WO2020156505A1 - 2-amionpyrimidine derivative, preparation method therefor and application thereof in medicines - Google Patents

2-amionpyrimidine derivative, preparation method therefor and application thereof in medicines Download PDF

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Publication number
WO2020156505A1
WO2020156505A1 PCT/CN2020/074091 CN2020074091W WO2020156505A1 WO 2020156505 A1 WO2020156505 A1 WO 2020156505A1 CN 2020074091 W CN2020074091 W CN 2020074091W WO 2020156505 A1 WO2020156505 A1 WO 2020156505A1
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Prior art keywords
general formula
compound
tautomer
racemate
pharmaceutically acceptable
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PCT/CN2020/074091
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French (fr)
Chinese (zh)
Inventor
陆标
王胜蓝
桂斌
贺峰
陶维康
Original Assignee
江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN202080005991.6A priority Critical patent/CN112996783B/en
Publication of WO2020156505A1 publication Critical patent/WO2020156505A1/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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present disclosure belongs to the field of medicine, and relates to an aminopyrimidine derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as an A 2a receptor and/ Or the use of an A 2b receptor dual antagonist and the use in the preparation of a medicament for the treatment of conditions or disorders improved by the inhibition of the A 2a receptor and/or the A 2b receptor.
  • an aminopyrimidine derivative represented by general formula (I) a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as an A 2a receptor and/ Or the use of an A 2b receptor dual antagonist and the use in the preparation of a medicament for the treatment of conditions or disorders improved by the inhibition of the A 2a receptor and/or the A 2b receptor.
  • Adenosine is a naturally occurring purine nucleoside and an endogenous regulator of many physiological functions. It plays an important role in the regulation of cardiovascular system, central nervous system, respiratory system, kidney, fat and platelet function.
  • adenosine is an important molecule in the interaction between tumors and immunity. Targeting adenosine pathway can effectively inhibit tumor progression and metastasis through multiple mechanisms.
  • the hypoxic tumor microenvironment provides a strong selective pressure for tumor cells, thereby increasing their aggressiveness.
  • the lack of oxygen supply leads to a lack of nutrition, forcing tumor cells and immune cells to compete for essential nutrients.
  • tumor cells may inhibit the proliferation and effector functions of lymphocytes, thereby evading immune surveillance, continuing to survive, and spreading to other organs.
  • adenosine The role of adenosine is mediated by the G protein-coupled receptor family.
  • G protein-coupled receptor family At present, there are known at least four subtypes of adenosine receptors, classified as A 1 , A 2a , A 2b and A 3 .
  • the A 1 and A 3 receptors inhibit the activity of the enzyme adenylate cyclase, while the A 2a and A 2b receptors stimulate the activity of the enzyme, thereby regulating the level of cyclic AMP in the cell.
  • Adenosine regulates a wide range of Physiological functions.
  • a 2a receptor (A 2a R) is widely distributed in the body. It is mainly expressed in the striatum in the central nervous system, and is also expressed in peripheral, heart, liver, lung, kidney and other tissues.
  • a 2b receptor (A 2b R) is also widely expressed in various tissues, but the expression level is low, and the affinity for adenosine is much lower than that of A 2a receptor. Therefore, people began to study A 2b receptor less.
  • adenosine A 2a receptors can play an important immunomodulatory role in many pathological processes such as ischemia, hypoxia, inflammation, trauma, and transplantation. This may be related to A 2a receptors in T cells and B cells. , Monocytes, macrophages, neutrophils and other immune cells have higher expression levels. In addition, the activation of A 2a receptor can promote the body to develop immune tolerance, and it is closely involved in the formation of tumor cells "immune escape” or "immune suppression", creating favorable conditions for the occurrence and development of tumors. Lokshin and colleagues (Cancer Res.
  • a 2a R activation on natural killer cells can increase cAMP and activate PKA, thereby inhibiting the killing of tumor cells by natural killer cells.
  • activation of A 2a receptor can promote the proliferation of tumor cells such as melanoma A375 cells, fibroblast NIH3T3 cells and pheochromocytoma PC12 cells, and its effect may be related to the activation of A 2a receptors on T cells.
  • T cell activation and proliferation are related to tumor cell adhesion and cytotoxicity to tumor cells; mice with A 2a receptor gene knockout can enhance the anti-tumor immune effect of CD8 + T cells and significantly inhibit tumor proliferation .
  • a 2a receptor antagonists can be used in the treatment of tumors.
  • Deepak Mittal et al. found that A 2b receptors are overexpressed in a variety of tumors and are associated with poor prognosis of triple-negative breast cancer, multiple myeloma and acute myeloid leukemia; overexpression of A 2b receptors promotes The proliferation and migration of tumor cells;
  • a 2b receptor inhibitors combined with chemotherapy drugs or immune checkpoint inhibitors can significantly reduce tumor metastasis in mouse triple-negative breast cancer models; knock out mice or human colon cancer cells
  • the A 2b receptor in the line significantly reduces the metastasis of colon cancer and the tumorigenicity of cells.
  • Both A 2a receptor and A 2b receptor have the effect of suppressing immunity. Therefore, it is necessary to further study the mutual regulation mechanism between the two. For example, when inhibiting A 2a receptor, whether it will increase the effect of adenosine on A 2b receptor Sensitivity. The study of A 2a receptor and A 2b receptor dual inhibitors has also become a direction worth exploring.
  • adenosine A 1 receptor is tissue ischemia/hypoxia, in the central, circulatory, digestive system, and skeletal muscles
  • adenosine accumulated outside the cell activates The A 1 receptor on the cell membrane initiates the corresponding protective mechanism, thereby increasing the cell's tolerance to hypoxia and hypoxia.
  • a 1 receptor Located on the immune cells in a hypoxic environment A 1 receptor can promote the cellular immune response.
  • a 1 receptors can also reduce free fatty acids and triglycerides, and participate in the regulation of blood sugar.
  • a 1 receptor may cause various adverse reactions in the body tissues (Chinese Pharmacological Bulletin, 2008, 24(5), 573-576). If reported in the literature, in animal models, blocking the A 1 receptor will cause adverse reactions such as anxiety and arousal (Basic&Clinical Pharmacology&Toxicology, 2011,109(3),203-7).
  • the adenosine A 3 receptor (as described in Gessi S et al., Pharmacol. Ther. 117(1), 2008, 123-140) can play a role in cardioprotection, and the A 3 receptor continues Blocking may increase the likelihood of complications caused by any pre-existing or developing ischemic heart disease, such as angina or heart failure.
  • the purpose of the present disclosure is to provide a compound represented by general formula (I), or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form or its pharmaceutically acceptable salt:
  • Ring A and Ring B are the same or different, and each independently is an aryl group or a heteroaryl group;
  • Ring C is a 7-14 membered polycyclic heterocyclic group
  • L is selected from bond, alkylene, O atom, S atom and NR 5 ;
  • R 1 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, deuterated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, Heterocyclic group, aryl group and heteroaryl group;
  • R 2 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, deuterated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and hetero Aryl;
  • R 3 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, deuterated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, Heterocyclic group, aryl group and heteroaryl group;
  • R 4 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, deuterated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, Heterocyclic group, aryl group and heteroaryl group;
  • R 5 is selected from hydrogen atom, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, cycloalkyl group and heterocyclic group;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2 or 3;
  • s 0, 1, 2, 3, 4, 5, or 6.
  • the compound represented by the general formula (I), or its tautomers, mesosomes, racemates, enantiomers, diastereomers Isomers, or mixtures thereof or pharmaceutically acceptable salts thereof which are compounds represented by the general formula (II), or tautomers, mesoisomers, racemates, enantiomers thereof Forms, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
  • Rings C, L, R 1 to R 4 , m, n and s are as defined in the compound of general formula (I).
  • G is selected from C(R 4 ) 2 , O atom and N atom;
  • p, q, r and t are the same or different, and each independently is 1 or 2;
  • R 4 is as defined in the compound of general formula (I).
  • the compound represented by the general formula (I), or its tautomers, mesosomes, racemates, enantiomers, diastereomers Isomer, or its mixture form or its pharmaceutically acceptable salt which is a compound represented by general formula (III), or its tautomer, meso, racemate, enantiomer Forms, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
  • G is selected from C(R 4 ) 2 , O atom or N atom;
  • p, q, r and t are the same or different, and each independently is 1 or 2;
  • s 0, 1, 2, 3 or 4;
  • L, R 1 to R 4 , m and n are as defined in the general formula (I).
  • the compound represented by the general formula (I), or its tautomers, mesosomes, racemates, enantiomers, diastereomers Isomer, or its mixture form or its pharmaceutically acceptable salt which is a compound represented by general formula (IIIaa):
  • G is selected from C(R 4 ) 2 , O atom or N atom;
  • p, q, r and t are the same or different, and each independently is 1 or 2;
  • s 0, 1, 2, 3 or 4;
  • R 1 to R 4 , m and n are as defined in the compound of general formula (I).
  • the compound represented by the general formula (I), or its tautomers, mesosomes, racemates, enantiomers, diastereomers An isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen atom.
  • Typical compounds of the present disclosure include but are not limited to:
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IA), or its tautomer, meso, racemate, enantiomer, diastereomer, or Mixture form or its pharmaceutically acceptable salt:
  • W is an amino protecting group; preferably tert-butoxycarbonyl
  • Ring A, ring B, ring C, L, R 1 to R 4 , m, n and s are as defined in the compound of general formula (I). It is an intermediate for the preparation of compounds of general formula (I).
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IIA), or its tautomer, meso, racemate, enantiomer, diastereomer, or Mixture form or its pharmaceutically acceptable salt:
  • W is an amino protecting group; preferably tert-butoxycarbonyl
  • Rings C, L, R 1 to R 4 , m, n and s are as defined in the compound of general formula (II). It is an intermediate for the preparation of compounds of general formula (II).
  • Another aspect of the present disclosure relates to the compound represented by general formula (IIIA), or its tautomer, meso, racemate, enantiomer, diastereomer, or Mixture form or its pharmaceutically acceptable salt:
  • W is an amino protecting group; preferably tert-butoxycarbonyl
  • G, L, R 1 to R 4 , m, n, s, p, q, r and t are as defined in the compound of general formula (III). It is an intermediate for the preparation of compounds of general formula (III).
  • Another aspect of the present disclosure relates to the compound represented by general formula (IIIa), or its tautomer, meso, racemate, enantiomer, diastereomer, or Mixture form or its pharmaceutically acceptable salt:
  • W is an amino protecting group; preferably tert-butoxycarbonyl
  • G, R 1 to R 4 , m, n, s, p, q, r, and t are as defined in the compound of general formula (IIIaa). It is an intermediate for the preparation of compounds of general formula (IIIaa).
  • Typical compounds of the present disclosure include but are not limited to:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IA), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
  • Ring A, ring B, ring C, L, W, R 1 to R 4 , m, n, and s are as defined in the compound of general formula (IA).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method has the following steps:
  • the compound of general formula (IA) removes the amino protecting group to obtain the compound of general formula (I),
  • W is an amino protecting group; preferably tert-butoxycarbonyl
  • Ring A, ring B, ring C, L, R 1 to R 4 , m, n and s are as defined in the compound of general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
  • Ring A, ring B, ring C, L, R 1 to R 4 , m, n and s are as defined in the compound of general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIA), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
  • Rings C, L, W, R 1 to R 4 , m, n and s are as defined in the compound of general formula (IIA).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
  • the compound of general formula (IIA) removes the amino protecting group to obtain the compound of general formula (II),
  • W is an amino protecting group; preferably tert-butoxycarbonyl
  • Rings C, L, R 1 to R 4 , m, n and s are as defined in the compound of general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
  • Rings C, L, R 1 to R 4 , m, n and s are as defined in the compound of general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIIA), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
  • G, L, W, R 1 to R 4 , m, n, s, p, q, r and t are as defined in the compound of general formula (IIIA).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III), or its tautomer, meso, racemate, enantiomer, diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
  • W is an amino protecting group; preferably tert-butoxycarbonyl
  • G, L, R 1 to R 4 , m, n, s, p, q, r and t are as defined in the compound of general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III), or its tautomer, meso, racemate, enantiomer, diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
  • G, L, R 1 to R 4 , m, n, s, p, q, r and t are as defined in the compound of general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIIa), or its tautomer, meso, racemate, enantiomer, diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
  • G, W, R 1 to R 4 , m, n, s, p, q, r and t are as defined in the compound of general formula (IIIa).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IIIaa), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
  • the compound of general formula (IIIa) removes the amino protecting group to obtain the compound of general formula (IIIaa),
  • W is an amino protecting group; preferably tert-butoxycarbonyl
  • G, R 1 to R 4 , m, n, s, p, q, r, and t are as defined in the compound of general formula (IIIaa).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IIIaa), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
  • G, R 1 to R 4 , m, n, s, p, q, r, and t are as defined in the compound of general formula (IIIaa).
  • Another aspect of the present disclosure relates to a pharmaceutical composition containing a therapeutically effective amount of the compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer Isomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • a pharmaceutical composition containing a therapeutically effective amount of the compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer Isomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure also relates to a method for preparing the above-mentioned pharmaceutical composition, which comprises combining the compound represented by each general formula or its tautomer, meso, racemate, enantiomer, and non-pair
  • the enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof are mixed with pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to the compound represented by the general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or mixture thereof, or The use of a pharmaceutically acceptable salt or a pharmaceutical composition containing the same in the preparation of a medicament for inhibiting A 2a receptor and/or A 2b receptor.
  • the present disclosure further relates to the compound represented by the general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or mixture thereof, or The use of a pharmaceutically acceptable salt or a pharmaceutical composition containing the same in the preparation of a medicament for the treatment of diseases or conditions that are improved by inhibiting the A 2a receptor and/or A 2b receptor.
  • the present disclosure further relates to the compound represented by the general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or mixture thereof, or A pharmaceutically acceptable salt or a pharmaceutical composition containing it is used in the preparation of treatment of cancer, depression, cognitive function disorders, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic lateral Cirrhosis, etc.), attention-related disorders, extrapyramidal syndrome, abnormal movement disorders, liver cirrhosis, liver fibrosis, fatty liver, skin fibrosis, sleep disorders, stroke, brain injury, neuroinflammation, and use in drugs for addictive behavior , Preferably for use in the preparation of drugs for treating cancer.
  • neurodegenerative disorders Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic lateral Cirrhosis, etc.
  • attention-related disorders extrapyramidal syndrome
  • abnormal movement disorders liver cirrhosis,
  • the present disclosure further relates to the compound represented by the general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or mixture thereof, or The use of a pharmaceutically acceptable salt or a pharmaceutical composition containing it in the preparation of a medicament for the treatment of cancer, wherein the cancer is selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer , Kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple bone marrow Tumor, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder cancer, gallbladder cancer, cholangiocarcinoma, choriocarcinoma and
  • the present disclosure further relates to the compound represented by the general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or mixture thereof, or The use of a pharmaceutically acceptable salt or a pharmaceutical composition containing the same in the preparation of a medicament for inhibiting A 2a receptor and/or A 2b receptor.
  • the present disclosure also relates to a method for inhibiting A 2a receptor and/or A 2b receptor, which comprises administering to a patient a therapeutically effective amount of a compound represented by general formula (I) or a tautomer or internal elimination Rotates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • a compound represented by general formula (I) or a tautomer or internal elimination Rotates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • the present disclosure also relates to a method for treating diseases or conditions improved by inhibiting A 2a receptor and/or A 2b receptor, which comprises administering a therapeutically effective amount of a compound represented by general formula (I) or Tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • the present disclosure relates to a treatment for cancer, depression, cognitive disorders, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic lateral sclerosis, etc.), attention-related disorders, Extrapyramidal syndrome, abnormal dyskinesia, liver cirrhosis, liver fibrosis, fatty liver, skin fibrosis, sleep disorders, stroke, brain injury, neuroinflammation and addictive behaviors, preferably cancer methods, which include administering effective treatment to patients in need.
  • the present disclosure further relates to a method for treating cancer, which comprises administering a therapeutically effective amount of a compound represented by general formula (I) or its tautomers, mesosomes, racemates, and enantiomers to a desired patient.
  • the present disclosure further relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, which is used as a medicine.
  • the present disclosure also relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, is used as an A 2a receptor and/or A 2b receptor antagonist.
  • the present disclosure also relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, is used for the treatment of diseases or conditions that are improved by inhibiting the A 2a receptor and/or A 2b receptor.
  • the present disclosure also relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition containing it, is used for the treatment of cancer, depression, cognitive function disorders, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease, or amyotrophic Lateral sclerosis, etc.), attention-related disorders, extrapyramidal syndrome, abnormal movement disorders, liver cirrhosis, liver fibrosis, fatty liver, skin fibrosis, sleep disorders, stroke, brain injury, neuroinflammation and addictive behaviors, preferably cancer .
  • the disease or condition ameliorated by inhibition of A 2a receptor and/or A 2b receptor is selected from cancer, depression, cognitive function disorders, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic lateral sclerosis, etc.), attention-related disorders, extrapyramidal syndrome, abnormal movement disorders, cirrhosis, liver fibrosis, fatty liver, skin fibrosis, sleep disorders, stroke, brain damage , Neuroinflammation and addictive behavior; preferably cancer, the cancer is selected from melanoma, brain tumor (glioma with malignant astroglioma and oligodendroglioma components, etc.), esophageal cancer , Stomach cancer, liver cancer, pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cancer, etc.), kidney cancer, breast cancer, ovarian cancer ,
  • the dosage of the compound or composition used in the treatment methods described in the present invention will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound. But as a general guide, a suitable unit dose can be 0.1-1000 mg.
  • the pharmaceutical composition of the present invention may contain one or more auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Shape agent and so on.
  • auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Shape agent and so on.
  • the composition may contain 0.1 to 99% by weight of the active compound.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs.
  • the oral composition may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, In order to provide pleasing and delicious medicinal preparations.
  • the tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
  • Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing.
  • the aqueous suspension may also contain one or more preservatives such as ethyl paraben or n-propyl paraben, one or more coloring agents, one or more flavoring agents and one or more sweeteners. Flavoring agent.
  • Oil suspensions can be formulated by suspending active ingredients in vegetable oils.
  • the oil suspension may contain thickeners.
  • the above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation.
  • dispersible powders and granules suitable for preparing aqueous suspensions can be provided with active ingredients and dispersing or wetting agents for mixing, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can illustrate the above examples. Other excipients such as sweeteners, flavoring agents and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.
  • composition of the present disclosure may also be in the form of an oil-in-water emulsion.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
  • Acceptable solvents or solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injection preparation may be a sterile injection oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is added to a mixture of water and glycerin to form a microemulsion.
  • the injection or microemulsion can be injected into the patient's bloodstream by local large-scale injection.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.
  • the pharmaceutical composition may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration.
  • the suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above.
  • the sterile injection preparation can also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oil can be conveniently used as a solvent or suspension medium.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycol.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient , The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best mode of treatment such as the mode of treatment, the daily dosage of the compound (I) or the amount of pharmaceutically acceptable salt
  • the type can be verified according to the traditional treatment plan.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably containing 1 to 6 carbon atoms Atom of the alkyl group.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms More preferred are lower alkyl groups containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl.
  • Alkyl groups may be substituted or unsubstituted.
  • substituents When substituted, substituents may be substituted at any available attachment point.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, and alkyl groups.
  • One or more substituents of oxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted.
  • alkylene refers to a saturated linear or branched aliphatic hydrocarbon group, which has two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is A straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 carbon atoms, more preferably an alkylene group containing 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene include but are not limited to methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 -) CH 2 -), 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), and 1,5-butylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -) Wait.
  • the alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy , Cycloalkylthio, heterocycloalkylthio and oxo groups are substituted by one or more substituents.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl , Hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl substituted by one or more substituents.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 10
  • the carbon atom more preferably contains 3 to 6 (e.g. 3, 4, 5 or 6) carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl groups, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings, which may contain one or more double bonds, but none of the rings have complete conjugate ⁇ electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 14 yuan, and most preferably 7 to 9 yuan.
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 14 yuan, and most preferably 7 to 9 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl preferably bicyclic or tricyclic, more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered , 5-membered/5-membered or 5-membered/6-membered bicycloalkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 14 yuan, and most preferably 7 to 9 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring includes the above-mentioned cycloalkyl groups (such as monocyclic, fused ring, spiro ring and bridged cycloalkyl) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein it is connected to the parent structure
  • the ring together is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; preferably phenylcyclopentyl, tetrahydronaphthyl.
  • Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from hydrogen, halogen, alkyl, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, heterocyclyloxy, aryl, and heteroaryl are substituted by one or more substituents replace.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) g (where g is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 14 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 7 to 14 ring atoms, of which 1-4 are heteroatoms; more preferably contains 7 to 9 ring atoms, of which 1-3 One is a heteroatom.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl and so on.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spirocyclic heterocyclic group refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between 5- to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S( O) Heteroatoms of g (where g is an integer of 0 to 2), and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 7 to 14 yuan, more preferably 7 to 9 yuan (for example, 7, 8, or 9).
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group.
  • Non-limiting examples of spiroheterocyclic groups include:
  • fused ring heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bonds, but none of the rings have a fully conjugated ⁇ -electron system, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) g (where g is an integer from 0 to 2), and the rest
  • the ring atoms are carbon. It is preferably a 7 to 14 membered condensed ring heterocyclic group, more preferably 7 to 9 membered (for example, 7, 8, or 9).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but no ring has complete A conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) g (where g is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 14 yuan, and most preferably 7 to 9 yuan (for example, 7, 8, or 9).
  • bridged heterocyclic groups include:
  • the heterocyclic ring includes the above heterocyclic groups (for example, monocyclic, fused ring, spiro ring and bridged heterocyclic group) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the parent structure is connected to The ring together is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, One or more substituents among alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene Base and naphthyl.
  • the aryl ring includes the above-mentioned aryl group fused on a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
  • the aryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably independently optionally selected from the group consisting of hydrogen, halogen, alkyl, and alkane. Substituted by one or more substituents of oxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, heterocyclyloxy, aryl and heteroaryl .
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl groups are preferably 5 to 10 members, more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, Imidazolyl, pyrazolyl, tetrazolyl, etc.
  • the heteroaryl ring includes the above-mentioned heteroaryl group fused on an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:
  • Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, One or more substituents among alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted.
  • amino protecting group is to keep the amino group unchanged when other parts of the molecule react, and to protect the amino group with a group that is easy to remove.
  • Non-limiting examples include tert-butyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.
  • the amino protecting group is preferably tert-butyl or tert-butoxycarbonyl.
  • heterocyclyloxy refers to heterocyclyl -O-, wherein heterocyclyl is as defined above.
  • heterocyclylalkyl refers to an alkyl group substituted with one or more heterocyclyl groups, wherein alkyl and heterocyclyl are as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • hydroxy refers to -OH.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • the compounds of the present disclosure also include compounds of formula (I) in various deuterated forms. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the compound of formula (I) in the deuterated form with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques using deuterated reagents.
  • Deuterated reagents include but are not limited to deuterated borane, tri-deuterated Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • “Optional” or “optionally” means that the event or environment described later can but does not have to occur, and the description includes the occasion where the event or environment occurs or does not occur.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but does not have to be present. The description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms independently of each other by a corresponding number of substituents, wherein each substituent has an independent (I.e. the substituents can be the same or different). It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present disclosure. Such salt is safe and effective when used in mammals, and has due biological activity.
  • the compounds of the present disclosure may also include isotopic derivatives thereof.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • 18 F-fluorine label 18 F isotope
  • 11 C-, 13 C-, or 14 C-rich Compounds in which collective carbons ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C- isotopes) replace carbon atoms are within the scope of the present disclosure.
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies.
  • therapeutically effective amount refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.
  • the present disclosure provides a novel structure of adenosine A 2b receptor antagonist with strong inhibitory activity.
  • compounds with this structure also have a good inhibitory effect on adenosine A 2a receptors, and are affected by adenosine A 1
  • the inhibitory effect of the body and adenosine A 3 receptor is weak. It is a novel structure of selective adenosine A 2a receptor and A 2b receptor dual inhibitor.
  • the preparation method of medicinal salt includes the following steps:
  • W is an amino protecting group, preferably tert-butoxycarbonyl
  • Ring A, ring B, ring C, L, R 1 to R 4 , m, n, and s are as defined in the general formula (I).
  • the catalysts include, but are not limited to CuSO 4, CuSO 4. 5H 2 O and CuI and the like.
  • Reagents that provide acidic conditions include, but are not limited to, trifluoroacetic acid, pyridine hydrobromide, hydrobromic acid, acetic acid, hydrochloric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, and sulfuric acid, preferably trifluoroacetic acid.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, tert-butanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane , Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the preparation method of medicinal salt includes the following steps:
  • Ring A, ring B, ring C, L, R 1 to R 4 , m, n, and s are as defined in the general formula (I).
  • the catalysts include, but are not limited to CuSO 4, CuSO 4. 5H 2 O and CuI and the like.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, tert-butanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane , Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the compound represented by the general formula (II) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or
  • the preparation method of medicinal salt includes the following steps:
  • W is an amino protecting group, preferably tert-butoxycarbonyl
  • Rings C, L, R 1 to R 4 , m, n and s are as defined in the general formula (II).
  • the catalysts include, but are not limited to CuSO 4, CuSO 4. 5H 2 O and CuI and the like.
  • Reagents that provide acidic conditions include, but are not limited to, trifluoroacetic acid, pyridine hydrobromide, hydrobromic acid, acetic acid, hydrochloric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, and sulfuric acid, preferably trifluoroacetic acid.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, tert-butanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane , Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the compound represented by the general formula (II) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or
  • the preparation method of medicinal salt includes the following steps:
  • Rings C, L, R 1 to R 4 , m, n and s are as defined in the general formula (II).
  • the catalysts include, but are not limited to CuSO 4, CuSO 4. 5H 2 O and CuI and the like.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, tert-butanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane , Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the preparation method of medicinal salt includes the following steps:
  • the compound of general formula (IIIB) and the compound of general formula (IID) undergo Click reaction in the presence of a catalyst to obtain the compound of general formula (IIIA); the compound of general formula (IIIA) removes the amino protecting group under acidic conditions to obtain Compound of general formula (III);
  • W is an amino protecting group, preferably tert-butoxycarbonyl
  • G, L, R 1 to R 4 , m, n, s, p, q, r, and t are as defined in the general formula (III).
  • the catalysts include, but are not limited to CuSO 4, CuSO 4. 5H 2 O and CuI and the like.
  • Reagents that provide acidic conditions include, but are not limited to, trifluoroacetic acid, pyridine hydrobromide, hydrobromic acid, acetic acid, hydrochloric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, and sulfuric acid, preferably trifluoroacetic acid.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, tert-butanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane , Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the preparation method of medicinal salt includes the following steps:
  • G, L, R 1 to R 4 , m, n, s, p, q, r, and t are as defined in the general formula (III).
  • the catalysts include, but are not limited to CuSO 4, CuSO 4. 5H 2 O and CuI and the like.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, tert-butanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane , Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the preparation method of medicinal salt includes the following steps:
  • the compound of general formula (IIIb) and the compound of general formula (IID) undergo Click reaction in the presence of a catalyst to obtain the compound of general formula (IIIa); the compound of general formula (IIIa) removes the amino protecting group under acidic conditions to obtain Compound of general formula (IIIaa);
  • W is an amino protecting group, preferably tert-butoxycarbonyl
  • G, R 1 to R 4 , m, n, s, p, q, r, and t are as defined in the general formula (IIIaa).
  • the catalysts include, but are not limited to CuSO 4, CuSO 4. 5H 2 O and CuI and the like.
  • Reagents that provide acidic conditions include, but are not limited to, trifluoroacetic acid, pyridine hydrobromide, hydrobromic acid, acetic acid, hydrochloric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, and sulfuric acid, preferably trifluoroacetic acid.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, tert-butanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane , Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the preparation method of medicinal salt includes the following steps:
  • G, R 1 to R 4 , m, n, s, p, q, r, and t are as defined in the general formula (IIIaa).
  • the catalysts include, but are not limited to CuSO 4, CuSO 4. 5H 2 O and CuI and the like.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, tert-butanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane , Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methylsilane
  • HPLC High performance liquid chromatography analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.
  • HPLC preparation uses Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs.
  • CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm.
  • the silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Darui Chemicals and other companies.
  • reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.
  • the microwave reaction uses CEM Discover-S 908860 type microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC), the developing reagent used in the reaction, the eluent system of column chromatography used in the purification of the compound, and the developing reagent system of thin-layer chromatography include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: acetone, E: dichloromethane/acetone system, F: ethyl acetate/dichloromethane system , G: ethyl acetate/dichloromethane/n-hexane, H: ethyl acetate/dichloromethane/acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound, a small amount of triethylamine and acetic acid can also be added Wait for alkaline or acidic reagents to adjust.
  • Methyl 6-bromopicolinate 1a (5.000g, 23.145mmol, prepared by the well-known method "Journal of Medicinal Chemistry, 2017, 60(2), 722-748"), 2-oxa-6- Azaspiro[3.3]heptane hemioxalate (7.340g, 25.460mmol, Nanjing Pharmaceutical Technology Co., Ltd.) and sodium bicarbonate (19.444g, 231.458mmol) were dissolved in 120mL of acetonitrile, heated to 70°C, and stirred React for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1b (1.118 g, yield: 20.62%).
  • reaction solution was cooled to room temperature, and compound 4b (300mg, 463.3 ⁇ mol), tris(dibenzylidene indeneacetone)dipalladium (55mg, 60.06 ⁇ mol), 4,5-bisdiphenylphosphine were added under argon atmosphere -9,9-Dimethylxanthene (70mg, 120.9 ⁇ mol), heated to 100°C and reacted overnight.
  • the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 4d (360 mg, yield: 114.3%). The product was directly used in the next reaction without purification.
  • the crude compound 4d (360 mg, 529.5 ⁇ mol) was dissolved in 10 mL of dichloromethane, 2.5 mL of trifluoroacetic acid was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 30 mL of dichloromethane. A saturated aqueous sodium bicarbonate solution was added to adjust the pH to greater than 7, and the liquids were separated. The aqueous phase was extracted with dichloromethane (20 mL ⁇ 3), and the organic phases were combined. It was dried over sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified with the eluent system A using a preparation plate to obtain the title compound 4 (20 mg, yield: 7.87%).
  • Ethyl 6-bromopicolinate 5a (1.0 g, 4.347 mmol, prepared by the well-known method "Tetrahedron, 2012, 68(24), 4701-4709"), 7-oxa-2-azaspiro [3.5]
  • Nonane hemioxalate (1.497 g, 4.347 mmol) and potassium carbonate (3.004 g, 21.736 mmol) were dissolved in 40 mL of N,N-dimethylformamide, the temperature was raised to 90° C., and the reaction was stirred for 65 hours.
  • morpholine-3-carboxylic acid methyl ester (440mg, 3.031mmol), compound 4b (900mg, 1.389mmol), cesium carbonate (1.97g, 6.046mmol), 4,5-bisdiphenyl Phosphine-9,9-dimethylxanthene (233mg, 402.6 ⁇ mol), tris(dibenzylidene indeneacetone) dipalladium (184mg, 200.9 ⁇ mol) were added to 40mL 1,4-dioxane and heated to React at 90°C for 16 hours.
  • reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified with a CombiFlash rapid preparation device using eluent system A to obtain the title compound 6a (413 mg, yield: 41.74%).
  • Test Example 1 The compounds of the present disclosure have an effect on adenosine A 2a receptor (adenosine A 2a receptor, A 2a R) cAMP signaling pathway, adenosine A 2b receptor (adenosine A 2b receptor, A 2b R) cAMP signaling pathway, and adenosine Determination of inhibitory activity of A 1 receptor (adenosine A 1 receptor, A 1 R) cAMP signaling pathway and adenosine A 3 receptor (adenosine A 3 receptor, A 3 R) cAMP signaling pathway.
  • the following method is used to determine the compounds of the present disclosure on the adenosine A 2a receptor (adenosine A 2a receptor, A 2a R) cAMP signaling pathway, adenosine A 2b receptor cAMP signaling pathway, adenosine A 1 receptor cAMP signaling pathway and adenosine Inhibitory activity of glycoside A 3 receptor cAMP signaling pathway.
  • Adenosine deaminase (sigma, 10102105001)
  • cAMP dynamic 2 kit (cAMP dynamic2kit) (Cisbio, 62AM4PEB)
  • PHERAstar multifunctional microplate reader (Cisbio, 62AM4PEB)
  • CHO-K1/A 2a R cells were cultured in DMEM/F12 medium containing 10% fetal bovine serum and 800 ⁇ g/ml bleomycin.
  • DMEM/F12 medium containing 10% fetal bovine serum and 800 ⁇ g/ml bleomycin.
  • buffer cells were digested with balanced salt buffer containing 20mM HEPES and 0.1% bovine serum albumin cells were resuspended and counted, cell density was adjusted to 106 cells / ml.
  • the final concentration of the compound is: 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256, 0.00512, 0.001024 nM, and the final concentration of ethylcarbazole is 20 nM.
  • the intracellular cAMP concentration was detected using cAMP dynamic 2 kit. Dilute cAMP-d2 and anti-cAMP-Eu-cryptate (Anti-cAMP-Eu-Cryptate) with cAMP lysis buffer at a ratio of 1:4. Add 5 ⁇ l of diluted cAMP-d2 to each well, then add 5 ⁇ l of diluted anti-cAMP-Eu-cryptate, and incubate for 1 hour at room temperature in the dark. Use PHERAstar multi-function microplate reader to read HTRF signal value. Graphpad Prism software was used to calculate the IC 50 value of the compound's inhibitory activity, as shown in Table 1.
  • CHO-K1/A 2b R was cultured in DMEM/F12 medium containing 10% fetal bovine serum and 1 mg/ml G418.
  • DMEM/F12 medium containing 10% fetal bovine serum and 1 mg/ml G418.
  • cell separation experiments using buffer cells were digested with balanced salt buffer containing 20mM HEPES and 0.1% bovine serum albumin cells were resuspended and counted, cell density was adjusted to 106 cells / ml.
  • Add 5 ⁇ l of cell suspension to each well of a 384-well plate, 2.5 ⁇ l of 4 ⁇ prepared with a balanced salt buffer containing 20mM HEPES, 0.1% bovine serum albumin, 54 ⁇ M rolipram and 2.7U/ml adenosine deaminase The concentration of the test compound was incubated at room temperature for 30 minutes.
  • ethylcarbazole Torcis, Torcis, BSA
  • a 4 ⁇ concentration of ethylcarbazole prepared with a balanced salt buffer containing 20mM HEPES, 0.1% bovine serum albumin, 54 ⁇ M rolipram and 2.7U/ml adenosine deaminase. 1691/10
  • the final concentration of the compound is: 100000, 10000, 1000, 100, 10, 1, 0.1 and 0 nM
  • the final concentration of ethylcarbazole is 1 ⁇ M.
  • the intracellular cAMP concentration was detected using cAMP dynamic 2 kit.
  • CHO-K1/A 1 R was cultured in DMEM/F12 medium containing 10% fetal bovine serum and 1 mg/ml G418.
  • the cells were digested with cell separation buffer, and then resuspended and counted in a balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin, and the cell density was adjusted to 5 ⁇ 10 5 cells/ml.
  • the final concentration of the compound is: 100000, 10000, 1000, 100, 10, 1, 0.1 and 0 nM, the final concentration of forskolin is 10 ⁇ M, and the final concentration of CPA is 10 nM.
  • the intracellular cAMP concentration was detected using cAMP dynamic 2 kit. Dilute cAMP-d2 and anti-cAMP-Eu-cryptate with cAMP lysis buffer at a ratio of 1:4. Add 12.5 ⁇ l of diluted cAMP-d2 to each well, then add 12.5 ⁇ l of diluted anti-cAMP-Eu-cryptate, and incubate for 1 hour at room temperature in the dark. Use PHERAstar multi-function microplate reader to read HTRF signal value. Graphpad Prism software was used to calculate the IC 50 value of the compound's inhibitory activity, see Table 1 or Table 2.
  • CHO-K1/A 3 R was cultured with DMEM/F12 medium containing 10% fetal bovine serum and 10 ⁇ g/ml puromycin.
  • the cells were digested with cell separation buffer, and the cells were resuspended in a balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin and counted, and the cell density was adjusted to 5 ⁇ 10 5 /ml.
  • the final concentration of the compound is: 100000, 10000, 1000, 100, 10, 1, 0.1 and 0 nM, the final concentration of forskolin is 10 ⁇ M, and the final concentration of 2Cl-IB-MECA is 5 nM.
  • the intracellular cAMP concentration was detected using cAMP dynamic 2 kit. Dilute cAMP-d2 and anti-cAMP-Eu-cryptate with cAMP lysis buffer at a ratio of 1:4. Add 12.5 ⁇ l of diluted cAMP-d2 to each well, then add 12.5 ⁇ l of diluted anti-cAMP-Eu-cryptate, and incubate for 1 hour at room temperature in the dark. Use PHERAstar multi-function microplate reader to read HTRF signal value. Graphpad Prism software was used to calculate the IC 50 value of the compound's inhibitory activity, see Table 1 or Table 2.
  • Table 1 The IC 50 value of the compound of the present disclosure on the adenosine A 2a receptor (adenosine A 2a receptor, A 2a R) cAMP signaling pathway inhibitory activity
  • Table 2 The IC 50 value of the compound of the present disclosure on the adenosine A 2b receptor (adenosine A 2b receptor, A 2b R) cAMP signaling pathway inhibitory activity

Abstract

The disclosure relates to a 2-aminopyrimidine derivative, a preparation method therefor and an application thereof in medicines. Specifically, the present disclosure relates to an aminopyrimidine derivative represented by general formula (I); a preparation method therefor; a pharmaceutical composition containing same; and uses thereof as a therapeutic agent, in particular as an A2a receptor and/or an A2b receptor antagonist, and in preparation of medicines for treatment of patients' conditions or symptoms relieved by inhibition of the A2a receptor and/or the A2b receptor. Each substituent group of the general formula (I) has the same definition as given in the specification.

Description

2-氨基嘧啶类衍生物、其制备方法及其在医药上的应用2-aminopyrimidine derivatives, their preparation method and their application in medicine 技术领域Technical field
本公开属于医药领域，涉及一种通式(I)所示的氨基嘧啶类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂，特别是作为A 2a受体和/或A 2b受体双拮抗剂的用途和在制备用于治疗通过对A 2a受体和/或A 2b受体的抑制而改善的病况或病症的药物中的用途。 The present disclosure belongs to the field of medicine, and relates to an aminopyrimidine derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as an A 2a receptor and/ Or the use of an A 2b receptor dual antagonist and the use in the preparation of a medicament for the treatment of conditions or disorders improved by the inhibition of the A 2a receptor and/or the A 2b receptor.
背景技术Background technique
腺苷是天然存在的嘌呤核苷，是许多生理功能的内源性调节剂。在心血管***、中枢神经、呼吸***、肾脏、脂肪和血小板的功能调节中发挥重要作用。Adenosine is a naturally occurring purine nucleoside and an endogenous regulator of many physiological functions. It plays an important role in the regulation of cardiovascular system, central nervous system, respiratory system, kidney, fat and platelet function.
在肿瘤研究中发现，腺苷是肿瘤与免疫相互作用中的重要分子，靶向腺苷通路可通过多重机制有效地抑制肿瘤进展和转移。低氧的肿瘤微环境为肿瘤细胞提供了一个强大的选择压力，从而增加它们的侵袭性。氧供的缺乏导致营养的缺乏，迫使肿瘤细胞和免疫细胞竞争必需的营养物质。在此过程中，肿瘤细胞可能会抑制淋巴细胞的增殖和效应功能，从而逃避免疫监视，继续生存，并可播散至其他器官。In tumor research, it has been found that adenosine is an important molecule in the interaction between tumors and immunity. Targeting adenosine pathway can effectively inhibit tumor progression and metastasis through multiple mechanisms. The hypoxic tumor microenvironment provides a strong selective pressure for tumor cells, thereby increasing their aggressiveness. The lack of oxygen supply leads to a lack of nutrition, forcing tumor cells and immune cells to compete for essential nutrients. During this process, tumor cells may inhibit the proliferation and effector functions of lymphocytes, thereby evading immune surveillance, continuing to survive, and spreading to other organs.
腺苷的作用由G蛋白偶联受体家族介导，目前已知至少有四种亚型的腺苷受体，分类为A 1、A 2a、A 2b和A 3。其中A 1和A 3受体抑制酶腺苷酸环化酶的活性，而A 2a和A 2b受体刺激该酶的活性，由此调节细胞中环AMP水平，通过这些受体，腺苷调节广泛的生理功能。 The role of adenosine is mediated by the G protein-coupled receptor family. At present, there are known at least four subtypes of adenosine receptors, classified as A 1 , A 2a , A 2b and A 3 . The A 1 and A 3 receptors inhibit the activity of the enzyme adenylate cyclase, while the A 2a and A 2b receptors stimulate the activity of the enzyme, thereby regulating the level of cyclic AMP in the cell. Through these receptors, adenosine regulates a wide range of Physiological functions.
A 2a受体(A 2aR)在机体分布较为广泛，在中枢神经***主要表达于纹状体，在外周、心、肝、肺、肾等组织也均有表达。A 2b受体(A 2bR)也广泛表达于各种组织中，但是表达量均较低，与腺苷的亲和力也远低于A 2a受体，因此最开始人们对A 2b受体的研究较少。 A 2a receptor (A 2a R) is widely distributed in the body. It is mainly expressed in the striatum in the central nervous system, and is also expressed in peripheral, heart, liver, lung, kidney and other tissues. A 2b receptor (A 2b R) is also widely expressed in various tissues, but the expression level is low, and the affinity for adenosine is much lower than that of A 2a receptor. Therefore, people began to study A 2b receptor less.
近来研究表明，在缺血低氧、炎症、创伤、移植等诸多病理过程中，腺苷A 2a受体的激活可以发挥重要的免疫调节作用，这可能与A 2a受体在T细胞、B细胞、单核巨噬细胞、中性粒细胞等多种免疫细胞上表达水平较高有关。此外，A 2a受体的活化可以促使机体产生免疫耐受，密切参与了肿瘤细胞“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。Lokshin及其同事(Cancer Res.2006Aug1；66(15):7758-65)证实自然杀伤细胞上的A 2aR活化可以通过升高cAMP和激活PKA，从而抑制自然杀伤细胞对肿瘤细胞的杀伤。还有研究表明，激活A 2a受体可以促进黑色素瘤A375细胞、成纤维瘤NIH3T3细胞及嗜铬细胞瘤PC12细胞等肿瘤细胞的增殖，其作用可能与T细胞上A 2a受体的活化可以抑制T细胞活化、增殖、与肿瘤细胞的黏附及对肿瘤细胞产生细胞毒性作用相关；而A 2a受体基因敲除的小鼠则可以加强CD8 +T细胞抗肿瘤的免疫作用,显著抑制肿瘤的 增殖。因此，A 2a受体拮抗剂可用于肿瘤的治疗。此外，Deepak Mittal等人研究发现，A 2b受体在多种肿瘤中过度表达，且与三阴性乳腺癌、多发性骨髓瘤和急性髓性白血病的不良预后相关；A 2b受体的过表达促进了肿瘤细胞的增殖和迁移；A 2b受体抑制剂与化疗药物或免疫检查点抑制剂联用可以显著降低小鼠三阴性乳腺癌模型中的肿瘤转移；敲除小鼠体内或人结肠癌细胞系中的A 2b受体显著降低结肠癌的转移和细胞的成瘤性。这些结果均表明，抑制A 2b受体可抑制肿瘤的转移，因此A 2b受体也有望成为***的一个理想靶点(Cancer Res.2016 Aug 1；76(15):4372-82)。 Recent studies have shown that the activation of adenosine A 2a receptors can play an important immunomodulatory role in many pathological processes such as ischemia, hypoxia, inflammation, trauma, and transplantation. This may be related to A 2a receptors in T cells and B cells. , Monocytes, macrophages, neutrophils and other immune cells have higher expression levels. In addition, the activation of A 2a receptor can promote the body to develop immune tolerance, and it is closely involved in the formation of tumor cells "immune escape" or "immune suppression", creating favorable conditions for the occurrence and development of tumors. Lokshin and colleagues (Cancer Res. 2006Aug1; 66(15):7758-65) demonstrated that A 2a R activation on natural killer cells can increase cAMP and activate PKA, thereby inhibiting the killing of tumor cells by natural killer cells. Studies have also shown that activation of A 2a receptor can promote the proliferation of tumor cells such as melanoma A375 cells, fibroblast NIH3T3 cells and pheochromocytoma PC12 cells, and its effect may be related to the activation of A 2a receptors on T cells. T cell activation and proliferation are related to tumor cell adhesion and cytotoxicity to tumor cells; mice with A 2a receptor gene knockout can enhance the anti-tumor immune effect of CD8 + T cells and significantly inhibit tumor proliferation . Therefore, A 2a receptor antagonists can be used in the treatment of tumors. In addition, Deepak Mittal et al. found that A 2b receptors are overexpressed in a variety of tumors and are associated with poor prognosis of triple-negative breast cancer, multiple myeloma and acute myeloid leukemia; overexpression of A 2b receptors promotes The proliferation and migration of tumor cells; A 2b receptor inhibitors combined with chemotherapy drugs or immune checkpoint inhibitors can significantly reduce tumor metastasis in mouse triple-negative breast cancer models; knock out mice or human colon cancer cells The A 2b receptor in the line significantly reduces the metastasis of colon cancer and the tumorigenicity of cells. These results all indicate that inhibition of A 2b receptor can inhibit tumor metastasis, so A 2b receptor is also expected to become an ideal target for tumor treatment (Cancer Res. 2016 Aug 1; 76(15):4372-82).
A 2a受体和A 2b受体都有抑制免疫的作用，因此需要深入研究这两者之间的相互调节机制，比如当抑制A 2a受体时，是否会增加腺苷对A 2b受体的敏感性。研究A 2a受体和A 2b受体双抑制剂也成为一个值得探索的方向。 Both A 2a receptor and A 2b receptor have the effect of suppressing immunity. Therefore, it is necessary to further study the mutual regulation mechanism between the two. For example, when inhibiting A 2a receptor, whether it will increase the effect of adenosine on A 2b receptor Sensitivity. The study of A 2a receptor and A 2b receptor dual inhibitors has also become a direction worth exploring.
尽管对多种腺苷受体亚型均具有显著生物学活性的化合物可具有治疗作用，但它们可导致不想要的副作用。例如腺苷A 1受体在组织缺血/缺氧时，在中枢、循环、消化***和骨骼肌中，细胞在处于缺氧和低氧的应激环境时，胞外聚集的腺苷通过激活胞膜上的A 1受体启动相应的保护机制，从而增加细胞对缺氧低氧的耐受。位于免疫细胞上的A 1受体在低氧环境中能促进细胞免疫应答。另外，A 1受体还能降低游离脂肪酸和甘油三酯，参与调节血糖。因此，A 1受体的持续阻断可能会引起机体组织中各种不良反应的发生(Chinese Pharmacological Bulletin,2008,24(5),573-576)。如有文献报道，在动物模型上，阻断A 1受体将会产生焦虑、觉醒等不良反应(Basic&Clinical Pharmacology&Toxicology,2011,109(3),203-7)。在心肌缺血期间，腺苷A 3受体(如Gessi S等人，Pharmacol.Ther.117(1),2008,123-140所述)能在心脏保护中发挥作用，A 3受体的持续阻断可能增加由任何预先存在的或正在发展的缺血性心脏病引起的并发症的可能性，所述缺血性心脏病诸如心绞痛或心衰。 Although compounds with significant biological activity on multiple adenosine receptor subtypes can have therapeutic effects, they can cause undesirable side effects. For example, when the adenosine A 1 receptor is tissue ischemia/hypoxia, in the central, circulatory, digestive system, and skeletal muscles, when cells are in a hypoxic and hypoxic stress environment, adenosine accumulated outside the cell activates The A 1 receptor on the cell membrane initiates the corresponding protective mechanism, thereby increasing the cell's tolerance to hypoxia and hypoxia. Located on the immune cells in a hypoxic environment A 1 receptor can promote the cellular immune response. In addition, A 1 receptors can also reduce free fatty acids and triglycerides, and participate in the regulation of blood sugar. Therefore, continuous blockade of A 1 receptor may cause various adverse reactions in the body tissues (Chinese Pharmacological Bulletin, 2008, 24(5), 573-576). If reported in the literature, in animal models, blocking the A 1 receptor will cause adverse reactions such as anxiety and arousal (Basic&Clinical Pharmacology&Toxicology, 2011,109(3),203-7). During myocardial ischemia, the adenosine A 3 receptor (as described in Gessi S et al., Pharmacol. Ther. 117(1), 2008, 123-140) can play a role in cardioprotection, and the A 3 receptor continues Blocking may increase the likelihood of complications caused by any pre-existing or developing ischemic heart disease, such as angina or heart failure.
目前，虽然已有许多化合物被开发为A 2a受体的拮抗剂用于治疗很多疾病，如WO2007116106、WO2009080197、WO2011159302、WO2011095625、WO2014101373、WO2015031221中所述。 At present, although many compounds have been developed as A 2a receptor antagonists for the treatment of many diseases, such as described in WO2007116106, WO2009080197, WO2011159302, WO2011095625, WO2014101373, WO2015031221.
发明内容Summary of the invention
本公开的目的在于提供一种通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：The purpose of the present disclosure is to provide a compound represented by general formula (I), or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form or its pharmaceutically acceptable salt:
Figure PCTCN2020074091-appb-000001
Figure PCTCN2020074091-appb-000001
其中：among them:
环A和环B相同或不同，且各自独立地为芳基或杂芳基；Ring A and Ring B are the same or different, and each independently is an aryl group or a heteroaryl group;
环C为7-14元多环杂环基；Ring C is a 7-14 membered polycyclic heterocyclic group;
L选自键、亚烷基、O原子、S原子和NR 5； L is selected from bond, alkylene, O atom, S atom and NR 5 ;
R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、氘代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基； R 1 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, deuterated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, Heterocyclic group, aryl group and heteroaryl group;
R 2选自氢原子、卤素、烷基、烷氧基、卤代烷基、氘代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基； R 2 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, deuterated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and hetero Aryl;
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、氘代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基； R 3 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, deuterated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, Heterocyclic group, aryl group and heteroaryl group;
R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、氘代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基； R 4 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, deuterated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, Heterocyclic group, aryl group and heteroaryl group;
R 5选自氢原子、烷基、氘代烷基、卤代烷基、羟烷基、环烷基和杂环基； R 5 is selected from hydrogen atom, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, cycloalkyl group and heterocyclic group;
m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
n为0、1、2或3；且n is 0, 1, 2 or 3; and
s为0、1、2、3、4、5或6。s is 0, 1, 2, 3, 4, 5, or 6.
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中：环A和环B相同或不同，且各自独立地为苯基或吡啶基。In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomers, mesosomes, racemates, enantiomers, diastereomers Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein: ring A and ring B are the same or different, and each independently is phenyl or pyridyl.
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其为通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomers, mesosomes, racemates, enantiomers, diastereomers Isomers, or mixtures thereof or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (II), or tautomers, mesoisomers, racemates, enantiomers thereof Forms, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
Figure PCTCN2020074091-appb-000002
Figure PCTCN2020074091-appb-000002
其中：among them:
环C、L、R 1～R 4、m、n和s如通式(I)化合物中所定义。 Rings C, L, R 1 to R 4 , m, n and s are as defined in the compound of general formula (I).
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中：环C选自7-14元螺环杂环基、7-14元稠环杂环基和7-14元桥环杂环基；优选为7-9元螺环杂环基或7-9元稠环杂环基。In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomers, mesosomes, racemates, enantiomers, diastereomers Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein: ring C is selected from the group consisting of 7-14 membered spirocyclic heterocyclic group, 7-14 membered fused ring heterocyclic group and 7-14 membered bridged heterocyclic ring Group; preferably a 7-9 membered spirocyclic heterocyclic group or a 7-9 membered condensed ring heterocyclic group.
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物，，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中：In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, mesosome, racemate, enantiomer, or non-pair Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein:
环C为
Figure PCTCN2020074091-appb-000003
Ring C is
Figure PCTCN2020074091-appb-000003
G选自C(R 4) 2、O原子和N原子； G is selected from C(R 4 ) 2 , O atom and N atom;
p、q、r和t相同或不同，且各自独立地为1或2；p, q, r and t are the same or different, and each independently is 1 or 2;
R 4如通式(I)化合物中所定义。 R 4 is as defined in the compound of general formula (I).
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其为通式(III)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomers, mesosomes, racemates, enantiomers, diastereomers Isomer, or its mixture form or its pharmaceutically acceptable salt, which is a compound represented by general formula (III), or its tautomer, meso, racemate, enantiomer Forms, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
Figure PCTCN2020074091-appb-000004
Figure PCTCN2020074091-appb-000004
其中：among them:
G选自C(R 4) 2、O原子或N原子； G is selected from C(R 4 ) 2 , O atom or N atom;
p、q、r和t相同或不同，且各自独立地为1或2；p, q, r and t are the same or different, and each independently is 1 or 2;
s为0、1、2、3或4；s is 0, 1, 2, 3 or 4;
L、R 1～R 4、m和n如通式(I)中所定义。在本公开一些优选的实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中所述的L为键或-CH 2-。 L, R 1 to R 4 , m and n are as defined in the general formula (I). In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomers, mesosomes, racemates, enantiomers, diastereomers Isomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein said L is a bond or -CH 2 -.
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其为通式(IIIaa)所示的化合物：In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomers, mesosomes, racemates, enantiomers, diastereomers Isomer, or its mixture form or its pharmaceutically acceptable salt, which is a compound represented by general formula (IIIaa):
Figure PCTCN2020074091-appb-000005
Figure PCTCN2020074091-appb-000005
其中：among them:
G选自C(R 4) 2、O原子或N原子； G is selected from C(R 4 ) 2 , O atom or N atom;
p、q、r和t相同或不同，且各自独立地为1或2；p, q, r and t are the same or different, and each independently is 1 or 2;
s为0、1、2、3或4；s is 0, 1, 2, 3 or 4;
R 1～R 4、m和n如通式(I)化合物中所定义。 R 1 to R 4 , m and n are as defined in the compound of general formula (I).
在本公开一些优选的实施方案中，所述的通式(III)或(IIIaa)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中，G为O原子。In some preferred embodiments of the present disclosure, the compound represented by the general formula (III) or (IIIaa), or its tautomer, mesosome, racemate, or enantiomer , Diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein G is an O atom.
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中：环C选自
Figure PCTCN2020074091-appb-000006
和
Figure PCTCN2020074091-appb-000007
In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomers, mesosomes, racemates, enantiomers, diastereomers Isomer, or its mixture form or its pharmaceutically acceptable salt, wherein: ring C is selected from
Figure PCTCN2020074091-appb-000006
with
Figure PCTCN2020074091-appb-000007
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 1相同或不同，且各自独立地选自选自氢原子、烷基、卤代烷基和氰基；m为0、1或2。 In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomers, mesosomes, racemates, enantiomers, diastereomers Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 1 is the same or different, and each is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group and a cyano group; m is 0, 1 or 2 .
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中：R 2选自氢原子、卤素和烷基；优选为氢原子；R 3相同或不同，且各自独立地选自氢原子、卤素和烷基；n为0、1或2。 In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomers, mesosomes, racemates, enantiomers, diastereomers Isomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein: R 2 is selected from a hydrogen atom, a halogen and an alkyl group; preferably a hydrogen atom; R 3 is the same or different, and each is independently selected from a hydrogen atom, Halogen and alkyl; n is 0, 1, or 2.
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 4为氢原子。 In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomers, mesosomes, racemates, enantiomers, diastereomers An isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen atom.
本公开的典型化合物包括但不限于：Typical compounds of the present disclosure include but are not limited to:
Figure PCTCN2020074091-appb-000008
Figure PCTCN2020074091-appb-000008
Figure PCTCN2020074091-appb-000009
Figure PCTCN2020074091-appb-000009
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐。Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof.
本公开的另一方面涉及通式(IA)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：Another aspect of the present disclosure relates to the compound represented by the general formula (IA), or its tautomer, meso, racemate, enantiomer, diastereomer, or Mixture form or its pharmaceutically acceptable salt:
Figure PCTCN2020074091-appb-000010
Figure PCTCN2020074091-appb-000010
其中：among them:
W为氨基保护基；优选为叔丁氧羰基；W is an amino protecting group; preferably tert-butoxycarbonyl;
环A、环B、环C、L、R 1～R 4、m、n和s如通式(I)化合物中所定义。其为制备通式(I)化合物的中间体。 Ring A, ring B, ring C, L, R 1 to R 4 , m, n and s are as defined in the compound of general formula (I). It is an intermediate for the preparation of compounds of general formula (I).
本公开的另一方面涉及通式(IIA)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：Another aspect of the present disclosure relates to the compound represented by the general formula (IIA), or its tautomer, meso, racemate, enantiomer, diastereomer, or Mixture form or its pharmaceutically acceptable salt:
Figure PCTCN2020074091-appb-000011
Figure PCTCN2020074091-appb-000011
其中：among them:
W为氨基保护基；优选为叔丁氧羰基；W is an amino protecting group; preferably tert-butoxycarbonyl;
环C、L、R 1～R 4、m、n和s如通式(II)化合物中所定义。其为制备通式(II)化合物的中间体。 Rings C, L, R 1 to R 4 , m, n and s are as defined in the compound of general formula (II). It is an intermediate for the preparation of compounds of general formula (II).
本公开的另一方面涉及通式(IIIA)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：Another aspect of the present disclosure relates to the compound represented by general formula (IIIA), or its tautomer, meso, racemate, enantiomer, diastereomer, or Mixture form or its pharmaceutically acceptable salt:
Figure PCTCN2020074091-appb-000012
Figure PCTCN2020074091-appb-000012
其中：among them:
W为氨基保护基；优选为叔丁氧羰基；W is an amino protecting group; preferably tert-butoxycarbonyl;
G、L、R 1～R 4、m、n、s、p、q、r和t如通式(III)化合物中所定义。其为制备通式(III)化合物的中间体。 G, L, R 1 to R 4 , m, n, s, p, q, r and t are as defined in the compound of general formula (III). It is an intermediate for the preparation of compounds of general formula (III).
本公开的另一方面涉及通式(IIIa)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：Another aspect of the present disclosure relates to the compound represented by general formula (IIIa), or its tautomer, meso, racemate, enantiomer, diastereomer, or Mixture form or its pharmaceutically acceptable salt:
Figure PCTCN2020074091-appb-000013
Figure PCTCN2020074091-appb-000013
其中：among them:
W为氨基保护基；优选为叔丁氧羰基；W is an amino protecting group; preferably tert-butoxycarbonyl;
G、R 1～R 4、m、n、s、p、q、r和t如通式(IIIaa)化合物中所定义。其为制备通式(IIIaa)化合物的中间体。 G, R 1 to R 4 , m, n, s, p, q, r, and t are as defined in the compound of general formula (IIIaa). It is an intermediate for the preparation of compounds of general formula (IIIaa).
本公开的典型化合物包括但不限于：Typical compounds of the present disclosure include but are not limited to:
Figure PCTCN2020074091-appb-000014
Figure PCTCN2020074091-appb-000014
Figure PCTCN2020074091-appb-000015
Figure PCTCN2020074091-appb-000015
本公开的另一方面涉及一种制备通式(IA)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IA), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
Figure PCTCN2020074091-appb-000016
Figure PCTCN2020074091-appb-000016
通式(IB)的化合物和通式(ID)的化合物发生Click反应，得到通式(IA)的化合物，The compound of general formula (IB) and the compound of general formula (ID) undergo a Click reaction to obtain the compound of general formula (IA),
其中：among them:
环A、环B、环C、L、W、R 1～R 4、m、n和s如通式(IA)化合物中所定义。 Ring A, ring B, ring C, L, W, R 1 to R 4 , m, n, and s are as defined in the compound of general formula (IA).
本公开的另一方面涉及一种制备通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method has the following steps:
Figure PCTCN2020074091-appb-000017
Figure PCTCN2020074091-appb-000017
通式(IA)的化合物脱去氨基保护基，得到通式(I)的化合物，The compound of general formula (IA) removes the amino protecting group to obtain the compound of general formula (I),
其中：among them:
W为氨基保护基；优选为叔丁氧羰基；W is an amino protecting group; preferably tert-butoxycarbonyl;
环A、环B、环C、L、R 1～R 4、m、n和s如通式(I)化合物中所定义。 Ring A, ring B, ring C, L, R 1 to R 4 , m, n and s are as defined in the compound of general formula (I).
本公开的另一方面涉及一种制备通式(I)所示的化合物，或其互变异构体、内 消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
Figure PCTCN2020074091-appb-000018
Figure PCTCN2020074091-appb-000018
通式(IB)的化合物和通式(IC)的化合物发生Click反应，得到通式(I)的化合物，The compound of general formula (IB) and the compound of general formula (IC) undergo a Click reaction to obtain a compound of general formula (I),
其中：among them:
环A、环B、环C、L、R 1～R 4、m、n和s如通式(I)化合物中所定义。 Ring A, ring B, ring C, L, R 1 to R 4 , m, n and s are as defined in the compound of general formula (I).
本公开的另一方面涉及一种制备通式(IIA)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIA), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
Figure PCTCN2020074091-appb-000019
Figure PCTCN2020074091-appb-000019
通式(IIB)的化合物和通式(IID)的化合物发生Click反应，得到通式(IIA)的化合物，The compound of general formula (IIB) and the compound of general formula (IID) undergo Click reaction to obtain the compound of general formula (IIA),
其中：among them:
环C、L、W、R 1～R 4、m、n和s如通式(IIA)化合物中所定义。 Rings C, L, W, R 1 to R 4 , m, n and s are as defined in the compound of general formula (IIA).
本公开的另一方面涉及一种制备通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
Figure PCTCN2020074091-appb-000020
Figure PCTCN2020074091-appb-000020
通式(IIA)的化合物脱去氨基保护基，得到通式(II)的化合物，The compound of general formula (IIA) removes the amino protecting group to obtain the compound of general formula (II),
其中：among them:
W为氨基保护基；优选为叔丁氧羰基；W is an amino protecting group; preferably tert-butoxycarbonyl;
环C、L、R 1～R 4、m、n和s如通式(II)化合物中所定义。 Rings C, L, R 1 to R 4 , m, n and s are as defined in the compound of general formula (II).
本公开的另一方面涉及一种制备通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
Figure PCTCN2020074091-appb-000021
Figure PCTCN2020074091-appb-000021
通式(IB)的化合物和通式(IIC)的化合物发生Click反应，得到通式(II)的化合物，The compound of general formula (IB) and the compound of general formula (IIC) undergo a Click reaction to obtain a compound of general formula (II),
其中：among them:
环C、L、R 1～R 4、m、n和s如通式(II)化合物中所定义。 Rings C, L, R 1 to R 4 , m, n and s are as defined in the compound of general formula (II).
本公开的另一方面涉及一种制备通式(IIIA)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIIA), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
Figure PCTCN2020074091-appb-000022
Figure PCTCN2020074091-appb-000022
通式(IIIB)的化合物和通式(IID)的化合物发生Click反应，得到通式(IIIA)的化合物，The compound of general formula (IIIB) and the compound of general formula (IID) undergo Click reaction to obtain the compound of general formula (IIIA),
其中：among them:
G、L、W、R 1～R 4、m、n、s、p、q、r和t如通式(IIIA)化合物中所定义。 G, L, W, R 1 to R 4 , m, n, s, p, q, r and t are as defined in the compound of general formula (IIIA).
本公开的另一方面涉及一种制备通式(III)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III), or its tautomer, meso, racemate, enantiomer, diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
Figure PCTCN2020074091-appb-000023
Figure PCTCN2020074091-appb-000023
通式(IIIA)的化合物脱去氨基保护基，得到通式(III)的化合物，The compound of general formula (IIIA) removes the amino protecting group to obtain the compound of general formula (III),
其中：among them:
W为氨基保护基；优选为叔丁氧羰基；W is an amino protecting group; preferably tert-butoxycarbonyl;
G、L、R 1～R 4、m、n、s、p、q、r和t如通式(III)化合物中所定义。 G, L, R 1 to R 4 , m, n, s, p, q, r and t are as defined in the compound of general formula (III).
本公开的另一方面涉及一种制备通式(III)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III), or its tautomer, meso, racemate, enantiomer, diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
Figure PCTCN2020074091-appb-000024
Figure PCTCN2020074091-appb-000024
通式(IIIB)的化合物和通式(IIC)的化合物发生Click反应，得到通式(III)的化合物，The compound of general formula (IIIB) and the compound of general formula (IIC) undergo Click reaction to obtain the compound of general formula (III),
其中：among them:
G、L、R 1～R 4、m、n、s、p、q、r和t如通式(III)化合物中所定义。 G, L, R 1 to R 4 , m, n, s, p, q, r and t are as defined in the compound of general formula (III).
本公开的另一方面涉及一种制备通式(IIIa)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIIa), or its tautomer, meso, racemate, enantiomer, diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
Figure PCTCN2020074091-appb-000025
Figure PCTCN2020074091-appb-000025
通式(IIIb)的化合物和通式(IID)的化合物发生Click反应，得到通式(IIIa)的化合物，The compound of general formula (IIIb) and the compound of general formula (IID) undergo Click reaction to obtain the compound of general formula (IIIa),
其中：among them:
G、W、R 1～R 4、m、n、s、p、q、r和t如通式(IIIa)化合物中所定义。 G, W, R 1 to R 4 , m, n, s, p, q, r and t are as defined in the compound of general formula (IIIa).
本公开的另一方面涉及一种制备通式(IIIaa)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IIIaa), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
Figure PCTCN2020074091-appb-000026
Figure PCTCN2020074091-appb-000026
通式(IIIa)的化合物脱去氨基保护基，得到通式(IIIaa)的化合物，The compound of general formula (IIIa) removes the amino protecting group to obtain the compound of general formula (IIIaa),
其中：among them:
W为氨基保护基；优选为叔丁氧羰基；W is an amino protecting group; preferably tert-butoxycarbonyl;
G、R 1～R 4、m、n、s、p、q、r和t如通式(IIIaa)化合物中所定义。 G, R 1 to R 4 , m, n, s, p, q, r, and t are as defined in the compound of general formula (IIIaa).
本公开的另一方面涉及一种制备通式(IIIaa)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IIIaa), or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method comprises the following steps:
Figure PCTCN2020074091-appb-000027
Figure PCTCN2020074091-appb-000027
通式(IIIb)的化合物和通式(IIC)的化合物发生Click反应，得到通式(IIIaa)的化合物，The compound of general formula (IIIb) and the compound of general formula (IIC) undergo a Click reaction to obtain a compound of general formula (IIIaa),
其中：among them:
G、R 1～R 4、m、n、s、p、q、r和t如通式(IIIaa)化合物中所定义。 G, R 1 to R 4 , m, n, s, p, q, r, and t are as defined in the compound of general formula (IIIaa).
本公开的另一方面涉及一种药物组合物，其含有治疗有效量的本公开通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。本公开还涉及一种制备上述药物组合物的方法，其包括将各通式所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐与药学上可接受的载体、稀释剂或赋形剂相混合。Another aspect of the present disclosure relates to a pharmaceutical composition containing a therapeutically effective amount of the compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer Isomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. The present disclosure also relates to a method for preparing the above-mentioned pharmaceutical composition, which comprises combining the compound represented by each general formula or its tautomer, meso, racemate, enantiomer, and non-pair The enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof are mixed with pharmaceutically acceptable carriers, diluents or excipients.
本公开进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物在制备抑制A 2a受体和/或A 2b受体的药物中的用途。 The present disclosure further relates to the compound represented by the general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or mixture thereof, or The use of a pharmaceutically acceptable salt or a pharmaceutical composition containing the same in the preparation of a medicament for inhibiting A 2a receptor and/or A 2b receptor.
本公开进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物在制备用于治疗通过对A 2a受体和/或A 2b受体抑制而改善的疾病或病 症的药物中的用途。 The present disclosure further relates to the compound represented by the general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or mixture thereof, or The use of a pharmaceutically acceptable salt or a pharmaceutical composition containing the same in the preparation of a medicament for the treatment of diseases or conditions that are improved by inhibiting the A 2a receptor and/or A 2b receptor.
本公开进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物在制备治疗癌症、抑郁、认知功能病症、神经退行性病症(帕金森氏病、亨廷顿氏病、阿尔茨海默氏病或肌萎缩性侧索硬化等)、注意力相关病症、锥体外症候群、异常运动障碍、肝硬化、肝纤维化、脂肪肝、皮肤纤维化、睡眠障碍、中风、脑损伤、神经炎症和成瘾行为的药物中的用途，优选为在制备治疗癌症的药物中的用途。The present disclosure further relates to the compound represented by the general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or mixture thereof, or A pharmaceutically acceptable salt or a pharmaceutical composition containing it is used in the preparation of treatment of cancer, depression, cognitive function disorders, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic lateral Cirrhosis, etc.), attention-related disorders, extrapyramidal syndrome, abnormal movement disorders, liver cirrhosis, liver fibrosis, fatty liver, skin fibrosis, sleep disorders, stroke, brain injury, neuroinflammation, and use in drugs for addictive behavior , Preferably for use in the preparation of drugs for treating cancer.
本公开进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物在制备治疗癌症的药物中的用途，其中所述的癌症选自黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、乳腺癌、卵巢癌、***癌、皮肤癌、神经母细胞瘤、肉瘤、骨软骨瘤、骨瘤、骨肉瘤、***瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱癌、胆囊癌、胆管癌、绒毛膜上皮癌和儿科肿瘤；优选为肺癌。The present disclosure further relates to the compound represented by the general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or mixture thereof, or The use of a pharmaceutically acceptable salt or a pharmaceutical composition containing it in the preparation of a medicament for the treatment of cancer, wherein the cancer is selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer , Kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple bone marrow Tumor, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder cancer, gallbladder cancer, cholangiocarcinoma, choriocarcinoma and pediatric tumor; preferably lung cancer.
本公开进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物在制备用于抑制A 2a受体和/或A 2b受体的药物中的用途。 The present disclosure further relates to the compound represented by the general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer or mixture thereof, or The use of a pharmaceutically acceptable salt or a pharmaceutical composition containing the same in the preparation of a medicament for inhibiting A 2a receptor and/or A 2b receptor.
本公开还涉及一种抑制A 2a受体和/或A 2b受体的方法，其包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物。 The present disclosure also relates to a method for inhibiting A 2a receptor and/or A 2b receptor, which comprises administering to a patient a therapeutically effective amount of a compound represented by general formula (I) or a tautomer or internal elimination Rotates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
本公开还涉及一种治疗通过对A 2a受体和/或A 2b受体抑制而改善的疾病或病症的方法，其包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物。 The present disclosure also relates to a method for treating diseases or conditions improved by inhibiting A 2a receptor and/or A 2b receptor, which comprises administering a therapeutically effective amount of a compound represented by general formula (I) or Tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
本公开涉及一种治疗癌症、抑郁、认知功能病症、神经退行性病症(帕金森氏病、亨廷顿氏病、阿尔茨海默氏病或肌萎缩性侧索硬化等)、注意力相关病症、锥体外症候群、异常运动障碍、肝硬化、肝纤维化、脂肪肝、皮肤纤维化、睡眠障碍、中风、脑损伤、神经炎症和成瘾行为，优选癌症的方法，其包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物。The present disclosure relates to a treatment for cancer, depression, cognitive disorders, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic lateral sclerosis, etc.), attention-related disorders, Extrapyramidal syndrome, abnormal dyskinesia, liver cirrhosis, liver fibrosis, fatty liver, skin fibrosis, sleep disorders, stroke, brain injury, neuroinflammation and addictive behaviors, preferably cancer methods, which include administering effective treatment to patients in need The amount of the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or its mixture form, or its medicine Salts, or pharmaceutical compositions containing them.
本公开进一步涉及一种治疗癌症的方法，其包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物，其中所述 的癌症选自黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、乳腺癌、卵巢癌、***癌、皮肤癌、神经母细胞瘤、肉瘤、骨软骨瘤、骨瘤、骨肉瘤、***瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱癌、胆囊癌、胆管癌、绒毛膜上皮癌和儿科肿瘤；优选为肺癌。The present disclosure further relates to a method for treating cancer, which comprises administering a therapeutically effective amount of a compound represented by general formula (I) or its tautomers, mesosomes, racemates, and enantiomers to a desired patient. Isomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, wherein the cancer is selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, Pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterus Cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder cancer, gallbladder cancer, cholangiocarcinoma, choriocarcinoma and pediatric tumor; preferably lung cancer.
本公开进一步涉及一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或包含其的药物组合物，其用作药物。The present disclosure further relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, which is used as a medicine.
本公开还涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物，其用作A 2a受体和/或A 2b受体拮抗剂。 The present disclosure also relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, is used as an A 2a receptor and/or A 2b receptor antagonist.
本公开还涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物，其用于治疗通过对A 2a受体和/或A 2b受体抑制而改善的疾病或病症。 The present disclosure also relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, is used for the treatment of diseases or conditions that are improved by inhibiting the A 2a receptor and/or A 2b receptor.
本公开还涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物，其用于治疗癌症、抑郁、认知功能病症、神经退行性病症(帕金森氏病、亨廷顿氏病、阿尔茨海默氏病或肌萎缩性侧索硬化等)、注意力相关病症、锥体外症候群、异常运动障碍、肝硬化、肝纤维化、脂肪肝、皮肤纤维化、睡眠障碍、中风、脑损伤、神经炎症和成瘾行为，优选癌症。The present disclosure also relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition containing it, is used for the treatment of cancer, depression, cognitive function disorders, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease, or amyotrophic Lateral sclerosis, etc.), attention-related disorders, extrapyramidal syndrome, abnormal movement disorders, liver cirrhosis, liver fibrosis, fatty liver, skin fibrosis, sleep disorders, stroke, brain injury, neuroinflammation and addictive behaviors, preferably cancer .
在本公开中，通过对A 2a受体和/或A 2b受体抑制而改善的疾病或病症选自癌症、抑郁、认知功能病症、神经退行性病症(帕金森氏病、亨廷顿氏病、阿尔茨海默氏病或肌萎缩性侧索硬化等)、注意力相关病症、锥体外症候群、异常运动障碍、肝硬化、肝纤维化、脂肪肝、皮肤纤维化、睡眠障碍、中风、脑损伤、神经炎症和成瘾行为；优选为癌症，所述癌症选自黑色素瘤、脑瘤(具有恶性的星形神经胶质和少突神经胶质细胞瘤成分的神经胶质瘤等)、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌(结肠癌、直肠癌等)、肺癌(非小细胞肺癌、小细胞肺癌、原发或转移性鳞状癌等)、肾癌、乳腺癌、卵巢癌、***癌、皮肤癌、神经母细胞瘤、肉瘤、骨软骨瘤、骨瘤、骨肉瘤、***瘤、睾丸肿瘤、子宫癌(子***、子宫内膜癌等)、头颈肿瘤(上颌骨癌、喉癌、咽癌、舌癌、口内癌等)、多发性骨髓瘤、恶性淋巴瘤(网状细胞肉瘤、淋巴肉瘤、霍奇金淋巴瘤等)、真性红细胞增多症、白血病(急性粒细胞白血病、慢性粒细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病等)、甲状腺肿瘤、输尿管肿瘤、***、胆囊癌、胆管癌、绒毛膜上皮癌和儿科肿瘤(尤因家族性肉瘤、维尔姆斯肉瘤、横纹肌肉瘤、血管肉瘤、胚胎睾丸癌、成神经细胞瘤、视网膜母细胞瘤、肝胚细胞瘤、肾母细胞瘤等)等；更优选为肺癌。 In the present disclosure, the disease or condition ameliorated by inhibition of A 2a receptor and/or A 2b receptor is selected from cancer, depression, cognitive function disorders, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic lateral sclerosis, etc.), attention-related disorders, extrapyramidal syndrome, abnormal movement disorders, cirrhosis, liver fibrosis, fatty liver, skin fibrosis, sleep disorders, stroke, brain damage , Neuroinflammation and addictive behavior; preferably cancer, the cancer is selected from melanoma, brain tumor (glioma with malignant astroglioma and oligodendroglioma components, etc.), esophageal cancer , Stomach cancer, liver cancer, pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cancer, etc.), kidney cancer, breast cancer, ovarian cancer , Prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer (cervical cancer, endometrial cancer, etc.), head and neck tumors (upper jaw Bone cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, intraoral cancer, etc.), multiple myeloma, malignant lymphoma (reticular cell sarcoma, lymphosarcoma, Hodgkin’s lymphoma, etc.), polycythemia vera, leukemia (acute Myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), thyroid tumors, ureteral tumors, bladder tumors, gallbladder cancer, cholangiocarcinoma, choriocarcinoma and pediatric tumors (Ewing familial sarcoma, Wilms sarcoma, rhabdomyosarcoma, hemangiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatoblastoma, Wilms tumor, etc.) etc.; more preferably lung cancer.
本发明中所述的治疗方法中所用化合物或组合物的剂量通常将随疾病的严重性、患者的体重和化合物的相对功效而改变。但作为一般性指导，合适的单位剂量可以是0.1～1000mg。The dosage of the compound or composition used in the treatment methods described in the present invention will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound. But as a general guide, a suitable unit dose can be 0.1-1000 mg.
本发明中所述药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。In addition to the active compound, the pharmaceutical composition of the present invention may contain one or more auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Shape agent and so on. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs. The oral composition may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, In order to provide pleasing and delicious medicinal preparations. The tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. The aqueous suspension may also contain one or more preservatives such as ethyl paraben or n-propyl paraben, one or more coloring agents, one or more flavoring agents and one or more sweeteners. Flavoring agent.
油混悬液可通过使活性成分悬浮于植物油中配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。Oil suspensions can be formulated by suspending active ingredients in vegetable oils. The oil suspension may contain thickeners. The above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation.
通过加入水可使适用于制备水混悬液的可分散粉末和颗粒提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂可说明上述的例子。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。By adding water, dispersible powders and granules suitable for preparing aqueous suspensions can be provided with active ingredients and dispersing or wetting agents for mixing, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can illustrate the above examples. Other excipients such as sweeteners, flavoring agents and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.
本公开的药物组合物也可以是水包油乳剂的形式。The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion.
药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Acceptable solvents or solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. The sterile injection preparation may be a sterile injection oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. Then the oil solution is added to a mixture of water and glycerin to form a microemulsion. The injection or microemulsion can be injected into the patient's bloodstream by local large-scale injection. Alternatively, it is best to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.
药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。The pharmaceutical composition may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injection preparation can also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oil can be conveniently used as a solvent or suspension medium.
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植 物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。The compounds of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug. Such substances include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycol.
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、***的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、通式化合物(I)的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。As is well known to those skilled in the art, the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient , The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best mode of treatment such as the mode of treatment, the daily dosage of the compound (I) or the amount of pharmaceutically acceptable salt The type can be verified according to the traditional treatment plan.
发明的详细说明Detailed description of the invention
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代。The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably containing 1 to 6 carbon atoms Atom of the alkyl group. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl 2-methylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers. More preferred are lower alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl. Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted. When substituted, substituents may be substituted at any available attachment point. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, and alkyl groups. One or more substituents of oxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted.
术语“亚烷基”指饱和的直链或支链脂肪族烃基，其具有2个从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子，更优选含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2-)、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)和1,5- 亚丁基(-CH 2CH 2CH 2CH 2CH 2-)等。亚烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基所取代。 The term "alkylene" refers to a saturated linear or branched aliphatic hydrocarbon group, which has two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is A straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 carbon atoms, more preferably an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene include but are not limited to methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 -) CH 2 -), 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), and 1,5-butylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -) Wait. The alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy , Cycloalkylthio, heterocycloalkylthio and oxo groups are substituted by one or more substituents.
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代。The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl , Hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl substituted by one or more substituents.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，优选包含3至10个碳原子，更优选包含3至6(例如3、4、5或6)个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 10 The carbon atom more preferably contains 3 to 6 (e.g. 3, 4, 5 or 6) carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl groups, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至14元，最优选为7至9元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：The term "spirocycloalkyl" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings, which may contain one or more double bonds, but none of the rings have complete conjugate Π electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 14 yuan, and most preferably 7 to 9 yuan. According to the number of shared spiro atoms between the ring and the ring, the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
Figure PCTCN2020074091-appb-000028
Figure PCTCN2020074091-appb-000028
术语“稠环烷基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至14元，最优选为7至9元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：The term "fused cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 yuan, more preferably 7 to 14 yuan, and most preferably 7 to 9 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably bicyclic or tricyclic, more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered , 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:
Figure PCTCN2020074091-appb-000029
Figure PCTCN2020074091-appb-000029
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至14元，最优选为7至9元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：The term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has complete Conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 14 yuan, and most preferably 7 to 9 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
Figure PCTCN2020074091-appb-000030
Figure PCTCN2020074091-appb-000030
所述环烷基环包括上述环烷基(例如单环、稠环、螺环和桥环环烷基)稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等；优选苯基并环戊基、四氢萘基。The cycloalkyl ring includes the above-mentioned cycloalkyl groups (such as monocyclic, fused ring, spiro ring and bridged cycloalkyl) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein it is connected to the parent structure The ring together is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; preferably phenylcyclopentyl, tetrahydronaphthyl.
环烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、杂环基氧基、芳基和杂芳基中的一个或多个取代基所取代。Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment. The substituents are preferably independently optionally selected from hydrogen, halogen, alkyl, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, heterocyclyloxy, aryl, and heteroaryl are substituted by one or more substituents replace.
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) g(其中g是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至14个环原子，其中1～4个是杂原子；更优选包含7至14个环原子，其中1-4是杂原子；更优选包含7至9个环原子，其中1-3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、四氢吡喃基、1,2.3.6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) g (where g is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 14 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 7 to 14 ring atoms, of which 1-4 are heteroatoms; more preferably contains 7 to 9 ring atoms, of which 1-3 One is a heteroatom. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl and so on. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
术语“螺环杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) g(其中g是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为7至14元，更优选为7至9元(例如7、8或9)。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂 环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括： The term "spirocyclic heterocyclic group" refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between 5- to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S( O) Heteroatoms of g (where g is an integer of 0 to 2), and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 7 to 14 yuan, more preferably 7 to 9 yuan (for example, 7, 8, or 9). According to the number of spiro atoms shared between the ring and the ring, the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiroheterocyclic groups include:
Figure PCTCN2020074091-appb-000031
Figure PCTCN2020074091-appb-000031
术语“稠环杂环基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) g(其中g是整数0至2)的杂原子，其余环原子为碳。优选为7至14元稠环杂环基，更优选为7至9元(例如7、8或9)。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括： The term "fused ring heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bonds, but none of the rings have a fully conjugated π-electron system, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) g (where g is an integer from 0 to 2), and the rest The ring atoms are carbon. It is preferably a 7 to 14 membered condensed ring heterocyclic group, more preferably 7 to 9 membered (for example, 7, 8, or 9). According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:
Figure PCTCN2020074091-appb-000032
Figure PCTCN2020074091-appb-000032
术语“桥环杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) g(其中g是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至14元，最优选为7至9元(例如7、8或9)。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括： The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but no ring has complete A conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) g (where g is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 14 yuan, and most preferably 7 to 9 yuan (for example, 7, 8, or 9). According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure PCTCN2020074091-appb-000033
Figure PCTCN2020074091-appb-000033
所述杂环基环包括上述杂环基(例如单环、稠环、螺环和桥环杂环基)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：The heterocyclic ring includes the above heterocyclic groups (for example, monocyclic, fused ring, spiro ring and bridged heterocyclic group) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the parent structure is connected to The ring together is a heterocyclic group, non-limiting examples of which include:
Figure PCTCN2020074091-appb-000034
Figure PCTCN2020074091-appb-000034
杂环基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代。The heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, One or more substituents among alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环包括上述芳基稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated π-electron system, preferably 6 to 10 members, such as benzene Base and naphthyl. The aryl ring includes the above-mentioned aryl group fused on a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
Figure PCTCN2020074091-appb-000035
Figure PCTCN2020074091-appb-000035
芳基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、杂环基氧基、芳基和杂芳基中的一个或多个取代基所取代。The aryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably independently optionally selected from the group consisting of hydrogen, halogen, alkyl, and alkane. Substituted by one or more substituents of oxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, heterocyclyloxy, aryl and heteroaryl .
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，更优选为5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、四唑基等。所述杂芳基环包括上述杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl groups are preferably 5 to 10 members, more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, Imidazolyl, pyrazolyl, tetrazolyl, etc. The heteroaryl ring includes the above-mentioned heteroaryl group fused on an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:
Figure PCTCN2020074091-appb-000036
Figure PCTCN2020074091-appb-000036
Figure PCTCN2020074091-appb-000037
Figure PCTCN2020074091-appb-000037
杂芳基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代。Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, One or more substituents among alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted.
术语“氨基保护基”是为了使分子其它部位进行反应时氨基保持不变，用易于脱去的基团对氨基进行保护。非限制性实施例包含叔丁基、叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基等。这些基团可任选地被选自卤素、烷氧基或硝基中的1-3个取代基所取代。所述氨基保护基优选为叔丁基或叔丁氧羰基。The term "amino protecting group" is to keep the amino group unchanged when other parts of the molecule react, and to protect the amino group with a group that is easy to remove. Non-limiting examples include tert-butyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro. The amino protecting group is preferably tert-butyl or tert-butoxycarbonyl.
术语“氧代基”指＝O。The term "oxo" refers to =O.
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。The term "heterocyclyloxy" refers to heterocyclyl -O-, wherein heterocyclyl is as defined above.
术语“杂环基烷基”指烷基被一个或多个杂环基取代，其中烷基和杂环基如上所定义。The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein alkyl and heterocyclyl are as defined above.
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
术语“羟基”指-OH。The term "hydroxy" refers to -OH.
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“氨基”指-NH 2。 The term "amino" refers to -NH 2 .
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO 2。 The term "nitro" refers to -NO 2 .
本公开的化合物还包括各种氘化形式的式(I)化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(I)化合物。在制备氘代形式的式(I)化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基 取代的情形。The compounds of the present disclosure also include compounds of formula (I) in various deuterated forms. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the compound of formula (I) in the deuterated form with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques using deuterated reagents. Deuterated reagents include but are not limited to deuterated borane, tri-deuterated Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc. "Optional" or "optionally" means that the event or environment described later can but does not have to occur, and the description includes the occasion where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but does not have to be present. The description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代，其中每个取代基都有独立的选项(即取代基可以相同，也可以不同)。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms independently of each other by a corresponding number of substituents, wherein each substituent has an independent (I.e. the substituents can be the same or different). It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。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。"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
“可药用盐”是指本公开化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。"Pharmaceutically acceptable salt" refers to the salt of the compound of the present disclosure. Such salt is safe and effective when used in mammals, and has due biological activity.
本公开的化合物还可包含其同位素衍生物。术语“同位素衍生物”指结构不同仅在于存在一种或多种同位素富集原子的化合物。例如，具有本公开的结构，除了用“氘”或“氚”代替氢，或者用 18F-氟标记( 18F同位素)代替氟，或者用 11C-， 13C-，或者 14C-富集的碳( 11C-， 13C-，或者 14C-碳标记； 11C-， 13C-，或者 14C-同位素)代替碳原子的化合物处于本公开的范围内。这样的化合物可用作例如生物学测定中的分析工具或探针，或者可以用作疾病的体内诊断成像示踪剂，或者作为药效学、药动学或受体研究的示踪剂。针对药物或药理学活性剂而言，术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。 The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, with the structure of the present disclosure, in addition to using "deuterium" or "tritium" instead of hydrogen, or using 18 F-fluorine label ( 18 F isotope) instead of fluorine, or using 11 C-, 13 C-, or 14 C-rich Compounds in which collective carbons ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C- isotopes) replace carbon atoms are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies. For drugs or pharmacologically active agents, the term "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.
因此本公开提供一种新型结构的强抑制活性的腺苷A 2b受体拮抗剂，同时具有此类结构的化合物对腺苷A 2a受体也具有很好的抑制作用，对腺苷A 1受体和腺苷A 3受体的抑制作用弱，是一种新型结构的选择性的腺苷A 2a受体和A 2b受体双抑制剂。 Therefore, the present disclosure provides a novel structure of adenosine A 2b receptor antagonist with strong inhibitory activity. At the same time, compounds with this structure also have a good inhibitory effect on adenosine A 2a receptors, and are affected by adenosine A 1 The inhibitory effect of the body and adenosine A 3 receptor is weak. It is a novel structure of selective adenosine A 2a receptor and A 2b receptor dual inhibitor.
本公开化合物的合成方法Synthetic method of the compound of the present disclosure
为了完成本公开的目的，本公开采用如下技术方案：In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical solutions:
方案一Option One
本公开通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：The compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or The preparation method of medicinal salt includes the following steps:
Figure PCTCN2020074091-appb-000038
Figure PCTCN2020074091-appb-000038
通式(IB)的化合物和通式(ID)的化合物在催化剂存在下，发生Click反应得到通式(IA)的化合物；通式(IA)的化合物在酸性条件下脱去氨基保护基，得到通式(I)的化合物；Compounds of general formula (IB) and compounds of general formula (ID) undergo Click reaction in the presence of a catalyst to obtain compounds of general formula (IA); compounds of general formula (IA) remove the amino protective group under acidic conditions to obtain Compound of general formula (I);
其中：among them:
W为氨基保护基，优选叔丁氧羰基；W is an amino protecting group, preferably tert-butoxycarbonyl;
环A、环B、环C、L、R 1～R 4、m、n和s如通式(I)中所定义。 Ring A, ring B, ring C, L, R 1 to R 4 , m, n, and s are as defined in the general formula (I).
所述的催化剂包括但不限于CuSO 4、CuSO 4 .5H 2O和CuI等。 The catalysts include, but are not limited to CuSO 4, CuSO 4. 5H 2 O and CuI and the like.
提供酸性条件的试剂包括但不限于三氟乙酸、吡啶氢溴酸盐、氢溴酸、乙酸、盐酸、硝酸、磷酸、对苯甲磺酸和硫酸，优选为三氟乙酸。Reagents that provide acidic conditions include, but are not limited to, trifluoroacetic acid, pyridine hydrobromide, hydrobromic acid, acetic acid, hydrochloric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, and sulfuric acid, preferably trifluoroacetic acid.
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、三氟乙酸、甲醇、乙醇、叔丁醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水或N,N-二甲基甲酰胺及其混合物。The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, tert-butanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane , Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
方案二Option II
本公开通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：The compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or The preparation method of medicinal salt includes the following steps:
Figure PCTCN2020074091-appb-000039
Figure PCTCN2020074091-appb-000039
通式(IB)的化合物和通式(IC)的化合物在催化剂存在下，发生Click反应得到通式(I)的化合物；Compounds of general formula (IB) and compounds of general formula (IC) undergo Click reaction in the presence of a catalyst to obtain compounds of general formula (I);
其中：among them:
环A、环B、环C、L、R 1～R 4、m、n和s如通式(I)中所定义。 Ring A, ring B, ring C, L, R 1 to R 4 , m, n, and s are as defined in the general formula (I).
所述的催化剂包括但不限于CuSO 4、CuSO 4 .5H 2O和CuI等。 The catalysts include, but are not limited to CuSO 4, CuSO 4. 5H 2 O and CuI and the like.
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、三氟乙酸、甲醇、乙醇、叔丁醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水或N,N-二甲基甲酰胺及其混合物。The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, tert-butanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane , Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
方案三third solution
本公开通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：The compound represented by the general formula (II) of the present disclosure, or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or The preparation method of medicinal salt includes the following steps:
Figure PCTCN2020074091-appb-000040
Figure PCTCN2020074091-appb-000040
通式(IIB)的化合物和通式(IID)的化合物在催化剂存在下，发生Click反应得到通式(IIA)的化合物；通式(IIA)的化合物在酸性条件下脱去氨基保护基，得到通式(II)的化合物；Compounds of general formula (IIB) and compounds of general formula (IID) undergo Click reaction in the presence of a catalyst to obtain compounds of general formula (IIA); compounds of general formula (IIA) remove the amino protective group under acidic conditions to obtain Compound of general formula (II);
其中：among them:
W为氨基保护基，优选叔丁氧羰基；W is an amino protecting group, preferably tert-butoxycarbonyl;
环C、L、R 1～R 4、m、n和s如通式(II)中所定义。 Rings C, L, R 1 to R 4 , m, n and s are as defined in the general formula (II).
所述的催化剂包括但不限于CuSO 4、CuSO 4 .5H 2O和CuI等。 The catalysts include, but are not limited to CuSO 4, CuSO 4. 5H 2 O and CuI and the like.
提供酸性条件的试剂包括但不限于三氟乙酸、吡啶氢溴酸盐、氢溴酸、乙酸、盐酸、硝酸、磷酸、对苯甲磺酸和硫酸，优选为三氟乙酸。Reagents that provide acidic conditions include, but are not limited to, trifluoroacetic acid, pyridine hydrobromide, hydrobromic acid, acetic acid, hydrochloric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, and sulfuric acid, preferably trifluoroacetic acid.
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、三氟乙酸、甲醇、乙醇、叔丁醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水或N,N-二甲基甲酰胺及其混合物。The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, tert-butanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane , Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
方案四Option Four
本公开通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：The compound represented by the general formula (II) of the present disclosure, or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or The preparation method of medicinal salt includes the following steps:
Figure PCTCN2020074091-appb-000041
Figure PCTCN2020074091-appb-000041
通式(IIB)的化合物和通式(IIC)的化合物在催化剂存在下，发生Click反应得到通式(II)的化合物；Compounds of general formula (IIB) and compounds of general formula (IIC) undergo Click reaction in the presence of a catalyst to obtain compounds of general formula (II);
其中：among them:
环C、L、R 1～R 4、m、n和s如通式(II)中所定义。 Rings C, L, R 1 to R 4 , m, n and s are as defined in the general formula (II).
所述的催化剂包括但不限于CuSO 4、CuSO 4 .5H 2O和CuI等。 The catalysts include, but are not limited to CuSO 4, CuSO 4. 5H 2 O and CuI and the like.
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、三氟乙酸、甲醇、乙醇、叔丁醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水或N,N-二甲基甲酰胺及其混合物。The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, tert-butanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane , Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
方案五Option Five
本公开通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：The compound represented by the general formula (III) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture form thereof, or The preparation method of medicinal salt includes the following steps:
Figure PCTCN2020074091-appb-000042
Figure PCTCN2020074091-appb-000042
通式(IIIB)的化合物和通式(IID)的化合物在催化剂存在下，发生Click反应得 到通式(IIIA)的化合物；通式(IIIA)的化合物在酸性条件下脱去氨基保护基，得到通式(III)的化合物；The compound of general formula (IIIB) and the compound of general formula (IID) undergo Click reaction in the presence of a catalyst to obtain the compound of general formula (IIIA); the compound of general formula (IIIA) removes the amino protecting group under acidic conditions to obtain Compound of general formula (III);
其中：among them:
W为氨基保护基，优选叔丁氧羰基；W is an amino protecting group, preferably tert-butoxycarbonyl;
G、L、R 1～R 4、m、n、s、p、q、r和t如通式(III)中所定义。 G, L, R 1 to R 4 , m, n, s, p, q, r, and t are as defined in the general formula (III).
所述的催化剂包括但不限于CuSO 4、CuSO 4 .5H 2O和CuI等。 The catalysts include, but are not limited to CuSO 4, CuSO 4. 5H 2 O and CuI and the like.
提供酸性条件的试剂包括但不限于三氟乙酸、吡啶氢溴酸盐、氢溴酸、乙酸、盐酸、硝酸、磷酸、对苯甲磺酸和硫酸，优选为三氟乙酸。Reagents that provide acidic conditions include, but are not limited to, trifluoroacetic acid, pyridine hydrobromide, hydrobromic acid, acetic acid, hydrochloric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, and sulfuric acid, preferably trifluoroacetic acid.
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、三氟乙酸、甲醇、乙醇、叔丁醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水或N,N-二甲基甲酰胺及其混合物。The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, tert-butanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane , Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
方案六Option Six
本公开通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：The compound represented by the general formula (III) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture form thereof, or The preparation method of medicinal salt includes the following steps:
Figure PCTCN2020074091-appb-000043
Figure PCTCN2020074091-appb-000043
通式(IIIB)的化合物和通式(IIC)的化合物在催化剂存在下，发生Click反应，得到通式(III)的化合物；The compound of general formula (IIIB) and the compound of general formula (IIC) undergo Click reaction in the presence of a catalyst to obtain the compound of general formula (III);
其中：among them:
G、L、R 1～R 4、m、n、s、p、q、r和t如通式(III)中所定义。 G, L, R 1 to R 4 , m, n, s, p, q, r, and t are as defined in the general formula (III).
所述的催化剂包括但不限于CuSO 4、CuSO 4 .5H 2O和CuI等。 The catalysts include, but are not limited to CuSO 4, CuSO 4. 5H 2 O and CuI and the like.
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、三氟乙酸、甲醇、乙醇、叔丁醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水或N,N-二甲基甲酰胺及其混合物。The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, tert-butanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane , Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
方案七Option Seven
本公开通式(IIIaa)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：The compound represented by the general formula (IIIaa) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or The preparation method of medicinal salt includes the following steps:
Figure PCTCN2020074091-appb-000044
Figure PCTCN2020074091-appb-000044
通式(IIIb)的化合物和通式(IID)的化合物在催化剂存在下，发生Click反应得到通式(IIIa)的化合物；通式(IIIa)的化合物在酸性条件下脱去氨基保护基，得到通式(IIIaa)的化合物；The compound of general formula (IIIb) and the compound of general formula (IID) undergo Click reaction in the presence of a catalyst to obtain the compound of general formula (IIIa); the compound of general formula (IIIa) removes the amino protecting group under acidic conditions to obtain Compound of general formula (IIIaa);
其中：among them:
W为氨基保护基，优选叔丁氧羰基；W is an amino protecting group, preferably tert-butoxycarbonyl;
G、R 1～R 4、m、n、s、p、q、r和t如通式(IIIaa)中所定义。 G, R 1 to R 4 , m, n, s, p, q, r, and t are as defined in the general formula (IIIaa).
所述的催化剂包括但不限于CuSO 4、CuSO 4 .5H 2O和CuI等。 The catalysts include, but are not limited to CuSO 4, CuSO 4. 5H 2 O and CuI and the like.
提供酸性条件的试剂包括但不限于三氟乙酸、吡啶氢溴酸盐、氢溴酸、乙酸、盐酸、硝酸、磷酸、对苯甲磺酸和硫酸，优选为三氟乙酸。Reagents that provide acidic conditions include, but are not limited to, trifluoroacetic acid, pyridine hydrobromide, hydrobromic acid, acetic acid, hydrochloric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, and sulfuric acid, preferably trifluoroacetic acid.
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、三氟乙酸、甲醇、乙醇、叔丁醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水或N,N-二甲基甲酰胺及其混合物。The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, tert-butanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane , Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
方案八Option Eight
本公开通式(IIIaa)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：The compound represented by the general formula (IIIaa) of the present disclosure or its tautomer, mesosome, racemate, enantiomer, diastereomer, or mixture thereof, or The preparation method of medicinal salt includes the following steps:
Figure PCTCN2020074091-appb-000045
Figure PCTCN2020074091-appb-000045
通式(IIIb)的化合物和通式(IIC)的化合物在催化剂存在下，发生Click反应， 得到通式(IIIaa)的化合物，The compound of general formula (IIIb) and the compound of general formula (IIC) undergo Click reaction in the presence of a catalyst to obtain the compound of general formula (IIIaa),
其中：among them:
G、R 1～R 4、m、n、s、p、q、r和t如通式(IIIaa)中所定义。 G, R 1 to R 4 , m, n, s, p, q, r, and t are as defined in the general formula (IIIaa).
所述的催化剂包括但不限于CuSO 4、CuSO 4 .5H 2O和CuI等。 The catalysts include, but are not limited to CuSO 4, CuSO 4. 5H 2 O and CuI and the like.
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、三氟乙酸、甲醇、乙醇、叔丁醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、乙二醇二甲醚、水或N,N-二甲基甲酰胺及其混合物。The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, tert-butanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane , Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
具体实施方式detailed description
以下结合实施例进一步描述本公开，但这些实施例并非限制着本公开的范围。The present disclosure is further described below in conjunction with embodiments, but these embodiments do not limit the scope of the present disclosure.
实施例Example
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。 The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo，型号：Finnigan LCQ advantage MAX)。FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX) is used for MS measurement.
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高压液相色谱仪。High performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.
手性HPLC分析测定使用Agilent1260DAD高效液相色谱仪。Chiral HPLC analysis and determination used Agilent 1260DAD high performance liquid chromatograph.
高效液相制备使用Waters 2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson-281制备型色谱仪。The HPLC preparation uses Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs.
手性制备使用Shimadzu LC-20AP制备型色谱仪。For chiral preparation, Shimadzu LC-20AP preparative chromatograph was used.
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm～0.2mm, and the size of thin layer chromatography separation and purification products is 0.4mm ~0.5mm.
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。The silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。 The average value of 50 measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。The known starting materials of the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Darui Chemicals and other companies.
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。There is no special description in the examples, and the reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。The argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。The pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.
微波反应使用CEM Discover-S 908860型微波反应器。The microwave reaction uses CEM Discover-S 908860 type microwave reactor.
实施例中无特殊说明，溶液是指水溶液。There is no special description in the examples, and the solution refers to an aqueous solution.
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。There are no special instructions in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，D：丙酮，E：二氯甲烷/丙酮体系，F：乙酸乙酯/二氯甲烷体系，G：乙酸乙酯/二氯甲烷/正己烷，H：乙酸乙酯/二氯甲烷/丙酮，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和醋酸等碱性或酸性试剂进行调节。The monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC), the developing reagent used in the reaction, the eluent system of column chromatography used in the purification of the compound, and the developing reagent system of thin-layer chromatography include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: acetone, E: dichloromethane/acetone system, F: ethyl acetate/dichloromethane system , G: ethyl acetate/dichloromethane/n-hexane, H: ethyl acetate/dichloromethane/acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound, a small amount of triethylamine and acetic acid can also be added Wait for alkaline or acidic reagents to adjust.
实施例1Example 1
3-(6-(1-((6-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)吡啶-2-基)甲基)-1H-1,2,3-***-4-基)-2-3-(6-(1-((6-(2-oxa-6-azaspiro[3.3]heptane-6-yl)pyridin-2-yl)methyl)-1H-1,2,3 -Triazol-4-yl)-2-
氨基嘧啶-4-基)-2-甲基苯甲腈1
Figure PCTCN2020074091-appb-000046
Aminopyrimidin-4-yl)-2-methylbenzonitrile 1
Figure PCTCN2020074091-appb-000046
Figure PCTCN2020074091-appb-000047
Figure PCTCN2020074091-appb-000047
第一步first step
6-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)吡啶-2-甲酸甲酯1bMethyl 6-(2-oxa-6-azaspiro[3.3]heptane-6-yl)pyridine-2-carboxylate 1b
依次将6-溴吡啶甲酸甲酯1a(5.000g,23.145mmol，采用公知的方法“Journal of Medicinal Chemistry,2017,60(2),722-748”制备而得)、2-氧杂-6-氮杂螺[3.3]庚烷半乙二酸盐(7.340g,25.460mmol，南京药石科技股份有限公司)和碳酸氢钠(19.444g,231.458mmol)溶解于120mL乙腈中，升温至70℃，搅拌反应17小时。反应液减压浓缩，残留物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题化合物1b(1.118g，产率：20.62％)。Methyl 6-bromopicolinate 1a (5.000g, 23.145mmol, prepared by the well-known method "Journal of Medicinal Chemistry, 2017, 60(2), 722-748"), 2-oxa-6- Azaspiro[3.3]heptane hemioxalate (7.340g, 25.460mmol, Nanjing Pharmaceutical Technology Co., Ltd.) and sodium bicarbonate (19.444g, 231.458mmol) were dissolved in 120mL of acetonitrile, heated to 70℃, and stirred React for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1b (1.118 g, yield: 20.62%).
MS m/z(ESI):235.2[M+1]。MS m/z(ESI): 235.2[M+1].
第二步Second step
(6-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)吡啶-2-基)甲醇1c(6-(2-oxa-6-azaspiro[3.3]heptane-6-yl)pyridin-2-yl)methanol 1c
将化合物1b(100mg,0.427mmol)溶解于5mL四氢呋喃中，冷却至0℃，加入四氢锂铝(100mg,0.427mmol)，升温至室温，搅拌反应0.5小时。反应液中加入0.1mL水，加入50ml乙酸乙酯，搅拌15分钟，过滤，滤液减压浓缩得到标题化合物1c(88mg，产率：100％)。Compound 1b (100mg, 0.427mmol) was dissolved in 5mL of tetrahydrofuran, cooled to 0°C, tetrahydrolithium aluminum (100mg, 0.427mmol) was added, the temperature was raised to room temperature, and the reaction was stirred for 0.5 hour. 0.1 mL of water was added to the reaction solution, 50 mL of ethyl acetate was added, stirred for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 1c (88 mg, yield: 100%).
MS m/z(ESI):207.1[M+1]。MS m/z(ESI): 207.1[M+1].
第三步third step
6-(6-(叠氮基甲基)吡啶-2-基)-2-氧杂-6-氮杂螺[3.3]庚烷1d6-(6-(Azidomethyl)pyridin-2-yl)-2-oxa-6-azaspiro[3.3]heptane 1d
氩气氛下，将化合物1c(88mg,0.427mmol)溶解于5mL甲苯中，冷却至0℃，加入叠氮磷酸二苯酯(141mg,0.512mmol)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(78mg,0.512mmol)，升温至室温，搅拌反应17小时。反应液减压浓缩，残留物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题化合物1d(62mg，产率：62.83％)。Under argon atmosphere, dissolve compound 1c (88mg, 0.427mmol) in 5mL toluene, cool to 0°C, add diphenyl azide phosphate (141mg, 0.512mmol) and 1,8-diazabicyclo[5.4.0 ] Undec-7-ene (78mg, 0.512mmol), warmed to room temperature, stirred and reacted for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1d (62 mg, yield: 62.83%).
MS m/z(ESI):232.1[M+1]。MS m/z(ESI): 232.1[M+1].
第四步the fourth step
3-(6-(1-((6-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)吡啶-2-基)甲基)-1H-1,2,3-***-4-基)-2-氨基嘧啶-4-基)-2-甲基苯甲腈13-(6-(1-((6-(2-oxa-6-azaspiro[3.3]heptane-6-yl)pyridin-2-yl)methyl)-1H-1,2,3 -Triazol-4-yl)-2-aminopyrimidin-4-yl)-2-methylbenzonitrile 1
依次将3-(2-氨基-6-乙炔基嘧啶-4-基)-2-甲基苯甲腈1e(150mg,0.64mmol，采用专利申请“WO2018136700中说明书第76页的实施例1”公开的方法制备而得)、化合物1d(193mg,0.835mmol)、五水合硫酸铜(16mg,0.064mmol)和L(+)-苏糖型-2,3,4,5,6-五羟基-2-己烯酸-4-内酯钠(64mg,0.323mmol)溶解于15mL叔丁醇和水(V/V＝2/1)的混合溶剂中，升温至60℃，搅拌2小时。将反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题化合物1(122.1mg，产率：40.96％)。Sequentially, 3-(2-amino-6-ethynylpyrimidin-4-yl)-2-methylbenzonitrile 1e (150mg, 0.64mmol, using patent application "Example 1 on page 76 of the specification in WO2018136700" was disclosed Prepared by the method), compound 1d (193mg, 0.835mmol), copper sulfate pentahydrate (16mg, 0.064mmol) and L(+)-threose-2,3,4,5,6-pentahydroxy-2 -Hexenoic acid-4-lactone sodium (64 mg, 0.323 mmol) was dissolved in 15 mL of a mixed solvent of tert-butanol and water (V/V=2/1), heated to 60°C, and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 1 (122.1 mg, yield: 40.96%).
MS m/z(ESI):466.1[M+1]。MS m/z(ESI): 466.1[M+1].
1H NMR(400MHz,DMSO-d 6):δ8.61(s,1H),7.90-7.88(m,1H),7.76-7.75(m,1H),7.53-7.49(m,2H),7.27(s,1H),6.89(brs,2H),6.49-6.47(m,1H),6.35-6.33(m,1H),5.61(s,2H),4.69(s,4H),4.06(s,4H),2.55(s,3H)。 1 H NMR (400MHz, DMSO-d 6 ): δ8.61 (s, 1H), 7.90-7.88 (m, 1H), 7.76-7.75 (m, 1H), 7.53-7.49 (m, 2H), 7.27 ( s, 1H), 6.89 (brs, 2H), 6.49-6.47 (m, 1H), 6.35-6.33 (m, 1H), 5.61 (s, 2H), 4.69 (s, 4H), 4.06 (s, 4H) ,2.55(s,3H).
实施例2Example 2
3-(6-(1-((6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)吡啶-2-基)甲基)-1H-1,2,3-***-4-基)-2-氨基嘧啶-4-基)-2-甲基苯甲腈23-(6-(1-((6-(2-oxa-7-azaspiro[3.5]nonane-7-yl)pyridin-2-yl)methyl)-1H-1,2,3 -Triazol-4-yl)-2-aminopyrimidin-4-yl)-2-methylbenzonitrile 2
Figure PCTCN2020074091-appb-000048
Figure PCTCN2020074091-appb-000048
Figure PCTCN2020074091-appb-000049
Figure PCTCN2020074091-appb-000049
第一步first step
6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)吡啶-2-甲酸甲酯2aMethyl 6-(2-oxa-7-azaspiro[3.5]nonane-7-yl)pyridine-2-carboxylate 2a
依次将化合物1a(141mg,0.653mmol)、2-氧杂-7-氮杂螺[3.5]壬烷半乙二酸盐(124mg,0.360mmol)和碳酸钾(452mg,3.271mmol)溶解于15mL N,N-二甲基甲酰胺中，升温至90℃，搅拌反应65小时。反应液中加入50ml水，乙酸乙酯萃取(30mL×4)，合并有机相，减压浓缩，残留物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题化合物2a(75mg,产率：43.80％)。Dissolve compound 1a (141mg, 0.653mmol), 2-oxa-7-azaspiro[3.5]nonane hemioxalate (124mg, 0.360mmol) and potassium carbonate (452mg, 3.271mmol) in 15mL in turn. In N-dimethylformamide, the temperature was raised to 90°C, and the reaction was stirred for 65 hours. Add 50ml of water to the reaction solution, extract with ethyl acetate (30mL×4), combine the organic phases, concentrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain the title compound 2a (75mg, yield: 43.80%).
MS m/z(ESI):263.2[M+1]。MS m/z(ESI): 263.2[M+1].
第二步Second step
(6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)吡啶-2-基)甲醇2b(6-(2-oxa-7-azaspiro[3.5]nonane-7-yl)pyridin-2-yl)methanol 2b
将化合物2a(75mg,0.286mmol)溶解于10mL四氢呋喃中，冷却至0℃，加入四氢锂铝(15mg,0.442mmol)，升温至室温，搅拌反应1小时。反应液中加入30ml水淬灭反应，乙酸乙酯萃取(30mL×3)，合并有机相用无水硫酸钠干燥15分钟，过滤，滤液减压浓缩得到标题化合物2b(65mg,产率：97.03％)。Compound 2a (75mg, 0.286mmol) was dissolved in 10mL of tetrahydrofuran, cooled to 0°C, tetrahydrolithium aluminum (15mg, 0.442mmol) was added, the temperature was raised to room temperature, and the reaction was stirred for 1 hour. The reaction solution was quenched by adding 30ml of water, extracted with ethyl acetate (30mL×3), the combined organic phase was dried over anhydrous sodium sulfate for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 2b (65mg, yield: 97.03%) ).
MS m/z(ESI):235.2[M+1]。MS m/z(ESI): 235.2[M+1].
第三步third step
7-(6-(叠氮基甲基)吡啶-2-基)-2-氧杂-7-氮杂螺[3.5]壬烷2c7-(6-(Azidomethyl)pyridin-2-yl)-2-oxa-7-azaspiro[3.5]nonane 2c
氩气氛下，将化合物2b(65mg,0.277mmol)溶解10mL甲苯中，冷却至0℃，加入叠氮磷酸二苯酯(87mg,0.336mmol)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(51mg,0.050mmol，上海韶远试剂有限公司)，升温至室温，搅拌反应17小时。反应液减压浓缩，残留物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题化合物2c(20mg,产率：27.80％)。Under argon atmosphere, dissolve compound 2b (65mg, 0.277mmol) in 10mL of toluene, cool to 0°C, add diphenyl azide phosphate (87mg, 0.336mmol) and 1,8-diazabicyclo[5.4.0] Undec-7-ene (51 mg, 0.050 mmol, Shanghai Shaoyuan Reagent Co., Ltd.) was heated to room temperature, and the reaction was stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2c (20 mg, yield: 27.80%).
MS m/z(ESI):260.1[M+1]。MS m/z(ESI): 260.1[M+1].
第四步the fourth step
2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯甲腈2e2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 2e
氩气氛下，依次将3-溴-2-甲基苯甲腈2d(42.5g,216.788mmol，采用公知的方法“Bioorganic and Medicinal Chemistry Letters,2011,21(2),644-651”制备而得)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧硼杂环戊烷)(69.0g，271.720mmol，上海韶远试剂有限公司)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(8.0g，10.933mmol)和乙酸钾(64.0g,652.114mmol)溶解于500mL1,4-二氧六环中，升温至90℃，搅拌反应4小时。过滤，滤液减压浓缩，残留物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题化合物2e(38.0g,产率：72.10％)。Under argon atmosphere, sequentially prepare 3-bromo-2-methylbenzonitrile 2d (42.5g, 216.788mmol, using the well-known method "Bioorganic and Medicinal Chemistry Letters, 2011, 21(2), 644-651" ), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (69.0g , 271.720mmol, Shanghai Shaoyuan Reagent Co., Ltd.), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (8.0g, 10.933mmol) and potassium acetate (64.0g, 652.114mmol) ) Was dissolved in 500 mL 1,4-dioxane, the temperature was raised to 90°C, and the reaction was stirred for 4 hours. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2e (38.0 g, yield: 72.10%).
第五步the fifth step
3-(2-双(叔丁氧基羰基)氨基-6-氯嘧啶-4-基)-2-甲基苯甲腈2g3-(2-bis(tert-butoxycarbonyl)amino-6-chloropyrimidin-4-yl)-2-methylbenzonitrile 2g
氩气氛下，依次将2-双(叔丁氧基羰基)氨基-4,6-二氯嘧啶2f(80.0g,219.645mmol，采用公知的方法“Chemistry-A European Journal,2005,11(2),662-668”制备而得)、化合物2e(28.0g，115.175mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(4.0g，5.467mmol)和碳酸钾(24.0g,173.654mmol)溶解于600mL1,4-二氧六环和水(V/V＝5/1)的混合溶剂中，搅拌反应4小时。分液，水相用乙酸乙酯萃取(200mL×3)，合并有机相用无水硫酸钠干燥15分钟，过滤，滤液减压浓缩，残留物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题化合物2g(39.6g,产率：77.28％)。In an argon atmosphere, 2-bis(tert-butoxycarbonyl)amino-4,6-dichloropyrimidine 2f (80.0g, 219.645mmol) was sequentially added using the well-known method "Chemistry-A European Journal, 2005, 11(2) , 662-668" prepared), compound 2e (28.0g, 115.175mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (4.0g, 5.467mmol) and Potassium carbonate (24.0 g, 173.654 mmol) was dissolved in 600 mL of a mixed solvent of 1,4-dioxane and water (V/V=5/1), and the reaction was stirred for 4 hours. After separation, the aqueous phase was extracted with ethyl acetate (200mL×3), the combined organic phases were dried with anhydrous sodium sulfate for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B. The title compound 2g (39.6g, yield: 77.28%) was obtained.
第六步Sixth step
3-(2-双(叔丁氧基羰基)氨基-6-((三异丙基硅基)乙炔基)嘧啶-4-基)-2-甲基苯甲腈2h3-(2-bis(tert-butoxycarbonyl)amino-6-((triisopropylsilyl)ethynyl)pyrimidin-4-yl)-2-methylbenzonitrile 2h
氩气氛下，依次将化合物2g(5.0g,11.238mmol)、三异丙基硅基乙炔(3.075g，16.861mmol)、二三苯基膦二氯化钯(158mg，0.225mmol)、碘化亚铜(86mg，0.452mmol)和三乙胺(3.412g,33.719mmol)溶解于220mL四氢呋喃中，回流搅拌反应17小时。反应液减压浓缩，残留物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题化合物2h(6.476g,产率：97.53％)。Under an argon atmosphere, compound 2g (5.0g, 11.238mmol), triisopropylsilylacetylene (3.075g, 16.861mmol), ditriphenylphosphine palladium dichloride (158mg, 0.225mmol), iodide Copper (86 mg, 0.452 mmol) and triethylamine (3.412 g, 33.719 mmol) were dissolved in 220 mL of tetrahydrofuran, and the reaction was stirred at reflux for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2h (6.476 g, yield: 97.53%).
MS m/z(ESI):591.2[M+1]。MS m/z(ESI):591.2[M+1].
第七步Seventh step
3-(2-双(叔丁氧基羰基)氨基-6-乙炔基嘧啶-4-基)-2-甲基苯甲腈2i3-(2-bis(tert-butoxycarbonyl)amino-6-ethynylpyrimidin-4-yl)-2-methylbenzonitrile 2i
将化合物2h(6.476g,10.961mmol)溶解于125mL四氢呋喃中，冷却至0℃，加入四丁基氟化铵(3.440g,13.157mmol)，搅拌反应30分钟。反应液中加入150mL饱和氯化铵溶液，乙酸乙酯萃取(150mL×3)，合并有机相减压浓缩，残留物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题化合物2i(3.021g,产率：63.43％)。Compound 2h (6.476 g, 10.961 mmol) was dissolved in 125 mL of tetrahydrofuran, cooled to 0° C., tetrabutylammonium fluoride (3.440 g, 13.157 mmol) was added, and the reaction was stirred for 30 minutes. 150mL saturated ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate (150mL×3), the combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2i (3.021g) , Yield: 63.43%).
MS m/z(ESI):435.2[M+1]。MS m/z(ESI): 435.2[M+1].
第八步Eighth step
3-(6-(1-((6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)吡啶-2-基)甲基)-1H-1,2,3-***-4-基)-2- 双(叔丁氧基羰基)氨基嘧啶-4-基)-2-甲基苯甲腈2j3-(6-(1-((6-(2-oxa-7-azaspiro[3.5]nonane-7-yl)pyridin-2-yl)methyl)-1H-1,2,3 -Triazol-4-yl)-2-bis(tert-butoxycarbonyl)aminopyrimidin-4-yl)-2-methylbenzonitrile 2j
依次将化合物2i(33mg,0.076mmol)、化合物2c(20mg,0.077mmol)、五水合硫酸铜(2mg,0.008mmol)和L(+)-苏糖型-2,3,4,5,6-五羟基-2-己烯酸-4-内酯钠(8mg,0.040mmol)溶解于9mL叔丁醇和水(V/V＝2/1)的混合溶剂中，升温至60℃，搅拌2小时。将反应液减压浓缩，残留物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题化合物2j(52mg，产率：98.68％)。Compound 2i (33mg, 0.076mmol), compound 2c (20mg, 0.077mmol), copper sulfate pentahydrate (2mg, 0.008mmol) and L(+)-threose-2,3,4,5,6- Sodium pentahydroxy-2-hexenoic acid-4-lactone (8 mg, 0.040 mmol) was dissolved in 9 mL of a mixed solvent of tert-butanol and water (V/V=2/1), the temperature was raised to 60° C., and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2j (52 mg, yield: 98.68%).
MS m/z(ESI):694.1[M+1]。MS m/z(ESI): 694.1[M+1].
第九步Step 9
3-(6-(1-((6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)吡啶-2-基)甲基)-1H-1,2,3-***-4-基)-2-氨基嘧啶-4-基)-2-甲基苯甲腈23-(6-(1-((6-(2-oxa-7-azaspiro[3.5]nonane-7-yl)pyridin-2-yl)methyl)-1H-1,2,3 -Triazol-4-yl)-2-aminopyrimidin-4-yl)-2-methylbenzonitrile 2
将化合物2j(52mg,0.075mmol)溶解于9mL二氯甲烷和三氟乙酸(V/V＝2/1)的混合溶剂中，搅拌反应1小时。反应液减压浓缩，加入50mL饱和碳酸氢钠溶液调节pH大于7，乙酸乙酯萃取(30mL×3)，合并有机相减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题化合物2(19.7 mg，产率：53.25％)。Compound 2j (52 mg, 0.075 mmol) was dissolved in 9 mL of a mixed solvent of dichloromethane and trifluoroacetic acid (V/V=2/1), and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, 50mL saturated sodium bicarbonate solution was added to adjust the pH to be greater than 7, ethyl acetate extraction (30mL×3), the combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A. The title compound 2 (19.7 mg, yield: 53.25%) was obtained.
MS m/z(ESI):494.2[M+1]。MS m/z(ESI): 494.2[M+1].
1H NMR(400MHz,DMSO-d 6):δ8.64(s,1H),7.90-7.88(m,1H),7.76-7.74(m,1H),7.53-7.49(m,2H),7.26(s,1H),6.89(brs,2H),6.80-6.78(m,1H),6.48-6.46(m,1H),5.61(s,2H),4.33-4.28(m,4H),3.44-3.40(m,4H),2.55(s,3H),1.76-1.70(m,4H)。 1 H NMR (400MHz, DMSO-d 6 ): δ8.64 (s, 1H), 7.90-7.88 (m, 1H), 7.76-7.74 (m, 1H), 7.53-7.49 (m, 2H), 7.26 ( s, 1H), 6.89 (brs, 2H), 6.80-6.78 (m, 1H), 6.48-6.46 (m, 1H), 5.61 (s, 2H), 4.33-4.28 (m, 4H), 3.44-3.40 ( m, 4H), 2.55 (s, 3H), 1.76-1.70 (m, 4H).
实施例3Example 3
3-(6-(1-((6-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)吡啶-2-基)甲基)-1H-1,2,3-***-4-基)-2-氨基嘧啶-4-基)-2-甲基苯甲腈33-(6-(1-((6-((2-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)pyridin-2-yl)methyl)-1H-1 ,2,3-Triazol-4-yl)-2-aminopyrimidin-4-yl)-2-methylbenzonitrile 3
Figure PCTCN2020074091-appb-000050
Figure PCTCN2020074091-appb-000050
第一步first step
6-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)吡啶-2-甲酸乙酯3b6-((2-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)pyridine-2-carboxylic acid ethyl ester 3b
依次将6-(溴甲基)吡啶甲酸乙酯3a(2.179g,8.927mmol，采用公知的方法“Journal of Inorganic Biochemistry,2012,112,49-58”制备而得)、2-氧杂-6-氮杂螺[3.3]庚烷半草酸盐(2.831g,9.820mmol)和碳酸氢钠(7.5g,89.279mmol)溶解于120mL乙腈中，升温至70℃，搅拌反应17小时。反应液减压浓缩，残留物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题化合物3b(685 mg,产率：29.25％)。Ethyl 6-(bromomethyl)picolinate 3a (2.179g, 8.927mmol, prepared by the well-known method "Journal of Inorganic Biochemistry, 2012, 112, 49-58"), 2-oxa-6 -Azaspiro[3.3]heptane hemioxalate (2.831g, 9.820mmol) and sodium bicarbonate (7.5g, 89.279mmol) were dissolved in 120mL of acetonitrile, heated to 70°C, and stirred for reaction for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 3b (685 mg, yield: 29.25%).
MS m/z(ESI):263.2[M+1]。MS m/z(ESI): 263.2[M+1].
第二步Second step
(6-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)吡啶-2-基)甲醇3c(6-((2-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)pyridin-2-yl)methanol 3c
将化合物3b(100mg,0.381mmol)溶解于10mL四氢呋喃中，冷却至0℃，加入四氢锂铝(20mg,0.590mmol)，升温至室温，搅拌反应1小时。反应液中加入0.5mL水，加入50mL乙酸乙酯，搅拌15分钟，过滤，滤液减压浓缩得到标题化合物3c(76mg,产率：90.5％)。Compound 3b (100 mg, 0.381 mmol) was dissolved in 10 mL of tetrahydrofuran, cooled to 0° C., tetrahydrolithium aluminum (20 mg, 0.590 mmol) was added, the temperature was raised to room temperature, and the reaction was stirred for 1 hour. 0.5 mL of water was added to the reaction solution, 50 mL of ethyl acetate was added, stirred for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 3c (76 mg, yield: 90.5%).
MS m/z(ESI):221.2[M+1]。MS m/z(ESI): 221.2[M+1].
第三步third step
6-((6-(叠氮基甲基)吡啶-2-基)甲基)-2-氧杂-6-氮杂螺[3.3]庚烷3d6-((6-(Azidomethyl)pyridin-2-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane 3d
氩气氛下，将化合物3c(76mg,0.345mmol)溶解于10mL甲苯中，冷却至0℃，加入叠氮磷酸二苯酯(108mg,0.417mmol)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(64mg,0.420mmol)，升温至室温，搅拌反应17小时。反应液减压浓缩，残留物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题化合物3d(82mg,产率：96.89％)。Under argon atmosphere, dissolve compound 3c (76mg, 0.345mmol) in 10mL of toluene, cool to 0°C, add diphenyl azide phosphate (108mg, 0.417mmol) and 1,8-diazabicyclo[5.4.0 ] Undec-7-ene (64mg, 0.420mmol), warmed to room temperature, stirred and reacted for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 3d (82 mg, yield: 96.89%).
MS m/z(ESI):246.2[M+1]。MS m/z(ESI): 246.2[M+1].
第四步the fourth step
3-(6-(1-((6-((2-氧杂-6-氮杂螺[3.3]庚烷-6-基)甲基)吡啶-2-基)甲基)-1H-1,2,3-***-4-基)-2-氨基嘧啶-4-基)-2-甲基苯甲腈33-(6-(1-((6-((2-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)pyridin-2-yl)methyl)-1H-1 ,2,3-Triazol-4-yl)-2-aminopyrimidin-4-yl)-2-methylbenzonitrile 3
依次将化合物1e(79mg,0.337mmol)、化合物3d(82mg,0.334mmol)、五水合硫酸铜(9mg,0.036mmol)和L(+)-苏糖型-2,3,4,5,6-五羟基-2-己烯酸-4-内酯钠(34mg,0.172mmol)溶解于12mL叔丁醇和水(V/V＝2/1)的混合溶剂中，升温至60℃，搅拌2小时。将反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题化合物3(25.3mg，产率：15.78％)。The compound 1e (79mg, 0.337mmol), compound 3d (82mg, 0.334mmol), copper sulfate pentahydrate (9mg, 0.036mmol) and L(+)-threose-2,3,4,5,6- Sodium pentahydroxy-2-hexenoic acid-4-lactone (34 mg, 0.172 mmol) was dissolved in 12 mL of a mixed solvent of tert-butanol and water (V/V=2/1), heated to 60° C., and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 3 (25.3 mg, yield: 15.78%).
MS m/z(ESI):480.2[M+1]。MS m/z(ESI): 480.2[M+1].
1H NMR(400MHz,DMSO-d 6):δ8.70(s,1H),7.90-7.88(m,1H),7.81-7.74(m,2H),7.53-7.49(m,1H),7.29-7.28(m,2H),7.21-7.19(m,1H),6.89(brs,2H),5.81(s,2H),4.55(s,4H),3.64(s,2H),3.39(s,4H),2.54(s,3H)。 1 H NMR (400MHz, DMSO-d 6 ): δ8.70 (s, 1H), 7.90-7.88 (m, 1H), 7.81-7.74 (m, 2H), 7.53-7.49 (m, 1H), 7.29- 7.28 (m, 2H), 7.21-7.19 (m, 1H), 6.89 (brs, 2H), 5.81 (s, 2H), 4.55 (s, 4H), 3.64 (s, 2H), 3.39 (s, 4H) ,2.54(s,3H).
实施例4Example 4
3-(2-氨基-6-(1-((6-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)吡啶-2-基)甲基)-1H-1,2,3-***-4-基)嘧啶-4-基)-2-甲基苯甲腈43-(2-Amino-6-(1-((6-(Tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)pyridin-2-yl)methyl)- 1H-1,2,3-Triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile 4
Figure PCTCN2020074091-appb-000051
Figure PCTCN2020074091-appb-000051
第一步first step
N-[4-[1-[(6-溴-2-吡啶基)甲基]***-4-基]-6-(3-氰基-2-甲基-苯基)嘧啶-2-基]-N-叔丁氧羰基-氨基甲酸叔丁酯4bN-[4-[1-[(6-Bromo-2-pyridyl)methyl]triazol-4-yl]-6-(3-cyano-2-methyl-phenyl)pyrimidine-2- Yl]-N-tert-Butoxycarbonyl-carbamic acid tert-butyl ester 4b
将2-(叠氮甲基)-6-溴吡啶4a(1.272g,5.970mmol,采用专利申请“WO2010011375中说明书第47页的实施例8”公开的方法制备而得)、化合物2i(2.45g,5.638mmol)、五水硫酸铜(20mg,80.10μmol)、L(+)-苏糖型-2,3,4,5,6-五羟基-2-己烯酸-4-内酯钠(80mg,403.8μmol)加入到40mL水和80mL叔丁醇的混合溶剂中，60℃反应16小时。将反应液冷却到室温，加压浓缩，残余物用二氯甲烷(100mL×3)萃取三次，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题化合物4b(3g,产率：82.16％)。The 2-(azidomethyl)-6-bromopyridine 4a (1.272g, 5.970mmol, prepared by the method disclosed in the patent application "Example 8 on page 47 of the specification in WO2010011375"), compound 2i (2.45g , 5.638mmol), copper sulfate pentahydrate (20mg, 80.10μmol), L(+)-threose-2,3,4,5,6-pentahydroxy-2-hexenoic acid-4-lactone sodium ( 80mg, 403.8μmol) was added to a mixed solvent of 40mL water and 80mL tert-butanol, and reacted at 60°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under pressure. The residue was extracted three times with dichloromethane (100mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was measured with a CombiFlash rapid preparation instrument. The eluent system B was purified to obtain the title compound 4b (3 g, yield: 82.16%).
第二步Second step
N-[4-[1-[[6-(1,3,3a,4,6,6a-六氢呋喃并[3,4-c]吡咯-5-基)-2-吡啶基]甲基]***-4-基]-6-(3-氰基-2-甲基-苯基)嘧啶-2-基]-N-叔丁氧羰基-氨基甲酸叔丁酯4dN-[4-[1-[[6-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-2-pyridyl]methyl ]Triazol-4-yl]-6-(3-cyano-2-methyl-phenyl)pyrimidin-2-yl]-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester 4d
将六氢-1H-呋喃并[3,4-c]吡咯盐酸盐4c(160mg,1.069mmol,采用公知的方法“Synthesis,2017,49(14),3112-3117”制备而得)、叔丁醇钠(174mg,1.810mmol)加入到20mL1,4-二氧六环中，加热到90℃反应30分钟。将反应液冷却到室温，再在氩气气氛下加入化合物4b(300mg,463.3μmol)、三(二亚苄基茚丙酮)二钯(55mg,60.06μmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(70mg,120.9μmol)，加热到100℃反应过夜。将反应液冷却到室温，过滤，滤液减压浓缩，得到粗品标题化合物4d(360mg,产率：114.3％)。产品不经纯化，直接用于下一步反应。The hexahydro-1H-furo[3,4-c]pyrrole hydrochloride 4c (160mg, 1.069mmol, prepared by the well-known method "Synthesis, 2017, 49(14), 3112-3117"), tertiary Sodium butoxide (174mg, 1.810mmol) was added to 20mL 1,4-dioxane and heated to 90°C for 30 minutes. The reaction solution was cooled to room temperature, and compound 4b (300mg, 463.3μmol), tris(dibenzylidene indeneacetone)dipalladium (55mg, 60.06μmol), 4,5-bisdiphenylphosphine were added under argon atmosphere -9,9-Dimethylxanthene (70mg, 120.9μmol), heated to 100℃ and reacted overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 4d (360 mg, yield: 114.3%). The product was directly used in the next reaction without purification.
第三步third step
3-(2-氨基-6-(1-((6-(四氢-1H-呋喃并[3,4-c]吡咯-5(3H)-基)吡啶-2-基)甲基)-1H-1,2,3-***-4-基)嘧啶-4-基)-2-甲基苯甲腈43-(2-Amino-6-(1-((6-(Tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)pyridin-2-yl)methyl)- 1H-1,2,3-Triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile 4
将粗品化合物4d(360mg,529.5μmol)溶解于10mL二氯甲烷中，加入2.5mL三氟乙酸，搅拌反应2小时。将反应液减压浓缩，残余物用30mL二氯甲烷溶解，加入饱和碳酸氢钠水溶液调节pH值大于7，分液，水相用二氯甲烷(20mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用制备板以洗脱剂体系A纯化，得到标题化合物4(20mg,产率：7.87％)。The crude compound 4d (360 mg, 529.5 μmol) was dissolved in 10 mL of dichloromethane, 2.5 mL of trifluoroacetic acid was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 30 mL of dichloromethane. A saturated aqueous sodium bicarbonate solution was added to adjust the pH to greater than 7, and the liquids were separated. The aqueous phase was extracted with dichloromethane (20 mL×3), and the organic phases were combined. It was dried over sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified with the eluent system A using a preparation plate to obtain the title compound 4 (20 mg, yield: 7.87%).
MS m/z(ESI):480.1[M+1]。MS m/z(ESI): 480.1[M+1].
1H NMR(400MHz,CDCl 3):δ8.38(s,1H),7.71-7.73(m,1H),7.67-7.71(m,1H),7.57(s,1H),7.41-7.47(m,2H),6.53(d,1H),6.37(d,1H),5.56(s,2H),5.14(s,2H),3.99-4.02(m,2H),3.71-3.75(m,2H),3.65-3.67(m,2H),3.43-3.47(m,2H),3.09-3.10(m,2H),2.65(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ8.38 (s, 1H), 7.71-7.73 (m, 1H), 7.67-7.71 (m, 1H), 7.57 (s, 1H), 7.41-7.47 (m, 2H), 6.53 (d, 1H), 6.37 (d, 1H), 5.56 (s, 2H), 5.14 (s, 2H), 3.99-4.02 (m, 2H), 3.71-3.75 (m, 2H), 3.65 -3.67 (m, 2H), 3.43-3.47 (m, 2H), 3.09-3.10 (m, 2H), 2.65 (s, 3H).
实施例5Example 5
3-(6-(1-((6-(7-氧杂-2-氮杂螺[3.5]壬烷-2-基)吡啶-2-基)甲基)-1H-1,2,3-***-4-基)-2-氨基嘧啶-4-基)-2-甲基苯甲腈53-(6-(1-((6-(7-oxa-2-azaspiro[3.5]nonane-2-yl)pyridin-2-yl)methyl)-1H-1,2,3 -Triazol-4-yl)-2-aminopyrimidin-4-yl)-2-methylbenzonitrile 5
Figure PCTCN2020074091-appb-000052
Figure PCTCN2020074091-appb-000052
第一步first step
6-(7-氧杂-2-氮杂螺[3.5]壬烷-2-基)吡啶-2-甲酸乙酯5b6-(7-oxa-2-azaspiro[3.5]nonane-2-yl)pyridine-2-ethyl carboxylate 5b
依次将6-溴吡啶甲酸乙酯5a(1.0g,4.347mmol，采用公知的方法“Tetrahedron,2012,68(24),4701-4709”制备而得)、7-氧杂-2-氮杂螺[3.5]壬烷半乙二酸盐(1.497g,4.347mmol)和碳酸钾(3.004g,21.736mmol)溶解于40mLN,N-二甲基甲酰胺中，升温至90℃，搅拌反应65小时。反应液中加入100mL水，乙酸乙酯萃取(100mL×3)， 合并有机相减压浓缩，残留物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题化合物5b(605mg,产率：50.37％)。Ethyl 6-bromopicolinate 5a (1.0 g, 4.347 mmol, prepared by the well-known method "Tetrahedron, 2012, 68(24), 4701-4709"), 7-oxa-2-azaspiro [3.5] Nonane hemioxalate (1.497 g, 4.347 mmol) and potassium carbonate (3.004 g, 21.736 mmol) were dissolved in 40 mL of N,N-dimethylformamide, the temperature was raised to 90° C., and the reaction was stirred for 65 hours. 100mL of water was added to the reaction solution, extracted with ethyl acetate (100mL×3), the combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 5b (605mg, yield: 50.37 %).
MS m/z(ESI):277.2[M+1]。MS m/z(ESI): 277.2[M+1].
第二步Second step
(6-(7-氧杂-2-氮杂螺[3.5]壬烷-2-基)吡啶-2-基)甲醇5c(6-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyridin-2-yl)methanol 5c
将化合物5b(605mg,2.189mmol)溶解于40mL四氢呋喃中，冷却至0℃，加入四氢锂铝(112mg,3.302mmol)，升温至室温，搅拌反应1小时。反应液中加入100mL水，乙酸乙酯萃取(100mL×3)，合并有机相用无水硫酸钠干燥15分钟，过滤，滤液减压浓缩得到标题化合物5c(510mg,产率：99.42％)。Compound 5b (605 mg, 2.189 mmol) was dissolved in 40 mL of tetrahydrofuran, cooled to 0° C., tetrahydrolithium aluminum (112 mg, 3.302 mmol) was added, the temperature was raised to room temperature, and the reaction was stirred for 1 hour. 100 mL of water was added to the reaction solution, extracted with ethyl acetate (100 mL×3), the combined organic phase was dried over anhydrous sodium sulfate for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 5c (510 mg, yield: 99.42%).
MS m/z(ESI):235.1[M+1]。MS m/z(ESI): 235.1[M+1].
第三步third step
2-(6-(叠氮基甲基)吡啶-2-基)-7-氧杂-2-氮杂螺[3.5]壬烷5d2-(6-(Azidomethyl)pyridin-2-yl)-7-oxa-2-azaspiro[3.5]nonane 5d
氩气氛下，将化合物5c(210mg,0.896mmol)溶解于30mL四氢呋喃和甲苯(V/V＝1/1)的混合溶剂中，冷却至0℃，加入叠氮磷酸二苯酯(279mg,1.076mmol)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(164mg,1.077mmol)，升温至室温，搅拌反应17小时。反应液减压浓缩，残留物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题化合物5d(64mg,产率：27.11％)。Under an argon atmosphere, compound 5c (210mg, 0.896mmol) was dissolved in 30mL of a mixed solvent of tetrahydrofuran and toluene (V/V=1/1), cooled to 0°C, and added diphenyl azide phosphate (279mg, 1.076mmol) ) And 1,8-diazabicyclo[5.4.0]undec-7-ene (164mg, 1.077mmol), warmed to room temperature, stirred and reacted for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 5d (64 mg, yield: 27.11%).
MS m/z(ESI):260.2[M+1]。MS m/z(ESI): 260.2[M+1].
第四步the fourth step
3-(6-(1-((6-(7-氧杂-2-氮杂螺[3.5]壬烷-2-基)吡啶-2-基)甲基)-1H-1,2,3-***-4-基)-2-氨基嘧啶-4-基)-2-甲基苯甲腈53-(6-(1-((6-(7-oxa-2-azaspiro[3.5]nonane-2-yl)pyridin-2-yl)methyl)-1H-1,2,3 -Triazol-4-yl)-2-aminopyrimidin-4-yl)-2-methylbenzonitrile 5
依次将化合物1e(34mg,0.145mmol)、化合物5d(64mg,0.247mmol)、五水合硫酸铜(4mg,0.016mmol)和L(+)-苏糖型-2,3,4,5,6-五羟基-2-己烯酸-4-内酯钠(15mg,0.076mmol)溶解于12mL叔丁醇和水(V/V＝2/1)的混合溶剂中，升温至60℃，搅拌2小时。将反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化，得到标题化合物5(37.2mg，产率：51.93％)。The compound 1e (34mg, 0.145mmol), compound 5d (64mg, 0.247mmol), copper sulfate pentahydrate (4mg, 0.016mmol) and L(+)-threose-2,3,4,5,6- Sodium pentahydroxy-2-hexenoic acid-4-lactone (15 mg, 0.076 mmol) was dissolved in 12 mL of a mixed solvent of tert-butanol and water (V/V=2/1), the temperature was raised to 60° C., and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 5 (37.2 mg, yield: 51.93%).
MS m/z(ESI):494.2[M+1]。MS m/z(ESI): 494.2[M+1].
1H NMR(400MHz,DMSO-d 6):δ8.62(s,1H),7.91-7.89(m,1H),7.76-7.74(m,1H),7.53-7.48(m,2H),7.26(s,1H),6.91(brs,2H),6.44-6.42(m,1H),6.34-6.32(m,1H),5.60(s,2H),3.67(s,4H),3.54-3.51(m,4H),2.55(s,3H),1.72-1.69(m,4H)。 1 H NMR (400MHz, DMSO-d 6 ): δ8.62 (s, 1H), 7.91-7.89 (m, 1H), 7.76-7.74 (m, 1H), 7.53-7.48 (m, 2H), 7.26 ( s,1H),6.91(brs,2H),6.44-6.42(m,1H),6.34-6.32(m,1H), 5.60(s,2H), 3.67(s,4H),3.54-3.51(m, 4H), 2.55 (s, 3H), 1.72-1.69 (m, 4H).
实施例6Example 6
4-(6-((4-(2-氨基-6-(3-氰基-2-甲基苯基)嘧啶-4-基)-1H-1,2,3-***-1-基)甲基)吡啶-2-基)***啉-3-羧酸64-(6-((4-(2-amino-6-(3-cyano-2-methylphenyl)pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl )Methyl)pyridin-2-yl)morpholine-3-carboxylic acid 6
Figure PCTCN2020074091-appb-000053
Figure PCTCN2020074091-appb-000053
第一步first step
4-[6-[[4-[2-[双(叔丁氧羰基)氨基]-6-(3-氰基-2-甲基-苯基)嘧啶-4-基]***-1-基]甲基]-2-吡啶基]***啉-3-羧酸甲酯6a4-[6-[[4-[2-[Bis(tert-butoxycarbonyl)amino]-6-(3-cyano-2-methyl-phenyl)pyrimidin-4-yl]triazole-1- Methyl]methyl]-2-pyridyl]morpholine-3-carboxylate 6a
在氩气气氛下，将***啉-3-羧酸甲酯(440mg,3.031mmol)、化合物4b(900mg,1.389mmol)、碳酸铯(1.97g,6.046mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(233mg,402.6μmol)、三(二亚苄基茚丙酮)二钯(184mg,200.9μmol)加入到40mL1,4-二氧六环中，加热到90℃反应16小时。将反应液冷却到室温，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题化合物6a(413mg，产率：41.74％)。Under argon atmosphere, morpholine-3-carboxylic acid methyl ester (440mg, 3.031mmol), compound 4b (900mg, 1.389mmol), cesium carbonate (1.97g, 6.046mmol), 4,5-bisdiphenyl Phosphine-9,9-dimethylxanthene (233mg, 402.6μmol), tris(dibenzylidene indeneacetone) dipalladium (184mg, 200.9μmol) were added to 40mL 1,4-dioxane and heated to React at 90°C for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified with a CombiFlash rapid preparation device using eluent system A to obtain the title compound 6a (413 mg, yield: 41.74%).
第二步Second step
4-[6-[[4-[2-氨基-6-(3-氰基-2-甲基-苯基)嘧啶-4-基]***-1-基]甲基]-2-吡啶基]***啉-3-羧酸甲酯6b4-[6-[[4-[2-Amino-6-(3-cyano-2-methyl-phenyl)pyrimidin-4-yl]triazol-1-yl]methyl]-2-pyridine Yl]morpholine-3-carboxylic acid methyl ester 6b
将化合物6a(413mg,580.2μmol)溶解于20mL二氯甲烷中，加入4mL三氟乙酸，搅拌反应2小时。将反应液减压浓缩，残余物中加入饱和碳酸氢钠水溶液调节至pH大于7，水相用二氯甲烷(30mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题化合物6b(330mg,产率：111.1％)。Compound 6a (413 mg, 580.2 μmol) was dissolved in 20 mL of dichloromethane, 4 mL of trifluoroacetic acid was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added to the residue to adjust the pH to greater than 7, the aqueous phase was extracted with dichloromethane (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was depressurized Concentrated, and the residue was purified with CombiFlash rapid preparation device using eluent system A to obtain the title compound 6b (330 mg, yield: 111.1%).
第三步third step
4-(6-((4-(2-氨基-6-(3-氰基-2-甲基苯基)嘧啶-4-基)-1H-1,2,3-***-1-基)甲基)吡啶-2-基)***啉-3-羧酸64-(6-((4-(2-amino-6-(3-cyano-2-methylphenyl)pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl )Methyl)pyridin-2-yl)morpholine-3-carboxylic acid 6
将化合物6b(250mg,488.7μmol)加入到20mL水和甲醇(V/V＝1/1)中，再加入氢氧化锂(41mg,977.0μmol)，反应搅拌16小时。将反应液减压浓缩，再加入1N盐酸调节pH至7。水相用二氯甲烷(30mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用制备板以洗脱剂体系A纯化，得到标题化合物6(50 mg，产率：20.56％)。Compound 6b (250 mg, 488.7 μmol) was added to 20 mL of water and methanol (V/V=1/1), lithium hydroxide (41 mg, 977.0 μmol) was added, and the reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and 1N hydrochloric acid was added to adjust the pH to 7. The aqueous phase was extracted with dichloromethane (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified with a preparation plate using eluent system A to obtain the title compound 6 (50 mg , Yield: 20.56%).
MS m/z(ESI):489.2[M+1]。MS m/z(ESI): 489.2[M+1].
1H NMR(400 MHz,DMSO-d 6):δ12.97(brs,1H),8.58(s,1H),7.86(d,1H),7.43(d,1H),7.46-7.50(m,2H),7.24(s,1H),6.84(s,2H),6.68(s,1H),6.47(s,1H),5.57(s,2H),4.77(s,1H),4.23-4.26(m,1H),3.80-3.89(m,2H),3.61-3.63(s,1H),3.44-3.46(m,1H),3.19-3.20(m,1H),2.52(s,3H)。 1 H NMR (400 MHz, DMSO-d 6 ): δ12.97 (brs, 1H), 8.58 (s, 1H), 7.86 (d, 1H), 7.43 (d, 1H), 7.46-7.50 (m, 2H) ), 7.24 (s, 1H), 6.84 (s, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 5.57 (s, 2H), 4.77 (s, 1H), 4.23-4.26 (m, 1H), 3.80-3.89 (m, 2H), 3.61-3.63 (s, 1H), 3.44-3.46 (m, 1H), 3.19-3.20 (m, 1H), 2.52 (s, 3H).
测试例：Test case:
生物学评价Biological evaluation
测试例1、本公开化合物对腺苷A 2a受体(adenosine A 2a receptor，A 2aR)cAMP信号通路、腺苷A 2b受体(adenosine A 2b receptor，A 2bR)cAMP信号通路、腺苷A 1受体(adenosine A 1 receptor，A 1R)cAMP信号通路和腺苷A 3受体(adenosine A 3 receptor，A 3R)cAMP信号通路抑制活性的测定。 Test Example 1. The compounds of the present disclosure have an effect on adenosine A 2a receptor (adenosine A 2a receptor, A 2a R) cAMP signaling pathway, adenosine A 2b receptor (adenosine A 2b receptor, A 2b R) cAMP signaling pathway, and adenosine Determination of inhibitory activity of A 1 receptor (adenosine A 1 receptor, A 1 R) cAMP signaling pathway and adenosine A 3 receptor (adenosine A 3 receptor, A 3 R) cAMP signaling pathway.
以下方法用来测定本公开化合物对腺苷A 2a受体(adenosine A 2a receptor，A 2a R)cAMP信号通路、腺苷A 2b受体cAMP信号通路、腺苷A 1受体cAMP信号通路和腺苷A 3受体cAMP信号通路的抑制活性。 The following method is used to determine the compounds of the present disclosure on the adenosine A 2a receptor (adenosine A 2a receptor, A 2a R) cAMP signaling pathway, adenosine A 2b receptor cAMP signaling pathway, adenosine A 1 receptor cAMP signaling pathway and adenosine Inhibitory activity of glycoside A 3 receptor cAMP signaling pathway.
实验方法简述如下：The experimental method is briefly described as follows:
一、实验材料及仪器1. Experimental materials and instruments
1.CHO-K1/A 2aR细胞(NM_000675.5)或CHO-K1/A 2bR细胞(NM_000676.2)或CHO-K1/A 1R细胞(NM_000674.2)或CHO-K1/A 3R细胞(NM_000677.3) 1.CHO-K1/A 2a R cell (NM_000675.5) or CHO-K1/A 2b R cell (NM_000676.2) or CHO-K1/A 1 R cell (NM_000674.2) or CHO-K1/A 3 R cell (NM_000677.3)
2.胎牛血清(Gibco,10099-141)2. Fetal bovine serum (Gibco, 10099-141)
3.博来霉素(Thermo,R25001)或G418(ENZO,ALX-380-013-G005)或嘌呤霉素(Thermo,10687-010)3. Bleomycin (Thermo, R25001) or G418 (ENZO, ALX-380-013-G005) or puromycin (Thermo, 10687-010)
4.DMEM/F12培养基(GE,SH30023.01)4.DMEM/F12 medium (GE, SH30023.01)
5.细胞分离缓冲液(Thermo Fisher,13151014)5. Cell separation buffer (Thermo Fisher, 13151014)
6.HEPES(Gibco,42360-099)6.HEPES (Gibco, 42360-099)
7.牛血清白蛋白(MP Biomedicals,219989725)7. Bovine serum albumin (MP Biomedicals, 219989725)
8.咯利普兰(sigma,R6520-10MG)8. Rolipram (sigma, R6520-10MG)
9.腺苷脱氨酶(sigma,10102105001)9. Adenosine deaminase (sigma, 10102105001)
10.毛喉素(sigma，F6886)10. Forskolin (sigma, F6886)
11. 2Cl-IB-MECA(Tocrics,1104/10)11. 2Cl-IB-MECA (Tocrics, 1104/10)
12.N6-环戊基腺苷(Tocris，1702/50)12. N6-Cyclopentyl Adenosine (Tocris, 1702/50)
13.平衡盐缓冲液(Thermo,14025-092)13.Balanced salt buffer (Thermo, 14025-092)
14.cAMP动态2试剂盒(cAMP dynamic2kit)(Cisbio,62AM4PEB)14.cAMP dynamic 2 kit (cAMP dynamic2kit) (Cisbio, 62AM4PEB)
15. 384孔板(Corning,4514)或(Nunc,267462#)15. 384-well plate (Corning,4514) or (Nunc,267462#)
16.乙基咔唑(Torcis,1691/10)16.Ethylcarbazole (Torcis, 1691/10)
17.PHERAstar多功能酶标仪(Cisbio,62AM4PEB)17. PHERAstar multifunctional microplate reader (Cisbio, 62AM4PEB)
二、实验步骤2. Experimental steps
2.1腺苷A 2a受体 2.1 Adenosine A 2a receptor
CHO-K1/A 2aR细胞用含有10％胎牛血清和800μg/ml博来霉素的DMEM/F12培养基进行培养。实验时使用细胞分离缓冲液消化细胞，用含有20mM HEPES和0.1％牛血清白蛋白的平衡盐缓冲液重悬细胞并计数，将细胞密度调整为10 6个/ml。在384孔板中每孔加入5μl细胞悬液，2.5μl用含有20mM HEPES、0.1％牛血清白蛋白、54μM咯利普兰和2.7U/ml腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的受试化合物，室温孵育30分钟。每孔再加入2.5μl用含有20mM HEPES、0.1％牛血清白蛋白、54μM咯利普兰和2.7U/ml腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的乙基咔唑，室温孵育30分钟。化合物终浓度是：10000、2000、400、80、16、3.2、0.64、0.128、0.0256、0.00512、0.001024nM，乙基咔唑终浓度是20nM。细胞内cAMP浓度使用cAMP动态2试剂盒检测。用cAMP裂解缓冲液按1：4的比例分别稀释cAMP-d2和抗cAMP-Eu-穴状化合物(Anti-cAMP-Eu-Cryptate)。每孔加入5μl稀释后的cAMP-d2，再加入5μl稀释后的抗cAMP-Eu-穴状化合物，室温避光孵育1小时。采用PHERAstar多功能酶标仪读取HTRF信号值。用Graphpad Prism软件计算化合物抑制活性的IC 50值，见表1。 CHO-K1/A 2a R cells were cultured in DMEM/F12 medium containing 10% fetal bovine serum and 800 μg/ml bleomycin. When cell separation experiments using buffer cells were digested with balanced salt buffer containing 20mM HEPES and 0.1% bovine serum albumin cells were resuspended and counted, cell density was adjusted to 106 cells / ml. Add 5μl of cell suspension to each well of a 384-well plate, 2.5μl of 4× prepared with a balanced salt buffer containing 20mM HEPES, 0.1% bovine serum albumin, 54μM rolipram and 2.7U/ml adenosine deaminase The concentration of the test compound was incubated at room temperature for 30 minutes. Add 2.5μl of 4× ethylcarbazole prepared with a balanced salt buffer containing 20mM HEPES, 0.1% bovine serum albumin, 54μM rolipram and 2.7U/ml adenosine deaminase to each well, and incubate at room temperature 30 minutes. The final concentration of the compound is: 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256, 0.00512, 0.001024 nM, and the final concentration of ethylcarbazole is 20 nM. The intracellular cAMP concentration was detected using cAMP dynamic 2 kit. Dilute cAMP-d2 and anti-cAMP-Eu-cryptate (Anti-cAMP-Eu-Cryptate) with cAMP lysis buffer at a ratio of 1:4. Add 5μl of diluted cAMP-d2 to each well, then add 5μl of diluted anti-cAMP-Eu-cryptate, and incubate for 1 hour at room temperature in the dark. Use PHERAstar multi-function microplate reader to read HTRF signal value. Graphpad Prism software was used to calculate the IC 50 value of the compound's inhibitory activity, as shown in Table 1.
2.2腺苷A 2b受体 2.2 Adenosine A 2b receptor
CHO-K1/A 2bR用含有10％胎牛血清和1mg/ml G418的DMEM/F12培养基进行培养。实验时使用细胞分离缓冲液消化细胞，用含有20mM HEPES和0.1％牛血清白蛋白的平衡盐缓冲液重悬细胞并计数，将细胞密度调整为10 6个/ml。在384孔板中每孔加入5μl细胞悬液，2.5μl用含有20mM HEPES、0.1％牛血清白蛋白、54μM咯利普兰和2.7U/ml腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的受试化合物，室温孵育30分钟。每孔再加入2.5μl用含有20mM HEPES、0.1％牛血清白蛋白、54μM咯利普兰和2.7U/ml腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的乙基咔唑(Torcis,1691/10)，室温孵育30分钟。化合物终浓度是：100000、10000、1000、100、10、1、0.1和0nM，乙基咔唑终浓度是1μM。细胞内cAMP浓度使用cAMP动态2试剂盒检测。用cAMP裂解缓冲液按1：4的比例分别稀释cAMP-d2和抗cAMP-Eu-穴状化合物。每孔加入5μl稀释后的cAMP-d2，再加入5μl稀释后的抗cAMP-Eu-穴状化合物，室温避光孵育1小时。采用PHERAstar多功能酶标仪读取HTRF信号值。用Graphpad Prism软件计算化合物抑制活性的IC 50值，见表2。 CHO-K1/A 2b R was cultured in DMEM/F12 medium containing 10% fetal bovine serum and 1 mg/ml G418. When cell separation experiments using buffer cells were digested with balanced salt buffer containing 20mM HEPES and 0.1% bovine serum albumin cells were resuspended and counted, cell density was adjusted to 106 cells / ml. Add 5μl of cell suspension to each well of a 384-well plate, 2.5μl of 4× prepared with a balanced salt buffer containing 20mM HEPES, 0.1% bovine serum albumin, 54μM rolipram and 2.7U/ml adenosine deaminase The concentration of the test compound was incubated at room temperature for 30 minutes. Add 2.5μl to each well with a 4× concentration of ethylcarbazole (Torcis, Torcis, BSA) prepared with a balanced salt buffer containing 20mM HEPES, 0.1% bovine serum albumin, 54μM rolipram and 2.7U/ml adenosine deaminase. 1691/10), incubate at room temperature for 30 minutes. The final concentration of the compound is: 100000, 10000, 1000, 100, 10, 1, 0.1 and 0 nM, and the final concentration of ethylcarbazole is 1 μM. The intracellular cAMP concentration was detected using cAMP dynamic 2 kit. Dilute cAMP-d2 and anti-cAMP-Eu-cryptate in the ratio of 1:4 with cAMP lysis buffer. Add 5μl of diluted cAMP-d2 to each well, then add 5μl of diluted anti-cAMP-Eu-cryptate, and incubate for 1 hour at room temperature in the dark. Use PHERAstar multi-function microplate reader to read HTRF signal value. Graphpad Prism software was used to calculate the IC 50 value of the compound's inhibitory activity, as shown in Table 2.
2.3腺苷A 1受体 2.3 Adenosine A 1 receptor
CHO-K1/A 1R用含有10％胎牛血清和1mg/mlG418的DMEM/F12培养基进行培养。实验时使用细胞分离缓冲液消化细胞，然后用含有20mM HEPES和0.1％牛血清白蛋白的平衡盐缓冲液重悬细胞并计数，将细胞密度调整为5×10 5个/ml。在384孔板中每孔加入12.5μl细胞悬液，6.25μl用含有20mM HEPES、0.1％牛血清白蛋白、54μM咯利普兰和2.7U/ml腺苷脱氨酶的平衡盐缓冲液配制的4×浓度 的受试化合物，室温孵育30分钟。每孔再加入6.25μl用含有20mM HEPES、0.1％牛血清白蛋白、54μM咯利普兰和2.7U/ml腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的毛喉素和N6-环戊基腺苷，室温孵育30分钟。化合物终浓度是：100000、10000、1000、100、10、1、0.1和0nM，毛喉素的终浓度是10μM，CPA的终浓度是10nM。细胞内cAMP浓度使用cAMP动态2试剂盒检测。用cAMP裂解缓冲液按照1：4的比例分别稀释cAMP-d2和抗cAMP-Eu-穴状化合物。每孔加入12.5μl稀释后的cAMP-d2，再加入12.5μl稀释后的抗cAMP-Eu-穴状化合物，室温避光孵育1小时。采用PHERAstar多功能酶标仪读取HTRF信号值。用Graphpad Prism软件计算化合物抑制活性的IC 50值，见表1或表2。 CHO-K1/A 1 R was cultured in DMEM/F12 medium containing 10% fetal bovine serum and 1 mg/ml G418. In the experiment, the cells were digested with cell separation buffer, and then resuspended and counted in a balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin, and the cell density was adjusted to 5×10 5 cells/ml. Add 12.5μl of cell suspension to each well of a 384-well plate, 6.25μl of 4 prepared with a balanced salt buffer containing 20mM HEPES, 0.1% bovine serum albumin, 54μM rolipram and 2.7U/ml adenosine deaminase × concentration of test compound, incubate at room temperature for 30 minutes. Add 6.25μl to each well with 4× concentration of forskolin and N6-ring prepared with a balanced salt buffer containing 20mM HEPES, 0.1% bovine serum albumin, 54μM rolipram and 2.7U/ml adenosine deaminase Amyladenosine, incubate at room temperature for 30 minutes. The final concentration of the compound is: 100000, 10000, 1000, 100, 10, 1, 0.1 and 0 nM, the final concentration of forskolin is 10 μM, and the final concentration of CPA is 10 nM. The intracellular cAMP concentration was detected using cAMP dynamic 2 kit. Dilute cAMP-d2 and anti-cAMP-Eu-cryptate with cAMP lysis buffer at a ratio of 1:4. Add 12.5μl of diluted cAMP-d2 to each well, then add 12.5μl of diluted anti-cAMP-Eu-cryptate, and incubate for 1 hour at room temperature in the dark. Use PHERAstar multi-function microplate reader to read HTRF signal value. Graphpad Prism software was used to calculate the IC 50 value of the compound's inhibitory activity, see Table 1 or Table 2.
2.4腺苷A 3受体 2.4 Adenosine A 3 receptor
CHO-K1/A 3R用含有10％胎牛血清和10μg/ml嘌呤霉素的DMEM/F12培养基进行培养。实验时使用细胞分离缓冲液消化细胞，用含有20mM HEPES和0.1％牛血清白蛋白的平衡盐缓冲液重悬细胞并计数，将细胞密度调整为5×10 5/ml。在384孔板中每孔加入12.5μl细胞悬液，6.25μl用含有20mM HEPES、0.1％牛血清白蛋白、54μM咯利普兰和2.7U/ml腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的受试化合物，室温孵育30分钟。每孔再加入6.25μl用含有20mM HEPES、0.1％牛血清白蛋白、54μM咯利普兰和2.7U/ml腺苷脱氨酶的平衡盐缓冲液配制的4×浓度的毛喉素和2Cl-IB-MECA，室温孵育30分钟。化合物终浓度是：100000、10000、1000、100、10、1、0.1和0nM，毛喉素的终浓度是10μM，2Cl-IB-MECA的终浓度是5nM。细胞内cAMP浓度使用cAMP动态2试剂盒检测。用cAMP裂解缓冲液按照1：4的比例分别稀释cAMP-d2和抗cAMP-Eu-穴状化合物。每孔加入12.5μl稀释后的cAMP-d2，再加入12.5μl稀释后的抗cAMP-Eu-穴状化合物，室温避光孵育1小时。采用PHERAstar多功能酶标仪读取HTRF信号值。用Graphpad Prism软件计算化合物抑制活性的IC 50值，见表1或表2。 CHO-K1/A 3 R was cultured with DMEM/F12 medium containing 10% fetal bovine serum and 10 μg/ml puromycin. In the experiment, the cells were digested with cell separation buffer, and the cells were resuspended in a balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin and counted, and the cell density was adjusted to 5×10 5 /ml. Add 12.5μl of cell suspension to each well of a 384-well plate, 6.25μl of 4 prepared with a balanced salt buffer containing 20mM HEPES, 0.1% bovine serum albumin, 54μM rolipram and 2.7U/ml adenosine deaminase × concentration of test compound, incubate at room temperature for 30 minutes. Add 6.25μl to each well with 4× concentration of forskolin and 2Cl-IB prepared with a balanced salt buffer containing 20mM HEPES, 0.1% bovine serum albumin, 54μM rolipram and 2.7U/ml adenosine deaminase -MECA, incubate at room temperature for 30 minutes. The final concentration of the compound is: 100000, 10000, 1000, 100, 10, 1, 0.1 and 0 nM, the final concentration of forskolin is 10 μM, and the final concentration of 2Cl-IB-MECA is 5 nM. The intracellular cAMP concentration was detected using cAMP dynamic 2 kit. Dilute cAMP-d2 and anti-cAMP-Eu-cryptate with cAMP lysis buffer at a ratio of 1:4. Add 12.5μl of diluted cAMP-d2 to each well, then add 12.5μl of diluted anti-cAMP-Eu-cryptate, and incubate for 1 hour at room temperature in the dark. Use PHERAstar multi-function microplate reader to read HTRF signal value. Graphpad Prism software was used to calculate the IC 50 value of the compound's inhibitory activity, see Table 1 or Table 2.
表1本公开化合物对腺苷A 2a受体(adenosine A 2a receptor，A 2aR)cAMP信号通路抑制活性的IC 50值 Table 1 The IC 50 value of the compound of the present disclosure on the adenosine A 2a receptor (adenosine A 2a receptor, A 2a R) cAMP signaling pathway inhibitory activity
Figure PCTCN2020074091-appb-000054
Figure PCTCN2020074091-appb-000054
-：为未测试。-: Not tested.
表2本公开化合物对腺苷A 2b受体(adenosine A 2b receptor，A 2bR)cAMP信号通路抑制活性的IC 50值 Table 2 The IC 50 value of the compound of the present disclosure on the adenosine A 2b receptor (adenosine A 2b receptor, A 2b R) cAMP signaling pathway inhibitory activity
Figure PCTCN2020074091-appb-000055
Figure PCTCN2020074091-appb-000055
-：为未测试。-: Not tested.
结论：从表1和表2中数据可以看出，本公开化合物当环C为7-14元多环杂环基时，对腺苷A 2a受体和腺苷A 2b受体均具有较好的抑制活性，对腺苷A 1受体和腺苷A 3受体抑制活性作用较弱，而阴性对照实施例6对腺苷A 1受体具有好的抑制活性，选择性差。 Conclusion: From the data in Table 1 and Table 2, it can be seen that when the ring C of the compound of the present disclosure is a 7-14 membered polycyclic heterocyclic group, it has a good effect on both adenosine A 2a receptor and adenosine A 2b receptor. The inhibitory activity of the adenosine A 1 receptor and the adenosine A 3 receptor is weak, while the negative control example 6 has a good inhibitory activity on the adenosine A 1 receptor with poor selectivity.
从表2中还可以看出，本公开化合物当环C为7-14元多环杂环基时，与阴性对照实施例6相比，对A 2b受体抑制活性相差了10-20倍。 It can also be seen from Table 2 that when the ring C of the compound of the present disclosure is a 7-14 membered polycyclic heterocyclic group, compared with the negative control Example 6, the inhibitory activity on the A 2b receptor is 10-20 times different.

Claims (23)

  1. 一种通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：A compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its forms or Medicinal salt:
    Figure PCTCN2020074091-appb-100001
    Figure PCTCN2020074091-appb-100001
    其中：among them:
    环A和环B相同或不同，且各自独立地为芳基或杂芳基；Ring A and Ring B are the same or different, and each independently is an aryl group or a heteroaryl group;
    环C为7-14元多环杂环基；Ring C is a 7-14 membered polycyclic heterocyclic group;
    L选自键、亚烷基、O原子、S原子和NR 5； L is selected from bond, alkylene, O atom, S atom and NR 5 ;
    R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、氘代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基； R 1 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, deuterated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, Heterocyclic group, aryl group and heteroaryl group;
    R 2选自氢原子、卤素、烷基、烷氧基、卤代烷基、氘代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基； R 2 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, deuterated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and hetero Aryl;
    R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、氘代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基； R 3 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, deuterated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, Heterocyclic group, aryl group and heteroaryl group;
    R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、氘代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基； R 4 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, deuterated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, Heterocyclic group, aryl group and heteroaryl group;
    R 5选自氢原子、烷基、氘代烷基、卤代烷基、羟烷基、环烷基和杂环基； R 5 is selected from hydrogen atom, alkyl group, deuterated alkyl group, halogenated alkyl group, hydroxyalkyl group, cycloalkyl group and heterocyclic group;
    m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
    n为0、1、2或3；且n is 0, 1, 2 or 3; and
    s为0、1、2、3、4、5或6。s is 0, 1, 2, 3, 4, 5, or 6.
  2. 根据权利要求1所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，The compound represented by the general formula (I) according to claim 1, or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture or its pharmaceutically acceptable salt,
    其中：among them:
    环A和环B相同或不同，且各自独立地为苯基或吡啶基。Ring A and Ring B are the same or different, and each independently is a phenyl group or a pyridyl group.
  3. 根据权利要求1或2所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其为通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映 异构体、非对映异构体、或其混合物形式或其可药用的盐：The compound represented by the general formula (I) according to claim 1 or 2, or its tautomer, meso, racemate, enantiomer, diastereomer, Or its mixture form or its pharmaceutically acceptable salt, which is a compound represented by general formula (II), or its tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, or their mixture forms or their pharmaceutically acceptable salts:
    Figure PCTCN2020074091-appb-100002
    Figure PCTCN2020074091-appb-100002
    其中：among them:
    环C、L、R 1～R 4、m、n和s如权利要求1中所定义。 Rings C, L, R 1 to R 4 , m, n, and s are as defined in claim 1.
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，The compound represented by the general formula (I) according to any one of claims 1 to 3, or its tautomer, meso, racemate, enantiomer, diastereomer Isomer, or its mixture form or its pharmaceutically acceptable salt,
    其中：among them:
    环C选自7-14元螺环杂环基、7-14元稠环杂环基和7-14元桥环杂环基。Ring C is selected from the group consisting of a 7-14 membered spirocyclic heterocyclic group, a 7-14 membered fused ring heterocyclic group and a 7-14 membered bridged heterocyclic group.
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，The compound represented by the general formula (I) according to any one of claims 1 to 4, or its tautomer, meso, racemate, enantiomer, diastereomer Isomer, or its mixture form or its pharmaceutically acceptable salt,
    其中：among them:
    环C为
    Figure PCTCN2020074091-appb-100003
    Ring C is
    Figure PCTCN2020074091-appb-100003
    G选自C(R 4) 2、O原子和N原子； G is selected from C(R 4 ) 2 , O atom and N atom;
    p、q、r和t相同或不同，且各自独立地为1或2；p, q, r and t are the same or different, and each independently is 1 or 2;
    R 4如权利要求1中所定义。 R 4 is as defined in claim 1.
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其为通式(III)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：The compound represented by the general formula (I) according to any one of claims 1 to 5, or its tautomer, meso, racemate, enantiomer, diastereomer Isomer, or its mixture form or its pharmaceutically acceptable salt, which is a compound represented by general formula (III), or its tautomer, meso, racemate, enantiomer Forms, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
    Figure PCTCN2020074091-appb-100004
    Figure PCTCN2020074091-appb-100004
    其中：among them:
    G选自C(R 4) 2、O原子或N原子； G is selected from C(R 4 ) 2 , O atom or N atom;
    p、q、r和t相同或不同，且各自独立地为1或2；p, q, r and t are the same or different, and each independently is 1 or 2;
    s为0、1、2、3或4；s is 0, 1, 2, 3 or 4;
    L、R 1～R 4、m和n如权利要求1中所定义。 L, R 1 to R 4 , m, and n are as defined in claim 1.
  7. 根据权利要求5或6所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中G为O原子。The compound represented by the general formula (I) according to claim 5 or 6, or its tautomer, meso, racemate, enantiomer, diastereomer, Or a mixture or a pharmaceutically acceptable salt thereof, wherein G is an O atom.
  8. 根据权利要求1至5中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，The compound represented by the general formula (I) according to any one of claims 1 to 5, or its tautomer, meso, racemate, enantiomer, diastereomer Isomer, or its mixture form or its pharmaceutically acceptable salt,
    其中：among them:
    环C选自
    Figure PCTCN2020074091-appb-100005
    Ring C is selected from
    Figure PCTCN2020074091-appb-100005
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中：L为键或-CH 2-。 The compound represented by the general formula (I) according to any one of claims 1 to 8, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein: L is a bond or -CH 2 -.
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中：R 1相同或不同，且各自独立地选自选自氢原子、烷基、卤代烷基和氰基；m为0、1或2。 The compound represented by the general formula (I) according to any one of claims 1 to 9, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein: R 1 is the same or different, and each is independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group and a cyano group; m is 0, 1, or 2.
  11. 根据权利要求1至10中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中：R 2选自氢原子、卤素和烷基；R 3相同或不同，且各自独立 地选自氢原子、卤素和烷基；n为0、1或2。 The compound represented by the general formula (I) according to any one of claims 1 to 10, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein: R 2 is selected from hydrogen atom, halogen and alkyl; R 3 is the same or different, and each is independently selected from hydrogen atom, halogen and alkyl; n is 0, 1, or 2.
  12. 根据权利要求1至11中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R 4为氢原子。 The compound represented by the general formula (I) according to any one of claims 1 to 11, or its tautomer, meso, racemate, enantiomer, diastereomer An isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen atom.
  13. 根据权利要求1至12中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中所述化合物选自：The compound represented by the general formula (I) according to any one of claims 1 to 12, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein the compound is selected from:
    Figure PCTCN2020074091-appb-100006
    Figure PCTCN2020074091-appb-100006
  14. 一种通式(IA)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐：A compound represented by the general formula (IA), or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its forms or Medicinal salt:
    Figure PCTCN2020074091-appb-100007
    Figure PCTCN2020074091-appb-100007
    其中：among them:
    W为氨基保护基；优选为叔丁氧羰基；W is an amino protecting group; preferably tert-butoxycarbonyl;
    环A、环B、环C、L、R 1～R 4、m、n和s如权利要求1中所定义。 Ring A, ring B, ring C, L, R 1 to R 4 , m, n, and s are as defined in claim 1.
  15. 根据权利要求14所述的通式(IA)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中所述化合物选自：The compound represented by general formula (IA) according to claim 14, or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
    Figure PCTCN2020074091-appb-100008
    Figure PCTCN2020074091-appb-100008
  16. 一种制备根据权利要求14或15所述的通式(IA)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括以下步骤：A method for preparing the compound represented by the general formula (IA) according to claim 14 or 15, or its tautomer, meso, racemate, enantiomer, diastereomer A method for constructing a structure, a mixture thereof, or a pharmaceutically acceptable salt thereof, the method includes the following steps:
    Figure PCTCN2020074091-appb-100009
    Figure PCTCN2020074091-appb-100009
    通式(IB)的化合物和通式(ID)的化合物发生Click反应，得到通式(IA)的化合物，The compound of general formula (IB) and the compound of general formula (ID) undergo a Click reaction to obtain the compound of general formula (IA),
    其中：among them:
    环A、环B、环C、L、W、R 1～R 4、m、n和s如权利要求14中所定义。 Ring A, ring B, ring C, L, W, R 1 to R 4 , m, n, and s are as defined in claim 14.
  17. 一种制备根据权利要求1至13中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括以下步骤：A method for preparing the compound represented by the general formula (I) according to any one of claims 1 to 13, or its tautomer, meso, racemate, enantiomer, A method for diastereoisomers, or mixtures thereof or pharmaceutically acceptable salts thereof, the method includes the following steps:
    Figure PCTCN2020074091-appb-100010
    Figure PCTCN2020074091-appb-100010
    通式(IA)的化合物脱去氨基保护基，得到通式(I)的化合物，The compound of general formula (IA) removes the amino protecting group to obtain the compound of general formula (I),
    其中：among them:
    W为氨基保护基；优选为叔丁氧羰基；W is an amino protecting group; preferably tert-butoxycarbonyl;
    环A、环B、环C、L、R 1～R 4、m、n和s如权利要求1中所定义。 Ring A, ring B, ring C, L, R 1 to R 4 , m, n, and s are as defined in claim 1.
  18. 一种制备根据权利要求1至13中任一项所述的通式(I)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐的方法，该方法包括以下步骤：A method for preparing the compound represented by the general formula (I) according to any one of claims 1 to 13, or its tautomer, meso, racemate, enantiomer, A method for diastereoisomers, or mixtures thereof or pharmaceutically acceptable salts thereof, the method includes the following steps:
    Figure PCTCN2020074091-appb-100011
    Figure PCTCN2020074091-appb-100011
    通式(IB)的化合物和通式(IC)的化合物发生Click反应，得到通式(I)的化合物，The compound of general formula (IB) and the compound of general formula (IC) undergo a Click reaction to obtain a compound of general formula (I),
    其中：among them:
    环A、环B、环C、L、R 1～R 4、m、n和s如权利要求1中所定义。 Ring A, ring B, ring C, L, R 1 to R 4 , m, n, and s are as defined in claim 1.
  19. 一种药物组合物，其含有治疗有效量的根据权利要求1至13中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition containing a therapeutically effective amount of the compound represented by the general formula (I) according to any one of claims 1 to 13 or its tautomer, mesosome, or racemate Isomers, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  20. 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求19所述的药物组合物在制备用于治疗通过对A 2a受体和/或A 2b受体抑制而改善的疾病或病症的药物中的用途。 The compound represented by the general formula (I) according to any one of claims 1 to 13 or its tautomer, meso, racemate, enantiomer, diastereomer The construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19 is prepared for the treatment of diseases or diseases ameliorated by inhibition of A 2a receptor and/or A 2b receptor Use in medicine for illness.
  21. 根据权利要求20所述的用途，其中所述的疾病或病症选自癌症、抑郁、认知功能病症、神经退行性病症、注意力相关病症、锥体外症候群、异常运动障碍、肝硬化、肝纤维化、脂肪肝、皮肤纤维化、睡眠障碍、中风、脑损伤、神经炎症和成瘾行为；优选为癌症。The use according to claim 20, wherein the disease or disorder is selected from cancer, depression, cognitive function disorders, neurodegenerative disorders, attention-related disorders, extrapyramidal syndrome, abnormal movement disorders, liver cirrhosis, liver fibers Metabolism, fatty liver, skin fibrosis, sleep disorders, stroke, brain injury, neuroinflammation and addictive behavior; preferably cancer.
  22. 根据权利要求21所述的用途，其中所述的癌症选自黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、乳腺癌、卵巢癌、***癌、皮肤癌、神经母细胞瘤、肉瘤、骨软骨瘤、骨瘤、骨肉瘤、***瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、 白血病、甲状腺肿瘤、输尿管肿瘤、膀胱癌、胆囊癌、胆管癌、绒毛膜上皮癌和儿科肿瘤；优选为肺癌。The use according to claim 21, wherein the cancer is selected from the group consisting of melanoma, brain tumor, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, Skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, Thyroid tumor, ureteral tumor, bladder cancer, gallbladder cancer, cholangiocarcinoma, choriocarcinoma and pediatric tumor; preferably lung cancer.
  23. 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求19所述的药物组合物在制备用于抑制A 2a受体和/或A 2b受体的药物中的用途。 The compound represented by the general formula (I) according to any one of claims 1 to 13 or its tautomer, meso, racemate, enantiomer, diastereomer Use of the construct, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of a medicament for inhibiting A 2a receptor and/or A 2b receptor.
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