WO2018130184A1 - 1,2,4-三嗪-3-胺类衍生物、其制备方法及其在医药上的应用 - Google Patents

1,2,4-三嗪-3-胺类衍生物、其制备方法及其在医药上的应用 Download PDF

Info

Publication number
WO2018130184A1
WO2018130184A1 PCT/CN2018/072308 CN2018072308W WO2018130184A1 WO 2018130184 A1 WO2018130184 A1 WO 2018130184A1 CN 2018072308 W CN2018072308 W CN 2018072308W WO 2018130184 A1 WO2018130184 A1 WO 2018130184A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
formula
cancer
mmol
Prior art date
Application number
PCT/CN2018/072308
Other languages
English (en)
French (fr)
Inventor
陆标
张俊珍
金芳芳
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
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 江苏恒瑞医药股份有限公司, 上海恒瑞医药有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to US16/477,011 priority Critical patent/US11014904B2/en
Priority to JP2019534645A priority patent/JP2020506885A/ja
Priority to CN201880001471.0A priority patent/CN108884061B/zh
Priority to EP18739200.6A priority patent/EP3569596A4/en
Publication of WO2018130184A1 publication Critical patent/WO2018130184A1/zh
Priority to US17/223,736 priority patent/US20210230138A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicine, and relates to a 1,2,4-triazin-3-amine derivative represented by the formula (I), a preparation method thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent , particularly as a 2a receptor antagonists of use and manufacture of a medicament for the treatment of a disorder or condition through inhibition of a 2a receptors in ameliorated.
  • Adenosine is a naturally occurring purine nucleoside and is 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 platelets.
  • adenosine The action of adenosine is mediated by the G-protein coupled receptor family, and at least four subtypes of adenosine receptors are currently known, 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 cells through which adenosine is widely regulated.
  • Physiological function The action of adenosine is mediated by the G-protein coupled receptor family, and at least four subtypes of adenosine receptors are currently known, 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 A 2a receptor (A 2a R) is widely distributed in the body, and is mainly expressed in the striatum in the central nervous system, and is also expressed in tissues such as the periphery, heart, liver, lung and kidney.
  • adenosine A 2a receptor antagonists have surprising efficacy in the treatment of neurodegenerative diseases, primarily Parkinson's disease, Huntington's disease or Alzheimer's disease (Trends in Neurosci. 2006, 29(11), 647-654; Expert Opinion on Therapeutic Patents, 2007, 17, 979-991, etc.). It can also be used to treat other central nervous system (CNS) related diseases such as depression, hyperactivity syndrome, sleep disorders and anxiety (Clin. Neuropharmacol.
  • CNS central nervous system
  • adenosine A 2a receptor antagonists have therapeutic potential as neuroprotective agents (see Jenner PJ Neurol. 2000; 24 7 Supp 12: 1143-50).
  • adenosine A 2a receptors may play an important immunomodulatory role in many pathological processes such as ischemia, hypoxia, inflammation, trauma, transplantation, etc., which may be related to A 2a receptors in T cells and B cells. It is related to the high expression levels of various immune cells such as mononuclear macrophages and neutrophils.
  • the activation of A 2a receptor can promote the body to produce immune tolerance, and closely participate in the formation of "immune escape” or "immunosuppression” of tumor cells, which creates favorable conditions for the occurrence and development of tumors. Lokshin and colleagues (Cancer Res.
  • a 2a R activation on natural killer cells can inhibit the killing of tumor cells by natural killer cells by increasing cAMP and activating PKA.
  • activation of activated A 2a receptors can promote the proliferation of tumor cells such as melanoma A375 cells, fibroblast NIH3T3 cells and pheochromocytoma PC12 cells, which may be related to the activation of A 2a receptors on T cells. Inhibition of T cell activation, proliferation, adhesion to tumor cells and cytotoxicity to tumor cells; while A 2a receptor knockout mice can enhance the anti-tumor immunity of CD8 + T cells, significantly inhibiting tumors proliferation.
  • a 2a receptor antagonists can be used for the treatment of tumors.
  • Deepak Mittal et al. found that A 2b receptor inhibitors combined with chemotherapeutic drugs or immunological checkpoint inhibitors can significantly reduce tumor metastasis in a mouse triple-negative breast cancer model; knockout mice or human colon cancer cell lines The A 2b receptor significantly reduces colon cancer metastasis and cell tumorigenicity; meanwhile, the study found that A 2b receptor is highly expressed in human triple negative breast cancer cell lines, and the expression level of A 2b receptor is closely related to tumor progression.
  • a 2b receptors are expected to be an ideal target for the treatment of tumors (Cancer Res. 2016 Aug 1; 76(15): 4372-82). Studying the A 2a receptor and the A 2b receptor dual inhibitor has also become a direction worth exploring.
  • adenosine A 1 receptor in tissue, ischemia, hypoxia, in the central, circulatory, digestive system and skeletal muscle, cells in the hypoxic and hypoxic stress environment extracellular accumulation of adenosine through activation a 1 starts the corresponding membrane receptor on protection mechanisms, thus increasing cellular tolerance to hypoxic hypoxia.
  • the A 1 receptor located on immune cells promotes a cellular immune response in a hypoxic environment.
  • the A 1 receptor also reduces free fatty acids and triglycerides and is involved in the regulation of blood sugar.
  • a 3 adenosine receptor e.g.
  • a 3 Sustained blockade of the receptor may increase the likelihood of complications caused by any pre-existing or developing ischemic heart disease, such as angina or heart failure.
  • WO2011095625 discloses a 1,2,4-triazin-4-amine derivative of the formula (A1) and its use in the treatment of a condition or disorder which is ameliorated by inhibition of the A 1 receptor or the A 2a receptor use.
  • This patent application discloses a total of more than 200 embodiments in which only five of the examples in which ring A is a fused aromatic ring, the data in the patent application shows that when ring A is a fused aromatic ring, the pair The inhibitory activity of A 2a R was weak (see Table 1).
  • Ring A of Example 1 (lxxii) is a naphthyl group
  • a derivative in which a nitrogen atom is introduced at the 5-position of the naphthyl group exhibits surprising activity
  • the inhibitory activity against A 2a R is Example 1 (lxxii) 30 to 1500 times or more.
  • Such strong inhibitory activity is not expected when reading WO2011095625.
  • the present invention provides a novel structure of a strong inhibitory activity of adenosine A 2a receptor antagonist, and a compound having such a structure also has a good inhibitory effect on the adenosine A 2b receptor, and the adenosine A 1 receptor
  • the adenosine A 3 receptor has a weak inhibitory effect and exhibits a good selectivity for the adenosine A 2a receptor.
  • the compound having such a structure exhibits an excellent antitumor effect and a pharmacopoemic absorption activity.
  • Ring A is an aryl or heteroaryl group
  • G 1 , G 2 , G 3 and G 4 are the same or different and are each independently selected from C, CH or N;
  • R 1 is selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 5 , -C(O)R 5 , -S(O) m R 5 , NH 2 S(O) m R 5 , -NR 6 R 7 , S(O) m NR 6 R 7 and -C(O) NR 6 R 7 ; wherein alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halo, alkyl, Substituted with one or more substituents of alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl
  • R 2 is the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • heteroaryl -OR 5 , -C(O)R 5 , -S(O) m R 5 , NH 2 S(O) m R 5 , -NR 6 R 7 , S(O) m NR 6 R 7 and -C(O)NR 6 R 7 ; wherein the alkyl group, alkoxy group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optional Substituted by one or more selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, Heterocyclyl, aryl, heteroaryl, -OR 5 , -C(O)R 5 , -S(O) m R 5 , NH 2 S(O) m R 5 , -NR 6 R 7 , S( O) m NR 6 R 7 and -C(O)NR 6 R 7 ; wherein alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are described.
  • Each is optionally independently selected from the group consisting of halogen, deuterium, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents in the group;
  • R 4 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • heteroaryl -OR 5 , -C(O)R 5 , -S(O) m R 5 , NH 2 S(O) m R 5 , -NR 6 R 7 , S(O) m NR 6 R 7 and -C(O)NR 6 R 7 ; wherein the alkyl group, alkoxy group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optional Substituted by one or more selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by
  • R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an amino group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 6 and R 7 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein the alkyl group, the cycloalkyl group, the heterocyclic group, and the aryl group
  • the base and heteroaryl are each independently optionally selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. Substituted by one or more substituents;
  • the R 6 and R 7 together with the nitrogen atom to which they are bonded form a heterocyclic group, wherein the heterocyclic group contains 1 to 2 hetero atoms which are the same or different from N, O and S, and
  • the heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. Substituted by a plurality of substituents;
  • n 0, 1 or 2;
  • r 0, 1, 2 or 3;
  • q 0, 1, or 2;
  • n 0, 1, 2, 3, 4 or 5.
  • Rings A, G 1 , G 2 , R 1 , R 3 , R 4 , r and n are as defined in the formula (I).
  • G 1 and G 2 are the same or different and are each independently CR a or N;
  • R a is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a hetero group.
  • an aryl group wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from a halogen, a halogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group. Substituting one or more substituents of a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R c is selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Rings A, R 1 , R 4 and n are as defined in formula (I).
  • the compound of the formula (I) is a compound of the formula (II):
  • Rings A, R 1 , R 3 , R 4 , r and n are as defined in the formula (I).
  • the compound of the formula (I), wherein the ring A is selected from the group consisting of phenyl, pyridyl, thienyl and furyl.
  • the compound of the formula (I) is a compound of the formula (III):
  • R 1 , R 3 , R 4 , r and n are as defined in the formula (I).
  • R 6 and R 7 are as defined in the formula (I);
  • the halogen is preferably a fluorine atom, a chlorine atom or a bromine atom
  • the alkyl group is preferably Methyl, ethyl, isopropyl or n-butyl
  • the alkoxy group is preferably a methoxy group or an ethoxy group
  • the cycloalkyl group is preferably a cyclopropyl group, a cyclopentyl group or a cyclohexyl group.
  • the compound of the formula (I) wherein the R 3 is the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a halogenated alkyl, alkoxy, cyano, cycloalkylheterocyclyl group, wherein said alkyl group and alkoxy group are each independently selected from the group consisting of halogen, halogen atom, hydroxyl group, cyano group, amino group, and nitrate Substituted by one or more substituents of a group, a cycloalkyl group and a heterocyclic group; the halogen is preferably a fluorine atom, a chlorine atom or a bromine atom, and the alkyl group is preferably a methyl group, an ethyl group, an isopropyl group or a n-butyl group.
  • the alkoxy group is preferably a methoxy group or an ethoxy group
  • the heterocyclic group is preferably a piperidinyl group, a piperazinyl group, a morpholinyl group or a tetrahydropyranyl group.
  • the compound of the formula (I) wherein the R 4 is the same or different and each independently is selected from the group consisting of a hydrogen atom, an alkyl group and a halogen.
  • Typical compounds of the invention include, but are not limited to:
  • a tautomer a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention relates to a process for the preparation of a compound of formula (I), which process comprises:
  • the compound of the formula (I-A) and the compound of the formula (I-B) are subjected to a coupling reaction to obtain a compound of the formula (I).
  • X is a halogen
  • Ring A, G 1 to G 4 , R 1 to R 4 , r, q and n are as defined in the formula (I).
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (Iaa), which process comprises:
  • a compound of the formula (Iaa-1) and a compound of the formula (I-B) are subjected to a coupling reaction to obtain a compound of the formula (Iaa).
  • X is a halogen
  • Rings A, G 1 , G 2 , R 1 , R 3 , R 4 , r and n are as defined in the formula (I).
  • Another aspect of the invention relates to a process for the preparation of a compound of formula (II), the process comprising:
  • X is a halogen
  • Rings A, R 1 , R 3 , R 4 , r and n are as defined in formula (I).
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (III) which comprises:
  • X is a halogen
  • R 1 , R 3 , R 4 , r and n are as defined in the formula (I).
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) according to the invention or a tautomer thereof, a mesogen, a racemic form , enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof for the manufacture for treating a condition or disorder by a 2a receptors to inhibition of the improved medicament.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof for the treatment by the a 2b receptor medicament for inhibiting a condition or disorder ameliorated in.
  • a 2a receptors or a disorder or a condition of A 2b receptor inhibition ameliorated selected from cancer, depression, cognitive disorders, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Al Alzheimer's disease or amyotrophic lateral sclerosis, attention-related disorders, extrapyramidal syndrome, abnormal dyskinesia, cirrhosis, liver fibrosis, fatty liver, cutaneous fibrosis, sleep disorders, stroke, brain damage, Neuroinflammation and addictive behavior; preferably cancer, selected from the group consisting of melanoma, brain tumors (gliomas with malignant astroglia and oligodendroglioma, etc.), esophageal cancer, Gastric 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 cell carcinoma, etc.), kidney cancer, breast cancer, ovarian
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the preparation of a cancer, depression, cognitive function disorder, neurodegenerative disorder (Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic lateral cord) Hardening, etc., attention-related disorders, extrapyramidal syndrome, abnormal dyskinesia, cirrhosis, liver fibrosis, fatty liver, cutaneous fibrosis, sleep disorders, stroke, brain injury, neuroinflammation and addictive behavior, preferably cancer drugs Use in.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for treating cancer, wherein the cancer is selected from the group consisting of melanoma, brain tumor (malignant astroglia and oligodendroglioma) Ingredients such as glioma, esophageal cancer, gastric 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 carcinoma) Etc.), kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment of lung cancer, preferably non-small cell lung cancer.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting the A2a receptor.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting an A2b receptor.
  • the invention also relates to a method of inhibiting an A2a receptor comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesogen, racemate thereof , enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present invention also relates to a method of inhibiting an A 2b receptor comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesogen thereof, a racemate thereof. , enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present invention further relates to a method of treating a condition or disorder by A 2a receptor inhibition and to improve the method comprising administering to a patient in need thereof a therapeutically effective amount of a Formula (I), or a tautomer thereof shown, A meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • a Formula (I) or a tautomer thereof shown, A meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present invention further relates to a method of treating by the method of A 2b receptor inhibition and improved condition or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a formula (I) or a compound represented tautomer, A meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • a formula (I) or a compound represented tautomer A meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present invention relates to 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 dyskinesia, cirrhosis, liver fibrosis, fatty liver, cutaneous fibrosis, sleep disorders, stroke, brain injury, neuroinflammation, and addictive behavior, preferably a method of cancer, which comprises administering a therapeutically effective treatment to a patient in need thereof Amount of the compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a drug thereof A salt, or a pharmaceutical composition comprising the same.
  • the invention further relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesogen, racemate, enantiomer thereof Isomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the cancer is selected from the group consisting of melanoma, brain tumor (malignant astroglia) And oligodendroglioma components such as glioma, esophageal cancer, gastric 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 cell carcinoma, etc., kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminom
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which is used as a medicament.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use as an A2a receptor antagonist.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use as an A2b receptor antagonist.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof, which by the treatment of a disorder or condition a 2a receptor inhibition ameliorated.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof, which is improved by the treatment of a disorder or condition a 2b receptor inhibition.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the treatment of cancer, depression, cognitive function disorders, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease or muscular atrophy) Lateral sclerosis, etc., attention-related disorders, extrapyramidal syndrome, abnormal dyskinesia, cirrhosis, liver fibrosis, fatty liver, cutaneous fibrosis, sleep disorders, stroke, brain injury, neuroinflammation and addictive behavior, preferably cancer .
  • a compound of the formula (I) or a tautomer a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the treatment of cancer, wherein the cancer is selected from the group consisting of melanoma, a brain tumor (a nerve having a malignant astroglia and a oligodendroglioma component) Glioma, etc.), esophageal cancer, gastric 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 cell carcinoma, etc.), Kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminom
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
  • the aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents. Flavor.
  • Oil suspensions can be formulated by suspending the active ingredient in vegetable oil.
  • the oil suspension may contain a thickening agent.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation.
  • Dispersible powders and granules suitable for use in the preparation of aqueous suspensions may be employed in the preparation of the active ingredient and dispersion or dispersing or suspending agents or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or
  • compositions of the invention 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 vehicles or solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then added to a mixture of water and glycerin to form a microemulsion.
  • the injection or microemulsion can be injected into the bloodstream of the patient by a local injection.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention.
  • 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 injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oils may conveniently be employed as a solvent or suspension medium.
  • the compounds of the invention may be administered in the form of a suppository for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • suitable non-irritating excipient include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
  • the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, and the patient's behavior.
  • the dosage, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment mode such as the mode of treatment, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt The type can be verified according to traditional treatment options.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group of 1 to 20 carbon atoms, preferably an alkyl group having 1 to 12 carbon atoms, more preferably 1 to 6 An alkyl group of a carbon atom.
  • 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,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, 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 Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is preferably independently independently selected from the group consisting of H atom, D atom, halogen, alkane. Substituted by one or more substituents in the group, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of a H atom, a D atom, a halogen, an alkyl group, an alkoxy group. Substituted by one or more substituents of haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, preferably from 3 to 10 The carbon atom, more preferably contains 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
  • the cycloalkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is preferably independently independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, Substituted by one or more substituents of alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
  • a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1, 2.3.6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, High piperazinyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is preferably independently independently selected from a hydrogen atom, a halogen, an alkyl group, Substituted by one or more substituents of alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups which are polycyclic rings having a conjugated ⁇ -electron system (ie, The ring group adjacent to a carbon atom is preferably 6 to 10 members such as a phenyl group and a naphthyl group.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is preferably independently independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkane. Substituted by one or more substituents of oxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is 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, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:
  • the heteroaryl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, which is preferably independently independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, Substituted by one or more substituents of alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted by one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxy refers to an -OH group.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • halogen means fluoro, chloro, bromo or iodo.
  • hydroxy refers to an -OH group.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
  • acyl halide refers to a compound containing a -C(O)-halogen group.
  • the invention also includes various compounds of formula (I) in deuterated form.
  • Each of the available hydrogen atoms attached to the carbon atom can be independently replaced by a deuterium atom.
  • Those skilled in the art will be able to synthesize a compound of formula (I) in deuterated form with reference to the relevant literature.
  • Commercially available deuterated starting materials can be used in the preparation of the compounds of formula (I) in deuterated form, or they can be synthesized using deuterated reagents using conventional techniques, including but not limited to deuterated borane, triterpenoids. Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with 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, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • a method for preparing a medicinal salt comprising the steps of:
  • the compound of the formula (A) and the boronic acid or boric acid ester compound are reacted under basic conditions in the presence of a catalyst to obtain a compound of the formula (I-A);
  • the compound of the formula (I-A) and the compound of the formula (I-B) are reacted under basic conditions in the presence of a catalyst to obtain a compound of the formula (I);
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, Potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide;
  • the catalyst includes, but is not limited to, palladium/carbon, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, bis(dibenzylideneacetone)palladium, chloro(2-dicyclohexylphosphino-2' , 4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium, [1,1'-double (two Phenylphosphino)ferrocene]palladium dichloride, 1,1'-bis(dibenzylphosphine)dichlorodipentadium iron palladium or tris(dibenzylideneacetone)dipalladium, preferably [1,1 '-bis(diphenylphosphino)ferrocene]palladium dichloride;
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, 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;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, 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;
  • X is a halogen
  • Ring A, G 1 to G 4 , R 1 to R 4 , r, q and n are as defined in the formula (I).
  • a method for preparing a medicinal salt comprising the steps of:
  • a compound of the formula (Iaa-2) and a boronic acid or a boronic acid ester compound are reacted under basic conditions in a catalyst to obtain a compound of the formula (Iaa-1);
  • the compound of the formula (Iaa-1) and the compound of the formula (I-B) are reacted under basic conditions in the presence of a catalyst to obtain a compound of the formula (Iaa);
  • X is a halogen
  • Rings A, G 1 , G 2 , R 1 , R 3 , R 4 , r and n are as defined in the formula (I).
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, Potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide.
  • the catalyst includes, but is not limited to, palladium/carbon, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, bis(dibenzylideneacetone)palladium, chloro(2-dicyclohexylphosphino-2' , 4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium, [1,1'-double (two Phenylphosphino)ferrocene]palladium dichloride, 1,1'-bis(dibenzylphosphine)dichlorodipentadium iron palladium or tris(dibenzylideneacetone)dipalladium, preferably [1,1 '-Bis(diphenylphosphino)ferrocene]palladium dichloride.
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, 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.
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, 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.
  • a method for preparing a medicinal salt comprising the steps of:
  • a compound of the formula (Ibb-2) and a boronic acid or a boric acid ester compound are reacted under basic conditions in a catalyst to obtain a compound of the formula (Ibb-1);
  • the compound of the formula (Ibb-1) and the compound of the formula (I-B) are reacted under basic conditions in the presence of a catalyst to obtain a compound of the formula (Ibb);
  • X is a halogen
  • Rings A, G 1 , G 2 , R 1 , R 3 , R 4 , r and n are as defined in the formula (I).
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, Potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide.
  • the catalyst includes, but is not limited to, palladium/carbon, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, bis(dibenzylideneacetone)palladium, chloro(2-dicyclohexylphosphino-2' , 4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium, [1,1'-double (two Phenylphosphino)ferrocene]palladium dichloride, 1,1'-bis(dibenzylphosphine)dichlorodipentadium iron palladium or tris(dibenzylideneacetone)dipalladium, preferably [1,1 '-Bis(diphenylphosphino)ferrocene]palladium dichloride.
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, 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.
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, 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.
  • a method for preparing a medicinal salt comprising the steps of:
  • a compound of the formula (B) and a boric acid or a boric acid ester compound are reacted under basic conditions in the presence of a catalyst to obtain a compound of the formula (II-A);
  • the compound of the formula (II-A) and the compound of the formula (I-B) are reacted under basic conditions in the presence of a catalyst to obtain a compound of the formula (II);
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, Potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide;
  • the catalyst includes, but is not limited to, palladium/carbon, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, bis(dibenzylideneacetone)palladium, chloro(2-dicyclohexylphosphino-2' , 4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium, [1,1'-double (two Phenylphosphino)ferrocene]palladium dichloride, 1,1'-bis(dibenzylphosphine)dichlorodipentadium iron palladium or tris(dibenzylideneacetone)dipalladium, preferably [1,1 '-bis(diphenylphosphino)ferrocene]palladium dichloride;
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, 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;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, 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;
  • X is a halogen
  • Rings A, R 1 , R 3 , R 4 , r and n are as defined in formula (I).
  • a method for preparing a medicinal salt comprising the steps of:
  • a compound of the formula (B) and a boric acid or a boric acid ester compound are reacted under basic conditions in the presence of a catalyst to obtain a compound of the formula (II-A);
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, potassium acetate, sodium t-butoxide, potassium t-butoxide and sodium n-butoxide, said inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, Potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide;
  • the catalyst includes, but is not limited to, palladium/carbon, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, bis(dibenzylideneacetone)palladium, chloro(2-dicyclohexylphosphino-2' , 4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium, [1,1'-double (two Phenylphosphino)ferrocene]palladium dichloride, 1,1'-bis(dibenzylphosphine)dichlorodipentadium iron palladium or tris(dibenzylideneacetone)dipalladium, preferably [1,1 '-bis(diphenylphosphino)ferrocene]palladium dichloride;
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, 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;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, 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;
  • X is a halogen
  • R 1 , R 3 , R 4 , r and n are as defined in the formula (I).
  • 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).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methyl silane
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
  • the CombiFlash Rapid Preparer uses the Combiflash Rf200 (TELEDYNE ISCO).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC), the developing agent used for the reaction, the column chromatography eluent system used for the purification of the compound, and the thin layer chromatography developing solvent system including: A: Methylene chloride/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether and ethyl acetate system, D: dichloromethane/ethyl acetate/methanol system, the volume ratio of the solvent is different depending on the polarity of the compound For adjustment, a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment.
  • TLC thin layer chromatography
  • A Methylene chloride/methanol system
  • B n-hexane/ethyl acetate system
  • C petroleum ether and ethyl acetate system
  • D dichloromethane/ethyl acetate/methanol
  • 6-Bromo-8-methylquinoline 1a (444 mg, 2.00 mmol, prepared by a known method "Journal of Organic Chemistry, 2014, 79 (11), 5379-5385" was sequentially added under an argon atmosphere.
  • (pinacol) diboron (508 mg, 2.00 mmol)
  • [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (292 mg, 0.40 mmol)
  • potassium acetate (588 mg, 6.00 Methyl) was dissolved in 10 mL of ethylene glycol dimethyl ether solution, heated to 80 ° C, and stirred for 12 hours. The reaction was quenched, cooled to room temperature, filtered, EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjj
  • the title product 1b (320 mg) was obtained in the titled product (yield: 59.5%).
  • 6-Bromo-8-fluoroquinoline 2a (226 mg, 1.00 mmol), bis(pinacolato)diboron (305 mg, 1.20 mmol), [1,1'-bis(diphenyl) were sequentially added under an argon atmosphere.
  • Phosphyl)ferrocene]palladium dichloride (146 mg, 0.20 mmol) and potassium acetate (294 mg, 3.00 mmol) were dissolved in 10 mL of ethylene glycol dimethyl ether solution, heated to 80 ° C, and stirred for 12 hours. The reaction was quenched, cooled to room temperature, filtered, and the filtrate was evaporated to dryness.
  • 6-bromoquinoline 3a (1.0 g, 4.80 mmol, bismuth), bis(pinacol) diboron (1.46 g, 5.76 mmol), [1,1'-bis(diphenyl) were sequentially added under an argon atmosphere.
  • the phosphinyl)ferrocene]palladium dichloride (0.7 g, 0.96 mmol) and potassium acetate (1.4 g, 14.40 mmol) were dissolved in 20 mL of a solution of ethylene glycol dimethyl ether, heated to 80 ° C, and stirred for 12 hours. The reaction was quenched, cooled to room temperature, filtered, and the filtrate was evaporated to dryness.
  • 6-Bromo-8-chloroquinoline 4a 300 mg, 1.24 mmol
  • bis(pinacol) diboron 378 mg, 1.49 mmol
  • [1,1'-bis(diphenylphosphine) were sequentially added under an argon atmosphere.
  • Base ferrocene] palladium dichloride (181 mg, 0.25 mmol
  • potassium acetate 364 mg, 3.72 mmol
  • 6-Bromo-1,2,4-triazine-3-ammonia 5a (1.0 g, 5.72 mmol, prepared by a known method "Journal of the American Chemical Society, 2015, 137 (26), 8388-8391") 6 mL of trifluoroacetic acid and 6 mL of dichloromethane were added to the reaction flask, and 2-methylfuran 5b (567 ⁇ L, 6.29 mmol) was added, and stirred at room temperature for 17 hours.
  • 2-Cyclopropylaniline 12a (1.0 g, 7.52 mmol, prepared by the method disclosed in the patent application "WO201314997”) was added to 100 mL of acetonitrile solvent, and N-bromosuccinimide (1.4 g, 7.89 mmol) was added. Ammonium acetate (58 mg, 0.075 mmol) was stirred for 2 hours to stop the reaction. After adding 60 mL of water and extracting with ethyl acetate (100 mL ⁇ 3), the organic phase was combined, washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate Purification by eluent system B gave the title product 12b (0.85 g).
  • 6-bromo-4-methylquinoline 14a (444 mg, 2 mmol, prepared by a known method "Tetrahedron, 2003, 59 (6), 813-819" was added in that order, and Alcohol) diboron (762 mg, 3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (292 mg, 0.4 mmol) and potassium acetate (588 mg, 6 mmol) dissolved in 20 mL The mixture was heated to 80 ° C in a dimethyl ether solution and stirred for 12 hours. The reaction was quenched, cooled to rt EtOAc (EtOAc)EtOAc.
  • reaction solution was cooled to room temperature, and the reaction mixture was evaporated. Water was added to the residue, and saturated sodium hydrogencarbonate was added dropwise to a mixture. The mixture was evaporated to ethyl acetate. The mixture was extracted three times with ethyl acetate. The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated. Purification with eluent system B using a CombiFlash flash ⁇ / RTI> ⁇ / RTI> to afford the title compound 16c (3.5 g).
  • 6-Bromo-8-methoxyquinoline 25a (530 mg, 2.2 mmol) was sequentially prepared under an argon atmosphere by a known method "Journal of the American Chemical Society, 2005, 127(1), 74-75". , bis (pinacol) diboron (845 mg, 3.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (162 mg, 0.22 mmol) and potassium acetate (652 mg, 6.65 mmol) was dissolved in 10 mL of 1,4 dioxane, heated to 80 ° C, and stirred for 3 hours. The reaction was quenched, cooled to room temperature, EtOAc (EtOAc)EtOAc.EtOAcjjjjjjjjjjjjj : 65%.
  • 6-bromo-3-methylquinoline 28a 250 mg, 1.13 mmol, prepared by the method disclosed in the patent application "WO2006132739A2"
  • bis(pinacol) diboron 429 mg, 1.69 mmol
  • [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride 165 mg, 0.225 mmol
  • potassium acetate 331 mg, 3.38 mmol
  • 6-bromo-3-methoxyquinoline 34a 120 mg, 0.5 mmol, prepared by the method disclosed in the patent application "WO2012009194A1"
  • bis(pinacol) diboron 192 mg
  • [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride 74 mg, 0.1 mmol
  • potassium acetate 148 mg, 1.5 mmol
  • Methyl 6-bromoquinoline-8-carboxylate 38a (400 mg, 1.5 mmol, prepared by the method disclosed in the patent application "WO2011020193A1") was dissolved in 15 mL of methanol, 5 mL of 40% aqueous ammonia was added dropwise, and the reaction was stirred overnight. The reaction mixture was extracted with water and ethyl acetate. EtOAc was evaporated, evaporated, evaporated, evaporated. , the title compound 38b (280 mg), yield: 74%
  • Lithium aluminum hydride (150.76 mg, 3.97 mmol) was added to 50 mL of tetrahydrofuran, and 6-bromoquinoline-4-carboxylic acid 40a (1.0 g, 3.97 mmol) was added in portions at 0 ° C, using a known method "Chinese Chemical Letters” , 2010, 21(1), 35-38" prepared), stirring was continued for 2 hours.
  • the title compound 40 (5 mg) was obtained by substituting the title compound 39a with compound 40c.
  • Example 39 Using the similar synthetic route of Example 39, the first starting material compound 39a was replaced with 6-bromo-4-chloroquinoline 43a (prepared by the well-known method "Journal of Medicinal Chemistry, 2015, 58(14), 5522-5537”). The title compound 43 (50 mg) was obtained.
  • Example 25 Using the similar synthetic route of Example 25, the first starting material compound 25a was replaced by the compound 44a, and the second step starting material compound 1c was replaced with the compound 8a to give the title compound 44 (40 mg).
  • the crude compound 48d (8.5 g, 33.96 mmol) was dissolved in 80 mL of dioxane, and 20 mL of aqueous ammonia was added, and the reaction was stirred for 1 hour. Concentration under reduced pressure and the residue was purified with EtOAc EtOAc.
  • Example 25 Using the similar synthetic route of Example 25, the first starting material compound 25a was replaced with the compound 51b, and the second step starting material compound 1c was replaced with the compound 8a to give the title compound 51 (55 mg).
  • Example 25 Using the similar synthetic route of Example 25, the first starting material compound 25a was replaced by the compound 52a, and the second step starting material compound 1c was replaced with the compound 8a to give the title compound 52 (18 mg).
  • 2-Amino-5-bromobenzonitrile 53a (500 mg, 2.54 mmol, prepared by a known method "European Journal of Medicinal Chemistry, 2014, 76, 341-343") was dissolved in 10 mL of tetrahydrofuran, cooled in an ice bath, argon Under an atmosphere, 12.69 mL of 1.0 M ethylmagnesium bromide was added dropwise and stirred for 2 hours. 6M hydrochloric acid was added and stirred for 2 hours. Add saturated sodium carbonate solution, extract with ethyl acetate (50 mL ⁇ 3), and combine the organic phase.
  • Example 25 Using the similar synthetic route of Example 25, the first starting material compound 25a was replaced with the compound 53c, and the second step starting material compound 1c was replaced with the compound 8a to give the title compound 53 (45 mg).
  • 6-Bromo-4-chloroquinazoline 55a (1.0 g, 4.10 mmol) was dissolved in 80 mL of methanol, and sodium methoxide (2.21 g, 41.05 mmol) was added, and the reaction was stirred for 3 hours. Spin dry, add water, filter, and filter cake to give the product 55b (0.55 g). Yield: 56.01%.
  • Test Example 1 the compounds of the present invention for the adenosine A 2a receptor (adenosine A 2a receptor, A 2a R) cAMP signaling pathway, A 2b adenosine receptor (adenosine A 2b receptor, A 2b R) cAMP signaling pathway, adenosine a 1 receptor (adenosine a 1 receptor, a 1 R) cAMP signaling pathway and a 3 adenosine receptor (adenosine a 3 receptor, a 3 R) cAMP signaling pathway inhibitory activity of.
  • the following method is used to assay the compounds of the present invention for the adenosine A 2a receptor (adenosine A 2a receptor, A 2a R) cAMP signaling pathway, adenosine A 2b receptor cAMP signal pathways, adenosine A 1 receptors and cAMP signal pathways glands Inhibitory activity of the glycoside A 3 receptor cAMP signaling pathway.
  • the experimental method is briefly described as follows:
  • CHO-K1/A 2a R cells NM_000675.5
  • CHO-K1/A 2b R cells NM_000676.2
  • CHO-K1/A 1 R cells NM_000674.2
  • CHO-K1/A 3 R cells NM_000677.3
  • Adenosine deaminase (sigma, 10102105001)
  • CHO-K1/A 2a R cells were cultured in DMEM/F12 medium containing 10% fetal bovine serum and 800 ⁇ g/ml bleomycin. The cells were digested with cell separation buffer at the time of the experiment, and the cells were resuspended in a balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin, and the cell density was adjusted to 10 6 /ml. Add 5 ⁇ l of cell suspension to each well in a 384-well plate, 2.5 ⁇ l of 4 ⁇ prepared with balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 ⁇ M rolipram and 2.7 U/ml adenosine deaminase.
  • test compound Concentration of test compound was incubated for 30 minutes at room temperature. Add 2.5 ⁇ l of each well to a 4 ⁇ concentration of ethyl carbazole prepared with 20 mM HEPES, 0.1% bovine serum albumin, 54 ⁇ M rolipram and 2.7 U/ml adenosine deaminase in each well, incubate at room temperature 30 minutes.
  • the final concentrations of the compounds were: 10,000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256, 0.00512, 0.001024 nM and the final concentration of ethyl carbazole was 20 nM. Intracellular cAMP concentrations were detected using the cAMP Dynamic 2 kit.
  • cAMP-d2 and anti-cAMP-Eu-Cryptate were separately diluted 1:4 with cAMP lysis buffer. 5 ⁇ l of the diluted cAMP-d2 was added to each well, and 5 ⁇ l of the diluted anti-cAMP-Eu-cryptate was added thereto, and the mixture was incubated at room temperature for 1 hour in the dark.
  • the HTRF signal value was read using a PHERAstar multi-function microplate reader.
  • the IC 50 values of the compound inhibitory activity were calculated using Graphpad Prism software, as shown in Table 1.
  • CHO-K1/A 2b R was cultured in DMEM/F12 medium containing 10% fetal calf serum and 1 mg/ml G418.
  • the cells were digested with cell separation buffer at the time of the experiment, and the cells were resuspended in a balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin, and the cell density was adjusted to 10 6 /ml.
  • test compound Concentration of test compound was incubated for 30 minutes at room temperature. Add 2.5 ⁇ l of each well to a 4 ⁇ concentration of ethyl carbazole (Torcis, prepared with 20 mM HEPES, 0.1% bovine serum albumin, 54 ⁇ M rolipram and 2.7 U/ml adenosine deaminase in each well). 1691/10), incubate for 30 minutes at room temperature. The final concentrations of the compounds were: 100,000, 10,000, 1000, 100, 10, 1, 0.1 and 0 nM, and the final concentration of ethyl carbazole was 1 ⁇ M. Intracellular cAMP concentrations were detected using the cAMP Dynamic 2 kit.
  • cAMP-d2 and anti-cAMP-Eu-cryptate were separately diluted 1:4 with cAMP lysis buffer. 5 ⁇ l of the diluted cAMP-d2 was added to each well, and 5 ⁇ l of the diluted anti-cAMP-Eu-cryptate was added thereto, and the mixture was incubated at room temperature for 1 hour in the dark.
  • the HTRF signal value was read using a PHERAstar multi-function microplate reader. Calculated using Graphpad Prism software compound to inhibit the activity of IC 50 values (Table 2).
  • CHO-K1/A 1 R was cultured in DMEM/F12 medium containing 10% fetal calf serum and 1 mg/ml G418.
  • the cells were digested with the cell separation buffer at the time of the experiment, and then the cells were resuspended 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 /ml.
  • 12.5 ⁇ l of cell suspension was added to each well in a 384-well plate, and 6.25 ⁇ l was prepared with a balanced salt buffer containing 20 mM HEPES, 0.1% bovine serum albumin, 54 ⁇ M rolipram and 2.7 U/ml adenosine deaminase.
  • the concentration of the test compound was incubated for 30 minutes at room temperature. Add 4.25 ⁇ l of each well to a 4 ⁇ concentration of forskolin and N6-ring prepared with 20 ⁇ m HEPES, 0.1% bovine serum albumin, 54 ⁇ M rolipram and 2.7 U/ml adenosine deaminase in each well. Amyl adenosine was incubated for 30 minutes at room temperature. The final concentrations of the compounds were: 100,000, 10,000, 1000, 100, 10, 1, 0.1 and 0 nM, the final concentration of forskolin was 10 ⁇ M, and the final concentration of CPA was 10 nM. Intracellular cAMP concentrations were detected using the cAMP Dynamic 2 kit.
  • cAMP-d2 and anti-cAMP-Eu-cryptate were separately diluted with cAMP lysis buffer in a ratio of 1:4. 12.5 ⁇ l of diluted cAMP-d2 was added to each well, and 12.5 ⁇ l of the diluted anti-cAMP-Eu-cryptate was added and incubated for 1 hour at room temperature in the dark.
  • the HTRF signal value was read using a PHERAstar multi-function microplate reader.
  • the IC 50 values of the compound inhibitory activity were calculated using Graphpad Prism software, as shown in Table 3.
  • CHO-K1/A 3 R was cultured in DMEM/F12 medium containing 10% fetal calf serum and 10 ⁇ g/ml puromycin. The cells were digested with cell separation buffer at the time of the experiment, and the cells were resuspended and counted with a balanced salt buffer containing 20 mM HEPES and 0.1% bovine serum albumin, and the cell density was adjusted to 5 ⁇ 10 5 /ml.
  • cAMP-d2 and anti-cAMP-Eu-cryptate were separately diluted with cAMP lysis buffer in a ratio of 1:4. 12.5 ⁇ l of diluted cAMP-d2 was added to each well, and 12.5 ⁇ l of the diluted anti-cAMP-Eu-cryptate was added and incubated for 1 hour at room temperature in the dark.
  • the HTRF signal value was read using a PHERAstar multi-function microplate reader.
  • the IC 50 values of the compound inhibitory activity were calculated using Graphpad Prism software, as shown in Table 3.
  • Table 1 Compound of the present invention the cAMP signaling pathway inhibition activity IC 50 values of the adenosine A 2a receptor (adenosine A 2a receptor, A 2a R).
  • the compound of the present invention has significant inhibitory activity on the adenosine A 2a receptor, and introduces a nitrogen atom in the thick aryl portion of the mother nucleus compared with the comparative example 1, so that the compound of the present invention inhibits the adenosine A 2a receptor.
  • Unexpected results were obtained. Compared with Example 3, the structural difference between the two was only the introduction of a nitrogen atom at the 5 position of the naphthyl group of Comparative Example 1 in Example 3, and the adenosine A 2a receptor was obtained.
  • the inhibitory activities differ by a factor of 225.
  • Table IC 50 values of the active compound 2 of the invention inhibit the adenosine A 2b receptor (adenosine A 2b receptor, A 2b R) cAMP signaling pathway.
  • the compound of the present invention has a good inhibitory activity on the adenosine A 2b receptor.
  • the compounds of the present invention have weak effects on adenosine A 1 receptor and adenosine A 3 receptor inhibitory activity, indicating that the compounds of the present invention are selective for adenosine A 2a receptor and adenosine A 2b receptor, especially Adenosine A 2a receptor.
  • Test Example 2 Mouse pharmacokinetic test of the compound of the present invention
  • Example 2 Using mouse as a test animal, the compound of Example 2, the compound of Example 3, the compound of Example 17, the compound of Example 18, the compound of Example 19, and Example 20 were intragastrically administered to mice by LC/MS/MS method. The concentration of the drug in the plasma at different times after the compound, the compound of Example 31 and Example 44. The pharmacokinetic behavior of the compounds of the invention in mice was investigated and their pharmacokinetic characteristics were evaluated.
  • Example 2 compound, Example 3 compound, Example 17 compound, Example 18 compound, Example 19 compound, Example 20 compound, Example 31 compound and Example 44.
  • mice 72 C57 mice, female, divided into 8 groups, 9 in each group, purchased from Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2013-0006.
  • a certain amount of the drug was weighed, and 5% by volume of DMSO, 5% by volume of tween 80, and 90% physiological saline were placed in a 0.1 mg/ml colorless clear liquid.
  • mice were intragastrically administered overnight after fasting, and the dose was 2.0 mg/kg, and the administration volume was 0.2 ml/10 g.
  • Example 2 The compound of Example 2, the compound of Example 3, the compound of Example 17, the compound of Example 18, the compound of Example 19, the compound of Example 20, the compound of Example 31 and Example 44 were administered by gavage in mice.
  • 0.1 ml of blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours after administration, placed in a heparinized test tube, and centrifuged at 3500 rpm for 10 minutes to separate the plasma, and stored at -20 °C.
  • the content of the test compound in the plasma of the mice after the intragastric administration of different concentrations of the drug was determined: 25 ⁇ l of the mouse plasma at each time after administration, 50 ⁇ l of camptothecin (100 ng/mL), 200 ⁇ l of acetonitrile, vortex The mixture was spun for 5 minutes, centrifuged for 10 minutes (4000 rpm), and plasma samples were taken for 5 ⁇ l of the supernatant for LC/MS/MS analysis.
  • the pharmacokinetic parameters of the compounds of the invention are as follows:
  • the compounds of the present invention have better pharmacological absorption and have pharmacokinetic advantages.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

本发明涉及1,2,4-三嗪-3-胺类衍生物、其制备方法及其在医药上的应用。具体而言，本发明涉及一种通式(I)所示的1,2,4-三嗪-3-胺类衍生物、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A2a受体拮抗剂的用途和在制备用于治疗通过对A2a受体的抑制而改善的病况或病症的药物中的用途，其中通式(I)的各取代基与说明书中的定义相同。

Description

1,2,4-三嗪-3-胺类衍生物、其制备方法及其在医药上的应用 技术领域
本发明属于医药领域，涉及一种通式(I)所示的1,2,4-三嗪-3-胺类衍生物、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受体拮抗剂的用途和在制备用于治疗通过对A 2a受体的抑制而改善的病况或病症的药物中的用途。
背景技术
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。在心血管系统、中枢神经、呼吸系统、肾脏、脂肪和血小板的功能调节中发挥重要作用。
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。
A 2a受体(A 2aR)在机体分布较为广泛，在中枢神经系统主要表达于纹状体，在外周、心、肝、肺、肾等组织也均有表达。数个临床前研究表明，腺苷A 2a受体拮抗剂对于治疗神经变性疾病，主要是帕金森病、亨廷顿病或阿尔茨海默病具有惊人疗效(Trends in Neurosci.2006,29(11),647-654；Expert Opinion on Therapeutic Patents,2007,17,979-991等)。而且也可以用于治疗其他中枢神经系统(CNS)相关的疾病例如抑郁、多动综合征、睡眠障碍和焦虑症(Clin.Neuropharmacol.2010,33,55-60；J.Neurosci.2010,30(48),16284-16292；Parkinsonisn Relat.Disord.2010,16(6),423-426；及其中的参考献:Mov.Disorders,2010,25(2),S305)。此外腺苷A 2a受体拮抗剂还具有作为神经保护剂的治疗潜力(参见Jenner P.J Neuro l.2000；24 7Supp12:1143-50)。
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,激活PKA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受体的活化可以促进黑色素瘤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。Deepak Mittal等人研究发现，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；同时，研究发现A 2b受体在人三阴性乳腺癌细胞系中高表达，且A 2b受体的表达程度与肿瘤进展密切相关。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受体有望成为治疗肿瘤的一个理想靶点(Cancer Res.2016 Aug 1；76(15):4372-82)。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。
尽管对多种腺苷受体亚型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、消化系统和骨骼肌中，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)。腺苷A 3受体(如Gessi S等人，Pharmacol.Ther.117(1),2008,123-140所述)在心肌缺血期间释放的腺苷在心脏中发挥强力的保护作用，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。
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。但仍有低溶解性、光敏性、低活性、低选择性和生物利用率较低等问题存在。
WO2011095625公开了通式(A1)所示的1,2,4-三嗪-4-胺衍生物及其在治疗通过对A 1受体或A 2a受体的抑制而改善的病况或病症中的用途。
Figure PCTCN2018072308-appb-000001
该专利申请总共公开了200多个实施例，其中环A为稠合芳香族环的实施例仅有5个，该专利申请中的数据显示，当环A为稠合芳香族环时，其对A 2aR的抑制活性较弱(见表1)。
表1专利申请WO2011095625中的实施例
Figure PCTCN2018072308-appb-000002
Figure PCTCN2018072308-appb-000003
其中实施例1(lxxii)的环A为萘基，我们现在发现在萘基的5位上引入氮原子的衍生物表现出惊人的活性，对A 2aR的抑制活性是实施例1(lxxii)的30至1500倍以上。如此强的抑制活性是在阅读WO2011095625时不可能预料到的。
因此本发明提供一种新型结构的强抑制活性的腺苷A 2a受体拮抗剂，同时具有此类结构的化合物对腺苷A 2b受体也具有较好的抑制作用，对腺苷A 1受体和腺苷A 3受体的抑制作用弱，对腺苷A 2a受体表现出较好的选择性。同时具有此类结构的化合物表现出优异的抑瘤效果和药代吸收活性。
发明内容
本发明的目的在于提供一种通式(I)所示的化合物：
Figure PCTCN2018072308-appb-000004
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为芳基或杂芳基；
G 1、G 2、G 3和G 4相同或不同，且各自独立地选自C、CH或N；
R 1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、杂芳基、-OR 5、-C(O)R 5、-S(O) mR 5、NH 2S(O) mR 5、-NR 6R 7、S(O) mNR 6R 7和-C(O)NR 6R 7；其中所述的烷基、烷氧基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、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；
R 2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、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基、-OR 5、-C(O)R 5、-S(O) mR 5、NH 2S(O) mR 5、-NR 6R 7、S(O) mNR 6R 7和-C(O)NR 6R 7；其中所述的烷基、烷氧基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、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；
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、杂芳基、-OR 5、-C(O)R 5、-S(O) mR 5、NH 2S(O) mR 5、-NR 6R 7、S(O) mNR 6R 7和-C(O)NR 6R 7；其中所述的烷基、烷氧基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、氘原子、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；
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、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基、-OR 5、-C(O)R 5、-S(O) mR 5、NH 2S(O) mR 5、-NR 6R 7、S(O) mNR 6R 7和-C(O)NR 6R 7；其中所述的烷基、烷氧基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、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；
R 5选自氢原子、烷基、卤代烷基、氨基、羟基、环烷基、杂环基、芳基和杂芳基；
R 6和R 7各自独立地选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、烷氧基、卤素、氨基、氰基、硝基、羟基、羟烷基、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；
或者，所述R 6和R 7与相连接的氮原子一起形成杂环基，其中所述的杂环基内含有1～2个相同或不同选自N、O和S的杂原子，并且所述的杂环基任选被选自 烷基、烷氧基、卤素、氨基、氰基、硝基、羟基、羟烷基、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；
m为0、1或2；
r为0、1、2或3；
q为0、1或2；且
n为0、1、2、3、4或5。
在本发明一个优选的实施方案中，其为通式(Iaa)所示的化合物：
Figure PCTCN2018072308-appb-000005
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、G 1、G 2、R 1、R 3、R 4、r和n如通式(I)中所定义。
在本发明一个优选的实施方案中，其为通式(Ibb)所示的化合物：
Figure PCTCN2018072308-appb-000006
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 1和G 2相同或不同，且各自独立地为CR a或N；
R a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；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、氘原子、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；
R c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；
环A、R 1、R 4和n如通式(I)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物为通式(II)所示的化合物：
Figure PCTCN2018072308-appb-000007
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、R 1、R 3、R 4、r和n如通式(I)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其中所述的环A选自苯基、吡啶基、噻吩基和呋喃基。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物为通式(III)所示的化合物：
Figure PCTCN2018072308-appb-000008
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、R 3、R 4、r和n如通式(I)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其中所述的R 1选自氢原子、卤素、烷基、烷氧基、氰基、环烷基、卤代烷基、杂环基和-C(O)NR 6R 7；R 6和R 7如通式(I)中所定义；所述卤素优选氟原子、氯原子或溴原子，所述烷基优选甲基、乙基、异丙基或正丁基，所述烷氧基优选甲氧基或乙氧基，所述环烷基优选环丙基、环戊基或环己基。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其中所述的R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、氘代烷基、烷氧基、氰基、环烷基杂环基，其中所述的烷基和烷氧基各自独立地任选被选自卤素、氘原子、羟基、氰基、氨基、硝基、环烷基和杂环基中的一个或多个取代基所取代；所述卤素优选氟原子、氯原子或溴原子，所述烷基优选甲基、乙基、异丙基或正丁基，所述烷氧基优选甲氧基或乙氧基，所述杂环基优选哌啶基、哌嗪基、吗啉基或四氢吡喃基。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物，其中所述的R 4相同或不同，且各自独立地选自氢原子、烷基和卤素。
本发明的典型化合物包括但不限于：
Figure PCTCN2018072308-appb-000009
Figure PCTCN2018072308-appb-000010
Figure PCTCN2018072308-appb-000011
Figure PCTCN2018072308-appb-000012
Figure PCTCN2018072308-appb-000013
Figure PCTCN2018072308-appb-000014
Figure PCTCN2018072308-appb-000015
Figure PCTCN2018072308-appb-000016
Figure PCTCN2018072308-appb-000017
Figure PCTCN2018072308-appb-000018
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。
本发明的另一方面涉及一种制备通式(I)所示的化合物的方法，该方法包括：
Figure PCTCN2018072308-appb-000019
通式(I-A)的化合物和通式(I-B)的化合物发生偶联反应，得到通式(I)的化合物，
其中：
X为卤素；
M为
Figure PCTCN2018072308-appb-000020
环A、G 1～G 4、R 1～R 4、r、q和n如通式(I)中所定义。
本发明的另一方面涉及一种制备通式(Iaa)所示的化合物的方法，该方法包括：
Figure PCTCN2018072308-appb-000021
通式(Iaa-1)的化合物和通式(I-B)的化合物发生偶联反应，得到通式(Iaa)的化合物，
其中：
X为卤素；
M为
Figure PCTCN2018072308-appb-000022
环A、G 1、G 2、R 1、R 3、R 4、r和n如通式(I)中所定义。
本发明的另一方面涉及一种制备通式(II)所示的化合物的方法，该方法包括：
Figure PCTCN2018072308-appb-000023
通式(II-A)的化合物和通式(I-B)的化合物发生偶联反应，得到通式(II)的化合物，
其中：
X为卤素；
M为
Figure PCTCN2018072308-appb-000024
环A、R 1、R 3、R 4、r和n如通式(I)中所定义。
本发明的另一方面涉及一种制备通式(III)所示的化合物的方法，该方法包括：
Figure PCTCN2018072308-appb-000025
通式(II-A)的化合物和通式(III-B)的化合物发生偶联反应，得到通式(III)的化合物，
其中：
X为卤素；
M为
Figure PCTCN2018072308-appb-000026
R 1、R 3、R 4、r和n如通式(I)中所定义。
本发明的另一方面涉及一种药物组合物，所述药物组合物含有治疗有效量的本发明通式(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。
本发明进一步涉及通式(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受体抑制而改善的病况或病症的药物中的用途。
本发明进一步涉及通式(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 2b受体抑制而改善的病况或病症的药物中的用途。
在本发明文中，通过对A 2a受体或对A 2b受体抑制而改善的病况或病症选自癌症、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、前列腺癌、皮肤癌、神经母细胞瘤、肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌(子宫颈癌、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、膀胱肿瘤、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。
本发明进一步涉及通式(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，优选癌症的药物中的用途。
本发明进一步涉及通式(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、前列腺癌、皮肤癌、神经母细胞瘤、肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌(子宫颈癌、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、膀胱肿瘤、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。
本发明进一步涉及通式(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肺癌，优选非小细胞肺癌的药物中的用途。
本发明进一步涉及通式(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受体的药物中的用途。
本发明进一步涉及通式(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 2b受体的药物中的用途。
本发明还涉及一种抑制A 2a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。
本发明还涉及一种抑制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。
本发明还涉及一种治疗通过对A 2a受体抑制而改善的病况或病症的方法，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。
本发明还涉及一种治疗通过对A 2b受体抑制而改善的病况或病症的方法，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。
本发明涉及一种治疗癌症、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。
本发明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、前列腺癌、皮肤癌、神经母细胞瘤、肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌(子宫颈癌、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、膀胱肿瘤、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。
本发明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。
本发明还涉及通式(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受体拮抗剂。
本发明还涉及通式(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 2b受体拮抗剂。
本发明还涉及通式(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，其治疗通过对A 2a受体抑制而改善的病况或病症。
本发明还涉及通式(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，其治疗通过对A 2b受体抑制而改善的病况或病症。
本发明还涉及通式(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。
本发明进一步涉及通式(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，其用于治疗癌症，其中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、前列腺癌、皮肤癌、神经母细胞瘤、肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌(子宫颈癌、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、膀胱肿瘤、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。
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。
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。
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。
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。
本发明的药物组合物也可以是水包油乳剂的形式。
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，最好按可保持本发明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。
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。
可按用于直肠给药的栓剂形式给予本发明化合物。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。
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、患者的行被、患者的饮食、给药时间、给药方式、排泄的速率、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。
发明的详细说明
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。
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，更优选为含有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H原子、D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、杂芳基中的一个或多个取代基所取代。
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H原子、D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、杂芳基中的一个或多个取代基所取代。
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。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、芳基、杂芳基中的一个或多个取代基所取代。
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) m(其中m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12个环原子，其中1～4个是杂原子；更优选包含3至10个环原子，其中1-4是杂原子；更优选包含5至6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。
所述杂环基环可以稠合于芳基、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：
Figure PCTCN2018072308-appb-000027
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、杂芳基中的一个或多个取代基所取代。
术语“芳基”指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，其为具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、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：
Figure PCTCN2018072308-appb-000028
Figure PCTCN2018072308-appb-000029
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、杂芳基中的一个或多个取代基所取代。
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。所述杂芳基环可以稠合于芳基、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：
Figure PCTCN2018072308-appb-000030
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、杂芳基中的一个或多个取代基所取代。
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。
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。
术语“羟基”指-OH基团。
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH基团。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“羰基”指C＝O。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基、环烷基如上所定义。
术语“酰卤”指含有-C(O)-卤素的基团的化合物。
本发明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。
“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。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。
“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。
“可药用盐”是指本发明化合物的盐，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。
本发明化合物的合成方法
为了完成本发明的目的，本发明采用如下技术方案：
方案一
本发明通式(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：
Figure PCTCN2018072308-appb-000031
第一步，通式(A)的化合物和硼酸或硼酸酯类化合物在催化剂存在下在碱性条件下，反应得到通式(I-A)的化合物；
第二步，通式(I-A)的化合物和通式(I-B)的化合物在催化剂存在下在碱性条件下，反应得到通式(I)的化合物；
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、乙酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂；
所述的催化剂包括但不限于钯/碳、四-三苯基膦钯、二氯化钯、醋酸钯、双(二亚芐基丙酮)钯、氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、1,1’-双(二苄基磷)二氯二戊铁钯或三(二亚苄基丙酮)二钯，优选为[1,1'-双(二苯基膦基)二茂铁]二氯化钯；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、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；
其中：
X为卤素；
M为
Figure PCTCN2018072308-appb-000032
环A、G 1～G 4、R 1～R 4、r、q和n如通式(I)中所定义。
方案二
本发明通式(Iaa)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：
Figure PCTCN2018072308-appb-000033
第一步，通式(Iaa-2)的化合物和硼酸或硼酸酯类化合物在催化剂存在下，在碱性条件下，反应得到通式(Iaa-1)的化合物；
第二步，通式(Iaa-1)的化合物和通式(I-B)的化合物在催化剂存在下在碱性条件下，反应得到通式(Iaa)的化合物；
其中：
X为卤素；
M为
Figure PCTCN2018072308-appb-000034
环A、G 1、G 2、R 1、R 3、R 4、r和n如通式(I)中所定义。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、乙酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂。
所述的催化剂包括但不限于钯/碳、四-三苯基膦钯、二氯化钯、醋酸钯、双(二亚芐基丙酮)钯、氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、1,1’-双(二苄基磷)二氯二戊铁钯或三(二亚苄基丙酮)二钯，优选为[1,1'-双(二苯基膦基)二茂铁]二氯化钯。
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、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。
方案三
本发明通式(Ibb)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：
Figure PCTCN2018072308-appb-000035
第一步，通式(Ibb-2)的化合物和硼酸或硼酸酯类化合物在催化剂存在下，在碱性条件下，反应得到通式(Ibb-1)的化合物；
第二步，通式(Ibb-1)的化合物和通式(I-B)的化合物在催化剂存在下在碱性条件下，反应得到通式(Ibb)的化合物；
其中：
X为卤素；
M为
Figure PCTCN2018072308-appb-000036
环A、G 1、G 2、R 1、R 3、R 4、r和n如通式(I)中所定义。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、乙酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂。
所述的催化剂包括但不限于钯/碳、四-三苯基膦钯、二氯化钯、醋酸钯、双(二亚芐基丙酮)钯、氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、1,1’-双(二苄基磷)二氯二戊铁钯或三(二亚苄基丙酮)二钯，优选为[1,1'-双(二苯基膦基)二茂铁]二氯化钯。
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、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。
方案四
本发明通式(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：
Figure PCTCN2018072308-appb-000037
第一步，通式(B)的化合物和硼酸或硼酸酯类化合物在催化剂存在下在碱性条件下，反应得到通式(II-A)的化合物；
第二步，通式(II-A)的化合物和通式(I-B)的化合物在催化剂存在下在碱性条件下，反应得到通式(II)的化合物；
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、乙酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂；
所述的催化剂包括但不限于钯/碳、四-三苯基膦钯、二氯化钯、醋酸钯、双(二亚芐基丙酮)钯、氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、1,1’-双(二苄基磷)二氯二戊铁钯或三(二亚苄基丙酮)二钯，优选为[1,1'-双(二苯基膦基)二茂铁]二氯化钯；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、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；
其中：
X为卤素；
M为
Figure PCTCN2018072308-appb-000038
环A、R 1、R 3、R 4、r和n如通式(I)中所定义。
方案五
本发明通式(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：
Figure PCTCN2018072308-appb-000039
第一步，通式(B)的化合物和硼酸或硼酸酯类化合物在催化剂存在下在碱性条件下，反应得到通式(II-A)的化合物；
第二步，通式(II-A)的化合物和通式(III-B)的化合物在催化剂存在下在碱性条件下，反应得到通式(III)的化合物；
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、乙酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂；
所述的催化剂包括但不限于钯/碳、四-三苯基膦钯、二氯化钯、醋酸钯、双(二亚芐基丙酮)钯、氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、1,1’-双(二苄基磷)二氯二戊铁钯或三(二亚苄基丙酮)二钯，优选为[1,1'-双(二苯基膦基)二茂铁]二氯化钯；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：醋酸、甲醇、乙醇、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；
其中：
X为卤素；
M为
Figure PCTCN2018072308-appb-000040
R 1、R 3、R 4、r和n如通式(I)中所定义。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例
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)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo,型号：Finnigan LCQ advantage MAX)。
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。
手性HPLC分析测定使用Agilent 1260DAD高效液相色谱仪。
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。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用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。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
手性制备柱层析使用Prep Star SD-1(Varian Instruments Inc.)或SFC-multigram(Berger Instruments Inc.)。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本发明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。
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。
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。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
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。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
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：石油醚和乙酸乙酯体系，D：二氯甲烷/乙酸乙酯/甲醇体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
6-(8-甲基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺
Figure PCTCN2018072308-appb-000041
第一步
8-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉1b
在氩气氛下依次加入6-溴-8-甲基喹啉1a(444mg，2.00mmol，采用公知的方法“Journal of Organic Chemistry,2014,79(11),5379-5385”制备而得)、双(频哪醇合)二硼(508mg，2.00mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(292mg，0.40mmol)和乙酸钾(588mg，6.00mmol)溶解于10mL乙二醇二甲醚溶液中，加热至80℃，搅拌12小时。停止反应，冷却至室温，过滤，滤液加入20mL乙酸乙酯，依次用水(10mL)洗涤，饱和氯化钠溶液(10mL)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用薄层色谱法以展开剂体系B纯化，得到标题产物1b(320mg)，产率：59.5％。
MS m/z(ESI):270.1[M+1]。
第二步
6-(8-甲基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺1
在氩气氛下依次加入1b(54mg，0.20mmol)、6-溴-5-苯基-1,2,4-三嗪-3-氨1c(50mg，0.20mmol，采用公知的方法“Journal of Medicinal Chemistry,2012,55(5),1898-1903”制备而得)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(29mg，0.04mmol)和碳酸钾(82mg，0.60mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，过滤，滤液减压浓缩，残余物中加入20mL乙酸乙酯，依次用水(10mL)洗涤，饱和氯化钠溶液(10mL)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用高效液相色谱法以展开剂体系A纯化，得到标题产物1(20mg)，产率：32.2％。
MS m/z(ESI):314.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.92(m,1H),8.22-8.24(d,1H),7.80(s,1H),7.57(s,1H),7.50-7.51(m,3H),7.43-7.45(m,3H),7.33-7.35(m,2H),2.62(s,3H)。
实施例2
6-(8-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺2
Figure PCTCN2018072308-appb-000042
第一步
8-氟-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉2b
在氩气氛下依次加入6-溴-8-氟喹啉2a(226mg，1.00mmol)、双(频哪醇合)二硼(305mg，1.20mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(146mg，0.20mmol)和乙酸钾(294mg，3.00mmol)溶解于10mL乙二醇二甲醚溶液中，加热至80℃，搅拌12小时。停止反应，冷却至室温，过滤，滤液减压蒸馏，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物2b(220mg)，产率：80.1％。
MS m/z(ESI):274.1[M+1]。
第二步
6-(8-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺2
在氩气氛下依次加入2b(109mg，0.40mmol)、1c(100mg，0.40mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(58mg，0.08mmol)和碳酸钾(156mg，1.20mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物2(20mg)，产率：15.9％。
MS m/z(ESI):318.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.95(m,1H),8.38-8.40(d,1H),7.91(s,1H),7.58-7.62(m,3H),7.41-7.46(m,4H),7.35-7.37(m,2H)。
实施例3
5-苯基-6-(喹啉-6-基)-1,2,4-三嗪-3-胺
Figure PCTCN2018072308-appb-000043
第一步
6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉3b
在氩气氛下依次加入6-溴喹啉3a(1.0g，4.80mmol，韶远)、双(频哪醇合)二硼(1.46g，5.76mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.7g，0.96mmol)和乙酸钾(1.4g，14.40mmol)溶解于20mL乙二醇二甲醚溶液中，加热至80℃，搅拌12小时。停止反应，冷却至室温，过滤，滤液减压蒸馏，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物3b(1.2g)，产率：98.4％。
MS m/z(ESI):256.1[M+1]。
第二步
5-苯基-6-(喹啉-6-基)-1,2,4-三嗪-3-胺3
在氩气氛下依次加入3b(203mg，0.80mmol)、1c(200mg，0.80mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(116mg，0.16mmol)和碳酸钾(330mg，2.40mmol)溶解于24mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物3(100mg)，产率：42.0％。
MS m/z(ESI):300.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.90-8.91(m,1H),8.32-8.34(d,1H),8.10(s,1H),7.89-7.91(d,1H),7.52-7.59(m,4H),7.43-7.44(m,3H),7.33-7.35(m,2H)。
实施例4
6-(8-氯喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺
Figure PCTCN2018072308-appb-000044
Figure PCTCN2018072308-appb-000045
第一步
8-氯-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉4b
在氩气氛下依次加入6-溴-8-氯喹啉4a(300mg，1.24mmol)、双(频哪醇合)二硼(378mg，1.49mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(181mg，0.25mmol)和乙酸钾(364mg，3.72mmol)溶解于50mL乙二醇二甲醚溶液中，加热至80℃，搅拌12小时。停止反应，冷却至室温，过滤，滤液减压蒸馏，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物4b(260mg)，产率：72.6％。
MS m/z(ESI):290.5[M+1]。
第二步
6-(8-氯喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺4
在氩气氛下依次加入4b(127mg，0.44mmol)、1c(100mg，0.40mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(58mg，0.08mmol)和碳酸钾(165mg，1.20mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，加入20mL乙酸乙酯，用饱和氯化钠溶液(10mL)洗涤，用无水硫酸钠干燥，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，得到标题产物4(30mg)，产率：20.5％。
MS m/z(ESI):334.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.01-9.02(m,1H),8.39-8.41(d,1H),8.05(s,1H),7.80(s,1H),7.59-7.66(m,3H),7.44-7.47(m,3H),7.36-7.38(m,2H)。
实施例5
5-(5-甲基呋喃-2-基)-6-(8-甲基喹啉-6-基)-1,2,4-三嗪-3-胺
Figure PCTCN2018072308-appb-000046
Figure PCTCN2018072308-appb-000047
第一步
6-溴-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-胺5c
将6-溴-1,2,4-三嗪-3-氨5a(1.0g，5.72mmol，采用公知的方法“Journal of the American Chemical Society,2015,137(26),8388-8391”制备而得)、6mL三氟乙酸和6mL二氯甲烷加入反应瓶中，加入2-甲基呋喃5b(567μL，6.29mmol)，室温搅拌17小时。停止反应，滴加饱和碳酸氢钠溶液调节pH>7，加入预制的30mL的氢氧化钾(962mg，17.14mmol)和六氰合铁酸钾(5.65g，17.14mmol)的水溶液，室温搅拌1小时。停止反应，反应液用乙酸乙酯萃取(150mL×3)，合并有机相，加入硅胶，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系C纯化，得到标题产物5c(450mg)，产率：30.9％。
MS m/z(ESI):257.3[M+1]。
第二步
5-(5-甲基呋喃-2-基)-6-(8-甲基喹啉-6-基)-1,2,4-三嗪-3-胺5
在氩气氛下依次加入5c(80mg，0.31mmol)、1b(127mg，0.47mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(23mg，0.031mmol)和碳酸钾(173mg，1.25mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至90℃，搅拌2小时。停止反应，冷却至室温，加入50mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，减压浓缩，残余物用薄层色谱法以展开剂体系B纯化，得到标题产物5(33mg)，产率：33.0％。
MS m/z(ESI):318.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.99-8.98(m,1H),8.41-8.39(m,1H),7.97(s,1H),7.69(s,1H),7.61-7.58(m,1H),7.39(s,2H),6.19-6.14(m,2H),2.75(s,3H),2.21(s,3H)。
实施例6
5-(呋喃-2-基)-6-(8-甲基喹啉-6-基)-1,2,4-三嗪-3-胺
Figure PCTCN2018072308-appb-000048
Figure PCTCN2018072308-appb-000049
第一步
6-溴-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-胺6a
将5a(1.0g，5.72mmol)、6mL三氟乙酸和6mL二氯甲烷加入反应瓶中，加入呋喃(457μL，6.29mmol)，室温搅拌17小时。停止反应，滴加饱和碳酸氢钠溶液调节pH>7，加入预制的20mL的氢氧化钾(962mg，17.14mmol)和六氰合铁酸钾(5.65g，17.14mmol)的水溶液，室温搅拌1小时。停止反应，反应液用二氯甲烷萃取(100mL×4)，合并有机相，加入硅胶，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系C纯化，得到标题产物6a(222mg)，产率：16.1％。
MS m/z(ESI):243.3[M+1]。
第二步
5-(呋喃-2-基)-6-(8-甲基喹啉-6-基)-1,2,4-三嗪-3-胺6
在氩气氛下依次加入6a(70mg，0.29mmol)、1b(86mg，0.32mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(21mg，0.029mmol)和碳酸钾(160mg，1.16mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至90℃，搅拌2小时。停止反应，冷却至室温，加入50mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，减压浓缩，残余物用薄层色谱法以展开剂体系B纯化，得到标题产物6(35mg)，产率：39.8％。
MS m/z(ESI):304.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.04-9.02(m,1H),8.21-8.19(m,1H),7.91(s,1H),7.68(s,1H),7.56(s,1H),7.50-7.47(m,1H),6.44-6.43(m,1H),6.38-6.36(m,1H),5.50(s,2H),2.86(s,3H)。
实施例7
6-(8-甲基喹啉-6-基)-5-(噻吩-2-基)-1,2,4-三嗪-3-胺
Figure PCTCN2018072308-appb-000050
第一步
6-溴-5-(噻吩-2-基)-1,2,4-三嗪-3-胺7a
将5a(1.0g，5.72mmol)、6mL三氟乙酸和6mL二氯甲烷加入反应瓶中，加入噻吩(503μL，6.29mmol)，室温搅拌17小时。停止反应，滴加饱和碳酸氢钠溶液调节pH>7，加入预制的30mL的氢氧化钾(962mg，17.14mmol)和六氰合铁酸钾(5.65g，17.14mmol)的水溶液，室温搅拌2小时。停止反应，反应液用乙酸乙酯萃取(50mL×3)，合并有机相，加入硅胶，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系C纯化，得到标题产物7a(400mg)，产率：27.2％。
MS m/z(ESI):259.2[M+1]。
第二步
6-(8-甲基喹啉-6-基)-5-(噻吩-2-基)-1,2,4-三嗪-3-胺7
在氩气氛下依次加入7a(70mg，0.27mmol)、1b(81mg，0.30mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(20mg，0.027mmol)和碳酸钾(150mg，1.09mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至90℃，搅拌2小时。停止反应，冷却至室温，加入50mL水，用乙酸乙酯萃取(50mL×3)，合并有机相，减压浓缩，残余物用薄层色谱法以展开剂体系B纯化，得到标题产物7(40mg)，产率：46.0％。
MS m/z(ESI):320.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.00-8.99(m,1H),8.42-8.40(m,1H),8.02(s,1H),7.77-7.76(m,1H),7.72(s,1H),7.62-7.59(m,1H),7.41(s,2H),6.94-6.92(m,1H),6.82-6.81(m,1H),2.75(s,3H)。
实施例8
5-(4-氟苯基)-6-(8-甲基喹啉-6-基)-1,2,4-三嗪-3-胺
Figure PCTCN2018072308-appb-000051
第一步
5-(4-氟苯基)-6-(8-甲基喹啉-6-基)-1,2,4-三嗪-3-胺8
在氩气氛下依次加入1b(100mg，0.37mmol)、6-溴-5-(4-氟苯基)-1,2,4-三嗪-3-胺8a(100mg，0.37mmol，采用公知的方法“Journal of Medicinal Chemistry,2012,55(5),1898-1903”制备而得)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(54mg，0.074mmol)和碳酸钾(154mg，1.12mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物8(15mg)，产率：12.2％。
MS m/z(ESI):332.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.92-8.93(m,1H),8.25-8.27(d,1H),7.80(s,1H),7.59(s,1H),7.48-7.55(m,5H),7.17-7.21(m,2H),2.64(s,3H)。
实施例9
5-苯基-6-(8-(三氟甲基)喹啉-6-基)-1,2,4-三嗪-3-胺9
Figure PCTCN2018072308-appb-000052
第一步
6-溴-8-(三氟甲基)喹啉9b
将2-氨基-5-溴三氟甲苯9a(1.1g，4.58mmol)、1,2,3-丙烷三醇(1.69g，18.3mmol)和硫酸铁(II)七水合物(204mg，0.73mmol)加入反应瓶中，冷却至0℃，滴加0.8mL硫酸，滴加完毕，加热至120℃，搅拌4小时。停止反应，冷却至室温，加入20mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物9b(0.9g)，产率：71.4％。
MS m/z(ESI):210.6[M+1]。
第二步
6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-8-(三氟甲基)喹啉9c
在氩气氛下依次加入9b(276mg，1.00mmol)、双(频哪醇合)二硼(381mg，1.50mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(146mg，0.20mmol)和乙酸钾(294mg，3.00mmol)溶解于15mL乙二醇二甲醚溶液中，加热至80℃，搅拌12小时。停止反应，冷却至室温，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪 以洗脱剂体系B纯化，得到标题产物9c(250mg)，产率：77.4％。
MS m/z(ESI):324.1[M+1]。
第三步
5-苯基-6-(8-(三氟甲基)喹啉-6-基)-1,2,4-三嗪-3-胺9
在氩气氛下依次加入9c(129mg，0.40mmol)、6-溴-5-苯基-1,2,4-三嗪-3-胺1c(100mg，0.40mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(58mg，0.08mmol)和碳酸钾(156mg，1.20mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，过滤，滤液减压浓缩，残余物中加入20mL乙酸乙酯，用饱和氯化钠溶液(10mL)洗涤，用无水硫酸钠干燥，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，得到标题产物9(50mg)，产率：34.2％。
MS m/z(ESI):368.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.04-9.05(m,1H),8.47-8.49(d,1H),8.39(s,1H),7.97(s,1H),7.63-7.71(m,3H),7.44-7.45(m,3H),7.34-7.38(m,2H)。
实施例10
6-(8-异丙基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺10
Figure PCTCN2018072308-appb-000053
第一步
6-溴-8-异丙基喹啉10b
将4-溴-2-异丙基苯胺10a(1.0g，4.70mmol，采用公知的方法“Synthesis,2013,45(17),2474-2480”制备而得)、1,2,3-丙烷三醇(2.1g，23.40mmol)和硫酸铁(II)七水合物(0.2g，0.75mmol)加入反应瓶中，冷却至0℃，滴加0.9mL硫酸，滴加完毕，加热至120℃，搅拌3小时。停止反应，冷却至室温，加入20mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液(20mL)洗涤，用无水硫酸钠干燥，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，得到标题产物10b(0.6g)，产率：51.7％。
MS m/z(ESI):251.1[M+1]。
第二步
8-异丙基-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉10c
在氩气氛下依次加入10b(600mg，2.40mmol)、双(频哪醇合)二硼(731mg，2.88mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(350mg，0.48mmol)和乙酸钾(705mg，7.20mmol)溶解于40mL乙二醇二甲醚溶液中，加热至80℃，搅拌4小时。停止反应，冷却至室温，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物10c(450mg)，产率：63.1％。
MS m/z(ESI):298.2[M+1]。
第三步
6-(8-异丙基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺10
在氩气氛下依次加入10c(118mg，0.40mmol)、6-溴-5-苯基-1,2,4-三嗪-3-氨1c(100mg，0.40mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(58mg，0.08mmol)和碳酸钾(165mg，1.20mmol)溶解于24mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物10(40mg)，产率：29.3％。
MS m/z(ESI):342.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.90-8.92(m,1H),8.36-8.38(d,1H),8.11(s,1H),7.51-7.53(m,3H),7.40-7.41(m,3H),7.33-7.35(m,2H),7.25(m,1H),4.10-4.12(m,1H),0.99-1.01(s,6H)。
实施例11
6-(8-乙基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺11
Figure PCTCN2018072308-appb-000054
第一步
6-溴-8-乙基喹啉11b
将4-溴-2-乙基苯胺11a(1.0g，5.00mmol，Alfa)、1,2,3-丙烷三醇(2.3g，25.00mmol)和硫酸铁(II)七水合物(0.22g，0.80mmol)加入反应瓶中，冷却至0℃，滴加0.9mL硫酸，滴加完毕，加热至120℃，搅拌2小时。停止反应，冷却至室温，加 入20mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液(20mL)洗涤，用无水硫酸钠干燥，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，得到标题产物11b(0.9g)，产率：76.3％。
MS m/z(ESI):237.1[M+1]。
第二步
8-乙基-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉11c
在氩气氛下依次加入11b(472mg，2.00mmol)、双(频哪醇合)二硼(610mg，2.40mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(292mg，0.40mmol)和乙酸钾(588mg，6.00mmol)溶解于30mL乙二醇二甲醚溶液中，加热至80℃，搅拌3小时。停止反应，冷却至室温，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得到标题产物11c(400mg)，产率：70.7％。
MS m/z(ESI):284.1[M+1]。
第三步
6-(8-乙基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺11
在氩气氛下依次加入11c(113mg，0.40mmol)、6-溴-5-苯基-1,2,4-三嗪-3-胺1c(100mg，0.40mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(58mg，0.08mmol)和碳酸钾(165mg，1.20mmol)溶解于24mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物11(20mg)，产率：15.3％。
MS m/z(ESI):328.4[M+1]。
1H NMR(400MHz,Pyridine-d 5)δ8.93-8.95(m,1H),8.52(br,2H),8.10(s,1H),8.06-8.10(m,1H),7.72(s,1H),7.65-7.67(m,2H),7.32-7.35(m,1H),7.26-7.28(m,3H),3.30-3.32(m,2H),1.22-1.25(t,3H)。
实施例12
6-(8-环丙基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺12
Figure PCTCN2018072308-appb-000055
Figure PCTCN2018072308-appb-000056
第一步
4-溴-2-环丙基苯胺12b
将2-环丙基苯胺12a(1.0g，7.52mmol，采用专利申请“WO201314997”公开的方法制备而得)加入100mL乙腈溶剂中，加入N-溴代琥珀酰亚胺(1.4g，7.89mmol)和乙酸铵(58mg，0.075mmol)，搅拌2小时，停止反应。加入60mL水，用乙酸乙酯萃取(100mL×3)，合并有机相，用饱和氯化钠溶液(50mL)洗涤，用无水硫酸钠干燥，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，得到标题产物12b(0.85g)，产率：53.5％。
MS m/z(ESI):213.1[M+1]。
第二步
6-溴-8-环丙基喹啉12c
将4-溴-2-乙基苯胺12b(500mg，2.36mmol)、1,2,3-丙烷三醇(1.08g，11.80mmol)和硫酸铁(II)七水合物(105mg，0.38mmol)加入反应瓶中，冷却至0℃，滴加0.5mL硫酸，滴加完毕，加热至120℃，搅拌2小时。停止反应，冷却至室温，加入50mL水，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和氯化钠溶液(50mL)洗涤，用无水硫酸钠干燥，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，得到标题产物12c(0.4g)，产率：68.5％。
MS m/z(ESI):249.1[M+1]。
第三步
8-环丙基-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉12d
在氩气氛下依次加入12c(100mg，0.40mmol)、双(频哪醇合)二硼(123mg，0.48mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(59mg，0.08mmol)和乙酸钾(118mg，1.20mmol)溶解于10mL乙二醇二甲醚溶液中，加热至80℃，搅拌4小时。停止反应，冷却至室温，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物12d(94mg)，产率：79.0％。
MS m/z(ESI):296.2[M+1]。
第四步
6-(8-环丙基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺12
在氩气氛下依次加入12d(94mg，0.32mmol)、6-溴-5-苯基-1,2,4-三嗪-3-胺1c(80mg，0.32mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(47mg，0.064mmol)和碳酸钾(132mg，0.96mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物12(10mg)，产率：9.2％。
MS m/z(ESI):340.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.92-8.94(m,1H),8.35-8.38(dd,1H),8.02(s,1H),7.43-7.57(m,3H),7.37-7.39(m,1H),7.34-7.36(m,4H),6.79-6.80(m,1H),3.06-3.08(m,1H),0.91-0.93(m,2H),0.29-0.30(m,2H)。
实施例13(对比例1)
6-(萘-2-基)-5-苯基-1,2,4-三嗪-3-胺
Figure PCTCN2018072308-appb-000057
6-(萘-2-基)-5-苯基-1,2,4-三嗪-3-胺13
在氩气氛下依次加入2-萘硼酸13a(55mg，0.32mmol)、6-溴-5-苯基-1,2,4-三嗪-3-胺1c(80mg，0.32mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(47mg，0.064mmol)和碳酸钾(132mg，0.96mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物13(20mg)，产率：21.3％。
MS m/z(ESI):299.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.02(s,1H),7.80-7.87(m,3H),7.31-7.52(m,10H)。
实施例14
6-(4-甲基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺14
Figure PCTCN2018072308-appb-000058
第一步
4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉14b
在氩气氛下，依次加入6-溴-4-甲基喹啉14a(444mg，2mmol，采用公知的方法“Tetrahedron,2003,59(6),813-819”制备而得)、双(频哪醇合)二硼(762mg，3mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(292mg，0.4mmol)和乙酸钾(588mg，6mmol)溶解于20mL二甲醚溶液中，加热至80℃，搅拌12小时。停止反应，冷却至室温，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物14b(460mg)，产率：85.5％。
MS m/z(ESI):270.4[M+1]。
第二步
6-(4-甲基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺14
在氩气氛下，依次加入化合物14b(107mg，0.4mmol)、化合物1c(100mg，0.4mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(58mg，0.08mmol)和碳酸钾(165mg，1.2mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物14(15mg)，产率：12％。
MS m/z(ESI):314.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.74-8.75(d,1H),8.02(m,1H),7.90-7.93(d,1H),7.71-7.73(d,1H),7.63(m,2H),7.42-7.44(m,3H),7.34-7.36(m,3H),2.46(s,3H)。
实施例15
6-(4-甲基喹唑啉-6-基)-5-苯基-1,2,4-三嗪-3-胺15
Figure PCTCN2018072308-appb-000059
Figure PCTCN2018072308-appb-000060
第一步
6-溴-4-甲基喹唑啉15b
将1-(2-氨基-5-溴苯基)乙酮15a(1g，4.67mmol，采用公知的方法“Journal of Medicinal Chemistry,2015,58(14),5522-5537”制备而得)，原甲酸三乙酯(1.04g，7.01mmol)和乙酸铵(540.15mg，7.01mmol)加入反应瓶中，110℃下，搅拌2小时。停止反应，冷却至室温，反应液用CombiFlash快速制备仪以洗脱剂体系B纯化，得标题产物15b(500mg)，产率：47.98％。
MS m/z(ESI):223.1[M+1]。
第二步
4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹唑啉15c
在氩气氛下依次加入化合物15b(360mg，1.61mmol)、双(频哪醇合)二硼(409.82mg，1.61mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(236.17mg，322.77μmol)和乙酸钾(475.16mg，4.84mmol)溶解于20mL二甲醚溶液中，加热至80℃，搅拌4小时。停止反应，冷却至室温，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物15c(330mg)，产率：75.7％。MS m/z(ESI):271.1[M+1]。
第三步
6-(4-甲基喹唑啉-6-基)-5-苯基-1,2,4-三嗪-3-胺15
在氩气氛下，依次加入化合物15c(108mg，399.80μmol)、化合物1c(100.38mg，399.80μmmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(58.51mg，79.96μmol)和碳酸钾(165mg，1.2mmol)溶解于12mL 1,4-二氧六环和水(V/V＝4:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物15(52mg)，产率：41.38％。
MS m/z(ESI):315.2[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.11(s,1H),8.22(s,1H),7.89-7.90(m,2H),7.59(m,2H),7.43-7.45(m,3H),7.34-7.38(m,2H),2.73(s,3H)。
实施例16
6-(8-氟-4-甲基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺16
Figure PCTCN2018072308-appb-000061
第一步
6-溴-8-氟-4-甲基喹啉16c
将4-溴-2-氟-苯胺16b(9.99g，52.58mmol，采用公知的方法“Tetrahedron Letters,2015,56(41),5646-5650”制备而得)溶于300mL 1,4-二氧六环中，滴加5mL硫酸，加热到回流，再缓慢滴加20mL丁-3-烯-2-酮16a(7.37g，105.15mmol，采用公知的方法“Tetrahedron Letters,2006,47(37),6635-6636”制备而得)的1,4-二氧六环溶液，滴加1.5小时，滴加完毕，回流2小时。反应液冷却至室温，反应液减压浓缩。残余物中加水，滴加饱和碳酸氢钠至混合液pH为10，乙酸乙酯萃取三次，合并有机相，饱和氯化钠溶液洗涤一次，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16c(3.5g)，产率：27.73％。
MS m/z(ESI):240.0[M+1]。
第二步
8-氟-4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉16d
在氩气氛下，将化合物16c(480mg，2.00mmol)、双(频哪醇合)二硼(761.59mg，3.00mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(292.60mg，399.88μmol)和乙酸钾(588.68mg，6.00mmol)加入20mL二甲醚中，加热至80℃，搅拌反应3小时。停止反应，冷却至室温，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物16d(460mg)，产率：80.12％。
MS m/z(ESI):288.1[M+1]。
第三步
6-(8-氟-4-甲基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺16
在氩气氛下，依次将化合物16d(110mg，383.09μmol)、化合物1c(96mg，383.09μmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(56mg，76.62μmol)和碳酸钾(158.60mg，1.15mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物16(18mg)，产 率：14.2％。
MS m/z(ESI):332.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.75-8.76(m,1H),7.78(s,1H),7.52-7.55(m,3H),7.41-7.43(m,4H),7.34-7.36(m,2H),2.42(s,3H)。
实施例17
5-(2-氟苯基)-6-(4-甲基喹啉-6-基)-1,2,4-三嗪-3-胺17
Figure PCTCN2018072308-appb-000062
在氩气氛下，依次将化合物14b(100mg，371.55μmol)、6-溴-5-(2-氟苯基)-1,2,4-三嗪-3-胺17a(99.97mg，371.55μmol，采用专利申请公开的方法“WO2016102672A2”制备而得)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(54mg，74.35μmol)和碳酸钾(153.82mg，1.11mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物17(50mg)，产率：40.6％。
MS m/z(ESI):332.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.70-8.71(m,1H),7.92-7.94(m,1H),7.84-7.87(m,1H),7.80(s,1H),7.60-7.67(m,3H),7.48-7.50(m,1H),7.09-7.36(m,2H),7.04-7.09(m,1H),2.32(s,3H)。
实施例18
5-(4-氟苯基)-6-(4-甲基喹啉-6-基)-1,2,4-三嗪-3-胺18
Figure PCTCN2018072308-appb-000063
Figure PCTCN2018072308-appb-000064
在氩气氛下，依次将化合物14b(100mg，371.55μmol)、化合物8a(99.97mg，371.55μmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(54.37mg，74.31μmol)和碳酸钾(153.82mg，1.11mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌反应2小时。停止反应，冷却至室温，过滤，滤液减压浓缩，残余物残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题产物18(15mg)，产率：12.18％。
MS m/z(ESI):332.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.76-8.77(m,1H),8.09(m,1H),7.92-7.95(d,1H),7.70-7.71(m,1H),7.53(m,2H),7.47-7.50(m,2H),7.39-7.40(m,1H),7.18-7.22(m,2H),2.52(s,3H)。
实施例19
5-(4-氟苯基)-6-(4-甲基喹唑啉-6-基)-1,2,4-三嗪-3-胺19
Figure PCTCN2018072308-appb-000065
氩气氛下，将化合物15c(100mg，370.19μmol)、化合物8a(99.61mg，370.19μmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(54.17mg，74.04μmol)和碳酸钾(153.26mg，1.11mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物19(50mg)，产率：40.64％。
MS m/z(ESI):333.2[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.12(s,1H),8.29(s,1H),7.88-7.90(m,2H),7.59(m,2H),7.47-7.51(m,2H),7.19-7.23(m,2H),2.78(s,3H)。
实施例20
6-(8-氟-4-甲基喹啉-6-基)-5-(4-氟苯基)-1,2,4-三嗪-3-胺20
Figure PCTCN2018072308-appb-000066
氩气氛下，将化合物8a(100mg，371.65μmol)、化合物16d(106.71mg，371.65μmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(54.39mg，74.33μmol)和碳酸钾(153.86mg，1.11mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物20(50mg)，产率：38.51％。
MS m/z(ESI):350.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.77-8.78(m,1H),7.83(s,1H),7.46-7.55(m,6H),7.19-7.21(m,2H),2.50(s,3H)。
实施例21
5-(2,4-二氟苯基)-6-(4-甲基喹啉-6-基)-1,2,4-三嗪-3-胺21
Figure PCTCN2018072308-appb-000067
氩气氛下，将化合物14b(68mg，252.65μmol)，6-溴-5-(2,4-二氟苯基)-1,2,4-三嗪-3-胺21a(72.53mg，252.65μmol，采用专利申请“WO2011095625A1”公开的方法制备而得)，[1,1’-双(二苯基膦基)二茂铁]二氯化钯(36.97mg，50.53μmol) 和碳酸钾(104.60mg，757.95μmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物21(40mg)，产率：50.99％。
MS m/z(ESI):350.2[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.74-8.75(m,1H),7.96-7.98(d,1H),7.85-7.89(m,2H),7.75-7.78(m,1H),7.65(m,2H),7.35-7.37(m,1H),7.28-7.30(m,1H),7.19-7.25(m,1H),2.42(s,3H)。
实施例22
5-(4-氟苯基)-6-[4-(三氘代甲基)-6-喹啉基]-1,2,4-三嗪-3-胺22
Figure PCTCN2018072308-appb-000068
第一步
6-溴-4-(三氘代甲基)喹啉22a
将化合物14a(222mg，999.64μmol)和苯甲酸(12.21mg，99.96μmol)溶于1mL重水中，100℃下，搅拌反应过夜。加入饱和碳酸氢钠溶液，用乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，将纯化后的固体和苯甲酸(12.21mg，99.96μmol)依次加入1mL重水中，100℃下，搅拌反应过夜。加入饱和碳酸氢钠溶液，用乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得标题化合物22a(100mg)，产率：44.44％。
MS m/z(ESI):225.0[M+1]。
第二步
6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-4-(三氘代甲基)喹啉22b
在氩气氛下，将化合物22a(100mg，444.25μmol)、双(频哪醇合)二硼(169.22mg，666.37μmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(65.01mg，88.85μmol)和乙酸钾(130.80mg，1.33mmol)加入10mL 1,4-二氧六环中，加热至80℃，搅拌4小时。停止反应，冷却至室温，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪 以洗脱剂体系B纯化，得到标题产物22b(70mg)，产率：57.9％。
MS m/z(ESI):273.1[M+1]。
第三步
5-(4-氟苯基)-6-[4-(三氘代甲基)-6-喹啉基]-1,2,4-三嗪-3-胺22
氩气氛下，将化合物22b(70mg，257.20μmol)、化合物8a(69.20mg，257.20μmol)，[1,1’-双(二苯基膦基)二茂铁]二氯化钯(37.64mg，51.44μmol)和碳酸钾(106.48mg，771.59μmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，过滤，滤液减压浓缩，冷却，过滤，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，所得粗品用薄层色谱法以展开剂体系A纯化，得标题化合物22(29mg)，产率：29.07％。
MS m/z(ESI):335.5[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.75-8.76(m,1H),8.08(s,1H),7.92-7.95(d,1H),7.68-7.70(d,1H),7.47-7.50(m,4H),7.38-7.39(m,1H),7.20-7.22(m,2H)。
实施例23
6-(4-甲氧基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺23
Figure PCTCN2018072308-appb-000069
氩气氛下，将4-甲氧基-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉23a(114mg，0.4mmol，采用专利申请“WO2011084402A1”公开的方法制备而得)和化合物1c(100mg，0.4mmol)，[1,1’-双(二苯基膦基)二茂铁]二氯化钯(58mg，0.08mmol)和碳酸钾(165mg，1.2mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物23(20mg)，产率：15.3％。
MS m/z(ESI):330.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.74-8.75(m,1H),8.30(m,1H),7.79-7.81(d,1H),7.48-7.51(m,3H),7.40-7.44(m,3H),7.33-7.35(m,2H),7.03-7.05(m,1H),4.02(s,3H)。
实施例24
6-(3-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺24
Figure PCTCN2018072308-appb-000070
第一步
3-氟喹啉-6-基三氟甲磺酸酯24b
将3-氟喹啉-6-醇24a(489mg，3mmol，采用公知的方法“Synlett,2014,25(6),858-862”制备而得)和吡啶(474mg，6mmol)溶于10mL二氯甲烷中，0℃条件下，滴加三氟甲酸酐(0.55mL，3.3mmol)，搅拌反应2小时。反应液中加入水，用二氯甲烷萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物24b(520mg)，产率：58.7％。
MS m/z(ESI):296.4[M+1]。
第二步
3-氟-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉24c
在氩气氛下，依次将化合物24b(100mg，0.34mmol)、双(频哪醇合)二硼(103mg，0.4mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(50mg，0.068mmol)和乙酸钾(100mg，1mmol)溶解于20mL二甲醚溶液中，加热至80℃，搅拌4小时。停止反应，冷却至室温，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物24c(70mg)，产率：76％。
MS m/z(ESI):274.4[M+1]。
第三步
6-(3-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺24
在氩气氛下，依次加入化合物24c(70mg，0.26mmol)、化合物1c(64mg，0.26mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(37mg，0.05mmol)和碳酸钾(106mg，0.77mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物24(20mg)，产率：25％。
MS m/z(ESI):318.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.94-8.95(m,1H),8.26-8.29(m,1H),8.17(m,1H),7.92-7.95(d,1H),7.51-7.55(m,3H),7.41-7.44(m,3H),7.34-7.36(m,2H)。
实施例25
6-(8-甲氧基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺25
Figure PCTCN2018072308-appb-000071
第一步
8-甲氧基-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉25b
在氩气氛下，依次将6-溴-8-甲氧基喹啉25a(530mg，2.2mmol，采用公知的方法“Journal of the American Chemical Society,2005,127(1),74-75”制备而得)、双(频哪醇合)二硼(845mg，3.3mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(162mg，0.22mmol)和乙酸钾(652mg，6.65mmol)溶解于10mL 1,4二氧六环中，加热至80℃，搅拌3小时。停止反应，冷却至室温，硅藻土过滤，滤饼用乙酸乙酯洗涤，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，得到标题产物25b(410mg)，产率：65％。
MS m/z(ESI):286.1[M+1]。
第二步
6-(8-甲氧基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺25
在氩气氛下，依次加入化合物25b(100mg，0.37mmol)、化合物1c(93mg，0.37mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(27mg，0.037mmol)和碳酸钾(10mg，0.074mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，反应液中加入水，乙酸乙酯萃取三次，合并有机相，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得到标题产物25(25mg)，产率：21％。
MS m/z(ESI):330.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.82(d,1H),8.25(d,1H),7.62(s,1H),7.51-7.53(m,3H),7.42-7.44(m,3H),7.34-7.36(m,2H),7.98(s,1H),3.65(s,3H)。
实施例26
5-(3-氟苯基)-6-(8-氟喹啉-6-基)-1,2,4-三嗪-3-胺26
Figure PCTCN2018072308-appb-000072
在氩气氛下，依次加入化合物2b(101.50mg,371.65μmol)、6-溴-5-(3-氟苯基)-1,2,4-三嗪-3-胺26a(100mg，71.65μmol，采用公知的方法“Journal of Medicinal Chemistry,2012,55(5),1898-1903”制备而得)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(54.39mg，74.33μmol)和碳酸钾(153.86mg，1.11mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物26(45mg)，产率：36.11％。
MS m/z(ESI):336.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.94(m,1H),8.37-8.39(m,1H),7.88(s,1H),7.53-7.61(m,3H),7.44-7.47(m,1H),7.26-7.35(m,3H),7.15-7.17(m,1H)。
实施例27
6-(4-氯喹啉-6-基)-5-(4-氟苯基)-1,2,4-三嗪-3-胺27
Figure PCTCN2018072308-appb-000073
在氩气氛下，依次加入4-氯-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉27a(200mg，690.69μmol，采用公知的方法“Journal of Medicinal Chemistry,2011,54(13),4735-4751”制备而得)、化合物8a(123.90mg，460.46μmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(67.38mg，92.09μmol)和碳酸钾(190.63mg，1.38mmol) 溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物27(25mg)，产率：15.43％。
MS m/z(ESI):352.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.85-8.86(m,1H),8.26(m,1H),8.02-8.04(d,1H),7.76-7.79(m,2H),7.60(m,2H),7.48-7.52(m,2H),7.19-7.23(m,2H)。
实施例28
6-(3-甲基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺28
Figure PCTCN2018072308-appb-000074
第一步
3-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉28b
在氩气氛下，依次加入6-溴-3-甲基喹啉28a(250mg，1.13mmol，采用专利申请公开的方法“WO2006132739A2”制备而得)、双(频哪醇合)二硼(429mg，1.69mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(165mg，0.225mmol)和乙酸钾(331mg，3.38mmol)溶解于20mL二甲醚溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物28b(240mg)，产率：79.2％。
MS m/z(ESI):270.1[M+1]。
第二步
6-(3-甲基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺28
在氩气氛下，依次加入化合物28b(107mg，0.4mmol)、化合物1c(100mg，0.4mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(58mg，0.08mmol)和碳酸钾(165mg，1.2mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物28(50mg)，产率：40％。
MS m/z(ESI):314.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.76-8.77(m,1H),7.06(s,1H),7.95-7.96(m,1H),7.85-7.87(d,1H),7.51-7.55(m,3H),7.41-7.43(m,3H),7.32-7.34(m,2H),2.47(s, 3H)。
实施例29
5-苯基-6-(喹唑啉-6-基)-1,2,4-三嗪-3-胺29
Figure PCTCN2018072308-appb-000075
第一步
6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹唑啉29b
在氩气氛下，依次加入6-溴喹唑啉29a(418mg，2mmol，采用公知的方法“Science of Synthesis,2004,16,573-749”制备而得)、双(频哪醇合)二硼(609mg，7.4mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(292mg，0.4mmol)和乙酸钾(588mg，6mmol)溶解于20mL二甲醚溶液中，加热至80℃，搅拌4小时。停止反应，冷却至室温，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物29b(450mg)，产率：87.9％。
MS m/z(ESI):257.1[M+1]。
第二步
5-苯基-6-(喹唑啉-6-基)-1,2,4-三嗪-3-胺29
在氩气氛下，依次将化合物29b(81mg，0.32mmol)、化合物1c(80mg，0.32mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(47mg，0.064mmol)和碳酸钾(132mg，0.96mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物29(10mg)，产率：5.1％。
MS m/z(ESI):301.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.60(s,1H),9.30(s,1H),8.31(s,1H),7.89-7.91(d,1H),7.80-7.82(m,1H),7.60(m,2H),7.42-7.44(m,3H),7.34-7.36(m,2H)。
实施例30
5-(4-氟苯基)-6-(喹啉-6-基)-1,2,4-三嗪-3-胺30
Figure PCTCN2018072308-appb-000076
在氩气氛下，将化合物3b(94.81mg，371.65μmol)、化合物8a(100mg，371.65μmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(54.39mg，74.33μmol)和碳酸钾(153.86mg，1.11mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物30(5mg)，产率：4.24％。
MS m/z(ESI):318.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.91-8.92(m,1H),8.36-8.38(d,1H),8.11-8.12(m,1H),7.92-7.94(d,1H),7.47-7.59(m,6H),7.17-7.21(m,2H)。
实施例31
6-(8-氟-4-甲基喹啉-6-基)-5-(2-氟苯基)-1,2,4-三嗪-3-胺31
Figure PCTCN2018072308-appb-000077
在氩气氛下，将化合物17a(100mg，371.65μmol)、化合物16d(106.71mg，371.65μmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(54.39mg，74.33μmol)和碳酸钾(153.86mg，1.11mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物31(50mg)，产率：38.51％。
MS m/z(ESI):350.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.74-8.75(m,1H),7.67-7.69(m,4H),7.59(s,1H),7.50-7.52(m,1H),7.36-7.41(m,2H),7.09-7.11(m,1H),2.31(s,3H)。
实施例32
5-(4-氟苯基)-6-(8-氟喹啉-6-基)-1,2,4-三嗪-3-胺32
Figure PCTCN2018072308-appb-000078
在氩气氛下，将化合物8a(100mg，371.65μmol)、化合物2b(101.50mg，371.65μmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(54.39mg，74.33μmol)和碳酸钾(153.86mg，1.11mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，所得粗品用薄层色谱法以展开剂体系D纯化，得到标题产物32(20mg)，产率：16.05％。
MS m/z(ESI):336.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.96-8.97(m,1H),8.41-8.43(d,1H),7.91(s,1H),7.64-7.66(m,1H),7.63(m,2H),7.46-7.52(m,3H),7.19-7.24(m,2H)。
实施例33
5-(2,4-二氟苯基)-6-(4-甲基喹唑啉-6-基)-1,2,4-三嗪-3-胺33
Figure PCTCN2018072308-appb-000079
Figure PCTCN2018072308-appb-000080
在氩气氛下，将化合物21a(100mg，349.56μmol)、化合物15c(94.43mg，349.56μmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(51.16mg，69.91μmol)和碳酸钾(144.72mg，1.05mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物33(55mg)，产率：44.91％。
MS m/z(ESI):351.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.11(s,1H),8.10(s,1H),8.02-8.04(d,1H),7.94-7.96(d,1H),7.72-7.79(m,3H),7.25-7.35(m,1H),7.15-7.25(m,1H),2.68(s,3H)。
实施例34
6-(3-甲氧基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺34
Figure PCTCN2018072308-appb-000081
第一步
3-甲氧基-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉34b
在氩气氛下，依次加入6-溴-3-甲氧基喹啉34a(120mg，0.5mmol，采用专利申请公开的方法“WO2012009194A1”制备而得)、双(频哪醇合)二硼(192mg，0.76mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(74mg，0.1mmol)和乙酸钾(148mg，1.5mmol)溶解于15mL二甲醚溶液中，加热至80℃，搅拌4小时。停止反应，冷却至室温，过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物34b(90mg)，产率：62.9％。
MS m/z(ESI):286.1[M+1]。
第二步
6-(3-甲氧基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺34
在氩气氛下，依次加入化合物34b(79mg，0.279mmol)、化合物1c(70mg，0.279mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(41mg，0.056mmol)和碳酸钾(115mg，0.84mmol)溶解于12mL 1,4-二氧六环和水(V/V＝5:1)的混合溶液中，加热至80℃，搅拌2小时。停止反应，冷却至室温，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，得到标题产物34(30mg)，产率：33％。
MS m/z(ESI):330.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.64-8.65(m,1H),8.03-8.04(m,1H),7.81-7.83(d,1H),7.75-7.76(m,1H),7.51(m,2H),7.42-7.45(m,3H),7.33-7.35(m,3H),3.91(s,3H)。
实施例35
5-(2-氟苯基)-6-(8-氟喹啉-6-基)-1,2,4-三嗪-3-胺35
Figure PCTCN2018072308-appb-000082
采用实施例32的合成路线，将第一步原料化合物8a替换为化合物17a，制得标题产物35(61mg)。
MS m/z(ESI):336.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.90-8.91(m,1H),8.29-8.31(d,1H),7.77(s,1H),7.60-7.66(m,3H),7.58-7.59(m,1H),7.42-7.49(m,2H),7.11-7.34(m,1H),7.08-7.11(m,1H)。
实施例36
5-苯基-6-(喹喔啉-6-基)-1,2,4-三嗪-3-胺36
Figure PCTCN2018072308-appb-000083
采用实施例23的合成路线，将第一步原料化合物23a替换为6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹喔啉36a(采用公知的方法“Organic Letters,2009,11(13),2860-2863”制备而得)，制得标题产物36(20mg)。
MS m/z(ESI):301.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.92-8.94(m,2H),8.03-8.05(m,2H),7.82-7.85(m,1H),7.60(m,2H),7.43-7.46(m,3H),7.34-7.36(m,2H)。
实施例37
6-(2-甲基喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺37
Figure PCTCN2018072308-appb-000084
采用实施例23的合成路线，将第一步原料化合物23a替换为2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)喹啉37a(采用公知的方法“Journal of the American Chemical Society,2015,137(4),1593-1600”制备而得)，制得标题产物37(20mg)。
MS m/z(ESI):314.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.19-8.21(d,1H),8.02(s,1H),7.78-7.80(d,1H),7.50-7.53(m,3H),7.40-7.43(m,4H),7.32-7.34(m,2H),2.65(s,3H)。
实施例38
6-(3-氨基-5-苯基-1,2,4-三嗪-6-基)喹啉-8-甲腈38
Figure PCTCN2018072308-appb-000085
第一步
6-溴喹啉-8-甲酰胺38b
将6-溴喹啉-8-甲酸甲酯38a(400mg，1.5mmol，采用专利申请公开的方法“WO2011020193A1”制备而得)溶于15mL甲醇中，滴加5mL的40％氨水，搅拌反应过夜。反应液中加入水、乙酸乙酯萃取三次，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化，得标题化合物38b(280mg)，产率：74％
MS m/z(ESI):251.0[M+1]。
第二步
6-溴喹啉-8-甲腈38c
将化合物38b(190mg，0.76mmol)溶于20mL二氯甲烷中，依次加入三乙胺(115mg，1.14mmol)和三氟乙酸酐(238mg，1.14mmol)，搅拌反应2小时。加入水，二氯甲烷萃取三次，合并有机相，有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用甲醇打浆，过滤，收集滤饼，得标题化合物(180mg)，产率：100％。
MS m/z(ESI):232.9[M+1]。
采用实施例11类似合成路线，将第二步原料化合物11b替换为38c，制得标题产物38(25mg)。
MS m/z(ESI):325.4[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.08(d,1H),8.51(d,1H),8.45(s,1H),8.13(s,1H),7.73(d,1H),7.71(brs,2H),7.43-7.45(m,3H),7.36-7.38(m,2H)。
实施例39
6-(3-吗啉喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺39
Figure PCTCN2018072308-appb-000086
第一步
4-(6-氯喹啉-3-基)吗啉39b
氩气氛下，将3-溴-6-氯喹啉39a(266mg，1.1mmol，采用公知的方法“Journal of Heterocyclic Chemistry,2015,52(4),1019-1025”制备而得)、吗啉(87mg，1mmol)、醋酸钯(12mg，0.05mmol)、(±)-2,2'-双-(二苯膦基)-1,1'-联萘(31mg，0.05mmol)和碳酸铯(652mg，2mmol)溶于10mL四氢呋喃中，加热至70℃，搅拌反应过夜。停止反应，冷却至室温，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，得到标题产物39b(180mg)，产率：66.2％
MS m/z(ESI):249.7[M+1]。
采用实施例11类似合成路线，将第二步原料化合物11b替换为39b，制得标题产物39(25mg)。
MS m/z(ESI):385.2[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.88(s,1H),7.93(s,1H),7.73-7.76(d,1H),7.40-7.52(m,6H),7.26-7.33(m,3H),3.80(m,4H),3.28(m,4H)。
实施例40
6-(4-(吗啉甲基)喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺40
Figure PCTCN2018072308-appb-000087
第一步
(6-溴喹啉-4-基)甲醇40b
将氢化铝锂(150.76mg，3.97mmol)加至50mL四氢呋喃中，0℃下，分批加入6-溴喹啉-4-羧酸40a(1.0g，3.97mmol，采用公知的方法“Chinese Chemical Letters,2010,21(1),35-38”制备而得)，继续搅拌2小时。加5mL水，用硅藻土过滤，乙酸乙酯洗涤滤饼，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，得到标题产物40b(250mg)，产率：26.5％。
第二步
6-溴-4-(氯甲基)喹啉40c
将化合物40b(250mg，1.05mmol)加至10mL二氯甲烷中，加入2mL氯化亚砜，搅拌反应3小时，反应液减压浓缩，旋干，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题产物40c(180mg)，产率：66.8％。
采用实施例39类似合成路线，将第一步原料化合物39a替换为化合物40c，制得标题产物40(5mg)。
MS m/z(ESI):399.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.82-8.83(m,1H),8.16(s,1H),7.98-8.00(d,1H),7.86-7.88(d,1H),7.53(m,2H),7.42-7.47(m,4H),7.35-7.37(m,2H),3.61(s,2H),3.49(m,4H),2.30(m,4H)。
实施例41
6-(3-(吗啉甲基)喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺41
Figure PCTCN2018072308-appb-000088
Figure PCTCN2018072308-appb-000089
采用实施例40类似合成路线，将第二步原料化合物40b替换为化合物28a，制得标题产物41(5mg)。
MS m/z(ESI):399.5[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.82-8.83(m,1H),8.16(s,1H),8.01-8.06(m,1H),7.84-7.86(d,1H),7.48-7.50(m,3H),7.37-7.41(m,3H),7.30-7.32(m,2H),3.64(s,2H),3.56(m,4H),2.39(m,4H)。
实施例42
6-(3-氨基-5-苯基-1,2,4-三嗪-6-基)喹啉-8-甲酰胺42
Figure PCTCN2018072308-appb-000090
采用实施例14合成路线，将第一步原料化合物14a替换为化合物38b，制得标题产物42(14mg)。
MS m/z(ESI):343.3[M+1]
1H NMR(400MHz,DMSO-d 6)δ10.16(s,1H),9.01(s,1H),8.55(s,1H),8.45(d,1H),8.19(s,1H),7.90(s,1H),7.64(d,1H),7.58(brs,2H),7.41-7.44(m,3H),7.33-7.35(m,2H)。
实施例43
6-(4-吗啉喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺43
Figure PCTCN2018072308-appb-000091
采用实施例39类似合成路线，将第一步原料化合物39a替换为6-溴-4-氯喹啉43a(采用公知的方法“Journal of Medicinal Chemistry,2015,58(14),5522-5537”制备而得)，制得标题化合物43(50mg)。
MS m/z(ESI):385.2[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.66-8.68(m,1H),8.01-8.02(m,2H),7.71(s,1H),7.46-7.48(m,4H),7.35-7.38(m,3H),6.92-6.93(m,1H),3.56-3.58(m,4H),2.71-2.73(m,4H)。
实施例44
6-(4-乙基喹啉-6-基)-5-(4-氟苯基)-1,2,4-三嗪-3-胺44
Figure PCTCN2018072308-appb-000092
第一步
6-溴-4-乙基喹啉44a
将化合物14a(500mg，2.25mmol)溶于50mL四氢呋喃中，-78℃下，滴加二异丙基胺基锂(723.54mg，6.75mmol)，搅拌反应1小时，加入碘甲烷(3.20g，22.51mmol)，逐渐升温到常温，搅拌过夜。加入饱和氯化铵水溶液，用乙酸乙酯萃取三次，合并有机相，用饱和氯化钠溶液洗一次，无水硫酸钠干燥，过滤，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物44a(480mg)，产率：90.3％。
采用实施例25类似合成路线，将第一步原料化合物25a替换为化合物44a，第二步原料化合物1c替换为化合物8a，制得标题化合物44(40mg)。
MS m/z(ESI):346.5[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.78-8.79(m,1H),7.98-8.03(m,2H),7.81-7.83(d,1H),7.47-7.51(m,4H),7.36-7.37(m,1H),7.17-7.22(m,2H),2.88-2.90(m,2H),1.05-1.09(t,3H)。
实施例45
6-(8-氟-4-甲基喹唑啉-6-基)-5-苯基-1,2,4-三嗪-3-胺45
Figure PCTCN2018072308-appb-000093
第一步
2-氨基-5-溴-3-氟苯腈45b
将2-氨基-3-氟苯甲腈45a(1g，7.35mmol，上海毕得医药科技有限公司)溶于50mL二氯甲烷中，加入N-溴代丁二酰亚胺(1.37g，7.71mmol)，搅拌反应16小时。加水，用二氯甲烷萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL)，无水硫酸钠干燥，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物45b(1.25g)，产率：79.13％。
MS m/z(ESI):215.0[M+1]。
第二步
1-(2-氨基-5-溴-3-氟苯基)乙烷-1-酮45c
将化合物45b(1g，4.65mmol)溶于60mL四氢呋喃中，在-10℃下，滴加甲基溴化镁(2.77g，23.25mmol)，反应液搅拌4小时，加水，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL)，无水硫酸钠干燥，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物45c(900mg)，产率：83.41％。
第三步
6-溴-8-氟4-甲基喹唑啉45d
将化合物45c(0.9g，3.88mmol)，原甲酸三乙酯(862mg，5.82mmol)和乙酸铵(448mg，5.82mmol)加入250mL单口瓶中，110℃下，搅拌2小时。冷却，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物45d(300mg)，产率：32.09％。
MS m/z(ESI):241.0[M+1]。
采用实施例34的合成路线，将第一步原料化合物34a替换为化合物45d，制得标题产物45(40mg)。产率：30.16％。
MS m/z(ESI):333.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.16(s,1H),8.03(s,1H),7.76-7.79(m,1H),7.65(br,2H),7.44-7.46(m,3H),7.38-7.40(m,2H),2.72(s,3H)。
实施例46
5-(4-氯苯基)-6-(4-甲基喹唑啉-6-基)-1,2,4-三嗪-3-胺46
Figure PCTCN2018072308-appb-000094
采用实施例15的合成路线，将第三步原料化合物1c替换为6-溴-5-(4-氯苯基)-1,2,4-三嗪-3-胺46a(采用专利申请公开的方法“WO201195625A1”制备而得)，制得标题产物46(42mg)，产率：34.38％。
MS m/z(ESI):348.8[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.12(s,1H),8.30(s,1H),7.87-7.90(m,2H),7.62(br,2H),7.45(m,4H),2.79(s,3H)。
实施例47
6-(4-乙基-8-氟喹啉-6-基)-5-苯基-1,2,4-三嗪-3-胺47
Figure PCTCN2018072308-appb-000095
第一步
6-溴-4-乙基-8-氟喹啉47a
氩气氛下，将化合物16c(480mg，2.00mmol)溶于10mL四氢呋喃中，-78℃下，滴加二异丙基氨基锂(257.02mg，2.40mmol)，搅拌1小时，再加入碘甲烷(297.98mg，2.10mmol)，搅拌2小时。加水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL)，无水硫酸钠干燥，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物47a(120mg)，产率：23.6％。
采用实施例14的合成路线，将第一步原料化合物14a替换为化合物47a，制得标题产物将47(30mg)。产率：37.37％。
MS m/z(ESI):346.5[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.81-8.82(m,1H),7.79(s,1H),7.58-7.66(m,1H),7.47(br,2H),7.36-7.45(m,6H),2.81-2.82(m,2H),0.99-1.03(t,3H)。
实施例48
5-(2-甲基吡啶-4-基)-6-(4-甲基喹啉-6-基)-1,2,4-三嗪-3-胺48
Figure PCTCN2018072308-appb-000096
第一步
2-(2-甲基吡啶-4-基)-2-氧代乙醛48b
将1-(2-甲基吡啶-4-基)乙基-1-酮48a(4.29g，31.74mmol，采用公知的方法“Journal of Medicinal Chemistry,2015,58(12),5028-5037”制备而得)溶于35mL二甲亚砜中，再加入35mL氢溴酸，55℃反应过夜。反应液直接用于下一步。
第二步
5-(2-甲基吡啶-4-基)-3-甲硫基-1,2,4-三嗪48c
将S-甲基异硫氨基脲氢碘酸盐(8.87g，38.06mmol)和碳酸氢钠(28g，333.31mmol)加入300mL乙醇中，然后缓慢地加入粗品化合物48b(4.73g,31.71mmol)反应液。加毕，80℃条件下，搅拌反应1小时。减压浓缩，加水，用乙酸乙酯萃取(100mL×2)，合并有机相，水洗(80mL×3)，饱和氯化钠溶液洗涤(80mL)，无水硫酸钠干燥，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题产物48c(5.6g)，产率：80.90％。
MS m/z(ESI):219.4[M+1]。
第三步
5-(2-甲基吡啶-4-基)-3-甲磺酰基-1,2,4-三嗪48d
将化合物48c(5.4g，24.74mmol)溶于180mL二氯甲烷，再加入间氯过氧苯甲酸(8g，46.36mmol)。搅拌反应3小时。过滤，滤液减压浓缩，得粗品标题产物 48d(8.5g)，产物不经纯化，直接用于下一步。
第四步
5-(2-甲基吡啶-4-基)-1,2,4-三嗪-3-胺48e
将粗品化合物48d(8.5g,33.96mmol)溶于80mL二氧六环中，加入20mL氨水，搅拌反应1小时。减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系A纯化，得到标题产物48e(1.6g)，产率：25.17％。
MS m/z(ESI):188.1[M+1]。
第五步
6-溴-5-(2-甲基吡啶-4-基)-1,2,4-三嗪-3-胺48f
将化合物48e(1.6g，8.55mmol)加入200mL乙腈中，再加入N-溴代丁二酰亚胺(3.80g，21.37mmol)和三氟乙酸(1.95g，17.09mmol)，搅拌64小时。减压浓缩，加入水，水相用乙酸乙酯萃取(100mL×3)，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，得到标题产物48f(1.87g)，产率：82.22％。
第六步
5-(2-甲基吡啶-4-基)-6-(4-甲基喹啉-6-基)-1,2,4-三嗪-3-胺48
氩气氛下，将化合物14b(100mg，375μmol)，化合物48f(101mg，375μmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(55mg，75μmol)和碳酸钾(155mg，1.13mmol)溶解于12mL 1,4-二氧六环和水(V:V＝5:1)的混合溶液中，80℃条件下，搅拌2小时。冷却，硅藻土过滤，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，得到标题产物48(30mg)，产率：24.31％。
MS m/z(ESI):329.5[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.75-8.77(m,1H),8.37-8.38(m,1H),8.07(s,1H),7.93-7.95(m,1H),7.70-7.72(m,1H),7.65(br,2H),7.38-7.40(m,2H),7.06-7.07(m,1H),2.50(s,3H),2.42(s,3H)。
实施例49
6-(4-环丙基喹啉-6-基)-5-(4-氟苯基)-1,2,4-三嗪-3-胺49
Figure PCTCN2018072308-appb-000097
Figure PCTCN2018072308-appb-000098
第一步
6-溴-4-碘喹啉49b
将5mL的4M氯化氢的1,4-二氧六环溶液加入6-溴-4-氯喹啉49a(1g，4.12mmol)中，搅拌反应10分钟，反应液减压浓缩备用。60mL乙腈加入到上述浓缩后的残留物中，再加入碘化钠(6.18g，41.24mmol)，回流下，搅拌反应16小时。反应液冷却至室温，减压浓缩，加饱和碳酸氢钠溶液，用乙酸乙酯萃取(20mL×3)，合并有机相，无水硫酸钠干燥，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物49b(850mg)，产率：61.72％。
MS m/z(ESI):333.9[M+1]。
第二步
6-溴-4-环丙基喹啉49c
氩气氛下，将化合物49b(350mg，1.05mmol)，环丙基硼酸(99mg，1.15mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(153mg，209μmol)和碳酸钾(433mg,3.14mmol)加入30mL的1,4-二氧六环中，80℃条件下，搅拌16小时。冷却，过滤，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物49c(110mg)，产率：42.30％。
MS m/z(ESI):250.1[M+1]。
采用实施例22的合成路线，将第二步原料化合物22a替换为化合物49c，制得到标题产物49(40mg)，产率：27.53％。
MS m/z(ESI):358.5[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.74-8.75(m,1H),8.34(s,1H),7.96-7.98(m,1H),7.78-7.80(m,1H),7.48-7.52(m,4H),7.18-7.22(m,2H),7.14-7.15(m,1H),2.27-2.28(m,1H),0.97-0.99(m,2H),0.71-0.73(m,2H)。
实施例50
6-(8-氟-4-甲基喹唑啉-6-基)5-(4-氟苯基)-1,2,4-三嗪-3-胺50
Figure PCTCN2018072308-appb-000099
采用实施例22的合成路线，将第二步原料化合物22a替换为化合物45d，制得标题产物50(54mg)。产率：41.48％。
MS m/z(ESI):351.0[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.18(s,1H),8.08(s,1H),7.76-7.79(m,1H),7.66(br,2H),7.49-7.53(m,2H),7.20-7.25(m,2H),2.77(s,3H)。
实施例51
6-(4-(二氟甲基)喹啉-6-基)-5-(4-氟苯基)-1,2,4-三嗪-3-胺51
Figure PCTCN2018072308-appb-000100
第一步
6-溴喹啉-4-甲醛51a
将化合物14a(1.0g，4.50mmol)溶于20mL 1,4-二氧六环中，加入2mL水，再加入二氧化硒(1.5g，13.51mmol),80℃条件下，搅拌反应16小时。反应液冷却至室温，加入饱和碳酸氢钠溶液，乙酸乙酯萃取(30mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤，硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以展开剂体系B纯化，得到标题化合物51a(670mg),产率：63.0％。
第二步
6-溴-4-(二氟甲基)喹啉51b
将化合物51a(670mg，2.84mmol)溶于20mL二氯甲烷中，滴加二乙氨基三氟化硫(915mg，5.68mmol)，搅拌反应16小时。加入饱和碳酸氢钠溶液，搅拌30分钟。二氯甲烷萃取(20mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤，硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱色谱法以展开剂体系B纯化，得到标题化合物51b(630mg)，产率：86.0％。
采用实施例25类似合成路线，将第一步原料化合物25a替换为化合物51b，第二步原料化合物1c替换为化合物8a，制得标题化合物51(55mg)。
MS m/z(ESI):368.5[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.05(d,1H),8.21(s,1H),8.08(d,1H),7.80(d,1H),7.75(d,1H),7.53(brs,2H),7.48(t,1H),7.47(q,2H),7.19(t,2H)。
实施例52
5-(4-氟苯基)-6-(4-(甲基-d3)喹唑啉-6-基)-1,2,4-三唑-3-胺52
Figure PCTCN2018072308-appb-000101
第一步
6-溴-4-(甲基-d3)喹唑啉52a
将化合物15b(200mg，0.90mmol)悬浮于4mL重水中，加入苯甲酸(10.95mg，0.09mmol)，100℃下，搅拌48小时。加入饱和碳酸氢钠溶液，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤，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，得标题化合物52a(150mg)，产率：74.0％。
采用实施例25类似合成路线，将第一步原料化合物25a替换为化合物52a，第二步原料化合物1c替换为化合物8a，制得标题化合物52(18mg)。
MS m/z(ESI):336.5[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.11(s,1H),8.28(s,1H),7.85-8.28(m,2H),7.59(brs,2H),7.46-7.50(m,2H),7.20(t,2H)。
实施例53
6-(4-乙基喹唑啉-6-基)-5-(4-氟苯基)-1,2,4-三嗪-3-胺53
Figure PCTCN2018072308-appb-000102
第一步
1-(2-氨基-5-溴苯基)丙-1-酮53b
将2-氨基-5-溴苯甲腈53a(500mg，2.54mmol，采用公知的方法“European Journal of Medicinal Chemistry,2014,76,341-343”制备而得)溶于10mL四氢呋喃中，冰浴冷却，氩气氛下，滴加12.69mL的1.0M乙基溴化镁，搅拌2小时。加入6M盐酸，搅拌2小时。加入饱和碳酸钠溶液，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤，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，得标题化合物53b(440mg)，产率：76.02％。
第二步
6-溴-4-乙基喹唑啉53c
将化合物53b(440mg，1.93mmol)，原甲酸三乙酯(857.68mg，5.79mmol)和醋酸铵(451.14mg，5.79mmol)混合，加热至110℃，搅拌反应16小时。加入饱和碳酸钠溶液，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤，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，得标题化合物53c(280mg)，产率：61.22％。
采用实施例25类似合成路线，将第一步原料化合物25a替换为化合物53c，第二步原料化合物1c替换为化合物8a，制得标题化合物53(45mg)。
MS m/z(ESI):347.5[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.15(s,1H),8.21(s,1H),7.94-8.01(m,2H),7.57(brs,2H),7.47-7.50(m,2H),7.20(t,2H),3.10(q,2H),1.16(t,3H)。
实施例54
5-(4-氟苯基)-6-[4-(三氟甲基)喹啉-6-基]-1,2,4-三嗪-3-胺54
Figure PCTCN2018072308-appb-000103
第一步
6-溴-4-三氟甲基喹啉-2(1H)-酮54b
三氟乙酰乙酸乙酯(1.24g，6.75mmol)和三乙胺(1.65g,16.28mmol)加入20mL 甲苯中，再3mL 2.7M滴加4-溴苯胺54a的甲苯溶液，回流条件下，搅拌16小时。反应液减压浓缩，加30mL二氯甲烷溶解，用水洗涤(20mL×2)，饱和氯化钠溶液洗涤(20mL)，无水硫酸钠干燥，过滤，滤液减压浓缩。所得中间体中加入6mL硫酸，100℃条件下，搅拌4小时，反应液冷却至室温，滴加饱和碳酸氢钠调pH大于10，用乙酸乙酯萃取(30mL×3)，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，得到标题产物54b(1.5g)，产率：63.70％。
MS m/z(ESI):291.9[M+1]。
第二步
6-溴-2-氯-4-(三氟甲基)喹啉54c
三氯氧磷(4.73g，30.82mmol)加入化合物54b(1.5g，5.14mmol)中，100℃条件下，搅拌5小时。冷却，加入冰水中，搅拌30分钟，用乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物54c(1.3g)。产率：81.52％。
第三步
6-溴-4-三氟甲基喹啉54d
将化合物54c(500mg,1.61mmol)溶于8mL三氟乙酸中，再加入锌粉(842mg,12.88mmol)，反应液搅拌16小时。过滤，减压浓缩。滴加1M氢氧化钠至残留物pH大于10，用乙酸乙酯萃取(30mL×3)，合并有机相，无水硫酸钠干燥，减压浓缩，残余物用CombiFlash快速制备仪以洗脱剂体系B纯化，得到标题产物54d(200mg)。产率：44.99％。
MS m/z(ESI):275.8[M+1]。
采用实施例22的合成路线，将第二步原料化合物22a替换为化合物54d，制得标题产物54(30mg)。
MS m/z(ESI):386.4[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.11-9.12(m,1H),8.19-8.21(m,1H),7.99-8.03(m,2H),7.93-7.94(m,1H),7.62(br,2H),7.47-7.50(m,2H),7.18-7.23(m,2H)。
实施例55
5-(4-氟苯基)-6-(4-甲氧基喹唑啉-6-基)-1,2,4-三嗪-3-胺55
Figure PCTCN2018072308-appb-000104
Figure PCTCN2018072308-appb-000105
第一步
6-溴-4-甲氧基喹唑啉55b
将6-溴-4-氯喹唑啉55a(1.0g，4.10mmol)溶于80mL甲醇中，加入甲醇钠(2.21g，41.05mmol)，搅拌反应3小时。旋干，加水，过滤，滤饼干燥得产物55b(0.55g)。产率：56.01％。
MS m/z(ESI):239.1[M+1]
采用实施例22的合成路线，将第二步原料化合物22a替换为化合物55b，制得标题产物55(40mg)。产率：31.29％。
MS m/z(ESI):349.2[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.82(s,1H),8.28(s,1H),7.81-7.83(m,1H),7.72-7.74(m,1H),7.56(br,2H),7.47-7.50(m,2H),7.18-7.22(m,2H),4.12(s,3H)。
测试例：
生物学评价
测试例1、本发明化合物对腺苷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。
以下方法用来测定本发明化合物对腺苷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。实验方法简述如下：
一、实验材料及仪器
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)
2.胎牛血清(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)
4.DMEM/F12培养基(GE,SH30023.01)
5.细胞分离缓冲液(Thermo Fisher,13151014)
6.HEPES(Gibco,42360-099)
7.牛血清白蛋白(MP Biomedicals,219989725)
8.咯利普兰(sigma,R6520-10MG)
9.腺苷脱氨酶(sigma,10102105001)
10.毛喉素(sigma，F6886)
11.2Cl-IB-MECA(Tocrics,1104/10)
12.N6-环戊基腺苷(Tocris，1702/50)
13.平衡盐缓冲液(Thermo,14025-092)
14.cAMP动态2试剂盒(cAMP dynamic 2kit)(Cisbio,62AM4PEB)
15.384孔板(Corning,4514)或(Nunc,267462#)
16.乙基咔唑(Torcis,1691/10)
17.PHERAstar多功能酶标仪(Cisbio,62AM4PEB)
二、实验步骤
2.1腺苷A 2a受体
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。
2.2腺苷A 2b受体
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。
2.3腺苷A 1受体
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3。
2.4腺苷A 3受体
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3。
表1本发明化合物对腺苷A 2a受体(adenosine A 2a receptor，A 2aR)cAMP信号通路抑制活性的IC 50值。
Figure PCTCN2018072308-appb-000106
Figure PCTCN2018072308-appb-000107
结论：本发明化合物对腺苷A 2a受体具有明显的抑制活性，与对比例1相比在母核的稠芳基部分引入氮原子，使得本发明化合物对腺苷A 2a受体的抑制作用取得了意料不到的效果，对比例1和实施例3相比，两者结构差异仅为实施例3在对 比例1的萘基的5位上引入了氮原子，对腺苷A 2a受体的抑制活性相差225倍。
表2本发明化合物对腺苷A 2b受体(adenosine A 2b receptor，A 2bR)cAMP信号通路抑制活性的IC 50值。
实施例编号 IC 50/nM(A 2bR)
3 47
4 4
5 46
14 3
15 7
16 18
17 22
19 25
22 7
23 17
25 4
45 25
46 18
52 14
结论：本发明化合物对腺苷A 2b受体具有较好的抑制活性。
表3本发明化合物对腺苷A 1受体(adenosine A 1 receptor，A 1R)cAMP信号通路和腺苷A 3受体cAMP信号通路抑制活性的IC 50值。
Figure PCTCN2018072308-appb-000108
Figure PCTCN2018072308-appb-000109
结论：本发明化合物对腺苷A 1受体和腺苷A 3受体抑制活性作用较弱，说明本发明化合物对腺苷A 2a受体和腺苷A 2b受体具有选择性，特别是对腺苷A 2a受体。
药代动力学评价
测试例2、本发明化合物的小鼠药代动力学测试
1、摘要
以小鼠为受试动物，应用LC/MS/MS法测定了小鼠灌胃给予实施例2化合物、实施例3化合物、实施例17化合物、实施例18化合物、实施例19化合物、实施例20化合物、实施例31化合物和实施例44后不同时刻血浆中的药物浓度。研究本发明化合物在小鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1试验药品
实施例2化合物、实施例3化合物、实施例17化合物、实施例18化合物、实施例19化合物、实施例20化合物、实施例31化合物和实施例44。
2.2试验动物
C57小鼠72只，雌性，平均分成8组，每组9只，购自上海杰思捷实验动物有限公司，动物生产许可证号：SCXK(沪)2013-0006。
2.3药物配制
称取一定量药物，加5％体积的DMSO、5％体积的tween80和90％生理盐水配置成0.1mg/ml无色澄清透明液体。
2.4给药
C57小鼠禁食过夜后灌胃给药，给药剂量均为2.0mg/kg，给药体积均为0.2ml/10g。
3、操作
小鼠灌胃给药实施例2化合物、实施例3化合物、实施例17化合物、实施例18化合物、实施例19化合物、实施例20化合物、实施例31化合物和实施例44，于给药前及给药后0.5，1.0，2.0，4.0，6.0，8.0，11.0，24.0小时采血0.1ml，置于肝素化试管中，3500转/分钟离心10分钟分离血浆，于-20℃保存。
测定不同浓度的药物灌胃给药后小鼠血浆中的待测化合物含量：取给药后各时刻的小鼠血浆25μl，加入内标溶液喜树碱50μl(100ng/mL)，乙腈200μl，涡旋混合5分钟，离心10分钟(4000转/分钟)，血浆样品取上清液5μl进行LC/MS/MS分析。
4、药代动力学参数结果
本发明化合物的药代动力学参数如下：
Figure PCTCN2018072308-appb-000110
结论：本发明化合物的药代吸收较好，具有药代动力学优势。

Claims (18)

  1. 一种通式(I)所示的化合物：
    Figure PCTCN2018072308-appb-100001
    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为芳基或杂芳基；
    G 1、G 2、G 3和G 4相同或不同，且各自独立地选自C、CH或N；
    R 1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、杂芳基、-OR 5、-C(O)R 5、-S(O) mR 5、NH 2S(O) mR 5、-NR 6R 7、S(O) mNR 6R 7和-C(O)NR 6R 7；其中所述的烷基、烷氧基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、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；
    R 2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、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基、-OR 5、-C(O)R 5、-S(O) mR 5、NH 2S(O) mR 5、-NR 6R 7、S(O) mNR 6R 7和-C(O)NR 6R 7；其中所述的烷基、烷氧基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、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；
    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、杂芳基、-OR 5、-C(O)R 5、-S(O) mR 5、NH 2S(O) mR 5、-NR 6R 7、S(O) mNR 6R 7和-C(O)NR 6R 7；其中所述的烷基、烷氧基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、氘原子、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；
    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、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基、-OR 5、-C(O)R 5、-S(O) mR 5、NH 2S(O) mR 5、-NR 6R 7、S(O) mNR 6R 7和-C(O)NR 6R 7；其中所述的烷基、烷氧基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被 选自卤素、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；
    R 5选自氢原子、烷基、卤代烷基、氨基、羟基、环烷基、杂环基、芳基和杂芳基；
    R 6和R 7各自独立地选自氢原子、烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自烷基、烷氧基、卤素、氨基、氰基、硝基、羟基、羟烷基、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；
    或者，所述R 6和R 7与相连接的氮原子一起形成杂环基，其中所述的杂环基内含有1～2个相同或不同选自N、O和S的杂原子，并且所述的杂环基任选被选自烷基、烷氧基、卤素、氨基、氰基、硝基、羟基、羟烷基、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；
    m为0、1或2；
    r为0、1、2或3；
    q为0、1或2；且
    n为0、1、2、3、4或5。
  2. 根据权利要求1所述的通式(I)所示的化合物，其为通式(Iaa)所示的化合物：
    Figure PCTCN2018072308-appb-100002
    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、G 1、G 2、R 1、R 3、R 4、r和n如权利要求1中所定义。
  3. 根据权利要求1或2所述的通式(I)所示的化合物，其为通式(II)所示的化合物：
    Figure PCTCN2018072308-appb-100003
    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、R 1、R 3、R 4、r和n如权利要求1中所定义。
  4. 根据权利要求1～3中任一项所述的通式(I)所示的化合物，其中所述的环A选自苯基、吡啶基、噻吩基和呋喃基。
  5. 根据权利要求1～4中任一项所述的通式(I)所示的化合物，其为通式(III)所示的化合物：
    Figure PCTCN2018072308-appb-100004
    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、R 3、R 4、r和n如权利要求1中所定义。
  6. 根据权利要求1～5中任一项所述的通式(I)所示的化合物，其中所述的R 1选自氢原子、卤素、烷基、烷氧基、氰基、环烷基、卤代烷基、杂环基和-C(O)NR 6R 7；R 6和R 7如权利要求1中所定义。
  7. 根据权利要求1～6中任一项所述的通式(I)所示的化合物，其中所述的R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、氘代烷基、烷氧基、氰基、环烷基杂环基，其中所述的烷基和烷氧基各自独立地任选被选自卤素、氘原子、羟基、氰基、氨基、硝基、环烷基和杂环基中的一个或多个取代基所取代。
  8. 根据权利要求1～7中任一项所述的通式(I)所示的化合物，其中所述的R 4相同或不同，且各自独立地选自氢原子、烷基和卤素。
  9. 根据权利要求1～8中任一项所述的通式(I)所示的化合物，其选自：
    Figure PCTCN2018072308-appb-100005
    Figure PCTCN2018072308-appb-100006
  10. 一种制备根据权利要求1所述的通式(I)所示的化合物的方法，该方法包括：
    Figure PCTCN2018072308-appb-100007
    通式(I-A)的化合物和通式(I-B)的化合物发生偶联反应，得到通式(I)的化合物，
    其中：
    X为卤素；
    M为
    Figure PCTCN2018072308-appb-100008
    环A、G 1～G 4、R 1～R 4、r、q和n如权利要求1中所定义。
  11. 一种制备根据权利要求2所述的通式(Iaa)所示的化合物的方法，该方法包括：
    Figure PCTCN2018072308-appb-100009
    通式(Iaa-1)的化合物和通式(I-B)的化合物发生偶联反应，得到通式(Iaa)的化合物，
    其中：
    X为卤素；
    M为
    Figure PCTCN2018072308-appb-100010
    环A、G 1、G 2、R 1、R 3、R 4、r和n如权利要求1中所定义。
  12. 一种药物组合物，所述药物组合物含有治疗有效量的根据权利要求1～9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，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  13. 根据权利要求1～9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、或其可药用的盐或根据权利要求12所述的药物组合物在制备用于治疗通过对A 2a受体的抑制而改善的病况或病症的药物中的用途。
  14. 根据权利要求1～9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、或其可药用的盐或根据权利要求12所述的药物组合物在制备用于治疗通过对A 2b受体的抑制而改善的病况或病症的药物中的用途。
  15. 根据权利要求13或14所述的用途，其中所述的病况或病症选自癌症、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。
  16. 根据权利要求15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、前列腺癌、皮肤癌、神经母细胞瘤、肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、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。
  17. 根据权利要求1～9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、或其可药用的盐或根据权利要求12所述的药物组合物在制备用于抑制A 2a受体的药物中的用途。
  18. 根据权利要求1～9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、或其可药用的盐或根据权利要求12所述的药物组合物在制备用于抑制A 2b受体的药物中的用途。
PCT/CN2018/072308 2017-01-13 2018-01-12 1,2,4-三嗪-3-胺类衍生物、其制备方法及其在医药上的应用 WO2018130184A1 (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US16/477,011 US11014904B2 (en) 2017-01-13 2018-01-12 1,2,4-triazine-3-amine derivative, preparation method therefor, and use thereof in medicine
JP2019534645A JP2020506885A (ja) 2017-01-13 2018-01-12 １，２，４−トリアジン−３−アミン誘導体、その製造方法、および医薬におけるその使用
CN201880001471.0A CN108884061B (zh) 2017-01-13 2018-01-12 1,2,4-三嗪-3-胺类衍生物、其制备方法及其在医药上的应用
EP18739200.6A EP3569596A4 (en) 2017-01-13 2018-01-12 1,2,4-TRIAZINE-3-AMINE DERIVATIVE, PROCESS OF PREPARATION AND USE IN MEDICINE
US17/223,736 US20210230138A1 (en) 2017-01-13 2021-04-06 1,2,4-triazine-3-amine derivative, preparation method therefor, and use thereof in medicine

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201710023970.7 2017-01-13
CN201710023970 2017-01-13
CN201710874488 2017-09-25
CN201710874488.4 2017-09-25

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US16/477,011 A-371-Of-International US11014904B2 (en) 2017-01-13 2018-01-12 1,2,4-triazine-3-amine derivative, preparation method therefor, and use thereof in medicine
US17/223,736 Continuation US20210230138A1 (en) 2017-01-13 2021-04-06 1,2,4-triazine-3-amine derivative, preparation method therefor, and use thereof in medicine

Publications (1)

Publication Number Publication Date
WO2018130184A1 true WO2018130184A1 (zh) 2018-07-19

Family

ID=62839274

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/072308 WO2018130184A1 (zh) 2017-01-13 2018-01-12 1,2,4-三嗪-3-胺类衍生物、其制备方法及其在医药上的应用

Country Status (6)

Country Link
US (2) US11014904B2 (zh)
EP (1) EP3569596A4 (zh)
JP (1) JP2020506885A (zh)
CN (1) CN108884061B (zh)
TW (1) TW201827422A (zh)
WO (1) WO2018130184A1 (zh)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110655509A (zh) * 2018-06-29 2020-01-07 江苏恒瑞医药股份有限公司 2-胺基嘧啶类衍生物、其制备方法及其在医药上的应用
CN110684020A (zh) * 2018-07-05 2020-01-14 江苏恒瑞医药股份有限公司 2-胺基嘧啶类衍生物、其制备方法及其在医药上的应用
WO2020011220A1 (zh) * 2018-07-12 2020-01-16 江苏恒瑞医药股份有限公司 杂芳基类衍生物、其制备方法及其在医药上的应用
WO2020083957A1 (en) 2018-10-24 2020-04-30 Leadxpro Ag Functionalized aminotriazines
WO2020135195A1 (zh) 2018-12-28 2020-07-02 四川科伦博泰生物医药股份有限公司 氨基吡啶类化合物及其制备方法和用途
CN111377906A (zh) * 2018-12-28 2020-07-07 四川科伦博泰生物医药股份有限公司 取代的吡嗪化合物及其制备方法和用途
CN111377873A (zh) * 2018-12-28 2020-07-07 四川科伦博泰生物医药股份有限公司 氨基嘧啶化合物及其制备方法和用途
WO2020146795A1 (en) 2019-01-11 2020-07-16 Omeros Corporation Methods and compositions for treating cancer
WO2020171499A1 (ko) * 2019-02-18 2020-08-27 한국과학기술연구원 단백질 키나아제 저해 활성을 갖는 신규한 피리도[3,4-d]피리미딘-8-온 유도체 및 이를 포함하는 암의 예방, 개선 또는 치료용 약학 조성물
RU2780168C1 (ru) * 2019-02-18 2022-09-20 Корея Инститьют Оф Сайенс Энд Текнолоджи Новое производное пиридо [3,4-d] пиримидин-8-она, обладающее ингибирующей протеинкиназы активностью, и фармацевтическая композиция для предупреждения, облегчения или лечения рака, содержащее указанное выше
CN115697994A (zh) * 2020-06-10 2023-02-03 江苏恒瑞医药股份有限公司 稠合喹唑啉类衍生物、其制备方法及其在医药上的应用
WO2023144559A1 (en) 2022-01-28 2023-08-03 AdoRx Therapeutics Limited Antagonist of adenosine receptors
US11884647B2 (en) 2019-10-18 2024-01-30 The Regents Of The University Of California Compounds and methods for targeting pathogenic blood vessels

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020011245A1 (zh) * 2018-07-13 2020-01-16 江苏恒瑞医药股份有限公司 一种1,2,4-三嗪-3-胺类衍生物的晶型及制备方法

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006132739A2 (en) 2005-05-03 2006-12-14 Smithkline Beecham Corporation Novel chemical compounds
WO2007116106A1 (es) 2006-04-12 2007-10-18 Palobiofarma, S.L. Nuevos compuestos como antagonistas de los receptores a1 de adenosina
WO2009080197A1 (de) 2007-12-20 2009-07-02 Bayer Schering Pharma Aktiengesellschaft Substituierte pyrrolo[2, 3-b]- und pyrazolo[3, 4-b] pyridine als adenosin rezeptor liganden
WO2011020193A1 (en) 2009-08-18 2011-02-24 Merck Frosst Canada Ltd. Renin inhibitors
WO2011084402A1 (en) 2009-12-21 2011-07-14 Merck Sharp & Dohme Corp. Tyrosine kinase inhibitors
WO2011095625A1 (en) 2010-02-05 2011-08-11 Heptares Therapeutics Limited 1,2,4-triazine-4-amine derivatives
WO2011159302A1 (en) 2010-06-17 2011-12-22 Janssen Pharmaceutica Nv Arylindenopyrimidines for treating neurodegenerative and movement disorders while minimizing cardiac toxicity
WO2012009194A1 (en) 2010-07-12 2012-01-19 Merck Sharp & Dohme Corp. Tyrosine kinase inhibitors
WO2013014997A1 (ja) 2011-07-26 2013-01-31 株式会社Ihi 自己磁性金属サレン錯体化合物
WO2014101373A1 (en) 2012-12-28 2014-07-03 Merck Sharp & Dohme Corp. Heterobicyclo-substituted-[1,2,4]triazolo[1,5-c]quinazolin-5-amine compounds for treatment of central nervous system disorder
WO2015031221A1 (en) 2013-08-29 2015-03-05 Merck Sharp & Dohme Corp. 2,2-difluorodioxolo a2a receptor antagonists
WO2016102672A2 (en) 2014-12-23 2016-06-30 Bergenbio As Pharmaceutically active compounds

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006132739A2 (en) 2005-05-03 2006-12-14 Smithkline Beecham Corporation Novel chemical compounds
WO2007116106A1 (es) 2006-04-12 2007-10-18 Palobiofarma, S.L. Nuevos compuestos como antagonistas de los receptores a1 de adenosina
WO2009080197A1 (de) 2007-12-20 2009-07-02 Bayer Schering Pharma Aktiengesellschaft Substituierte pyrrolo[2, 3-b]- und pyrazolo[3, 4-b] pyridine als adenosin rezeptor liganden
WO2011020193A1 (en) 2009-08-18 2011-02-24 Merck Frosst Canada Ltd. Renin inhibitors
WO2011084402A1 (en) 2009-12-21 2011-07-14 Merck Sharp & Dohme Corp. Tyrosine kinase inhibitors
CN102822150A (zh) * 2010-02-05 2012-12-12 赫普泰雅治疗有限公司 1,2,4-三嗪-4-胺衍生物
WO2011095625A1 (en) 2010-02-05 2011-08-11 Heptares Therapeutics Limited 1,2,4-triazine-4-amine derivatives
WO2011159302A1 (en) 2010-06-17 2011-12-22 Janssen Pharmaceutica Nv Arylindenopyrimidines for treating neurodegenerative and movement disorders while minimizing cardiac toxicity
WO2012009194A1 (en) 2010-07-12 2012-01-19 Merck Sharp & Dohme Corp. Tyrosine kinase inhibitors
WO2013014997A1 (ja) 2011-07-26 2013-01-31 株式会社Ihi 自己磁性金属サレン錯体化合物
WO2014101373A1 (en) 2012-12-28 2014-07-03 Merck Sharp & Dohme Corp. Heterobicyclo-substituted-[1,2,4]triazolo[1,5-c]quinazolin-5-amine compounds for treatment of central nervous system disorder
WO2015031221A1 (en) 2013-08-29 2015-03-05 Merck Sharp & Dohme Corp. 2,2-difluorodioxolo a2a receptor antagonists
WO2016102672A2 (en) 2014-12-23 2016-06-30 Bergenbio As Pharmaceutically active compounds

Non-Patent Citations (29)

* Cited by examiner, † Cited by third party
Title
"Parkinson's disease, Huntington's disease or Alzheimer's disease", TRENDS IN NEUROSCI., vol. 29, no. 11, 2006, pages 647 - 654
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, vol. 109, no. 3, 2011, pages 203 - 7
CANCER RES., vol. 66, no. 15, 1 August 2006 (2006-08-01), pages 7758 - 65
CANCER RES., vol. 76, no. 15, 1 August 2016 (2016-08-01), pages 4372 - 82
CHINESE CHEMICAL LETTERS, vol. 21, no. 1, 2010, pages 35 - 38
CHINESE PHARMACOLOGICAL BULLETIN, vol. 24, no. 5, 2008, pages 573 - 576
CLIN. NEUROPHARMACOL., vol. 33, 2010, pages 55 - 60
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 76, 2014, pages 341 - 343
EXPERT OPINION ON THERAPEUTIC PATENTS, vol. 17, 2007, pages 979 - 991
GESSI S ET AL., PHARMACOL. THER., vol. 117, no. 1, 2008, pages 123 - 140
J. NEUROSCI., vol. 30, no. 48, 2010, pages 16284 - 16292
JENNER P., J NEURO 1, vol. 24, no. 2, 2000, pages 1143 - 50
JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 52, no. 4, 2015, pages 1019 - 1025
JOURNAL OF MEDICINAL CHEMISTRY, vol. 54, no. 13, 2011, pages 4735 - 4751
JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 5, 2012, pages 1898 - 1903
JOURNAL OF MEDICINAL CHEMISTRY, vol. 58, no. 12, 2015, pages 5028 - 5037
JOURNAL OF ORGANIC CHEMISTRY, vol. 79, no. 11, 2014, pages 5379 - 5385
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 127, no. 1, 2005, pages 74 - 75
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 137, no. 26, 2015, pages 1593 - 1600
MOV. DISORDERS, vol. 25, no. 2, 2010, pages S305
ORGANIC LETTERS, vol. 11, no. 13, 2009, pages 2860 - 2863
PARKINSONISN RELAT. DISORD., vol. 16, no. 6, 2010, pages 423 - 426
SCIENCE OF SYNTHESIS, vol. 16, 2004, pages 573 - 749
See also references of EP3569596A4 *
SYNLETT, vol. 25, no. 6, 2014, pages 858 - 862
SYNTHESIS, vol. 45, no. 17, 2013, pages 2474 - 2480
TETRAHEDRON LETTERS, vol. 47, no. 37, 2006, pages 6635 - 6636
TETRAHEDRON LETTERS, vol. 56, no. 41, 2015, pages 5646 - 5650
TETRAHEDRON, vol. 59, no. 6, 2003, pages 813 - 819

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110655509B (zh) * 2018-06-29 2023-01-24 江苏恒瑞医药股份有限公司 2-胺基嘧啶类衍生物、其制备方法及其在医药上的应用
CN110655509A (zh) * 2018-06-29 2020-01-07 江苏恒瑞医药股份有限公司 2-胺基嘧啶类衍生物、其制备方法及其在医药上的应用
CN110684020A (zh) * 2018-07-05 2020-01-14 江苏恒瑞医药股份有限公司 2-胺基嘧啶类衍生物、其制备方法及其在医药上的应用
CN110684020B (zh) * 2018-07-05 2023-01-20 江苏恒瑞医药股份有限公司 2-胺基嘧啶类衍生物、其制备方法及其在医药上的应用
WO2020011220A1 (zh) * 2018-07-12 2020-01-16 江苏恒瑞医药股份有限公司 杂芳基类衍生物、其制备方法及其在医药上的应用
CN111094254A (zh) * 2018-07-12 2020-05-01 江苏恒瑞医药股份有限公司 杂芳基类衍生物、其制备方法及其在医药上的应用
CN111094254B (zh) * 2018-07-12 2022-07-26 江苏恒瑞医药股份有限公司 杂芳基类衍生物、其制备方法及其在医药上的应用
CN112955441A (zh) * 2018-10-24 2021-06-11 里德埃克斯普洛股份公司 官能化氨基三嗪
WO2020083957A1 (en) 2018-10-24 2020-04-30 Leadxpro Ag Functionalized aminotriazines
CN111377906A (zh) * 2018-12-28 2020-07-07 四川科伦博泰生物医药股份有限公司 取代的吡嗪化合物及其制备方法和用途
CN111377873A (zh) * 2018-12-28 2020-07-07 四川科伦博泰生物医药股份有限公司 氨基嘧啶化合物及其制备方法和用途
CN111377873B (zh) * 2018-12-28 2023-03-28 四川科伦博泰生物医药股份有限公司 氨基嘧啶化合物及其制备方法和用途
WO2020135195A1 (zh) 2018-12-28 2020-07-02 四川科伦博泰生物医药股份有限公司 氨基吡啶类化合物及其制备方法和用途
CN111377906B (zh) * 2018-12-28 2022-09-02 四川科伦博泰生物医药股份有限公司 取代的吡嗪化合物及其制备方法和用途
EP3904348A4 (en) * 2018-12-28 2022-10-19 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. AMINOPYRIDINE COMPOUND, METHOD FOR PREPARATION AND USE
WO2020146795A1 (en) 2019-01-11 2020-07-16 Omeros Corporation Methods and compositions for treating cancer
RU2780168C1 (ru) * 2019-02-18 2022-09-20 Корея Инститьют Оф Сайенс Энд Текнолоджи Новое производное пиридо [3,4-d] пиримидин-8-она, обладающее ингибирующей протеинкиназы активностью, и фармацевтическая композиция для предупреждения, облегчения или лечения рака, содержащее указанное выше
WO2020171499A1 (ko) * 2019-02-18 2020-08-27 한국과학기술연구원 단백질 키나아제 저해 활성을 갖는 신규한 피리도[3,4-d]피리미딘-8-온 유도체 및 이를 포함하는 암의 예방, 개선 또는 치료용 약학 조성물
AU2020225048B2 (en) * 2019-02-18 2023-02-23 Korea Institute Of Science And Technology Novel pyrido(3,4-d)pyrimidin-8-one derivative having protein kinase inhibitory activity, and pharmaceutical composition for preventing, alleviating, or treating cancer, comprising same
JP2022521901A (ja) * 2019-02-18 2022-04-13 コリア・インスティテュート・オブ・サイエンス・アンド・テクノロジー タンパク質キナーゼ阻害活性を有する新規なピリド［３，４－ｄ］ピリミジン－８－オン誘導体およびこれを含む癌の予防、改善または治療用薬学組成物
JP7262599B2 (ja) 2019-02-18 2023-04-21 コリア・インスティテュート・オブ・サイエンス・アンド・テクノロジー タンパク質キナーゼ阻害活性を有する新規なピリド［３，４－ｄ］ピリミジン－８－オン誘導体およびこれを含む癌の予防、改善または治療用薬学組成物
US11884647B2 (en) 2019-10-18 2024-01-30 The Regents Of The University Of California Compounds and methods for targeting pathogenic blood vessels
CN115697994A (zh) * 2020-06-10 2023-02-03 江苏恒瑞医药股份有限公司 稠合喹唑啉类衍生物、其制备方法及其在医药上的应用
WO2023144559A1 (en) 2022-01-28 2023-08-03 AdoRx Therapeutics Limited Antagonist of adenosine receptors

Also Published As

Publication number Publication date
US20190352278A1 (en) 2019-11-21
CN108884061A (zh) 2018-11-23
TW201827422A (zh) 2018-08-01
JP2020506885A (ja) 2020-03-05
CN108884061B (zh) 2021-11-16
US20210230138A1 (en) 2021-07-29
US11014904B2 (en) 2021-05-25
EP3569596A1 (en) 2019-11-20
EP3569596A4 (en) 2020-08-26

Similar Documents

Publication Publication Date Title
CN108884061B (zh) 1,2,4-三嗪-3-胺类衍生物、其制备方法及其在医药上的应用
TWI772386B (zh) 雜芳基并[4,3-c]嘧啶-5-胺類衍生物、其製備方法及其在醫藥上的使用
JP6856543B2 (ja) ブロモドメイン阻害剤
CN108558889B (zh) 布罗莫结构域抑制剂
CN102365277B (zh) Jun n-末端激酶抑制剂
KR102098606B1 (ko) 신규 아민 유도체 또는 그 염
WO2017084494A1 (zh) 苯并呋喃类衍生物、其制备方法及其在医药上的应用
WO2016169421A1 (zh) 咪唑并异吲哚类衍生物、其制备方法及其在医药上的应用
CA2977626C (en) Substituted pyrimidine compounds as phosphatidylinositol 3-kinase .delta. inhibitor and use thereof
CN105936635B (zh) 作为磷脂酰肌醇3-激酶δ抑制剂的化合物及其应用
TWI701251B (zh) 吡唑并[1,5-a][1,3,5]三-2-胺類衍生物、其製備方法及其在醫藥上的應用
JP3290664B2 (ja) ３環性ベンゾアゼピンおよびベンゾチアゼピン誘導体
CN111094254B (zh) 杂芳基类衍生物、其制备方法及其在医药上的应用
CN108467386B (zh) 稠杂芳基取代的1,2,4-三嗪-3-胺类衍生物、其制备方法及其在医药上的应用
WO2022089219A1 (zh) 芳基酰胺化合物、包含其的药物组合物及其制备方法和用途
WO2020156505A1 (zh) 2-氨基嘧啶类衍生物、其制备方法及其在医药上的应用
CN110684020B (zh) 2-胺基嘧啶类衍生物、其制备方法及其在医药上的应用
CN110655509B (zh) 2-胺基嘧啶类衍生物、其制备方法及其在医药上的应用
CN118005637A (zh) 一种稠合三环类parp1抑制剂、其制备方法及用途
WO2022022630A1 (zh) 氧杂氮杂螺环类衍生物、其制备方法及其在医药上的应用

Legal Events

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

Ref document number: 18739200

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2019534645

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2018739200

Country of ref document: EP

Effective date: 20190813