dysregulation of B cell activation, leading to many autoimmune and inflammatory diseases.
  • XLA X-linked agammaglobulinemia
  • BTK hematological malignancies
  • BTK inhibitors have become a hot topic of research as anti-inflammatory and/or anti-cancer drugs (Mohamed et al., Immunol. Rev., 228:58-73, 2009; Pan, Drug News perspective, 21:357-362, 2008; Rokosz et al., Expert Opin. Ther.
  • Zanubrutinib (BGB-3111) is a BTK selective inhibitor that can form a covalent bond with the cysteine in the BTK active site, thereby inhibiting BTK activity.
  • Zanubrutinib capsules (BRUKINSA, Zanubrutinib capsules) were developed by BeiGene, Ltd. and were approved for marketing in the United States in November 2019 and in China in June 2020. They can be used to treat adult mantle cell lymphoma (MCL) who have received at least one previous treatment and adult chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who have received at least one previous treatment.
  • MCL mantle cell lymphoma
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • zanubrutinib capsules The recommended dose of zanubrutinib capsules is 160 mg per dose, taken orally, twice daily. Zanubrutinib is administered twice daily, indicating that its half-life is relatively short and that there is a large room for optimization of its pharmacokinetic properties.
  • the object of the present invention is to provide a deuterated pyrazolopyrimidine derivative and a preparation method and pharmaceutical composition, conjugate and application thereof.
  • the deuterated pyrazolopyrimidine derivative provided by the present invention optimizes the pharmacokinetic properties of zanubrutinib and is expected to have better treatment compliance and effect.
  • the present invention provides a deuterated pyrazolopyrimidine derivative having a structure as shown in Formula I or an optical isomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof;
  • At least one of X 1 , X 2 , X 3 , X 4 , X 5 and X 6 is deuterium.
  • X 4 , X 5 and X 6 are all hydrogen, or at least one of them is deuterium.
  • X 4 , X 5 and X 6 are all hydrogen, and at least one of X 1 , X 2 and X 3 is deuterium, or at least two of them are deuterium, or all of them are deuterium.
  • At least one of X 4 , X 5 and X 6 is deuterium, and X 1 , X 2 and X 3 are all hydrogen, or at least one is deuterium, or at least two are deuterium, or all are deuterium.
  • At least two of X 4 , X 5 and X 6 are deuterium, and X 1 , X 2 and X 3 are all hydrogen, or at least one is deuterium, or at least two are deuterium, or all are deuterium.
  • X 4 , X 5 and X 6 are all deuterium, and X 1 , X 2 and X 3 are all hydrogen, or at least one is deuterium, or at least two are deuterium, or all are deuterium.
  • the deuterated pyrazolopyrimidine derivative is at least one of the following compounds:
  • the present invention provides a method for preparing the deuterated pyrazolopyrimidine derivatives described in the above technical solution, comprising the following steps:
  • the compound X603, the first base reagent and the second solvent are mixed to perform an ester hydrolysis reaction to obtain a compound X604;
  • the compound X604 is mixed with an acyl chloride reagent to undergo an acyl chloride reaction to obtain an intermediate compound; the intermediate compound, malononitrile, a reducing agent and a third solvent are mixed to undergo a nucleophilic reaction to obtain a compound X606;
  • the compound X606, a methylating agent, a second base agent and a fourth solvent are mixed to perform a methylation reaction to obtain a compound X608;
  • the compound X608, hydrazine hydrate and a fifth solvent are mixed to perform a first cyclization reaction to obtain a compound X610;
  • the compound X614, the acid reagent, the first catalyst and the seventh solvent are mixed, and a reduction reaction is performed in a hydrogen atmosphere to obtain a compound X615;
  • the compound X615, hydrochloric acid and an eighth solvent are mixed to carry out a deprotection reaction to obtain a racemic compound X616;
  • the racemic compound X616, a chiral resolution agent and a ninth solvent are mixed to perform chiral resolution to obtain a compound X617;
  • the compound X617, a third alkaline reagent, a hydrogen peroxide solution, dimethyl sulfoxide and a tenth solvent are mixed to carry out a cyanohydrolysis reaction to obtain a compound X618;
  • the compound X618, the compound X619, the fourth base reagent and the eleventh solvent are mixed to form an amide to obtain a deuterated pyrazolopyrimidine derivative having a structure shown in Formula I;
  • X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are as defined in Formula I; said Z is hydrogen or deuterium, and said Y is a halogen atom;
  • step (1) There is no order of precedence between step (1) and step (2).
  • the present invention provides a method for preparing trideuterated acryloyl chloride and polydeuterated phenol, comprising the following steps:
  • the polydeuterated phenols are 3,4,5-trideuterated phenol, 2,3,5,6-tetradeuterated phenol and 2,6-dideuterated phenol;
  • the preparation method of the 3,4,5-trideuterated phenol comprises the following steps:
  • the compound PD541, the fifth base reagent, the second catalyst and the thirteenth solvent are mixed, and trideuterated phenol is reacted in a deuterium atmosphere to obtain 3,4,5-trideuterated phenol;
  • the preparation method of the 2,3,5,6-tetradeuterated phenol comprises the following steps:
  • the compound PD545, the sixth alkaline reagent, the third catalyst and the fourteenth solvent are mixed, and the mixture is reacted in a deuterium atmosphere to form tetradeuterated phenol to obtain 2,3,5,6-tetradeuterated phenol;
  • the preparation method of the 2,6-dideuterophenol comprises the following steps:
  • the present invention provides a pharmaceutical composition, comprising an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient is at least one of the deuterated pyrazolopyrimidine derivatives, optical isomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof and solvates thereof described in the above technical solution.
  • the present invention provides a combination, comprising a first active ingredient and a second active ingredient; the first active ingredient is at least one of the deuterated pyrazolopyrimidine derivatives, optical isomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof and solvates thereof described in the above technical solution; and the second active ingredient is an agent having therapeutic activity for allergic diseases, autoimmune diseases, inflammatory diseases or cancers.
  • the present invention provides use of the deuterated pyrazolopyrimidine derivatives, optical isomers, pharmaceutically acceptable salts, hydrates, solvates, pharmaceutical compositions or combinations thereof described in the above technical solutions in the preparation of BTK inhibitors.
  • the present invention provides use of the deuterated pyrazolopyrimidine derivatives, optical isomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, the pharmaceutical compositions described in the above technical solutions, or the conjugates described in the above technical solutions in the preparation of drugs for treating diseases associated with undesirable BTK activity, wherein the diseases are allergic diseases, autoimmune diseases, inflammatory diseases, or cancers.
  • the allergic disease comprises atopic dermatitis, contact dermatitis or itch.
  • the autoimmune disease comprises rheumatoid arthritis, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, teratogenic arthritis, osteoarthritis, traumatic arthritis, gouty arthritis, Reiter's syndrome, polychondritis, acute synovitis, spondylitis, glomerulonephritis with nephrotic syndrome, glomerulonephritis without nephrotic syndrome, autoimmune blood system disorders, hemolytic anemia, aplastic anemia, idiopathic thrombocytopenia, neutropenia, autoimmune gastritis, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, host versus graft disease, allograft rejection, chronic thyroiditis, Graves' disease, scleroderma, primary biliary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus or psoriasis.
  • the inflammatory disease comprises acute active hepatitis, chronic active hepatitis, pancreatitis, vasculitis, inflammatory pain, uveitis, conjunctivitis, keratoconjunctivitis, otitis media, periodontal disease, bronchitis, rhinitis or sinusitis.
  • the cancer comprises non-Hodgkin lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, B-cell chronic lymphocytic leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia with mature B cells, B-cell lymphoma caused by chronic active B-cell receptor signaling, or bone disease associated with multiple myeloma.
  • the present invention provides a deuterated pyrazolopyrimidine derivative or an optical isomer thereof, a pharmaceutically acceptable salt, a hydrate or a solvate thereof.
  • the deuterated pyrazolopyrimidine derivative provided by the present invention has good pharmacokinetic properties, which is conducive to reducing the dosage and/or reducing toxic side effects.
  • the deuterated pyrazolopyrimidine derivative provided by the present invention can inhibit BTK activity and can be used to prepare BTK inhibitors and to prepare drugs for treating diseases associated with undesirable BTK activity (such as allergic diseases, autoimmune diseases, inflammatory diseases or cancer).
  • the present invention provides a method for preparing the deuterated pyrazolopyrimidine derivative.
  • the synthetic route of the deuterated pyrazolopyrimidine derivative provided by the present invention is reasonably designed, and a deuterated pyrazolopyrimidine derivative with a specific deuterated site can be obtained in a targeted manner.
  • the present invention provides a deuterated pyrazolopyrimidine derivative having a structure as shown in Formula I or an optical isomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof;
  • At least one of X 1 , X 2 , X 3 , X 4 , X 5 and X 6 is deuterium.
  • X 4 , X 5 and X 6 are preferably all hydrogen, and at least one of X 1 , X 2 and X 3 is preferably deuterium, or at least two of them are preferably deuterium, or all of them are preferably deuterium.
  • At least one of X 4 , X 5 and X 6 is preferably deuterium, and X 1 , X 2 and X 3 are all hydrogen, or at least one is preferably deuterium, or at least two are preferably deuterium, or all are preferably deuterium.
  • At least two of X 4 , X 5 and X 6 are preferably deuterium, and X 1 , X 2 and X 3 are all hydrogen, or at least one is deuterium, or at least two are deuterium, or all are deuterium.
  • X 4 , X 5 and X 6 are preferably all deuterium, and X 1 , X 2 and X 3 are all hydrogen, or preferably at least one is deuterium, or preferably at least two are deuterium, or preferably all are deuterium.
  • the deuterated pyrazolopyrimidine derivative is preferably at least one of the following compounds:
  • the present invention provides a method for preparing the deuterated pyrazolopyrimidine derivatives described in the above technical solution, comprising the following steps:
  • the compound X603, the first base reagent and the second solvent are mixed to perform an ester hydrolysis reaction to obtain a compound X604;
  • the compound X604 is mixed with an acyl chloride reagent to undergo an acyl chloride reaction to obtain an intermediate compound; the intermediate compound, malononitrile, a reducing agent and a third solvent are mixed to undergo a nucleophilic reaction to obtain a compound X606;
  • the compound X606, a methylating agent, a second base agent and a fourth solvent are mixed to perform a methylation reaction to obtain a compound X608;
  • the compound X608, hydrazine hydrate and a fifth solvent are mixed to perform a first cyclization reaction to obtain a compound X610;
  • the compound X614, the acid reagent, the first catalyst and the seventh solvent are mixed, and a reduction reaction is performed in a hydrogen atmosphere to obtain a compound X615;
  • the compound X615, hydrochloric acid and an eighth solvent are mixed to carry out a deprotection reaction to obtain a racemic compound X616;
  • the racemic compound X616, a chiral resolution agent and a ninth solvent are mixed to perform chiral resolution to obtain a compound X617;
  • the compound X617, a third alkaline reagent, a hydrogen peroxide solution, dimethyl sulfoxide and a tenth solvent are mixed to carry out a cyanohydrolysis reaction to obtain a compound X618;
  • the compound X618, the compound X619, the fourth base reagent and the eleventh solvent are mixed to form an amide to obtain a deuterated pyrazolopyrimidine derivative having a structure shown in Formula I;
  • X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are as defined in Formula I; said Z is hydrogen or deuterium, and said Y is a halogen atom;
  • step (1) There is no order of precedence between step (1) and step (2).
  • the raw materials used are commercially available products well known to those skilled in the art or are prepared by methods well known to those skilled in the art.
  • the present invention prepares compound X610 and compound X613 respectively, and then uses the two to prepare a deuterated pyrazolopyrimidine derivative having a structure shown in formula I, which is described in detail below.
  • reaction formula for preparing compound X610 is as follows, wherein the methylating agent is specifically described by taking dimethyl sulfate (compound X607) as an example:
  • the present invention mixes compound X601, compound X602, a drying agent and a first solvent, and performs an etherification reaction to obtain compound X603.
  • the compound X601 is phenol or deuterated phenol; in an embodiment of the present invention, according to the structure of the deuterated pyrazolopyrimidine derivative, the deuterated phenol is specifically any one of the following compounds: Species (the preparation methods of some compounds are described in detail later):
  • Y in the compound X602 is a halogen atom, that is, the compound X602 is ethyl 4-halobenzoate; the halogen atom is preferably -F, -Cl, -Br or -I, more preferably -F.
  • the desiccant preferably includes potassium carbonate, sodium carbonate or cesium carbonate, more preferably potassium carbonate; the first solvent preferably includes dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile or acetone.
  • the dosage ratio of the compound X601, the compound X602, the desiccant and the first solvent is preferably 50.5mmol: (45-55)mmol: (90-110)mmol: (50-70)mL, more preferably 50.5mmol: 49.5mmol: 99.1mmol: 60mL.
  • the present invention preferably mixes compound X601 and compound X602 with a first solvent, and then adds a desiccant to the resulting mixed solution to perform an etherification reaction; when the desiccant is added, the temperature of the mixed solution is preferably 125 to 135°C, more preferably 130°C.
  • the temperature of the etherification reaction is preferably 125 to 135°C, more preferably 130°C; the time is preferably 20 to 30h, more preferably 24h.
  • the present invention generates compound X603 by reacting compound X601 with compound X602 in the presence of a desiccant; in particular, deuterated diphenyl ether is generated by reacting deuterated phenol with compound X602 (such as ethyl 4-fluorobenzoate) in the presence of a desiccant (such as potassium carbonate), and no hydrogen-deuterium exchange is involved in the reaction process, which is conducive to ensuring that a deuterated pyrazolopyrimidine derivative with a specific deuterated site is finally obtained.
  • a desiccant such as potassium carbonate
  • the present invention preferably extracts the obtained product system with ethyl acetate, dries the organic layer with anhydrous magnesium sulfate, filters, concentrates the filtrate, and purifies the obtained residue by silica gel column chromatography to obtain compound X603.
  • the eluent used for the purification is preferably ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is preferably 1: (9-11), more preferably 1: 10; the boiling range of the petroleum ether is preferably 60-90°C.
  • the present invention mixes the compound X603, the first alkaline reagent and the second solvent, and performs an ester hydrolysis reaction to obtain compound X604.
  • the first alkaline reagent preferably includes an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution or an aqueous lithium hydroxide solution, and is more preferably an aqueous sodium hydroxide solution.
  • the concentration of the first alkaline reagent is preferably 0.5-1.5 mol/L, and is more preferably 1 mol/L;
  • the second solvent is preferably a tetrahydrofuran-ethanol mixed solvent, wherein the volume ratio of tetrahydrofuran to ethanol is preferably 1: (0.8-1.2), and is more preferably 1: 1.
  • the amount ratio of the compound X603, the first alkaline reagent and the second solvent is preferably 18.2 mmol: (4-6) mL: (15-25) mL, and is more preferably 18.2 mmol: 5 mL: 20 mL.
  • the present invention does not specifically limit the manner in which the compound X603, the first alkaline reagent and the second solvent are mixed, and uniform mixing can be achieved.
  • the temperature of the ester hydrolysis reaction is preferably 75-85°C, and the ester hydrolysis reaction is more preferably carried out under the condition of system reflux (80°C); the time of the ester hydrolysis reaction is preferably 3.5-4.5h, and more preferably 4h.
  • the ester hydrolysis reaction of the compound X603 is carried out in the presence of the first alkali reagent, and the reaction is thorough; especially when the compound X603 is a deuterated compound, the process of the ester hydrolysis reaction in the presence of the first alkali reagent (such as sodium hydroxide aqueous solution) does not involve hydrogen-deuterium exchange, which is conducive to ensuring that a deuterated pyrazolopyrimidine derivative with a specific deuterated site is finally obtained.
  • the first alkali reagent such as sodium hydroxide aqueous solution
  • the present invention preferably adds concentrated hydrochloric acid or concentrated sulfuric acid to the obtained product system to adjust the pH value to 2.5-3.5, and then extracts with ethyl acetate or toluene, and the organic layer is dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain compound X604.
  • the concentration of the concentrated hydrochloric acid is preferably 36-38wt%
  • the concentration of the concentrated sulfuric acid is preferably 96-98wt%.
  • the present invention preferably uses concentrated hydrochloric acid or concentrated sulfuric acid to adjust the pH value of the system to 3.
  • the present invention mixes the compound X604 with an acyl chloride reagent to form an acyl chloride reaction.
  • the acyl chloride reagent preferably includes thionyl chloride or phosphorus pentachloride; taking thionyl chloride as an example, the amount ratio of the compound X604 to thionyl chloride is preferably 17.3 mmol: (45-55) mL, and more preferably 17.3 mmol: 50 mL.
  • the temperature of the acyl chloride formation reaction is preferably 75-85°C, and it is more preferred to carry out the acyl chloride formation reaction under the condition of system reflux (80°C); the time of the acyl chloride formation reaction is preferably 3.5-4.5h, and more preferably 4h.
  • the present invention preferably concentrates the obtained product system to remove the unreacted acyl chloride reagent, and the obtained oily substance is the intermediate compound, and the structural formula is specifically shown as follows:
  • the present invention mixes the intermediate compound, malononitrile (compound X605), a reducing agent and a third solvent to perform a nucleophilic reaction to obtain compound X606.
  • the reducing agent is preferably sodium hydride; and the third solvent is preferably tetrahydrofuran.
  • the amount ratio of compound X604, malononitrile, reducing agent and third solvent is preferably 17.3 mmol: (47-57) mmol: (47-57) mmol: (900-950) mL, and more preferably 17.3 mmol: 51.9 mmol: 51.9 mmol: 920 mL.
  • the present invention preferably mixes the intermediate compound, malononitrile and reducing agent with a third solvent respectively to obtain an intermediate compound solution, a malononitrile solution and a reducing agent liquid; then, under 0°C, the reducing agent liquid is added dropwise to the malononitrile solution, and after the addition is complete, the intermediate compound solution is added and stirred for 20 to 30 minutes, and then a nucleophilic reaction is carried out; the dropping rate of the reducing agent liquid is preferably 5 to 7 mL/min, and more preferably 6 mL/min.
  • the temperature of the nucleophilic reaction is preferably 20 to 30°C, and the nucleophilic reaction is preferably carried out at room temperature (25°C); the time of the nucleophilic reaction is preferably 12 to 20 hours, and more preferably 16 hours.
  • the present invention preferably cools the obtained liquid to 0°C and quenches the reaction with hydrochloric acid, and then extracts the obtained product system with ethyl acetate or toluene, washes the organic layer with water and saturated brine in turn, and then dries with anhydrous sodium sulfate, filters, and concentrates the filtrate to obtain compound X606.
  • the concentration of hydrochloric acid used to quench the reaction is preferably 0.5 to 1.5 mol/L, more preferably 1 mol/L.
  • the present invention mixes the compound X606, a methylating agent, a second alkaline agent and a fourth solvent to carry out a methylation reaction to obtain compound X608.
  • the methylating agent preferably includes dimethyl sulfate or methyl iodide;
  • the second alkaline agent is preferably sodium carbonate; and
  • the fourth solvent is preferably dioxane.
  • the amount ratio of compound X604, methylating agent, second alkaline agent and fourth solvent is preferably 17.3mmol: (47-57)mmol: (47-57)mmol: (45-55)mL, and more preferably 17.3mmol: 51.9mmol: 51.9mmol: 50mL.
  • the present invention preferably dissolves compound X606 in the fourth solvent, and then adds the second alkaline agent and the methylating agent to the resulting mixed solution to carry out a methylation reaction.
  • the temperature of the methylation reaction is preferably 85-95°C, more preferably 90°C; the time is preferably 3.5-4.5h, more preferably 4h.
  • the present invention preferably concentrates the obtained product system to remove the solvent, mixes the obtained residue with water, and then extracts with ethyl acetate or toluene, and the organic layer is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated.
  • the obtained residue is purified by silica gel column chromatography to obtain compound X608.
  • the eluent used for the purification is preferably ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate and petroleum ether is preferably 1: (9-11), more preferably 1: 10; the boiling range of the petroleum ether is preferably 60-90°C.
  • the present invention mixes the compound X608, hydrazine hydrate and the fifth solvent to perform a first cyclization reaction to obtain compound X610.
  • the hydrazine hydrate is preferably used in the form of a hydrazine hydrate aqueous solution, and the concentration of the hydrazine hydrate aqueous solution is preferably 80-90wt%, more preferably 85wt%; the fifth solvent is preferably ethanol.
  • the usage ratio of the compound X608, the hydrazine hydrate aqueous solution and the fifth solvent is preferably 10mmol: (1.8-2.2) mL: (65-75) mL, more preferably 10 mmol: 2 mL: 70 mL.
  • the compound X608 is preferably mixed with the fifth solvent, and then an aqueous hydrazine hydrate solution is added dropwise to the resulting mixture to perform a first cyclization reaction; the dropping rate of the aqueous hydrazine hydrate solution is preferably 0.8-1.2 mL/min, more preferably 1 mL/min.
  • the temperature of the first cyclization reaction is preferably 85-95°C, and the first cyclization reaction is more preferably performed under system reflux (90°C); the time of the first cyclization reaction is preferably 3.5-4.5 h, more preferably 4 h, and the time of the first cyclization reaction is calculated from the completion of the dropwise addition of the aqueous hydrazine hydrate solution.
  • the present invention preferably cools the resulting product system to room temperature, removes the solvent by rotary evaporation, mixes the resulting residue with water, stirs for 3-5 min at room temperature to precipitate, collects the precipitate and dries it to obtain compound X610.
  • reaction formula for preparing compound X613 is as follows:
  • the present invention mixes compound X611 and compound X612 to form a conjugated double bond reaction to obtain compound X613.
  • the molar ratio of compound X611 to compound X612 is preferably 21.1:(70-80), and more preferably 21.1:75.
  • the temperature of the conjugated double bond formation reaction is preferably 105-115°C, and more preferably 110°C; the time is preferably 45-50h, and more preferably 48h.
  • the present invention preferably concentrates the obtained product system, mixes the residue with a precipitation solvent, precipitates the precipitate, filters, and evaporates the solvent in the filter cake to obtain compound X613.
  • the precipitation solvent preferably includes petroleum ether, n-hexane or cyclohexane.
  • reaction formula for preparing a deuterated pyrazolopyrimidine derivative having a structure shown in Formula I based on the compound X610 and the compound X613 is as follows:
  • the present invention mixes the compound X610 and the compound X613 with a sixth solvent to carry out a second cyclization reaction to obtain compound X614.
  • the sixth solvent is preferably an acetic acid-toluene mixed solvent, wherein the volume ratio of acetic acid to toluene is preferably (3.5-4.5):1, and more preferably 4:1.
  • the dosage ratio of the compound X610, the compound X613 and the sixth solvent is preferably 10mmol:10-12mmol:(75-85)mL, and more preferably 10mmol:11mmol:80mL.
  • the present invention preferably adds compound X613 and the sixth solvent to the compound X610 to carry out a second cyclization reaction.
  • the temperature of the second cyclization reaction is preferably 95-105°C, and more preferably 100°C; the time is preferably 7.5-8.5h, and more preferably 8h.
  • the present invention preferably cools the obtained product system to room temperature and then concentrates it, and the residue is precipitated with methanol, filtered, and the filter cake is washed with methanol and dried. After drying, compound X614 was obtained.
  • the present invention mixes the compound X614, the acid reagent, the first catalyst and the seventh solvent, and performs a reduction reaction in a hydrogen atmosphere to obtain compound X615.
  • the acid reagent preferably includes D-(+)-dibenzoyltartaric acid or acetic acid, more preferably D-(+)-dibenzoyltartaric acid;
  • the first catalyst is preferably a Pd/C catalyst, and the content of Pd in the Pd/C catalyst is preferably 10wt%;
  • the seventh solvent is preferably tetrahydrofuran.
  • the dosage ratio of the compound X614, the acid reagent and the seventh solvent is preferably 7.7mmol: (7.5-8)mmol: (55-65)mL, more preferably 7.7mmol: 7.7mmol: 60mL; the mass of the first catalyst is preferably 8-12% of the mass of the compound X614, more preferably 10%.
  • the present invention preferably adds the first catalyst to the mixture of compound X614, the acid reagent and the seventh solvent under N2 protection conditions, and then passes hydrogen into the system for reduction reaction.
  • the temperature of the reduction reaction is preferably 35-45°C, more preferably 40°C; the heating rate to the temperature of the reduction reaction is preferably 1-5°C/min, more preferably 2-4°C/min; the time of the reduction reaction is preferably 16-32h, more preferably 24h.
  • the reduction reaction of the compound X614 is carried out in the presence of an acid reagent, and the reaction yield is high; especially when the compound X614 is a deuterated compound, the reduction reaction in the presence of an acid reagent (such as D-(+)-dibenzoyltartaric acid) does not involve hydrogen-deuterium exchange, which is conducive to ensuring that a deuterated pyrazolopyrimidine derivative with a specific deuterated site is finally obtained, and the reaction yield is high.
  • an acid reagent such as D-(+)-dibenzoyltartaric acid
  • the present invention preferably cools the obtained product system to room temperature, filters, washes the filter cake with tetrahydrofuran, concentrates the filtrate and the washing liquid, mixes the residue with dichloromethane or 1,2-dichloroethane, and then washes with a saturated sodium bicarbonate aqueous solution, concentrates, precipitates the residue with a precipitant, filters, washes the filter cake with methanol, and obtains compound X614 after drying.
  • the precipitant is preferably a mixture of methyl tert-butyl ether and hexane, and the volume ratio of methyl tert-butyl ether to hexane is preferably 1: (2.5-3.5), more preferably 1: 3; the hexane is preferably n-hexane or cyclohexane.
  • the present invention mixes the compound X615, hydrochloric acid and the eighth solvent to perform a deprotection reaction to obtain a racemic compound X616.
  • the eighth solvent is preferably ethyl acetate.
  • the present invention preferably mixes compound X615 with part of the eighth solvent to obtain a suspension of compound X615; HCl is mixed with the remaining eighth solvent, and then the obtained HCl mixed solution is added to the suspension of compound X615 to perform a deprotection reaction;
  • the concentration of the suspension of compound X615 is preferably 0.1-0.2 mol/L, more preferably 0.148 mol/L;
  • the concentration of HCl in the HCl mixed solution is preferably 3.5-4.5 mol/L, more preferably 4 mol/L;
  • the volume ratio of the suspension of compound X615 to the HCl mixed solution is preferably 50:(8-12), more preferably 50:10.
  • the temperature of the deprotection reaction is preferably 20 to 30°C, and the deprotection reaction can be carried out at room temperature; the time of the deprotection reaction is preferably 1.5 to 2.5 hours, more preferably 2 hours.
  • the present invention preferably concentrates the obtained product system, mixes the residue with water, adjusts the pH value of the system to 13 to 13.5 within 1 hour at 15 to 20°C with an alkali metal hydroxide aqueous solution, and then extracts with dichloromethane or 1,2-dichloroethane, and the organic layer is dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain the racemic compound X616.
  • the alkali metal hydroxide in the alkali metal hydroxide aqueous solution preferably includes lithium hydroxide, potassium hydroxide or cesium hydroxide, and the concentration of the alkali metal hydroxide aqueous solution is preferably 0.5 to 1.5 mol/L, more preferably 1 mol/L; the pH value of the system is further preferably adjusted to 13.2 using the alkali metal hydroxide aqueous solution.
  • the present invention mixes the racemic compound X616, a chiral resolution agent and a ninth solvent to perform chiral resolution to obtain compound X617.
  • the chiral resolution agent preferably includes D-(+)-dibenzoyltartaric acid (D-DBTA), (+)-tartaric acid, (+)-camphoric acid or L-(+)-glycine.
  • the ninth solvent is preferably an ethanol-water-acetic acid mixed solvent, wherein the volume ratio of ethanol, water and acetic acid is preferably (6.5-7.5): (2.8-3.3): 1.
  • the dosage ratio of the racemic compound X616, the chiral resolution agent and the ninth solvent is preferably 7.1 mmol: (8-9) mmol: (80-90) mL.
  • the method of obtaining compound X617 by chiral resolution of the present invention preferably comprises the following steps: mixing racemic compound X616 with part of the ninth solvent to obtain a solution of compound X616; mixing a chiral resolution agent with the remaining ninth solvent to obtain a chiral resolution compound X617; The method comprises the steps of: adding the chiral separation reagent solution to a solution of compound X616 at 50 to 60° C., and performing a first stirring treatment at 65 to 75° C.
  • the alkali in the aqueous alkali solution preferably includes lithium hydroxide, sodium hydroxide, potassium hydroxide or cesium hydroxide, and the concentration of the aqueous alkali solution is preferably 0.5 to 1.5 mol/L.
  • the present invention mixes the compound X617, the third alkaline reagent, the aqueous hydrogen peroxide solution, dimethyl sulfoxide and the tenth solvent to carry out a cyanolysis reaction to obtain compound X618.
  • the third alkaline reagent is preferably an aqueous sodium hydroxide solution, and the concentration of the aqueous sodium hydroxide solution is preferably 4.5-5.5 mol/L, more preferably 5 mol/L; the concentration of the aqueous hydrogen peroxide solution is preferably 28-32 wt%, more preferably 30 wt%; the tenth solvent is preferably ethanol.
  • the amount ratio of the compound X617, the third alkaline reagent, the aqueous hydrogen peroxide solution, dimethyl sulfoxide and the tenth solvent is preferably 2.0 mmol: (4-6) mL: (4-6) mL: (4-6) mL: (4-6) mL, more preferably 2.0 mmol: 5 mL: 5 mL: 5 mL: 5 mL.
  • the present invention preferably mixes the compound X617, dimethyl sulfoxide and the tenth solvent, and then adds the third alkaline reagent and the aqueous hydrogen peroxide solution to carry out a cyanolysis reaction.
  • the temperature of the cyanohydrolysis reaction is preferably 75 to 85°C, more preferably 80°C; the time is preferably 5.5 to 6.5h, more preferably 6h.
  • the cyanohydrolysis reaction of the compound X617 is carried out in the presence of a third alkaline reagent, and the reaction is thorough; especially when the compound X617 is a deuterated compound, the process of the cyanohydrolysis reaction in the presence of a third alkaline reagent (such as sodium hydroxide aqueous solution) does not involve hydrogen-deuterium exchange, which is conducive to ensuring that a deuterated pyrazolopyrimidine derivative with a specific deuterated site is finally obtained.
  • a third alkaline reagent such as sodium hydroxide aqueous solution
  • the present invention preferably concentrates the obtained product system to remove the tenth solvent, then extracts with ethyl acetate or toluene, and the organic layer is dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain compound X618.
  • the present invention mixes the compound X618, compound X619 (the preparation method of some compounds is described in detail later), the fourth base reagent and the eleventh solvent, and performs an amide reaction to obtain a deuterated pyrazolopyrimidine derivative having a structure shown in Formula I.
  • the fourth base reagent is preferably sodium carbonate;
  • the eleventh solvent is preferably an acetonitrile-water mixed solvent, wherein the volume ratio of acetonitrile to water is preferably 5: (3.5-4.5), and more preferably 5: 4.
  • the amount ratio of the compound X618, compound X619, the fourth base reagent and the eleventh solvent is preferably 1.2 mmol: (2-2.8) mmol: (4.4-5.2) mmol: (40-50) mL, and more preferably 1.2 mmol: 2.4 mmol: 4.8 mmol: 45 mL.
  • the present invention preferably mixes the compound X618 with water and part of acetonitrile to obtain a solution of the compound X618; mixes the compound X619 with the remaining acetonitrile to obtain a solution of the compound X619; adds a fourth base reagent to the obtained solution of the compound X618, and then drips the solution of the compound X619 at -2 to 2°C to carry out an amide reaction;
  • the volume ratio of water to acetonitrile in the solution of the compound X618 is preferably 1:(0.8 to 1.2), more preferably 1:1; the solution of the compound X619 is more preferably dripped at 0°C.
  • the temperature of the amide reaction is preferably 20 to 30°C, and the amide reaction can be carried out at room temperature; the time of the amide reaction is preferably 0.5 to 1.5h, more preferably 1h; the time of the amide reaction is specifically calculated after the dripping of the solution of the compound X619 is completed.
  • the present invention preferably extracts the obtained product system with ethyl acetate or toluene, dries the organic layer with anhydrous sodium sulfate, filters, concentrates the filtrate, and purifies the obtained residue by silica gel column chromatography to obtain a deuterated pyrazolopyrimidine derivative having a structure shown in Formula I.
  • the eluent used for the purification is preferably ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is preferably 1: (9-11), more preferably 1: 10; the boiling range of the petroleum ether is preferably 60-90°C.
  • the present invention provides a method for preparing polydeuterated phenols, wherein the polydeuterated phenols are 3,4,5-trideuterated phenol (compound D541), 2,3,5,6-tetradeuterated phenol (compound D545) and 2,6-dideuterated phenol (compound D546), and the structure
  • the formulas are as follows:
  • the preparation method of 3,4,5-trideuterated phenol comprises the following steps:
  • the fifth alkali reagent is preferably triethylamine; the second catalyst is preferably a Pd/C catalyst, and the content of Pd in the Pd/C catalyst is preferably 10wt%; the thirteenth solvent is preferably methanol.
  • the dosage ratio of the compound PD541, the fifth alkali reagent and the thirteenth solvent is preferably 75.9mmol: (90-95)mmol: (450-550)mL, more preferably 75.9mmol: 91.2mmol: 500mL; the mass of the second catalyst is preferably 2.5-3.5% of the mass of the compound PD541, more preferably 3%.
  • the compound PD541 is preferably dissolved in the thirteenth solvent, the fifth alkali reagent and the second catalyst are added, the reaction bottle containing the obtained reaction liquid is sealed, the gas in the bottle is replaced three times with high-purity argon, and then replaced twice with deuterium gas (D 2 ), and a deuterium gas (D 2 ) ball is connected to perform a trideuterated phenol reaction.
  • the temperature of the trideuterated phenol formation reaction is preferably 15 to 35°C, more preferably 20 to 30°C, and the trideuterated phenol formation reaction can be carried out at room temperature; the time of the trideuterated phenol formation reaction is preferably 2.5 to 3.5 hours, more preferably 3 hours.
  • the present invention preferably filters the obtained product system to remove solids, distills the obtained filtrate at normal pressure, collects the 181 to 187°C fraction, and obtains 3,4,5-trideuterated phenol.
  • the preparation method of 2,3,5,6-tetradeuterated phenol comprises the following steps:
  • the sixth alkaline reagent is preferably triethylamine; the third catalyst is preferably a Pd/C catalyst, and the content of Pd in the Pd/C catalyst is preferably 10wt%; the fourteenth solvent is preferably methanol.
  • the dosage ratio of the compound PD545, the sixth alkaline reagent and the fourteenth solvent is preferably 75.4mmol: (90-95)mmol: (450-550)mL, more preferably 75.4mmol: 90.5mmol: 500mL; the mass of the third catalyst is preferably 2.5-3.5% of the mass of the compound PD545, more preferably 3%.
  • the present invention preferably dissolves the compound PD545 in the fourteenth solvent, adds the sixth alkaline reagent and the third catalyst, seals the reaction bottle containing the obtained reaction liquid, replaces the gas in the bottle with high-purity argon three times, and then replaces it with hydrogen twice, connects a hydrogen balloon, and performs a tetradeuterated phenol reaction.
  • the temperature of the tetradeuterated phenol formation reaction is preferably 15 to 35° C., more preferably 20 to 30° C., and the tetradeuterated phenol formation reaction can be carried out at room temperature; the time of the tetradeuterated phenol formation reaction is preferably After the tetradeuterated phenol reaction, the product system is preferably filtered to remove solids, and the filtrate is distilled at normal pressure to collect the fraction at 181 to 187° C. to obtain 2,3,5,6-tetradeuterated phenol.
  • the preparation method of 2,6-dideuterated phenol comprises the following steps:
  • Phenol, potassium acetate, iridium catalyst and the fifteenth solvent are mixed and reacted in a deuterium atmosphere to form dideuterated phenol to obtain 2,6-dideuterated phenol.
  • the iridium catalyst is preferably C 43 H 57 ClIrN 3 , which can be prepared by a method well known to those skilled in the art (such as reference Organic Letters, 2021, 9297-9302);
  • the fifteenth solvent is preferably tetrahydrofuran, specifically anhydrous tetrahydrofuran.
  • the amount ratio of phenol, potassium acetate, iridium catalyst and fifteenth solvent is preferably 10mmol: (9-11)mmol: (0.18-0.22)mmol: (80-120)mL, more preferably 10mmol: 10mmol: 0.2mmol: 100mL.
  • the present invention preferably adds iridium catalyst, potassium acetate and phenol to the reaction bottle, seals the reaction bottle and introduces deuterium gas (D 2 ) with a balloon, and then adds the fifteenth solvent to carry out the dideuterated phenol reaction.
  • the temperature of the reaction to form dideuterated phenol is preferably 45 to 55° C., more preferably 50° C.; the time of the reaction to form dideuterated phenol is preferably 10 to 15 hours, more preferably 12 hours.
  • the present invention preferably filters the obtained product system, washes the filter residue with the fifteenth solvent, combines the filtrate and the washing liquid obtained by washing, and concentrates under reduced pressure to obtain 2,6-dideuterated phenol.
  • the present invention also provides a method for preparing trideuterated acryloyl chloride, comprising the following steps:
  • the twelfth solvent is preferably N,N-dimethylformamide (DMF).
  • the volume ratio of the compound PD543, oxalyl chloride and the twelfth solvent is preferably 3: (3.4-3.8): (0.05-0.07), and more preferably 3: 3.6: 0.06.
  • the present invention preferably adds the twelfth solvent and oxalyl chloride to tetradeuterated acrylic acid in sequence to carry out a deuterated acyl chloride reaction.
  • the temperature of the deuterated acyl chloride reaction is preferably 15-35°C, and more preferably 20-30°C.
  • the deuterated acyl chloride reaction can be carried out at room temperature; the time of the deuterated acyl chloride reaction is preferably 30-50min, and more preferably 40min.
  • the present invention preferably concentrates the obtained product system under reduced pressure to obtain trideuterated acryloyl chloride (i.e., compound D543).
  • the present invention provides a pharmaceutical composition, comprising an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient is at least one of the deuterated pyrazolopyrimidine derivative, its optical isomer, its pharmaceutically acceptable salt, its hydrate and its solvate described in the above technical solution.
  • the content of the active ingredient in the pharmaceutical composition is preferably a unit dose of a therapeutically effective amount.
  • the present invention provides a combination, comprising a first active ingredient and a second active ingredient; the first active ingredient is at least one of the deuterated pyrazolopyrimidine derivative, its optical isomer, its pharmaceutically acceptable salt, its hydrate and its solvate described in the above technical solution; the second active ingredient is an agent having therapeutic activity for allergic diseases, autoimmune diseases, inflammatory diseases or cancer.
  • the content of the first active ingredient in the combination is preferably a unit dose of a therapeutically effective amount.
  • the present invention provides the use of the deuterated pyrazolopyrimidine derivatives, their optical isomers, their pharmaceutically acceptable salts, their hydrates, their solvates, the pharmaceutical compositions described in the above technical solutions, or the conjugates described in the above technical solutions in the preparation of BTK inhibitors.
  • the deuterated pyrazolopyrimidine derivatives provided by the present invention have the effect of inhibiting BTK activity, so the deuterated pyrazolopyrimidine derivatives, their optical isomers, their pharmaceutically acceptable salts, their hydrates, their solvates, the pharmaceutical compositions described in the above technical solutions, or the conjugates described in the above technical solutions are used. It can be used to prepare BTK inhibitors.
  • the present invention provides use of the deuterated pyrazolopyrimidine derivatives, optical isomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, the pharmaceutical compositions described in the above technical solutions, or the conjugates described in the above technical solutions in the preparation of drugs for treating diseases associated with undesirable BTK activity, wherein the diseases are allergic diseases, autoimmune diseases, inflammatory diseases, or cancers.
  • the allergic disease preferably includes atopic dermatitis, contact dermatitis or wet itch; the autoimmune disease preferably includes rheumatoid arthritis, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, teratogenic arthritis, osteoarthritis, traumatic arthritis, gouty arthritis, Reiter's syndrome, polychondritis, acute synovitis, spondylitis, glomerulonephritis with nephrotic syndrome, glomerulonephritis without nephrotic syndrome, autoimmune blood system disorders, hemolytic anemia, aplastic anemia, idiopathic thrombocytopenia, neutropenia, autoimmune gastritis, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, host-versus-graft disease, allograft rejection, chronic
  • the inflammatory disease preferably comprises acute active hepatitis, chronic active hepatitis, pancreatitis, vasculitis, inflammatory pain, uve
  • deuterated drugs refer to drugs in which some or all hydrogen atoms in the drug molecule are replaced with deuterium. Since the shape and volume of deuterium in drug molecules are similar to those of hydrogen, deuterated drugs will retain the biological activity and selectivity of the original drug. Since the C-D bond is more stable than the C-H bond, the C-D bond of deuterated drugs is less likely to break during chemical reactions, and its half-life may be extended. However, due to the complexity of the 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.
  • Deuterium substitution at certain sites not only fails to extend the half-life, but may shorten it (Scott L. Harbeson, Roger D. Tung. Deuterium in Drug Discovery and Development, P405-406), deteriorating 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, so the sites that can be substituted by deuterium are unpredictable.
  • deuterium substitution can lead to metabolic switching, which can potentially lead to different proportions of known metabolites and new metabolites. This new metabolic property can change the toxicity, clearance rate and/or in vivo exposure of the drug, so the change in its properties caused by the metabolic switching of the deuterated drug is unpredictable.
  • the deuterated pyrazolopyrimidine derivatives provided by the present invention have good pharmacokinetic properties and have a longer elimination half-life compared with zabutinib, which is conducive to reducing the dosage and/or reducing toxic side effects.
  • the deuterated pyrazolopyrimidine derivatives provided by the present invention have the effect of inhibiting BTK activity, can be used to prepare BTK inhibitors and prepare drugs for treating diseases mediated by BTK (such as allergic diseases, autoimmune diseases, inflammatory diseases or cancer), and can also be used to prepare drugs for treating organ fibrosis diseases or immune inflammatory diseases.
  • Phenol-5d (compound D501, 5.0 g, 50.5 mmol), ethyl 4-fluorobenzoate (compound D502, 7.7 g, 49.5 mmol) and dimethyl sulfoxide (60 mL) were mixed, and potassium carbonate (13.7 g, 99.1 mmol) was added to the resulting mixture at 130°C with stirring, and the stirring reaction was maintained for 24 hours; after the reaction was completed, the resulting product system was extracted with ethyl acetate (100 mL ⁇ 3), the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated.
  • the hydrogen nuclear magnetic resonance spectrum of the compound D503 is: 1 HNMR (400 MHz, CDCl 3 ) ⁇ 8.2 (2H), 7.2 (2H), 4.55 (2H), 1.6 (3H).
  • the compound DA01 was dissolved in tetrahydrofuran (750 mL) to obtain a compound DA01 solution; malononitrile (compound D505, 3.4 g, 51.9 mmol) was mixed with anhydrous tetrahydrofuran (20 mL) to obtain a malononitrile solution; sodium hydride (2.1 g, 51.9 mmol) was mixed with tetrahydrofuran (150 mL) to obtain a sodium hydride suspension; the sodium hydride suspension was added dropwise to the malononitrile solution at 0°C for 25 min, and after the addition was complete, the compound DA01 solution was added and stirred for 30 min, and then stirred for reaction at room temperature (25°C) for 16 h, the obtained feed solution was cooled to 0°C and quenched with 1 mol/L hydrochloric acid (100 mL); the obtained product system was extracted with ethyl acetate (50 mL ⁇ 3), the organic layers
  • the compound D506 was dissolved in dioxane (50 mL), sodium carbonate (5.5 g, 51.9 mmol) and dimethyl sulfate (compound D507, 6.5 g, 51.9 mmol) were added, and the mixture was reacted at 90° C. for 4 h. After the reaction, the obtained product system was concentrated to remove the solvent, and the obtained residue was mixed with deionized water (100 mL), and then extracted with ethyl acetate (70 mL ⁇ 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • the nuclear magnetic resonance hydrogen spectrum of the compound D513 is: 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.6 (1H), 5.05 (1H), 4.1 (2H), 3.1 (3H), 3.0-2.6 (5H), 2.4 (1H), 1.76 (2H), 1.6 (2H), 1.46 (9H).
  • compound D508 (2.9 g, 10 mmol) was added to ethanol (70 mL), and then an aqueous solution of hydrazine hydrate (compound D509) (2 mL, mass fraction of 85%, 0.96 g, 10 mmol) was added dropwise at a rate of 1 mL/min. After the addition was completed, the mixture was refluxed at 90 °C for 4 h. After the reaction was completed, the product system was cooled to room temperature, the solvent was removed by rotary evaporation, the residue was mixed with water (50 mL), stirred at room temperature for 5 min, the white precipitate was collected, and compound D510 was obtained after drying.
  • the compound D513 (3.0 g, 11 mmol) and an acetic acid-toluene mixed solvent (80 mL, the volume ratio of acetic acid to toluene is 4:1) are added to the compound D510 (2.7 g, 10 mmol), and the mixture is reacted at 100°C for 8 h. After the reaction, the obtained product system is cooled to room temperature and concentrated. The residue is precipitated with methanol (30 mL), filtered, and the filter cake is washed with methanol and dried to obtain the compound D514.
  • the hydrogen nuclear magnetic resonance spectrum of the compound D514 is: 1 H NMR (400 MHz, DMSO) ⁇ 8.8 (1H), 8.1 (2H), 7.34 (1H), 7.2 (2H), 4.2 (2H), 3.75 (1H), 2.97 (2H), 2.1 (2H), 1.7 (2H), 1.4 (9H).
  • a Pd/C catalyst (380 mg, the Pd content of the Pd/C catalyst is 10 wt%) was added to a reactor containing tetrahydrofuran (60 mL), compound D514 (3.8 g, 7.7 mmol) and D-(+)-dibenzoyltartaric acid (D-DBTA, 2.8 g, 7.7 mmol), and H2 was introduced into the reactor by balloon, and the temperature was raised at 2°C/min. The reaction mixture was heated from room temperature to 40°C and stirred for 24 hours. After the reaction, the product system was cooled to room temperature and filtered. The filter cake was washed with tetrahydrofuran. The filtrate and the washing liquid were concentrated.
  • the hydrogen nuclear magnetic resonance spectrum of the compound D515 is: 1 HNMR (400 MHz, CDCl 3 ) ⁇ 7.9 (2H), 7.04 (2H), 5.35 (1H), 4.2 (2H), 4.12-4.00 (1H), 3.40 (2H), 2.80-2.6 (2H), 2.3 (1H), 2.1-1.90 (3H), 1.7 (1H), 1.45 (9H), 1.4-1.1 (1H).
  • Ethanol, water and acetic acid were mixed in a volume ratio of 7:3:1 to obtain an ethanol-water-acetic acid mixed solvent; D-(+)-dibenzoyltartaric acid (D-DBTA, 3.1 g, 8.5 mmol) was dissolved in the ethanol-water-acetic acid mixed solvent (15 mL) to obtain a D-DBTA solution; the racemic compound D516 (2.8 g, 7.1 mmol) was dissolved in the ethanol-water-acetic acid mixed solvent (70 mL) to obtain a racemic compound D516 solution; the D-DBTA solution was added to the racemic compound D516 solution at 55° C., and then stirred at 70° C.
  • D-DBTA D-(+)-dibenzoyltartaric acid
  • the obtained product system was cooled and crystallized, and the obtained solid material was separated by centrifugation, and the obtained solid material was successively treated with the ethanol-water-acetic acid mixed solvent (10 mL) and acetic acid.
  • the solid material was washed with ethanol (10 mL), dispersed in the ethanol-water-acetic acid mixed solvent (50 mL), stirred at 70 ° C for 4 h, and then cooled and crystallized and filtered.
  • a white solid mixture (specifically a combination of compound D517 and D-DBTA, as well as some free D-DBTA); the white solid mixture was mixed with dichloromethane (70 mL) and a 1 mol/L sodium hydroxide aqueous solution (30 mL), and stirred at room temperature for 2 h to hydrolyze the combination of compound D517 and D-DBTA to generate compound D517 and D-DBTA; then extracted with dichloromethane (50 mL ⁇ 3), combined the organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated the filtrate to obtain compound D517.
  • dichloromethane 70 mL
  • a 1 mol/L sodium hydroxide aqueous solution (30 mL)
  • the hydrogen nuclear magnetic resonance spectrum of the compound D517 is: 1 HNMR (400 MHz, CDCl 3 ) ⁇ 7.9(2H),7.04(2H),5.2(1H),4.05(1H),3.4(2H),3.1(2H),2.6(2H),2.3(1H),2.2-2.1(1H),2.1-1.9(1H),1.7(1H),1.6-1.4(1H),1.5-1.3(1H),1.4-1.2(1H).
  • the crude product of the compound D518 (500 mg, 1.2 mmol) was mixed with an acetonitrile-water mixed solvent (40 mL, the volume ratio of acetonitrile to water was 1:1), and then sodium carbonate (509 mg, 4.8 mmol) was added, and then an acetonitrile solution (5 mL) of acryloyl chloride (compound D519, 217 mg, 2.4 mmol) was added dropwise at 0°C. After the addition was complete, the reaction was stirred at room temperature for 1 h.
  • the obtained product system was extracted with ethyl acetate (50 mL ⁇ 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • the hydrogen nuclear magnetic resonance spectrum of the compound D200 is: 1 HNMR (400 MHz, CDCl 3 ) ⁇ 7.5 (2H), 7.04 (2H), 6.7-6.4 (2H), 6.2 (1H), 5.6 (1H), 5.4 (2H), 4.7 (1H), 4.2-3.9 (2H), 3.4 (2H), 3.0 (1H), 2.7-2.4 (2H), 2.2-1.9 (2H), 1.8 (1H), 1.6 (1H), 1.4 (1H), 1.4-1.2 (1H).
  • Compound D201 was prepared according to the method of Example 1, except that compound D501 in step (1) was replaced by compound D540; the structural formulas of compound D540 and compound D201 are shown below:
  • the hydrogen nuclear magnetic resonance spectrum of the compound D201 is: 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.5 (2H), 7.3-7.5 (2H), 7.1-7.0 (2H), 6.7-6.4 (2H), 6.2 (1H), 5.6 (1H), 5.4 (2H), 4.7 (1H), 4.2-3.9 (2H), 3.4 (2H), 3.0 (1H), 2.7-2.2 (2H), 2.2-1.9 (2H), 1.7-1.9 (1H), 1.6 (1H), 1.45 (1H), 1.4-1.2 (1H).
  • compound D202 was prepared according to the method of Example 1, except that compound D501 in step (1) was replaced by compound D541; the structural formula of compound D202 is shown below:
  • the hydrogen nuclear magnetic resonance spectrum of the compound D202 is: 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.5 (2H), 7.1-7.0 (4H), 6.7-6.4 (2H), 6.2 (1H), 5.6 (1H), 5.4 (2H), 4.7 (1H), 4.2-3.9 (2H), 3.4 (2H), 3.0 (1H), 2.7-2.2 (2H), 2.2-1.9 (2H), 1.7-1.9 (1H), 1.6 (1H), 1.45 (1H), 1.4-1.2 (1H).
  • Compound D203 was prepared according to the method of Example 1, except that compound D501 in step (1) was replaced by compound D542; the structural formulas of compound D542 and compound D203 are shown below:
  • the hydrogen nuclear magnetic resonance spectrum of the compound D203 is: 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.5 (2H), 7.3-7.5 (2H), 7.1-7.0 (4H), 6.7-6.4 (2H), 6.2 (1H), 5.6 (1H), 5.4 (2H), 4.7 (1H), 4.2-3.9 (2H), 3.4 (2H), 3.0 (1H), 2.7-2.2 (2H), 2.2-1.9 (2H), 1.7-1.9 (1H), 1.6 (1H), 1.45 (1H), 1.4-1.2 (1H).
  • N,N-dimethylformamide (DMF, 0.06 mL) was added to tetradeuterated acrylic acid (compound PD543, 3.0 mL), and then oxalyl chloride (3.6 mL) was added, and the mixture was stirred at room temperature for 40 min; after the reaction, the obtained product system was concentrated under reduced pressure to obtain compound D543.
  • the compound D543 had no signal in the hydrogen spectrum.
  • compound D204 was prepared according to the method of Example 1, except that compound D501 in step (1) was replaced by phenol (compound D544), and acryloyl chloride (compound D519) in step (7) was replaced by compound D543; the structural formulas of compound D544 and compound D204 are shown below:
  • the hydrogen nuclear magnetic resonance spectrum of the compound D204 is: 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.5 (2H), 7.3-7.5 (2H), 7.15 (1H), 7.1-7.0 (4H), 5.6 (1H), 5.4 (2H), 4.7 (1H), 4.2-3.9 (2H), 3.4 (2H), 3.0 (1H), 2.7-2.2 (2H), 2.2-1.9 (2H), 1.7-1.9 (1H), 1.6 (1H), 1.45 (1H), 1.4-1.2 (1H).
  • Compound D205 was prepared according to the method of Example 1, except that acryloyl chloride (compound D519) in step (7) was replaced by trideuterated acryloyl chloride (compound D543); the structural formula of the compound D205 is shown below:
  • the hydrogen nuclear magnetic resonance spectrum of the compound D205 is: 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.5 (2H), 7.1-7.0 (2H), 5.6 (1H), 5.4 (2H), 4.7 (1H), 4.2-3.9 (2H), 3.4 (2H), 3.0 (1H), 2.7-2.2 (2H), 2.2-1.9 (2H), 1.7-1.9 (1H), 1.6 (1H), 1.45 (1H), 1.4-1.2 (1H).
  • Compound D206 was prepared according to the method of Example 1, except that compound D501 in step (1) was replaced by compound D540, and acryloyl chloride (compound D519) in step (7) was replaced by trideuterated acryloyl chloride (compound D543); the structural formula of compound D206 is shown below:
  • Compound D207 was prepared according to the method of Example 1, except that compound D501 in step (1) was replaced by compound D541, and acryloyl chloride (compound D519) in step (7) was replaced by trideuterated acryloyl chloride (compound D543); the structural formula of compound D207 is shown below:
  • the hydrogen nuclear magnetic resonance spectrum of the compound D207 is: 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.5 (2H), 7.1-7.0 (4H), 5.6 (1H), 5.4 (2H), 4.7 (1H), 4.2-3.9 (2H), 3.4 (2H), 3.0 (1H), 2.7-2.2 (2H), 2.2-1.9 (2H), 1.7-1.9 (1H), 1.6 (1H), 1.45 (1H), 1.4-1.2 (1H).
  • Compound D208 was prepared according to the method of Example 1, except that compound D501 in step (1) was replaced by compound D542, and acryloyl chloride (compound D519) in step (7) was replaced by trideuterated acryloyl chloride (compound D543); the structural formula of compound D208 is shown below:
  • the hydrogen nuclear magnetic resonance spectrum of the compound D208 is: 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.5 (2H), 7.3-7.5 (2H), 7.1-7.0 (4H), 5.6 (1H), 5.4 (2H), 4.7 (1H), 4.2-3.9 (2H), 3.4 (2H), 3.0 (1H), 2.7-2.2 (2H), 2.2-1.9 (2H), 1.7-1.9 (1H), 1.6 (1H), 1.45 (1H), 1.4-1.2 (1H).
  • the hydrogen nuclear magnetic resonance spectrum of the compound D209 is: 1 HNMR (400 MHz, CDCl 3 ) ⁇ 7.5 (2H), 7.15 (1H), 7.1-7.0 (2H), 6.7-6.4 (2H), 6.2 (1H), 5.6 (1H), 5.4 (2H), 4.7 (1H), 4.2-3.9 (2H), 3.4 (2H), 3.0 (1H), 2.7-2.2 (2H), 2.2-1.9 (2H), 1.9-1.7 (1H), 1.6 (1H), 1.45 (1H), 1.4-1.2 (1H).
  • compound D210 was prepared according to the method of Example 1, except that compound D501 in step (1) was replaced by compound D546; the structural formula of compound D210 is shown below:
  • the hydrogen nuclear magnetic resonance spectrum of the compound D210 is: 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.5 (2H), 7.5-7.3 (2H), 7.15 (1H), 7.1-7.0 (2H), 6.7-6.4 (2H), 6.2 (1H), 5.6 (1H), 5.4 (2H), 4.7 (1H), 4.2-3.9 (2H), 3.4 (2H), 3.0 (1H), 2.7-2.2 (2H), 2.2-1.9 (2H), 1.9-1.7 (1H), 1.6 (1H), 1.45 (1H), 1.4-1.2 (1H).
  • the hydrogen nuclear magnetic resonance spectrum of the compound D211 is: 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.5 (2H), 7.15 (1H), 7.10-7.00 (4H), 6.7-6.4 (2H), 6.24 (1H), 5.65 (1H), 5.4 (2H), 4.75 (1H), 4.2-3.9 (2H), 3.4 (2H), 3.0 (1H), 2.7-2.2 (2H), 2.3-1.9 (2H), 1.9-1.7 (1H), 1.6 (1H), 1.46 (1H), 1.3 (1H).
  • Compound D212 was prepared according to the method of Example 1, except that compound D501 in step (1) was replaced by compound D545, and acryloyl chloride (compound D519) in step (7) was replaced by trideuterated acryloyl chloride (compound D543); the structural formula of compound D212 is shown below:
  • the hydrogen nuclear magnetic resonance spectrum of the compound D212 is: 1 HNMR (400 MHz, CDCl 3 ) ⁇ 7.5 (2H), 7.15 (1H), 7.1-7.0 (2H), 5.6 (1H), 5.4 (2H), 4.7 (1H), 4.2-3.9 (2H), 3.4 (2H), 3.0 (1H), 2.7-2.2 (2H), 2.2-1.9 (2H), 1.9-1.7 (1H), 1.6 (1H), 1.45 (1H), 1.4-1.2 (1H).
  • Compound D213 was prepared according to the method of Example 1, except that compound D501 in step (1) was replaced by compound D546, and acryloyl chloride (compound D519) in step (7) was replaced by trideuterated acryloyl chloride (compound D543); the structural formula of compound D213 is shown below:
  • the hydrogen nuclear magnetic resonance spectrum of the compound D213 is: 1 H NMR (400 MHz, CDCl 3 ) ⁇ 7.5 (2H), 7.3-7.5 (2H), 7.15 (1H), 7.1-7.0 (2H), 5.6 (1H), 5.4 (2H), 4.7 (1H), 4.2-3.9 (2H), 3.4 (2H), 3.0 (1H), 2.7-2.2 (2H), 2.2-1.9 (2H), 1.9-1.7 (1H), 1.6 (1H), 1.45 (1H), 1.2-1.4 (1H).
  • Compound D214 was prepared according to the method of Example 1, except that compound D501 in step (1) was replaced by compound D547, and acryloyl chloride (compound D519) in step (7) was replaced by trideuterated acryloyl chloride (compound D543); the structural formula of compound D214 is shown below:
  • the hydrogen nuclear magnetic resonance spectrum of the compound D214 is: 1 HNMR (400 MHz, CDCl 3 ) ⁇ 7.5 (2H), 7.15 (1H), 7.1-7.0 (4H), 5.6 (1H), 5.4 (2H), 4.7 (1H), 4.2-3.9 (2H), 3.4 (2H), 3.0 (1H), 2.7-2.2 (2H), 2.2-1.9 (2H), 1.9-1.7 (1H), 1.6 (1H), 1.45 (1H), 1.2-1.4 (1H).
  • 96 male Sprague-Dawley rats (7-8 weeks old, weighing about 220 g) were divided into 16 groups (zanubrutinib group, compound D200 group, compound D201 group, compound D202 group, compound D203 group, compound D204 group, compound D205 group, compound D206 group, compound D207 group, compound D208 group, compound D209 group, compound D210 group, compound D211 group, compound D212 group, compound D213 group and compound D214 group).
  • mice in each group were given a single oral administration of 30 mg/kg dose of zanubrutinib, compound D200, compound D201, compound D202, compound D203, compound D204, compound D205, compound D206, compound D207, compound D208, compound D209, compound D210, compound D211, compound D212, compound D213 and compound D214 according to the groups, and the pharmacokinetic differences of each compound were compared.
  • each rat was fed with a standard feed and fasted 12 h before administration; the administration solution was prepared with methylcellulose (MC) and water (0.5 g of methylcellulose was added to every 100 mL of water); 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h and 24 h after administration were blood collection time points, 0.25 mL of blood was collected from the orbital venous plexus of each rat and placed in a centrifuge tube coated with sodium heparin solution, and then the centrifuge tube was immediately and gently inverted at least 5 times to ensure sufficient mixing and then placed on ice; the blood sample was then centrifuged at a temperature of 4 ° C and a speed of 12000 rpm for 4 min to separate the plasma from the red blood cells in the blood sample; 100 ⁇ L of plasma was aspirated with a pipette and placed in a clean plastic centrifuge tube, the sample number and blood collection time
  • ATP and substrate Biotin-AVLESEEELYSSARQ-NH 2
  • ATP and substrate Biotin-AVLESEEELYSSARQ-NH 2
  • the BTKpTyr223 cell assay can be used to detect the level of BTKTyr223 phosphorylation in cells.
  • the kinase activity of BTK depends on the phosphorylation of the Tyr223 site. This experiment uses this detection method to determine the inhibitory activity of zanubrutinib and the deuterated pyrazolopyrimidine derivatives provided by the present invention on BTKTyr223 phosphorylation, as follows:
  • Ramos cells were cultured in vitro with RPMI1640 medium containing 0.5% fetal bovine serum to a certain cell density, and then the cell suspension was collected, centrifuged, resuspended and diluted to 4 ⁇ 10 6 cells/mL with fresh medium, and 25 ⁇ L of cell suspension was added to each well of a 96-well plate.
  • Zebutinib and deuterated pyrazolopyrimidine derivatives were diluted with medium to different concentration gradients, and then 5 ⁇ L of different concentrations of compounds (6X) were added to each well of the 96-well plate and placed in a 37°C incubator for 1 hour.
  • the IC 50 values of each compound were fitted by graphpadPrism 9 software, and the specific results are shown in Table 3. As can be seen from Table 3, zabutinib and the deuterated pyrazolopyrimidine derivatives provided by the present invention have good inhibitory activity against BTKTyr223 phosphorylation.
  • Tumor cell xenograft models can be used to evaluate the inhibitory effect of drugs on tumor growth in vivo.
  • This experiment used the established human TMD-8 cell xenograft tumor model to evaluate the anti-tumor effects of zanubrutinib and the deuterated pyrazolopyrimidine derivatives provided by the present invention, as follows:
  • TMD-8 cells were cultured in RPMI1640 medium containing 10% FBS to a certain cell mass, and the cell suspension was collected and centrifuged at 1000rpm for 5min. After discarding the medium, the cells were resuspended in PBS precooled at 4°C and diluted to 2 ⁇ 108 cells/mL, and then the cell suspension was mixed with an equal volume of matrigel and placed on ice for later use. Before tumor bearing, the right back skin of NOD-SCID mice was disinfected with 75% ethanol, and then 100 ⁇ L (1 ⁇ 107 cells/mouse) of TMD-8 cell suspension was injected with a syringe. After slow injection, the subcutaneous bulge was slowly drawn out, and the needle was pressed to prevent cell overflow.
  • mice After 7 to 10 days of tumor bearing, when the tumor volume grew to more than 100 mm3, the animals were randomly divided into 17 groups, namely control group, 6 mg/kg zanubrutinib group, 6 mg/kg compound D200 group, 6 mg/kg compound D201 group, 6 mg/kg compound D202 group, 6 mg/kg compound D203 group, 6 mg/kg compound D204 group, 6 mg/kg compound D205 group, 6 mg/kg compound D206 group, 6 mg/kg compound D207 group, 6 mg/kg compound D208 group, 6 mg/kg compound D209 group, 6 mg/kg compound D210 group, 6 mg/kg compound D211 group, 6 mg/kg compound D212 group, 6 mg/kg compound D213 group and 6 mg/kg compound D214 group, with 5 to 10 mice in each group.
  • control group 6 mg/kg zanubrutinib group, 6 mg/kg compound D200 group, 6 mg/kg compound D201 group, 6 mg/kg compound D202 group, 6 mg/kg compound D203 group, 6 mg/
  • mice in the drug administration group were gavaged with 6 mg/kg of the test compound once in the morning and evening every day. From the start of drug administration, the tumor volume and body weight of the mice were measured every other day.
  • the tumor inhibition rate of each group at 40 days of drug administration was calculated, as shown in Table 4.
  • the tumor inhibition rate of compounds D200-D202, D204-D208 is significantly better than that of zanubrutinib
  • the tumor inhibition rate of compounds D203, D209, D213-D214 is slightly better than that of zanubrutinib
  • the tumor inhibition rate of compounds D210-D212 is slightly lower than that of zanubrutinib.
  • REC1 cells were cultured in RPMI1640 medium containing 10% FBS to a certain cell mass, and the cell suspension was collected and centrifuged at 1000rpm for 5min. After discarding the medium, the cells were resuspended in PBS precooled at 4°C and diluted to 2 ⁇ 108 cells/mL, and then the cell suspension was mixed with an equal volume of matrigel and placed on ice for later use. Before tumor bearing, the right back skin of NOD-SCID mice was disinfected with 75% ethanol, and then 100 ⁇ L (1 ⁇ 107 cells/mouse) of REC1 cell suspension was injected with a syringe. After slow injection, the subcutaneous bulge was slowly drawn out, and the needle was pressed to prevent cell overflow.
  • mice After 7 to 10 days of tumor bearing, when the tumor volume grew to more than 100 mm3, the animals were randomly divided into 17 groups, namely control group, 6 mg/kg zanubrutinib group, 6 mg/kg compound D200 group, 6 mg/kg compound D201 group, 6 mg/kg compound D202 group, 6 mg/kg compound D203 group, 6 mg/kg compound D204 group, 6 mg/kg compound D205 group, 6 mg/kg compound D206 group, 6 mg/kg compound D207 group, 6 mg/kg compound D208 group, 6 mg/kg compound D209 group, 6 mg/kg compound D210 group, 6 mg/kg compound D211 group, 6 mg/kg compound D212 group, 6 mg/kg compound D213 group and 6 mg/kg compound D214 group, with 5 to 10 mice in each group.
  • control group 6 mg/kg zanubrutinib group, 6 mg/kg compound D200 group, 6 mg/kg compound D201 group, 6 mg/kg compound D202 group, 6 mg/kg compound D203 group, 6 mg/
  • mice in the drug administration group were gavaged with 6 mg/kg of the test compound once in the morning and evening every day. From the start of drug administration, the tumor volume and body weight of the mice were measured every other day.
  • the tumor inhibition rate of each group at 40 days of drug administration was calculated, and the specific results are shown in Table 5.
  • the tumor inhibition rates of compounds D200-D208 and compounds D213-214 are significantly better than those of zanubrutinib
  • the tumor inhibition rates of compounds D209 and D212 are slightly better than those of zanubrutinib
  • the tumor inhibition rates of compounds D210-D211 are slightly lower than those of zanubrutinib.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Neurology (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Oncology (AREA)
  • Transplantation (AREA)
  • Pain & Pain Management (AREA)
  • Pulmonology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Epidemiology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明提供了氘代吡唑并嘧啶衍生物及其制备方法和药物组合物、结合物及应用，属于医药技术领域。本发明提供的氘代吡唑并嘧啶衍生物的药代动力学性质良好，有利于降低使用剂量和/或降低毒副作用。本发明提供的氘代吡唑并嘧啶衍生物能够抑制BTK活性，可以用于制备BTK抑制剂以及制备治疗与不期望的BTK活性相关的疾病(如过敏性疾病、自身免疫性疾病、炎症疾病或癌症)的药物。

Description

氘代吡唑并嘧啶衍生物及其制备方法和药物组合物、结合物及应用
本申请要求于2023年01月09日提交中国专利局、申请号为CN2023100275164、发明名称为“氘代吡唑并嘧啶衍生物及其制备方法和药物组合物、结合物及应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及医药技术领域，具体涉及氘代吡唑并嘧啶衍生物及其制备方法和药物组合物、结合物及应用。
背景技术
布鲁顿酪氨酸激酶(Bruton’s tyrosine kinase，BTK)属于Tec酪氨酸激酶家族(Vetrie et al.,Nature,361:226-233,1993；Bradshaw Cell Signal.,22:1175-84,2010)。BTK主要在大多数造血细胞如B细胞、肥大细胞和巨噬细胞中表达(Smith et al.,J.Immunol.,152:557-565,1994)，并且位于骨髓、脾脏和淋巴结组织中。BTK在B细胞受体(B-cell receptor，BCR)和FcR信号通路中起着重要的作用，这些信号通路参与B细胞发育、分化(Khan，Immunol.Res.,23:147,2001)。BTK被上游Src家族激酶活化，一旦被活化，BTK会反过来使PLCγ磷酸化，进而影响B细胞的功能和存活(Humphries et al.,J.Biol.Chem.,279:37651,2004)。因此这些信号通路必须被精确地调节。编码BTK的基因中的突变会导致人的遗传性B细胞特异性免疫缺陷疾病，被称为X-连锁无丙种球蛋白血症(X-linked agammaglobulinemia，XLA)(Conley et al.,Annu.Rev.Immunol.,27:199-227,2009)。BCR介导信号的异常可能会导致B细胞活化的失调，进而导致许多自身免疫性疾病和炎症疾病。
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 et al.,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，故BTK抑制剂作为抗炎和/或抗癌药物成为人们研究热点(Mohamed et al.,Immunol.Rev.,228:58-73,2009；Pan,Drug News perspect,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)。
泽布替尼(Zanubrutinib，BGB-3111)是BTK选择性抑制剂，其能够与BTK活性位点中的半胱氨酸形成共价键，从而抑制BTK活性。泽布替尼胶囊(百悦泽，BRUKINSA，Zanubrutinib capsules)由百济神州有限公司研发，2019年11月在美国获批上市，2020年6月在中国获批上市，可以用于治疗既往至少接受过一种治疗的成人套细胞淋巴瘤(MCL)以及既往至少接受过一种治疗的成人慢性淋巴细胞白血病(CLL)/小淋巴细胞淋巴瘤(SLL)。
泽布替尼胶囊的推荐剂量为每次160mg，口服，每日两次。泽布替尼每日给药两次，提示其半衰期相对较短，药代动力学特性有较大的优化空间。
发明内容
本发明的目的在于提供一种氘代吡唑并嘧啶衍生物及其制备方法和药物组合物、结合物及应用，本发明提供的氘代吡唑并嘧啶衍生物优化了泽布替尼的药代动力学特性，预期具有更好的治疗顺应性和效果。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了一种具有式I所示结构的氘代吡唑并嘧啶衍生物或其光学异构体、药学上可接受的盐、水合物或溶剂化物；
式I中X1、X2、X3、X4、X5和X6中至少一个是氘。
优选地，所述X4、X5和X6均为氢，或者至少一个是氘。
优选地，所述X4、X5和X6均为氢，且所述X1、X2和X3中至少一个是氘，或者至少两个是氘，或者均为氘。
优选地，所述X4、X5和X6中至少一个是氘，且所述X1、X2和X3均为氢，或者至少一个是氘，或者至少两个是氘，或者均为氘。
优选地，所述X4、X5和X6中至少两个是氘，且所述X1、X2和X3均为氢，或者至少一个是氘，或者至少两个是氘，或者均为氘。
优选地，所述X4、X5和X6均为氘，且所述X1、X2和X3均为氢，或者至少一个是氘，或者至少两个是氘，或者均为氘。
优选地，所述氘代吡唑并嘧啶衍生物为以下化合物中的至少一种：

本发明提供了上述技术方案所述氘代吡唑并嘧啶衍生物的制备方法，包括以下步骤：
(1)将化合物X601、化合物X602、干燥剂与第一溶剂混合，进行成醚反应，得到化合物X603；
将所述化合物X603、第一碱试剂与第二溶剂混合，进行酯水解反应，得到化合物X604；
将所述化合物X604与酰氯化试剂混合，进行成酰氯反应，得到中间体化合物；将所述中间体化合物、丙二腈、还原剂与第三溶剂混合，进行亲核反应，得到化合物X606；
将所述化合物X606、甲基化试剂、第二碱试剂与第四溶剂混合，进行甲基化反应，得到化合物X608；
将所述化合物X608、水合肼与第五溶剂混合，进行第一成环反应，得到化合物X610；
(2)将化合物X611与化合物X612混合，进行成共轭双键反应，得到化合物X613；
(3)将所述化合物X610、化合物X613与第六溶剂混合，进行第二成环反应，得到化合物X614；
将所述化合物X614、酸试剂、第一催化剂与第七溶剂混合，在氢气氛围中进行还原反应，得到化合物X615；
将所述化合物X615、盐酸与第八溶剂混合，进行脱保护反应，得到外消旋体化合物X616；
将所述外消旋体化合物X616、手性拆分试剂与第九溶剂混合，进行手性拆分，得到化合物X617；
将所述化合物X617、第三碱试剂、过氧化氢水溶液、二甲基亚砜与第十溶剂混合，进行氰水解反应，得到化合物X618；
将所述化合物X618、化合物X619、第四碱试剂与第十一溶剂混合，进行成酰胺反应，得到具有式I所示结构的氘代吡唑并嘧啶衍生物；
所述化合物X601、化合物X602、化合物X603、化合物X604、化合物X606、化合物X608、化合物X610、化合物X611、化合物X612、化合物X613、化合物X614、化合物X615、外消旋体化合物X616、化合物X617、化合物X618与化合物X619的结构式依次如下所示：

所述X1、X2、X3、X4、X5和X6如式I所定义；所述Z为氢或氘，所述Y为卤素原子；
所述步骤(1)与步骤(2)无先后顺序。
本发明提供了一种三氘代丙烯酰氯及多氘代苯酚的制备方法，包括以下步骤：
将化合物PD543、草酰氯与第十二溶剂混合，进行成氘代酰氯反应，得到三氘代丙烯酰氯；所述化合物PD543与三氘代丙烯酰氯的结构式依次如下所示：
所述多氘代苯酚为3,4,5-三氘代苯酚、2,3,5,6-四氘代苯酚和2,6-二氘代苯酚；
所述3,4,5-三氘代苯酚的制备方法包括以下步骤：
将化合物PD541、第五碱试剂、第二催化剂与第十三溶剂混合，在氘气氛围中进行成三氘代苯酚反应，得到3,4,5-三氘代苯酚；
所述2,3,5,6-四氘代苯酚的制备方法包括以下步骤：
将化合物PD545、第六碱试剂、第三催化剂与第十四溶剂混合，在氘气氛围中进行成四氘代苯酚反应，得到2,3,5,6-四氘代苯酚；
所述2,6-二氘代苯酚的制备方法包括以下步骤：
将苯酚、乙酸钾、铱催化剂与第十五溶剂混合，在氘气氛围中进行成二氘代苯酚反应，得到2,6-二氘代苯酚；
所述化合物PD541与化合物PD545的结构式依次如下所示：
本发明提供了一种药物组合物，包括活性成分和药学上可接受的载体，所述活性成分为上述技术方案所述氘代吡唑并嘧啶衍生物、其光学异构体、其药学上可接受的盐、其水合物和其溶剂化物中的至少一种。
本发明提供了一种结合物，包括第一活性成分和第二活性成分；所述第一活性成分为上述技术方案所述氘代吡唑并嘧啶衍生物、其光学异构体、其药学上可接受的盐、其水合物和其溶剂化物中的至少一种；所述第二活性成分为对过敏性疾病、自身免疫性疾病、炎症疾病或癌症具有治疗活性的试剂。
本发明提供了上述技术方案所述氘代吡唑并嘧啶衍生物、其光学异构体、其药学上可接受的盐、其水合物、其溶剂化物、上述技术方案所述药物组合物或上述技术方案所述结合物在制备BTK抑制剂中的应用。
本发明提供了上述技术方案所述氘代吡唑并嘧啶衍生物、其光学异构体、其药学上可接受的盐、其水合物、其溶剂化物、上述技术方案所述药物组合物或上述技术方案所述结合物在制备治疗与不期望的BTK活性相关的疾病的药物中的应用，所述疾病为过敏性疾病、自身免疫性疾病、炎症疾病或癌症。
优选地，所述过敏性疾病包括特应性皮炎、接触性皮炎或湿痒。
优选地，所述自身免疫性疾病包括类风湿性关节炎、银屑病性关节炎、感染性关节炎、进行性慢性关节炎、致畸性关节炎、骨关节炎、创伤性关节炎、痛风性关节炎、Reiter氏综合症、多软骨炎、急性滑膜炎、脊椎炎、有肾病综合症的肾小球肾炎、没有肾病综合症的肾小球肾炎、自身免疫性血液系统病症、溶血性贫血、再生障碍性贫血、特发性血小板减少症、嗜中性白血球减少症、自身免疫性胃炎、自身免疫性炎性肠病、溃病性结肠炎、Crohn氏病、宿主抗移植物病、同种异体移植物排斥、慢性甲状腺炎、格雷夫斯氏病、硬皮病、原发性胆汁性肝硬化、重症肌无力、多发性硬化症、系统性红斑狼疮或银屑病。
优选地，所述炎症疾病包括急性活动性肝炎、慢性活动性肝炎、胰腺炎、血管炎、炎性痛、葡萄膜炎、结膜炎、角膜结膜炎、中耳炎、牙周病、支气管炎、鼻炎或窦炎。
优选地，所述癌症包括非霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤、B细胞慢性淋巴细胞性白血病、急性成淋巴细胞性白血病、具有成熟B细胞的急性成淋巴细胞性白血病、由慢性活动型B细胞受体信号传导引起的B细胞淋巴瘤或与多发性骨髓瘤相关的骨病。
本发明提供了一种氘代吡唑并嘧啶衍生物或其光学异构体、药学上可接受的盐、水合物或溶剂化物，本发明提供的氘代吡唑并嘧啶衍生物的药代动力学性质良好，有利于降低使用剂量和/或降低毒副作用。本发明提供的氘代吡唑并嘧啶衍生物能够抑制BTK活性，可以用于制备BTK抑制剂以及制备治疗与不期望的BTK活性相关的疾病(如过敏性疾病、自身免疫性疾病、炎症疾病或癌症)的药物。
本发明提供了所述氘代吡唑并嘧啶衍生物的制备方法，本发明提供的氘代吡唑并嘧啶衍生物的合成路线设计合理，能够针对性得到具有特定氘代位点的氘代吡唑并嘧啶衍生物。
具体实施方式
本发明提供了一种具有式I所示结构的氘代吡唑并嘧啶衍生物或其光学异构体、药学上可接受的盐、水合物或溶剂化物；
式I中X1、X2、X3、X4、X5和X6中至少一个是氘。
在本发明中，所述X4、X5和X6优选均为氢，且所述X1、X2和X3中优选至少一个是氘，或者优选至少两个是氘，或者优选均为氘。
在本发明中，所述X4、X5和X6中优选至少一个是氘，且所述X1、X2和X3均为氢，或者优选至少一个是氘，或者优选至少两个是氘，或者优选均为氘。
在本发明中，所述X4、X5和X6中优选至少两个是氘，且所述X1、X2和X3均为氢，或者优选至少一个是氘，或者优选至少两个是氘，或者优选均为氘。
在本发明中，所述X4、X5和X6优选均为氘，且所述X1、X2和X3均为氢，或者优选至少一个是氘，或者优选至少两个是氘，或者优选均为氘。
在本发明中，所述氘代吡唑并嘧啶衍生物优选为以下化合物中的至少一种：

本发明提供了上述技术方案所述氘代吡唑并嘧啶衍生物的制备方法，包括以下步骤：
(1)将化合物X601、化合物X602、干燥剂与第一溶剂混合，进行成醚反应，得到化合物X603；
将所述化合物X603、第一碱试剂与第二溶剂混合，进行酯水解反应，得到化合物X604；
将所述化合物X604与酰氯化试剂混合，进行成酰氯反应，得到中间体化合物；将所述中间体化合物、丙二腈、还原剂与第三溶剂混合，进行亲核反应，得到化合物X606；
将所述化合物X606、甲基化试剂、第二碱试剂与第四溶剂混合，进行甲基化反应，得到化合物X608；
将所述化合物X608、水合肼与第五溶剂混合，进行第一成环反应，得到化合物X610；
(2)将化合物X611与化合物X612混合，进行成共轭双键反应，得到化合物X613；
(3)将所述化合物X610、化合物X613与第六溶剂混合，进行第二成环反应，得到化合物X614；
将所述化合物X614、酸试剂、第一催化剂与第七溶剂混合，在氢气氛围中进行还原反应，得到化合物X615；
将所述化合物X615、盐酸与第八溶剂混合，进行脱保护反应，得到外消旋体化合物X616；
将所述外消旋体化合物X616、手性拆分试剂与第九溶剂混合，进行手性拆分，得到化合物X617；
将所述化合物X617、第三碱试剂、过氧化氢水溶液、二甲基亚砜与第十溶剂混合，进行氰水解反应，得到化合物X618；
将所述化合物X618、化合物X619、第四碱试剂与第十一溶剂混合，进行成酰胺反应，得到具有式I所示结构的氘代吡唑并嘧啶衍生物；
所述化合物X601、化合物X602、化合物X603、化合物X604、化合物X606、化合物X608、化合物X610、化合物X611、化合物X612、化合物X613、化合物X614、化合物X615、外消旋体化合物X616、化合物X617、化合物X618与化合物X619的结构式依次如下所示：

所述X1、X2、X3、X4、X5和X6如式I所定义；所述Z为氢或氘，所述Y为卤素原子；
所述步骤(1)与步骤(2)无先后顺序。
在本发明中，若无特殊说明，所用原料均为本领域技术人员熟知的市售商品或采用本领域技术人员熟知的方法制备得到。
本发明分别制备化合物X610与化合物X613，然后再利用二者制备具有式I所示结构的氘代吡唑并嘧啶衍生物，下面进行详细说明。
在本发明中，制备化合物X610的反应式如下所示，其中甲基化试剂具体以硫酸二甲酯(化合物X607)为例进行说明：
本发明将化合物X601、化合物X602、干燥剂与第一溶剂混合，进行成醚反应，得到化合物X603。在本发明中，所述化合物X601为苯酚或氘代苯酚；在本发明的实施例中，根据所述氘代吡唑并嘧啶衍生物的结构，所述氘代苯酚具体为以下化合物中的任一 种(部分化合物的制备方法在后文详述)：
在本发明中，所述化合物X602中Y为卤素原子，即所述化合物X602为4-卤代苯甲酸乙酯；所述卤素原子优选为-F、-Cl、-Br或-I，更优选为-F。在本发明中，所述干燥剂优选包括碳酸钾、碳酸钠或碳酸铯，更优选为碳酸钾；所述第一溶剂优选包括二甲亚砜、N,N-二甲基甲酰胺、乙腈或丙酮。在本发明中，所述化合物X601、化合物X602、干燥剂与第一溶剂的用量比优选为50.5mmol：(45～55)mmol：(90～110)mmol：(50～70)mL，更优选为50.5mmol：49.5mmol：99.1mmol：60mL。本发明优选将化合物X601、化合物X602与第一溶剂混合，然后向所得混合液中加入干燥剂，进行成醚反应；加入所述干燥剂时，所述混合液的温度优选为125～135℃，更优选为130℃。在本发明中，所述成醚反应的温度优选为125～135℃，更优选为130℃；时间优选为20～30h，更优选为24h。本发明在干燥剂存在条件下通过化合物X601与化合物X602反应生成化合物X603；尤其是在干燥剂(如碳酸钾)存在条件下基于氘代苯酚与化合物X602(如4-氟苯甲酸乙酯)反应生成氘代二苯醚，反应过程中不涉及氢氘交换，有利于保证最终得到具有特定氘代位点的氘代吡唑并嘧啶衍生物。所述成醚反应后，本发明优选将所得产物体系经乙酸乙酯萃取，有机层用无水硫酸镁干燥，过滤，将滤液进行浓缩，所得残留物采用硅胶柱色谱法进行纯化，得到化合物X603。在本发明中，所述纯化采用的洗脱剂优选为乙酸乙酯和石油醚，所述乙酸乙酯和石油醚的体积比优选为1：(9～11)，更优选为1：10；所述石油醚的沸程优选为60～90℃。
得到化合物X603后，本发明将所述化合物X603、第一碱试剂与第二溶剂混合，进行酯水解反应，得到化合物X604。在本发明中，所述第一碱试剂优选包括氢氧化钠水溶液、氢氧化钾水溶液或氢氧化锂水溶液，更优选为氢氧化钠水溶液，所述第一碱试剂的浓度优选为0.5～1.5mol/L，更优选为1mol/L；所述第二溶剂优选为四氢呋喃-乙醇混合溶剂，其中四氢呋喃与乙醇的体积比优选为1：(0.8～1.2)，更优选为1：1。在本发明中，所述化合物X603、第一碱试剂与第二溶剂的用量比优选为18.2mmol：(4～6)mL：(15～25)mL，更优选为18.2mmol：5mL：20mL。本发明对所述化合物X603、第一碱试剂与第二溶剂混合的方式没有特殊限定，能够实现均匀混合即可。在本发明中，所述酯水解反应的温度优选为75～85℃，更优选在体系回流(80℃)条件下进行所述酯水解反应；所述酯水解反应的时间优选为3.5～4.5h，更优选为4h。在本发明中，所述化合物X603的酯水解反应在第一碱试剂存在条件下进行，反应彻底；尤其是当所述化合物X603为氘代化合物时，在第一碱试剂(如氢氧化钠水溶液)存在条件下进行酯水解反应的过程中不涉及氢氘交换，有利于保证最终得到具有特定氘代位点的氘代吡唑并嘧啶衍生物。所述酯水解反应后，本发明优选向所得产物体系中加入浓盐酸或浓硫酸调节pH值为2.5～3.5，然后采用乙酸乙酯或甲苯萃取，有机层用无水硫酸钠干燥，过滤，将滤液进行浓缩，得到化合物X604。在本发明中，所述浓盐酸的浓度优选为36～38wt％，所述浓硫酸的浓度优选为96～98wt％；本发明优选采用浓盐酸或浓硫酸调节体系pH值为3。
得到化合物X604后，本发明将所述化合物X604与酰氯化试剂混合，进行成酰氯反 应，得到中间体化合物。在本发明中，所述酰氯化试剂优选包括二氯亚砜或五氯化磷；以所述酰氯化试剂为二氯亚砜为例，所述化合物X604与二氯亚砜的用量比优选为17.3mmol：(45～55)mL，更优选为17.3mmol：50mL。在本发明中，所述成酰氯反应的温度优选为75～85℃，更优选在体系回流(80℃)条件下进行所述成酰氯反应；所述成酰氯反应的时间优选为3.5～4.5h，更优选为4h。所述成酰氯反应后，本发明优选将所得产物体系进行浓缩以去除未反应的酰氯化试剂，得到的油状物为中间体化合物，结构式具体如下所示：
得到中间体化合物后，本发明将所述中间体化合物、丙二腈(化合物X605)、还原剂与第三溶剂混合，进行亲核反应，得到化合物X606。在本发明中，所述还原剂优选为氢化钠；所述第三溶剂优选为四氢呋喃。在本发明中，以所述化合物X604的添加量为基准计，所述化合物X604、丙二腈、还原剂与第三溶剂的用量比优选为17.3mmol：(47～57)mmol：(47～57)mmol：(900～950)mL，更优选为17.3mmol：51.9mmol：51.9mmol：920mL。本发明优选将所述中间体化合物、丙二腈以及还原剂分别与第三溶剂混合，得到中间体化合物溶液、丙二腈溶液以及还原剂料液；然后在0℃条件下，向所述丙二腈溶液中滴加所述还原剂料液，滴加完毕后加入所述中间体化合物溶液并搅拌20～30min，然后进行亲核反应；所述还原剂料液的滴加速率优选为5～7mL/min，更优选为6mL/min。在本发明中，所述亲核反应的温度优选为20～30℃，更优选在室温(25℃)条件下进行所述亲核反应；所述亲核反应的时间优选为12～20h，更优选为16h。达到所述亲核反应的时间后，本发明优选将所得料液冷却至0℃并用盐酸淬灭反应，然后将所得产物体系用乙酸乙酯或甲苯萃取，有机层依次用水与饱和食盐水洗涤，再用无水硫酸钠干燥，过滤，将滤液进行浓缩，得到化合物X606。在本发明中，淬灭反应所用盐酸的浓度优选为0.5～1.5mol/L，更优选为1mol/L。
得到化合物X606后，本发明将所述化合物X606、甲基化试剂、第二碱试剂与第四溶剂混合，进行甲基化反应，得到化合物X608。在本发明中，所述甲基化试剂优选包括硫酸二甲酯或碘甲烷；所述第二碱试剂优选为碳酸钠；所述第四溶剂优选为二噁烷。在本发明中，以所述化合物X604的添加量为基准计，所述化合物X604、甲基化试剂、第二碱试剂与第四溶剂的用量比优选为17.3mmol：(47～57)mmol：(47～57)mmol：(45～55)mL，更优选为17.3mmol：51.9mmol：51.9mmol：50mL。本发明优选将化合物X606溶于第四溶剂中，然后向所得混合液中加入第二碱试剂以及甲基化试剂，进行甲基化反应。在本发明中，所述甲基化反应的温度优选为85～95℃，更优选为90℃；时间优选为3.5～4.5h，更优选为4h。所述甲基化反应后，本发明优选将所得产物体系进行浓缩以除去溶剂，将所得剩余物与水混合，然后采用乙酸乙酯或甲苯萃取，有机层经无水硫酸钠干燥，过滤，将滤液进行浓缩，所得残留物采用硅胶柱色谱法进行纯化，得到化合物X608。在本发明中，所述纯化采用的洗脱剂优选为乙酸乙酯和石油醚，所述乙酸乙酯和石油醚的体积比优选为1：(9～11)，更优选为1：10；所述石油醚的沸程优选为60～90℃。
得到化合物X608后，本发明将所述化合物X608、水合肼与第五溶剂混合，进行第一成环反应，得到化合物X610。在本发明中，所述水合肼优选以水合肼水溶液形式使用，所述水合肼水溶液的浓度优选为80～90wt％，更优选为85wt％；所述第五溶剂优选为乙醇。在本发明中，所述化合物X608、水合肼水溶液与第五溶剂的用量比优选为10mmol： (1.8～2.2)mL：(65～75)mL，更优选为10mmol：2mL：70mL。本发明优选将所述化合物X608与第五溶剂混合，然后向所得混合液中滴加水合肼水溶液，进行第一成环反应；所述水合肼水溶液的滴加速率优选为0.8～1.2mL/min，更优选为1mL/min。在本发明中，所述第一成环反应的温度优选为85～95℃，更优选在体系回流(90℃)条件下进行所述第一成环反应；所述第一成环反应的时间优选为3.5～4.5h，更优选为4h，所述第一成环反应的时间以所述水合肼水溶液滴加完毕开始计。所述第一成环反应后，本发明优选将所得产物体系冷却至室温，经旋转蒸发除去溶剂，将所得剩余物与水混合，在室温条件下搅拌3～5min析出沉淀，收集所述沉淀并干燥，得到化合物X610。
在本发明中，制备化合物X613的反应式如下所示：
本发明将化合物X611与化合物X612混合，进行成共轭双键反应，得到化合物X613。在本发明中，所述化合物X611与化合物X612的摩尔比优选为21.1：(70～80)，更优选为21.1：75。在本发明中，所述成共轭双键反应的温度优选为105～115℃，更优选为110℃；时间优选为45～50h，更优选为48h。所述成共轭双键反应后，本发明优选将所得产物体系进行浓缩，将剩余物与沉淀溶剂混合，析出沉淀物，过滤，挥干滤饼中溶剂，得到化合物X613。在本发明中，所述沉淀溶剂优选包括石油醚、正己烷或环己烷。
在本发明中，基于所述化合物X610以及化合物X613制备具有式I所示结构的氘代吡唑并嘧啶衍生物的反应式如下所示：
本发明将所述化合物X610、化合物X613与第六溶剂混合，进行第二成环反应，得到化合物X614。在本发明中，所述第六溶剂优选为乙酸-甲苯混合溶剂，其中乙酸与甲苯的体积比优选为(3.5～4.5)：1，更优选为4：1。在本发明中，所述化合物X610、化合物X613与第六溶剂的用量比优选为10mmol：10～12mmol：(75～85)mL，更优选为10mmol：11mmol：80mL。本发明优选将化合物X613与第六溶剂加入到所述化合物X610中，进行第二成环反应。在本发明中，所述第二成环反应的温度优选为95～105℃，更优选为100℃；时间优选为7.5～8.5h，更优选为8h。所述第二成环反应后，本发明优选将所得产物体系冷却至室温后进行浓缩，剩余物经甲醇沉淀，过滤，滤饼用甲醇洗涤，干 燥后得到化合物X614。
得到化合物X614后，本发明将所述化合物X614、酸试剂、第一催化剂与第七溶剂混合，在氢气氛围中进行还原反应，得到化合物X615。在本发明中，所述酸试剂优选包括D-(+)-二苯甲酰酒石酸或醋酸，更优选为D-(+)-二苯甲酰酒石酸；所述第一催化剂优选为Pd/C催化剂，所述Pd/C催化剂中Pd的含量优选为10wt％；所述第七溶剂优选为四氢呋喃。在本发明中，所述化合物X614、酸试剂与第七溶剂的用量比优选为7.7mmol：(7.5～8)mmol：(55～65)mL，更优选为7.7mmol：7.7mmol：60mL；所述第一催化剂的质量优选为化合物X614质量的8～12％，更优选为10％。本发明优选在N2保护条件下，向化合物X614、酸试剂和第七溶剂的混合物中加入第一催化剂，然后向体系中通入氢气进行还原反应。在本发明中，所述还原反应的温度优选为35～45℃，更优选为40℃；升温至所述还原反应的温度的升温速率优选为1～5℃/min，更优选为2～4℃/min；所述还原反应的时间优选为16～32h，更优选为24h。在本发明中，所述化合物X614的还原反应在酸试剂存在条件下进行，反应收率高；尤其是当所述化合物X614为氘代化合物时，在酸试剂(如D-(+)-二苯甲酰酒石酸)存在条件下进行还原反应的过程中不涉及氢氘交换，有利于保证最终得到具有特定氘代位点的氘代吡唑并嘧啶衍生物，且反应收率高。所述还原反应后，本发明优选将所得产物体系冷却至室温，过滤，滤饼用四氢呋喃洗涤，将滤液以及洗涤液进行浓缩，剩余物与二氯甲烷或1,2-二氯乙烷混合，然后用饱和碳酸氢钠水溶液洗涤，浓缩后将剩余物用沉淀剂进行沉淀，过滤，滤饼用甲醇洗涤，干燥后得到化合物X614。在本发明中，所述沉淀剂优选为甲基叔丁基醚与己烷的混合物，所述甲基叔丁基醚与己烷的体积比优选为1：(2.5～3.5)，更优选为1：3；所述己烷优选为正己烷或环己烷。
得到化合物X615后，本发明将所述化合物X615、盐酸与第八溶剂混合，进行脱保护反应，得到外消旋体化合物X616。在本发明中，所述第八溶剂优选为乙酸乙酯。本发明优选将化合物X615与部分第八溶剂混合，得到化合物X615混悬液；将HCl与剩余第八溶剂混合，然后将所得HCl混合液加入到所述化合物X615混悬液中，进行脱保护反应；所述化合物X615混悬液的浓度优选为0.1～0.2mol/L，更优选为0.148mol/L；所述HCl混合液中HCl的浓度优选为3.5～4.5mol/L，更优选为4mol/L；所述化合物X615混悬液与HCl混合液的体积比优选为50：(8～12)，更优选为50：10。在本发明中，所述脱保护反应的温度优选为20～30℃，具体可以在室温条件下进行所述脱保护反应；所述脱保护反应的时间优选为1.5～2.5h，更优选为2h。所述脱保护反应后，本发明优选将所得产物体系进行浓缩，剩余物与水混合，在15～20℃条件下用碱金属氢氧化物水溶液在1h内将体系的pH值调节至13～13.5，然后用二氯甲烷或1,2-二氯乙烷萃取，有机层用无水硫酸钠干燥，过滤，将滤液进行浓缩，得到外消旋体化合物X616。在本发明中，所述碱金属氢氧化物水溶液中碱金属氢氧化物优选包括氢氧化锂、氢氧化钾或氢氧化铯，所述碱金属氢氧化物水溶液的浓度优选为0.5～1.5mol/L，更优选为1mol/L；采用所述碱金属氢氧化物水溶液将体系pH值进一步优选调节至13.2。
得到外消旋体化合物X616后，本发明将所述外消旋体化合物X616、手性拆分试剂与第九溶剂混合，进行手性拆分，得到化合物X617。在本发明中，所述手性拆分试剂优选包括D-(+)-二苯甲酰酒石酸(D-DBTA)、(+)-酒石酸、(+)-樟脑酸或L-(+)-甘氨酸。在本发明中，所述第九溶剂优选为乙醇-水-乙酸混合溶剂，其中乙醇、水与乙酸的体积比优选为(6.5～7.5)：(2.8～3.3)：1。在本发明中，所述外消旋体化合物X616、手性拆分试剂与第九溶剂的用量比优选为7.1mmol：(8～9)mmol：(80～90)mL。本发明通过手性拆分得到化合物X617的方法，优选包括以下步骤：将外消旋体化合物X616与部分第九溶剂混合，得到化合物X616溶液；将手性拆分试剂与剩余第九溶剂混合，得到手性拆 分试剂溶液；向50～60℃的化合物X616溶液中加入所述手性拆分试剂溶液，在65～75℃条件下进行第一搅拌处理3.5～4.5h；然后将所得产物体系进行冷却结晶，经离心分离，所得固体物料依次用所述第九溶剂以及乙醇洗涤，将洗涤后固体物料分散于所述第九溶剂中，在65～75℃条件下进行第二搅拌处理3.5～4.5h；之后经冷却结晶以及过滤，重复所述第二搅拌处理的过程两次，得到白色固体混合物；将所述白色固体混合物与二氯甲烷(或1,2-二氯乙烷)以及碱水溶液混合，在20～30℃条件下搅拌1.5～2.5h，用二氯甲烷(或1,2-二氯乙烷)萃取，有机层用无水硫酸钠干燥，过滤，将滤液进行浓缩，得到化合物X617。在本发明中，所述碱水溶液中碱优选包括氢氧化锂、氢氧化钠、氢氧化钾或氢氧化铯，所述碱水溶液的浓度优选为0.5～1.5mol/L。
得到化合物X617后，本发明将所述化合物X617、第三碱试剂、过氧化氢水溶液、二甲基亚砜与第十溶剂混合，进行氰水解反应，得到化合物X618。在本发明中，所述第三碱试剂优选为氢氧化钠水溶液，所述氢氧化钠水溶液的浓度优选为4.5～5.5mol/L，更优选为5mol/L；所述过氧化氢水溶液的浓度优选为28～32wt％，更优选为30wt％；所述第十溶剂优选为乙醇。在本发明中，所述化合物X617、第三碱试剂、过氧化氢水溶液、二甲基亚砜与第十溶剂的用量比优选为2.0mmol：(4～6)mL：(4～6)mL：(4～6)mL：(4～6)mL，更优选为2.0mmol：5mL：5mL：5mL：5mL。本发明优选将所述化合物X617、二甲基亚砜与第十溶剂混合，然后加入所述第三碱试剂以及过氧化氢水溶液，进行氰水解反应。在本发明中，所述氰水解反应的温度优选为75～85℃，更优选为80℃；时间优选为5.5～6.5h，更优选为6h。在本发明中，所述化合物X617的氰水解反应在第三碱试剂存在条件下进行，反应彻底；尤其是当所述化合物X617为氘代化合物时，在第三碱试剂(如氢氧化钠水溶液)存在条件下进行氰水解反应的过程中不涉及氢氘交换，有利于保证最终得到具有特定氘代位点的氘代吡唑并嘧啶衍生物。所述氰水解反应后，本发明优选将所得产物体系进行浓缩以去除第十溶剂，再经乙酸乙酯或甲苯萃取，有机层用无水硫酸钠干燥，过滤，将滤液进行浓缩，得到化合物X618。
得到化合物X618后，本发明将所述化合物X618、化合物X619(部分化合物的制备方法在后文详述)、第四碱试剂与第十一溶剂混合，进行成酰胺反应，得到具有式I所示结构的氘代吡唑并嘧啶衍生物。在本发明中，所述第四碱试剂优选为碳酸钠；所述第十一溶剂优选为乙腈-水混合溶剂，其中乙腈与水的体积比优选为5：(3.5～4.5)，更优选为5：4。在本发明中，所述化合物X618、化合物X619、第四碱试剂与第十一溶剂的用量比优选为1.2mmol：(2～2.8)mmol：(4.4～5.2)mmol：(40～50)mL，更优选为1.2mmol：2.4mmol：4.8mmol：45mL。本发明优选将所述化合物X618与水以及部分乙腈混合，得到化合物X618溶液；将化合物X619与剩余乙腈混合，得到化合物X619溶液；向所得化合物X618溶液中加入第四碱试剂，之后在-2～2℃条件下滴加化合物X619溶液，进行成酰胺反应；所述化合物X618溶液中水与乙腈的体积比优选为1：(0.8～1.2)，更优选为1：1；所述化合物X619溶液更优选在0℃条件下滴加。在本发明中，所述成酰胺反应的温度优选为20～30℃，具体可以在室温条件下进行所述成酰胺反应；所述成酰胺反应的时间优选为0.5～1.5h，更优选为1h；所述成酰胺反应的时间具体以化合物X619溶液滴加完毕计。所述成酰胺反应后，本发明优选将所得产物体系用乙酸乙酯或甲苯萃取，有机层用无水硫酸钠干燥，过滤，将滤液进行浓缩，所得残留物采用硅胶柱色谱法进行纯化，得到具有式I所示结构的氘代吡唑并嘧啶衍生物。在本发明中，所述纯化采用的洗脱剂优选为乙酸乙酯和石油醚，所述乙酸乙酯和石油醚的体积比优选为1：(9～11)，更优选为1：10；所述石油醚的沸程优选为60～90℃。
本发明提供了多氘代苯酚的制备方法，所述多氘代苯酚为3,4,5-三氘代苯酚(化合物D541)、2,3,5,6-四氘代苯酚(化合物D545)和2,6-二氘代苯酚(化合物D546)，结构 式依次如下所示：
下面分别对所述3,4,5-三氘代苯酚、2,3,5,6-四氘代苯酚和2,6-二氘代苯酚的制备方法进行详细说明。
在本发明中，所述3,4,5-三氘代苯酚的制备方法包括以下步骤：
将化合物PD541、第五碱试剂、第二催化剂与第十三溶剂混合，在氘气氛围中进行成三氘代苯酚反应，得到3,4,5-三氘代苯酚；所述化合物PD541的结构式如下所示：
在本发明中，所述第五碱试剂优选为三乙胺；所述第二催化剂优选为Pd/C催化剂，所述Pd/C催化剂中Pd的含量优选为10wt％；所述第十三溶剂优选为甲醇。在本发明中，所述化合物PD541、第五碱试剂与第十三溶剂的用量比优选为75.9mmol：(90～95)mmol：(450～550)mL，更优选为75.9mmol：91.2mmol：500mL；所述第二催化剂的质量优选为所述化合物PD541质量的2.5～3.5％，更优选为3％。本发明优选将化合物PD541溶于第十三溶剂中，加入第五碱试剂和第二催化剂，将盛放有所得反应料液的反应瓶密封，用高纯氩置换三次瓶中气体，再用氘气(D2)置换两次，上接氘气(D2)球，进行成三氘代苯酚反应。在本发明中，所述成三氘代苯酚反应的温度优选为15～35℃，更优选为20～30℃，具体可以在室温条件下进行所述成三氘代苯酚反应；所述成三氘代苯酚反应的时间优选为2.5～3.5h，更优选为3h。所述成三氘代苯酚反应后，本发明优选将所得产物体系进行抽滤除去固体，所得滤液在常压下蒸馏，收集181～187℃馏分，得到3,4,5-三氘代苯酚。
在本发明中，所述2,3,5,6-四氘代苯酚的制备方法包括以下步骤：
将化合物PD545、第六碱试剂、第三催化剂与第十四溶剂混合，在氘气氛围中进行成四氘代苯酚反应，得到2,3,5,6-四氘代苯酚；所述化合物PD545的结构式如下所示：
在本发明中，所述第六碱试剂优选为三乙胺；所述第三催化剂优选为Pd/C催化剂，所述Pd/C催化剂中Pd的含量优选为10wt％；所述第十四溶剂优选为甲醇。在本发明中，所述化合物PD545、第六碱试剂与第十四溶剂用量比优选为75.4mmol：(90～95)mmol：(450～550)mL，更优选为75.4mmol：90.5mmol：500mL；所述第三催化剂的质量优选为所述化合物PD545质量的2.5～3.5％，更优选为3％。本发明优选将化合物PD545溶于第十四溶剂中，加入第六碱试剂和第三催化剂，将盛放有所得反应料液的反应瓶密封，用高纯氩置换三次瓶中气体，再用氢气置换两次，上接氢气球，进行成四氘代苯酚反应。在本发明中，所述成四氘代苯酚反应的温度优选为15～35℃，更优选为20～30℃，具体可以在室温条件下进行所述成四氘代苯酚反应；所述成四氘代苯酚反应的时间优选为 2.5～3.5h，更优选为3h。所述成四氘代苯酚反应后，本发明优选将所得产物体系进行抽滤除去固体，所得滤液在常压下蒸馏，收集181～187℃馏分，得到2,3,5,6-四氘代苯酚。
在本发明中，所述2,6-二氘代苯酚的制备方法包括以下步骤：
将苯酚、乙酸钾、铱催化剂与第十五溶剂混合，在氘气氛围中进行成二氘代苯酚反应，得到2,6-二氘代苯酚。
在本发明中，所述铱催化剂优选为C43H57ClIrN3，采用本领域技术人员熟知的方法制备得到即可(如可参考文献Organic Letters，2021，9297-9302)；所述第十五溶剂优选为四氢呋喃，具体为无水四氢呋喃。在本发明中，所述苯酚、乙酸钾、铱催化剂与第十五溶剂的用量比优选为10mmol：(9～11)mmol：(0.18～0.22)mmol：(80～120)mL，更优选为10mmol：10mmol：0.2mmol：100mL。本发明优选向反应瓶中加入铱催化剂、乙酸钾和苯酚，将反应瓶密封并用气球引入氘气(D2)，然后加入第十五溶剂，进行成二氘代苯酚反应。在本发明中，所述成二氘代苯酚反应的温度优选为45～55℃，更优选为50℃；所述成二氘代苯酚反应的时间优选为10～15h，更优选为12h。所述成二氘代苯酚反应后，本发明优选将所得产物体系过滤，滤渣用第十五溶剂洗涤，将滤液以及洗涤所得洗液合并，减压浓缩，得到2,6-二氘代苯酚。
本发明还提供了一种三氘代丙烯酰氯的制备方法，包括以下步骤：
将化合物PD543、草酰氯与第十二溶剂混合，进行成氘代酰氯反应，得到三氘代丙烯酰氯；所述化合物PD543与三氘代丙烯酰氯的结构式依次如下所示：
在本发明中，所述第十二溶剂优选为N,N-二甲基甲酰胺(DMF)。在本发明中，所述化合物PD543、草酰氯与第十二溶剂的体积比优选为3：(3.4～3.8)：(0.05～0.07)，更优选为3：3.6：0.06。本发明优选向四氘代丙烯酸中依次加入第十二溶剂和草酰氯，进行成氘代酰氯反应。在本发明中，所述成氘代酰氯反应的温度优选为15～35℃，更优选为20～30℃，具体可以在室温条件下进行所述成氘代酰氯反应；所述成氘代酰氯反应的时间优选为30～50min，更优选为40min。所述成氘代酰氯反应后，本发明优选将所得产物体系减压浓缩，得到三氘代丙烯酰氯化(即化合物D543)。
本发明提供了一种药物组合物，包括活性成分和药学上可接受的载体，所述活性成分为上述技术方案所述氘代吡唑并嘧啶衍生物、其光学异构体、其药学上可接受的盐、其水合物和其溶剂化物中的至少一种。在本发明中，所述药物组合物中活性成分的含量优选为治疗有效量的单位剂量。
本发明提供了一种结合物，包括第一活性成分和第二活性成分；所述第一活性成分为上述技术方案所述氘代吡唑并嘧啶衍生物、其光学异构体、其药学上可接受的盐、其水合物和其溶剂化物中的至少一种；所述第二活性成分为对过敏性疾病、自身免疫性疾病、炎症疾病或癌症具有治疗活性的试剂。在本发明中，所述结合物中第一活性成分的含量优选为治疗有效量的单位剂量。
本发明提供了上述技术方案所述氘代吡唑并嘧啶衍生物、其光学异构体、其药学上可接受的盐、其水合物、其溶剂化物、上述技术方案所述药物组合物或上述技术方案所述结合物在制备BTK抑制剂中的应用。本发明提供的氘代吡唑并嘧啶衍生物具有抑制BTK活性的作用，因此所述氘代吡唑并嘧啶衍生物、其光学异构体、其药学上可接受的盐、其水合物、其溶剂化物、上述技术方案所述药物组合物或上述技术方案所述结合物 可以用于制备BTK抑制剂。
本发明提供了上述技术方案所述氘代吡唑并嘧啶衍生物、其光学异构体、其药学上可接受的盐、其水合物、其溶剂化物、上述技术方案所述药物组合物或上述技术方案所述结合物在制备治疗与不期望的BTK活性相关的疾病的药物中的应用，所述疾病为过敏性疾病、自身免疫性疾病、炎症疾病或癌症。在本发明中，所述过敏性疾病优选包括特应性皮炎、接触性皮炎或湿痒；所述自身免疫性疾病优选包括类风湿性关节炎、银屑病性关节炎、感染性关节炎、进行性慢性关节炎、致畸性关节炎、骨关节炎、创伤性关节炎、痛风性关节炎、Reiter氏综合症、多软骨炎、急性滑膜炎、脊椎炎、有肾病综合症的肾小球肾炎、没有肾病综合症的肾小球肾炎、自身免疫性血液系统病症、溶血性贫血、再生障碍性贫血、特发性血小板减少症、嗜中性白血球减少症、自身免疫性胃炎、自身免疫性炎性肠病、溃病性结肠炎、Crohn氏病、宿主抗移植物病、同种异体移植物排斥、慢性甲状腺炎、格雷夫斯氏病、硬皮病、原发性胆汁性肝硬化、重症肌无力、多发性硬化症、系统性红斑狼疮或银屑病；所述炎症疾病优选包括急性活动性肝炎、慢性活动性肝炎、胰腺炎、血管炎、炎性痛、葡萄膜炎、结膜炎、角膜结膜炎、中耳炎、牙周病、支气管炎、鼻炎或窦炎；所述癌症优选包括非霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、套细胞淋巴瘤(MCL)、B细胞慢性淋巴细胞性白血病、急性成淋巴细胞性白血病、具有成熟B细胞的急性成淋巴细胞性白血病、由慢性活动型B细胞受体信号传导引起的B细胞淋巴瘤或与多发性骨髓瘤相关的骨病。在本发明中，所述药物的剂型优选包括胶囊、片剂或注射剂；所述药物的给药方式优选包括口服或注射，所述注射优选为静脉注射；给药剂量优选为15～750mg/天。
在药学领域中，氘代药物是指将药物分子中的部分或全部氢原子替换为氘。由于氘在药物分子中形状和体积与氢接近，氘代药物一殷会保留原来药物的生物活性和选择性。由于C-D键比C-H键更稳定，使得氘代药物在化学反应过程中，C-D键更不容易断裂，其半衰期可能会延长。但是，由于生物系统的代谢过程复杂，药物在生物体内的药代动力学性质受到多方面因素影响，也表现出相应的复杂性。与相应的非氘代药物相比，氘代药物药代动力学性质的变化表现出极大的偶然性和不可预测性。某些位点的氘代非但不能延长半衰期，反而可能会使其缩短(Scott L.Harbeson,RogerD.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，因此，可氘代的位点是不可预期的。另外，氘代可导致代谢转换(metabolic switching)，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改变药物的毒性、清除率和/或体内暴露量，因此氘代药物的代谢转换导致的其性质改变是不可预测的。本发明提供的氘代吡唑并嘧啶衍生物的药代动力学性质良好，与泽布替尼相比具有较长的消除半衰期，有利于降低使用剂量和/或降低毒副作用。本发明提供的氘代吡唑并嘧啶衍生物具有抑制BTK活性的作用，可以用于制备BTK抑制剂以及制备治疗由BTK介导的疾病(如过敏性疾病、自身免疫性疾病、炎症疾病或癌症)的药物，还可以用于制备治疗器官纤维化疾病或免疫炎症疾病的药物。
下面将结合本发明中的实施例，对本发明中的技术方案进行清楚、完整地描述。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1化合物D200的合成
(1)制备化合物D503，反应式如下所示：
将苯酚-5d(化合物D501，5.0g，50.5mmol)、4-氟苯甲酸乙酯(化合物D502，7.7g，49.5mmol)与二甲亚砜(60mL)混合，在130℃且搅拌条件下向所得混合液中加入碳酸钾(13.7g，99.1mmol)，维持搅拌反应24h；反应结束后，所得产物体系经乙酸乙酯萃取(100mL×3)，合并有机层，用无水硫酸镁干燥，过滤，将滤液进行浓缩，所得残留物采用硅胶柱色谱法进行纯化(按体积比计，所用洗脱剂为乙酸乙酯：石油醚＝1：10，所述石油醚的沸程为60～90℃)，得到化合物D503(4.5g，36％)。所述化合物D503的核磁共振氢谱为：1HNMR(400MHz,CDCl3)δ8.2(2H),7.2(2H),4.55(2H),1.6(3H)。
(2)制备化合物D504，反应式如下所示：
向化合物D503(4.5g，18.2mmol)中加入四氢呋喃-乙醇混合溶剂(20mL，四氢呋喃与乙醇的体积比为1：1)与浓度为1mol/L的氢氧化钠水溶液(5mL)，加热至80℃，保持回流状态反应4h；反应结束后，向所得产物体系中加入浓盐酸(36～38wt％)酸化至pH值为3，然后采用乙酸乙酯萃取(70mL×3)，合并有机层，用无水硫酸钠干燥，过滤，将滤液进行浓缩，得到化合物D504。所述化合物D504的核磁共振氢谱为：1HNMR(400MHz,DMSO)δ12.8(1H),7.95(2H),7.0(2H)。
(3)制备化合物D508，反应式如下所示：
将化合物D504(3.8g，17.3mmol)与二氯亚砜(50mL)混合，在80℃且搅拌条件下回流反应4h；反应结束后，将所得产物体系浓缩以去除二氯亚砜，得到的油状物为化合物DA01；
将所述化合物DA01溶解于四氢呋喃(750mL)中，得到化合物DA01溶液；将丙二腈(化合物D505，3.4g，51.9mmol)与无水四氢呋喃(20mL)混合，得到丙二腈溶液；将氢化钠(2.1g，51.9mmol)与四氢呋喃(150mL)混合，得到氢化钠混悬液；在0℃条件下，向所述丙二腈溶液中滴加所述氢化钠混悬液，滴加时间为25min，滴加完毕后加入所述化合物DA01溶液并搅拌30min，然后在室温(25℃)条件下搅拌反应16h，将所得料液冷却至0℃并用浓度为1mol/L的盐酸(100mL)淬灭反应；将所得产物体系用乙酸乙酯萃取(50mL×3)，合并有机层，依次用水与饱和食盐水洗涤，再用无水硫酸钠干燥，过滤，将滤液进行浓缩，得到化合物D506；
将所述化合物D506溶解于二噁烷(50mL)中，加入碳酸钠(5.5g，51.9mmol)和硫酸二甲酯(化合物D507，6.5g，51.9mmol)，在90℃条件下反应4h；反应结束后，将所得产物体系进行浓缩以除去溶剂，将所得剩余物与去离子水(100mL)混合，然后用乙酸乙酯萃取(70mL×3)，合并有机层，用无水硫酸钠干燥，过滤，将滤液进行浓缩， 所得残留物采用硅胶柱色谱法进行纯化(按体积比计，所用洗脱剂为乙酸乙酯：石油醚＝1：10，所述石油醚的沸程为60～90℃)，得到化合物D508。所述化合物D508的核磁共振氢谱为：1H NMR(400MHz,CDCl3)δ7.5(2H),7.1(2H),3.98(3H)。
(4)制备化合物D514，反应式如下所示：
将4-乙酰哌啶-1-羧酸叔丁酯(化合物D511，4.8g，21.1mmol)与N,N-二甲基甲酰胺二甲缩醛(化合物D512，10mL，8.9g，75mmol)混合，在110℃条件下搅拌反应48h；反应结束后，将所得产物体系进行浓缩，剩余物与石油醚混合，析出沉淀物，过滤，挥干滤饼中溶剂，得到化合物D513。所述化合物D513的核磁共振氢谱为：1H NMR(400MHz,CDCl3)δ7.6(1H),5.05(1H),4.1(2H),3.1(3H),3.0-2.6(5H),2.4(1H),1.76(2H),1.6(2H),1.46(9H)。
在室温条件下，将化合物D508(2.9g，10mmol)加入乙醇(70mL)中，然后以1mL/min速率滴加水合肼(化合物D509)水溶液(2mL，质量分数为85％，0.96g，10mmol)，加料完毕后于90℃条件下回流反应4h；反应结束后，将所得产物体系冷却至室温，经旋转蒸发除去溶剂，将所得剩余物与水(50mL)混合，在室温条件下搅拌5min，收集白色沉淀，干燥后得化合物D510。
将所述化合物D513(3.0g，11mmol)与乙酸-甲苯混合溶剂(80mL，乙酸与甲苯的体积比为4：1)加入到所述化合物D510(2.7g，10mmol)中，在100℃条件下反应8h；反应结束后，将所得产物体系冷却至室温后进行浓缩，剩余物经甲醇(30mL)沉淀，过滤，滤饼用甲醇洗涤，干燥后得到化合物D514。所述化合物D514的核磁共振氢谱为：1H NMR(400MHz,DMSO)δ8.8(1H),8.1(2H),7.34(1H),7.2(2H),4.2(2H),3.75(1H),2.97(2H),2.1(2H),1.7(2H),1.4(9H)。
(5)制备化合物D515，反应式如下所示：
在N2保护条件下，向盛放有四氢呋喃(60mL)、化合物D514(3.8g，7.7mmol)和D-(+)-二苯甲酰酒石酸(D-DBTA，2.8g，7.7mmol)的反应器中加入Pd/C催化剂(380mg，所述Pd/C催化剂中Pd的含量为10wt％)，用气球将H2引入反应器，以2℃/min升温速 率从室温加热至40℃并搅拌反应24h；反应结束后，将所得产物体系冷却至室温，过滤，滤饼用四氢呋喃洗涤，将滤液以及洗涤液进行浓缩，剩余物与二氯甲烷(DCM，100mL)混合，然后用饱和碳酸氢钠水溶液(50mL)洗涤，浓缩后将剩余物用甲基叔丁基醚-正己烷混合试剂(100mL，所述甲基叔丁基醚和正己烷的体积比为1：3)沉淀，过滤，滤饼用甲醇洗涤，干燥后得到化合物D515。所述化合物D515的核磁共振氢谱为：1HNMR(400MHz,CDCl3)δ7.9(2H),7.04(2H),5.35(1H),4.2(2H),4.12-4.00(1H),3.40(2H),2.80-2.6(2H),2.3(1H),2.1-1.90(3H),1.7(1H),1.45(9H),1.4-1.1(1H)。
(6)制备化合物D517
将化合物D515(3.6g，7.4mmol)与乙酸乙酯(50mL)混合，得到化合物D515混悬液；在室温条件下，向所述化合物D515混悬液中加入盐酸的乙酸乙酯溶液(10mL，所述盐酸的乙酸乙酯溶液中HCl的浓度为4mol/L)，搅拌反应2h；反应结束后将所得产物体系进行浓缩，剩余物与水(50mL)混合，在20℃条件下用浓度为1mol/L的氢氧化钠水溶液在1h内将体系的pH值调节至13.2，然后用二氯甲烷萃取(50mL×3)，合并有机层，用无水硫酸钠干燥，过滤，将滤液进行浓缩，得到外消旋体化合物D516。
将乙醇、水与乙酸按体积比为7：3：1的比例混合，得到乙醇-水-乙酸混合溶剂；将D-(+)-二苯甲酰酒石酸(D-DBTA，3.1g，8.5mmol)溶解于所述乙醇-水-乙酸混合溶剂(15mL)中，得到D-DBTA溶液；将所述外消旋体化合物D516(2.8g，7.1mmol)溶解于所述乙醇-水-乙酸混合溶剂(70mL)中，得到外消旋体化合物D516溶液；向55℃的外消旋体化合物D516溶液中加入所述D-DBTA溶液，之后在70℃条件下搅拌反应4h；反应结束后，将所得产物体系进行冷却结晶，经离心分离，所得固体物料依次用所述乙醇-水-乙酸混合溶剂(10mL)以及乙醇(10mL)洗涤，将洗涤后固体物料分散于所述乙醇-水-乙酸混合溶剂(50mL)中，在70℃条件下搅拌4h，之后经冷却晶体以及过滤，重复此过程两次去除R构型化合物，得到白色固体混合物(具体为化合物D517与D-DBTA的结合物，同时还有部分游离D-DBTA)；将所述白色固体混合物与二氯甲烷(70mL)以及浓度为1mol/L的氢氧化钠水溶液(30mL)混合，在室温条件下搅拌2h，使化合物D517与D-DBTA的结合物水解生成化合物D517与D-DBTA；之后用二氯甲烷萃取(50mL×3)，合并有机层，用无水硫酸钠干燥，过滤，将滤液进行浓缩，得到化合物D517。所述化合物D517的核磁共振氢谱为：1HNMR(400MHz,CDCl3)δ7.9(2H),7.04(2H),5.2(1H),4.05(1H),3.4(2H),3.1(2H),2.6(2H),2.3(1H),2.2-2.1(1H),2.1-1.9(1H),1.7(1H),1.6-1.4(1H),1.5-1.3(1H),1.4-1.2(1H)。
(7)制备化合物D200，反应式如下所示：
将化合物D517(795mg，2.0mmol)、二甲基亚砜(5mL)与乙醇(5mL)混合，然后加入浓度为5mol/L的氢氧化钠水溶液(5mL)和浓度为30wt％的双氧水溶液(5mL)，在80℃条件下搅拌反应6h；反应结束后，将所得产物体系进行浓缩以去除乙醇，再经乙酸乙酯萃取(50mL×3)，合并有机层，用无水硫酸钠干燥，过滤，将滤液进行浓缩，得到化合物D518的粗产物。
将所述化合物D518(500mg，1.2mmol)的粗产物与乙腈-水混合溶剂(40mL，乙腈与水的体积比为1:1)混合，然后加入碳酸钠(509mg，4.8mmol)，之后在0℃条件下滴加丙烯酰氯(化合物D519，217mg，2.4mmol)的乙腈溶液(5mL)，滴加完毕后在室温条件下搅拌反应1h；反应结束后，将所得产物体系用乙酸乙酯萃取(50mL×3)，合并有机层，用无水硫酸钠干燥，过滤，将滤液进行浓缩，所得残留物采用硅胶柱色谱法进行纯化(按体积比计，所用洗脱剂为乙酸乙酯：石油醚＝1：10，所述石油醚的沸程为60～90℃)，得到化合物D200。所述化合物D200的核磁共振氢谱为：1HNMR(400MHz,CDCl3)δ7.5(2H),7.04(2H),6.7-6.4(2H),6.2(1H),5.6(1H),5.4(2H),4.7(1H),4.2-3.9(2H),3.4(2H),3.0(1H),2.7-2.4(2H),2.2-1.9(2H),1.8(1H),1.6(1H),1.4(1H),1.4-1.2(1H)。
实施例2
按照实施例1的方法制备化合物D201，不同之处仅在于将步骤(1)中化合物D501替换为化合物D540；所述化合物D540以及化合物D201的结构式如下所示：
所述化合物D201的核磁共振氢谱为：1H NMR(400MHz,CDCl3)δ7.5(2H),7.3-7.5(2H),7.1-7.0(2H),6.7-6.4(2H),6.2(1H),5.6(1H),5.4(2H),4.7(1H),4.2-3.9(2H),3.4(2H),3.0(1H),2.7-2.2(2H),2.2-1.9(2H),1.7-1.9(1H),1.6(1H),1.45(1H),1.4-1.2(1H)。
实施例3
制备3,4,5-三氘代苯酚(化合物D541)，反应式如下所示：
将化合物PD541(15g，75.9mmol)溶于500mL甲醇中，加入三乙胺(12.7mL，91.2mmol)和Pd/C催化剂(450mg，所述Pd/C催化剂中Pd的含量为10wt％)，将盛放有所得反应料液的反应瓶密封，用高纯氩置换三次瓶中气体，再用氘气(D2)置换两次，上接氘气(D2)球，室温条件下反应3h；反应结束后，将所得产物体系进行抽滤除去固 体，所得滤液在常压下蒸馏，收集181～187℃馏分，得到化合物D541。所述化合物D541的核磁共振氢谱为：1HNMR(400MHz,CDCl3)δ6.7(2H)，5.1(1H)。
然后按照实施例1的方法制备化合物D202，不同之处仅在于将步骤(1)中化合物D501替换为化合物D541；所述化合物D202的结构式如下所示：
所述化合物D202的核磁共振氢谱为：1H NMR(400MHz,CDCl3)δ7.5(2H),7.1-7.0(4H),6.7-6.4(2H),6.2(1H),5.6(1H),5.4(2H),4.7(1H),4.2-3.9(2H),3.4(2H),3.0(1H),2.7-2.2(2H),2.2-1.9(2H),1.7-1.9(1H),1.6(1H),1.45(1H),1.4-1.2(1H)。
实施例4
按照实施例1的方法制备化合物D203，不同之处仅在于将步骤(1)中化合物D501替换为化合物D542；所述化合物D542以及化合物D203的结构式如下所示：
所述化合物D203的核磁共振氢谱为：1H NMR(400MHz,CDCl3)δ7.5(2H),7.3-7.5(2H),7.1-7.0(4H),6.7-6.4(2H),6.2(1H),5.6(1H),5.4(2H),4.7(1H),4.2-3.9(2H),3.4(2H),3.0(1H),2.7-2.2(2H),2.2-1.9(2H),1.7-1.9(1H),1.6(1H),1.45(1H),1.4-1.2(1H)。
实施例5
制备三氘代丙烯酰氯(化合物D543)，反应式如下所示：
向四氘代丙烯酸(化合物PD543，3.0mL)中加入N,N-二甲基甲酰胺(DMF，0.06mL)，然后加入草酰氯(3.6mL)，在室温条件下搅拌反应40min；反应结束后，将所得产物体系减压浓缩，得到化合物D543。所述化合物D543氢谱无信号。
然后按照实施例1的方法制备化合物D204，不同之处仅在于将步骤(1)中化合物D501替换为苯酚(化合物D544)，且将步骤(7)中丙烯酰氯(化合物D519)替换为化合物D543；所述化合物D544以及化合物D204的结构式如下所示：
所述化合物D204的核磁共振氢谱为：1H NMR(400MHz,CDCl3)δ7.5(2H),7.3-7.5(2H),7.15(1H),7.1-7.0(4H),5.6(1H),5.4(2H),4.7(1H),4.2-3.9(2H),3.4(2H),3.0(1H),2.7-2.2(2H),2.2-1.9(2H),1.7-1.9(1H),1.6(1H),1.45(1H),1.4-1.2(1H)。
实施例6
按照实施例1的方法制备化合物D205，不同之处仅在于将步骤(7)中丙烯酰氯(化合物D519)替换为三氘代丙烯酰氯(化合物D543)；所述化合物D205的结构式如下所示：
所述化合物D205的核磁共振氢谱为：1H NMR(400MHz,CDCl3)δ7.5(2H),7.1-7.0(2H),5.6(1H),5.4(2H),4.7(1H),4.2-3.9(2H),3.4(2H),3.0(1H),2.7-2.2(2H),2.2-1.9(2H),1.7-1.9(1H),1.6(1H),1.45(1H),1.4-1.2(1H)。
实施例7
按照实施例1的方法制备化合物D206，不同之处仅在于将步骤(1)中化合物D501替换为化合物D540，且将步骤(7)中丙烯酰氯(化合物D519)替换为三氘代丙烯酰氯(化合物D543)；所述化合物D206的结构式如下所示：
所述化合物D206的核磁共振氢谱为：1H NMR(400MHz,CDCl3)δ7.5(2H),7.3-7.5(2H),7.1-7.0(2H),5.6(1H),5.4(2H),4.7(1H),4.2-3.9(2H),3.4(2H),3.0(1H),2.7-2.2(2H),2.2-1.9(2H),1.7-1.9(1H),1.6(1H),1.45(1H),1.4-1.2(1H)。
实施例8
按照实施例1的方法制备化合物D207，不同之处仅在于将步骤(1)中化合物D501替换为化合物D541，且将步骤(7)中丙烯酰氯(化合物D519)替换为三氘代丙烯酰氯(化合物D543)；所述化合物D207的结构式如下所示：
所述化合物D207的核磁共振氢谱为：1H NMR(400MHz,CDCl3)δ7.5(2H),7.1-7.0(4H),5.6(1H),5.4(2H),4.7(1H),4.2-3.9(2H),3.4(2H),3.0(1H),2.7-2.2(2H),2.2-1.9(2H),1.7-1.9(1H),1.6(1H),1.45(1H),1.4-1.2(1H)。
实施例9
按照实施例1的方法制备化合物D208，不同之处仅在于将步骤(1)中化合物D501替换为化合物D542，且将步骤(7)中丙烯酰氯(化合物D519)替换为三氘代丙烯酰氯(化合物D543)；所述化合物D208的结构式如下所示：
所述化合物D208的核磁共振氢谱为：1H NMR(400MHz,CDCl3)δ7.5(2H),7.3-7.5(2H),7.1-7.0(4H),5.6(1H),5.4(2H),4.7(1H),4.2-3.9(2H),3.4(2H),3.0(1H),2.7-2.2(2H),2.2-1.9(2H),1.7-1.9(1H),1.6(1H),1.45(1H),1.4-1.2(1H)。
实施例10
制备2,3,5,6-四氘代苯酚(化合物D545)，反应式如下所示：
将化合物PD545(10g，75.4mmol)溶于500mL甲醇中，加入三乙胺(12.6mL，90.5mmol)和Pd/C催化剂(300mg，所述Pd/C催化剂中Pd的含量为10wt％)，将盛放有所得反应料液的反应瓶密封，用高纯氩置换三次瓶中气体，再用氢气置换两次，上接氢气球，室温条件下反应3h；反应结束后，将所得产物体系进行抽滤除去固体，所得滤液在常压下蒸馏，收集181～187℃馏分，得到化合物D545。所述化合物D545的核磁共振氢谱为：1HNMR(400MHz,CDCl3)δ6.9(1H),5.1(1H)。
然后按照实施例1的方法制备化合物D209，不同之处仅在于将步骤(1)中化合物D501替换为化合物D545；所述化合物D209的结构式如下所示：
所述化合物D209的核磁共振氢谱为：1HNMR(400MHz,CDCl3)δ7.5(2H),7.15(1H),7.1-7.0(2H),6.7-6.4(2H),6.2(1H),5.6(1H),5.4(2H),4.7(1H),4.2-3.9(2H),3.4(2H),3.0(1H),2.7-2.2(2H),2.2-1.9(2H),1.9-1.7(1H),1.6(1H),1.45(1H),1.4-1.2(1H)。
实施例11
制备2,6-二氘代苯酚(化合物D546)，反应式如下所示：
向反应瓶中加入铱催化剂(168mg，0.2mmol，C43H57ClIrN3；所述C43H57ClIrN3制备方法见Organic Letters，2021，9297-9302)、乙酸钾(981mg，10mmol)和苯酚(941mg，10mmol)，将反应瓶密封并用气球引入氘气(D2)，然后加入无水四氢呋喃(100mL)，将反应瓶在50℃油浴中加热反应12h；反应结束后，将所得产物体系过滤，滤渣用无水四氢呋喃(3×25mL)洗涤，将滤液以及洗涤所得洗液合并，减压浓缩，得到化合物D546。所述化合物D546的氢谱为：1HNMR(400MHz,CDCl3)δ7.4-7.2(2H),7.0-6.9(1H),5.1(1H)。
然后按照实施例1的方法制备化合物D210，不同之处仅在于将步骤(1)中化合物D501替换为化合物D546；所述化合物D210的结构式如下所示：
所述化合物D210的核磁共振氢谱为：1H NMR(400MHz,CDCl3)δ7.5(2H),7.5-7.3(2H),7.15(1H),7.1-7.0(2H),6.7-6.4(2H),6.2(1H),5.6(1H),5.4(2H),4.7(1H),4.2-3.9(2H),3.4(2H),3.0(1H),2.7-2.2(2H),2.2-1.9(2H),1.9-1.7(1H),1.6(1H),1.45(1H),1.4-1.2(1H)。
实施例12
按照实施例1的方法制备化合物D211，不同之处仅在于将步骤(1)中化合物D501替换为化合物D547；所述化合物D547以及化合物D211的结构式如下所示：
所述化合物D211的核磁共振氢谱为：1H NMR(400MHz,CDCl3)δ7.5(2H),7.15(1H),7.10-7.00(4H),6.7-6.4(2H),6.24(1H),5.65(1H),5.4(2H),4.75(1H),4.2-3.9(2H),3.4(2H),3.0(1H),2.7-2.2(2H),2.3-1.9(2H),1.9-1.7(1H),1.6(1H),1.46(1H),1.3(1H)。
实施例13
按照实施例1的方法制备化合物D212，不同之处仅在于将步骤(1)中化合物D501替换为化合物D545，且将步骤(7)中丙烯酰氯(化合物D519)替换为成三氘代丙烯酰氯(化合物D543)；所述化合物D212的结构式如下所示：
所述化合物D212的核磁共振氢谱为：1HNMR(400MHz,CDCl3)δ7.5(2H),7.15(1H),7.1-7.0(2H),5.6(1H),5.4(2H),4.7(1H),4.2-3.9(2H),3.4(2H),3.0(1H),2.7-2.2(2H),2.2-1.9(2H),1.9-1.7(1H),1.6(1H),1.45(1H),1.4-1.2(1H)。
实施例14
按照实施例1的方法制备化合物D213，不同之处仅在于将步骤(1)中化合物D501替换为化合物D546，且将步骤(7)中丙烯酰氯(化合物D519)替换为成三氘代丙烯酰氯(化合物D543)；所述化合物D213的结构式如下所示：
所述化合物D213的核磁共振氢谱为：1H NMR(400MHz,CDCl3)δ7.5(2H),7.3-7.5(2H),7.15(1H),7.1-7.0(2H),5.6(1H),5.4(2H),4.7(1H),4.2-3.9(2H),3.4(2H),3.0(1H),2.7-2.2(2H),2.2-1.9(2H),1.9-1.7(1H),1.6(1H),1.45(1H),1.2-1.4(1H)。
实施例15
按照实施例1的方法制备化合物D214，不同之处仅在于将步骤(1)中化合物D501替换为化合物D547，且将步骤(7)中丙烯酰氯(化合物D519)替换为成三氘代丙烯酰氯(化合物D543)；所述化合物D214的结构式如下所示：
所述化合物D214的核磁共振氢谱为：1HNMR(400MHz,CDCl3)δ7.5(2H),7.15(1H),7.1-7.0(4H),5.6(1H),5.4(2H),4.7(1H),4.2-3.9(2H),3.4(2H),3.0(1H),2.7-2.2(2H),2.2-1.9(2H),1.9-1.7(1H),1.6(1H),1.45(1H),1.2-1.4(1H)。
测试例1药代动力学评价
将96只雄性Sprague-Dawley大鼠(7～8周龄，体重约220g)，分成16组(泽布替尼组、化合物D200组、化合物D201组、化合物D202组、化合物D203组、化合物D204组、化合物D205组、化合物D206组、化合物D207组、化合物D208组、化合物D209组、化合物D210组、化合物D211组、化合物D212组、化合物D213组和化合物D214 组)，每组6只，按照分组分别单次灌胃给药30mg/kg剂量的泽布替尼、化合物D200、化合物D201、化合物D202、化合物D203、化合物D204、化合物D205、化合物D206、化合物D207、化合物D208、化合物D209、化合物D210、化合物D211、化合物D212、化合物D213和化合物D214，比较各化合物的药代动力学差异。
具体的，各大鼠采用标准饲料喂养，给药前12h开始禁食；采用甲基纤维素(MC)以及水配制给药溶液(每100mL水中添加0.5g甲基纤维素)；给药后0.25h、0.5h、1h、2h、4h、6h、8h、10h、12h和24h为采血时间点，从各大鼠眼眶静脉丛采血0.25mL，置于涂布肝素钠溶液的离心管中，之后立即温和的颠倒离心管至少5次，保证充分混合后放置于冰上；之后将血样在温度为4℃且转速为12000rpm条件下离心4min，将血样中的血浆与红细胞分离；用移液器吸出100μL血浆置于干净的塑料离心管中，标明样品编号和采血时间点，保存于-80℃冰箱中备用；将血浆样品进行LC-MS/MS测定，采用非房室模型计算药时曲线下面积AUC0-t、最大血药浓度Cmax和消除半衰期t1/2，结果见表1。
表1各化合物在大鼠中的药代动力学评价结果
由表1可知，与泽布替尼相比，化合物D200、化合物D201、化合物D202、化合物D203、化合物D204、化合物D205、化合物D206、化合物D207、化合物D208、化合物D212、化合物D213和化合物D214具有更大的体内暴露量(药时曲线下面积AUC0-t和最大血药浓度Cmax)以及更长的消除半衰期t1/2，化合物D209、化合物D210和化合物D211具有更大的最大血药浓度Cmax。这预示着与泽布替尼相比，本发明提供的氘代吡唑并嘧啶衍生物可能具有更好的体内药效活性。
测试例2BTK激酶实验
本实验通过体外激酶活性测试方法检测泽布替尼以及本发明提供的氘代吡唑并嘧啶衍生物对BTK激酶活性的抑制作用，其中BTK激酶实验基于HTRF方法检测，具体如 下：
采用含有50mMTris(pH＝7.4)、10mMMgCl2、2mM MnCl2、0.1mM EDTA、1mM DTT、20nM SEB、0.1％BSA和0.005％tween-20的酶活buffer分别稀释人重组BTK(ab205800)、泽布替尼以及氘代吡唑并嘧啶衍生物，然后将人重组BTK分别与不同浓度的泽布替尼以及氘代吡唑并嘧啶衍生物在室温条件下混匀孵育1h加入384孔板中，随后，依次向384孔板中加入ATP和底物(Biotin-AVLESEEELYSSARQ-NH2)继续室温孵育1h引发反应。用含有50mMHEPES(pH＝7.0)、800mM KF、20mM EDTA、0.1％BSA和连接Eu穴合物的终止buffer稀释p-Tyr66抗体和链霉亲和素标记的XL665至特定浓度，然后将p-Tyr66抗体和XL665依次加入到上述各孔中，混合均匀后室温继续孵育1h。孵育结束后，将384孔板置于TECAN spark多功能微孔板检测仪中读取620nm和665nm TR-FRET荧光值。剩余活性ratio＝(665nm/620nm)×104，抑制率为IR＝1-Ri/R0，其中R0是阴性对照的ratio值，Ri是实验组的ratio值。各化合物的IC50值通过graphpadPrism9软件拟合得到，具体结果如表2所示。由表2可知，泽布替尼以及本发明提供的氘代吡唑并嘧啶衍生物均有较好的BTK激酶抑制活性。
表2各化合物的BTK激酶实验测试结果
测试例3细胞内BTKpTyr223检测
BTKpTyr223细胞实验可用于检测细胞内的BTKTyr223位点磷酸化的水平，BTK的激酶活性取决于Tyr223位点的磷酸化。本实验利用该检测方法测定泽布替尼以及本发明提供的氘代吡唑并嘧啶衍生物对BTKTyr223磷酸化的抑制活性，具体如下：
在体外用含0.5％胎牛血清的RPMI1640培养基培养Ramos细胞至一定细胞密度，然后收集细胞悬液，离心后用新鲜培养基重悬并稀释至4×106cells/mL，向96孔板中每孔加入25μL细胞悬液。用培养基稀释泽布替尼以及氘代吡唑并嘧啶衍生物至不同的浓度梯度，随后向96孔板中各孔加入5μL不同浓度的化合物(6X)并置于37℃培养箱中孵育1h。孵育结束后向孔板中加入10μL4X lysis buffer，室温下震荡孵育30min。然后取16μL细胞裂解液转入96浅孔板中，随后向各孔加入2μL phopho-BTK d2抗体及2μL phopho-BTK Eucryptate抗体，覆上封板膜后室温孵育过夜。孵育结束后将孔板置于TECAN spark多功能微孔板检测仪中读取620nm和665nm TR-FRET荧光值。剩余活性ratio＝(665nm/620nm)×104，抑制率为IR＝1-Ri/R0，其中R0是阴性对照的ratio值，Ri是实验组的ratio值。各化合物的IC50值通过graphpadPrism 9软件拟合得到，具体结果如表3所示。由表3可知，泽布替尼以及本发明提供的氘代吡唑并嘧啶衍生物均有较好的BTKTyr223磷酸化的抑制活性。
表3各化合物的细胞内BTKpTyr223检测结果

测试例4在人TMD-8细胞异种移植瘤模型中的作用效果
肿瘤细胞的异种移植瘤模型可以用于评价药物在体内对肿瘤生长的抑制作用。本实验利用建立的人TMD-8细胞异种移植瘤模型评价泽布替尼以及本发明提供的氘代吡唑并嘧啶衍生物的抗肿瘤效果，具体如下：
在含10％FBS的RPMI1640培养基中培养TMD-8细胞至一定细胞量，收集细胞悬液，1000rpm离心5min，弃培养基后用4℃预冷的PBS重悬细胞并稀释至2×108个细胞/mL，然后将细胞悬液与等体积的matrigel混合均匀，置于冰上备用。荷瘤前NOD-SCID小鼠右侧背部皮肤经75％乙醇消毒，随后用注射器注入100μL(1×107个细胞/只)TMD-8细胞悬液，缓慢注射后皮下鼓起，缓慢抽出针头，并按压进针口防止细胞溢出。荷瘤7～10天后，待瘤体积生长至100mm3以上，将动物随机分为17组，分别为对照组、6mg/kg泽布替尼组、6mg/kg化合物D200组、6mg/kg化合物D201组、6mg/kg化合物D202组、6mg/kg化合物D203组、6mg/kg化合物D204组、6mg/kg化合物D205组、6mg/kg化合物D206组、6mg/kg化合物D207组、6mg/kg化合物D208组、6mg/kg化合物D209组、6mg/kg化合物D210组、6mg/kg化合物D211组、6mg/kg化合物D212组、6mg/kg化合物D213组和6mg/kg化合物D214组，每组5～10只小鼠。分组后，给药组小鼠每日早晚各一次灌胃给药6mg/kg的待测化合物，从给药开始，隔日测量小鼠瘤体积和体重。瘤体积V＝a×b2/2，其中a为肿瘤长径，b为肿瘤短径；肿瘤生长抑制率％TGI＝100×(1-药物t/对照t)。计算各组给药40天时的抑瘤率，具体如表4所示。由表4可知，化合物D200～D202、D204～D208的抑瘤率明显优于泽布替尼，化合物D203、D209、D213～D214的抑瘤率略优于泽布替尼，化合物D210～D212的抑瘤率略低于泽布替尼。
表4各化合物在人TMD-8细胞异种移植瘤模型中的作用结果
测试例5在人REC1细胞异种移植瘤模型中的作用效果
本实验利用建立的人REC1细胞异种移植瘤模型评价泽布替尼以及本发明提供的氘 代吡唑并嘧啶衍生物的抗肿瘤效果，具体如下：
在含10％FBS的RPMI1640培养基中培养REC1细胞至一定细胞量，收集细胞悬液，1000rpm离心5min，弃培养基后用4℃预冷的PBS重悬细胞并稀释至2×108个细胞/mL，然后将细胞悬液与等体积的matrigel混合均匀，置于冰上备用。荷瘤前NOD-SCID小鼠右侧背部皮肤经75％乙醇消毒，随后用注射器注入100μL(1×107个细胞/只)REC1细胞悬液，缓慢注射后皮下鼓起，缓慢抽出针头，并按压进针口防止细胞溢出。荷瘤7～10天后，待瘤体积生长至100mm3以上，将动物随机分为17组，分别为对照组、6mg/kg泽布替尼组、6mg/kg化合物D200组、6mg/kg化合物D201组、6mg/kg化合物D202组、6mg/kg化合物D203组、6mg/kg化合物D204组、6mg/kg化合物D205组、6mg/kg化合物D206组、6mg/kg化合物D207组、6mg/kg化合物D208组、6mg/kg化合物D209组、6mg/kg化合物D210组、6mg/kg化合物D211组、6mg/kg化合物D212组、6mg/kg化合物D213组和6mg/kg化合物D214组，每组5～10只小鼠。分组后，给药组小鼠每日早晚各一次灌胃给药6mg/kg的待测化合物，从给药开始，隔日测量小鼠瘤体积和体重。瘤体积V＝a×b2/2，其中a为肿瘤长径，b为肿瘤短径；肿瘤生长抑制率％TGI＝100×(1-药物t/对照t)。计算各组给药40天时的抑瘤率，具体结果如表5所示。由表5可知，化合物D200～D208、化合物D213～214的抑瘤率明显优于泽布替尼，化合物D209、D212的抑瘤率略优于泽布替尼，化合物D210～D211的抑瘤率略低于泽布替尼。
表5各化合物在人REC1细胞异种移植瘤模型中的作用结果
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (17)

  1. 一种具有式I所示结构的氘代吡唑并嘧啶衍生物或其光学异构体、药学上可接受的盐、水合物或溶剂化物；
    式I中X1、X2、X3、X4、X5和X6中至少一个是氘。
  2. 根据权利要求1所述的氘代吡唑并嘧啶衍生物，其特征在于，所述X4、X5和X6均为氢，或者至少一个是氘。
  3. 根据权利要求2所述的氘代吡唑并嘧啶衍生物，其特征在于，所述X4、X5和X6均为氢，且所述X1、X2和X3中至少一个是氘，或者至少两个是氘，或者均为氘。
  4. 根据权利要求2所述的氘代吡唑并嘧啶衍生物，其特征在于，所述X4、X5和X6中至少一个是氘，且所述X1、X2和X3均为氢，或者至少一个是氘，或者至少两个是氘，或者均为氘。
  5. 根据权利要求2所述的氘代吡唑并嘧啶衍生物，其特征在于，所述X4、X5和X6中至少两个是氘，且所述X1、X2和X3均为氢，或者至少一个是氘，或者至少两个是氘，或者均为氘。
  6. 根据权利要求2所述的氘代吡唑并嘧啶衍生物，其特征在于，所述X4、X5和X6均为氘，且所述X1、X2和X3均为氢，或者至少一个是氘，或者至少两个是氘，或者均为氘。
  7. 根据权利要求2～6任一项所述的氘代吡唑并嘧啶衍生物，其特征在于，所述氘代吡唑并嘧啶衍生物为以下化合物中的至少一种：

  8. 权利要求1～7任一项所述氘代吡唑并嘧啶衍生物的制备方法，包括以下步骤：
    (1)将化合物X601、化合物X602、干燥剂与第一溶剂混合，进行成醚反应，得到化合物X603；
    将所述化合物X603、第一碱试剂与第二溶剂混合，进行酯水解反应，得到化合物X604；
    将所述化合物X604与酰氯化试剂混合，进行成酰氯反应，得到中间体化合物；将所述中间体化合物、丙二腈、还原剂与第三溶剂混合，进行亲核反应，得到化合物X606；
    将所述化合物X606、甲基化试剂、第二碱试剂与第四溶剂混合，进行甲基化反应，得到化合物X608；
    将所述化合物X608、水合肼与第五溶剂混合，进行第一成环反应，得到化合物X610；
    (2)将化合物X611与化合物X612混合，进行成共轭双键反应，得到化合物X613；
    (3)将所述化合物X610、化合物X613与第六溶剂混合，进行第二成环反应，得到化合物X614；
    将所述化合物X614、酸试剂、第一催化剂与第七溶剂混合，在氢气氛围中进行还原反应，得到化合物X615；
    将所述化合物X615、盐酸与第八溶剂混合，进行脱保护反应，得到外消旋体化合物X616；
    将所述外消旋体化合物X616、手性拆分试剂与第九溶剂混合，进行手性拆分，得到化合物X617；
    将所述化合物X617、第三碱试剂、过氧化氢水溶液、二甲基亚砜与第十溶剂混合，进行氰水解反应，得到化合物X618；
    将所述化合物X618、化合物X619、第四碱试剂与第十一溶剂混合，进行成酰胺反应，得到具有式I所示结构的氘代吡唑并嘧啶衍生物；
    所述化合物X601、化合物X602、化合物X603、化合物X604、化合物X606、化合物X608、化合物X610、化合物X611、化合物X612、化合物X613、化合物X614、化合物X615、外消旋体化合物X616、化合物X617、化合物X618与化合物X619的结构式依次如下所示：
    所述X1、X2、X3、X4、X5和X6如式I所定义；所述Z为氢或氘，所述Y为卤素原子；
    所述步骤(1)与步骤(2)无先后顺序。
  9. 一种三氘代丙烯酰氯及多氘代苯酚的制备方法，包括以下步骤：
    将化合物PD543、草酰氯与第十二溶剂混合，进行成氘代酰氯反应，得到三氘代丙烯酰氯；所述化合物PD543与三氘代丙烯酰氯的结构式依次如下所示：
    所述多氘代苯酚为3,4,5-三氘代苯酚、2,3,5,6-四氘代苯酚和2,6-二氘代苯酚；
    所述3,4,5-三氘代苯酚的制备方法包括以下步骤：
    将化合物PD541、第五碱试剂、第二催化剂与第十三溶剂混合，在氘气氛围中进行成三氘代苯酚反应，得到3,4,5-三氘代苯酚；
    所述2,3,5,6-四氘代苯酚的制备方法包括以下步骤：
    将化合物PD545、第六碱试剂、第三催化剂与第十四溶剂混合，在氘气氛围中进行成四氘代苯酚反应，得到2,3,5,6-四氘代苯酚；
    所述2,6-二氘代苯酚的制备方法包括以下步骤：
    将苯酚、乙酸钾与铱催化剂混合，在氘气氛围中进行成二氘代苯酚反应，得到2,6-二氘代苯酚；
    所述化合物PD541与化合物PD545的结构式依次如下所示：
  10. 一种药物组合物，包括活性成分和药学上可接受的载体，所述活性成分为权利要求1～7任一项所述氘代吡唑并嘧啶衍生物、其光学异构体、其药学上可接受的盐、其水合物和其溶剂化物中的至少一种。
  11. 一种结合物，包括第一活性成分和第二活性成分；所述第一活性成分为权利要求1～7任一项所述氘代吡唑并嘧啶衍生物、其光学异构体、其药学上可接受的盐、其水合物和其溶剂化物中的至少一种；所述第二活性成分为对过敏性疾病、自身免疫性疾病、炎症疾病或癌症具有治疗活性的试剂。
  12. 权利要求1～11任一项所述氘代吡唑并嘧啶衍生物、其光学异构体、其药学上可接受的盐、其水合物、其溶剂化物、权利要求10所述药物组合物或权利要求11所述结合物在制备BTK抑制剂中的应用。
  13. 权利要求1～11任一项所述氘代吡唑并嘧啶衍生物、其光学异构体、其药学上可接受的盐、其水合物、其溶剂化物、权利要求10所述药物组合物或权利要求11所述结合物在制备治疗与不期望的BTK活性相关的疾病的药物中的应用，所述疾病为过敏性疾病、自身免疫性疾病、炎症疾病或癌症。
  14. 根据权利要求13所述的应用，其特征在于，所述过敏性疾病包括特应性皮炎、接触性皮炎或湿痒。
  15. 根据权利要求13所述的应用，其特征在于，所述自身免疫性疾病包括类风湿性关节炎、银屑病性关节炎、感染性关节炎、进行性慢性关节炎、致畸性关节炎、骨关节炎、创伤性关节炎、痛风性关节炎、Reiter氏综合症、多软骨炎、急性滑膜炎、脊椎炎、有肾病综合症的肾小球肾炎、没有肾病综合症的肾小球肾炎、自身免疫性血液系统病症、溶血性贫血、再生障碍性贫血、特发性血小板减少症、嗜中性白血球减少症、自身免疫性胃炎、自身免疫性炎性肠病、溃病性结肠炎、Crohn氏病、宿主抗移植物病、同种异体移植物排斥、慢性甲状腺炎、格雷夫斯氏病、硬皮病、原发性胆汁性肝硬化、重症肌无力、多发性硬化症、系统性红斑狼疮或银屑病。
  16. 根据权利要求13所述的应用，其特征在于，所述炎症疾病包括急性活动性肝炎、慢性活动性肝炎、胰腺炎、血管炎、炎性痛、葡萄膜炎、结膜炎、角膜结膜炎、中耳炎、牙周病、支气管炎、鼻炎或窦炎。
  17. 根据权利要求13所述的应用，其特征在于，所述癌症包括非霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤、B细胞慢性淋巴细胞性白血病、急性成淋巴细胞性白血病、具有成熟B细胞的急性成淋巴细胞性白血病、由慢性活动型B细胞受体信号传导引起的B细胞淋巴瘤或与多发性骨髓瘤相关的骨病。
PCT/CN2024/070622 2023-01-09 2024-01-04 氘代吡唑并嘧啶衍生物及其制备方法和药物组合物、结合物及应用 WO2024149150A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202310027516.4 2023-01-09
CN202310027516.4A CN118307541A (zh) 2023-01-09 2023-01-09 氘代吡唑并嘧啶衍生物及其制备方法和药物组合物、结合物及应用

Publications (1)

Publication Number Publication Date
WO2024149150A1 true WO2024149150A1 (zh) 2024-07-18

Family

ID=91721162

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/070622 WO2024149150A1 (zh) 2023-01-09 2024-01-04 氘代吡唑并嘧啶衍生物及其制备方法和药物组合物、结合物及应用

Country Status (2)

Country Link
CN (1) CN118307541A (zh)
WO (1) WO2024149150A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104507946A (zh) * 2012-07-30 2015-04-08 康塞特医药品有限公司 氘代依鲁替尼
CN105254694A (zh) * 2014-07-14 2016-01-20 正大天晴药业集团股份有限公司 氘代核苷衍生物
CN109563099A (zh) * 2016-08-16 2019-04-02 百济神州有限公司 (s)-7-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺的晶型、其制备和用途
CN117430610A (zh) * 2023-10-11 2024-01-23 宁夏医科大学 一种氘代稠合杂环化合物及其制备方法和应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104507946A (zh) * 2012-07-30 2015-04-08 康塞特医药品有限公司 氘代依鲁替尼
CN105254694A (zh) * 2014-07-14 2016-01-20 正大天晴药业集团股份有限公司 氘代核苷衍生物
CN109563099A (zh) * 2016-08-16 2019-04-02 百济神州有限公司 (s)-7-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺的晶型、其制备和用途
CN117430610A (zh) * 2023-10-11 2024-01-23 宁夏医科大学 一种氘代稠合杂环化合物及其制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
闫方 等 (YAN, FANG ET AL.): "氘代药物的药代动力学优势及其临床研究进展 (Pharmacokinetic Advantage and Clinical Development of Deuterated Drugs)", 中国临床药理学杂志 (THE CHINESE JOURNAL OF CLINICAL PHARMACOLOGY), vol. 36, no. 16, 26 August 2020 (2020-08-26), XP055931460, DOI: 10.13699/j.cnki.1001-6821.2020.16.048 *

Also Published As

Publication number Publication date
CN118307541A (zh) 2024-07-09

Similar Documents

Publication Publication Date Title
TWI707852B (zh) Tyk2 抑制劑及其用途
WO2021190467A1 (zh) 含螺环的喹唑啉化合物
CA3200245A1 (en) Benzimidazole derivative and preparation method therefor and medical use thereof
WO2017118277A1 (zh) 一种btk激酶抑制剂的结晶形式及其制备方法
WO2021088945A1 (zh) 作为shp2抑制剂的化合物及其应用
WO2023003002A1 (ja) 縮環ピリダジン化合物
WO2021213317A1 (zh) Hpk1抑制剂及其制备方法和用途
CN117946166A (zh) Cot调节剂及其使用方法
WO2024032747A1 (zh) 三环类化合物及其医药用途
WO2018072742A1 (zh) 一种咪唑并异吲哚类衍生物的游离碱的结晶形式及其制备方法
WO2024149150A1 (zh) 氘代吡唑并嘧啶衍生物及其制备方法和药物组合物、结合物及应用
WO2023193563A1 (zh) 一种噻吩并吡啶化合物的晶型a、制备方法及其药物组合物
EP4310080A1 (en) Polymorphic forms of compound and preparation method therefor and application thereof
CN118055924A (zh) 含吡啶基的化合物
WO2021228216A1 (zh) 可用作RORγ调节剂的联芳基类化合物
TWI745764B (zh) 一種鴉片類物質受體激動劑的結晶形式及製備方法
WO2021233133A1 (zh) 用作ret激酶抑制剂的化合物及其应用
WO2024222900A1 (zh) 含三唑基的化合物
TWI717859B (zh) 一種鴉片類物質受體激動劑的結晶形式及製備方法
WO2024222827A1 (zh) 一种噻吩并嘧啶类化合物的盐型、晶型及其制备方法和应用
WO2022144002A1 (zh) 2,5-二酮哌嗪类化合物衍生物、其制备方法、药物组合物及其用途
WO2023011428A1 (zh) Ripk1抑制剂的晶型及其酸式盐和其酸式盐的晶型
WO2023131017A1 (zh) 一种稠环衍生物的晶型、其制备方法及其应用
US11225462B2 (en) Crystal forms of oxypyridine amide derivative and preparation method therefor
WO2024012425A1 (zh) 作为ripk1抑制剂的杂环化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24741149

Country of ref document: EP

Kind code of ref document: A1