WO2019141096A1 - Substituted urea compound and preparation method and use thereof - Google Patents

Substituted urea compound and preparation method and use thereof Download PDF

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Publication number
WO2019141096A1
WO2019141096A1 PCT/CN2019/070390 CN2019070390W WO2019141096A1 WO 2019141096 A1 WO2019141096 A1 WO 2019141096A1 CN 2019070390 W CN2019070390 W CN 2019070390W WO 2019141096 A1 WO2019141096 A1 WO 2019141096A1
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group
compound
alkyl
membered
nitrogen
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PCT/CN2019/070390
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French (fr)
Chinese (zh)
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刘金明
何婷
蔡家强
王利春
王晶翼
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四川科伦博泰生物医药股份有限公司
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Publication of WO2019141096A1 publication Critical patent/WO2019141096A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the adenosine receptor is a G protein-coupled receptor (GPCRs), and the family of receptors mainly includes four receptors A1, A2a, A2b and A3. Among them, the A2a and A2b receptors are coupled to the Gs protein that activates adenylate cyclase, and stimulate the production of intracellular cyclic adenosine monophosphate (cAMP).
  • GPCRs G protein-coupled receptor
  • A2a and A2b receptors are coupled to the Gs protein that activates adenylate cyclase, and stimulate the production of intracellular cyclic adenosine monophosphate (cAMP).
  • adenosine A2a receptor antagonists have a good application prospect in the pharmaceutical industry as a tumor therapeutic drug.
  • adenosine A2a receptors are also associated with Parkinson's disease, Alzheimer's disease, AIDS cerebral palsy, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, multiple system atrophy, cerebral ischemia , attention deficit hyperactivity disorder, sleep disorders, anxiety disorders, mood disorders, epilepsy, neuralgia, migraine and other diseases.
  • Corvus' CPI-444 is a compound that antagonizes the adenosine A2a receptor and is currently in Phase I clinical studies. The indication is a tumor. Prior to this, CPI-444 was used in clinical trials for the treatment of central nervous system diseases. .
  • WO 01/62233 and WO2002014282 A1 disclose that an aminopyridine compound has an antagonistic effect on the adenosine A2a receptor, and discloses a therapeutic agent which can be used as a drug for Parkinson's disease or Alzheimer's disease.
  • R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl-, R 8 R 9 NC 1-6 alkyl-, 5-6 a heterocyclic group -C 1-6 alkyl-, 5-6 membered heteroaryl-C 1-6 alkyl- and 5-6 membered heteroaryl, wherein said heterocyclic group and heteroaryl group are optionally Substituted by one or more substituents independently selected from the group consisting of hydroxy, halo, amino, C 1-6 alkyl and C 1-6 alkoxy;
  • R 3 is C 1-6 alkyl or C 3-6 cycloalkyl
  • R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen and halogen;
  • R 8 and R 9 are each independently selected from hydrogen and C 1-6 alkyl.
  • R 8 and R 9 are as defined herein.
  • a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form a piperazinyl group.
  • a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof wherein: R 8 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof wherein: R 9 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, which is selected from:
  • Hal 1 and Hal 2 are each independently the same or different halogens, such as Cl, Br or I;
  • Y is a boric acid or borate group, preferably -B(OH) 2 or The remaining groups are as defined above.
  • Step A Compound II-1 is reacted with a halogenating agent to obtain Compound II-2;
  • substitution reaction of compound II-1 with a halogenating agent gives compound II-2.
  • the substitution reaction is preferably carried out in a solvent in the presence of a strong base.
  • the strong base may be LiHMDS, NaHMDS, LDA, n-butyllithium, t-butyllithium or the like, preferably n-butyllithium.
  • the halogenating agent may be N-bromosuccinimide, N-iodosuccinimide, bromine and iodine, preferably iodine.
  • the base may be an inorganic base such as potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably potassium phosphate.
  • the coupling reaction is carried out in a suitable organic solvent, which may be selected from the group consisting of 1,4-dioxane and N,N-dimethylformamide, for example 1,4-dioxane Six rings.
  • the coupling reaction is carried out in a suitable protective atmosphere, such as a nitrogen atmosphere.
  • the coupling reaction is carried out at a suitable temperature, which may be from 70 to 100 ° C, preferably 80 ° C.
  • the coupling reaction is carried out for a suitable period of time, which may be from 1 to 8 hours, preferably 3 hours.
  • Hal 1 and Hal 2 are each independently the same or different halogens, such as Cl, Br or I;
  • Y is a boric acid or borate group, preferably -B(OH) 2 or The remaining groups are as defined above.
  • Step A Compound III-1 is reacted with IN-a to obtain compound III-2;
  • Hal 1 is halogen, such as Cl, Br or I, preferably Br;
  • Y is a boric acid or borate group, preferably -B(OH) 2 or The remaining groups are as defined above.
  • Compound IV-1 is reacted with DMF-DMA to give compound IV-2.
  • This reaction is preferably carried out under solvent free conditions. However, the reaction can also be carried out in a solvent which can dissolve the raw material to some extent without inhibiting the reaction, such as 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone. , benzene or toluene, etc.
  • the reaction temperature is usually from room temperature to 120 ° C, preferably 80 ° C.
  • the reaction time is usually from 6 to 24 hours, preferably 12 hours.
  • Step B Compound IV-2 is reacted with hydrazine to give compound IV-3;
  • Compound IV-3 is reacted with a halogenating agent in a solvent to give compound IV-4.
  • the halogenating agent used may be N-bromosuccinimide or bromine, preferably N-bromosuccinimide.
  • the solvent to be used is long as it does not inhibit the reaction and can dissolve the raw material to some extent, such as N,N-dimethylformamide, N-methylpyrrolidone, methanol, ethanol, tetrahydrofuran, 1,4-dioxane.
  • the ring and dimethoxyethane and the like are preferably N,N-dimethylformamide.
  • the reaction temperature is usually -20 ° C to room temperature, preferably 0 ° C to room temperature.
  • the reaction time is usually from 1 to 24 hours, preferably from 12 hours.
  • Step D Compound IV-4 is reacted with IN-b to give compound IV-5;
  • Compound V-1 is reacted with an oxidizing agent in a solvent to obtain Compound V-2.
  • the oxidizing agent used may be selenium dioxide, potassium permanganate, sodium periodate, hydrogen peroxide or the like, preferably selenium dioxide.
  • the reaction can be carried out to a certain extent in a solvent which can dissolve the raw materials without inhibiting the reaction, such as 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone or the above organic
  • a mixed solvent of a solvent and water preferably a mixed solvent of 1,4-dioxane and water.
  • the reaction temperature is usually from room temperature to 120 ° C, preferably 110 ° C.
  • the reaction time is usually from 3 to 14 hours, preferably 5 hours.
  • Step F Compound V-6 is reacted with compound IN-e to obtain compound V-7;
  • Compound V-6 is coupled with compound compound IN-e to give compound V-7.
  • the coupling reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is a palladium metal catalyst such as tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, bis(triphenylphosphine)palladium dichloride, palladium acetate, preferably [1,1'-bis(diphenyl) Phosphyl)ferrocene]palladium dichloride dichloromethane complex.
  • the base may be an inorganic base such as cesium carbonate, potassium carbonate, sodium carbonate, potassium hydrogencarbonate or sodium hydrogencarbonate, preferably cesium carbonate.
  • the coupling reaction is carried out in a suitable organic solvent or a mixed solvent of an organic solvent and water, which may be selected from 1,4-dioxane, N,N-dimethylformamide or the like.
  • a mixed solvent of an organic solvent and water for example, a mixed solvent of 1,4-dioxane and water.
  • the coupling reaction is carried out in a suitable protective atmosphere, such as a nitrogen atmosphere.
  • the coupling reaction is carried out at a suitable temperature, which may be from 70 to 100 ° C, preferably 80 ° C.
  • the coupling reaction is carried out for a suitable period of time, which may be from 1 to 24 hours, such as 8 hours.
  • Step G Compound V-7 is reacted with compound IN-f to obtain compound V-8;
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.
  • the MS was measured using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.
  • the instrument model used was Agilent 1260, the column was Waters XBridge Prep C18 OBD (19 mm ⁇ 150 mm ⁇ 5.0 ⁇ m); the column temperature was 25 ° C; the flow rate was 20.0 mL / min; the detection wavelength was 214 nm; the elution gradient was as follows:
  • the microwave reaction was carried out using a Biotage Initiator + (400 W, RT ⁇ 300 ° C) microwave reactor.
  • the second step preparation of 5-chloro-3-fluoro-4-(5-methylfuran-2-yl)pyridin-2-amine
  • Example 13 1-(5-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl)pyrimidine-2 Preparation of -yl)-3-(2-morpholin-4-yl-ethyl)-urea (Compound 13)
  • Example 36 1-(6-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(5-methylfuran-2-yl)-1, Preparation of 2,4-triazin-3-yl)-3-methylurea (Compound 36)
  • Cell culture medium Ham's F12 medium (Gibco, 11765054) containing 10% fetal bovine serum, 200 ⁇ g/ml Zeocin and 100 ⁇ g/ml Hygromycin B
  • Kit cAMP Assay Kit (CISBIO 62AM4PEC)
  • CHO-K1 cells stably expressing the ADORA2a receptor i.e., adenosine A2a receptor
  • ADORA2a receptor i.e., adenosine A2a receptor
  • test compound was diluted with DMSO to prepare a 10 mM stock solution of the test compound, and the stock solution was diluted with the experimental buffer to obtain a test compound solution of different working concentrations.
  • the positive working concentration of the positive agonist NECA was 10 ⁇ M; the positive antagonist ZM241385 was the highest working concentration of 1 ⁇ M, and was further diluted to different concentrations with the experimental buffer.
  • Plate 1 was added to 5 ⁇ l of the diluted positive agonist NECA, and 5 ⁇ l of the assay buffer was added to the wells and incubated for 0.5 hours at room temperature. After the detection reagent in the kit was added according to the instructions of the CISBIO kit, the incubation was continued for 1 hour, and the fluorescent signal was read by the PheraStar microplate reader to obtain the original data.
  • Compound number IC 50 (nM) range 1 10 ⁇ IC 50 ⁇ 30 2 30 ⁇ IC 50 ⁇ 100 3 IC 50 ⁇ 3 4 10 ⁇ IC 50 ⁇ 30 5 30 ⁇ IC 50 ⁇ 100 6 10 ⁇ IC 50 ⁇ 30
  • Table 1 indicates that the compounds of the present application have a good inhibitory effect on intracellular cAMP of the downstream signal factor of the A2a receptor at the cellular level.
  • the compounds of the present application were administered to male SD rats by intravenous (IV) and gavage (PO), respectively, to examine the pharmacokinetic characteristics.
  • IV and PO were administered at a dose of 1 mg/kg and 5 mg/kg, respectively, and the vehicle of IV was a mixture of 5% DMSO, 5% Solutol (polyethylene glycol-15 hydroxystearate) and 90% physiological saline, PO The solvent was 0.5% MC (sodium methylcellulose).
  • 3 rats were administered IV in parallel in the IV-administered group, before administration (0 h) and 0.083, 0.25, 0.5, 1, 2, 4, 6 and 8 h after administration, respectively. The blood was collected in parallel at the time point.
  • the exposure amount (AUC last ) of the compound 8 and the compound 34 of the present application administered by IV at a dose of 1 mg/kg was 431 h*ng/mL and 490 h*ng/mL, respectively.
  • the corresponding maximum plasma concentrations ( Cmax ) were 665 ng/mL and 547 ng/mL, respectively, indicating that Compound 8 and Compound 34 of the present application have excellent drug exposure in rats by IV administration.

Abstract

Provided is a substituted urea compound, and a preparation method and use thereof. More particularly, the invention relates to a substituted urea compound or a pharmaceutically acceptable salt, a stereoisomer, a polymorphic substance, a solvate, an N-oxide, an isotopically labeled compound, a metabolite or a prodrug thereof. Also provided are a method of preparing the compound, an intermediate, a pharmaceutical composition comprising the compound, and therapeutic uses thereof. The compound or the pharmaceutical composition thereof is capable of inhibiting adenosine A2a receptor activity and can be used for treating or preventing a disease associated with the adenosine A2a receptor, particularly for treating a tumor.

Description

取代脲类化合物及其制备方法和用途Substituted urea compound and preparation method and use thereof
本申请是以CN申请号为201810051542.X，申请日为2018年01月19日的申请为基础，并主张其优先权，该CN申请的公开内容在此作为整体引入本申请中。The present application is based on the application of the CN application number 201810051542.X, the application date being January 19, 2018, and the priority of which is hereby incorporated by reference.
技术领域Technical field
本申请属于医药领域，具体涉及取代脲类化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药。本申请还涉及所述化合物的制备方法、中间体、包含所述化合物的药物组合物以及它们的治疗用途。The present application belongs to the field of medicine, and in particular to substituted urea compounds or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof. . The present application also relates to methods of preparing the compounds, intermediates, pharmaceutical compositions comprising the compounds, and therapeutic uses thereof.
背景技术Background technique
腺苷是一种体内抑制炎症和免疫应答的信号分子，细胞外腺苷主要有2种来源，细胞内腺苷的转运和细胞外腺嘌呤核苷的水解。腺苷能在多种类型的肿瘤组织中产生并在肿瘤微环境中维持较高水平。肿瘤微环境中腺苷产生的主要途径是在肿瘤细胞表面高表达的CD73酶可以催化AMP产生胞外腺苷，进而导致肿瘤微环境中腺苷维持高浓度。腺苷受体是一种G蛋白偶联受体(GPCRs)，该家族受体主要包括A1、A2a、A2b和A3四种受体。其中，A2a和A2b受体与活化腺苷酸环化酶的Gs蛋白偶联，刺激产生细胞内环磷酸腺苷(cAMP)。Adenosine is a signaling molecule that inhibits inflammation and immune response in vivo. There are two main sources of extracellular adenosine, the transport of intracellular adenosine and the hydrolysis of extracellular adenosine. Adenosine can be produced in many types of tumor tissue and maintains high levels in the tumor microenvironment. The main pathway for adenosine production in the tumor microenvironment is that CD73, which is highly expressed on the surface of tumor cells, can catalyze the production of extracellular adenosine by AMP, which leads to a high concentration of adenosine in the tumor microenvironment. The adenosine receptor is a G protein-coupled receptor (GPCRs), and the family of receptors mainly includes four receptors A1, A2a, A2b and A3. Among them, the A2a and A2b receptors are coupled to the Gs protein that activates adenylate cyclase, and stimulate the production of intracellular cyclic adenosine monophosphate (cAMP).
腺苷A2a受体表达于免疫***中的一些细胞表面，如T细胞、NK细胞、巨噬细胞和树突状细胞。肿瘤产生的腺苷能与肿瘤组织浸润免疫细胞表面的腺苷A2a受体相互作用，使免疫细胞内cAMP量升高，抑制免疫细胞攻击肿瘤的能力，使机体发生免疫耐受，进而使肿瘤细胞能够逃避机体的免疫监视，主要表现在两个方面：(1)阻断能杀伤肿瘤细胞的免疫细胞活化和发挥功能；(2)增加能抑制免疫细胞对肿瘤细胞应答的调节T细胞(T-regs)数量。在肿瘤细胞向癌细胞演化形成的过程中，它们利用这些机制来逃避免疫***的监视和攻击，提高自己的生存率。腺苷A2a受体基因敲除的小鼠可以加强CD8+T细胞抗肿瘤的免疫作用，显著抑制肿瘤的增殖，将黑色素瘤或淋巴瘤细胞移植到野生型小鼠体内比移植到腺苷A2a受体基因敲除小鼠体内更容易生长，并且腺苷A2a受体基因敲除小鼠对肿瘤疫苗有更好的应答。The adenosine A2a receptor is expressed on some cell surfaces in the immune system, such as T cells, NK cells, macrophages, and dendritic cells. The adenosine produced by the tumor can interact with the adenosine A2a receptor on the surface of the immune cell infiltrating the tumor tissue, increase the amount of cAMP in the immune cell, inhibit the ability of the immune cell to attack the tumor, and cause the body to undergo immune tolerance, thereby making the tumor cell The ability to evade the body's immune surveillance is mainly manifested in two aspects: (1) blocking the activation and function of immune cells that can kill tumor cells; and (2) increasing regulatory T cells that can suppress the response of immune cells to tumor cells (T- Regs) quantity. In the process of tumor cell evolution to cancer cells, they use these mechanisms to evade surveillance and attack of the immune system and improve their survival rate. Adenosine A2a receptor knockout mice can enhance the anti-tumor immunity of CD8+ T cells, significantly inhibit tumor proliferation, and transplant melanoma or lymphoma cells into wild-type mice than to adenosine A2a. Somatic knockout mice are more likely to grow in vivo, and adenosine A2a receptor knockout mice have a better response to tumor vaccines.
腺苷A2a受体在免疫细胞上高水平表达，腺苷A2a受体的活化可以促使机体产生免疫耐受，促使肿瘤细胞“免疫逃逸”或“免疫抑制”的形成，为肿瘤的发生发展创造了有利条件。腺苷A2a受体拮抗剂直接靶向免疫细胞表面腺苷A2a受体，抑制该受体的活化，进而抑制免疫细胞内cAMP的产生，消除由腺苷A2a受体激活介导的T细胞免疫功能抑制，达到肿瘤治疗的效果。因此，腺苷A2a受体拮抗剂作为肿瘤治疗药物在医药行业具有良好的应用前景。除肿瘤外，腺苷A2a受体还与帕金森病、阿尔茨海默病、AIDS脑症、多发性硬化症、肌萎缩性侧索硬化症、亨廷顿氏病、多***萎缩症、脑缺血、注意力缺陷多动性障碍、睡眠障碍、焦虑性障碍、情绪障碍、癫痫、神经痛、偏头痛等疾病相关。The adenosine A2a receptor is highly expressed on immune cells, and the activation of adenosine A2a receptor can promote the body to produce immune tolerance, promote the formation of "immune escape" or "immunosuppression" of tumor cells, and create a tumor for development. Favorable conditions. Adenosine A2a receptor antagonist directly targets the adenosine A2a receptor on the surface of immune cells, inhibits the activation of this receptor, thereby inhibiting the production of cAMP in immune cells and eliminating the immune function of T cells mediated by adenosine A2a receptor activation. Inhibition, to achieve the effect of tumor treatment. Therefore, adenosine A2a receptor antagonists have a good application prospect in the pharmaceutical industry as a tumor therapeutic drug. In addition to tumors, adenosine A2a receptors are also associated with Parkinson's disease, Alzheimer's disease, AIDS cerebral palsy, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, multiple system atrophy, cerebral ischemia , attention deficit hyperactivity disorder, sleep disorders, anxiety disorders, mood disorders, epilepsy, neuralgia, migraine and other diseases.
Corvus公司的CPI-444是对腺苷A2a受体具有拮抗作用的化合物，目前处于I期临床研究，适应症是肿瘤，在此之前，CPI-444曾用于治疗中枢神经***疾病的临床试验中。WO01/62233和WO2002014282A1公开了氨基吡啶化合物对腺苷A2a受体具有拮抗作用，并公开了可做为帕金森病或老年痴呆药物的治疗剂。WO01/62233、WO2003035639A1、WO2004016605A1和WO2005079801A1公开了氨基嘧啶 化合物对腺苷A2a受体具有拮抗作用，并公开了可做为帕金森病或神经痛等疾病的治疗剂。WO2011095625A1公开了一种氨基三嗪化合物对腺苷A2a受体具有拮抗作用，并公开了可做为运动障碍、中风、或帕金森病的治疗剂。Corvus' CPI-444 is a compound that antagonizes the adenosine A2a receptor and is currently in Phase I clinical studies. The indication is a tumor. Prior to this, CPI-444 was used in clinical trials for the treatment of central nervous system diseases. . WO 01/62233 and WO2002014282 A1 disclose that an aminopyridine compound has an antagonistic effect on the adenosine A2a receptor, and discloses a therapeutic agent which can be used as a drug for Parkinson's disease or Alzheimer's disease. WO01/62233, WO2003035639A1, WO2004016605A1 and WO2005079801A1 disclose that an aminopyrimidine compound has an antagonistic action on the adenosine A2a receptor, and discloses a therapeutic agent which can be used as a disease such as Parkinson's disease or neuralgia. WO2011095625A1 discloses an aminotriazine compound having an antagonistic effect on adenosine A2a receptor, and discloses a therapeutic agent which can be used as a dyskinesia, stroke, or Parkinson's disease.
因此，腺苷A2a受体拮抗剂作为药物在医药行业具有良好的应用前景。为了达到更好的肿瘤治疗效果，更好地满足市场需求，亟需开发出新的高效低毒的腺苷A2a受体拮抗剂。Therefore, adenosine A2a receptor antagonists have a good application prospect in the pharmaceutical industry as a drug. In order to achieve better tumor treatment effects and better meet market demand, it is urgent to develop new high-efficiency and low-toxic adenosine A2a receptor antagonists.
发明内容Summary of the invention
本申请涉及式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：The present application is directed to a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein:
Figure PCTCN2019070390-appb-000001
Figure PCTCN2019070390-appb-000001
A 1为N或CR 5； A 1 is N or CR 5 ;
A 2为N或CR 6； A 2 is N or CR 6 ;
A 3为N或CR 7； A 3 is N or CR 7 ;
且当A 1为CR 5时，A 2和A 3不同时为N； And when A 1 is CR 5 , A 2 and A 3 are not N at the same time;
R 1和R 2各自独立地选自氢、C 1-6烷基、C 1-6烷氧基-C 1-6烷基-、R 8R 9N-C 1-6烷基-、5-6元杂环基-C 1-6烷基-、5-6元杂芳基-C 1-6烷基-和5-6元杂芳基，其中所述杂环基和杂芳基任选地被独立地选自下列的一个或多个取代基取代：羟基、卤素、氨基、C 1-6烷基和C 1-6烷氧基； R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl-, R 8 R 9 NC 1-6 alkyl-, 5-6 a heterocyclic group -C 1-6 alkyl-, 5-6 membered heteroaryl-C 1-6 alkyl- and 5-6 membered heteroaryl, wherein said heterocyclic group and heteroaryl group are optionally Substituted by one or more substituents independently selected from the group consisting of hydroxy, halo, amino, C 1-6 alkyl and C 1-6 alkoxy;
或者，R 1和R 2连同其相连的氮原子形成4-7元含氮杂环基、5-10元含氮并杂环基、5-10元含氮螺杂环基或5-10元含氮桥杂环基，其中所述含氮杂环基、含氮并杂环基、含氮螺杂环基和含氮桥杂环基任选地被独立地选自下列的一个或多个取代基取代：羟基、卤素、氰基、C 1-6烷基和C 1-6烷氧基； Alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-7 membered nitrogen-containing heterocyclic group, a 5-10 membered nitrogen-containing heterocyclic group, a 5-10 membered nitrogen-containing spiroheterocyclic group or 5-10 members. a nitrogen-containing bridged heterocyclic group, wherein the nitrogen-containing heterocyclic group, nitrogen-containing heterocyclic group, nitrogen-containing spiroheterocyclic group, and nitrogen-containing bridged heterocyclic group are optionally independently selected from one or more of the following Substituent substitution: hydroxy, halogen, cyano, C 1-6 alkyl and C 1-6 alkoxy;
R 3为C 1-6烷基或C 3-6环烷基； R 3 is C 1-6 alkyl or C 3-6 cycloalkyl;
R 4为氢或C 1-6烷基； R 4 is hydrogen or C 1-6 alkyl;
R 5、R 6和R 7各自独立地选自氢和卤素； R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen and halogen;
R 8和R 9各自独立地选自氢和C 1-6烷基。 R 8 and R 9 are each independently selected from hydrogen and C 1-6 alkyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：A 1为N。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Where: A 1 is N.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：A 2为N。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Where: A 2 is N.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：A 3为N。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, , where: A 3 is N.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：A 1为CR 5，R 5的定义如本申请所述。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Where: A 1 is CR 5 and R 5 is as defined herein.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：A 2为CR 6，R 6的定义如本申请所述。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Where: A 2 is CR 6 and R 6 is as defined herein.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：A 3为CR 7，R 7的定义如本申请所述。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Where: A 3 is CR 7 and R 7 is as defined herein.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其具有式II、式III、式IV或式V的结构，其中：In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, , having the structure of Formula II, Formula III, Formula IV or Formula V, wherein:
Figure PCTCN2019070390-appb-000002
Figure PCTCN2019070390-appb-000002
R 1、R 2、R 3、R 4、R 5和R 7定义如式I中所述。 R 1 , R 2 , R 3 , R 4 , R 5 and R 7 are as defined in formula I.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, ,among them:
R 1和R 2各自独立地选自氢、C 1-4烷基、C 1-2烷氧基-C 1-2烷基-、R 8R 9N-C 1-2烷基-、6元杂环基-C 1-2烷基-、6元杂芳基-C 1-2烷基-和5元杂芳基，其中所述杂环基和杂芳基任选地被C 1-4烷基取代； R 1 and R 2 are each independently selected from hydrogen, C 1-4 alkyl, C 1-2 alkoxy-C 1-2 alkyl-, R 8 R 9 NC 1-2 alkyl-, 6-membered hetero a cyclo-C 1-2 alkyl-, 6-membered heteroaryl-C 1-2 alkyl- and 5-membered heteroaryl group, wherein the heterocyclic group and heteroaryl are optionally C 1-4 alkane Base substitution
或者，R 1和R 2连同其相连的氮原子形成5-6元含氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基或5-10元含氮桥杂环基，其中所述含氮杂环基、含氮并杂环基、螺杂环基和含氮桥杂环基任选地被独立地选自下列的取代基取代：羟基、卤素、氰基、C 1-4烷基和C 1-4烷氧基； Alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-6 membered nitrogen-containing heterocyclic group, a 8-10 membered nitrogen-containing heterocyclic group, a 7-10 membered nitrogen-containing spiroheterocyclic group or 5-10 members. a nitrogen-containing bridged heterocyclic group, wherein the nitrogen-containing heterocyclic group, the nitrogen-containing heterocyclic group, the spiroheterocyclic group, and the nitrogen-containing bridged heterocyclic group are optionally substituted with a substituent independently selected from the group consisting of a hydroxyl group, Halogen, cyano, C 1-4 alkyl and C 1-4 alkoxy;
优选地，Preferably,
R 1和R 2各自独立地选自氢、C 1-4烷基、C 1-2烷氧基-C 1-2烷基-、R 8R 9N-C 1-2烷基-、6元杂环基-C 1-2烷基-、6元杂芳基-C 1-2烷基-和5元杂芳基，其中所述杂环基和杂芳基任选地被甲基、乙基和异丙基取代； R 1 and R 2 are each independently selected from hydrogen, C 1-4 alkyl, C 1-2 alkoxy-C 1-2 alkyl-, R 8 R 9 NC 1-2 alkyl-, 6-membered hetero a cyclo-C 1-2 alkyl-, 6-membered heteroaryl-C 1-2 alkyl- and 5-membered heteroaryl group, wherein the heterocyclic group and heteroaryl are optionally methyl, ethyl And isopropyl substitution;
或者，R 1和R 2连同其相连的氮原子形成5-6元含氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基或5-10元含氮桥杂环基，其中所述含氮杂环基、含氮并杂环基、螺杂环基和含氮桥杂 环基任选地被独立地选自下列的取代基取代：羟基、氟、氯、溴、碘、氰基、甲基、乙基、异丙基、甲氧基和乙氧基； Alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-6 membered nitrogen-containing heterocyclic group, a 8-10 membered nitrogen-containing heterocyclic group, a 7-10 membered nitrogen-containing spiroheterocyclic group or 5-10 members. a nitrogen-containing bridged heterocyclic group, wherein the nitrogen-containing heterocyclic group, the nitrogen-containing heterocyclic group, the spiroheterocyclic group, and the nitrogen-containing bridged heterocyclic group are optionally substituted with a substituent independently selected from the group consisting of a hydroxyl group, Fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, isopropyl, methoxy and ethoxy;
特别优选地，Particularly preferably,
R 1和R 2各自独立地选自氢、甲基、甲氧基-乙基-、二甲基氨基-乙基-、吗啉-1-基-乙基-、吡啶-2-基-甲基-、吡啶-3-基-甲基-、吡啶-4-基-甲基-和1-甲基-1H-吡唑-4-基-； R 1 and R 2 are each independently selected from the group consisting of hydrogen, methyl, methoxy-ethyl-, dimethylamino-ethyl-, morpholin-1-yl-ethyl-, pyridin-2-yl- Base-, pyridin-3-yl-methyl-, pyridin-4-yl-methyl- and 1-methyl-1H-pyrazol-4-yl-;
或者，R 1和R 2连同它们共同连接的氮原子形成哌啶基、吡咯烷基、吗啉基、哌嗪基、氮杂螺[3.3]庚烷基、5,6,7,8-四氢-1,6-萘啶基、5,6,7,8-四氢-1,7-萘啶基、(3aR,6aS)-六氢环戊[c]吡咯基、8-氮杂双环[3.2.1]辛烷基、6,7-二氢-5H-吡咯[3,4-b]吡啶基-或六氢吡嗪并[2,1-c][1,4]噁嗪基-，其中所述哌啶基、吡咯烷基、吗啉基、哌嗪基、氮杂螺[3.3]庚烷基、5,6,7,8-四氢-1,6-萘啶基、5,6,7,8-四氢-1,7-萘啶基、(3aR,6aS)-六氢环戊[c]吡咯基、8-氮杂双环[3.2.1]辛烷基、6,7-二氢-5H-吡咯[3,4-b]吡啶基-或六氢吡嗪并[2,1-c][1,4]噁嗪基-任选地被独立地选自下列的取代基取代：羟基、氟、氰基、甲基和甲氧基。 Alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached form a piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azaspiro[3.3]heptanyl, 5,6,7,8-tetra Hydrogen-1,6-naphthyridinyl, 5,6,7,8-tetrahydro-1,7-naphthyridinyl, (3aR,6aS)-hexahydrocyclopenta[c]pyrrolyl, 8-azabicyclo [3.2.1] Octyl, 6,7-dihydro-5H-pyrrole[3,4-b]pyridyl- or hexahydropyrazino[2,1-c][1,4]oxazinyl - wherein the piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azaspiro[3.3]heptyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 5,6,7,8-tetrahydro-1,7-naphthyridinyl, (3aR,6aS)-hexahydrocyclopenta[c]pyrrolyl, 8-azabicyclo[3.2.1]octyl, 6 , 7-dihydro-5H-pyrrole[3,4-b]pyridinyl- or hexahydropyrazino[2,1-c][1,4]oxazinyl-optionally, independently selected from the following Substituent substitution: hydroxy, fluoro, cyano, methyl and methoxy.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, ,among them:
R 1和R 2各自独立地选自氢、C 1-4烷基、C 1-2烷氧基-C 1-2烷基-、R 8R 9N-C 1-2烷基-、6元杂环基-C 1-2烷基-、6元杂芳基-C 1-2烷基-和5元杂芳基，其中所述6元杂环基、6元杂芳基和5元杂芳基任选地被C 1-4烷基取代； R 1 and R 2 are each independently selected from hydrogen, C 1-4 alkyl, C 1-2 alkoxy-C 1-2 alkyl-, R 8 R 9 NC 1-2 alkyl-, 6-membered hetero a cyclo-C 1-2 alkyl-, 6-membered heteroaryl-C 1-2 alkyl- and 5-membered heteroaryl group wherein the 6-membered heterocyclic group, 6-membered heteroaryl group and 5-membered heteroaryl group The base is optionally substituted by a C 1-4 alkyl group;
或者，R 1和R 2连同其相连的氮原子形成5-6元含氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基或5-10元含氮桥杂环基，其中所述5-6元含氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基和5-10元含氮桥杂环基任选地被独立地选自下列的的一个或多个取代基单取代或多取代：羟基、卤素、氰基、C 1-4烷基和C 1-4烷氧基， Alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-6 membered nitrogen-containing heterocyclic group, a 8-10 membered nitrogen-containing heterocyclic group, a 7-10 membered nitrogen-containing spiroheterocyclic group or 5-10 members. a nitrogen-containing bridged heterocyclic group wherein the 5-6 membered nitrogen-containing heterocyclic group, 8-10 membered nitrogen-containing heterocyclic group, 7-10 membered nitrogen-containing spiroheterocyclic group, and 5-10 membered nitrogen-containing bridged The cyclo group is optionally mono- or polysubstituted with one or more substituents independently selected from the group consisting of hydroxy, halo, cyano, C 1-4 alkyl and C 1-4 alkoxy,
其中R 8和R 9的定义如本申请所述。 Wherein R 8 and R 9 are as defined herein.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2各自独立地选自氢、C 1-4烷基、C 1-2烷氧基-C 1-2烷基-、R 8R 9N-C 1-2烷基-、6元杂环基-C 1-2烷基-、6元杂芳基-C 1-2烷基-和5元杂芳基，其中所述6元杂环基、6元杂芳基和5元杂芳基任选地被独立地选自下列的一个或多个取代基单取代或多取代：甲基、乙基、正丙基或异丙基； In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-2 alkoxy-C 1-2 alkyl-, R 8 R 9 NC 1-2 alkyl-, 6-membered heterocyclyl-C 1-2 alkyl-, 6-membered heteroaryl-C 1-2 alkyl- and 5-membered heteroaryl, wherein the 6-membered heterocyclic group, 6-membered heteroaryl group and 5 The heteroaryl group is optionally mono- or polysubstituted by one or more substituents independently selected from the group consisting of methyl, ethyl, n-propyl or isopropyl;
或者，R 1和R 2连同其相连的氮原子形成5-6元含氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基或5-10元含氮桥杂环基，其中所述含5-6元氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基和5-10元含氮桥杂环基任选地被独立地选自下列的一个或多个取代基单取代或多取代：羟基、氟、氯、溴、碘、氰基、甲基、乙基、异丙基、甲氧基和乙氧基； Alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-6 membered nitrogen-containing heterocyclic group, a 8-10 membered nitrogen-containing heterocyclic group, a 7-10 membered nitrogen-containing spiroheterocyclic group or 5-10 members. a nitrogen-containing bridged heterocyclic group, wherein the 5- to 6-membered azacyclic group, the 8-10 membered nitrogen-containing heterocyclic group, the 7-10 membered nitrogen-containing spiroheterocyclic group, and the 5-10 membered nitrogen-containing bridged The cyclo group is optionally mono- or polysubstituted with one or more substituents independently selected from the group consisting of hydroxy, fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, isopropyl, methoxy. And ethoxylated;
其中R 8和R 9的定义如本申请所述。 Wherein R 8 and R 9 are as defined herein.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, ,among them:
R 1和R 2各自独立地选自氢、C 1-4烷基、C 1-2烷氧基-C 1-2烷基-、R 8R 9N-C 1-2烷基-、6元杂环基-C 1-2烷基-、6元杂芳基-C 1-2烷基-和5元杂芳基，其中所述6元杂环基、6元杂芳基和5元杂芳基任选地被C 1-4烷基取代，其中R 8和R 9的定义如本申请所述。 R 1 and R 2 are each independently selected from hydrogen, C 1-4 alkyl, C 1-2 alkoxy-C 1-2 alkyl-, R 8 R 9 NC 1-2 alkyl-, 6-membered hetero a cyclo-C 1-2 alkyl-, 6-membered heteroaryl-C 1-2 alkyl- and 5-membered heteroaryl group wherein the 6-membered heterocyclic group, 6-membered heteroaryl group and 5-membered heteroaryl group The group is optionally substituted by C 1-4 alkyl, wherein R 8 and R 9 are as defined herein.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同其相连的氮原子形成5-6元含氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基或5-10元含氮桥杂环基，其中所述5-6元含氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基和5-10元含氮桥杂环基任选地被独立地选自下列的一个或多个取代基单取代或多取代：羟基、卤素、氰基、C 1-4烷基和C 1-4烷氧基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-6 membered nitrogen-containing heterocyclic group, a 8-10 membered nitrogen-containing heterocyclic group, a 7-10 membered nitrogen-containing spiroheterocyclic group or 5-10 a nitrogen-containing bridged heterocyclic group, wherein the 5-6 membered nitrogen-containing heterocyclic group, 8-10 membered nitrogen-containing heterocyclic group, 7-10 membered nitrogen-containing spiroheterocyclic group, and 5-10 membered nitrogen-containing bridge The heterocyclic group is optionally mono- or polysubstituted with one or more substituents independently selected from the group consisting of hydroxy, halo, cyano, C 1-4 alkyl and C 1-4 alkoxy.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同其相连的氮原子形成5-6元含氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基或5-10元含氮桥杂环基，其中所述含5-6元氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基和5-10元含氮桥杂环基任选地被独立地选自下列的一个或多个取代基单取代或多取代：羟基、氟、氯、溴、碘、氰基、甲基、乙基、异丙基、甲氧基和乙氧基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-6 membered nitrogen-containing heterocyclic group, a 8-10 membered nitrogen-containing heterocyclic group, a 7-10 membered nitrogen-containing spiroheterocyclic group or 5-10 a nitrogen-containing bridged heterocyclic group, wherein the 5- to 6-membered azacyclic group, the 8-10 membered nitrogen-containing heterocyclic group, the 7-10 membered nitrogen-containing spiroheterocyclic group, and the 5-10 membered nitrogen-containing bridge The heterocyclic group is optionally mono- or polysubstituted with one or more substituents independently selected from the group consisting of hydroxy, fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, isopropyl, methoxy. Base and ethoxy group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, ,among them:
R 1和R 2各自独立地选自氢、甲基、甲氧基乙基-、二甲基氨基-乙基-、吗啉-1-基-乙基-、吗啉-4-基-乙基-、吡啶-2-基-甲基-、吡啶-3-基-甲基-、吡啶-4-基-甲基-和1-甲基-1H-吡唑-4-基-。 R 1 and R 2 are each independently selected from the group consisting of hydrogen, methyl, methoxyethyl-, dimethylamino-ethyl-, morpholin-1-yl-ethyl-, morpholin-4-yl-B Base-, pyridin-2-yl-methyl-, pyridin-3-yl-methyl-, pyridin-4-yl-methyl- and 1-methyl-1H-pyrazol-4-yl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, ,among them:
R 1选自氢、甲基、甲氧基乙基-、二甲基氨基-乙基-、吗啉-1-基-乙基-、吗啉-4-基-乙基-、吡啶-2-基-甲基-、吡啶-3-基-甲基-、吡啶-4-基-甲基-和1-甲基-1H-吡唑-4-基-。 R 1 is selected from the group consisting of hydrogen, methyl, methoxyethyl-, dimethylamino-ethyl-, morpholin-1-yl-ethyl-, morpholin-4-yl-ethyl-, pyridine-2 -yl-methyl-, pyridin-3-yl-methyl-, pyridin-4-yl-methyl- and 1-methyl-1H-pyrazol-4-yl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1为氢。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 is hydrogen.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1为甲基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 is a methyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1为甲氧基乙基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 is methoxyethyl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1为二甲基氨基-乙基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 is dimethylamino-ethyl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1为吗啉-1-基-乙基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 is morpholin-1-yl-ethyl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1为吗啉-4-基-乙基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 is morpholin-4-yl-ethyl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1为吡啶-2-基-甲基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 is pyridin-2-yl-methyl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1为吡啶-3-基-甲基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 is pyridin-3-yl-methyl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1为吡啶-4-基-甲基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 is pyridin-4-yl-methyl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1为1-甲基-1H-吡唑-4-基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 is 1-methyl-1H-pyrazol-4-yl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, ,among them:
R 2选自氢、甲基、甲氧基乙基-、二甲基氨基-乙基-、吗啉-1-基-乙基-、吗啉-4-基-乙基-、吡啶-2-基-甲基-、吡啶-3-基-甲基-、吡啶-4-基-甲基-和1-甲基-1H-吡唑-4-基-。 R 2 is selected from the group consisting of hydrogen, methyl, methoxyethyl-, dimethylamino-ethyl-, morpholin-1-yl-ethyl-, morpholin-4-yl-ethyl-, pyridine-2 -yl-methyl-, pyridin-3-yl-methyl-, pyridin-4-yl-methyl- and 1-methyl-1H-pyrazol-4-yl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 2为氢。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 2 is hydrogen.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 2为甲基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 2 is a methyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 2为甲氧基乙基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 2 is methoxyethyl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 2为二甲基氨基-乙基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 2 is dimethylamino-ethyl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 2为吗啉-1-基-乙基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 2 is morpholin-1-yl-ethyl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 2为吗啉-4-基-乙基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 2 is morpholin-4-yl-ethyl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 2为吡啶-2-基-甲基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 2 is pyridin-2-yl-methyl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 2为吡啶-3-基-甲基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 2 is pyridin-3-yl-methyl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 2为吡啶-4-基-甲基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 2 is pyridin-4-yl-methyl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 2为1-甲基-1H-吡唑-4-基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 2 is 1-methyl-1H-pyrazol-4-yl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, ,among them:
R 1和R 2连同它们共同连接的氮原子形成哌啶基、吡咯烷基、吗啉基、哌嗪基、氮杂螺[3.3]庚烷基、5,6,7,8-四氢-1,6-萘啶基、5,6,7,8-四氢-1,7-萘啶基、(3aR,6aS)-六氢环戊[c]吡咯基、8-氮杂双环[3.2.1]辛烷基、6,7-二氢-5H-吡咯[3,4-b]吡啶基-或六氢吡嗪并[2,1-c][1,4]噁嗪基-，其中所述哌啶基、吡咯烷基、吗啉基、哌嗪基、氮杂螺[3.3]庚烷基、5,6,7,8-四氢-1,6-萘啶基、5,6,7,8-四氢-1,7-萘啶 基、(3aR,6aS)-六氢环戊[c]吡咯基、8-氮杂双环[3.2.1]辛烷基、6,7-二氢-5H-吡咯[3,4-b]吡啶基-或六氢吡嗪并[2,1-c][1,4]噁嗪基-任选地被独立地选自下列的一个或多个取代基单取代或多取代：羟基、氟、氰基、甲基和甲氧基。 R 1 and R 2 together with the nitrogen atom to which they are attached form a piperidinyl group, a pyrrolidinyl group, a morpholinyl group, a piperazinyl group, an azaspiro[3.3]heptyl group, a 5,6,7,8-tetrahydro- 1,6-naphthyridinyl, 5,6,7,8-tetrahydro-1,7-naphthyridinyl, (3aR,6aS)-hexahydrocyclopenta[c]pyrrolyl, 8-azabicyclo[3.2 .1]octyl, 6,7-dihydro-5H-pyrrole[3,4-b]pyridyl- or hexahydropyrazino[2,1-c][1,4]oxazinyl-, Wherein the piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azaspiro[3.3]heptyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 5, 6,7,8-tetrahydro-1,7-naphthyridinyl, (3aR,6aS)-hexahydrocyclopenta[c]pyrrolyl, 8-azabicyclo[3.2.1]octyl, 6,7 -Dihydro-5H-pyrrole[3,4-b]pyridinyl- or hexahydropyrazino[2,1-c][1,4]oxazinyl-optionally selected independently from one of the following Or a plurality of substituents may be mono- or poly-substituted: hydroxy, fluoro, cyano, methyl and methoxy.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成哌啶基、4-甲氧基-哌啶基-、4-羟基-哌啶基、3-羟基-哌啶基、4,4-二氟-哌啶基、4-氰基-哌啶基、吡咯烷基、2-甲基吡咯烷基-、2,2-二甲基吡咯烷基-、3-甲氧基吡咯烷基-、3,3-二氟吡咯烷基、吗啉基、哌嗪基、N-甲基哌嗪基-、氮杂螺[3.3]庚烷基-或六氢吡嗪并[2,1-c][1,4]噁嗪基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form a piperidinyl group, 4-methoxy-piperidinyl-, 4-hydroxy-piperidinyl, 3-hydroxy-piperidinyl, 4, 4 -difluoro-piperidinyl, 4-cyano-piperidinyl, pyrrolidinyl, 2-methylpyrrolidinyl-, 2,2-dimethylpyrrolidinyl-, 3-methoxypyrrolidinyl -, 3,3-difluoropyrrolidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl-, azaspiro[3.3]heptyl- or hexahydropyrazino[2,1- c] [1,4]oxazinyl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成哌啶基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form a piperidinyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成4-甲氧基-哌啶基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-methoxy-piperidinyl- group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成4-羟基-哌啶基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-hydroxy-piperidinyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成3-羟基-哌啶基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form a 3-hydroxy-piperidinyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成4,4-二氟-哌啶基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form a 4,4-difluoro-piperidinyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成4-氰基-哌啶基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-cyano-piperidinyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成吡咯烷基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form a pyrrolidinyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成2-甲基吡咯烷基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form a 2-methylpyrrolidinyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成2,2-二甲基吡咯烷基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form 2,2-dimethylpyrrolidinyl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成3-甲氧基吡咯烷基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form a 3-methoxypyrrolidinyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成3,3-二氟吡咯烷基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form a 3,3-difluoropyrrolidinyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成吗啉基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form a morpholinyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成哌嗪基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form a piperazinyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成N-甲基哌嗪基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form an N-methylpiperazinyl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成氮杂螺[3.3]庚烷基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form azaspiro[3.3]heptanyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成六氢吡嗪并[2,1-c][1,4]噁嗪基-。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 1 and R 2 together with the nitrogen atom to which they are attached form a hexahydropyrazino[2,1-c][1,4]oxazinyl-.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3为C 1-4烷基；优选地，R 3为异丙基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 3 is C 1-4 alkyl; preferably, R 3 is isopropyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3为甲基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 3 is a methyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3为乙基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 3 is an ethyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3为正丙基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 3 is a n-propyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3为异丙基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 3 is isopropyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3为正丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 3 is n-butyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3为异丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 3 is isobutyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3为仲丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 3 is a sec-butyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3为叔丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 3 is a tert-butyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4为氢或C 1-4烷基；优选地，R 4为氢或甲基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 4 is hydrogen or C 1-4 alkyl; preferably, R 4 is hydrogen or methyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 4 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4为氢。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 4 is hydrogen.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4为甲基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 4 is a methyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4为乙基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 4 is an ethyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4为正丙基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 4 is a n-propyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4为异丙基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 4 is isopropyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4为正丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 4 is n-butyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4为异丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 4 is isobutyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4为仲丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 4 is a sec-butyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4为叔丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 4 is a tert-butyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 5、R 6和R 7各自独立地选自氢、氟、氯、溴和碘；优选地，R 5、R 6和R 7各自独立地选自氢和氟。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine and iodine; preferably, R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen and fluorine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 5、R 6和R 7各自独立地选自氢、氟、氯、溴和碘。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine and iodine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 5、R 6和R 7各自独立地选自氢和氟。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen and fluorine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 5、R 6和R 7各自独立地为氢。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 5 , R 6 and R 7 are each independently hydrogen.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 5、R 6和R 7各自独立地为氟。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 5 , R 6 and R 7 are each independently fluorine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 5、R 6和R 7各自独立地为氯。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 5 , R 6 and R 7 are each independently chlorine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 5、R 6和R 7各自独立地为溴。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 5 , R 6 and R 7 are each independently bromine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 5、R 6和R 7各自独立地为碘。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 5 , R 6 and R 7 are each independently iodine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 5为氢。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 5 is hydrogen.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 5为氟。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 5 is fluorine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 5为氯。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Where: R 5 is chlorine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 5溴。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, , wherein: R 5 bromine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 5为碘。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 5 is iodine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 6为氢。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 6 is hydrogen.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 6为氟。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 6 is fluorine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 6为氯。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Where: R 6 is chlorine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 6溴。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, , wherein: R 6 bromine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 6为碘。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 6 is iodine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 7为氢。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 7 is hydrogen.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 7为氟。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 7 is fluorine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 7为氯。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Where: R 7 is chlorine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 5溴。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, , wherein: R 5 bromine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 7为碘。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, , wherein: R 7 is iodine.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 8和R 9各自独立地选自氢和C 1-4烷基；优选地，R 8和R 9各自独立地选自氢和甲基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 8 and R 9 are each independently selected from hydrogen and C 1-4 alkyl; preferably, R 8 and R 9 are each independently selected from hydrogen and methyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 8为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 8 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 9为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 9 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 8为乙基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 8 is an ethyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 8为正丙基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 8 is a n-propyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 8为异丙基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 8 is isopropyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 8为正丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 8 is n-butyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 8为异丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 8 is isobutyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 8为仲丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 8 is a sec-butyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 8为叔丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 8 is a tert-butyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 9为乙基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 9 is ethyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 9为正丙基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 9 is a n-propyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 9为异丙基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 9 is isopropyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 9为正丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 9 is n-butyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 9为异丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 9 is isobutyl.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 9为仲丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 9 is a sec-butyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 9为叔丁基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 9 is a tert-butyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 8和R 9各自独立地为甲基。在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 8为甲基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 8 and R 9 are each independently methyl. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 8 is a methyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 9为甲基。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 9 is a methyl group.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 8为氢。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 8 is hydrogen.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 9为氢。 In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, Wherein: R 9 is hydrogen.
在部分实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其选自：In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, , which is selected from:
Figure PCTCN2019070390-appb-000003
Figure PCTCN2019070390-appb-000003
Figure PCTCN2019070390-appb-000004
Figure PCTCN2019070390-appb-000004
Figure PCTCN2019070390-appb-000005
Figure PCTCN2019070390-appb-000005
Figure PCTCN2019070390-appb-000006
Figure PCTCN2019070390-appb-000006
Figure PCTCN2019070390-appb-000007
Figure PCTCN2019070390-appb-000007
本申请所述化合物中的原子可以被其同位素替代。例如 12C可被其同位素 13C或 14C替代； 1H可被 2H(D，氘)或 3H(T，氚)替代等。本申请包括式I所述化合物以及式I化合物中的任意原子经其同位素替换后得到的同位素标记的化合物。 Atoms in the compounds described herein may be replaced by their isotopes. For example, 12 C can be replaced by its isotope 13 C or 14 C; 1 H can be replaced by 2 H (D, 氘) or 3 H (T, 氚). The present application includes isotopically-labeled compounds of the compounds of formula I and any of the compounds of formula I which have been subjected to their isotopic substitutions.
本申请还涉及制备所述化合物的方法，其包括以下合成路线：The application also relates to a method of preparing the compound comprising the following synthetic route:
合成路线一：式II的化合物的制备方法Synthetic Route 1: Preparation of Compounds of Formula II
Figure PCTCN2019070390-appb-000008
Figure PCTCN2019070390-appb-000008
其中：Hal 1和Hal 2各自独立地为相同或不同的卤素，例如Cl、Br或I；Y为硼酸或硼酸酯基团，优选为-B(OH) 2或者
Figure PCTCN2019070390-appb-000009
其余基团如上文所定义。 Wherein: Hal 1 and Hal 2 are each independently the same or different halogens, such as Cl, Br or I; Y is a boric acid or borate group, preferably -B(OH) 2 or
Figure PCTCN2019070390-appb-000009
The remaining groups are as defined above.
步骤A：化合物II-1与卤化剂反应得到化合物II-2；Step A: Compound II-1 is reacted with a halogenating agent to obtain Compound II-2;
化合物II-1与卤化剂发生取代反应得到化合物II-2。所述取代反应优选在强碱的存在下在溶剂中进行。所述强碱可以是LiHMDS、NaHMDS、LDA、正丁基锂和叔丁基锂等，优选正丁基锂。所述卤化剂可以是N-溴代丁二酰亚胺、N-碘代丁二酰亚胺、溴素和碘，优选碘。所用溶剂只要其不抑制反应并且可以在一定程度上溶解原料即可，可选四氢呋喃、***、甲苯，优选四氢呋喃。所述取代反应优选在适合的保护气氛(例如氮气环境)下进行。所述取代反应优选在适合的温度下进行，所述温度可以是-78℃至-20℃，优选-78℃。所述取代反应需进行合适的时间，所述时间可以是10分钟至1小时，优选30分钟。Substitution reaction of compound II-1 with a halogenating agent gives compound II-2. The substitution reaction is preferably carried out in a solvent in the presence of a strong base. The strong base may be LiHMDS, NaHMDS, LDA, n-butyllithium, t-butyllithium or the like, preferably n-butyllithium. The halogenating agent may be N-bromosuccinimide, N-iodosuccinimide, bromine and iodine, preferably iodine. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and may dissolve the starting material to some extent, and optionally tetrahydrofuran, diethyl ether or toluene, preferably tetrahydrofuran. The substitution reaction is preferably carried out under a suitable protective atmosphere such as a nitrogen atmosphere. The substitution reaction is preferably carried out at a suitable temperature, which may be from -78 ° C to -20 ° C, preferably from -78 ° C. The substitution reaction is carried out for a suitable period of time, which may be from 10 minutes to 1 hour, preferably 30 minutes.
步骤B：化合物II-2与IN-a反应得到化合物II-3；Step B: Compound II-2 is reacted with IN-a to obtain compound II-3;
化合物II-2与化合物IN-a发生偶联反应得到化合物II-3。所述偶联反应优选在金属催化剂和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、二(三苯基膦)二氯化钯、醋酸钯，优选[1,1'-双(二苯基膦基)二茂铁]二氯化钯。所述碱可以是无机碱，例如碳酸钾、碳酸铯、碳酸钠、碳酸氢钠、碳酸氢钾，优选碳酸钾。优选地，所述偶联反应在适合的有机溶剂或有机溶剂和水的混合溶剂中进行，所述有机溶剂可选1,4-二氧六环、N,N-二甲基甲酰胺或上述有机溶剂和水的混合溶剂，例如是1,4-二氧六环和水的混合溶剂。优选地，所述偶联反应在适合的保护气氛(例如氮气环境)下进行。优选地，所述偶联反应在适合的温度下进行，所述温度可以是70-100℃，优选80℃。优选地，所述偶联反应进行合适的时间，所述时间可以是1-8小时，例如4小时。Compound II-2 is coupled with compound IN-a to give compound II-3. The coupling reaction is preferably carried out in the presence of a metal catalyst and a base. Preferably, the metal catalyst is a palladium metal catalyst such as tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, bis(triphenylphosphine)palladium dichloride, palladium acetate, preferably [1,1'-bis(diphenyl) Phosphyl)ferrocene]palladium dichloride. The base may be an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably potassium carbonate. Preferably, the coupling reaction is carried out in a suitable organic solvent or a mixed solvent of an organic solvent and water, which may be selected from 1,4-dioxane, N,N-dimethylformamide or the like. A mixed solvent of an organic solvent and water, for example, a mixed solvent of 1,4-dioxane and water. Preferably, the coupling reaction is carried out in a suitable protective atmosphere, such as a nitrogen atmosphere. Preferably, the coupling reaction is carried out at a suitable temperature, which may be from 70 to 100 ° C, preferably 80 ° C. Preferably, the coupling reaction is carried out for a suitable period of time, which may be from 1 to 8 hours, such as 4 hours.
步骤C：化合物II-3与IN-b反应得到化合物II-4；Step C: Compound II-3 is reacted with IN-b to obtain compound II-4;
化合物II-3与化合物IN-b发生偶联反应得到化合物II-4。所述偶联反应优选在金属催化剂和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、二(三苯基膦)二氯化钯、醋酸钯，二氯二叔丁基-(4-二甲基氨基苯基)膦钯，优选二氯二叔丁基-(4-二甲基氨基苯基)膦钯。所述碱可以是无机碱，例如磷酸钾、碳酸钾、碳酸铯、碳酸钠、碳酸氢钠、碳酸氢钾，优选磷酸钾。优选地，所述偶联反应在适合的有机溶剂中进行，所述有机溶剂可选自1,4-二氧六环和N,N-二甲基甲酰胺，例如是1,4-二氧六环。优选地，所述偶联反应在适合的保护气氛(例如氮气环境)下进行。优选地，所述偶联反应在适合的温度下进行，所述温度可以是70-100℃，优选80℃。优选地，所述偶联反应进行合适的时间，所述时间可以是1-8小时，优选3小时。The coupling reaction of the compound II-3 with the compound IN-b gives the compound II-4. The coupling reaction is preferably carried out in the presence of a metal catalyst and a base. Preferably, the metal catalyst is a palladium metal catalyst such as tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, bis(triphenylphosphine)palladium dichloride, palladium acetate, dichlorodi-tert-butyl-(4-dimethyl Phenylaminophenyl)phosphine palladium, preferably dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium. The base may be an inorganic base such as potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably potassium phosphate. Preferably, the coupling reaction is carried out in a suitable organic solvent, which may be selected from the group consisting of 1,4-dioxane and N,N-dimethylformamide, for example 1,4-dioxane Six rings. Preferably, the coupling reaction is carried out in a suitable protective atmosphere, such as a nitrogen atmosphere. Preferably, the coupling reaction is carried out at a suitable temperature, which may be from 70 to 100 ° C, preferably 80 ° C. Preferably, the coupling reaction is carried out for a suitable period of time, which may be from 1 to 8 hours, preferably 3 hours.
步骤D：将化合物II-4的氨基转换成异氰酸酯再与IN-c反应得到式II的化合物；Step D: converting an amino group of compound II-4 to an isocyanate and reacting with IN-c to obtain a compound of formula II;
化合物II-4与三光气反应，将氨基转换成异氰酸酯，再与化合物IN-c反应得到式II的化合物。所述反应优选在适合的有机溶剂和碱中进行。所述有机溶剂可选自直链或环状醚类(例如四氢呋喃或***等)、1,4-二氧六环、二氯甲烷、二甲基亚砜及其任意组合，优选四氢呋喃。所述碱是有机碱，例如N,N-二异丙基乙胺、三乙胺、吡啶、4-二甲氨基吡啶，优选N,N-二异丙基乙胺。所述反应优选在适合的温度下进行。所述温度可以是-40℃至60℃，例如0-25℃。所述反应优选进行合适的时间，优选0.5-2小时。Compound II-4 is reacted with triphosgene to convert the amino group to an isocyanate which is then reacted with compound IN-c to give a compound of formula II. The reaction is preferably carried out in a suitable organic solvent and base. The organic solvent may be selected from linear or cyclic ethers (e.g., tetrahydrofuran or diethyl ether, etc.), 1,4-dioxane, dichloromethane, dimethyl sulfoxide, and any combination thereof, preferably tetrahydrofuran. The base is an organic base such as N,N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, preferably N,N-diisopropylethylamine. The reaction is preferably carried out at a suitable temperature. The temperature may be from -40 ° C to 60 ° C, such as from 0 to 25 ° C. The reaction is preferably carried out for a suitable period of time, preferably from 0.5 to 2 hours.
合成路线二：式III的化合物的制备方法Synthesis route 2: Preparation method of compound of formula III
Figure PCTCN2019070390-appb-000010
其中：Hal 1和Hal 2各自独立地为相同或不同的卤素，例如Cl、Br或I；Y为硼酸或硼酸酯基团，优选为-B(OH) 2或者
Figure PCTCN2019070390-appb-000011
其余基团如上文所定义。
Figure PCTCN2019070390-appb-000010
Wherein: Hal 1 and Hal 2 are each independently the same or different halogens, such as Cl, Br or I; Y is a boric acid or borate group, preferably -B(OH) 2 or
Figure PCTCN2019070390-appb-000011
The remaining groups are as defined above.
步骤A：化合物III-1与IN-a反应得到化合物III-2；Step A: Compound III-1 is reacted with IN-a to obtain compound III-2;
化合物III-1与化合物IN-a发生偶联反应得到化合物III-2。所述偶联反应优选在金属催化剂和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、二(三苯基膦)二氯化钯、醋酸钯，优选[1,1'-双(二苯基膦基)二茂铁]二氯化钯。所述碱可以是无机碱，例如碳酸钾、碳酸铯、碳酸钠、碳酸氢钠、碳酸氢钾，优选碳酸钾。优选地，所述偶联反应在适合的有机溶剂或有机溶剂和水的混合溶剂中进行，所述有机溶剂可选1,4-二氧六环、N,N-二甲基甲酰胺或上述有机溶剂和水的混合溶剂，例如是1,4-二氧六环和水的混合溶剂。优选地，所述偶联反应在适合的保护气氛(例如氮气环境)下进行。优选地，所述偶联反应在适合的温度下进行，所述温度可以是70-100℃，优选80℃。优选地，所述偶联反应进行合适的时间，所述时间可以是1-8小时，例如4小时。Compound III-1 is coupled with compound IN-a to give compound III-2. The coupling reaction is preferably carried out in the presence of a metal catalyst and a base. Preferably, the metal catalyst is a palladium metal catalyst such as tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, bis(triphenylphosphine)palladium dichloride, palladium acetate, preferably [1,1'-bis(diphenyl) Phosphyl)ferrocene]palladium dichloride. The base may be an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably potassium carbonate. Preferably, the coupling reaction is carried out in a suitable organic solvent or a mixed solvent of an organic solvent and water, which may be selected from 1,4-dioxane, N,N-dimethylformamide or the like. A mixed solvent of an organic solvent and water, for example, a mixed solvent of 1,4-dioxane and water. Preferably, the coupling reaction is carried out in a suitable protective atmosphere, such as a nitrogen atmosphere. Preferably, the coupling reaction is carried out at a suitable temperature, which may be from 70 to 100 ° C, preferably 80 ° C. Preferably, the coupling reaction is carried out for a suitable period of time, which may be from 1 to 8 hours, such as 4 hours.
步骤B：化合物III-2与IN-b反应得到化合物III-3；Step B: Compound III-2 is reacted with IN-b to obtain compound III-3;
化合物III-2与化合物IN-b发生偶联反应得到化合物III-3。所述偶联反应优选在金属催化剂和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、二(三苯基膦)二氯化钯、醋酸钯，优选[1,1'-双(二苯基膦基)二茂铁]二氯化钯。所述碱可以是无机碱，例如碳酸钾、碳酸铯、碳酸钠、碳酸氢钠、碳酸氢钾，优选碳酸钾。优选地，所述偶联反应在适合的有机溶剂中进行，所述有机溶剂可选1,4-二氧六环和N,N-二甲基甲酰胺，例如是1,4-二氧六环。优选地，所述偶联反应在适合的保护气氛(例如氮气环境)下进行。优选地，所述偶联反应在适合的温度下进行，所述温度可以是70-100℃，优选80℃。优选地，所述偶联反应进行合适的时间，所述时间可以是1-8小时，优选3小时。Compound III-2 is coupled with compound IN-b to give compound III-3. The coupling reaction is preferably carried out in the presence of a metal catalyst and a base. Preferably, the metal catalyst is a palladium metal catalyst such as tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, bis(triphenylphosphine)palladium dichloride, palladium acetate, preferably [1,1'-bis(diphenyl) Phosphyl)ferrocene]palladium dichloride. The base may be an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably potassium carbonate. Preferably, the coupling reaction is carried out in a suitable organic solvent, optionally 1,4-dioxane and N,N-dimethylformamide, for example 1,4-dioxane ring. Preferably, the coupling reaction is carried out in a suitable protective atmosphere, such as a nitrogen atmosphere. Preferably, the coupling reaction is carried out at a suitable temperature, which may be from 70 to 100 ° C, preferably 80 ° C. Preferably, the coupling reaction is carried out for a suitable period of time, which may be from 1 to 8 hours, preferably 3 hours.
步骤C：将化合物III-3的氨基转换成异氰酸酯再与IN-c反应得到式III的化合物；Step C: converting an amino group of compound III-3 to an isocyanate and reacting with IN-c to obtain a compound of formula III;
化合物III-3与三光气反应，将氨基转换成异氰酸酯，再与化合物IN-c反应得到式III的化合物。所述反应优选在适合的有机溶剂和碱中进行。所述有机溶剂可选自直链或环状醚类(例如四氢呋喃或***等)、1,4-二氧六环、二氯甲烷、二甲基亚砜及其任意组合，优选四氢呋喃。所述碱可以是有机碱，例如N,N-二异丙基乙胺、三乙胺、吡啶、4-二甲氨基吡啶，优选N,N-二异丙基乙 胺。所述反应优选在适合的温度下进行。所述温度可以是-40℃至60℃，例如0-25℃。所述反应优选进行合适的时间，例如0.5-2小时。Compound III-3 is reacted with triphosgene to convert the amino group to an isocyanate which is then reacted with compound IN-c to give a compound of formula III. The reaction is preferably carried out in a suitable organic solvent and base. The organic solvent may be selected from linear or cyclic ethers (e.g., tetrahydrofuran or diethyl ether, etc.), 1,4-dioxane, dichloromethane, dimethyl sulfoxide, and any combination thereof, preferably tetrahydrofuran. The base may be an organic base such as N,N-diisopropylethylamine, triethylamine, pyridine or 4-dimethylaminopyridine, preferably N,N-diisopropylethylamine. The reaction is preferably carried out at a suitable temperature. The temperature may be from -40 ° C to 60 ° C, such as from 0 to 25 ° C. The reaction is preferably carried out for a suitable period of time, for example 0.5 to 2 hours.
合成路线三：式IV的化合物的制备方法Scheme 3: Method for preparing a compound of formula IV
Figure PCTCN2019070390-appb-000012
Figure PCTCN2019070390-appb-000012
其中：Hal 1为卤素，例如Cl、Br或I，优选为Br；Y为硼酸或硼酸酯基团，优选为-B(OH) 2或者
Figure PCTCN2019070390-appb-000013
其余基团如上文所定义。 Wherein: Hal 1 is halogen, such as Cl, Br or I, preferably Br; Y is a boric acid or borate group, preferably -B(OH) 2 or
Figure PCTCN2019070390-appb-000013
The remaining groups are as defined above.
步骤A：化合物IV-1与DMF-DMA反应得到化合物IV-2；Step A: Compound IV-1 is reacted with DMF-DMA to obtain compound IV-2;
化合物IV-1与DMF-DMA反应得到化合物IV-2。该反应优选在无溶剂条件下进行。然而，该反应也能在一定程度上能溶解原料而不会抑制反应的溶剂中进行，如1,4-二氧六环、N,N-二甲基甲酰胺、四氢呋喃、N-甲基吡咯烷酮、苯或甲苯等。反应温度通常为室温到120℃，优选80℃。反应时间通常是6-24小时，优选12小时。Compound IV-1 is reacted with DMF-DMA to give compound IV-2. This reaction is preferably carried out under solvent free conditions. However, the reaction can also be carried out in a solvent which can dissolve the raw material to some extent without inhibiting the reaction, such as 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone. , benzene or toluene, etc. The reaction temperature is usually from room temperature to 120 ° C, preferably 80 ° C. The reaction time is usually from 6 to 24 hours, preferably 12 hours.
步骤B：化合物IV-2与胍反应得到化合物IV-3；Step B: Compound IV-2 is reacted with hydrazine to give compound IV-3;
化合物IV-3可以通过胍与步骤A中制备的化合物IV-2在碱的存在下反应来制备。所使用的胍可以与酸例如盐酸、氢溴酸、硫酸或乙酸形成盐，优选形成盐酸盐。所使用的碱只要其不抑制反应即可，包括碱金属碳酸盐如碳酸钾、碳酸铯、碳酸钠或碱金属醇盐如甲醇钠、乙醇钠、叔丁醇钾，优选碳酸钾。所使用的溶剂只要其不抑制反应并且可以在一定程度上溶解原料和碱即可，如N,N-二甲基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜和乙醇等，优选乙醇。反应温度通常为室温到120℃，优选80℃。反应时间通常是12-36小时，优选24小时。Compound IV-3 can be produced by reacting hydrazine with compound IV-2 prepared in Step A in the presence of a base. The hydrazine used may form a salt with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or acetic acid, preferably to form a hydrochloride. The base to be used is not particularly limited as long as it does not inhibit the reaction, and includes an alkali metal carbonate such as potassium carbonate, cesium carbonate, sodium carbonate or an alkali metal alkoxide such as sodium methoxide, sodium ethoxide or potassium t-butoxide, preferably potassium carbonate. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting material and the base to some extent, such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, ethanol, etc., preferably ethanol. . The reaction temperature is usually from room temperature to 120 ° C, preferably 80 ° C. The reaction time is usually from 12 to 36 hours, preferably 24 hours.
步骤C：化合物IV-3与卤化剂反应得到化合物IV-4；Step C: Compound IV-3 is reacted with a halogenating agent to give compound IV-4;
化合物IV-3与卤化剂在溶剂中反应得到化合物IV-4。所使用的卤化剂可以是N-溴代丁二酰亚胺或溴素，优选N-溴代丁二酰亚胺。所使用的溶剂只要其不抑制反应并且可以在一定程度上溶解原料即可，如N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲醇、乙醇、四氢呋喃、1,4-二氧六环和二甲氧基乙烷等，优选N,N-二甲基甲酰胺。反应温度通常为-20℃到室温，优选0℃到室温。反应时间通常是1-24小时，优选12小时。Compound IV-3 is reacted with a halogenating agent in a solvent to give compound IV-4. The halogenating agent used may be N-bromosuccinimide or bromine, preferably N-bromosuccinimide. The solvent to be used is long as it does not inhibit the reaction and can dissolve the raw material to some extent, such as N,N-dimethylformamide, N-methylpyrrolidone, methanol, ethanol, tetrahydrofuran, 1,4-dioxane. The ring and dimethoxyethane and the like are preferably N,N-dimethylformamide. The reaction temperature is usually -20 ° C to room temperature, preferably 0 ° C to room temperature. The reaction time is usually from 1 to 24 hours, preferably from 12 hours.
步骤D：化合物IV-4与IN-b反应得到化合物IV-5；Step D: Compound IV-4 is reacted with IN-b to give compound IV-5;
化合物IV-4与化合物IN-b发生偶联反应得到化合物IV-5。所述偶联反应优选在金属催化剂和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、二(三苯基膦)二氯化钯、醋酸钯，优选[1,1'-双(二苯基膦基)二茂铁]二氯化钯。所述碱可以是无机碱，例如碳酸钾、碳酸铯、碳酸钠、碳酸氢钠、碳酸氢钾，优选碳酸钾。优选地，所述偶联反应在适合的有机溶剂或有机溶剂和水的混合溶剂中进行，所述有机溶剂可选1,4-二氧六环、N,N-二甲基甲酰胺或上述有机溶剂和水的混合溶剂，例如是1,4-二氧六环和水的混合溶剂。优选地，所述偶联反应在适合的保护气氛(例如氮气环境)下进行。优选地，所述偶联反应在适合的温度下进行，所述温度可以是70-100℃，优选80℃。优选地，所述偶联反应进行合适的时间，所述时间可以是1-8小时，例如4小时。Compound IV-4 is coupled with compound IN-b to give compound IV-5. The coupling reaction is preferably carried out in the presence of a metal catalyst and a base. Preferably, the metal catalyst is a palladium metal catalyst such as tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, bis(triphenylphosphine)palladium dichloride, palladium acetate, preferably [1,1'-bis(diphenyl) Phosphyl)ferrocene]palladium dichloride. The base may be an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably potassium carbonate. Preferably, the coupling reaction is carried out in a suitable organic solvent or a mixed solvent of an organic solvent and water, which may be selected from 1,4-dioxane, N,N-dimethylformamide or the like. A mixed solvent of an organic solvent and water, for example, a mixed solvent of 1,4-dioxane and water. Preferably, the coupling reaction is carried out in a suitable protective atmosphere, such as a nitrogen atmosphere. Preferably, the coupling reaction is carried out at a suitable temperature, which may be from 70 to 100 ° C, preferably 80 ° C. Preferably, the coupling reaction is carried out for a suitable period of time, which may be from 1 to 8 hours, such as 4 hours.
步骤E：将化合物IV-5的氨基转换成异氰酸酯再与IN-c反应得到式(IV)的化合物；Step E: converting an amino group of compound IV-5 to an isocyanate and reacting with IN-c to obtain a compound of formula (IV);
化合物IV-5与三光气反应，将氨基转换成异氰酸酯，再与IN-c反应得到式(IV)的化合物。所述反应优选在适合的有机溶剂和碱中进行。所述有机溶剂可选自直链或环状醚类(例如四氢呋喃或***等)、1,4-二氧六环、二氯甲烷、二甲基亚砜及其任意组合，优选四氢呋喃。所述碱可以是有机碱，例如N,N-二异丙基乙胺、三乙胺、吡啶、4-二甲氨基吡啶，优选N,N-二异丙基乙胺。所述反应优选在适合的温度下进行。所述温度可以是-40℃至60℃，例如0-25℃。所述反应优选进行合适的时间，例如0.5-2小时。Compound IV-5 is reacted with triphosgene to convert the amino group to an isocyanate which is then reacted with IN-c to give a compound of formula (IV). The reaction is preferably carried out in a suitable organic solvent and base. The organic solvent may be selected from linear or cyclic ethers (e.g., tetrahydrofuran or diethyl ether, etc.), 1,4-dioxane, dichloromethane, dimethyl sulfoxide, and any combination thereof, preferably tetrahydrofuran. The base may be an organic base such as N,N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, preferably N,N-diisopropylethylamine. The reaction is preferably carried out at a suitable temperature. The temperature may be from -40 ° C to 60 ° C, such as from 0 to 25 ° C. The reaction is preferably carried out for a suitable period of time, for example 0.5 to 2 hours.
合成路线四：式V的化合物的制备方法Synthetic Route 4: Method for Preparing Compound of Formula V
Figure PCTCN2019070390-appb-000014
Figure PCTCN2019070390-appb-000014
其中：Hal 1为卤素，例如Cl、Br或I，优选为Br；Y为硼酸或硼酸酯基团，优选为-B(OH) 2或者
Figure PCTCN2019070390-appb-000015
其余基团如上文所定义。 Wherein: Hal 1 is halogen, such as Cl, Br or I, preferably Br; Y is a boric acid or borate group, preferably -B(OH) 2 or
Figure PCTCN2019070390-appb-000015
The remaining groups are as defined above.
步骤A：化合物V-1与氧化剂反应得到化合物V-2；Step A: Compound V-1 is reacted with an oxidizing agent to obtain Compound V-2;
化合物V-1与氧化剂在溶剂中反应得到化合物V-2。所使用的氧化剂可以是二氧化硒、高锰酸钾、高碘酸钠、过氧化氢等，优选二氧化硒。该反应能在一定程度上能溶解原料而不会抑制反应的溶剂中进行，如1,4-二氧六环、N,N-二甲基甲酰胺、四氢呋喃、N-甲基吡咯烷酮或上述有机溶剂和水的混合溶剂，优选1,4-二氧六环和水的混合溶剂。反应温度通常为室温到120℃，优选110℃。反应时间通常是3-14小时，优选5小时。Compound V-1 is reacted with an oxidizing agent in a solvent to obtain Compound V-2. The oxidizing agent used may be selenium dioxide, potassium permanganate, sodium periodate, hydrogen peroxide or the like, preferably selenium dioxide. The reaction can be carried out to a certain extent in a solvent which can dissolve the raw materials without inhibiting the reaction, such as 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone or the above organic A mixed solvent of a solvent and water, preferably a mixed solvent of 1,4-dioxane and water. The reaction temperature is usually from room temperature to 120 ° C, preferably 110 ° C. The reaction time is usually from 3 to 14 hours, preferably 5 hours.
步骤B：化合物V-2与化合物IN-d反应得到化合物V-3；Step B: Compound V-2 is reacted with compound IN-d to obtain compound V-3;
化合物V-3可以通过化合物IN-d与步骤A中制备的化合物V-2在碱的存在下反应来制备。所使用的S-甲基异硫氨基脲(IN-d)可以与酸例如盐酸、氢碘酸、硫酸或乙酸形成盐，优选形成氢碘酸盐。所使用的碱只要其不抑制反应即可，包括碱金属碳酸盐如碳酸氢钠、碳酸钠、碳酸氢钾、碳酸钾、碳酸铯或碱金属醇盐如甲醇钠、乙醇钠、叔丁醇钾，优选碳酸氢钠。所使用的溶剂只要其不抑制反应并且可以在一定程度上溶解原料和碱即可，如N,N-二甲基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜和乙醇等，优选乙醇。反应温度通常为室温到120℃，优选80℃。反应时间通常是1-12小时，优选4小时。Compound V-3 can be produced by reacting compound IN-d with compound V-2 prepared in Step A in the presence of a base. The S-methylisothiosemicarbazide (IN-d) used may form a salt with an acid such as hydrochloric acid, hydroiodic acid, sulfuric acid or acetic acid, preferably hydroiodide. The base to be used is not particularly limited as long as it does not inhibit the reaction, and includes an alkali metal carbonate such as sodium hydrogencarbonate, sodium carbonate, potassium hydrogencarbonate, potassium carbonate, cesium carbonate or an alkali metal alkoxide such as sodium methoxide, sodium ethoxide or t-butanol. Potassium, preferably sodium bicarbonate. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting material and the base to some extent, such as N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, ethanol, etc., preferably ethanol. . The reaction temperature is usually from room temperature to 120 ° C, preferably 80 ° C. The reaction time is usually from 1 to 12 hours, preferably 4 hours.
步骤C：化合物V-3与氧化剂反应得到化合物V-4；Step C: Compound V-3 is reacted with an oxidizing agent to give compound V-4;
化合物V-3与氧化剂在溶剂中反应得到化合物V-4。所使用的氧化剂可以是过氧化物如间氯过氧苯甲酸、过氧单磺酸钾、过氧化氢或无机氧化物三氧化铬、高碘酸、高锰酸钾，优选间氯过氧苯甲酸。所使用的溶剂只要其不抑制反应并且可以在一定程度上溶解原料即可，如二氯甲烷、四氢呋喃、1,4-二氧六环和乙腈等，优选二氯甲烷。反应温度通常为-20℃到室温，优选0℃到室温。反应时间通常是1-12小时，优选4小时。Compound V-3 is reacted with an oxidizing agent in a solvent to give compound V-4. The oxidizing agent used may be a peroxide such as m-chloroperoxybenzoic acid, potassium peroxymonosulfonate, hydrogen peroxide or inorganic oxide chromium trioxide, periodic acid, potassium permanganate, preferably m-chloroperoxybenzene. Formic acid. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and may dissolve the starting material to some extent, such as dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile or the like, preferably dichloromethane. The reaction temperature is usually -20 ° C to room temperature, preferably 0 ° C to room temperature. The reaction time is usually from 1 to 12 hours, preferably 4 hours.
步骤D：化合物V-4与氨反应得到化合物V-5；Step D: Compound V-4 is reacted with ammonia to give compound V-5;
使化合物V-4与氨发生反应以得到化合物V-5。所使用的氨可以是氨气、氨的水溶液或氨的有机溶剂如氨的1,4-二氧六环溶液，优选氨的1,4-二氧六环溶液。该反应优选在氨的1,4-二氧六环溶液中进行，无需另加其他溶剂。然而，该反应也能在一定程度上能溶解原料而不会抑制反应的溶剂中进行，如1,4-二氧六环、N,N-二甲基甲酰胺、四氢呋喃、N-甲基吡咯烷酮等。反应温度通常为室温到120℃，优选60℃。反应时间通常是1-12小时，优选4小时。Compound V-4 is reacted with ammonia to give compound V-5. The ammonia used may be an aqueous solution of ammonia, ammonia or an organic solvent of ammonia such as 1,4-dioxane solution of ammonia, preferably a 1,4-dioxane solution of ammonia. The reaction is preferably carried out in a solution of ammonia in 1,4-dioxane without the need for additional solvents. However, the reaction can also be carried out in a solvent which can dissolve the raw material to some extent without inhibiting the reaction, such as 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone. Wait. The reaction temperature is usually from room temperature to 120 ° C, preferably 60 ° C. The reaction time is usually from 1 to 12 hours, preferably 4 hours.
步骤E：化合物V-5与卤化剂反应得到化合物V-6；Step E: compound V-5 is reacted with a halogenating agent to obtain compound V-6;
化合物V-5与卤化剂在溶剂中反应得到化合物V-6。所使用的卤化剂可以是N-溴代丁二酰亚胺或溴素，优选N-溴代丁二酰亚胺。所使用的溶剂只要其不抑制反应并且可以在一定程度上溶解原料即可，如N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲醇、乙醇、四氢呋喃、1,4-二氧六环和二甲氧基乙烷等，优选N,N-二甲基甲酰胺。反应温度通常为-20℃到室温，优选0℃到室温。反应时间通常是1-8小时，优选2小时。Compound V-5 is reacted with a halogenating agent in a solvent to obtain Compound V-6. The halogenating agent used may be N-bromosuccinimide or bromine, preferably N-bromosuccinimide. The solvent to be used is long as it does not inhibit the reaction and can dissolve the raw material to some extent, such as N,N-dimethylformamide, N-methylpyrrolidone, methanol, ethanol, tetrahydrofuran, 1,4-dioxane. The ring and dimethoxyethane and the like are preferably N,N-dimethylformamide. The reaction temperature is usually -20 ° C to room temperature, preferably 0 ° C to room temperature. The reaction time is usually from 1 to 8 hours, preferably 2 hours.
步骤F：化合物V-6与化合物IN-e反应得到化合物V-7；Step F: Compound V-6 is reacted with compound IN-e to obtain compound V-7;
化合物V-6与化合物化合物IN-e发生偶联反应得到化合物V-7。所述偶联反应优选在金属催化剂和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、二(三苯基膦)二氯化钯、醋酸钯，优选[1,1'-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷络合物。所述碱可以是无机碱，例如碳酸铯、碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠，优选碳酸铯。优选地，所述偶联反应在适合的有机溶剂或有机溶剂和水的混合溶剂中进行，所述有机溶剂可选1,4-二氧六环、N,N-二甲基甲酰胺或上述有机溶剂和水的混合溶剂，例如是1,4-二氧六环和水的混合溶剂。优选地，所述偶联反应在适合的保护气氛(例如氮气环境)下进行。优选地，所述偶联反应在适合的温度下进行，所述温度可以是70-100℃，优选80℃。优选地，所述偶联反应进行合适的时间，所述时间可以是1-24小时，例如8小时。Compound V-6 is coupled with compound compound IN-e to give compound V-7. The coupling reaction is preferably carried out in the presence of a metal catalyst and a base. Preferably, the metal catalyst is a palladium metal catalyst such as tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, bis(triphenylphosphine)palladium dichloride, palladium acetate, preferably [1,1'-bis(diphenyl) Phosphyl)ferrocene]palladium dichloride dichloromethane complex. The base may be an inorganic base such as cesium carbonate, potassium carbonate, sodium carbonate, potassium hydrogencarbonate or sodium hydrogencarbonate, preferably cesium carbonate. Preferably, the coupling reaction is carried out in a suitable organic solvent or a mixed solvent of an organic solvent and water, which may be selected from 1,4-dioxane, N,N-dimethylformamide or the like. A mixed solvent of an organic solvent and water, for example, a mixed solvent of 1,4-dioxane and water. Preferably, the coupling reaction is carried out in a suitable protective atmosphere, such as a nitrogen atmosphere. Preferably, the coupling reaction is carried out at a suitable temperature, which may be from 70 to 100 ° C, preferably 80 ° C. Preferably, the coupling reaction is carried out for a suitable period of time, which may be from 1 to 24 hours, such as 8 hours.
步骤G：化合物V-7与化合物IN-f反应得到化合物V-8；Step G: Compound V-7 is reacted with compound IN-f to obtain compound V-8;
化合物V-7与化合物IN-f在碱的存在下反应得到化合物V-8。所使用的碱只要其不抑制反应即可，通常选择有机碱，如N,N-二异丙基乙胺、三乙胺、吡啶和4-二甲氨基吡啶，优选N,N-二异丙基乙胺。所使用的溶剂只要其不抑制反应并且可以在一定程度上溶解原料即可，如二氯甲烷、四氢呋喃、1,4-二氧六环、***、乙腈等，优选四氢呋喃。反应温度通常为0℃到60℃，优选室温。反应时间通常是1-24小时，优选12小时。Compound V-7 is reacted with compound IN-f in the presence of a base to give compound V-8. The base to be used is usually an organic base such as N,N-diisopropylethylamine, triethylamine, pyridine and 4-dimethylaminopyridine, preferably N,N-diisopropyl, as long as it does not inhibit the reaction. Ethylethylamine. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting material to some extent, such as dichloromethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetonitrile or the like, preferably tetrahydrofuran. The reaction temperature is usually from 0 ° C to 60 ° C, preferably room temperature. The reaction time is usually from 1 to 24 hours, preferably from 12 hours.
步骤H：化合物V-8与化合物IN-c反应得到式(V)的化合物；Step H: Compound V-8 is reacted with compound IN-c to give a compound of formula (V);
化合物V-8与化合物IN-c在碱的存在下反应得到式(V)的化合物。所使用的碱只要其不抑制反应即可，通常选择有机碱，如N,N-二异丙基乙胺、三乙胺、吡啶和4-二甲氨基吡啶，优选N,N-二异丙基乙胺。所使用的溶剂只要其不抑制反应并且可以在一定程度上溶解原料即可，如二氯甲烷、四氢呋喃、1,4-二氧六环、***、乙腈等，优选四氢呋喃。反应温度通常为0℃到60℃，优选室温。反应时间通常是1-12小时，优选4小时。Compound V-8 is reacted with compound IN-c in the presence of a base to give a compound of formula (V). The base to be used is usually an organic base such as N,N-diisopropylethylamine, triethylamine, pyridine and 4-dimethylaminopyridine, preferably N,N-diisopropyl, as long as it does not inhibit the reaction. Ethylethylamine. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and can dissolve the starting material to some extent, such as dichloromethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetonitrile or the like, preferably tetrahydrofuran. The reaction temperature is usually from 0 ° C to 60 ° C, preferably room temperature. The reaction time is usually from 1 to 12 hours, preferably 4 hours.
上述各反应步骤的具体条件为本领域公知，对此本申请不作具体限定。根据本申请的教导结合本领域公知常识，本领域技术人员可以对通式中的各取代基进行选择替换以制备得到不同的化合物，这些选择和替换均在本申请的保护范围之内。The specific conditions of each of the above reaction steps are well known in the art, and the present application is not specifically limited. In accordance with the teachings of the present application, in conjunction with the common general knowledge in the art, those skilled in the art can select and replace each substituent in the formula to prepare a different compound, and such selections and substitutions are within the scope of the present application.
本申请还涉及药物组合物，其包含式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，以及任选地，一种或多种药学上可接受的载体或赋形剂。The present application also relates to a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite thereof, or a pharmaceutically acceptable salt thereof Or a prodrug, and optionally one or more pharmaceutically acceptable carriers or excipients.
本申请还涉及药物制剂，其包含式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，或者其药物组合物。The present application also relates to a pharmaceutical formulation comprising a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite thereof, or Prodrug, or a pharmaceutical composition thereof.
本申请还涉及式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药、其药物组合物或药物制剂在制备作为腺苷A2a受体拮抗剂的药物中的用途。The present application also relates to a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a medicament thereof Use of a composition or pharmaceutical formulation in the manufacture of a medicament as an adenosine A2a receptor antagonist.
本申请还涉及式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药、其药物组合物或药物制剂在制备用于治疗或预防与腺苷A2a受体有关的疾病的药物中的用途。The present application also relates to a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a medicament thereof Use of a composition or pharmaceutical formulation for the manufacture of a medicament for the treatment or prevention of a disease associated with the adenosine A2a receptor.
本申请还涉及一种治疗或预防与腺苷A2a受体有关疾病的方法，其包括向有需要的受试者施用有效量的本申请式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药、其药物组合物或药物制剂。The present application also relates to a method of treating or preventing a disease associated with adenosine A2a receptor comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, a stereo Isomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, pharmaceutical compositions or pharmaceutical formulations thereof.
本申请还涉及式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药、其药物组合物或药物制剂，其用于抑制腺苷A2a受体活性。The present application also relates to a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a medicament thereof A composition or pharmaceutical preparation for inhibiting adenosine A2a receptor activity.
本申请还涉及式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药、其药物组合物或药物制剂，其用于治疗或预防与腺苷A2a受体有关的疾病。The present application also relates to a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a medicament thereof A composition or pharmaceutical preparation for the treatment or prevention of a disease associated with the adenosine A2a receptor.
在部分实施方案中，所述与腺苷A2a受体有关的疾病为肿瘤。所述肿瘤包括但不限于：乳腺 癌、卵巢癌、结直肠癌、黑色素瘤、非小细胞肺癌、小细胞肺癌、胃肠道间质瘤、***、胰腺癌、***癌、胃癌、慢性髓样白细胞过多症、肝癌、淋巴瘤、腹膜癌和软组织肉瘤。In some embodiments, the disease associated with the adenosine A2a receptor is a tumor. The tumor includes but is not limited to: breast cancer, ovarian cancer, colorectal cancer, melanoma, non-small cell lung cancer, small cell lung cancer, gastrointestinal stromal tumor, cervical cancer, pancreatic cancer, prostate cancer, gastric cancer, chronic marrow Leukocytosis, liver cancer, lymphoma, peritoneal cancer, and soft tissue sarcoma.
本申请中，所述药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。In the present application, the purpose of the pharmaceutical composition is to promote administration to an organism, to facilitate absorption of the active ingredient and to exert biological activity.
所述赋形剂是指在药物制剂中除主药以外的附加物。其性质稳定，与主药无配伍禁忌，不产生副作用，不影响疗效，在常温下不易变形、干裂、霉变、虫蛀、对人体无害、无生理作用，不与主药产生化学或物理作用，不影响主药的含量测定等。The excipient refers to an addenda other than the main drug in the pharmaceutical preparation. Its nature is stable, no compatibility with the main drug, no side effects, no effect on the effect, not easy to deform, chapped, mildew, insects, harmless to the human body, no physiological effects at room temperature, does not produce chemical or physical with the main drug The effect does not affect the determination of the content of the main drug.
本申请的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药可以通过以下途径给药：胃肠外、局部、静脉内、口服、皮下、动脉内、真皮内、经皮、直肠、颅内、腹膜内、鼻内、肌内途径或作为吸入剂。所述药物组合物可以任选地与在治疗各种疾病中至少有一定效果的其它试剂联合给药。A compound of the present application, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, can be administered by the following route: stomach Parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular routes or as an inhaler. The pharmaceutical composition may optionally be administered in combination with other agents that have at least some effect in the treatment of various diseases.
本申请的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药可根据给药途径配成各种适宜的剂型。The compound of the present application, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, may be formulated according to the route of administration. A suitable dosage form.
本申请所述的药物组合物或适宜的剂型可以含有0.01mg至1000mg的本申请化合物。The pharmaceutical compositions or suitable dosage forms described herein may contain from 0.01 mg to 1000 mg of a compound of the present application.
当口服用药时，本申请的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药可制成任意口服可接受的制剂形式。The compound of the present application, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, can be prepared when administered orally. Any orally acceptable form of preparation.
当皮肤局部施用时，本申请的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药可制成适当的软膏、洗剂或霜剂制剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。A compound of the present application, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, when administered topically to the skin In the form of a suitable ointment, lotion or cream preparation, the active ingredient is suspended or dissolved in one or more carriers.
本申请的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液或无菌注射溶液。The compound of the present application, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, may also be administered in the form of a sterile injectable preparation. Including sterile injectable water or oil suspension or sterile injectable solutions.
在本申请的实施方案中，进行合适的体外或体内测定来确定本申请药物组合物的效果以及给药是否适用于治疗个体所患疾病或医学疾病状态。这些测定的实例在下文非限制性实施例结合具体疾病或医学治疗进行了描述。通常，足以实现预防或治疗效果的本申请组合物的有效量为约0.001mg/千克体重/天至约10,000mg/千克体重/天。剂量和频率根据制剂在受试者中的半衰期而不同。也可以根据是预防性处理还是治疗性处理而不同。在预防性应用中，以相对低频率的间隔长期给予相对低的剂量。在治疗性应用中，有时需要以相对短的间隔给予相对高的剂量，直至疾病的进展被延缓或停止，例如直至个体表现出疾病症状的部分或完全改善，在此之后，可以给予患者预防方案。In embodiments of the present application, suitable in vitro or in vivo assays are performed to determine the efficacy of the pharmaceutical compositions of the present application and whether the administration is suitable for treating a disease or medical condition in a subject. Examples of such assays are described below in connection with specific diseases or medical treatments in non-limiting embodiments. Generally, an effective amount of a composition of the present application sufficient to achieve a prophylactic or therapeutic effect is from about 0.001 mg/kg body weight/day to about 10,000 mg/kg body weight/day. The dosage and frequency will vary depending on the half-life of the formulation in the subject. It can also be different depending on whether it is a preventive treatment or a therapeutic treatment. In prophylactic applications, relatively low doses are administered chronically at relatively low frequency intervals. In therapeutic applications, it is sometimes desirable to administer relatively high doses at relatively short intervals until the progression of the disease is delayed or stopped, for example until the individual exhibits partial or complete improvement in the symptoms of the disease, after which a prophylactic regimen can be administered to the patient. .
以下对本申请的术语进行解释，对于特定的术语，如果本申请中的含义与本领域技术人员通常理解的含义不一致，以本申请中的含义为准；如果在本申请中没有定义，则其具有本领域技术人员通常理解的含义。除非有相反陈述，本申请中使用的术语具有下述含义：The terminology of the present application is explained below. For a specific term, if the meaning in the present application is inconsistent with the meaning commonly understood by those skilled in the art, the meaning in the present application shall prevail; if it is not defined in the present application, it has The meanings as commonly understood by those skilled in the art. Unless otherwise stated, the terms used in this application have the following meanings:
本申请所用术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。The terms "including", "comprising", "having", "containing" or "comprising", as used herein, and other variants thereof, are inclusive or open, and do not exclude other Listed elements or method steps.
本申请所用术语“氢”及所述的各基团中的氢，是指氕(H)、氘(D)或氚(T)。The term "hydrogen" as used herein and hydrogen in each of the groups refers to hydrazine (H), hydrazine (D) or hydrazine (T).
本申请所用术语“卤素”是指氟、氯、溴或碘。The term "halogen" as used herein, refers to fluoro, chloro, bromo or iodo.
本申请所用术语“C 1-6烷基”是指具有1-6个碳原子的直链或支链烷基，例如C 1-4烷基、C 1-2烷基、C 1烷基、C 2烷基、C 3烷基、C 4烷基、C 5烷基或C 6烷基。具体的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。 The term "C 1-6 alkyl" as used herein, refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, such as C 1-4 alkyl, C 1-2 alkyl, C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl or C 6 alkyl. Specific examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
本申请所用术语“C 1-6烷氧基”是指通过氧原子连接至母体分子部分的如上文所定义的C 1-6烷基，例如C 1-4烷氧基、C 1-2烷氧基、C 1烷氧基、C 2烷氧基、C 3烷氧基、C 4烷氧基、C 5烷氧基或C 6烷氧基。C 1-6烷氧基的代表性实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基。 The term " C1-6 alkoxy" as used herein, refers to a C1-6 alkyl group, as defined above, appended to the parent molecular moiety through an oxygen atom, for example, C1-4 alkoxy, C1-2 alkane. Oxy, C 1 alkoxy, C 2 alkoxy, C 3 alkoxy, C 4 alkoxy, C 5 alkoxy or C 6 alkoxy. Representative examples of C1-6 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy.
本申请所用术语“5-6元杂环基”是指至少含有一个杂原子(例如，含有1个、2个、3个、4个或5个)的且环原子数为5-6个的饱和或部分饱和的且不具有芳香性的单环环状基团，所述杂原子为氮原子、氧原子和/或硫原子，任选地，环状结构中的环原子(例如碳原子或硫原子)可以被氧代。例如，本申请所述的“5-6元杂环基”含有1-2个杂原子，例如含有1个氮原子、氧原子或硫原子，或含有1个氮原子和1个氧原子。所述“5-6元杂环基”例如为“5-6元饱和杂环基”、“5-6元含氧杂环基”、“5-6元含氮杂环基”、“5-6元饱和含氮杂环基”等。“5-6元杂环基”的具体实例包括但不仅限于：1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、1,4-二氧杂环己二烯基、四氢呋喃基、二氢吡咯基、吡咯烷基、咪唑烷基、4,5-二氢咪唑基、吡唑烷基、4,5-二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基等。The term "5-6 membered heterocyclyl" as used herein, refers to a radical containing at least one heteroatom (eg, containing 1, 2, 3, 4 or 5) and having 5 to 6 ring atoms. a saturated or partially saturated and non-aromatic monocyclic cyclic group, said hetero atom being a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally a ring atom in a cyclic structure (eg, a carbon atom or The sulfur atom can be substituted by oxo. For example, a "5-6 membered heterocyclic group" as used herein has 1-2 heteroatoms, for example containing one nitrogen atom, an oxygen atom or a sulfur atom, or one nitrogen atom and one oxygen atom. The "5-6 membered heterocyclic group" is, for example, "5-6 membered saturated heterocyclic group", "5-6 membered oxygen-containing heterocyclic group", "5-6 membered nitrogen-containing heterocyclic group", "5" -6-membered saturated nitrogen-containing heterocyclic group" and the like. Specific examples of the "5-6 membered heterocyclic group" include, but are not limited to, 1,4-dioxanyl group, 1,3-dioxanyl group, and 1,3-dioxol group. Alkyl, 1,4-dioxadienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5- Dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothiophenyl, and the like.
本申请所用术语“5-6元杂芳基”是指含有5-6个环成员的单环芳香族基团，且所述环成员中至少1个至多4个(例如1、2、3或4个)为选自N、O和S的杂原子，例如5元杂芳基、6元杂芳基等。具体的实例包括但不限于呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、咪唑基、吡唑基、1,2,3-***基、1,2,4-***基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、2H-1,2-噁嗪基、4H-1,2-噁嗪基、6H-1,2-噁嗪基、4H-1,3-噁嗪基、6H-1,3-噁嗪基、4H-1,4-噁嗪基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基等。The term "5-6 membered heteroaryl" as used herein, refers to a monocyclic aromatic group containing 5 to 6 ring members, and at least 1 to 4 of the ring members (eg 1, 2, 3 or Four) are heteroatoms selected from N, O and S, such as a 5-membered heteroaryl group, a 6-membered heteroaryl group and the like. Specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3- Triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3 , 4-oxadiazolyl, pyridyl, 2-pyridinone, 4-pyridinone, pyrimidinyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, pyridazinyl, pyrazinyl, 1,2,3- Triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl and the like.
本申请所用术语“4-7元含氮杂环基”是指至少含有一个氮原子(例如，含有1个、2个、3个、4个或5个)的且环原子数为4-7个的饱和或部分饱和的且不具有芳香性的单环环状基团，“4-7元含氮杂环”的具体实例包括但不仅限于：氮杂环丁烷基、二氢吡咯基、吡咯烷基、咪唑烷基、4,5-二氢咪唑基、吡唑烷基、4,5-二氢吡唑基、哌啶基、吗啉基、哌嗪基等。The term "4-7 membered nitrogen-containing heterocyclic group" as used herein, means having at least one nitrogen atom (for example, containing 1, 2, 3, 4 or 5) and having 4 to 7 ring atoms. Specific saturated or partially saturated and non-aromatic monocyclic cyclic groups, and specific examples of the "4-7 membered nitrogen-containing heterocyclic ring" include, but are not limited to, azetidinyl, dihydropyrrolyl, Pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, piperidinyl, morpholinyl, piperazinyl and the like.
本申请所用术语“5-10元含氮并杂环基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的含有5-10个环原子的、且至少一个环原子为氮原子的、饱和或部分饱和的、非芳香性环状基团，所述的并环中其中一个环可以为芳香性环，但并环整体不具备芳香性，任选地，环状结构中的环原子(例如碳原子或硫原子)可以被氧代，包括但不限于“5-10元含氮并杂环基”、“8-10元含氮并杂环基”等，具体实例包括但不仅限于：吡咯烷基并环丙基、环戊基并氮杂环丙基、吡咯烷基并环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、吡咯烷基并哌嗪基、吡咯烷基并吗啉基、哌啶基并吗啉基、苯并吡咯烷基、吡啶基并哌啶基、吗啉基并哌嗪基、环戊基并吡咯烷基、吡啶并吡咯烷基等。The term "5-10 membered nitrogen-containing heterocyclic group" as used herein, refers to a group of 5-10 ring atoms formed by two or more ring structures sharing two adjacent atoms with each other, and at least a saturated or partially saturated, non-aromatic cyclic group having a ring atom of a nitrogen atom, wherein one of the rings may be an aromatic ring, but the ring is not aromatic at all, optionally A ring atom (for example, a carbon atom or a sulfur atom) in the cyclic structure may be substituted by oxo, including but not limited to "5-10 membered nitrogen-containing heterocyclic group", "8-10 membered nitrogen-containing heterocyclic group", and the like. Specific examples include, but are not limited to, pyrrolidino-cyclopropyl, cyclopentyl-azacyclopropyl, pyrrolidinocyclobutyl, pyrrolidinopyrrolidinyl, pyrrolidinopiperidinyl, Pyrrolidinopiperazinyl, pyrrolidinomorpholino, piperidinylmorpholinyl, benzopyrrolidinyl, pyridylpiperidinyl, morpholinylpiperazinyl, cyclopentylpyrrole Alkyl, pyridopyrrolidinyl and the like.
本申请所用术语“5-10元含氮螺杂环基”是指由两个或两个以上环状结构彼此共用一个环原子所 形成的、含有5-10个环原子(其中至少一个环原子为氮原子)的环状结构，包括“5-10元饱和螺杂环基”和“5-10元不饱和螺杂环基”。任选地，环状结构中的环原子(例如碳原子或硫原子)可以被氧代。“5-10元含氮螺杂环基”包括例如“7-10元含氮螺杂环基”、“7-9元含氮螺杂环基”、“7-9元含氮饱和螺杂环基”、“8-9元含氮饱和螺杂环基”等。具体实例包括但不仅限于：
Figure PCTCN2019070390-appb-000016
Figure PCTCN2019070390-appb-000017
Figure PCTCN2019070390-appb-000018
等。 The term "5-10 membered nitrogen-containing spiroheterocyclyl" as used herein, refers to a ring atom formed by the sharing of one ring atom with two or more ring structures, each having at least one ring atom. The cyclic structure of the nitrogen atom includes "5-10 membered saturated spiroheterocyclyl" and "5-10 membered unsaturated spiroheterocyclyl". Optionally, a ring atom (eg, a carbon atom or a sulfur atom) in the cyclic structure may be substituted by oxo. The "5-10 membered nitrogen-containing spiroheterocyclyl group" includes, for example, "7-10 membered nitrogen-containing spiroheterocyclyl group", "7-9 membered nitrogen-containing spiroheterocyclyl group", and "7-9 membered nitrogen-containing saturated spiro group". "Cycloalkyl group", "8-9 membered nitrogen-containing saturated spiroheterocyclic group", and the like. Specific examples include, but are not limited to:
Figure PCTCN2019070390-appb-000016
Figure PCTCN2019070390-appb-000017
Figure PCTCN2019070390-appb-000018
Wait.
本申请所用术语“5-10元含氮桥杂环基”是指由两个或两个以上环状结构彼此共用两个非相邻的环原子所形成的、含有5-10个环原子(其中至少一个环原子为氮原子)的环状结构，包括“5-10元饱和桥杂环基”和“5-10元不饱和桥杂环基”。任选地，环状结构中的环原子(例如碳原子或硫原子)可以被氧代。“5-10元含氮桥杂环基”包括例如“7-10元含氮桥杂环基”、“7-8元含氮饱和桥杂环基”、“7-9元含氮饱和桥杂环基”等。具体实例包括但不仅限于：
Figure PCTCN2019070390-appb-000019
Figure PCTCN2019070390-appb-000020
Figure PCTCN2019070390-appb-000021
等。 The term "5-10 membered nitrogen-containing bridged heterocyclic group" as used herein, refers to a group of 5 to 10 ring atoms formed by two or more ring structures sharing two non-adjacent ring atoms with each other ( A cyclic structure in which at least one of the ring atoms is a nitrogen atom includes "5-10 membered saturated bridge heterocyclic group" and "5-10 membered unsaturated bridged heterocyclic group". Optionally, a ring atom (eg, a carbon atom or a sulfur atom) in the cyclic structure may be substituted by oxo. "5-10 membered nitrogen-containing bridged heterocyclic group" includes, for example, "7-10 membered nitrogen-containing bridged heterocyclic group", "7-8 membered nitrogen-containing saturated bridged heterocyclic group", and "7-9 membered nitrogen-containing saturated bridge" Heterocyclic group" and the like. Specific examples include, but are not limited to:
Figure PCTCN2019070390-appb-000019
Figure PCTCN2019070390-appb-000020
Figure PCTCN2019070390-appb-000021
Wait.
如果取代基被描述为“任选地被…取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。If a substituent is described as "optionally substituted with", the substituent may be unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together independently The optional substituents selected are substituted. If the nitrogen of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected. Substitute substitution.
本申请所用术语“一个或多个”是指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。The term "one or more" as used herein, refers to one or more than one, such as two, three, four, five, or ten, under reasonable conditions.
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。Unless otherwise indicated, a point of attachment of a substituent, as used herein, may come from any suitable position of the substituent.
本申请所用术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如1个、2个、3个或4个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本申请的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。The term "stereoisomer" as used herein, denotes an isomer formed by at least one asymmetric center. In a compound having one or more (eg, 1, 2, 3, or 4) asymmetric centers, which can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Separate diastereomers. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present application may exist as a mixture of two or more structurally different forms (generally referred to as tautomers) in a rapidly equilibrating manner. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.
除非另外指明，否则本申请的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构 体及其混合物)的形式存在。本申请的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。Unless otherwise indicated, the compounds of the present application are intended to be stereoisomers (including cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof exist. The compounds of the present application may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).
本申请涵盖本申请的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。The present application encompasses all possible crystalline forms or polymorphs of the compounds of the present application, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
还应当理解，本申请的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本申请中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、溶剂合物、N-氧化物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本申请的化合物或其代谢物或残余物。因此，当在本文中提及“本申请的化合物”时，也意在涵盖化合物的上述各种衍生物形式。It will also be understood that certain compounds of the present application may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives. In the present application, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, N-oxides, metabolites or prodrugs, after administration to a patient in need thereof The compound of the present application or a metabolite or residue thereof can be provided directly or indirectly. Thus, when reference is made herein to a "compound of the present application," it is also intended to encompass the various derivative forms described above for the compound.
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物；本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist,Comprehensive Organic Synthesis,vol.7,pp 748-750；A.R.Katritzky和A.J.Boulton,Eds.,Academic Press；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry,vol.22,pp 390-392,A.R.Katritzky和A.J.Boulton,Eds.,Academic Press。Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides because nitrogen requires the use of a lone pair of electrons to oxidize to oxides; those skilled in the art will recognize that N-oxides can be formed. Nitrogen-containing heterocycle. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. The synthesis of N-oxides for the preparation of heterocyclic and tertiary amines is well known to those skilled in the art and includes the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl groups. Hydrogen peroxide such as t-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane oxidize heterocyclic and tertiary amines. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature, see for example: TLGilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; ARKatritzky and AJ Boulton, Eds., Academic Press And GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, ARKatritzky and AJ Boulton, Eds., Academic Press.
本申请的化合物可以溶剂化物(如水合物)的形式存在，其中本申请的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。The compounds of the present application may exist in the form of a solvate (e.g., a hydrate) wherein the compound of the present application contains a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.
本申请的化合物或其药学上可接受的盐还可以形成溶剂合物，例如醇合物等。The compound of the present application or a pharmaceutically acceptable salt thereof may also form a solvate such as an alcoholate or the like.
本申请的化合物还可以是前药或以或可在体内代谢变化后释放出所述活性成分的形式。选择和制备适当的前药衍生物是本领域技术人员公知技术。The compounds of the present application may also be in the form of a prodrug or the release of the active ingredient after or after metabolic changes in the body. The selection and preparation of suitable prodrug derivatives are well known to those skilled in the art.
本申请的化合物还可以是化学保护的形式，所述保护基可保护在化合物的活性基团(如氨基)上，所述保护基可在体内代谢释放出活性成分。选择和制备适当的化学保护的形式是本领域技术人员公知技术。The compounds of the present application may also be in a chemically protected form which protects the active group of the compound (e.g., an amino group) which is metabolized in vivo to release the active ingredient. The selection and preparation of suitable chemical protection forms are well known to those skilled in the art.
本申请所用术语“药学上可接受的”是指物质或组合物必须与构成制剂的其他组分和/或用其治疗的哺乳动物在化学和/或毒理学上相容。The term "pharmaceutically acceptable" as used herein means that the substance or composition must be chemically and/or toxicologically compatible with the other components that make up the formulation and/or the mammals treated therewith.
本申请所用术语“药学上可接受的盐”包括与药学上可以接受的无机酸或者有机酸、或者无机碱或有机碱形成的常规盐。合适的酸加成盐的例子包括盐酸、氢溴酸、硫酸、磷酸、硝酸、高氯酸、富马酸、乙酸、丙酸、琥珀酸、羟基乙酸、甲酸、乳酸、马来酸、酒石酸、柠檬酸、扑酸、丙二酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、富马酸、甲苯磺酸、甲磺酸、萘-2-磺酸、苯磺酸、羟基萘甲酸、氢碘酸、苹果酸、鞣酸等形成的盐。合适的碱加成盐的例子包括钠、钾、镁、锂、铝、钙、锌、N,N’-二苄基乙二胺、氯代普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因等形成的盐。The term "pharmaceutically acceptable salt" as used herein, includes a conventional salt formed with a pharmaceutically acceptable inorganic or organic acid, or an inorganic or organic base. Examples of suitable acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid, Citric acid, pamoic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonate A salt formed from an acid, a hydroxynaphthoic acid, hydroiodic acid, malic acid, citric acid or the like. Examples of suitable base addition salts include sodium, potassium, magnesium, lithium, aluminum, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylene a salt formed by an amine, N-methylglucamine, procaine or the like.
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。用于制备本申请的化合物的药学上可接受的盐的方法为本领域技术人员已知的。For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present application are known to those skilled in the art.
本申请所用术语“药物组合物”包括包含治疗有效量的本申请式I的化合物的产品，以及直接地或间接地由本申请式I化合物的组合产生的任何产品。The term "pharmaceutical composition" as used herein, includes a product comprising a therapeutically effective amount of a compound of Formula I herein, as well as any product produced directly or indirectly from a combination of the compounds of Formula I herein.
本申请所用术语“有效量”是指足以实现所需治疗效果的量，例如，实现减轻与待治疗疾病相关的症状的量。The term "effective amount" as used herein, refers to an amount sufficient to achieve the desired therapeutic effect, for example, to achieve a reduction in the symptoms associated with the condition to be treated.
本申请所用的术语“治疗”目的是减轻或消除所针对的疾病状态或病症。如果受试者按照本文所述方法接受了治疗量的化合物、其光学异构体或其药学上可接受的盐或其药物组合物，该受试者一种或多种指征和症状表现出可观察到的和/或可检测出的降低或改善，则受试者被成功地“治疗”了。还应当理解，所述的疾病状态或病症的治疗的不仅包括完全地治疗，还包括未达到完全地治疗，但实现了一些生物学或医学相关的结果。The term "treatment" as used herein is intended to alleviate or eliminate the disease state or condition being addressed. If the subject receives a therapeutic amount of a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein, the subject exhibits one or more indications and symptoms Observable and/or detectable reduction or improvement, the subject is successfully "treated". It will also be appreciated that the treatment of the disease state or condition includes not only complete treatment, but also failure to achieve complete treatment, but achieving some biological or medical related results.
本申请中所述的化合物，若名称与结构式不一致，以化合物结构为准。The compounds described in the present application, if the names are inconsistent with the structural formula, are based on the structure of the compounds.
发明的有益效果Advantageous effects of the invention
通过大量研究，令人惊奇地发现，本申请的化合物能够抑制腺苷A2a受体，并且含有不易通过血脑屏障的基团，能极大降低进脑量，同时具有良好的药代动力学性质。因此，本申请化合物能够消除由腺苷A2a受体激活介导的T细胞免疫功能抑制，达到肿瘤治疗的效果，并且能够避免由于抑制中枢神经***的腺苷A2a受体而引起的相关副作用。Through extensive research, it has been surprisingly found that the compounds of the present application are capable of inhibiting the adenosine A2a receptor and containing a group that does not easily cross the blood-brain barrier, which can greatly reduce the amount of brain and have good pharmacokinetic properties. . Therefore, the compound of the present application can eliminate the inhibition of T cell immune function mediated by adenosine A2a receptor activation, achieve the effect of tumor treatment, and can avoid related side effects caused by inhibition of the adenosine A2a receptor of the central nervous system.
具体实施方式Detailed ways
下面将结合实施例对本申请的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本申请，而不应视为限定本申请的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。The embodiments of the present application are described in detail below with reference to the embodiments, but those skilled in the art will understand that the following examples are only intended to illustrate the application, and should not be construed as limiting the scope of the application. Those who do not specify the specific conditions in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are conventional products that can be obtained commercially.
以下实施例中，化合物的结构通过核磁共振( 1H NMR)或质谱(MS)来确定。 1H NMR的测定采用JEOL Eclipse 400核磁仪，测定溶剂为氘代甲醇(CD 3OD)、氘代氯仿(CDCl 3)或六氘代二甲基亚砜(DMSO-d 6)，内标为四甲基硅烷(TMS)，化学位移(δ)以10 -6(ppm)作为单位给出。 In the following examples, the structure of the compound was determined by nuclear magnetic resonance ( 1 H NMR) or mass spectrometry (MS). 1 H NMR was measured using a JEOL Eclipse 400 nuclear magnetic apparatus. The solvent was deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or hexamethyl dimethyl sulfoxide (DMSO-d 6 ). The internal standard was Tetramethylsilane (TMS), chemical shift (δ) is given in units of 10 -6 (ppm).
以下实施例中，MS的测定用Agilent(ESI)质谱仪，生产商：Agilent，型号：Agilent 6120B。In the following examples, the MS was measured using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.
以下实施例中的纯化方法A中：In the purification method A in the following examples:
采用的仪器型号为Agilent 1260，色谱柱为Waters SunFire Prep C18OBD(19mm×150mm×5.0μm)；色谱柱温为25℃；流速为20.0mL/min；检测波长为214nm；洗脱梯度如下：The instrument model used was Agilent 1260, the column was Waters SunFire Prep C18OBD (19 mm × 150 mm × 5.0 μm); the column temperature was 25 ° C; the flow rate was 20.0 mL / min; the detection wavelength was 214 nm; the elution gradient was as follows:
0min：10％A，90％B；0min: 10% A, 90% B;
16.0min：90％A，10％B，16.0min: 90% A, 10% B,
其中流动相A为100％乙腈；流动相B为0.05wt％甲酸水溶液。Wherein mobile phase A is 100% acetonitrile; mobile phase B is 0.05 wt% aqueous formic acid.
以下实施例中的纯化方法B中：In the purification method B in the following examples:
采用的仪器型号为Agilent 1260，色谱柱为Waters XBridge Prep C18 OBD(19mm×150mm×5.0μm)；色谱柱温为25℃；流速为20.0mL/min；检测波长为214nm；洗脱梯度如下：The instrument model used was Agilent 1260, the column was Waters XBridge Prep C18 OBD (19 mm × 150 mm × 5.0 μm); the column temperature was 25 ° C; the flow rate was 20.0 mL / min; the detection wavelength was 214 nm; the elution gradient was as follows:
0min：10％A，90％B；0min: 10% A, 90% B;
16.0min：90％A，10％B，16.0min: 90% A, 10% B,
其中流动相A为100％乙腈；流动相B为0.05wt％甲酸铵水溶液。Wherein mobile phase A is 100% acetonitrile; mobile phase B is 0.05 wt% aqueous ammonium formate solution.
以下实施例中，薄层色谱硅胶板(TLC)使用Merck产的铝板(20×20cm)，薄层层析分离纯化采用的硅胶板是烟台产GF 254(20×20cm，厚度为0.4～0.5mm)。In the following examples, a thin-layer chromatography silica gel plate (TLC) was prepared using an aluminum plate (20×20 cm) manufactured by Merck, and the silica gel plate used for separation and purification by thin layer chromatography was GF 254 (20×20 cm, thickness 0.4-0.5 mm). ).
以下实施例中，反应的监测采用薄层色谱法(TLC)或LC-MS，使用的展开剂体系有：二氯甲烷和甲醇体系，正己烷和乙酸乙酯体系，石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节或者加入三乙胺等进行调节。In the following examples, the reaction was monitored by thin layer chromatography (TLC) or LC-MS using a developing solvent system: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, petroleum ether and ethyl acetate systems. The volume ratio of the solvent is adjusted depending on the polarity of the compound or by adding triethylamine or the like.
以下实施例中，微波反应使用Biotage Initiator+(400W,RT～300℃)微波反应器。In the following examples, the microwave reaction was carried out using a Biotage Initiator + (400 W, RT ~ 300 ° C) microwave reactor.
以下实施例中，柱层析一般使用200～300目硅胶为载体。洗脱剂的体系包括：二氯甲烷和甲醇体系，石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺进行调节。In the following examples, column chromatography generally uses 200 to 300 mesh silica gel as a carrier. The system of the eluent includes: a dichloromethane and methanol system, a petroleum ether and an ethyl acetate system, and the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may also be adjusted by adding a small amount of triethylamine.
以下实施例中，如无特殊说明，反应的温度为室温(20℃～35℃)。In the following examples, the temperature of the reaction was room temperature (20 ° C to 35 ° C) unless otherwise specified.
以下实施例中，所使用的试剂购自Acros Organics、Aldrich Chemical Company、特伯化学等公司。In the following examples, the reagents used were purchased from companies such as Acros Organics, Aldrich Chemical Company, and Tebe Chemical.
在常规的合成法以及本申请的化合物和中间体合成例中，各缩写的意思如以下所示。In the conventional synthesis method and the synthesis examples of the compounds and intermediates of the present application, the meanings of the respective abbreviations are as follows.
缩写abbreviation 含义meaning
DMFDMF N,N-二甲基甲酰胺N,N-dimethylformamide
dppfDppf 1,1'-双(二苯基膦基)二茂铁1,1'-bis(diphenylphosphino)ferrocene
TLCTLC 薄层色谱法Thin layer chromatography
Pd(dppf)Cl 2 Pd(dppf)Cl 2 [1,1'-双(二苯基膦基)二茂铁]二氯化钯[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
Pd(amphos)Cl 2 Pd(amphos)Cl 2 二氯二叔丁基-(4-二甲基氨基苯基)膦钯Dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium
DIPEADIPEA N,N-二异丙基乙胺N,N-diisopropylethylamine
中间体的制备：Preparation of intermediates:
中间体制备例1：1-异丙基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2(1H)-酮的制备Intermediate Preparation Example 1:1-Isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2 (1H )- Preparation of ketone
Figure PCTCN2019070390-appb-000022
Figure PCTCN2019070390-appb-000022
第一步：5-溴-1-异丙基吡啶-2(1H)-酮的制备First step: Preparation of 5-bromo-1-isopropylpyridine-2(1H)-one
将异丙基碘(73.7g,433.6mmol)、碳酸铯(141.3g,433.7mmol)和2-羟基-5-溴吡啶(50.0g,287.4mmol)加入到1,4-二氧六环(600mL)中，升温至85℃，反应过夜。反应完毕，冷却至室温，过滤，浓缩，剩余物在乙酸乙酯/石油醚(乙酸乙酯:石油醚＝1:10(v/v))的混合溶剂中打浆纯化，得到本步骤的标题化合物(45.2g，收率：73％)。Isopropyl iodide (73.7 g, 433.6 mmol), cesium carbonate (141.3 g, 433.7 mmol) and 2-hydroxy-5-bromopyridine (50.0 g, 287.4 mmol) were added to 1,4-dioxane (600 mL) In the case, the temperature was raised to 85 ° C and the reaction was carried out overnight. After the reaction is completed, it is cooled to room temperature, filtered, and concentrated. The residue is purified by ethyl acetate / petroleum ether (ethyl acetate: petroleum ether = 1:10 (v / v)) (45.2 g, yield: 73%).
MS m/z(ESI):216.2[M+H] +。 MS m/z (ESI): 216.2 [M+H] + .
第二步：1-异丙基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2(1H)-酮的制备The second step: 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)- Preparation of ketone
氮气氛围下，向5-溴-1-异丙基吡啶-2(1H)-酮(22.3g,103.2mmol)的1,4-二氧六环溶液(500mL)中依次加入联硼酸频哪醇酯(65.5g,257.9mmol)、醋酸钾(20.2g,205.8mmol)、Pd(dppf)Cl 2(3.8g,5.2mmol)和dppf(2.9g,5.2mmol)，升温至80℃，反应12小时。反应完毕后，冷却至室温，浓缩反应液，剩余物加水稀释，并用乙酸乙酯萃取，合并有机相，干燥，过滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯:石油醚＝3:1(v/v))，得到本步骤的标题化合物(22.0g，收率：81％)。 To a solution of 5-bromo-1-isopropylpyridine-2(1H)-one (22.3 g, 103.2 mmol) in 1,4-dioxane (500 mL) was added borazoic acid pinacol under nitrogen atmosphere. Ester (65.5g, 257.9mmol), potassium acetate (20.2g, 205.8mmol), Pd(dppf)Cl 2 (3.8g, 5.2mmol) and dppf (2.9g, 5.2mmol), heated to 80 ° C, 12 hours reaction . After the completion of the reaction, the mixture was cooled to room temperature, and the mixture was evaporated. EtOAcjjjjjjjjjjjj Ethyl ester: petroleum ether = 3:1 (v/v))ield of the title compound (22.0 g, yield: 81%).
MS m/z(ESI):264.2[M+H] +。 MS m/z (ESI): 264.2 [M+H] + .
中间体制备例2：6'-氨基-1-异丙基-2'-(5-甲基呋喃-2-基)-[3,3'-联吡啶]-6(1H)-酮的制备Intermediate Preparation 2: Preparation of 6'-Amino-1-isopropyl-2'-(5-methylfuran-2-yl)-[3,3'-bipyridyl]-6(1H)-one
Figure PCTCN2019070390-appb-000023
Figure PCTCN2019070390-appb-000023
第一步：5-溴-6-(5-甲基呋喃-2-基)吡啶-2-胺的制备First step: Preparation of 5-bromo-6-(5-methylfuran-2-yl)pyridin-2-amine
将5,6-二溴吡啶-2-胺(1.0g,4.0mmol)加入到1,4-二氧六环(10mL)和水(5mL)的混合溶剂中，然后依次加入(5-甲基呋喃-2-基)硼酸(0.6g,4.8mmol)、碳酸钾(1.1g,8.0mmol)和Pd(dppf)Cl 2(0.3g,0.4mmol)，氮气置换3次后，升温至80℃，反应4小时。反应完毕后，冷却至室温，将反应液倒入水中，乙酸乙酯萃取，合并有机相，干燥，过滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯:石油醚＝1:1(v/v))，得到本步骤的标题化合物(0.7g，收率：70％)。 Add 5,6-dibromopyridin-2-amine (1.0 g, 4.0 mmol) to a mixed solvent of 1,4-dioxane (10 mL) and water (5 mL), and then add (5-methyl) Furan-2-yl)boronic acid (0.6 g, 4.8 mmol), potassium carbonate (1.1 g, 8.0 mmol) and Pd(dppf)Cl 2 (0.3 g, 0.4 mmol) were replaced with nitrogen three times and then warmed to 80 ° C. Reaction for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, and the mixture was evaporated. Petroleum ether = 1:1 (v/v)) gave the title compound (0.7 g, yield: 70%).
MS m/z(ESI):253.2[M+H] +。 MS m/z (ESI): 253.2 [M+H] + .
第二步：6'-氨基-1-异丙基-2'-(5-甲基呋喃-2-基)-[3,3'-联吡啶]-6(1H)-酮的制备Second step: Preparation of 6'-amino-1-isopropyl-2'-(5-methylfuran-2-yl)-[3,3'-bipyridyl]-6(1H)-one
将5-溴-6-(5-甲基呋喃-2-基)吡啶-2-胺(0.7g,2.8mmol)加入到1,4-二氧六环(10mL)和水(5mL)的混合溶剂中，然后依次加入1-异丙基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2(1H)-酮(0.9g,3.3mmol)、碳酸钾(0.8g,5.6mmol)和Pd(dppf)Cl 2(0.2g,0.3mmol)，氮气置换3次后，升温至80℃，反应3小时。反应完毕后，冷却至室温，将反应液倒入水中，乙酸乙酯萃取，合并有机相干燥，过滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯:石油醚＝3:1(v/v))，得到本步骤的标题化合物(0.6g，收率：70％)。 Add 5-bromo-6-(5-methylfuran-2-yl)pyridin-2-amine (0.7 g, 2.8 mmol) to a mixture of 1,4-dioxane (10 mL) and water (5 mL) In the solvent, 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2 (1H) was added in that order. )-ketone (0.9 g, 3.3 mmol), potassium carbonate (0.8 g, 5.6 mmol), and Pd(dppf)Cl 2 (0.2 g, 0.3 mmol) were replaced with nitrogen three times, and then the mixture was heated to 80 ° C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, and the reaction mixture was poured into water, ethyl acetate was evaporated, and the organic phase was combined, dried, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum Ether = 3:1 (v/v)) gave the title compound (0.6 g, yield: 70%).
MS m/z(ESI):310.1[M+H] +。 MS m/z (ESI): 310.1 [M+H] + .
中间体制备例3：5-溴-4-(5-甲基呋喃-2-基)嘧啶-2-胺的制备Intermediate Preparation Example 3: Preparation of 5-bromo-4-(5-methylfuran-2-yl)pyrimidin-2-amine
Figure PCTCN2019070390-appb-000024
Figure PCTCN2019070390-appb-000024
第一步：3-(二甲基氨基)-1-(5-甲基呋喃-2-基)丙-2-烯-1-酮的制备First step: Preparation of 3-(dimethylamino)-1-(5-methylfuran-2-yl)prop-2-en-1-one
将1-(5-甲基呋喃-2-基)乙酮(5.0g,40.3mmol)加入到N,N-二甲基甲酰胺二甲基缩醛(50mL)中，氮气置换，升温至80℃反应过夜，然后浓缩反应液，剩余物-在无水***中打浆，抽滤，滤饼用无水***洗涤，干燥，得到本步骤的标题化合物粗品(6.5g，收率：90％)。Add 1-(5-methylfuran-2-yl)ethanone (5.0 g, 40.3 mmol) to N,N-dimethylformamide dimethyl acetal (50 mL). After the reaction mixture was stirred at rt EtOAc (EtOAc)EtOAc.
MS m/z(ESI):180.1[M+H] +。 MS m/z (ESI): 180.1 [M+H] + .
第二步：4-(5-甲基呋喃-2-基)嘧啶-2-胺的制备Second step: Preparation of 4-(5-methylfuran-2-yl)pyrimidine-2-amine
将3-(二甲基氨基)-1-(5-甲基呋喃-2-基)丙-2-烯-1-酮(6.5g,36.3mmol)、盐酸胍(3.8g,39.7mmol)和碳酸钾(10.0g,72.4mmol)加入到无水乙醇(100mL)中，升温至80℃，反应24小时，浓缩反应液，剩余物加水稀释，抽滤，无水***洗涤滤饼，干燥，得到本步骤的标题化合物粗品(5.5g，收率：86％)。3-(Dimethylamino)-1-(5-methylfuran-2-yl)prop-2-en-1-one (6.5 g, 36.3 mmol), guanidine hydrochloride (3.8 g, 39.7 mmol) and Potassium carbonate (10.0 g, 72.4 mmol) was added to absolute ethanol (100 mL), and the temperature was raised to 80 ° C, and the reaction was carried out for 24 hours. The reaction mixture was concentrated, the residue was diluted with water, filtered, filtered and dried with diethyl ether. The title compound was crude (5.5 g, yield: 86%).
MS m/z(ESI):176.1[M+H] +。 MS m/z (ESI): 176.1 [M+H] + .
第三步：5-溴-4-(5-甲基呋喃-2-基)嘧啶-2-胺的制备The third step: preparation of 5-bromo-4-(5-methylfuran-2-yl)pyrimidine-2-amine
将4-(5-甲基呋喃-2-基)嘧啶-2-胺(5.0g,28.5mmol)加入到无水DMF(50mL)中，冷却至0℃，加入N-溴代丁二酰亚胺(5.3g,29.8mmol)，维持0℃搅拌1小时后，自然升至室温搅拌过夜，然后浓缩反应液，剩余物加水稀释，抽滤，无水***洗涤滤饼，干燥，得到本步骤的标题化合物(5.0g，收率：69％)。Add 4-(5-methylfuran-2-yl)pyrimidin-2-amine (5.0 g, 28.5 mmol) to dry DMF (50 mL). The amine (5.3 g, 29.8 mmol) was stirred at 0 ° C for 1 hour, then naturally warmed to room temperature and stirred overnight, then the reaction mixture was concentrated, the residue was diluted with water, filtered, filtered and dried with diethyl ether. The title compound (5.0 g, yield: 69%).
MS m/z(ESI):254.1[M+H] +。 MS m/z (ESI): 254.1 [M+H] + .
中间体制备例4：5-(2-氨基-4-(5-甲基呋喃-2-基)嘧啶-5-基)-1-异丙基吡啶-2(1H)-酮的制备Intermediate Preparation Example 4: Preparation of 5-(2-amino-4-(5-methylfuran-2-yl)pyrimidin-5-yl)-1-isopropylpyridine-2(1H)-one
Figure PCTCN2019070390-appb-000025
Figure PCTCN2019070390-appb-000025
将5-溴-4-(5-甲基呋喃-2-基)嘧啶-2-胺(2.0g,7.9mmol)加入到1,4-二氧六环(20mL)和水(10mL)的混合溶剂中，然后依次加入1-异丙基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2(1H)-酮(2.5g,9.5mmol)、碳酸钾(2.2g,15.8mmol)和Pd(dppf)Cl 2(0.6g,0.8mmol)，氮气置换3次后，升温至100℃，反应4小时。反应完毕后，反应液冷却至室温，倒入水中，乙酸乙酯萃取，合并有机相，干燥，过滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝3/1)，得到标题化合物(2.0g，收率：82％)。 Add 5-bromo-4-(5-methylfuran-2-yl)pyrimidin-2-amine (2.0 g, 7.9 mmol) to a mixture of 1,4-dioxane (20 mL) and water (10 mL) In the solvent, 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2 (1H) was added in that order. )-ketone (2.5 g, 9.5 mmol), potassium carbonate (2.2 g, 15.8 mmol) and Pd(dppf)Cl 2 (0.6 g, 0.8 mmol) were replaced with nitrogen three times, and then the mixture was heated to 100 ° C for 4 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, poured into water, ethyl acetate was evaporated, and the organic phase was combined, dried, filtered, and the filtrate was concentrated, the residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum Ether = 3/1) gave the title compound (2.0 g, yield: 82%).
MS m/z(ESI):311.1[M+H] +。 MS m/z (ESI): 311.1 [M+H] + .
中间体制备例5：5-(2-氨基-4-(呋喃-2-基)嘧啶-5-基)-1-异丙基吡啶-2(1H)-酮的制备Intermediate Preparation Example 5: Preparation of 5-(2-amino-4-(furan-2-yl)pyrimidin-5-yl)-1-isopropylpyridine-2(1H)-one
Figure PCTCN2019070390-appb-000026
Figure PCTCN2019070390-appb-000026
第一步：3-(二甲基氨基)-1-(甲基呋喃-2-基)丙-2-烯-1-酮的制备First step: Preparation of 3-(dimethylamino)-1-(methylfuran-2-yl)prop-2-en-1-one
将1-(呋喃-2-基)乙酮(5.0g,45.4mmol)加入到N,N-二甲基甲酰胺二甲基缩醛(50mL)中，氮气置换，升温至80℃反应过夜，反应液冷却至室温，浓缩，剩余物在无水***中打浆，抽滤，用无水***洗涤滤饼，得到本步骤的标题化合物粗品(7.1g，收率：95％)。1-(Furan-2-yl)ethanone (5.0 g, 45.4 mmol) was added to N,N-dimethylformamide dimethyl acetal (50 mL), which was replaced with nitrogen and warmed to 80 ° C overnight. The reaction mixture was cooled to room temperature, EtOAc (EtOAc m.
MS m/z(ESI):166.1[M+H] +。 MS m/z (ESI): 166.1 [M+H] + .
第二步：4-(呋喃-2-基)嘧啶-2-胺的制备Step 2: Preparation of 4-(furan-2-yl)pyrimidine-2-amine
将3-(二甲基氨基)-1-(呋喃-2-基)丙-2-烯-1-酮(6.1g,36.9mmol)、盐酸胍(3.9g,40.8mmol)和碳酸钾(10.0g,72.4mmol)加入到无水乙醇(100mL)中，升温至80℃，反应24小时，反应液冷却至室温，浓缩，剩余物在无水***(60mL)中打浆，抽滤，无水***洗涤滤饼，得到本步骤的标题化合物粗品(5.0g，收率：85％)。3-(Dimethylamino)-1-(furan-2-yl)prop-2-en-1-one (6.1 g, 36.9 mmol), guanidine hydrochloride (3.9 g, 40.8 mmol) and potassium carbonate (10.0) g, 72.4 mmol) was added to absolute ethanol (100 mL), warmed to 80 ° C, and reacted for 24 hours. The reaction mixture was cooled to room temperature, concentrated, and the residue was purified from anhydrous diethyl ether (60 mL). The filter cake was washed to give the title compound (5.0 g, yield: 85%).
MS m/z(ESI):162.1[M+H] +。 MS m/z (ESI): 1621. [M+H] + .
第三步：5-溴-4-(呋喃-2-基)嘧啶-2-胺的制备The third step: preparation of 5-bromo-4-(furan-2-yl)pyrimidine-2-amine
将4-(呋喃-2-基)嘧啶-2-胺(1.0g,6.2mmol)加入无水到DMF(10mL)中，冷却至0℃，加入N-溴代丁二酰亚胺(1.2g,6.5mmol)，维持0℃搅拌1小时，加水稀释，抽滤，无水***洗涤滤饼，得到本步骤的标题化合物粗品(1.2g，收率：80％)。4-(Furan-2-yl)pyrimidin-2-amine (1.0 g, 6.2 mmol) was added to dryness in DMF (10 mL), cooled to 0 ° C, and N-bromosuccinimide (1.2 g) The mixture was stirred at 0 ° C for 1 hr.
MS m/z(ESI):240.1[M+H] +。 MS m / z (ESI): 240.1 [M + H] +.
第四步：5-(2-氨基-4-(呋喃-2-基)嘧啶-5-基)-1-异丙基吡啶-2(1H)-酮的制备Fourth step: Preparation of 5-(2-amino-4-(furan-2-yl)pyrimidin-5-yl)-1-isopropylpyridine-2(1H)-one
将5-溴-4-(呋喃-2-基)嘧啶-2-胺(1.0g,4.2mmol)加入到1,4-二氧六环(10mL)和水(5mL)的混合溶剂中，然后依次加入1-异丙基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2(1H)-酮(2.2g,8.4mmol)、碳酸钾(1.1g,8.3mmol)和Pd(dppf)Cl 2(0.3g,0.4mmol)，氮气置换3次后，升温至100℃，反应4小时。反应完毕后，反应液冷却至室温，倒入水中，乙酸乙酯萃取，合并有机相，干燥，过滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝2/1)，得到本步骤的标题化合物(1.0g，收率：83％)。 Add 5-bromo-4-(furan-2-yl)pyrimidin-2-amine (1.0 g, 4.2 mmol) to a mixed solvent of 1,4-dioxane (10 mL) and water (5 mL), then 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one was added in sequence ( 2.2 g, 8.4 mmol), potassium carbonate (1.1 g, 8.3 mmol) and Pd(dppf)Cl 2 (0.3 g, 0.4 mmol) were replaced with nitrogen three times, and then heated to 100 ° C for 4 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, poured into water, ethyl acetate was evaporated, and the organic phase was combined, dried, filtered, and the filtrate was concentrated, the residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum Ether = 2/1) gave the title compound (1.0 g, yield: 83%).
MS m/z(ESI):297.1[M+H] +。 MS m/z (ESI): 297.1 [M+H] + .
中间体制备例6：(6-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-基)氨基甲酸苯酯的制备Intermediate Preparation Example 6: (6-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(5-methylfuran-2-yl)-1, Preparation of phenyl 2,4-triazin-3-yl)carbamate
Figure PCTCN2019070390-appb-000027
Figure PCTCN2019070390-appb-000027
第一步：2-(5-甲基呋喃-2-基)-2-乙二醛的制备First step: Preparation of 2-(5-methylfuran-2-yl)-2-ethanedialdehyde
氮气氛围下，向二氧化硒(3.3g,29.7mmol)的1,4-二氧六环(50mL)溶液中加入水(5mL)，升温至60℃，搅拌0.5小时至二氧化硒完全溶解，向其中加入5-甲基-2-乙酰基呋喃(1.2g,9.7mmol)， 反应混合物加热至110℃，反应5小时。反应液冷却至室温，抽滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝1/1)，得到本步骤的标题化合物(1.2g，收率：92％)。Under a nitrogen atmosphere, water (5 mL) was added to a solution of selenium dioxide (3.3 g, 29.7 mmol) in 1,4-dioxane (50 mL), and the mixture was heated to 60 ° C, and stirred for 0.5 hour until the selenium dioxide was completely dissolved. 5-Methyl-2-acetylfuran (1.2 g, 9.7 mmol) was added thereto, and the reaction mixture was heated to 110 ° C for 5 hours. The reaction mixture was cooled to room temperature, filtered, EtOAcjjjjjjjjjjjj Rate: 92%).
MS m/z(ESI):139.1[M+H] +。 MS m/z (ESI): 139.1 [M+H] + .
第二步：5-(5-甲基呋喃-2-基)-3-(甲硫基)-1,2,4-三嗪的制备Second step: Preparation of 5-(5-methylfuran-2-yl)-3-(methylthio)-1,2,4-triazine
向S-甲基异硫氨基脲碘酸盐(2.3g,9.9mmol)的水溶液中加入碳酸氢钠(2.1g,25.0mmol)，反应混合物搅拌0.5小时，然后加入2-(5-甲基呋喃-2-基)-2-乙二醛(1.2g,8.7mmol)的乙醇(20mL)溶液。反应混合物加热回流反应4小时，冷却至室温，抽滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯:石油醚＝1:5(v/v))，得到本步骤的标题化合物(930.0mg，收率：52％)。To an aqueous solution of S-methylisothiouronium iodate (2.3 g, 9.9 mmol) was added sodium hydrogencarbonate (2.1 g, 25.0 mmol), and the mixture was stirred for 0.5 hour, then 2-(5-methylfuran) A solution of 2-yl)-2-glyoxal (1.2 g, 8.7 mmol) in ethanol (20 mL). The reaction mixture was heated to reflux for 4 hrs, cooled to room temperature, filtered, filtered, and the residue was purified to silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:5 (v/v)) The title compound (930.0 mg, yield: 52%) was obtained.
MS m/z(ESI):208.4[M+H] +。 MS m/z (ESI): 208.4 [M+H] + .
第三步：5-(5-甲基呋喃-2-基)-3-(甲基磺酰基)-1,2,4-三嗪的制备Third step: Preparation of 5-(5-methylfuran-2-yl)-3-(methylsulfonyl)-1,2,4-triazine
冰浴下，向5-(5-甲基呋喃-2-基)-3-(甲硫基)-1,2,4-三嗪(900.0mg,4.3mmol)的二氯甲烷(20mL)溶液中，分批次加入间氯过氧苯甲酸(1.5g,8.6mmol)，反应混合物于室温搅拌4小时，抽滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯:石油醚＝5:1(v/v))，得到本步骤的标题化合物(886.0mg，收率：89％)。To a solution of 5-(5-methylfuran-2-yl)-3-(methylthio)-1,2,4-triazine (900.0 mg, 4.3 mmol) in dichloromethane (20 mL) The m-chloroperoxybenzoic acid (1.5 g, 8.6 mmol) was added in portions, the reaction mixture was stirred at room temperature for 4 hr, filtered, filtered, and then evaporated. Ethyl ester: petroleum ether = 5:1 (v/v)) (yield: 89%, yield: 89%).
MS m/z(ESI):240.3[M+H] +。 MS m / z (ESI): 240.3 [M + H] +.
第四步：5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-胺的制备The fourth step: preparation of 5-(5-methylfuran-2-yl)-1,2,4-triazin-3-amine
向5-(5-甲基呋喃-2-基)-3-(甲基磺酰基)-1,2,4-三嗪(850.0mg,3.6mmol)的1,4-二氧六环(10mL)溶液中加入氨的1,4-二氧六环溶液(0.4mol/L,40mL)，反应混合物加热至60℃，反应4小时。反应完毕反应液冷却至室温，浓缩，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯:石油醚＝5:1(v/v))，得到本步骤的标题化合物(570.0mg，收率：90％)。To 5-(5-methylfuran-2-yl)-3-(methylsulfonyl)-1,2,4-triazine (850.0 mg, 3.6 mmol) 1,4-dioxane (10 mL) A solution of ammonia in 1,4-dioxane (0.4 mol/L, 40 mL) was added to the solution, and the reaction mixture was heated to 60 ° C for 4 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, and the residue was evaporated. Mg, yield: 90%).
MS m/z(ESI):177.2[M+H] +。 MS m/z (ESI): 177.2 [M+H] + .
第五步：6-溴-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-胺的制备Step 5: Preparation of 6-bromo-5-(5-methylfuran-2-yl)-1,2,4-triazin-3-amine
冰浴下，向5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-胺(500.0mg,2.8mmol)的DMF(6mL)溶液中分批次加入N-溴代丁二酰亚胺(505.0mg,2.8mmol)，反应混合物室温反应2小时，反应液倒入水中，乙酸乙酯萃取，合并有机相，干燥，过滤，浓缩滤液，得到本步骤的标题化合物(570.0mg，收率：80％)。To a batch of N-(5-methylfuran-2-yl)-1,2,4-triazin-3-amine (500.0 mg, 2.8 mmol) in DMF (6 mL) - bromosuccinimide (505.0 mg, 2.8 mmol), the reaction mixture was reacted at room temperature for 2 hours, the reaction mixture was poured into water, ethyl acetate was evaporated, and the organic phase was combined, dried, filtered, Compound (570.0 mg, yield: 80%).
MS m/z(ESI):255.2[M+H] +。 MS m/z (ESI): 255.2 [M+H] + .
第六步：5-(3-氨基-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-6-基)-1-异丙基吡啶-2(1H)-酮的制备Step 6: 5-(3-Amino-5-(5-methylfuran-2-yl)-1,2,4-triazin-6-yl)-1-isopropylpyridine-2 (1H) - Preparation of ketone
6-溴-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-胺(550.0mg,2.2mmol)、1-异丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2(1H)-酮(694.0mg,2.6mmol)和碳酸铯(1.4g,4.3mmol)加入到1,4-二氧六环(20mL)中，置换氮气三次，依次加入水(0.4mL)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(163.0mg,0.2mmol)，反应混合物加热至80℃，反应8小时，反应液冷却至室温，浓缩，剩余物用硅胶柱层析色谱法纯化(洗脱剂：甲醇:二氯甲烷＝1:10(v/v))，得到本步骤的标题化合物(479.0mg，收率：70％)。6-Bromo-5-(5-methylfuran-2-yl)-1,2,4-triazin-3-amine (550.0 mg, 2.2 mmol), 1-isopropyl-4-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one (694.0 mg, 2.6 mmol) and cesium carbonate (1.4 g, 4.3 Ment) was added to 1,4-dioxane (20 mL), replacing nitrogen three times, followed by water (0.4 mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride Dichloromethane complex (163.0 mg, 0.2 mmol), the reaction mixture was heated to 80 ° C, and the reaction was allowed to stand for 8 hours. The reaction mixture was cooled to room temperature and then concentrated. The title compound (479.0 mg, yield: 70%) was obtained.
MS m/z(ESI):312.3[M+H] +。 MS m/z (ESI): 3121. [M+H] + .
第七步：(6-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-基)氨基甲酸苯酯的制备Step 7: (6-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(5-methylfuran-2-yl)-1,2, Preparation of phenyl 4-triazin-3-yl)carbamate
冰浴下，向5-(3-氨基-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-6-基)-1-异丙基吡啶-2(1H)-酮(62.0mg,0.2mmol)的四氢呋喃(4mL)溶液中，依次加入DIPEA(52.0mg,0.4mmol)和氯甲酸苯酯(63.0mg,0.4mmol)，反应混合物室温反应过夜，浓缩反应液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯:石油醚＝5:1(v/v))，得到本步骤的标题化合物(65.0mg，收率：75％)。5-(3-Amino-5-(5-methylfuran-2-yl)-1,2,4-triazin-6-yl)-1-isopropylpyridine-2 (1H) - ketone (62.0 mg, 0.2 mmol) in tetrahydrofuran (4 mL), EtOAc (EtOAc (EtOAc) The residue was purified by silica gel column chromatography chromatography eluting elut elut elut elut elut
MS m/z(ESI):432.4[M+H] +。 MS m/z (ESI): 432.4 [M+H] + .
中间体制备例7：6'-氨基-5'-氟-1-异丙基-4'-(5-甲基呋喃-2-基)-[3,3'-联吡啶]-6(1H)-酮的制备Intermediate Preparation Example 7: 6'-Amino-5'-fluoro-1-isopropyl-4'-(5-methylfuran-2-yl)-[3,3'-bipyridine]-6 (1H )- Preparation of ketone
Figure PCTCN2019070390-appb-000028
Figure PCTCN2019070390-appb-000028
第一步：5-氯-3-氟-4-碘吡啶-2-胺的制备First step: Preparation of 5-chloro-3-fluoro-4-iodopyridin-2-amine
将5-氯-3-氟-吡啶-2-胺(147.0mg,1.0mmol)加入到四氢呋喃(5mL)中，置换氮气三次，用干冰-丙酮浴降温至-78℃，缓慢滴加正丁基锂(1.3mL,2.5mmol,2M)，同时控制反应温度不超过-55℃，加完后，反应混合物在-78℃下搅拌1.5小时。向反应液中加入碘(1.3g,5.1mmol)的四氢呋喃(5mL)溶液(控制反应温度不超过-55℃)，加完后，反应液在-78℃下搅拌反应30分钟。向反应液中滴加饱和硫代硫酸钠溶液淬灭反应，搅拌10分钟，静置，分层，水相用乙酸乙酯萃取，合并有机相并用饱和硫代硫酸钠洗涤两次，干燥，过滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯:石油醚＝1:3(v/v))，得到本步骤的标题化合物(194.0mg，收率：71％)。Add 5-chloro-3-fluoro-pyridin-2-amine (147.0 mg, 1.0 mmol) to tetrahydrofuran (5 mL), replace nitrogen three times, cool to -78 ° C with dry ice-acetone bath, slowly add n-butyl Lithium (1.3 mL, 2.5 mmol, 2 M) while controlling the reaction temperature did not exceed -55 ° C. After the addition, the reaction mixture was stirred at -78 ° C for 1.5 hours. A solution of iodine (1.3 g, 5.1 mmol) in tetrahydrofuran (5 mL) was added to the reaction mixture (control reaction temperature did not exceed -55 ° C). After the addition, the reaction mixture was stirred at -78 ° C for 30 minutes. The reaction mixture was quenched with a saturated aqueous solution of sodium thiosulfate, and the mixture was stirred for 10 minutes, and then stood, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate. The organic phase was combined and washed twice with saturated sodium thiosulfate. The filtrate was concentrated, and the residue was purified mjjjjjjjjjjjjjjjjjj %).
MS m/z(ESI):273.2[M+H] +。 MS m / z (ESI): 273.2 [M + H] +.
第二步：5-氯-3-氟-4-(5-甲基呋喃-2-基)吡啶-2-胺的制备The second step: preparation of 5-chloro-3-fluoro-4-(5-methylfuran-2-yl)pyridin-2-amine
5-氯-3-氟-4-碘吡啶-2-胺(190.0mg,0.7mmol)加入到1,4-二氧六环(5mL)和水(1mL)的混合溶剂中，然后依次加入(5-甲基呋喃-2-基)硼酸(105.4mg,0.8mmol)、碳酸铯(454.7mg,1.4mmol)和Pd(dppf)Cl 2(56.9mg,0.07mmol)，氮气置换3次后，升温至80℃，搅拌反应4小时，反应完毕后，冷却至室温，将反应液倒入水中，乙酸乙酯萃取，合并有机相，干燥，过滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯:石油醚＝1:2(v/v))，得到本步骤的标题化合物(100.0mg，收率：63％)。 5-Chloro-3-fluoro-4-iodopyridin-2-amine (190.0 mg, 0.7 mmol) was added to a mixed solvent of 1,4-dioxane (5 mL) and water (1 mL), and then added ( 5-methylfuran-2-yl)boronic acid (105.4 mg, 0.8 mmol), cesium carbonate (454.7 mg, 1.4 mmol), and Pd(dppf)Cl 2 (56.9 mg, 0.07 mmol). The reaction was stirred at 80 ° C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature. The reaction mixture was poured into water, ethyl acetate was evaporated, and the organic phase was combined, dried, filtered, and the filtrate was evaporated. (eluent: ethyl acetate: petroleum ether = 1 : 2 (v/v)) to give the title compound (100.0 mg, yield: 63%).
MS m/z(ESI):227.2[M+H] +。 MS m/z (ESI): 227.2 [M+H] + .
第三步：6'-氨基-5'-氟-1-异丙基-4'-(5-甲基呋喃-2-基)-[3,3'-联吡啶]-6(1H)-酮的制备The third step: 6'-amino-5'-fluoro-1-isopropyl-4'-(5-methylfuran-2-yl)-[3,3'-bipyridyl]-6(1H)- Preparation of ketone
将5-氯-3-氟-4-(5-甲基呋喃-2-基)吡啶-2-胺(600.0mg,2.6mmol)加入到1,4-二氧六环(12mL)和水(4mL)的混合溶剂中，然后依次加入1-异丙基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2(1H)-酮(1.4g,5.3mmol)、磷酸钾(1.7g,8.0mmol)，然后氮气置换下加入Pd(amphos)Cl 2(187.4mg,0.3mmol)，升温至100℃，搅拌反应6小时，反应完毕后，冷却至室温，反应液倒入水中，乙酸乙酯萃取，合并乙酸乙酯层，干燥，浓缩，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯:石油醚＝2:1(v/v))，得到本步骤的标题化合物(0.8g，收率：94％)。 Add 5-chloro-3-fluoro-4-(5-methylfuran-2-yl)pyridin-2-amine (600.0 mg, 2.6 mmol) to 1,4-dioxane (12 mL) and water ( 4 mL) of a mixed solvent, followed by the sequential addition of 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine -2(1H)-one (1.4g, 5.3mmol), potassium phosphate (1.7g, 8.0mmol), then Pd(amphos)Cl 2 (187.4mg, 0.3mmol) was added under nitrogen, heated to 100 ° C, stirred After the reaction is completed for 6 hours, the reaction mixture is cooled to room temperature, and the mixture is poured into water, ethyl acetate is evaporated, ethyl acetate layer is combined, dried, concentrated, and the residue is purified by silica gel column chromatography (eluent: ethyl acetate Ester: petroleum ether = 2:1 (v/v)), the title compound (0.8 g, yield: 94%).
MS m/z(ESI):328.2[M+H] +。 MS m/z (ESI): 328.2 [M+H] + .
实施例Example
实施例1：1-(1'-异丙基-2-(5-甲基呋喃-2-基)-6'-氧代-1',6'-二氢-[3,3'-联吡啶]-6-基)-3-甲基脲的制备(化合物1)Example 1: 1-(1'-isopropyl-2-(5-methylfuran-2-yl)-6'-oxo-1',6'-dihydro-[3,3'-linked Preparation of pyridine]-6-yl)-3-methylurea (Compound 1)
Figure PCTCN2019070390-appb-000029
Figure PCTCN2019070390-appb-000029
将6'-氨基-1-异丙基-2'-(5-甲基呋喃-2-基)-[3,3'-联吡啶]-6(1H)-酮(100.0mg,0.3mmol)溶于四氢呋喃(2mL)，0℃下加入DIPEA(0.6mL,3.2mmol)和三光气(89.0mg,0.3mmol)。混合物维持在0℃搅拌0.5小时，然后加入甲胺的四氢呋喃溶液(0.3mL,2mol/L,0.6mmol)并在0℃下反应1小时。反应完毕后，向反应液中加水，乙酸乙酯萃取，合并有机相，干燥，过滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯)，得到标题化合物(5.0mg，收率：5％)。6'-Amino-1-isopropyl-2'-(5-methylfuran-2-yl)-[3,3'-bipyridyl]-6(1H)-one (100.0 mg, 0.3 mmol) Dissolved in tetrahydrofuran (2 mL), DIPEA (0.6 mL, 3.2 mmol. The mixture was stirred at 0 ° C for 0.5 hour, then a solution of methylamine in tetrahydrofuran (0.3 mL, 2 mol/L, 0.6 mmol) was added and reacted at 0 ° C for 1 hour. After completion of the reaction, water was added to the reaction mixture, and the mixture was evaporated. 5.0 mg, yield: 5%).
MS m/z(ESI):367.1[M+H] + MS m/z (ESI): 367.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.46(s,1H),8.38-8.36(m,1H),7.66(d,J＝2.0Hz,1H),7.60(d,J＝8.4Hz,1H),7.24(d,J＝8.8Hz,2H),6.41(d,J＝9.2Hz,1H),6.22(d,J＝2.8Hz,1H),6.16(d,J＝2.4Hz,1H),5.11-5.07(m,1H),2.78(s,3H),2.25(s,3H),1.27(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.46 (s, 1H), 8.38-8.36 (m, 1H), 7.66 (d, J = 2.0Hz, 1H), 7.60 (d, J = 8.4Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.41 (d, J = 9.2 Hz, 1H), 6.22 (d, J = 2.8 Hz, 1H), 6.16 (d, J = 2.4 Hz, 1H) , 5.11-5.07 (m, 1H), 2.78 (s, 3H), 2.25 (s, 3H), 1.27 (d, J = 6.8 Hz, 6H).
实施例2：3-(1'-异丙基-2-(5-甲基呋喃-2-基)-6'-氧代-1',6'-二氢-[3,3'-联吡啶]-6-基)-1,1-二甲基脲的制备(化合物2)Example 2: 3-(1'-isopropyl-2-(5-methylfuran-2-yl)-6'-oxo-1',6'-dihydro-[3,3'-linked Preparation of pyridine]-6-yl)-1,1-dimethylurea (Compound 2)
Figure PCTCN2019070390-appb-000030
Figure PCTCN2019070390-appb-000030
用二甲胺的四氢呋喃溶液代替实施例1中的甲胺的四氢呋喃溶液，以类似实施例1的所述的方法，合成得到标题化合物(5.0mg，收率：8％)。The title compound (5.0 mg, yield: 8%) was obtained by the procedure of the procedure of Example 1 in the THF of THF.
MS m/z(ESI):381.1[M+H] + MS m/z (ESI): 381.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:8.87(s,1H),7.73-7.70(m,1H),7.63-7.60(m,2H),7.22(dd,J＝9.2,2.4Hz,1H),6.39-6.33(m,2H),6.14-6.13(m,1H),5.14-5.06(m,1H),2.96(s,6H),2.20(s,3H),1.27(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 8.87 (s, 1H), 7.73-7.70 (m, 1H), 7.63-7.60 (m, 2H), 7.22 (dd, J = 9.2,2.4Hz, 1H ), 6.39-6.33 (m, 2H), 6.14 - 6.13 (m, 1H), 5.14 - 5.06 (m, 1H), 2.96 (s, 6H), 2.20 (s, 3H), 1.27 (d, J = 6.8) Hz, 6H).
实施例3：1-(1'-异丙基-2-(5-甲基呋喃-2-基)-6'-氧代-1',6'-二氢-[3,3'-联吡啶]-6-基)-3-(吡啶-2-基甲基)脲的制备(化合物3)Example 3: 1-(1'-isopropyl-2-(5-methylfuran-2-yl)-6'-oxo-1',6'-dihydro-[3,3'-linked Preparation of pyridine]-6-yl)-3-(pyridin-2-ylmethyl)urea (Compound 3)
Figure PCTCN2019070390-appb-000031
Figure PCTCN2019070390-appb-000031
用2-氨甲基吡啶代替实施例1中的甲胺的四氢呋喃溶液，以类似实施例1所述的方法，合成得到标题化合物(53.0mg，收率：70％)。The title compound (53.0 mg, yield: 70%) was obtained.
MS m/z(ESI):444.1[M+H] + MS m/z (ESI): 444.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.23(s,1H),8.65(s,1H),8.54-8.52(m,1H),7.80-7.76(m,1H),7.65-7.60(m,2H),7.40-7.18(m,4H),6.41-6.38(m,2H),6.14-6.13(m,1H),5.10-5.07(m,1H),4.56(d,J＝6.4Hz,2H),2.09(s,3H),1.28(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.23 (s, 1H), 8.65 (s, 1H), 8.54-8.52 (m, 1H), 7.80-7.76 (m, 1H), 7.65-7.60 (m , 2H), 7.40-7.18 (m, 4H), 6.41-6.38 (m, 2H), 6.14-6.13 (m, 1H), 5.10-5.07 (m, 1H), 4.56 (d, J = 6.4 Hz, 2H ), 2.09 (s, 3H), 1.28 (d, J = 6.8 Hz, 6H).
实施例4：N-(1'-异丙基-2-(5-甲基呋喃-2-基)-6'-氧代-1',6'-二氢-[3,3'-联吡啶]-6-基)哌啶-1-甲酰胺的制备(化合物4)Example 4: N-(1'-isopropyl-2-(5-methylfuran-2-yl)-6'-oxo-1',6'-dihydro-[3,3'-linked Preparation of pyridine]-6-yl)piperidine-1-carboxamide (Compound 4)
Figure PCTCN2019070390-appb-000032
Figure PCTCN2019070390-appb-000032
用哌啶代替实施例1中的甲胺的四氢呋喃溶液，以类似实施例1所述的方法，合成得到标题化合物(56.0mg，收率：55％)。The title compound (56.0 mg, yield: 55%) was obtained.
MS m/z(ESI):421.2[M+H] + MS m/z (ESI): 421.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.14(s,1H),7.70-7.67(m,1H),7.61-7.59(m,2H),7.22-7.19(m,1H),6.39-6.34(m,2H),6.14-6.13(m,1H),5.10-5.07(m,1H),3.46-3.44(m,4H),2.50(s,2H),2.20(s,3H),1.58-1.49(m,4H),1.28(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.14 (s, 1H), 7.70-7.67 (m, 1H), 7.61-7.59 (m, 2H), 7.22-7.19 (m, 1H), 6.39-6.34 (m, 2H), 6.14-6.13 (m, 1H), 5.10-5.07 (m, 1H), 3.46-3.44 (m, 4H), 2.50 (s, 2H), 2.20 (s, 3H), 1.58-1.49 (m, 4H), 1.28 (d, J = 6.8 Hz, 6H).
实施例5：3-羟基-N-(1'-异丙基-2-(5-甲基呋喃-2-基)-6'-氧代-1',6'-二氢-[3,3'-联吡啶]-6-基)哌啶-1-甲酰胺的制备(化合物5)Example 5: 3-Hydroxy-N-(1'-isopropyl-2-(5-methylfuran-2-yl)-6'-oxo-1',6'-dihydro-[3, Preparation of 3'-bipyridyl]-6-yl)piperidine-1-carboxamide (Compound 5)
Figure PCTCN2019070390-appb-000033
Figure PCTCN2019070390-appb-000033
用3-羟基哌啶代替实施例1中的甲胺的四氢呋喃溶液，以类似实施例1所述的方法，合成得到标题化合物(32.0mg，收率：23％)。The title compound (32.0 mg, yield: 23%) was obtained.
MS m/z(ESI):437.1[M+H] + MS m/z (ESI): 437.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.12(s,1H),7.68-7.66(m,1H),7.61-7.59(m,2H),7.22-7.19(m,1H),6.39-6.33(m,2H),6.14-6.13(m,1H),5.10-5.04(m,1H),4.87-4.86(m,1H),3.90-3.86(m,1H),3.73-3.70(m,1H),3.51-3.47(m,1H),3.06-3.01(m,2H),2.24(s,3H),1.84-1.80(m,1H),1.71-1.68(m,1H),1.41-1.34(m,2H),1.29(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.12 (s, 1H), 7.68-7.66 (m, 1H), 7.61-7.59 (m, 2H), 7.22-7.19 (m, 1H), 6.39-6.33 (m, 2H), 6.14-6.13 (m, 1H), 5.10-5.04 (m, 1H), 4.87-4.86 (m, 1H), 3.90-3.86 (m, 1H), 3.73-3.70 (m, 1H) , 3.51-3.47 (m, 1H), 3.06-3.01 (m, 2H), 2.24 (s, 3H), 1.84-1.80 (m, 1H), 1.71-1.68 (m, 1H), 1.41-1.34 (m, 2H), 1.29 (d, J = 6.8 Hz, 6H).
实施例6：4-羟基-N-(1'-异丙基-2-(5-甲基呋喃-2-基)-6'-氧代-1',6'-二氢-[3,3'-联吡啶]-6-基)哌啶-1-甲酰胺的制备(化合物6)Example 6: 4-Hydroxy-N-(1'-isopropyl-2-(5-methylfuran-2-yl)-6'-oxo-1',6'-dihydro-[3, Preparation of 3'-bipyridyl]-6-yl)piperidine-1-carboxamide (Compound 6)
Figure PCTCN2019070390-appb-000034
Figure PCTCN2019070390-appb-000034
用4-羟基哌啶代替实施例1中的甲胺的四氢呋喃溶液，以类似实施例1所述的方法，合成得到标题化合物(40.0mg，收率：28％)。The title compound (40.0 mg, yield: 28%) was obtained.
MS m/z(ESI):437.1[M+H] + MS m/z (ESI): 437.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.20(s,1H),7.69-7.67(m,1H),7.61-7.59(m,2H),7.22-7.19(m,1H),6.39-6.33(m,2H),6.14-6.13(m,1H),5.10-5.06(m,1H),4.72-4.71(m,1H),3.87-3.83(m,2H),3.67-3.66(m,1H),3.11-3.05(m,2H),2.24(s,3H),1.76-1.72(m,2H),1.35-1.31(m,2H),1.29(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.20 (s, 1H), 7.69-7.67 (m, 1H), 7.61-7.59 (m, 2H), 7.22-7.19 (m, 1H), 6.39-6.33 (m, 2H), 6.14-6.13 (m, 1H), 5.10-5.06 (m, 1H), 4.72-4.71 (m, 1H), 3.87-3.83 (m, 2H), 3.67-3.66 (m, 1H) , 3.11-3.05 (m, 2H), 2.24 (s, 3H), 1.76-1.72 (m, 2H), 1.35 - 1.31 (m, 2H), 1.29 (d, J = 6.8 Hz, 6H).
实施例7：4,4-二氟-N-(1'-异丙基-2-(5-甲基呋喃-2-基)-6'-氧代-1',6'-二氢-[3,3'-联吡啶]-6-基)哌啶-1-甲酰胺的制备(化合物7)Example 7: 4,4-Difluoro-N-(1'-isopropyl-2-(5-methylfuran-2-yl)-6'-oxo-1',6'-dihydro- Preparation of [3,3'-bipyridyl]-6-yl)piperidine-1-carboxamide (Compound 7)
Figure PCTCN2019070390-appb-000035
Figure PCTCN2019070390-appb-000035
用4,4-二氟哌啶盐酸盐代替实施例1中的甲胺的四氢呋喃溶液，以类似实施例1所述的方法，合成得到标题化合物(40.0mg，收率：27％)。The title compound (40.0 mg, yield: 27%) was obtained.
MS m/z(ESI):457.2[M+H] + MS m/z (ESI): 457.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.49(s,1H),7.69-7.62(m,3H),7.22-7.19(m,1H),6.39-6.32(m,2H),6.14-6.13(m,1H),5.10-5.06(m,1H),3.61-3.59(m,4H),2.24(s,3H),2.05-1.95(m,4H),1.28(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.49 (s, 1H), 7.69-7.62 (m, 3H), 7.22-7.19 (m, 1H), 6.39-6.32 (m, 2H), 6.14-6.13 (m, 1H), 5.10-5.06 (m, 1H), 3.61-3.59 (m, 4H), 2.24 (s, 3H), 2.05-1.95 (m, 4H), 1.28 (d, J = 6.8 Hz, 6H) ).
实施例8：3-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)-1,1-二甲基脲的制备(化合物8)Example 8: 3-(5-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl)pyrimidine-2 -Base)-1,1-Dimethylurea Preparation (Compound 8)
Figure PCTCN2019070390-appb-000036
Figure PCTCN2019070390-appb-000036
将5-(2-氨基-4-(5-甲基呋喃-2-基)嘧啶-5-基)-1-异丙基吡啶-2(1H)-酮(100.0mg,0.3mmol)溶于四氢呋喃(2mL)，0℃下加入DIPEA(0.6mL,3.2mmol)和三光气(89.0mg,0.3mmol)。混合物在0℃下搅拌0.5小时，加入二甲胺盐酸盐(48.9mg,0.6mmol)并在0℃下继续反应1小时。反应完毕后，向反应液中加水，乙酸乙酯萃取，合并有机相，干燥，过滤，浓缩滤液，剩余物用制备型高效液相色谱仪纯化(纯化方法B)，得到标题化合物(15.0mg，收率：13％)。Dissolve 5-(2-amino-4-(5-methylfuran-2-yl)pyrimidin-5-yl)-1-isopropylpyridine-2(1H)-one (100.0 mg, 0.3 mmol) Tetrahydrofuran (2 mL) was added DIPEA (0.6 mL, 3.2 mmol) and phosgene (89.0 mg, 0.3 mmol) at 0 °C. The mixture was stirred at 0 ° C for 0.5 h, dimethylamine hydrochloride (48.9 mg, 0.6 mmol) was added and the reaction was continued at 0 ° C for one hour. After the completion of the reaction, water was added to the reaction mixture, and ethyl acetate was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Yield: 13%).
MS m/z(ESI):382.3[M+H] + MS m/z (ESI): 382.3 [M+H] +
1H NMR(400MHz,CD 3OD)δ:8.36(s,1H),7.76(d,J＝2.4Hz,1H),7.43(dd,J＝9.2,2.4Hz,1H),6.91(d,J＝3.2Hz,1H),6.61(d,J＝9.2Hz,1H),6.18(dd,J＝3.2,0.8Hz,1H),5.30-5.19(m,1H),3.08(s,6H),2.23(s,3H),1.41(d,J＝6.8Hz,6H)。 1 H NMR (400 MHz, CD 3 OD) δ: 8.36 (s, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.43 (dd, J = 9.2, 2.4 Hz, 1H), 6.91 (d, J) =3.2 Hz, 1H), 6.61 (d, J = 9.2 Hz, 1H), 6.18 (dd, J = 3.2, 0.8 Hz, 1H), 5.30-5.19 (m, 1H), 3.08 (s, 6H), 2.23 (s, 3H), 1.41 (d, J = 6.8 Hz, 6H).
实施例9：1-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)脲的制备(化合物9)Example 9: 1-(5-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl)pyrimidine-2 -base) urea preparation (compound 9)
Figure PCTCN2019070390-appb-000037
Figure PCTCN2019070390-appb-000037
用氨的1,4-二氧六环溶液代替实施例8中二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(30.0mg，收率：27％)。The title compound (30.0 mg, yield: 27%) was obtained.
MS m/z(ESI):354.2[M+H] + MS m/z (ESI): 354.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.66(s,1H),8.64(s,1H),8.42(s,1H),7.82(d,J＝2.4Hz,1H),7.33(dd,J＝9.2,2.4Hz,1H),7.12(s,1H),6.62(d,J＝3.6Hz,1H),6.45(d,J＝9.2Hz,1H),6.29(d,J＝2.4Hz,1H),5.14-5.06(m,1H),2.26(s,3H),1.29(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.66 (s, 1H), 8.64 (s, 1H), 8.42 (s, 1H), 7.82 (d, J = 2.4Hz, 1H), 7.33 (dd, J=9.2, 2.4 Hz, 1H), 7.12 (s, 1H), 6.62 (d, J = 3.6 Hz, 1H), 6.45 (d, J = 9.2 Hz, 1H), 6.29 (d, J = 2.4 Hz, 1H), 5.14 - 5.06 (m, 1H), 2.26 (s, 3H), 1.29 (d, J = 6.8 Hz, 6H).
实施例10：1-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)-3-甲基脲的制备(化合物10)Example 10: 1-(5-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl)pyrimidine-2 Preparation of -yl)-3-methylurea (Compound 10)
Figure PCTCN2019070390-appb-000038
Figure PCTCN2019070390-appb-000038
用甲胺的四氢呋喃溶液代替实施例8中二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(20.0mg，收率：17％)。The title compound (20.0 mg, yield: 17%) was obtained.
MS m/z(ESI):368.2[M+H] + MS m/z (ESI): 368.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.66(s,1H),8.42(s,1H),7.82(d,J＝2.4Hz,1H),7.33(dd,J＝9.2,2.4Hz,1H),7.12(s,1H),6.62(d,J＝3.6Hz,1H),6.45(d,J＝9.2Hz,1H),6.29(d,J＝2.4Hz,1H),5.14-5.06(m,1H),2.72(s,3H),2.26(s,3H),1.29(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.66 (s, 1H), 8.42 (s, 1H), 7.82 (d, J = 2.4Hz, 1H), 7.33 (dd, J = 9.2,2.4Hz, 1H), 7.12 (s, 1H), 6.62 (d, J = 3.6 Hz, 1H), 6.45 (d, J = 9.2 Hz, 1H), 6.29 (d, J = 2.4 Hz, 1H), 5.14 - 5.06 ( m, 1H), 2.72 (s, 3H), 2.26 (s, 3H), 1.29 (d, J = 6.8 Hz, 6H).
实施例11：1-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)-3-(2-甲氧基乙基)脲的制备(化合物11)Example 11:1-(5-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl)pyrimidine-2 Preparation of -yl)-3-(2-methoxyethyl)urea (Compound 11)
Figure PCTCN2019070390-appb-000039
Figure PCTCN2019070390-appb-000039
用2-甲氧基乙胺代替实施例8中二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(10.0mg，收率：8％)。The title compound (10.0 mg, yield: 8%) was obtained by the procedure of the procedure of Example 8 to give the title compound.
MS m/z(ESI):412.1[M+H] + MS m/z (ESI): 412.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.86(s,1H),9.38(s,1H),8.43(s,1H),7.81(d,J＝2.0Hz,1H),7.35-7.32(m,1H),6.88(d,J＝3.6Hz,1H),6.44(d,J＝9.2Hz,1H),6.33(d,J＝2.8Hz,1H),5.14-5.07(m,1H),3.50-3.45(m,4H),3.30(s,3H),2.24(s,3H),1.29(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.86 (s, 1H), 9.38 (s, 1H), 8.43 (s, 1H), 7.81 (d, J = 2.0Hz, 1H), 7.35-7.32 ( m,1H), 6.88 (d, J = 3.6 Hz, 1H), 6.44 (d, J = 9.2 Hz, 1H), 6.33 (d, J = 2.8 Hz, 1H), 5.14 - 5.07 (m, 1H), 3.50-3.45 (m, 4H), 3.30 (s, 3H), 2.24 (s, 3H), 1.29 (d, J = 6.8 Hz, 6H).
实施例12：1-(2-(二甲基氨基)乙基)-3-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)脲的制备(化合物12)Example 12: 1-(2-(Dimethylamino)ethyl)-3-(5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4 Preparation of (-(5-methylfuran-2-yl)pyrimidin-2-yl)urea (Compound 12)
Figure PCTCN2019070390-appb-000040
Figure PCTCN2019070390-appb-000040
用N,N-二甲基乙二胺代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(10.0mg，收率：14％)。The title compound (10.0 mg, yield: 14%) was obtained.
MS m/z(ESI):425.2[M+H] + MS m/z (ESI): 425.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.81(s,1H),9.22(t,J＝4.8Hz,1H),8.43(s,1H),7.80(d,J＝2.4Hz,1H),7.34(dd,J＝9.2,2.4Hz,1H),7.15(d,J＝3.2Hz,1H),6.44(d,J＝9.2Hz,1H),6.34(d,J＝2.4Hz,1H),5.21-5.03(m,1H),3.43-3.36(m,2H),2.50(s,3H),2.46(t,J＝6.0Hz,2H),2.22(d,J＝2.4Hz,6H),1.29(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.81 (s, 1H), 9.22 (t, J = 4.8Hz, 1H), 8.43 (s, 1H), 7.80 (d, J = 2.4Hz, 1H) , 7.34 (dd, J = 9.2, 2.4 Hz, 1H), 7.15 (d, J = 3.2 Hz, 1H), 6.44 (d, J = 9.2 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H) , 5.21-5.03 (m, 1H), 3.43-3.36 (m, 2H), 2.50 (s, 3H), 2.46 (t, J = 6.0 Hz, 2H), 2.22 (d, J = 2.4 Hz, 6H), 1.29 (d, J = 6.8 Hz, 6H).
实施例13：1-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)-3-(2-吗啉-4-基-乙基)-脲的制备(化合物13)Example 13: 1-(5-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl)pyrimidine-2 Preparation of -yl)-3-(2-morpholin-4-yl-ethyl)-urea (Compound 13)
Figure PCTCN2019070390-appb-000041
Figure PCTCN2019070390-appb-000041
用2-吗啉-4-基乙胺代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(15.0mg，收率：16％)。The title compound (15.0 mg, yield: 16%) was obtained.
MS m/z(ESI):408.3[M+H] + MS m/z (ESI): 408.3 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.29(s,1H),8.39(s,1H),7.78(d,J＝2.4Hz,1H),7.30(dd,J＝9.2,2.4Hz,1H),6.63(d,J＝3.2Hz,1H),6.43(d,J＝9.6Hz,1H),6.25(dd,J＝3.2,0.8Hz,1H),5.18-5.01(m,1H),3.42(s,4H),2.24(s,3H),1.84(s,4H),1.30(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.29 (s, 1H), 8.39 (s, 1H), 7.78 (d, J = 2.4Hz, 1H), 7.30 (dd, J = 9.2,2.4Hz, 1H), 6.63 (d, J = 3.2 Hz, 1H), 6.43 (d, J = 9.6 Hz, 1H), 6.25 (dd, J = 3.2, 0.8 Hz, 1H), 5.18-5.01 (m, 1H), 3.42 (s, 4H), 2.24 (s, 3H), 1.84 (s, 4H), 1.30 (d, J = 6.8 Hz, 6H).
实施例14：1-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)-3-(1-甲基-1H-吡唑-4-基)脲的制备(化合物14)Example 14: 1-(5-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl)pyrimidine-2 Preparation of -yl)-3-(1-methyl-1H-pyrazol-4-yl)urea (Compound 14)
Figure PCTCN2019070390-appb-000042
Figure PCTCN2019070390-appb-000042
用1-甲基-1H-吡唑-4-胺代替实施例8中二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(5.0mg，收率：4％)。Substituting 1-methyl-1H-pyrazole-4-amine for the dimethylamine hydrochloride of Example 8 to give the title compound (5.0 mg, yield: 4%). .
MS m/z(ESI):434.2[M+H] + MS m/z (ESI): 434.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:11.53(s,1H),10.29(s,1H),8.48(s,1H),7.90(s,1H),7.87(d,J＝2.4Hz,1H),7.47(s,1H),7.38-7.35(m,1H),6.54(d,J＝3.2Hz,1H),6.48(d,J＝9.2Hz,1H),6.33(d,J＝2.8Hz,1H),5.20-5.02(m,1H),3.83(s,3H),2.38(s,3H),1.30(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 11.53 (s, 1H), 10.29 (s, 1H), 8.48 (s, 1H), 7.90 (s, 1H), 7.87 (d, J = 2.4Hz, 1H), 7.47 (s, 1H), 7.38-7.35 (m, 1H), 6.54 (d, J = 3.2 Hz, 1H), 6.48 (d, J = 9.2 Hz, 1H), 6.33 (d, J = 2.8) Hz, 1H), 5.20-5.02 (m, 1H), 3.83 (s, 3H), 2.38 (s, 3H), 1.30 (d, J = 6.8 Hz, 6H).
实施例15：4-氰基-N-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)哌啶-1-甲酰胺的制备(化合物15)Example 15: 4-cyano-N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2- Preparation of pyrimido-2-yl)piperidine-1-carboxamide (Compound 15)
Figure PCTCN2019070390-appb-000043
Figure PCTCN2019070390-appb-000043
用4-氰基哌啶代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(33.0mg，收率：31％)。The title compound (33.0 mg, yield: 31%) was obtained.
MS m/z(ESI):447.3[M+H] + MS m/z (ESI): 447.3 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.63(s,1H),8.38(s,1H),7.79(d,J＝2.4Hz,1H),7.30(dd,J＝9.2,2.4Hz,1H),6.60(d,J＝3.2Hz,1H),6.43(d,J＝9.2Hz,1H),6.25(dd,J＝3.6,0.8Hz,1H),5.17-5.03(m,1H),3.75-3.65(m,2H),3.33-3.24(m,2H),3.11(s,1H),2.24(s,3H),1.97-1.84(m,2H),1.81-1.65(m,2H),1.30(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.63 (s, 1H), 8.38 (s, 1H), 7.79 (d, J = 2.4Hz, 1H), 7.30 (dd, J = 9.2,2.4Hz, 1H), 6.60 (d, J = 3.2 Hz, 1H), 6.43 (d, J = 9.2 Hz, 1H), 6.25 (dd, J = 3.6, 0.8 Hz, 1H), 5.17-5.03 (m, 1H), 3.75-3.65(m,2H),3.33-3.24(m,2H),3.11(s,1H), 2.24(s,3H),1.97-1.84(m,2H),1.81-1.65(m,2H), 1.30 (d, J = 6.8 Hz, 6H).
实施例16：3-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)-1-甲基-1-(吡啶-2-基甲基)脲的制备(化合物16)Example 16: 3-(5-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl)pyrimidine-2 Preparation of 1-yl-1-yl-1-(pyridin-2-ylmethyl)urea (Compound 16)
Figure PCTCN2019070390-appb-000044
Figure PCTCN2019070390-appb-000044
用N-甲基-1-吡啶-2-甲胺代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(25.0mg，收率：32％)。Substituting N-methyl-1-pyridine-2-methylamine for the dimethylamine hydrochloride of Example 8 to give the title compound (25.0 mg, yield: 32%). ).
MS m/z(ESI):459.2[M+H] + MS m/z (ESI): 459.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.77(s,1H),8.58(d,J＝4.4Hz,1H),8.42(s,1H),7.85-7.79(m,2H),7.40(d,J＝8.0Hz,1H),7.35-7.30(m,2H),6.66(d,J＝3.2Hz,1H),6.44(d,J＝9.2Hz,1H),6.26(dd,J＝3.2,0.8Hz,1H),5.19-5.00(m,1H),4.66(s,2H),3.00(s,3H),2.24(s,3H),1.30(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.77 (s, 1H), 8.58 (d, J = 4.4Hz, 1H), 8.42 (s, 1H), 7.85-7.79 (m, 2H), 7.40 ( d, J = 8.0 Hz, 1H), 7.35-7.30 (m, 2H), 6.66 (d, J = 3.2 Hz, 1H), 6.44 (d, J = 9.2 Hz, 1H), 6.26 (dd, J = 3.2 , 0.8Hz, 1H), 5.19-5.00 (m, 1H), 4.66 (s, 2H), 3.00 (s, 3H), 2.24 (s, 3H), 1.30 (d, J = 6.8 Hz, 6H).
实施例17：1-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)-3-(吡啶-3-基甲基)脲的制备(化合物17)Example 17: 1-(5-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl)pyrimidine-2 Preparation of -yl)-3-(pyridin-3-ylmethyl)urea (Compound 17)
Figure PCTCN2019070390-appb-000045
Figure PCTCN2019070390-appb-000045
用3-氨甲基吡啶代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(8.0mg，收率：11％)。The title compound (8.0 mg, yield: 11%) was obtained.
MS m/z(ESI):445.2[M+H] + MS m/z (ESI): 445.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:10.04(s,1H),9.81(t,J＝5.6Hz,1H),8.61(s,1H),8.49(d,J＝3.2Hz,1H),8.43(s,1H),7.83(d,J＝2.4Hz,1H),7.78(d,J＝7.6Hz,1H),7.39(dd,J＝7.6,4.8Hz,1H),7.33(dd,J＝9.2,2.4Hz,1H),6.48-6.44(m,2H),6.24(d,J＝2.8Hz,1H),5.16-5.03(m,1H),4.56(d,J＝5.6Hz,2H),2.14(s,3H),1.28(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 10.04 (s, 1H), 9.81 (t, J = 5.6Hz, 1H), 8.61 (s, 1H), 8.49 (d, J = 3.2Hz, 1H) , 8.43 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.39 (dd, J = 7.6, 4.8 Hz, 1H), 7.33 (dd, J=9.2, 2.4 Hz, 1H), 6.48-6.44 (m, 2H), 6.24 (d, J = 2.8 Hz, 1H), 5.16-5.03 (m, 1H), 4.56 (d, J = 5.6 Hz, 2H) ), 2.14 (s, 3H), 1.28 (d, J = 6.8 Hz, 6H).
实施例18：(S)-N-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)-2-甲基吡咯烷-1-甲酰胺的制备(化合物18)Example 18: (S)-N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl) Preparation of pyrimidine-2-yl)-2-methylpyrrolidin-1-carboxamide (Compound 18)
Figure PCTCN2019070390-appb-000046
Figure PCTCN2019070390-appb-000046
用(S)-2-甲基吡咯烷代替实施例8中二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(30.0mg，收率：22％)。The title compound (30.0 mg, yield: 22%) was obtained by the titled compound (3).
MS m/z(ESI):422.2[M+H] + MS m/z (ESI): 422.2 [M+H] +
1H NMR(400MHz,CD 3OD)δ:8.36(s,1H),7.77(d,J＝2.4Hz,1H),7.45-7.42(m,1H),6.88(d,J＝3.2Hz,1H),6.61(d,J＝9.2Hz,1H),6.18(d,J＝3.2Hz,1H),5.38-5.14(m,1H),4.26-4.08(m,1H),3.70-3.57(m,1H),3.54-3.52(m,1H),2.24(s,3H),2.10-2.04(m,2H),1.96-1.93(m,1H),1.69-1.67(m,1H),1.40(d,J＝6.8Hz,6H),1.27(t,J＝6.4Hz,3H)。 1 H NMR (400 MHz, CD 3 OD) δ: 8.36 (s, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.45-7.42 (m, 1H), 6.88 (d, J = 3.2 Hz, 1H) ), 6.61 (d, J = 9.2 Hz, 1H), 6.18 (d, J = 3.2 Hz, 1H), 5.38-5.14 (m, 1H), 4.26 - 4.08 (m, 1H), 3.70 - 3.57 (m, 1H), 3.54-3.52 (m, 1H), 2.24 (s, 3H), 2.10-2.04 (m, 2H), 1.96-1.93 (m, 1H), 1.69-1.67 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H), 1.27 (t, J = 6.4 Hz, 3H).
实施例19：N-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)-2,2-二甲基吡咯烷-1-甲酰胺的制备(化合物19)Example 19: N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl)pyrimidine-2 Preparation of 2-yl-2,2-dimethylpyrrolidin-1-carboxamide (Compound 19)
Figure PCTCN2019070390-appb-000047
Figure PCTCN2019070390-appb-000047
用2,2-二甲基吡咯烷盐酸盐代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(35.0mg，收率：25％)。Substituting 2,2-dimethylpyrrolidine hydrochloride for the dimethylamine hydrochloride of Example 8 to give the title compound (35.0 mg, yield: 25%). .
MS m/z(ESI):436.2[M+H] + MS m/z (ESI): 436.2 [M+H] +
1H NMR(400MHz,CD 3OD)δ:8.35(s,1H),7.77(d,J＝2.4Hz,1H),7.44-7.41(m,1H),6.87(d,J＝3.2Hz,1H),6.61(d,J＝9.2Hz,1H),6.18(dd,J＝3.2,0.8Hz,1H),5.37-5.16(m,1H),3.65(t,J＝6.4Hz,2H),2.24(s,3H),2.02-1.83(m,4H),1.53(s,6H),1.41(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, CD 3 OD) δ: 8.35 (s, 1H), 7.77 (d, J = 2.4Hz, 1H), 7.44-7.41 (m, 1H), 6.87 (d, J = 3.2Hz, 1H ), 6.61 (d, J = 9.2 Hz, 1H), 6.18 (dd, J = 3.2, 0.8 Hz, 1H), 5.37-5.16 (m, 1H), 3.65 (t, J = 6.4 Hz, 2H), 2.24 (s, 3H), 2.02-1.83 (m, 4H), 1.53 (s, 6H), 1.41 (d, J = 6.8 Hz, 6H).
实施例20：N-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)-3-甲氧基吡咯烷-1-甲酰胺的制备(化合物20)Example 20: N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl)pyrimidine-2 Preparation of 3-yl-3-methoxypyrrolidine-1-carboxamide (Compound 20)
Figure PCTCN2019070390-appb-000048
Figure PCTCN2019070390-appb-000048
用3-甲氧基吡咯烷代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(30.0mg，收率：40％)。The title compound (30.0 mg, yield: 40%) was obtained by the titled compound (yield: 40%) of 3-dimethylpyr.
MS m/z(ESI):438.2[M+H] + MS m/z (ESI): 438.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.36(s,1H),8.40(s,1H),7.79(d,J＝2.4Hz,1H),7.31(dd,J＝9.2,2.4Hz,1H),6.65(d,J＝3.2Hz,1H),6.43(d,J＝9.2Hz,1H),6.25(dd,J＝3.6,0.8Hz,1H),5.17-4.99(m,1H),3.97(s,1H),3.51(s,4H),3.25(s,3H),2.24(s,3H),2.03-1.83(m,2H),1.30(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.36 (s, 1H), 8.40 (s, 1H), 7.79 (d, J = 2.4Hz, 1H), 7.31 (dd, J = 9.2,2.4Hz, 1H), 6.65 (d, J = 3.2 Hz, 1H), 6.43 (d, J = 9.2 Hz, 1H), 6.25 (dd, J = 3.6, 0.8 Hz, 1H), 5.17 - 4.99 (m, 1H), 3.97 (s, 1H), 3.51 (s, 4H), 3.25 (s, 3H), 2.24 (s, 3H), 2.03-1.83 (m, 2H), 1.30 (d, J = 6.8 Hz, 6H).
实施例21：3,3-二氟-N-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)吡咯-1-甲酰胺的制备(化合物21)Example 21: 3,3-Difluoro-N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran- Preparation of 2-yl)pyrimidin-2-yl)pyrrole-1-carboxamide (Compound 21)
Figure PCTCN2019070390-appb-000049
Figure PCTCN2019070390-appb-000049
用3,3-二氟吡咯盐酸盐代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(10.0mg，收率：9％)。The title compound (10.0 mg, yield: 9%) was obtained by the procedure of the procedure of Example 8 by using 3,3-difluoropyrrole hydrochloride.
MS m/z(ESI):444.2[M+H] + MS m/z (ESI): 444.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.60(s,1H),8.42(s,1H),7.80(s,1H),7.32-7.30(m,1H),6.64(s,1H),6.43(d,J＝9.6Hz,1H),6.26(s,1H),5.12-5.08(m,1H),3.89-3.83(m,2H),3.69-3.67(m,2H),3.34-3.35(m,2H),2.24(s,3H),1.29(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.60 (s, 1H), 8.42 (s, 1H), 7.80 (s, 1H), 7.32-7.30 (m, 1H), 6.64 (s, 1H), 6.43 (d, J = 9.6 Hz, 1H), 6.26 (s, 1H), 5.12 - 5.08 (m, 1H), 3.89 - 3.83 (m, 2H), 3.69 - 3.67 (m, 2H), 3.34 - 3.35 ( m, 2H), 2.24 (s, 3H), 1.29 (d, J = 6.8 Hz, 6H).
实施例22：N-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)哌啶-1-甲酰胺的制备(化合物22)Example 22: N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl)pyrimidine-2 Preparation of -yl)piperidine-1-carboxamide (Compound 22)
Figure PCTCN2019070390-appb-000050
Figure PCTCN2019070390-appb-000050
用哌啶代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(15.0mg，收率：11％)。The title compound (15.0 mg, yield: 11%) was obtained.
MS m/z(ESI):422.2[M+H] + MS m/z (ESI): 422.2 [M+H] +
1H NMR(400MHz,CD 3OD)δ:8.34(s,1H),7.76(d,J＝2.4Hz,1H),7.43(dd,J＝9.2,2.4Hz,1H),6.91(d,J＝3.2Hz,1H),6.61(d,J＝9.2Hz,1H),6.19-6.17(m,1H),5.27-5.23(m,1H),3.55-3.58(m,4H),2.22(s,3H),1.70-1.64(m,6H),1.40(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, CD 3 OD) δ: 8.34 (s, 1H), 7.76 (d, J = 2.4Hz, 1H), 7.43 (dd, J = 9.2,2.4Hz, 1H), 6.91 (d, J =3.2 Hz, 1H), 6.61 (d, J = 9.2 Hz, 1H), 6.19-6.17 (m, 1H), 5.27-5.23 (m, 1H), 3.55-3.58 (m, 4H), 2.22 (s, 3H), 1.70-1.64 (m, 6H), 1.40 (d, J = 6.8 Hz, 6H).
实施例23：3-羟基-N-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)哌啶-1-甲酰胺的制备(化合物23)Example 23: 3-Hydroxy-N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl) Preparation of pyrimidine-2-yl)piperidine-1-carboxamide (Compound 23)
Figure PCTCN2019070390-appb-000051
Figure PCTCN2019070390-appb-000051
用3-羟基哌啶代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(5.0mg，收率：4％)。The title compound (5.0 mg, yield: 4%) was obtained.
MS m/z(ESI):438.1[M+H] + MS m/z (ESI): 438.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.47(brs,1H),8.37(s,1H),7.78(s,1H),7.30(dd,J＝9.6,1.6Hz,1H),6.63-6.62(m,1H),6.44-6.42(m,1H),6.24(d,J＝2.0Hz,1H),5.13-5.07(m,1H),4.89-4.87(m,1H),3.88-3.85(m,1H),3.72-3.69(m,1H),3.35-3.31(m,1H),3.01-2.96(m,1H),2.82-2.77(m,1H),2.23(s,3H),1.86-1.83(m,1H),1.75-1.67(m,1H),1.46-1.38(m,1H),1.29(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.47 (brs, 1H), 8.37 (s, 1H), 7.78 (s, 1H), 7.30 (dd, J = 9.6,1.6Hz, 1H), 6.63- 6.62 (m, 1H), 6.44-6.42 (m, 1H), 6.24 (d, J = 2.0 Hz, 1H), 5.13-5.07 (m, 1H), 4.89-4.87 (m, 1H), 3.88-3.85 ( m, 1H), 3.72-3.69 (m, 1H), 3.35-3.31 (m, 1H), 3.01-2.96 (m, 1H), 2.82-2.77 (m, 1H), 2.23 (s, 3H), 1.86- 1.83 (m, 1H), 1.75-1.67 (m, 1H), 1.46-1.38 (m, 1H), 1.29 (d, J = 6.8 Hz, 6H).
实施例24：4-羟基-N-[5-(1-异丙基-6-氧代-3-吡啶基)-4-(5-甲基-2-呋喃基)嘧啶-2-基]哌啶-1-甲酰胺的制备(化合物24)Example 24: 4-Hydroxy-N-[5-(1-isopropyl-6-oxo-3-pyridyl)-4-(5-methyl-2-furyl)pyrimidin-2-yl] Preparation of piperidine-1-carboxamide (Compound 24)
Figure PCTCN2019070390-appb-000052
Figure PCTCN2019070390-appb-000052
用4-羟基哌啶代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(31.0mg，收率：22％)。The title compound (31.0 mg, yield: 22%) was obtained.
MS m/z(ESI):438.1[M+H] + MS m/z (ESI): 438.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.53(brs,1H),8.37(s,1H),7.78(d,J＝2.0Hz,1H),7.30(dd,J＝9.2,2.4Hz,1H),6.61-6.60(m,1H),6.44-6.42(m,1H),6.24(d,J＝2.4Hz,1H),5.12-5.07(m,1H),4.75-4.74(m,1H),3.81-3.78(m,2H),3.68-3.67(m,1H),3.12-3.07(m,2H),2.24(s,3H),1.75-1.73(m,1H),1.40-1.38(m,2H),1.29(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.53 (brs, 1H), 8.37 (s, 1H), 7.78 (d, J = 2.0Hz, 1H), 7.30 (dd, J = 9.2,2.4Hz, 1H), 6.61-6.60 (m, 1H), 6.44-6.42 (m, 1H), 6.24 (d, J = 2.4 Hz, 1H), 5.12-5.07 (m, 1H), 4.75-4.74 (m, 1H) , 3.81-3.78 (m, 2H), 3.68-3.67 (m, 1H), 3.12-3.07 (m, 2H), 2.24 (s, 3H), 1.75-1.73 (m, 1H), 1.40-1.38 (m, 2H), 1.29 (d, J = 6.8 Hz, 6H).
实施例25：N-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)-4-甲氧基哌啶-1-甲酰胺的制备(化合物25)Example 25: N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl)pyrimidine-2 Preparation of -yl)-4-methoxypiperidine-1-carboxamide (Compound 25)
Figure PCTCN2019070390-appb-000053
Figure PCTCN2019070390-appb-000053
用4-甲氧基哌啶代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(48.0mg，收率：33％)。The title compound (48.0 mg, yield: 33%) was obtained.
MS m/z(ESI):452.2[M+H] + MS m/z (ESI): 452.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.55(s,1H),8.37(s,1H),7.78(d,J＝2.4Hz,1H),7.31-7.28(m,1H),6.59(d,J＝3.2Hz,1H),6.43(d,J＝9.2Hz,1H),6.25-6.24(m,1H),5.12-5.08(m,1H),3.76-3.71(m,2H),3.40-3.36(m,1H),3.26(s,3H),3.19-3.13(m,2H),2.24(s,3H),1.86-1.82(m,2H),1.45-1.30(m,2H),1.28(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.55 (s, 1H), 8.37 (s, 1H), 7.78 (d, J = 2.4Hz, 1H), 7.31-7.28 (m, 1H), 6.59 ( d, J = 3.2 Hz, 1H), 6.43 (d, J = 9.2 Hz, 1H), 6.25-6.24 (m, 1H), 5.12 - 5.08 (m, 1H), 3.76 - 3.71 (m, 2H), 3.40 -3.36(m,1H), 3.26(s,3H), 3.19-3.13(m,2H), 2.24(s,3H),1.86-1.82(m,2H),1.45-1.30(m,2H),1.28 (d, J = 6.8 Hz, 6H).
实施例26：4,4-二氟-N-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)哌啶-1-甲酰胺的制备(化合物26)Example 26: 4,4-Difluoro-N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran- Preparation of 2-yl)pyrimidin-2-yl)piperidine-1-carboxamide (Compound 26)
Figure PCTCN2019070390-appb-000054
Figure PCTCN2019070390-appb-000054
用4,4-二氟哌啶盐酸盐代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(17.0mg，收率：14％)。The title compound (17.0 mg, yield: 14%) was obtained.
MS m/z(ESI):458.1[M+H] + MS m/z (ESI): 458.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.76(s,1H),8.39(s,1H),7.79(s,1H),7.31-7.29(m,1H),6.59(d,J＝2.8Hz,1H),6.43(d,J＝9.6Hz,1H),6.25(s,1H),5.12-5.08(m,1H),3.57-3.56(m,4H),2.24(s,3H),2.04-2.02(m,4H),1.29(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.76 (s, 1H), 8.39 (s, 1H), 7.79 (s, 1H), 7.31-7.29 (m, 1H), 6.59 (d, J = 2.8 Hz, 1H), 6.43 (d, J = 9.6 Hz, 1H), 6.25 (s, 1H), 5.12-5.08 (m, 1H), 3.57-3.56 (m, 4H), 2.24 (s, 3H), 2.04 -2.02 (m, 4H), 1.29 (d, J = 6.8 Hz, 6H).
实施例27：N-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)吗啉-4-甲酰胺的制备(化合物27)Example 27: N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl)pyrimidine-2 -Base) Preparation of morpholine-4-carboxamide (Compound 27)
Figure PCTCN2019070390-appb-000055
Figure PCTCN2019070390-appb-000055
用吗啉代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(20.0mg，收率：15％)。The title compound (20.0 mg, yield: 15%) was obtained.
MS m/z(ESI):424.1[M+H] + MS m/z (ESI): 424.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.72(s,1H),8.39(s,1H),7.79(d,J＝2.4Hz,1H),7.30(dd,J＝9.2,2.0Hz,1H),6.64(d,J＝3.2Hz,1H),6.43(d,J＝9.2Hz,1H),6.26-6.25(m,1H),5.14-5.07(m,1H),3.62-3.60(m,4H),3.46-3.43(m,4H),2.25(s,3H),1.29(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.72 (s, 1H), 8.39 (s, 1H), 7.79 (d, J = 2.4Hz, 1H), 7.30 (dd, J = 9.2,2.0Hz, 1H), 6.64 (d, J = 3.2 Hz, 1H), 6.43 (d, J = 9.2 Hz, 1H), 6.26-6.25 (m, 1H), 5.14 - 5.07 (m, 1H), 3.62-3.60 (m) , 4H), 3.46-3.43 (m, 4H), 2.25 (s, 3H), 1.29 (d, J = 6.8 Hz, 6H).
实施例28：N-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)-4-甲基哌嗪-1-甲酰胺的制备(化合物28)Example 28: N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl)pyrimidine-2 -Based 4-methylpiperazine-1-carboxamide (Compound 28)
Figure PCTCN2019070390-appb-000056
Figure PCTCN2019070390-appb-000056
用N-甲基哌嗪代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(15.0mg，收率：11％)。The title compound (15.0 mg, yield: 11%) was obtained.
MS m/z(ESI):437.2[M+H] + MS m/z (ESI): 437.2 [M+H] +
1H NMR(400MHz,CD 3OD)δ:8.36(s,1H),7.76(d,J＝2.4Hz,1H),7.43(dd,J＝9.2,2.4Hz,1H),6.92(d,J＝3.2Hz,1H),6.61(d,J＝9.2Hz,1H),6.18(dd,J＝3.2,0.8Hz,1H),5.33-5.13(m,1H),3.73-3.55(m,4H),2.58-2.45(m,4H),2.34(s,3H),2.22(s,3H),1.40(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, CD 3 OD) δ: 8.36 (s, 1H), 7.76 (d, J = 2.4Hz, 1H), 7.43 (dd, J = 9.2,2.4Hz, 1H), 6.92 (d, J =3.2 Hz, 1H), 6.61 (d, J = 9.2 Hz, 1H), 6.18 (dd, J = 3.2, 0.8 Hz, 1H), 5.33-5.13 (m, 1H), 3.73 - 3.55 (m, 4H) , 2.58-2.45 (m, 4H), 2.34 (s, 3H), 2.22 (s, 3H), 1.40 (d, J = 6.8 Hz, 6H).
实施例29：N-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)-2-氮杂螺[3.3]庚烷-2-甲酰胺的制备(化合物29)Example 29: N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl)pyrimidine-2 Preparation of 2-yl)-2-azaspiro[3.3]heptane-2-carboxamide (Compound 29)
Figure PCTCN2019070390-appb-000057
Figure PCTCN2019070390-appb-000057
用2-氮杂螺[3.3]庚烷草酸盐代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(38.0mg，收率：34％)。The title compound (38.0 mg, yield: 34%) was obtained by the procedure of the procedure of the the the ).
MS m/z(ESI):434.2[M+H] + MS m/z (ESI): 434.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.47(s,1H),8.39(s,1H),7.78-7.71(m,1H),7.31-7.28(m,1H),6.64-6.62(m,1H),6.44-6.41(m,1H),6.26-6.25(m,1H),5.13-5.06(m,1H),3.96(s,4H),2.23(s,3H),2.15-2.09(m,4H),1.80-1.73(m,2H),1.29(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.47 (s, 1H), 8.39 (s, 1H), 7.78-7.71 (m, 1H), 7.31-7.28 (m, 1H), 6.64-6.62 (m , 1H), 6.44-6.41 (m, 1H), 6.26-6.25 (m, 1H), 5.13-5.06 (m, 1H), 3.96 (s, 4H), 2.23 (s, 3H), 2.15-2.09 (m , 4H), 1.80 - 1.73 (m, 2H), 1.29 (d, J = 6.8 Hz, 6H).
实施例30：(S)-N-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)六氢吡嗪并[2,1-c][1,4]噁嗪-8(1H)-甲酰胺的制备(化合物30)Example 30: (S)-N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl) Preparation of pyrimidin-2-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxamide (Compound 30)
Figure PCTCN2019070390-appb-000058
Figure PCTCN2019070390-appb-000058
用(S)-八氢吡嗪并[2,1-c][1,4]噁嗪代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(16.0mg，收率：10％)。The title was synthesized by the method described in Example 8 using (S)-octahydropyrazino[2,1-c][1,4]oxazine instead of the dimethylamine hydrochloride of Example 8. Compound (16.0 mg, yield: 10%).
MS m/z(ESI):479.2[M+H] + MS m/z (ESI): 479.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.61(s,1H),8.38(s,1H),7.78(m,J＝2.4Hz,1H),7.31-7.20(m,1H),6.62(d,J＝3.2Hz,1H),6.43(d,J＝9.2Hz,1H),6.25-6.24(m,1H),5.12-5.08(m,1H),4.03-4.00(m,1H),3.91-3.88(m,1H),3.76-3.67(m,2H),3.54-3.51(m,1H),3.12-3.07(m,1H),3.01-2.96(m,1H),2.73-2.63(m,2H),2.24(s,3H),2.21-2.09(m,4H),1.29(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.61 (s, 1H), 8.38 (s, 1H), 7.78 (m, J = 2.4Hz, 1H), 7.31-7.20 (m, 1H), 6.62 ( d, J = 3.2 Hz, 1H), 6.43 (d, J = 9.2 Hz, 1H), 6.25-6.24 (m, 1H), 5.12 - 5.08 (m, 1H), 4.03-4.00 (m, 1H), 3.91 -3.88 (m, 1H), 3.76-3.67 (m, 2H), 3.54-3.51 (m, 1H), 3.12-3.07 (m, 1H), 3.01-2.96 (m, 1H), 2.73-2.63 (m, 2H), 2.24 (s, 3H), 2.21-2.09 (m, 4H), 1.29 (d, J = 6.8 Hz, 6H).
实施例31：1-(4-(呋喃-2-基)-5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)嘧啶-2-基)脲的制备(化合物31)Example 31:1-(4-(furan-2-yl)-5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-2-yl)urea Preparation (Compound 31)
Figure PCTCN2019070390-appb-000059
Figure PCTCN2019070390-appb-000059
将5-(2-氨基-4-(呋喃-2-基)嘧啶-5-基)-1-异丙基吡啶-2(1H)-酮(100.0mg,0.3mmol)溶于四氢呋喃(2mL)，0℃下加入DIPEA(0.6mL,3.4mmol)和三光气(89.0mg,0.3mmol)。混合物维持0℃搅拌0.5小时，加入氨的1,4-二氧六环溶液(0.4mol/L,1.5mL,0.6mmol)并在0℃下反应1小时。反应完毕后，向反应液中加水，乙酸乙酯萃取，合并有机相，干燥，过滤，浓缩滤液，剩余物经制备型高效液相色谱分离(纯化方法B)，得到标题化合物(20.0mg，收率：20％)。5-(2-Amino-4-(furan-2-yl)pyrimidin-5-yl)-1-isopropylpyridine-2(1H)-one (100.0 mg, 0.3 mmol) was dissolved in tetrahydrofuran (2 mL) DIPEA (0.6 mL, 3.4 mmol) and triphosgene (89.0 mg, 0.3 mmol) were added at 0 °C. The mixture was kept at 0 ° C for 0.5 hour, and a solution of ammonia in 1,4-dioxane (0.4 mol/L, 1.5 mL, 0.6 mmol) was added and reacted at 0 ° C for 1 hour. After the completion of the reaction, water was added to the reaction mixture, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjj Rate: 20%).
MS m/z(ESI):340.1[M+H] + MS m/z (ESI): 340.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.74(s,1H),8.62(s,1H),8.48(s,1H),7.90(d,J＝0.8Hz,1H),7.84(d,J＝2.4Hz,1H),7.36-7.33(m,1H),7.17(s,1H),6.73-6.72(m,1H),6.65-6.64(m,1H),6.46-6.44(m,1H),5.11-5.08(m,1H),1.29(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.74 (s, 1H), 8.62 (s, 1H), 8.48 (s, 1H), 7.90 (d, J = 0.8Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.36-7.33 (m, 1H), 7.17 (s, 1H), 6.73-6.72 (m, 1H), 6.65-6.64 (m, 1H), 6.46-6.44 (m, 1H) , 5.11-5.08 (m, 1H), 1.29 (d, J = 6.8 Hz, 6H).
实施例32：1-(4-(呋喃-2-基)-5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)嘧啶-2-基)-3-甲基脲的制备(化合物32)Example 32: 1-(4-(furan-2-yl)-5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-2-yl)- Preparation of 3-methylurea (Compound 32)
Figure PCTCN2019070390-appb-000060
Figure PCTCN2019070390-appb-000060
用甲氨的四氢呋喃溶液代替实施例31中的氨的1,4-二氧六环溶液，以类似实施例31所述的方法，合成得到标题化合物(30.0mg，收率：25％)。The 1,4-dioxane solution of the ammonia in Example 31 was replaced with a solution of the ammonia in tetrahydrofuran to give the title compound (30.0 mg, yield: 25%).
MS m/z(ESI):354.2[M+H] + MS m/z (ESI): 354.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.88(s,1H),9.05(d,J＝4.8Hz,1H),8.47(s,1H),7.90-7.83(m,2H),7.35-7.32(m,1H),6.82(d,J＝3.2Hz,1H),6.66-6.64(m,1H),6.44(d,J＝9.2Hz,1H),5.11-5.08(m,1H),2.83(s,3H),1.29(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.88 (s, 1H), 9.05 (d, J = 4.8Hz, 1H), 8.47 (s, 1H), 7.90-7.83 (m, 2H), 7.35- 7.32 (m, 1H), 6.82 (d, J = 3.2 Hz, 1H), 6.66-6.64 (m, 1H), 6.44 (d, J = 9.2 Hz, 1H), 5.11-5.08 (m, 1H), 2.83 (s, 3H), 1.29 (d, J = 6.8 Hz, 6H).
实施例33：3-(4-(呋喃-2-基)-5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)嘧啶-2-基)-1,1-二甲基脲的制备(化合物33)Example 33: 3-(4-(furan-2-yl)-5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-2-yl)- Preparation of 1,1-dimethylurea (Compound 33)
Figure PCTCN2019070390-appb-000061
Figure PCTCN2019070390-appb-000061
用二甲胺的四氢呋喃溶液代替实施例31中的氨的1,4-二氧六环溶液，以类似实施例31所述的方法，合成得到标题化合物(10.0mg，收率：8％)。The title compound (10.0 mg, yield: 8%) was obtained by the procedure of the procedure of Example 31, using the THF of dimethylamine in THF.
MS m/z(ESI):368.1[M+H] + MS m/z (ESI): 368.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.43(s,1H),8.44(s,1H),7.82-7.79(m,2H),7.33-7.30(m,1H),6.80(d,J＝3.6Hz,1H),6.62-6.61(m,1H),6.42(d,J＝9.6Hz,1H),5.11-5.08(m,1H),2.94(s,6H),1.29(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.43 (s, 1H), 8.44 (s, 1H), 7.82-7.79 (m, 2H), 7.33-7.30 (m, 1H), 6.80 (d, J = 3.6 Hz, 1H), 6.62-6.61 (m, 1H), 6.42 (d, J = 9.6 Hz, 1H), 5.11-5.08 (m, 1H), 2.94 (s, 6H), 1.29 (d, J = 6.8 Hz, 6H).
实施例34：3-(6-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-基)-1,1-二甲基脲的制备(化合物34)Example 34: 3-(6-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(5-methylfuran-2-yl)-1, Preparation of 2,4-triazin-3-yl)-1,1-dimethylurea (Compound 34)
Figure PCTCN2019070390-appb-000062
Figure PCTCN2019070390-appb-000062
向(6-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-基)氨基甲酸苯酯(50.0mg,0.1mmol)的四氢呋喃(2mL)溶液中，加入二甲胺的四氢呋喃(2mol/L,0.5mL)溶液，反应混合物室温搅拌4小时，浓缩，所得剩余物经制备型高效液相色谱仪纯化(纯化方法A)，得到标题化合物(9.0mg，收率：24％)。To (6-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(5-methylfuran-2-yl)-1,2,4-tri A solution of phenylamine-3-yl)carbamate (50.0 mg, 0.1 mmol) in EtOAc (2 mL) The residue obtained was purified by preparative high-purity liquid chromatography (purification method A) to give the title compound (9.0 mg, yield: 24%).
MS m/z(ESI):383.2[M+H] + MS m/z (ESI): 383.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.92(s,1H),8.03(d,J＝2.4Hz,1H),7.56(dd,J＝9.2,2.4Hz,1H),6.84(d,J＝3.6Hz,1H),6.50(d,J＝9.2Hz,1H),6.35(d,J＝3.2Hz,1H),5.24-5.03(m,1H),2.98(s,6H),2.30(s,3H),1.29(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.92 (s, 1H), 8.03 (d, J = 2.4Hz, 1H), 7.56 (dd, J = 9.2,2.4Hz, 1H), 6.84 (d, J = 3.6 Hz, 1H), 6.50 (d, J = 9.2 Hz, 1H), 6.35 (d, J = 3.2 Hz, 1H), 5.24 - 5.03 (m, 1H), 2.98 (s, 6H), 2.30 ( s, 3H), 1.29 (d, J = 6.8 Hz, 6H).
实施例35：1-(6-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-基)脲的制备(化合物35)Example 35: 1-(6-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(5-methylfuran-2-yl)-1, Preparation of 2,4-triazin-3-yl)urea (Compound 35)
Figure PCTCN2019070390-appb-000063
Figure PCTCN2019070390-appb-000063
用氨的四氢呋喃溶液代替实施例34中的二甲胺的四氢呋喃溶液，以类似实施例34所述的方法，合成得到标题化合物(10.0mg，收率：24％)。The title compound (10.0 mg, yield: 24%) was obtained from the titled compound (yield: 24%).
MS m/z(ESI):355.2[M+H] + MS m/z (ESI): 355.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:10.14(brs,1H),8.22(brs,1H),8.04(d,J＝2.4Hz,1H),7.55(dd,J＝9.2,2.4Hz,1H),7.26(brs,1H),6.88(d,J＝3.6Hz,1H),6.51(d,J＝9.2Hz,1H),6.39(d,J＝3.2Hz,1H),5.13(dt,J＝13.6,6.8Hz,1H),2.32(s,3H),1.28(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 10.14 (brs, 1H), 8.22 (brs, 1H), 8.04 (d, J = 2.4Hz, 1H), 7.55 (dd, J = 9.2,2.4Hz, 1H), 7.26 (brs, 1H), 6.88 (d, J = 3.6 Hz, 1H), 6.51 (d, J = 9.2 Hz, 1H), 6.39 (d, J = 3.2 Hz, 1H), 5.13 (dt, J = 13.6, 6.8 Hz, 1H), 2.32 (s, 3H), 1.28 (d, J = 6.8 Hz, 6H).
实施例36：1-(6-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-基)-3-甲基脲的制备(化合物36)Example 36: 1-(6-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(5-methylfuran-2-yl)-1, Preparation of 2,4-triazin-3-yl)-3-methylurea (Compound 36)
Figure PCTCN2019070390-appb-000064
Figure PCTCN2019070390-appb-000064
用甲胺的四氢呋喃溶液代替实施例34中的二甲胺的四氢呋喃溶液，以类似实施例34所述的方法，合成得到标题化合物(20.0mg，收率：45％)。The title compound (20.0 mg, yield: 45%) was obtained from the titled compound (yield: 45%).
MS m/z(ESI):369.2[M+H] + MS m/z (ESI): 369.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:10.26(s,1H),8.71(d,J＝4.8Hz,1H),8.04(d,J＝2.4Hz,1H),7.55(dd,J＝9.2,2.4Hz,1H),6.92(d,J＝3.6Hz,1H),6.50(d,J＝9.2Hz,1H),6.39(dd,J＝3.6,0.8Hz,1H),5.13(dt,J＝13.6,6.8Hz,1H),2.83(d,J＝4.8Hz,3H),2.33(s,3H),1.28(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 10.26 (s, 1H), 8.71 (d, J = 4.8Hz, 1H), 8.04 (d, J = 2.4Hz, 1H), 7.55 (dd, J = 9.2, 2.4 Hz, 1H), 6.92 (d, J = 3.6 Hz, 1H), 6.50 (d, J = 9.2 Hz, 1H), 6.39 (dd, J = 3.6, 0.8 Hz, 1H), 5.13 (dt, J = 13.6, 6.8 Hz, 1H), 2.83 (d, J = 4.8 Hz, 3H), 2.33 (s, 3H), 1.28 (d, J = 6.8 Hz, 6H).
实施例37：N-(6-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-基)吡咯烷-1-甲酰胺的制备(化合物37)Example 37: N-(6-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(5-methylfuran-2-yl)-1, Preparation of 2,4-triazin-3-yl)pyrrolidine-1-carboxamide (Compound 37)
Figure PCTCN2019070390-appb-000065
Figure PCTCN2019070390-appb-000065
用吡咯烷代替实施例34中的二甲胺的四氢呋喃溶液，以类似实施例34所述的方法，合成得到标题化合物(8.0mg，收率：17％)。The title compound (8.0 mg, yield: 17%) was obtained from the title compound (yield: 17%).
MS m/z(ESI):409.2[M+H] + MS m/z (ESI): 409.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.82(s,1H),8.03(d,J＝2.4Hz,1H),7.56(dd,J＝9.2,2.8Hz,1H),6.84(d,J＝3.6Hz,1H),6.50(d,J＝9.2Hz,1H),6.35(dd,J＝3.6,0.8Hz,1H),5.13(dt,J＝13.6,6.8Hz,1H),3.57-3.33(m,4H),2.30(s,3H),1.92-1.78(m,4H),1.29(d,J＝6.8Hz,6H) 1 H NMR (400MHz, DMSO- d 6) δ: 9.82 (s, 1H), 8.03 (d, J = 2.4Hz, 1H), 7.56 (dd, J = 9.2,2.8Hz, 1H), 6.84 (d, J=3.6 Hz, 1H), 6.50 (d, J=9.2 Hz, 1H), 6.35 (dd, J=3.6, 0.8 Hz, 1H), 5.13 (dt, J=13.6, 6.8 Hz, 1H), 3.57- 3.33 (m, 4H), 2.30 (s, 3H), 1.92-1.78 (m, 4H), 1.29 (d, J = 6.8 Hz, 6H)
实施例38：N-(6-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-基)吗啉-4-甲酰胺的制备(化合物38)Example 38: N-(6-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(5-methylfuran-2-yl)-1, Preparation of 2,4-triazin-3-yl)morpholine-4-carboxamide (Compound 38)
Figure PCTCN2019070390-appb-000066
Figure PCTCN2019070390-appb-000066
用吗啉代替实施例34中的二甲胺的四氢呋喃溶液，以类似实施例34所述的方法，合成得到标题化合物(10.0mg，收率：20％)。The title compound (10.0 mg, yield: 20%) was obtained.
MS m/z(ESI):425.2[M+H] + MS m/z (ESI): 425.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:10.14(s,1H),8.03(d,J＝2.4Hz,1H),7.56(dd,J＝9.2,2.8Hz,1H),6.83(d,J＝3.6Hz,1H),6.50(d,J＝9.2Hz,1H),6.41-6.29(m,1H),5.13(dt,J＝13.6,6.8Hz,1H),3.74-3.58(m,4H),3.58-3.43(m,4H),2.31(s,3H),1.27(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 10.14 (s, 1H), 8.03 (d, J = 2.4Hz, 1H), 7.56 (dd, J = 9.2,2.8Hz, 1H), 6.83 (d, J=3.6 Hz, 1H), 6.50 (d, J=9.2 Hz, 1H), 6.41-6.29 (m, 1H), 5.13 (dt, J=13.6, 6.8 Hz, 1H), 3.74-3.58 (m, 4H) ), 3.58-3.43 (m, 4H), 2.31 (s, 3H), 1.27 (d, J = 6.8 Hz, 6H).
实施例39：3-(5-氟-1'-异丙基-4-(5-甲基呋喃-2-基)-6'-氧代-1',6'-二氢-[3,3'-联吡啶]-6-基)-1,1-二甲基脲的制备(化合物39)Example 39: 3-(5-Fluoro-1'-isopropyl-4-(5-methylfuran-2-yl)-6'-oxo-1',6'-dihydro-[3, Preparation of 3'-bipyridyl]-6-yl)-1,1-dimethylurea (Compound 39)
Figure PCTCN2019070390-appb-000067
Figure PCTCN2019070390-appb-000067
将6'-氨基-5'-氟-1-异丙基-4'-(5-甲基呋喃-2-基)-[3,3'-联吡啶]-6(1H)-酮(200.0mg,0.6mmol)溶于四氢呋喃(6mL)，0℃下加入DIPEA(0.4g,3.1mmol)和三光气(178.1mg,0.6mmol)。混合物维持0℃搅拌0.5小时，然后加入二甲胺的四氢呋喃溶液(0.6mL,1.2mmol,2M)并在0℃下反应1小时。反应完毕后，向反应液中加水，乙酸乙酯萃取，合并有机相，干燥，过滤，浓缩滤液，剩余物用制备型高效液相色谱仪纯化(纯化方法A)，得到标题化合物(10.0mg，收率：4％)。6'-Amino-5'-fluoro-1-isopropyl-4'-(5-methylfuran-2-yl)-[3,3'-bipyridyl]-6(1H)-one (200.0 M, 0.6 mmol) was dissolved in tetrahydrofuran (6 mL). DIPEA (0.4 g, &lt;RTI ID=0.0&gt; The mixture was stirred at 0 ° C for 0.5 hours, then a solution of dimethylamine in tetrahydrofuran (0.6 mL, 1.2 mmol, 2M) was obtained and reacted at 0 ° C for 1 hour. After the completion of the reaction, water was added to the reaction mixture, and ethyl acetate was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Yield: 4%).
MS m/z(ESI):399.1[M+H] + MS m/z (ESI): 399.1 [M+H] +
1H NMR(400MHz,CD 3OD)δ:8.10(s,1H),7.65(d,J＝2.4Hz,1H),7.35-7.32(m,1H),6.77-6.75(m,1H),6.55(d,J＝9.2Hz,1H),6.19-6.18(m,1H),5.23-5.20(m,1H),3.07(s,6H),2.14(s,3H),1.36(d,J＝6.8Hz,6H)。 1 H NMR (400 MHz, CD 3 OD) δ: 8.10 (s, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.35-7.32 (m, 1H), 6.77-6.75 (m, 1H), 6.55 (d, J = 9.2 Hz, 1H), 6.19-6.18 (m, 1H), 5.23-5.20 (m, 1H), 3.07 (s, 6H), 2.14 (s, 3H), 1.36 (d, J = 6.8) Hz, 6H).
实施例40：1-(5-氟-1'-异丙基-4-(5-甲基呋喃-2-基)-6'-氧代-1',6'-二氢-[3,3'-联吡啶]-6-基)-3-甲基脲的制备(化合物40)Example 40: 1-(5-Fluoro-1'-isopropyl-4-(5-methylfuran-2-yl)-6'-oxo-1',6'-dihydro-[3, Preparation of 3'-bipyridyl]-6-yl)-3-methylurea (Compound 40)
Figure PCTCN2019070390-appb-000068
Figure PCTCN2019070390-appb-000068
用甲胺的四氢呋喃溶液代替实施例39中的二甲胺的四氢呋喃溶液，以类似实施例39所述的方法，合成得到标题化合物(10.0mg，收率：4％)。The title compound (10.0 mg, yield: 4%) was obtained by the procedure of the procedure of Example 39.
MS m/z(ESI):385.1[M+H] + MS m/z (ESI): 385.1 [M+H] +
1H NMR(400MHz,CD 3OD)δ:8.00(s,1H),7.61(d,J＝2.4Hz,1H),7.33-7.30(m,1H),6.75-6.73(m,1H),6.54(d,J＝8.8Hz,1H),6.41(d,J＝9.6Hz,1H),6.19-6.18(m,1H),5.23-5.20(m,1H),2.91(s,3H),2.14(s,3H),1.35(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, CD 3 OD) δ: 8.00 (s, 1H), 7.61 (d, J = 2.4Hz, 1H), 7.33-7.30 (m, 1H), 6.75-6.73 (m, 1H), 6.54 (d, J = 8.8 Hz, 1H), 6.41 (d, J = 9.6 Hz, 1H), 6.19-6.18 (m, 1H), 5.23-5.20 (m, 1H), 2.91 (s, 3H), 2.14 ( s, 3H), 1.35 (d, J = 6.8 Hz, 6H).
实施例41：3-羟基-N-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)吡咯烷-1-甲酰胺的制备(化合物41)Example 41: 3-Hydroxy-N-(5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl) Preparation of pyrimidine-2-yl)pyrrolidine-1-carboxamide (Compound 41)
Figure PCTCN2019070390-appb-000069
Figure PCTCN2019070390-appb-000069
用3-羟基吡咯烷代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(25.0mg，收率：35％)。The title compound (25.0 mg, yield: 35%) was obtained by the procedure of the procedure of Example 8 by using 3-hydroxypyrrolidine.
MS m/z(ESI):424.2[M+H] + MS m/z (ESI): 424.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.31(s,1H),8.39(s,1H),7.79(d,J＝2.4Hz,1H),7.30(dd,J＝9.2,2.4Hz,1H),6.65(d,J＝3.2Hz,1H),6.43(d,J＝9.2Hz,1H),6.29-6.20(m,1H),5.18-5.07(m,1H),4.98(d,J＝2.8Hz,1H),4.29(s,1H),3.50(s,2H),3.31-3.29(m,2H),2.23(s,3H),1.90-1.81(m,2H),1.30(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.31 (s, 1H), 8.39 (s, 1H), 7.79 (d, J = 2.4Hz, 1H), 7.30 (dd, J = 9.2,2.4Hz, 1H), 6.65 (d, J = 3.2 Hz, 1H), 6.43 (d, J = 9.2 Hz, 1H), 6.29-6.20 (m, 1H), 5.18-5.07 (m, 1H), 4.98 (d, J) = 2.8 Hz, 1H), 4.29 (s, 1H), 3.50 (s, 2H), 3.31-3.29 (m, 2H), 2.23 (s, 3H), 1.90 - 1.81 (m, 2H), 1.30 (d, J = 6.8 Hz, 6H).
实施例42：3-(5-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)-1-甲基-1-(吡啶-4-基甲基)脲的制备(化合物42)Example 42: 3-(5-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(5-methylfuran-2-yl)pyrimidine-2 Preparation of -yl)-1-methyl-1-(pyridin-4-ylmethyl)urea (Compound 42)
Figure PCTCN2019070390-appb-000070
Figure PCTCN2019070390-appb-000070
用N-甲基-N-(4-吡啶甲基)胺代替实施例8中的二甲胺盐酸盐，以类似实施例8所述的方法，合成得到标题化合物(15.0mg，收率：20％)。Substituting N-methyl-N-(4-pyridylmethyl)amine for the dimethylamine hydrochloride of Example 8 to give the title compound (15.0 mg, yield: 20%).
MS m/z(ESI):459.3[M+H] + MS m/z (ESI): 459.3 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.64(s,1H),8.55(d,J＝5.2Hz,2H),8.42(s,1H),7.79(d,J＝2.4Hz,1H),7.39-7.24(m,3H),6.62(d,J＝3.2Hz,1H),6.44(d,J＝9.2Hz,1H),6.32-6.22(m,1H),5.20-5.05(m,1H),4.63(s,2H),2.99(s,3H),2.24(s,3H),1.30(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.64 (s, 1H), 8.55 (d, J = 5.2Hz, 2H), 8.42 (s, 1H), 7.79 (d, J = 2.4Hz, 1H) , 7.39-7.24(m,3H), 6.62(d,J=3.2Hz,1H),6.44(d,J=9.2Hz,1H),6.32-6.22(m,1H),5.20-5.05(m,1H ), 4.63 (s, 2H), 2.99 (s, 3H), 2.24 (s, 3H), 1.30 (d, J = 6.8 Hz, 6H).
实施例43：1-(1'-异丙基-2-(5-甲基呋喃-2-基)-6'-氧代-1',6'-二氢-[3,3'-联吡啶]-6-基)3-(吡啶-3-基甲基)脲的制备(化合物43)Example 43: 1-(1'-Isopropyl-2-(5-methylfuran-2-yl)-6'-oxo-1',6'-dihydro-[3,3'-linked Preparation of pyridine]-6-yl)3-(pyridin-3-ylmethyl)urea (Compound 43)
Figure PCTCN2019070390-appb-000071
Figure PCTCN2019070390-appb-000071
用3-氨甲基吡啶代替实施例1中的甲胺的四氢呋喃溶液，以类似实施例1所述的方法，合成得到标题化合物(40.0mg，收率：53％)。The title compound (40.0 mg, yield: 53%) was obtained.
MS m/z(ESI):444.1[M+H] + MS m/z (ESI): 444.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.64(s,1H),9.27(s,1H),8.59(s,1H),8.49-8.48(m,1H),7.77-7.60(m,3H),7.40-7.36(m,1H),7.26-7.16(m,2H),6.42-6.39(m,1H),6.09-6.08(m,2H),5.10-5.07(m,1H),4.51(d,J＝6.4Hz,2H),2.10(s,3H),1.28(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.64 (s, 1H), 9.27 (s, 1H), 8.59 (s, 1H), 8.49-8.48 (m, 1H), 7.77-7.60 (m, 3H ), 7.40-7.36 (m, 1H), 7.26-7.16 (m, 2H), 6.42-6.39 (m, 1H), 6.09-6.08 (m, 2H), 5.10-5.07 (m, 1H), 4.51 (d) , J = 6.4 Hz, 2H), 2.10 (s, 3H), 1.28 (d, J = 6.8 Hz, 6H).
实施例44：N-(1'-异丙基-2-(5-甲基呋喃-2-基)-6'-氧代-1',6'-二氢-[3,3'-联吡啶]-6-基)4-甲氧基哌啶-1-甲酰胺的制备(化合物44)Example 44: N-(1'-isopropyl-2-(5-methylfuran-2-yl)-6'-oxo-1',6'-dihydro-[3,3'-linked Preparation of pyridine]-6-yl) 4-methoxypiperidine-1-carboxamide (Compound 44)
Figure PCTCN2019070390-appb-000072
Figure PCTCN2019070390-appb-000072
用4-甲氧基哌啶代替实施例1中的甲胺的四氢呋喃溶液，以类似实施例1所述的方法，合成得到标题化合物(35.0mg，收率：45％)。The title compound (35.0 mg, yield: 45%) was obtained by the titled compound (yield: 45%).
MS m/z(ESI):451.1[M+H] + MS m/z (ESI): 451.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.24(s,1H),7.69-7.59(m,3H),7.22-7.19(m,1H),6.39-6.33(m,2H),6.14-6.13(m,1H),5.08-5.06(m,1H),3.82-3.78(m,2H),3.37-3.34(m,1H),3.31(s,3H),3.19-3.12(m,2H),2.10(s,3H),1.86-1.82(m,2H),1.42-1.38(m,2H),1.28(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.24 (s, 1H), 7.69-7.59 (m, 3H), 7.22-7.19 (m, 1H), 6.39-6.33 (m, 2H), 6.14-6.13 (m, 1H), 5.08-5.06 (m, 1H), 3.82-3.78 (m, 2H), 3.37-3.34 (m, 1H), 3.31 (s, 3H), 3.19-3.12 (m, 2H), 2.10 (s, 3H), 1.86-1.82 (m, 2H), 1.42-1.38 (m, 2H), 1.28 (d, J = 6.8 Hz, 6H).
实施例45：N-(1'-异丙基-2-(5-甲基呋喃-2-基)-6'-氧代-1',6'-二氢-[3,3'-联吡啶]-6-基)吗啉-4-甲酰胺的制备(化合物45)Example 45: N-(1'-isopropyl-2-(5-methylfuran-2-yl)-6'-oxo-1',6'-dihydro-[3,3'-linked Preparation of pyridine]-6-yl)morpholine-4-carboxamide (Compound 45)
Figure PCTCN2019070390-appb-000073
Figure PCTCN2019070390-appb-000073
用吗啉代替实施例1中的甲胺的四氢呋喃溶液，以类似实施例1所述的方法，合成得到标题化合物(46.0mg，收率：64％)。The title compound (46.0 mg, yield: 64%) was obtained from the title compound (yield: 64%).
MS m/z(ESI):423.1[M+H] + MS m/z (ESI): 423.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.28(s,1H),7.70-7.61(m,3H),7.23-7.20(m,1H),6.39-6.33(m,2H),6.14-6.13(m,1H),5.10-5.06(m,1H),3.61-3.59(m,4H),3.48-3.46(m,4H),2.20(s,3H),1.27(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.28 (s, 1H), 7.70-7.61 (m, 3H), 7.23-7.20 (m, 1H), 6.39-6.33 (m, 2H), 6.14-6.13 (m, 1H), 5.10-5.06 (m, 1H), 3.61-3.59 (m, 4H), 3.48-3.46 (m, 4H), 2.20 (s, 3H), 1.27 (d, J = 6.8 Hz, 6H) ).
实施例46：1-(2-(二甲基氨基)乙基)-3-(1'-异丙基-2-(5-甲基呋喃-2-基)-6'-氧代-1',6'-二氢-[3,3'-联吡啶]-6-基)脲的制备(化合物46)Example 46: 1-(2-(Dimethylamino)ethyl)-3-(1'-isopropyl-2-(5-methylfuran-2-yl)-6'-oxo-1 Preparation of ',6'-dihydro-[3,3'-bipyridyl]-6-yl)urea (Compound 46)
Figure PCTCN2019070390-appb-000074
Figure PCTCN2019070390-appb-000074
用N',N'-二甲基乙烷-1,2-二胺代替实施例1中的甲胺的四氢呋喃溶液，以类似实施例1所述的方法，合成得到标题化合物(23.0mg，收率：42％)。The title compound (23.0 mg, obtained by the method described in Example 1) was obtained by the procedure of the same procedure as in Example 1 by using N-, N'-dimethylethane-1,2-diamine. Rate: 42%).
MS m/z(ESI):424.1[M+H] + MS m/z (ESI): 424.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.51(s,1H),8.73(s,1H),8.18(s,1H),7.64-7.60(m,1H),7.26-7.23(m,1H),7.13-7.11(m,1H),6.58-6.57(m,1H),6.41-6.39(m,1H),6.19-6.18(m,1H),5.13-5.06(m,1H),3.89-3.77(m,2H),3.52-3.48(m,2H),2.20(s,3H),2.19(s,6H),1.27(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.51 (s, 1H), 8.73 (s, 1H), 8.18 (s, 1H), 7.64-7.60 (m, 1H), 7.26-7.23 (m, 1H ), 7.13 - 7.11 (m, 1H), 6.58-6.57 (m, 1H), 6.41-6.39 (m, 1H), 6.19-6.18 (m, 1H), 5.13-5.06 (m, 1H), 3.89-3.77 (m, 2H), 3.52-3.48 (m, 2H), 2.20 (s, 3H), 2.19 (s, 6H), 1.27 (d, J = 6.8 Hz, 6H).
实施例47：1-(1'-异丙基-2-(5-甲基呋喃-2-基)-6'-氧代-1',6'-二氢-[3,3'-联吡啶]-6-基)-3-(2-吗啉乙基)脲的制备(化合物47)Example 47: 1-(1'-isopropyl-2-(5-methylfuran-2-yl)-6'-oxo-1',6'-dihydro-[3,3'-linked Preparation of pyridine]-6-yl)-3-(2-morpholinoethyl)urea (Compound 47)
Figure PCTCN2019070390-appb-000075
Figure PCTCN2019070390-appb-000075
用2-吗啉乙胺代替实施例1中的甲胺的四氢呋喃溶液，以类似实施例1所述的方法，合成得到标题化合物(36.0mg，收率：60％)。The title compound (36.0 mg, yield: 60%) was obtained by the titled compound (yield: 60%).
MS m/z(ESI):466.1[M+H] + MS m/z (ESI): 466.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ:9.51(s,1H),8.53(s,1H),7.65-7.59(m,2H),7.25-7.20(m,2H),6.41-6.35(m,2H),6.16-6.15(m,1H),5.12-5.06(m,1H),3.37-3.32(m,4H),2.50-2.41(m,8H),2.20(s,3H),1.27(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, DMSO- d 6) δ: 9.51 (s, 1H), 8.53 (s, 1H), 7.65-7.59 (m, 2H), 7.25-7.20 (m, 2H), 6.41-6.35 (m , 2H), 6.16-6.15 (m, 1H), 5.12-5.06 (m, 1H), 3.37-3.32 (m, 4H), 2.50-2.41 (m, 8H), 2.20 (s, 3H), 1.27 (d , J = 6.8 Hz, 6H).
药效筛选方法及数据Drug screening methods and data
实验例1.对腺苷A2a受体抑制作用的细胞学研究实验Experimental Example 1. Cytological study on inhibition of adenosine A2a receptor
细胞株、试剂与耗材Cell lines, reagents and consumables
细胞株：ADORA2a/CHO-K1(GenScript M00246)Cell line: ADORA2a/CHO-K1 (GenScript M00246)
细胞培养基：Ham’s F12培养基(Gibco，11765054)，其中含10％胎牛血清、200μg/ml Zeocin和100μg/ml Hygromycin BCell culture medium: Ham's F12 medium (Gibco, 11765054) containing 10% fetal bovine serum, 200 μg/ml Zeocin and 100 μg/ml Hygromycin B
试剂盒：cAMP Assay Kit(CISBIO 62AM4PEC)Kit: cAMP Assay Kit (CISBIO 62AM4PEC)
阳性激动剂：NECA(Sigma，E2387)Positive agonist: NECA (Sigma, E2387)
阳性拮抗剂：ZM241385(Tocris，14A/199342)Positive antagonist: ZM241385 (Tocris, 14A/199342)
384孔板：GREINER BIO-ONE384-well plate: GREINER BIO-ONE
实验缓冲液：HBSS,含20mM HEPES，pH调节为7.4Experimental buffer: HBSS, containing 20 mM HEPES, pH adjusted to 7.4
仪器instrument
酶标仪：PheraStar，BMG LabtechMicroplate reader: PheraStar, BMG Labtech
实验方法experimental method
将稳定表达ADORA2a受体(即腺苷A2a受体)的CHO-K1细胞培养于含有Ham’s F12培养基的10cm培养皿中，在37℃，5％CO 2培养箱中培养。当细胞汇合度达到90％时，进行消化处理收集细胞。重悬细胞后，将细胞悬液接种于384孔板。 CHO-K1 cells stably expressing the ADORA2a receptor (i.e., adenosine A2a receptor) were cultured in a 10 cm culture dish containing Ham's F12 medium, and cultured at 37 ° C in a 5% CO 2 incubator. When the cell confluence reached 90%, the cells were collected by digestion. After resuspending the cells, the cell suspension was seeded in a 384-well plate.
用DMSO稀释待测化合物配制得到10mM的待测化合物储备液，用实验缓冲液稀释储备液，得到不同工作浓度的待测化合物溶液。阳性激动剂NECA最高工作浓度为10μM；阳性拮抗剂ZM241385最高工作浓度为1μM，并分别用实验缓冲液进一步稀释成不同浓度。The test compound was diluted with DMSO to prepare a 10 mM stock solution of the test compound, and the stock solution was diluted with the experimental buffer to obtain a test compound solution of different working concentrations. The positive working concentration of the positive agonist NECA was 10 μM; the positive antagonist ZM241385 was the highest working concentration of 1 μM, and was further diluted to different concentrations with the experimental buffer.
按照3000个细胞/5μl将细胞分别接种于用于检测阳性激动剂NECA的384孔板(板1)和用于检测阳性拮抗剂ZM241385和待测化合物的384孔板(板2)。板2放入细胞培养箱，于37℃，5％CO 2继续培养约2小时。 The cells were seeded separately in 384-well plates (plate 1) for detection of the positive agonist NECA and 384-well plates (plate 2) for detecting the positive antagonist ZM241385 and the test compound, according to 3000 cells/5 μl. Plate 2 was placed in a cell culture incubator and cultured at 37 ° C, 5% CO 2 for about 2 hours.
板1实验孔加入5μl稀释后的阳性激动剂NECA，空白孔加入5μl实验缓冲液，室温孵育0.5小时。按照CISBIO试剂盒说明书，加入试剂盒中的检测试剂后，继续孵育1小时，PheraStar酶标仪读取荧光信号，获得原始数据。Plate 1 was added to 5 μl of the diluted positive agonist NECA, and 5 μl of the assay buffer was added to the wells and incubated for 0.5 hours at room temperature. After the detection reagent in the kit was added according to the instructions of the CISBIO kit, the incubation was continued for 1 hour, and the fluorescent signal was read by the PheraStar microplate reader to obtain the original data.
根据各孔信号值计算相应的R值(R＝665nM波长信号/620nM波长信号×10000)，数据采集和分析使用Excel和GraphPad Prism 6软件程序，根据R值计算阳性激动剂NECA的激活率，激活率％＝(R 激 动剂-R 空白)/(R 激动剂100-R 空白)×100％，其中，R 激动剂是指实验孔R值、R 激动剂100是指加入最高工作浓度的阳性激动剂NECA的实验孔的R值、R 空白是指空白孔R值。进而根据阳性激动剂NECA的激活率得到其EC 80。 Calculate the corresponding R value according to the signal value of each well (R=665nM wavelength signal/620nM wavelength signal×10000), data acquisition and analysis using Excel and GraphPad Prism 6 software program, calculate the activation rate of positive agonist NECA according to R value, activate rate% = (R agonist -R blank) / (R 100 -R agonist blank) × 100%, wherein, R agonist refers to experimental wells R value, R agonist was added 100 refers to the highest working concentration of positive The R value and the R blank of the experimental well of the agonist NECA refer to the blank well R value. Furthermore, its EC 80 is obtained according to the activation rate of the positive agonist NECA.
取出板2，实验孔加入2.5μl的稀释后的阳性激动剂NECA(工作浓度为NECA的EC 80)与2.5μl的稀释后拮抗剂(即阳性拮抗剂ZM241385或待测化合物)的混合物，激动剂孔加入5μl稀释后的阳性激动剂NECA(工作浓度为NECA的EC 80)，空白孔加入5μl实验缓冲液，室温孵育0.5小时。按照CISBIO试剂盒说明书，加入CISBIO试剂盒中的检测试剂，继续孵育1小时，酶标仪读取荧光信号。 Plate 2 was removed and a mixture of 2.5 μl of the diluted positive agonist NECA (working concentration NECA EC 80 ) and 2.5 μl of the diluted antagonist (ie positive antagonist ZM241385 or test compound), agonist, was removed from the experimental wells. 5 μl of the diluted positive agonist NECA (EC 80 at a working concentration of NECA) was added to the wells, and 5 μl of the assay buffer was added to the wells and incubated for 0.5 hour at room temperature. According to the CISBIO kit instructions, add the detection reagent in the CISBIO kit and continue to incubate for 1 hour. The microplate reader reads the fluorescent signal.
根据各孔信号值计算相应的R值(R＝665nM波长信号/620nM波长信号×10000)，数据采集和分析使用Excel和GraphPad Prism 6软件程序，根据R值计算待测化合物的抑制率：抑制率％＝(R 化合物-R 激动剂80)/(R 空白-R 激动剂80)×100％，其中，R 化合物是指加入待测化合物的实验孔R值、R 激动剂80是指激动剂孔的R值、R 空白是指空白孔R值。IC 50范围由待测化合物抑制率(％)判断，结果详见表1。 Calculate the corresponding R value according to the signal value of each well (R=665nM wavelength signal/620nM wavelength signal×10000), data acquisition and analysis using Excel and GraphPad Prism 6 software program, calculate the inhibition rate of the test compound according to R value: inhibition rate %=(R compound- R agonist 80 )/(R blank- R agonist 80 )×100%, wherein the R compound refers to the experimental well R value of the test compound added, and the R agonist 80 refers to the agonist pore. The R value and R blank refer to the blank hole R value. The IC 50 range is judged by the inhibition rate (%) of the test compound, and the results are shown in Table 1.
表1 本申请化合物对腺苷A2a受体下游信号因子胞内cAMP的抑制作用Table 1 Inhibition of intracellular cAMP by a compound of the present application on adenosine A2a receptor downstream signaling factor
化合物编号Compound number IC 50(nM)范围 IC 50 (nM) range
11 10<IC 50<30 10<IC 50 <30
22 30<IC 50<100 30<IC 50 <100
33 IC 50<3 IC 50 <3
44 10<IC 50<30 10<IC 50 <30
55 30<IC 50<100 30<IC 50 <100
66 10<IC 50<30 10<IC 50 <30
77 30<IC 50<100 30<IC 50 <100
88 3<IC 50<10 3<IC 50 <10
99 30<IC 50<100 30<IC 50 <100
1010 10<IC 50<30 10<IC 50 <30
1111 30<IC 50<100 30<IC 50 <100
1212 10<IC 50<30 10<IC 50 <30
1313 30<IC 50<100 30<IC 50 <100
1414 30<IC 50<100 30<IC 50 <100
1515 IC 50<3 IC 50 <3
1616 3<IC 50<10 3<IC 50 <10
1717 10<IC 50<30 10<IC 50 <30
1818 30<IC 50<100 30<IC 50 <100
1919 30<IC 50<100 30<IC 50 <100
2020 30<IC 50<100 30<IC 50 <100
21twenty one 30<IC 50<100 30<IC 50 <100
22twenty two 10<IC 50<30 10<IC 50 <30
23twenty three 10<IC 50<30 10<IC 50 <30
24twenty four 10<IC 50<30 10<IC 50 <30
2525 3<IC 50<10 3<IC 50 <10
2626 10<IC 50<30 10<IC 50 <30
2727 3<IC 50<10 3<IC 50 <10
2828 10<IC 50<30 10<IC 50 <30
2929 30<IC 50<100 30<IC 50 <100
3030 10<IC 50<30 10<IC 50 <30
3131 30<IC 50<100 30<IC 50 <100
3232 30<IC 50<100 30<IC 50 <100
3333 10<IC 50<30 10<IC 50 <30
3434 30<IC 50<100 30<IC 50 <100
3535 30<IC 50<100 30<IC 50 <100
3636 30<IC 50<100 30<IC 50 <100
3737 30<IC 50<100 30<IC 50 <100
3838 10<IC 50<30 10<IC 50 <30
3939 30<IC 50<100 30<IC 50 <100
4040 30<IC 50<100 30<IC 50 <100
4141 30<IC 50<100 30<IC 50 <100
4242 3<IC 50<10 3<IC 50 <10
4343 IC 50<3 IC 50 <3
4444 10<IC 50<30 10<IC 50 <30
4545 10<IC 50<30 10<IC 50 <30
4646 3<IC 50<10 3<IC 50 <10
4747 10<IC 50<30 10<IC 50 <30
表1中的数据表明本申请化合物对细胞水平A2a受体下游信号因子胞内cAMP具有良好的抑制作用。The data in Table 1 indicates that the compounds of the present application have a good inhibitory effect on intracellular cAMP of the downstream signal factor of the A2a receptor at the cellular level.
实验例2：大鼠药代动力学(PK)和脑组织分布研究Experimental Example 2: Rat pharmacokinetics (PK) and brain tissue distribution
分别通过静脉(IV)和灌胃(PO)给予雄性SD大鼠本申请的化合物，考察药代动力学特点。IV和PO的给药剂量分别是1mg/kg和5mg/kg，IV的溶媒为5％DMSO、5％Solutol(聚乙二醇-15羟基硬脂酸酯)和90％生理盐水的混合物，PO的溶媒为0.5％MC(甲基纤维素钠)。为获得血浆样品，在IV给药组中，对3只大鼠平行IV给药，分别在给药前(0h)以及给药后0.083、0.25、0.5、1、2、4、6和8h等时间点平行收集血液，在PO给药组中，对3只大鼠平行PO给药，分别在给药前(0h)以及给药后0.25、0.5、1、2、4、6和8h等时间点平行收集血液，血液采用EDTA.K 2抗凝，离心后得到血浆样品，保存于-80℃。为获得脑组织匀浆液，分别在PO给药后0.25h、0.5h、1h、2h和8h，或0.5h、1h、2h和8h等时间点处死大鼠，每个时间点处死三只大鼠获得三个平行脑组织样品，并将每个脑组织样品匀浆，获得脑组织匀浆液，保存于-80℃。血浆样品和脑组织匀浆液经沉淀蛋白处理后进行LC-MS/MS分析。应用WinNonlin 6.3软件，采用非房室模型计算药代动力学参数，结果见表2和表3。 The compounds of the present application were administered to male SD rats by intravenous (IV) and gavage (PO), respectively, to examine the pharmacokinetic characteristics. IV and PO were administered at a dose of 1 mg/kg and 5 mg/kg, respectively, and the vehicle of IV was a mixture of 5% DMSO, 5% Solutol (polyethylene glycol-15 hydroxystearate) and 90% physiological saline, PO The solvent was 0.5% MC (sodium methylcellulose). To obtain plasma samples, 3 rats were administered IV in parallel in the IV-administered group, before administration (0 h) and 0.083, 0.25, 0.5, 1, 2, 4, 6 and 8 h after administration, respectively. The blood was collected in parallel at the time point. In the PO administration group, 3 rats were administered with parallel PO, respectively, before administration (0 h) and at 0.25, 0.5, 1, 2, 4, 6 and 8 h after administration. Blood was collected in parallel, blood was anticoagulated with EDTA.K 2 , and plasma samples were obtained after centrifugation and stored at -80 °C. In order to obtain brain tissue homogenate, the rats were sacrificed at 0.25h, 0.5h, 1h, 2h and 8h, or 0.5h, 1h, 2h and 8h after PO administration, and three rats were sacrificed at each time point. Three parallel brain tissue samples were obtained, and each brain tissue sample was homogenized to obtain a brain tissue homogenate, which was stored at -80 °C. Plasma samples and brain tissue homogenates were processed by precipitation protein and analyzed by LC-MS/MS. The pharmacokinetic parameters were calculated using WinNonlin 6.3 software using a non-compartmental model. The results are shown in Tables 2 and 3.
表2：通过IV给药的化合物在大鼠体内血液中的药代动力学参数Table 2: Pharmacokinetic parameters of compounds administered by IV in blood of rats
Figure PCTCN2019070390-appb-000076
Figure PCTCN2019070390-appb-000076
如表2所示，通过以1mg/kg的剂量IV给药的本申请的化合物8和化合物34在大鼠体内的暴露量(AUC last)分别为431h*ng/mL和490h*ng/mL，对应的最大血药浓度(C max)分别为665ng/mL和547ng/mL，表明本申请的化合物8和化合物34通过IV给药在大鼠体内具有优良的药物暴露量。 As shown in Table 2, the exposure amount (AUC last ) of the compound 8 and the compound 34 of the present application administered by IV at a dose of 1 mg/kg was 431 h*ng/mL and 490 h*ng/mL, respectively. The corresponding maximum plasma concentrations ( Cmax ) were 665 ng/mL and 547 ng/mL, respectively, indicating that Compound 8 and Compound 34 of the present application have excellent drug exposure in rats by IV administration.
表3：PO给药的化合物在大鼠体内的药代动力学参数Table 3: Pharmacokinetic parameters of compounds administered by PO in rats
Figure PCTCN2019070390-appb-000077
Figure PCTCN2019070390-appb-000077
如表3所示，通过以5mg/kg的剂量PO给药的本申请的化合物8和化合物34在大鼠血液的AUC last分别为871h*ng/mL和1911h*ng/mL，在大鼠脑组织的AUC last分别为35.9h*ng/g和37.6h*ng/g。由此可得，化合物8和化合物34在大鼠血液的AUC last和脑组织的AUC last的比值分别为24/1和51/1，表明本申请的化合物8和化合物34通过PO给药在大鼠血液***中具有优良的药物暴露量，并且二者透过血脑屏障的可能性很小。 As shown in Table 3, the AUC last of the compound 8 and the compound 34 of the present application administered by PO at a dose of 5 mg/kg in the rat blood were 871 h*ng/mL and 1911 h*ng/mL, respectively, in the rat brain. The AUC last of the tissues were 35.9 h*ng/g and 37.6 h*ng/g, respectively. Thus, the ratio of the AUC last of the compound 8 and the compound 34 in the blood of the rat to the AUC last of the brain tissue was 24/1 and 51/1, respectively, indicating that the compound 8 and the compound 34 of the present application were administered by PO in the large There is excellent drug exposure in the blood system of the mouse, and the possibility of both passing through the blood-brain barrier is small.
经计算，与静脉给药相比，大鼠口服化合物8的生物利用度为40.4％，大鼠口服化合物34的生物利用度为78.0％。表明本申请的化合物(例如化合物8和化合物34)在大鼠体内具有优良的口服吸收效果。It was calculated that the bioavailability of the oral compound 8 in rats was 40.4% compared with the intravenous administration, and the bioavailability of the oral compound 34 in rats was 78.0%. It is shown that the compounds of the present application (for example, Compound 8 and Compound 34) have an excellent oral absorption effect in rats.
尽管本申请的具体实施方式已经得到详细的描述，但本领域技术人员将理解：根据已经申请的所有教导，可以对细节进行各种修改和变动，并且这些改变均在本申请的保护范围之内。本申请的全部范围由所附权利要求及其任何等同物给出。While the embodiments of the present invention have been described in detail, it will be understood by those skilled in the art . The full scope of the application is given by the appended claims and any equivalents thereof.

Claims (18)

  1. 式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：A compound of formula I or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein:
    Figure PCTCN2019070390-appb-100001
    Figure PCTCN2019070390-appb-100001
    A 1为N或CR 5； A 1 is N or CR 5 ;
    A 2为N或CR 6； A 2 is N or CR 6 ;
    A 3为N或CR 7； A 3 is N or CR 7 ;
    且当A 1为CR 5时，A 2和A 3不同时为N； And when A 1 is CR 5 , A 2 and A 3 are not N at the same time;
    R 1和R 2各自独立地选自氢、C 1-6烷基、C 1-6烷氧基-C 1-6烷基-、R 8R 9N-C 1-6烷基-、5-6元杂环基-C 1-6烷基-、5-6元杂芳基-C 1-6烷基-和5-6元杂芳基，其中所述5-6元杂环基和5-6元杂芳基任选地被独立地选自下列的一个或多个取代基取代：羟基、卤素、氨基、C 1-6烷基和C 1-6烷氧基； R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl-, R 8 R 9 NC 1-6 alkyl-, 5-6 a heterocyclic group -C 1-6 alkyl-, 5-6 membered heteroaryl-C 1-6 alkyl- and 5-6 membered heteroaryl, wherein said 5-6 membered heterocyclic group and 5- The 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halo, amino, C 1-6 alkyl, and C 1-6 alkoxy;
    或者，R 1和R 2连同其相连的氮原子形成4-7元含氮杂环基、5-10元含氮并杂环基、5-10元含氮螺杂环基或5-10元含氮桥杂环基，其中所述4-7元含氮杂环基、5-10元含氮并杂环基、5-10元含氮螺杂环基和5-10元含氮桥杂环基任选地被独立地选自下列的一个或多个取代基单取代或多取代：羟基、卤素、氰基、C 1-6烷基和C 1-6烷氧基； Alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-7 membered nitrogen-containing heterocyclic group, a 5-10 membered nitrogen-containing heterocyclic group, a 5-10 membered nitrogen-containing spiroheterocyclic group or 5-10 members. a nitrogen-containing bridged heterocyclic group wherein the 4-7 membered nitrogen-containing heterocyclic group, 5-10 membered nitrogen-containing heterocyclic group, 5-10 membered nitrogen-containing spiroheterocyclyl group, and 5-10 membered nitrogen-containing bridged The cyclo group is optionally mono- or polysubstituted with one or more substituents independently selected from the group consisting of hydroxy, halo, cyano, C 1-6 alkyl and C 1-6 alkoxy;
    R 3为C 1-6烷基或C 3-6环烷基； R 3 is C 1-6 alkyl or C 3-6 cycloalkyl;
    R 4为氢或C 1-6烷基； R 4 is hydrogen or C 1-6 alkyl;
    R 5、R 6和R 7各自独立地选自氢和卤素； R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen and halogen;
    R 8和R 9各自独立地选自氢和C 1-6烷基。 R 8 and R 9 are each independently selected from hydrogen and C 1-6 alkyl.
  2. 权利要求1所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式II、式III、式IV或式V所示的结构，其中：The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein the compound Having the structure shown in Formula II, Formula III, Formula IV or Formula V, wherein:
    Figure PCTCN2019070390-appb-100002
    Figure PCTCN2019070390-appb-100002
    R 1、R 2、R 3、R 4、R 5和R 7如权利要求1中所定义。 R 1 , R 2 , R 3 , R 4 , R 5 and R 7 are as defined in claim 1.
  3. 权利要求1或2所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein:
    R 1和R 2各自独立地选自氢、C 1-4烷基、C 1-2烷氧基-C 1-2烷基-、R 8R 9N-C 1-2烷基-、6元杂环基-C 1-2烷基-、6元杂芳基-C 1-2烷基-和5元杂芳基，其中所述6元杂环基、6元杂芳基和5元杂芳基任选地被C 1-4烷基取代； R 1 and R 2 are each independently selected from hydrogen, C 1-4 alkyl, C 1-2 alkoxy-C 1-2 alkyl-, R 8 R 9 NC 1-2 alkyl-, 6-membered hetero a cyclo-C 1-2 alkyl-, 6-membered heteroaryl-C 1-2 alkyl- and 5-membered heteroaryl group wherein the 6-membered heterocyclic group, 6-membered heteroaryl group and 5-membered heteroaryl group The base is optionally substituted by a C 1-4 alkyl group;
    或者，R 1和R 2连同其相连的氮原子形成5-6元含氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基或5-10元含氮桥杂环基，其中所述5-6元含氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基和5-10元含氮桥杂环基任选地被独立地选自下列的的一个或多个取代基单取代或多取代：羟基、卤素、氰基、C 1-4烷基和C 1-4烷氧基； Alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-6 membered nitrogen-containing heterocyclic group, a 8-10 membered nitrogen-containing heterocyclic group, a 7-10 membered nitrogen-containing spiroheterocyclic group or 5-10 members. a nitrogen-containing bridged heterocyclic group wherein the 5-6 membered nitrogen-containing heterocyclic group, 8-10 membered nitrogen-containing heterocyclic group, 7-10 membered nitrogen-containing spiroheterocyclic group, and 5-10 membered nitrogen-containing bridged The cyclo group is optionally mono- or polysubstituted with one or more substituents independently selected from the group consisting of hydroxy, halo, cyano, C 1-4 alkyl and C 1-4 alkoxy;
    优选地，Preferably,
    R 1和R 2各自独立地选自氢、C 1-4烷基、C 1-2烷氧基-C 1-2烷基-、R 8R 9N-C 1-2烷基-、6元杂环基-C 1-2烷基-、6元杂芳基-C 1-2烷基-和5元杂芳基，其中所述6元杂环基、6元杂芳基和5元杂芳基任选地被独立地选自下列的一个或多个取代基单取代或多取代：甲基、乙基、正丙基或异丙基； R 1 and R 2 are each independently selected from hydrogen, C 1-4 alkyl, C 1-2 alkoxy-C 1-2 alkyl-, R 8 R 9 NC 1-2 alkyl-, 6-membered hetero a cyclo-C 1-2 alkyl-, 6-membered heteroaryl-C 1-2 alkyl- and 5-membered heteroaryl group wherein the 6-membered heterocyclic group, 6-membered heteroaryl group and 5-membered heteroaryl group The base is optionally mono- or polysubstituted with one or more substituents independently selected from the group consisting of methyl, ethyl, n-propyl or isopropyl;
    或者，R 1和R 2连同其相连的氮原子形成5-6元含氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基或5-10元含氮桥杂环基，其中所述含5-6元氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基和5-10元含氮桥杂环基任选地被独立地选自下列的一个或多个取代基单取代或多取代：羟基、氟、氯、溴、碘、氰基、甲基、乙基、异丙基、甲氧基和乙氧基； Alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-6 membered nitrogen-containing heterocyclic group, a 8-10 membered nitrogen-containing heterocyclic group, a 7-10 membered nitrogen-containing spiroheterocyclic group or 5-10 members. a nitrogen-containing bridged heterocyclic group, wherein the 5- to 6-membered azacyclic group, the 8-10 membered nitrogen-containing heterocyclic group, the 7-10 membered nitrogen-containing spiroheterocyclic group, and the 5-10 membered nitrogen-containing bridged The cyclo group is optionally mono- or polysubstituted with one or more substituents independently selected from the group consisting of hydroxy, fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, isopropyl, methoxy. And ethoxylated;
    R 8和R 9如权利要求1中所定义。 R 8 and R 9 are as defined in claim 1.
  4. 权利要求1或2所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein:
    R 1和R 2各自独立地选自氢、C 1-4烷基、C 1-2烷氧基-C 1-2烷基-、R 8R 9N-C 1-2烷基-、6元杂环基-C 1-2烷基-、6元杂芳基-C 1-2烷基-和5元杂芳基，其中所述6元杂环基、6元杂芳基和5元杂芳基任选地被C 1-4烷基取代； R 1 and R 2 are each independently selected from hydrogen, C 1-4 alkyl, C 1-2 alkoxy-C 1-2 alkyl-, R 8 R 9 NC 1-2 alkyl-, 6-membered hetero a cyclo-C 1-2 alkyl-, 6-membered heteroaryl-C 1-2 alkyl- and 5-membered heteroaryl group wherein the 6-membered heterocyclic group, 6-membered heteroaryl group and 5-membered heteroaryl group The base is optionally substituted by a C 1-4 alkyl group;
    或者，R 1和R 2连同其相连的氮原子形成5-6元含氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基或5-10元含氮桥杂环基，其中所述5-6元含氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基和5-10元含氮桥杂环基任选地被独立地选自下列的取代基取代：羟基、卤素、氰基、C 1-4烷基和C 1-4烷氧基； Alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-6 membered nitrogen-containing heterocyclic group, a 8-10 membered nitrogen-containing heterocyclic group, a 7-10 membered nitrogen-containing spiroheterocyclic group or 5-10 members. a nitrogen-containing bridged heterocyclic group wherein the 5-6 membered nitrogen-containing heterocyclic group, 8-10 membered nitrogen-containing heterocyclic group, 7-10 membered nitrogen-containing spiroheterocyclic group, and 5-10 membered nitrogen-containing bridged The cyclo group is optionally substituted with a substituent independently selected from the group consisting of hydroxy, halo, cyano, C 1-4 alkyl and C 1-4 alkoxy;
    优选地，Preferably,
    R 1和R 2各自独立地选自氢、C 1-4烷基、C 1-2烷氧基-C 1-2烷基-、R 8R 9N-C 1-2烷基-、6元杂环基-C 1-2烷基-、6元杂芳基-C 1-2烷基-和5元杂芳基，其中所述6元杂环基、6元杂芳基和5元杂芳基任选地被甲基、乙基和异丙基取代； R 1 and R 2 are each independently selected from hydrogen, C 1-4 alkyl, C 1-2 alkoxy-C 1-2 alkyl-, R 8 R 9 NC 1-2 alkyl-, 6-membered hetero a cyclo-C 1-2 alkyl-, 6-membered heteroaryl-C 1-2 alkyl- and 5-membered heteroaryl group wherein the 6-membered heterocyclic group, 6-membered heteroaryl group and 5-membered heteroaryl group The base is optionally substituted with methyl, ethyl and isopropyl;
    或者，R 1和R 2连同其相连的氮原子形成5-6元含氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基或5-10元含氮桥杂环基，其中所述含5-6元氮杂环基、8-10元含氮并杂环基、7-10元 含氮螺杂环基和5-10元含氮桥杂环基任选地被独立地选自下列的取代基取代：羟基、氟、氯、溴、碘、氰基、甲基、乙基、异丙基、甲氧基和乙氧基； Alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-6 membered nitrogen-containing heterocyclic group, a 8-10 membered nitrogen-containing heterocyclic group, a 7-10 membered nitrogen-containing spiroheterocyclic group or 5-10 members. a nitrogen-containing bridged heterocyclic group, wherein the 5- to 6-membered azacyclic group, the 8-10 membered nitrogen-containing heterocyclic group, the 7-10 membered nitrogen-containing spiroheterocyclic group, and the 5-10 membered nitrogen-containing bridged The cyclo group is optionally substituted with a substituent independently selected from the group consisting of hydroxy, fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, isopropyl, methoxy and ethoxy;
    R 8和R 9如权利要求1中所定义。 R 8 and R 9 are as defined in claim 1.
  5. 权利要求1或2所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein:
    R 1和R 2各自独立地选自氢、C 1-4烷基、C 1-2烷氧基-C 1-2烷基-、R 8R 9N-C 1-2烷基-、6元杂环基-C 1-2烷基-、6元杂芳基-C 1-2烷基-和5元杂芳基，其中所述6元杂环基、6元杂芳基和5元杂芳基任选地被C 1-4烷基取代，其中R 8和R 9如权利要求1中所定义； R 1 and R 2 are each independently selected from hydrogen, C 1-4 alkyl, C 1-2 alkoxy-C 1-2 alkyl-, R 8 R 9 NC 1-2 alkyl-, 6-membered hetero a cyclo-C 1-2 alkyl-, 6-membered heteroaryl-C 1-2 alkyl- and 5-membered heteroaryl group wherein the 6-membered heterocyclic group, 6-membered heteroaryl group and 5-membered heteroaryl group Is optionally substituted by C 1-4 alkyl, wherein R 8 and R 9 are as defined in claim 1;
    优选地，Preferably,
    R 1和R 2各自独立地选自氢、C 1-4烷基、C 1-2烷氧基-C 1-2烷基-、R 8R 9N-C 1-2烷基-、6元杂环基-C 1-2烷基-、6元杂芳基-C 1-2烷基-和5元杂芳基，其中所述6元杂环基、6元杂芳基和5元杂芳基任选地被独立地选自下列的一个或多个取代基单取代或多取代：甲基、乙基、正丙基或异丙基，其中R 8和R 9如权利要求1中所定义。 R 1 and R 2 are each independently selected from hydrogen, C 1-4 alkyl, C 1-2 alkoxy-C 1-2 alkyl-, R 8 R 9 NC 1-2 alkyl-, 6-membered hetero a cyclo-C 1-2 alkyl-, 6-membered heteroaryl-C 1-2 alkyl- and 5-membered heteroaryl group wherein the 6-membered heterocyclic group, 6-membered heteroaryl group and 5-membered heteroaryl group The group is optionally mono- or polysubstituted by one or more substituents independently selected from methyl, ethyl, n-propyl or isopropyl, wherein R 8 and R 9 are as defined in claim 1. .
  6. 权利要求1或2所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein:
    R 1和R 2连同其相连的氮原子形成5-6元含氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基或5-10元含氮桥杂环基，其中所述5-6元含氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基和5-10元含氮桥杂环基任选地被独立地选自下列的一个或多个取代基单取代或多取代：羟基、卤素、氰基、C 1-4烷基和C 1-4烷氧基； R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-6 membered nitrogen-containing heterocyclic group, a 8-10 membered nitrogen-containing heterocyclic group, a 7-10 membered nitrogen-containing spiroheterocyclic group or a 5-10 membered nitrogen-containing group. A bridged heterocyclic group wherein the 5-6 membered nitrogen-containing heterocyclic group, 8-10 membered nitrogen-containing heterocyclic group, 7-10 membered nitrogen-containing spiroheterocyclyl group, and 5-10 membered nitrogen-containing bridged heterocyclic group Monosubstituted or polysubstituted, optionally with one or more substituents independently selected from the group consisting of hydroxy, halo, cyano, C 1-4 alkyl and C 1-4 alkoxy;
    优选地，R 1和R 2连同其相连的氮原子形成5-6元含氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基或5-10元含氮桥杂环基，其中所述含5-6元氮杂环基、8-10元含氮并杂环基、7-10元含氮螺杂环基和5-10元含氮桥杂基环任选地被独立地选自下列的一个或多个取代基单取代或多取代：羟基、氟、氯、溴、碘、氰基、甲基、乙基、异丙基、甲氧基和乙氧基。 Preferably, R 1 and R 2 together with the nitrogen atom to which they are attached form a 5-6 membered nitrogen-containing heterocyclic group, a 8-10 membered nitrogen-containing heterocyclic group, a 7-10 membered nitrogen-containing spiroheterocyclyl group or 5-10. a nitrogen-containing bridged heterocyclic group, wherein the 5- to 6-membered azacyclic group, the 8-10 membered nitrogen-containing heterocyclic group, the 7-10 membered nitrogen-containing spiroheterocyclic group, and the 5-10 membered nitrogen-containing bridge The heterocyclyl ring is optionally mono- or polysubstituted with one or more substituents independently selected from the group consisting of hydroxy, fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, isopropyl, methoxy Base and ethoxy group.
  7. 权利要求1或2所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein:
    R 1和R 2各自独立地选自氢、甲基、甲氧基乙基、二甲基氨基-乙基-、吗啉-1-基-乙基-、吗啉-4-基-乙基-、吡啶-2-基-甲基-、吡啶-3-基-甲基-、吡啶-4-基-甲基-和1-甲基-1H-吡唑-4-基-。 R 1 and R 2 are each independently selected from the group consisting of hydrogen, methyl, methoxyethyl, dimethylamino-ethyl-, morpholin-1-yl-ethyl-, morpholin-4-yl-ethyl -, pyridin-2-yl-methyl-, pyridin-3-yl-methyl-, pyridin-4-yl-methyl- and 1-methyl-1H-pyrazol-4-yl-.
  8. 权利要求1或2所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein:
    R 1和R 2连同它们共同连接的氮原子形成哌啶基、吡咯烷基、吗啉基、哌嗪基、氮杂螺[3.3]庚烷基、5,6,7,8-四氢-1,6-萘啶基、5,6,7,8-四氢-1,7-萘啶基、(3aR,6aS)-六氢环戊[c]吡咯基、8-氮杂双环[3.2.1]辛烷基、6,7-二氢-5H-吡咯[3,4-b]吡啶基-或六氢吡嗪并[2,1-c][1,4]噁嗪基-，其中所述哌啶 基、吡咯烷基、吗啉基、哌嗪基、氮杂螺[3.3]庚烷基、5,6,7,8-四氢-1,6-萘啶基、5,6,7,8-四氢-1,7-萘啶基、(3aR,6aS)-六氢环戊[c]吡咯基、8-氮杂双环[3.2.1]辛烷基、6,7-二氢-5H-吡咯[3,4-b]吡啶基-或六氢吡嗪并[2,1-c][1,4]噁嗪基-任选地被独立地选自下列的一个或多个取代基单取代或多取代：羟基、氟、氰基、甲基和甲氧基； R 1 and R 2 together with the nitrogen atom to which they are attached form a piperidinyl group, a pyrrolidinyl group, a morpholinyl group, a piperazinyl group, an azaspiro[3.3]heptyl group, a 5,6,7,8-tetrahydro- 1,6-naphthyridinyl, 5,6,7,8-tetrahydro-1,7-naphthyridinyl, (3aR,6aS)-hexahydrocyclopenta[c]pyrrolyl, 8-azabicyclo[3.2 .1]octyl, 6,7-dihydro-5H-pyrrole[3,4-b]pyridyl- or hexahydropyrazino[2,1-c][1,4]oxazinyl-, Wherein the piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azaspiro[3.3]heptyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, 5, 6,7,8-tetrahydro-1,7-naphthyridinyl, (3aR,6aS)-hexahydrocyclopenta[c]pyrrolyl, 8-azabicyclo[3.2.1]octyl, 6,7 -Dihydro-5H-pyrrole[3,4-b]pyridinyl- or hexahydropyrazino[2,1-c][1,4]oxazinyl-optionally selected independently from one of the following Or a plurality of substituents mono- or poly-substituted: hydroxy, fluoro, cyano, methyl and methoxy;
    优选地，R 1和R 2连同它们共同连接的氮原子形成哌啶基、4-甲氧基-哌啶基-、4-羟基-哌啶基、3-羟基-哌啶基、4,4-二氟-哌啶基、4-氰基-哌啶基、吡咯烷基、2-甲基吡咯烷基-、2,2-二甲基吡咯烷基-、3-甲氧基吡咯烷基-、3,3-二氟吡咯烷基、吗啉基、哌嗪基、N-甲基哌嗪基-、氮杂螺[3.3]庚烷基或六氢吡嗪并[2,1-c][1,4]噁嗪基-。 Preferably, R 1 and R 2 together with the nitrogen atom to which they are attached form a piperidinyl group, 4-methoxy-piperidinyl-, 4-hydroxy-piperidinyl, 3-hydroxy-piperidinyl, 4,4 -difluoro-piperidinyl, 4-cyano-piperidinyl, pyrrolidinyl, 2-methylpyrrolidinyl-, 2,2-dimethylpyrrolidinyl-, 3-methoxypyrrolidinyl -, 3,3-difluoropyrrolidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl-, azaspiro[3.3]heptyl or hexahydropyrazino[2,1-c ][1,4]oxazinyl-.
  9. 权利要求1-8任一项所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3为C 1-4烷基；优选地，R 3为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；进一步优选地，R 3为异丙基。 The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein: R 3 is C 1-4 alkyl; preferably, R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; Preferably, R 3 is isopropyl.
  10. 权利要求1-9任一项所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4为氢或C 1-4烷基；优选地，R 4为氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；进一步优选地，R 4为氢或甲基。 The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein: R 4 is hydrogen or C 1-4 alkyl; preferably, R 4 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert Butyl; further preferably, R 4 is hydrogen or methyl.
  11. 权利要求1-10任一项所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 5、R 6和R 7各自独立地选自氢、氟、氯、溴和碘；优选地，R 5、R 6和R 7各自独立地选自氢和氟。 The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein: R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine and iodine; preferably, R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen and fluorine.
  12. 权利要求1-11任一项所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 8和R 9各自独立地选自氢和C 1-4烷基；优选地，R 8和R 9各自独立地选自氢和甲基；更优选地，R 8和R 9各自独立地为甲基。 A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof. Wherein: R 8 and R 9 are each independently selected from hydrogen and C 1-4 alkyl; preferably, R 8 and R 9 are each independently selected from hydrogen and methyl; more preferably, R 8 and R 9 are each Independently methyl.
  13. 权利要求1-12任一项所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物选自：The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein the compound is selected from the group consisting of
    Figure PCTCN2019070390-appb-100003
    Figure PCTCN2019070390-appb-100003
    Figure PCTCN2019070390-appb-100004
    Figure PCTCN2019070390-appb-100004
    Figure PCTCN2019070390-appb-100005
    Figure PCTCN2019070390-appb-100005
    Figure PCTCN2019070390-appb-100006
    Figure PCTCN2019070390-appb-100006
  14. 药物组合物，其包含权利要求1-13任一项所述化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，以及任选的一种或多种药学上可接受的载体或赋形剂。A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof, A metabolite or prodrug, and optionally one or more pharmaceutically acceptable carriers or excipients.
  15. 药物制剂，其包含权利要求1-13任一项所述化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药、或权利要求14的药物组合物。A pharmaceutical preparation comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolism thereof A prodrug, or a pharmaceutical composition of claim 14.
  16. 权利要求1-13任一项所述化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药、权利要求14的药物组合物或权利要求15的药物制剂在制备作为腺苷A2a受体拮抗剂的药物中的用途，或在制备用于治疗和/或预防与腺苷A2a受体有关的疾病的药物中的用途，A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, prodrug thereof, Use of the pharmaceutical composition of claim 14 or the pharmaceutical preparation of claim 15 in the manufacture of a medicament as an adenosine A2a receptor antagonist, or in the preparation of a medicament for the treatment and/or prevention of adenosine A2a receptor-related diseases Use in medicine,
    优选地，所述的与腺苷A2a受体有关的疾病为肿瘤，Preferably, the disease associated with the adenosine A2a receptor is a tumor,
    优选地，所述的肿瘤包括但不限于：乳腺癌、卵巢癌、结直肠癌、黑色素瘤、非小细胞肺癌、小细胞肺癌、胃肠道间质瘤、***、胰腺癌、***癌、胃癌、慢性髓样白细胞过多症、肝癌、淋巴瘤、腹膜癌和软组织肉瘤。Preferably, the tumor includes, but is not limited to, breast cancer, ovarian cancer, colorectal cancer, melanoma, non-small cell lung cancer, small cell lung cancer, gastrointestinal stromal tumor, cervical cancer, pancreatic cancer, prostate cancer, Gastric cancer, chronic myeloid leukemia, liver cancer, lymphoma, peritoneal cancer, and soft tissue sarcoma.
  17. 权利要求1至13任一项所述化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药、权利要求14的药物组合物或权利要求15的药物制剂，其用于抑制腺苷A2a受体活性，或用于治疗和/或预防与腺苷A2a受体有关的疾病，A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, The pharmaceutical composition according to claim 14 or the pharmaceutical preparation according to claim 15 for inhibiting adenosine A2a receptor activity or for treating and/or preventing a disease associated with adenosine A2a receptor,
    优选地，所述的与腺苷A2a受体有关的疾病为肿瘤，Preferably, the disease associated with the adenosine A2a receptor is a tumor,
    优选地，所述的肿瘤包括但不限于：乳腺癌、卵巢癌、结直肠癌、黑色素瘤、非小细胞肺癌、小细胞肺癌、胃肠道间质瘤、***、胰腺癌、***癌、胃癌、慢性髓样白细胞过多症、肝癌、淋巴瘤、腹膜癌和软组织肉瘤。Preferably, the tumor includes, but is not limited to, breast cancer, ovarian cancer, colorectal cancer, melanoma, non-small cell lung cancer, small cell lung cancer, gastrointestinal stromal tumor, cervical cancer, pancreatic cancer, prostate cancer, Gastric cancer, chronic myeloid leukemia, liver cancer, lymphoma, peritoneal cancer, and soft tissue sarcoma.
  18. 一种治疗和/或预防与腺苷A2a受体有关的疾病的方法，其包括向有需要的受试者施用有效量的权利要求1至13任一项所述化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、 N-氧化物、同位素标记的化合物、代谢物或前药、权利要求14的药物组合物或权利要求15的药物制剂，A method of treating and/or preventing a disease associated with adenosine A2a receptor, comprising administering an effective amount of the compound of any one of claims 1 to 13 or a pharmaceutically acceptable thereof to a subject in need thereof a salt, a stereoisomer, a polymorph, a solvate, an N-oxide, an isotope-labeled compound, a metabolite or a prodrug, a pharmaceutical composition according to claim 14, or a pharmaceutical preparation according to claim 15.
    优选地，所述的与腺苷A2a受体有关的疾病为肿瘤，Preferably, the disease associated with the adenosine A2a receptor is a tumor,
    优选地，所述的肿瘤包括但不限于：乳腺癌、卵巢癌、结直肠癌、黑色素瘤、非小细胞肺癌、小细胞肺癌、胃肠道间质瘤、***、胰腺癌、***癌、胃癌、慢性髓样白细胞过多症、肝癌、淋巴瘤、腹膜癌和软组织肉瘤。Preferably, the tumor includes, but is not limited to, breast cancer, ovarian cancer, colorectal cancer, melanoma, non-small cell lung cancer, small cell lung cancer, gastrointestinal stromal tumor, cervical cancer, pancreatic cancer, prostate cancer, Gastric cancer, chronic myeloid leukemia, liver cancer, lymphoma, peritoneal cancer, and soft tissue sarcoma.
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