HK1261711A1 - 1,2,4-triazine-3-amine derivative, preparation method therefor, and use thereof in medicine - Google Patents

Description

1,2,4- triazine -3- amine derivant, preparation method and its application in medicine Technical field

The invention belongs to field of medicaments, it is related to 1,2,4- triazine -3- amine derivants shown in a kind of logical formula (I), preparation method and pharmaceutical composition as well as therapeutic agent containing the derivative, especially as A _2aThe purposes of receptor antagonist and preparation for treat by A _2aThe inhibition of receptor and the purposes in the drug of the improved patient's condition or illness.

Background technique

Adenosine is naturally occurring purine nucleosides, is the endogenous modulator of many physiological functions.It plays a significant role in the function point analysis of cardiovascular system, nervous centralis, respiratory system, kidney, fat and blood platelet.

The effect of adenosine is mediated by g protein coupled receptor family, is currently known the adenosine receptor at least there are four types of hypotype, is classified as A ₁、A _2a、A _2bAnd A ₃.Wherein A ₁And A ₃The activity of receptor inhibition enzyme adenyl cyclase, and A _2aAnd A _2bThus the activity of the receptor for stimulating enzyme adjusts cell middle ring AMP level, by these receptors, adenosine adjusts extensive physiological function.

A _2aReceptor (A _2aR) relatively broad in body distribution, it is mainly expressed in corpus straitum in central nervous system, also has expression in tissues such as periphery, the heart, liver, lung, kidneys.Several preclinical studies show adenosine A _2aFor receptor antagonist for treating neurodegenerative disease, mainly Parkinson's disease, Huntington disease or Alzheimer disease has surprising curative effect (Trends in Neurosci.2006,29 (11), 647-654；Expert Opinion on Therapeutic Patents, 2007,17,979-991 etc.).And it can be used for treating other relevant diseases of central nervous system (CNS) such as depression, hyperkinetic syndrome, sleep disturbance and anxiety disorder (Clin.Neuropharmacol.2010,33,55-60；J.Neurosci.2010,30(48),16284-16292；Parkinsonisn Relat.Disord.2010,16(6),423-426；And reference therein is offered: Mov.Disorders, 2010,25 (2), S305).Furthermore adenosine A _2aReceptor antagonist also have as neuroprotective agent treatment potentiality (l.2000 referring to Jenner P.J Neuro；24 7Supp12:1143-50).

Recently research have indicated that in many pathologic processes such as hypoxia-ischemia, inflammation, wound, transplanting, adenosine A _2aThe activation of receptor can play important immunoregulation effect, this may be with A _2aReceptor expression on the panimmunities cell such as T cell, B cell, mononuclear macrophage, neutrophil leucocyte is higher related.In addition, A _2aThe activation of receptor can promote body to generate immune tolerance, take part in the formation of tumour cell " immunologic escape " or " immunosupress " closely, create advantage for the occurrence and development of tumour.Lokshin and its colleague (Cancer Res.2006Aug1；66 (15): 7758-65) confirm natural killer cells on A _2aR activation can activate the killing of PKA suppression of natural killer cells against tumor cells by increasing cAMP.There are also studies have shown that activation A _2aThe activation of receptor can promote melanoma A375 cell, at the proliferation of the tumour cells such as fibroma NIH3T3 cell and pheochromocytoma PC12 cell, may be with A in T cell _2aThe activation of receptor can inhibit T cell activation, proliferation, to tumour cell stick and to tumour cell generate cytotoxic effect it is related；And A _2aThe mouse that acceptor gene knocks out can then reinforce CD8 ⁺The antitumor immunization of T cell, significantly inhibits the proliferation of tumour.Therefore, A _2aReceptor antagonist can be used for the treatment of tumour.Deepak Mittal et al. is the study found that A _2bThe metastases in mouse triple negative breast cancer model can be significantly reduced in acceptor inhibitor and the combination of chemotherapeutics or immunologic test point inhibitor；A in knock-out mice body or in human colon cancer cell line _2bReceptor significantly reduces the transfer of colon cancer and the Tumor formation of cell；Meanwhile research finds A _2bReceptor high expression in people's triple negative breast cancer cell line, and A _2bThe expression degree and tumour progression of receptor are closely related.These results show to inhibit A _2bReceptor can inhibit the transfer of tumour, therefore A _2bReceptor is expected to become a promising target (the Cancer Res.2016 Aug 1 for the treatment of tumour；76(15):4372-82).Study A _2aReceptor and A _2bReceptor double inhibitors, which also become one, is worth the direction explored.

Although there is the compound of significant biological activity can have therapeutic effect a variety of adenosine receptor subtypes, they can lead to undesired side effect.Such as adenosine A ₁Receptor is in tissue ischemia/anoxic, in maincenter, circulation, digestive system and skeletal muscle, cell in anoxic and hypoxemia stress environment when, the adenosine of extracellular aggregation passes through the A on activation after birth ₁The corresponding protection mechanism of receptor promoter, to increase tolerance of the cell to anoxic hypoxemia.A on immunocyte ₁Receptor can promote cellullar immunologic response in low-oxygen environment.In addition, A ₁Receptor can also reduce free fatty acid and triglycerides, participate in adjusting blood glucose.Therefore, A ₁The sustained blockade of receptor may cause the generation (Chinese Pharmacological Bulletin, 2008,24 (5), 573-576) of various adverse reactions in body tissue.As it has been reported that blocking A on animal model ₁Receptor will generate the adverse reactions such as anxiety, awakening (Basic&Clinical Pharmacology&Toxicology, 2011,109 (3), 203-7).Adenosine A ₃The adenosine that receptor (such as Gessi S et al., Pharmacol.Ther.117 (1), described in 2008,123-140) discharges during myocardial ischemia plays the protective effect of strength, A in heart ₃The sustained blockade of receptor can increase a possibility that complication as caused by ischemic heart disease that is any pre-existing or developing, the ischemic heart disease such as angina pectoris or heart failure.

Although currently, being developed as A there are many compound _2aThe antagonist of receptor is for treating many diseases, as described in WO2007116106, WO2009080197, WO2011159302, WO2011095625, WO2014101373, WO2015031221.But still the problems such as with the presence of low-solubility, light sensitivity, low activity, lower low selectivity and bioavailability.

WO2011095625 discloses 1,2,4- triazine -4- amine derivative shown in general formula (A1) and its in treatment by A ₁Receptor or A _2aThe inhibition of receptor and the purposes in the improved patient's condition or illness.

The patent application discloses a embodiment more than 200 in total, and middle ring A is that the embodiment of fused aromatic ring only has 5, and the data in the patent application are shown, when ring A is fused aromatic ring, to A _2aThe inhibitory activity of R is weaker (being shown in Table 1).

Embodiment in 1 patent application WO2011095625 of table

Wherein the ring A of embodiment 1 (lxxii) is naphthalene, we have now found that 5 upper derivatives for introducing nitrogen-atoms in naphthalene show surprising activity, to A _2aThe inhibitory activity of R is 30 to 1500 times or more of embodiment 1 (lxxii).So strong inhibitory activity can not be expected when reading WO2011095625.

Therefore the present invention provides a kind of adenosine A of new structural strong inhibitory activity _2aReceptor antagonist, while having the compound of this class formation to adenosine A _2bReceptor also has good inhibiting effect, to adenosine A ₁Receptor and adenosine A ₃The inhibiting effect of receptor is weak, to adenosine A _2aReceptor shows preferable selectivity.There is the compound of this class formation to show excellent tumor killing effect and medicine generation simultaneously and absorb activity.

Summary of the invention

The purpose of the present invention is to provide a kind of logical formula (I) compounds represented:

Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt,

Wherein:

Ring A is aryl or heteroaryl；

G ¹、G ²、G ³And G ⁴It is identical or different, and it is each independently selected from C, CH or N；

R ¹Selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-OR ⁵、-C(O)R ⁵、-S(O) _mR ⁵、NH ₂S(O) _mR ⁵、-NR ⁶R ⁷、S(O) _mNR ⁶R ⁷With-C (O) NR ⁶R ⁷；Wherein alkyl, alkoxy, halogenated alkyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl and heteroaryl；

R ²It is identical or different, and it is each independently selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-OR ⁵、-C(O)R ⁵、-S(O) _mR ⁵、NH ₂S(O) _mR ⁵、-NR ⁶R ⁷、S(O) _mNR ⁶R ⁷With-C (O) NR ⁶R ⁷；Wherein alkyl, alkoxy, halogenated alkyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl and heteroaryl；

R ³It is identical or different, and it is each independently selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, deuteroalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-OR ⁵、-C(O)R ⁵、-S(O) _mR ⁵、NH ₂S(O) _mR ⁵、-NR ⁶R ⁷、S(O) _mNR ⁶R ⁷With-C (O) NR ⁶R ⁷；Wherein alkyl, alkoxy, halogenated alkyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in halogen, D-atom, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl and heteroaryl；

R ⁴It is identical or different, and it is each independently selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-OR ⁵、-C(O)R ⁵、-S(O) _mR ⁵、NH ₂S(O) _mR ⁵、-NR ⁶R ⁷、S(O) _mNR ⁶R ⁷With-C (O) NR ⁶R ⁷；Wherein alkyl, alkoxy, halogenated alkyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl and heteroaryl；

R ⁵Selected from hydrogen atom, alkyl, halogenated alkyl, amino, hydroxyl, naphthenic base, heterocycle, aryl and heteroaryl；

R ⁶And R ⁷It is each independently selected from hydrogen atom, alkyl, halogenated alkyl, naphthenic base, heterocycle, aryl and heteroaryl；Wherein alkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

Alternatively, the R ⁶And R ⁷Heterocycle is formed together with the nitrogen-atoms being connected, wherein in the heterocycle containing 1~2 identical or different hetero atom selected from N, O and S, and the heterocycle is optionally replaced one or more substituent groups in alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

M is 0,1 or 2；

R is 0,1,2 or 3；

Q is 0,1 or 2；And

N is 0,1,2,3,4 or 5.

In a preferred embodiment of the present invention, it is general formula (Iaa) compound represented:

Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt,

Wherein

Ring A, G ¹、G ²、R ¹、R ³、R ⁴, r and n be as defined in logical formula (I).

In a preferred embodiment of the present invention, it is general formula (Ibb) compound represented:

Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt,

Wherein

G ¹And G ²It is identical or different, and it is each independently CR ^aOr N；

R ^aSelected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, deuteroalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl and heteroaryl；Wherein alkyl, alkoxy, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in halogen, D-atom, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl and heteroaryl；

R ^cSelected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl and heteroaryl；

Ring A, R ¹、R ⁴With n as defined in logical formula (I).

In a preferred embodiment of the present invention, the logical formula (I) compound represented is logical formula (II) compound represented:

Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt,

Its middle ring A, R ¹、R ³、R ⁴, r and n be as defined in logical formula (I).

In a preferred embodiment of the present invention, the logical formula (I) compound represented, wherein the ring A is selected from phenyl, pyridyl group, thienyl and furyl.

In a preferred embodiment of the present invention, the logical formula (I) compound represented is logical formula (III) compound represented:

Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt,

Wherein R ¹、R ³、R ⁴, r and n be as defined in logical formula (I).

In a preferred embodiment of the present invention, the logical formula (I) compound represented, wherein the R ¹Selected from hydrogen atom, halogen, alkyl, alkoxy, cyano, naphthenic base, halogenated alkyl, heterocycle and-C (O) NR ⁶R ⁷；R ⁶And R ⁷As defined in logical formula (I)；The preferred fluorine atom of the halogen, chlorine atom or bromine atom, the preferred methyl of the alkyl, ethyl, isopropyl or normal-butyl, the preferred methoxy or ethoxy of alkoxy, the preferred cyclopropyl of the naphthenic base, cyclopenta or cyclohexyl.

In a preferred embodiment of the present invention, the logical formula (I) compound represented, wherein the R ³It is identical or different, and it is each independently selected from hydrogen atom, halogen, alkyl, halogenated alkyl, deuteroalkyl, alkoxy, cyano, naphthenic base heterocycle, wherein the alkyl and alkoxy are each independently optionally replaced one or more substituent groups in halogen, D-atom, hydroxyl, cyano, amino, nitro, naphthenic base and heterocycle；The preferred fluorine atom of the halogen, chlorine atom or bromine atom, the preferred methyl of the alkyl, ethyl, isopropyl or normal-butyl, the preferred methoxy or ethoxy of alkoxy, the preferred piperidyl of the heterocycle, piperazinyl, morpholinyl or THP trtrahydropyranyl.

In a preferred embodiment of the present invention, the logical formula (I) compound represented, wherein the R ⁴It is identical or different, and it is each independently selected from hydrogen atom, alkyl and halogen.

Typical compound of the invention includes but is not limited to:

Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt.

Another aspect of the present invention relates to a kind of methods for preparing logical formula (I) compound represented, this method comprises:

Coupling reaction occurs for the compound of general formula (I-A) and the compound of general formula (I-B), obtains the compound of logical formula (I),

Wherein:

X is halogen；

M is

Ring A, G ¹~G ⁴、R ¹~R ⁴, r, q and n be as defined in logical formula (I).

Another aspect of the present invention relates to a kind of methods for preparing general formula (Iaa) compound represented, this method comprises:

Coupling reaction occurs for the compound of general formula (Iaa-1) and the compound of general formula (I-B), obtains the compound of general formula (Iaa),

Wherein:

X is halogen；

M is

Ring A, G ¹、G ²、R ¹、R ³、R ⁴, r and n be as defined in logical formula (I).

Another aspect of the present invention relates to a kind of methods for preparing logical formula (II) compound represented, this method comprises:

Coupling reaction occurs for the compound of general formula (II-A) and the compound of general formula (I-B), obtains the compound of logical formula (II),

Wherein:

X is halogen；

M is

Ring A, R ¹、R ³、R ⁴, r and n be as defined in logical formula (I).

Another aspect of the present invention relates to a kind of methods for preparing logical formula (III) compound represented, this method comprises:

Coupling reaction occurs for the compound of general formula (II-A) and the compound of general formula (III-B), obtains the compound of logical formula (III),

Wherein:

X is halogen；

M is

R ¹、R ³、R ⁴, r and n be as defined in logical formula (I).

Another aspect of the present invention relates to a kind of pharmaceutical compositions, the present invention that described pharmaceutical composition contains therapeutically effective amount leads to or mixtures thereof formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer form, or its officinal salt and one or more pharmaceutically acceptable carriers, diluent or excipient.

The invention further relates to or mixtures thereof logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer forms, or its officinal salt, or comprising its pharmaceutical composition preparation for treat by A _2aReceptor inhibits and the purposes in the drug of the improved patient's condition or illness.

The invention further relates to or mixtures thereof logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer forms, or its officinal salt, or comprising its pharmaceutical composition preparation for treat by A _2bReceptor inhibits and the purposes in the drug of the improved patient's condition or illness.

In text of the invention, by A _2aReceptor or to A _2bReceptor inhibits and the improved patient's condition or illness are selected from the outer syndrome of cancer, depression, cognitive function illness, Neurodegenerative conditions (Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic lateral sclerosis etc.), attention associated disease, cone, abnormal movement disorders, cirrhosis, liver fibrosis, fatty liver, fibrosis of skin, sleep disturbance, apoplexy, cerebral injury, neuroinflamation and Addictive Behaviors；Preferably cancer, the cancer is selected from melanoma, brain tumor (has pernicious astroglia and the glioma of Oligodendroglioma ingredient etc.), the cancer of the esophagus, gastric cancer, liver cancer, cancer of pancreas, colorectal cancer (colon cancer, carcinoma of the rectum etc.), lung cancer (non-small cell lung cancer, Small Cell Lung Cancer, primary or metastatic carcinoma squamosum etc.), kidney, breast cancer, oophoroma, prostate cancer, cutaneum carcinoma, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, orchioncus, uterine cancer (cervix cancer, carcinoma of endometrium etc.), H/N tumors (cancer of maxilla, laryngocarcinoma, pharynx cancer, tongue cancer, cancer etc. in mouthful), Huppert's disease, malignant lymphoma (reticulosarcoma, lymphosarcoma, Hodgkin lymphoma etc.), polycythemia vera, (acute grain is thin for leukaemia Born of the same parents' leukaemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia etc.), thyroid tumors, tumor of ureter, tumor of bladder, gallbladder cancer, cholangiocarcinoma, chorioepithelioma and pediatric tumors (especially because of familial sarcoma, Willms sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testis cancer, neuroblastoma, retinoblastoma, hepatoblastoma, nephroblastoma etc.) etc.；More preferably lung cancer.

The invention further relates to logical formula (I) compound represented or its tautomers, mesomer, racemic modification, enantiomter, or mixtures thereof diastereoisomer form, or its officinal salt, or comprising its pharmaceutical composition preparation treating cancer, depression, cognitive function illness, Neurodegenerative conditions (Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic lateral sclerosis etc.), attention associated disease, the outer syndrome of cone, abnormal movement disorders, cirrhosis, liver fibrosis, fatty liver, fibrosis of skin, sleep disturbance, apoplexy, cerebral injury, neuroinflamation and Addictive Behaviors, it is preferred that the purposes in the drug of cancer.

The invention further relates to logical formula (I) compound represented or its tautomers, mesomer, racemic modification, enantiomter, or mixtures thereof diastereoisomer form, or its officinal salt, or comprising its pharmaceutical composition preparation treating cancer drug in purposes, wherein the cancer is selected from melanoma, brain tumor (has pernicious astroglia and the glioma of Oligodendroglioma ingredient etc.), the cancer of the esophagus, gastric cancer, liver cancer, cancer of pancreas, colorectal cancer (colon cancer, carcinoma of the rectum etc.), lung cancer (non-small cell lung cancer, Small Cell Lung Cancer, primary or metastatic carcinoma squamosum etc.), kidney, breast cancer, oophoroma, prostate cancer, cutaneum carcinoma, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, orchioncus, uterine cancer (cervix cancer , carcinoma of endometrium etc.), H/N tumors (cancer of maxilla, laryngocarcinoma, pharynx cancer, tongue cancer, cancer etc. in mouthful), Huppert's disease, malignant lymphoma (reticulosarcoma, lymphosarcoma, Hodgkin lymphoma etc.), polycythemia vera, leukaemia (acute myeloblastic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia etc.), thyroid tumors, tumor of ureter, tumor of bladder, gallbladder cancer, cholangiocarcinoma, chorioepithelioma and pediatric tumors are (especially because of familial sarcoma, Willms sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testis cancer, neuroblastoma, retinoblastoma, hepatoblastoma, nephroblastoma etc.) etc..

The invention further relates to or mixtures thereof logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer forms, or its officinal salt, or lung cancer, the preferably purposes in the drug of non-small cell lung cancer are treated in preparation comprising its pharmaceutical composition.

The invention further relates to or mixtures thereof logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer forms, or its officinal salt, or comprising its pharmaceutical composition preparation for inhibiting A _2aPurposes in the drug of receptor.

The invention further relates to or mixtures thereof logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer forms, or its officinal salt, or comprising its pharmaceutical composition preparation for inhibiting A _2bPurposes in the drug of receptor.

The invention further relates to a kind of inhibition A _2aThe method of receptor, it includes giving or mixtures thereof logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, the diastereoisomer of required bacterium form, or its officinal salt, or the pharmaceutical composition comprising it.

The invention further relates to a kind of inhibition A _2bThe method of receptor, it includes giving or mixtures thereof logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, the diastereoisomer of required bacterium form, or its officinal salt, or the pharmaceutical composition comprising it.

The invention further relates to a kind of treatments by A _2aReceptor inhibits and the method for the improved patient's condition or illness, it includes giving or mixtures thereof logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, the diastereoisomer of required bacterium form, or its officinal salt, or the pharmaceutical composition comprising it.

The invention further relates to a kind of treatments by A _2bReceptor inhibits and the method for the improved patient's condition or illness, it includes giving or mixtures thereof logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, the diastereoisomer of required bacterium form, or its officinal salt, or the pharmaceutical composition comprising it.

The present invention relates to a kind for the treatment of cancers, depression, cognitive function illness, Neurodegenerative conditions (Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic lateral sclerosis etc.), attention associated disease, the outer syndrome of cone, abnormal movement disorders, cirrhosis, liver fibrosis, fatty liver, fibrosis of skin, sleep disturbance, apoplexy, cerebral injury, neuroinflamation and Addictive Behaviors, it is preferred that the method for cancer, it includes the logical formula (I) compound represented or its tautomer for giving required bacterium, mesomer, racemic modification, enantiomter, or mixtures thereof diastereoisomer form, or its officinal salt, or the pharmaceutical composition comprising it.

The invention further relates to a kind of methods for the treatment of cancer, it includes the logical formula (I) compound represented or its tautomer for giving required bacterium, mesomer, racemic modification, enantiomter, or mixtures thereof diastereoisomer form, or its officinal salt, or the pharmaceutical composition comprising it, wherein the cancer is selected from melanoma, brain tumor (has pernicious astroglia and the glioma of Oligodendroglioma ingredient etc.), the cancer of the esophagus, gastric cancer, liver cancer, cancer of pancreas, colorectal cancer (colon cancer, carcinoma of the rectum etc.), lung cancer (non-small cell lung cancer, Small Cell Lung Cancer, primary or metastatic carcinoma squamosum etc.), kidney, breast cancer, oophoroma, prostate cancer, cutaneum carcinoma, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testis Tumour, uterine cancer (cervix cancer, carcinoma of endometrium etc.), H/N tumors (cancer of maxilla, laryngocarcinoma, pharynx cancer, tongue cancer, cancer etc. in mouthful), Huppert's disease, malignant lymphoma (reticulosarcoma, lymphosarcoma, Hodgkin lymphoma etc.), polycythemia vera, leukaemia (acute myeloblastic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia etc.), thyroid tumors, tumor of ureter, tumor of bladder, gallbladder cancer, cholangiocarcinoma, chorioepithelioma and pediatric tumors are (especially because of familial sarcoma, Willms sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testis cancer, neuroblastoma, retinoblastoma, hepatoblastoma, nephroblastoma etc.) etc..

The invention further relates to a kind of logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its officinal salt or comprising its pharmaceutical composition, be used as drug.

The invention further relates to or mixtures thereof logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer form or its officinal salts, or comprising its pharmaceutical composition, are used as A _2aReceptor antagonist.

The invention further relates to or mixtures thereof logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer form or its officinal salts, or comprising its pharmaceutical composition, are used as A _2bReceptor antagonist.

The invention further relates to or mixtures thereof logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer forms, or its officinal salt, or the pharmaceutical composition comprising it, it treats by A _2aReceptor inhibits and the improved patient's condition or illness.

The invention further relates to or mixtures thereof logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer forms, or its officinal salt, or the pharmaceutical composition comprising it, it treats by A _2bReceptor inhibits and the improved patient's condition or illness.

The invention further relates to logical formula (I) compound represented or its tautomers, mesomer, racemic modification, enantiomter, or mixtures thereof diastereoisomer form, or its officinal salt, or the pharmaceutical composition comprising it, it is used for treating cancer, depression, cognitive function illness, Neurodegenerative conditions (Parkinson's disease, Huntington's disease, Alzheimer's disease or amyotrophic lateral sclerosis etc.), attention associated disease, the outer syndrome of cone, abnormal movement disorders, cirrhosis, liver fibrosis, fatty liver, fibrosis of skin, sleep disturbance, apoplexy, cerebral injury, neuroinflamation and Addictive Behaviors, it is preferred that cancer.

The invention further relates to logical formula (I) compound represented or its tautomers, mesomer, racemic modification, enantiomter, or mixtures thereof diastereoisomer form, or its officinal salt, or the pharmaceutical composition comprising it, it is used for treating cancer, wherein the cancer is selected from melanoma, brain tumor (has pernicious astroglia and the glioma of Oligodendroglioma ingredient etc.), the cancer of the esophagus, gastric cancer, liver cancer, cancer of pancreas, colorectal cancer (colon cancer, carcinoma of the rectum etc.), lung cancer (non-small cell lung cancer, Small Cell Lung Cancer, primary or metastatic carcinoma squamosum etc.), kidney, breast cancer, oophoroma, prostate cancer, cutaneum carcinoma, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, orchioncus, uterine cancer (cervix cancer, carcinoma of endometrium Deng), H/N tumors (cancer of maxilla, laryngocarcinoma, pharynx cancer, tongue cancer, cancer etc. in mouthful), Huppert's disease, malignant lymphoma (reticulosarcoma, lymphosarcoma, Hodgkin lymphoma etc.), polycythemia vera, leukaemia (acute myeloblastic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia etc.), thyroid tumors, tumor of ureter, tumor of bladder, gallbladder cancer, cholangiocarcinoma, chorioepithelioma and pediatric tumors are (especially because of familial sarcoma, Willms sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testis cancer, neuroblastoma, retinoblastoma, hepatoblastoma, nephroblastoma etc.) etc..

Pharmaceutical composition containing active constituent, which can be, is suitable for oral form, such as tablet, dragee, pastille, water or oil suspension, dispersible powder or particle, lotion, hard or soft capsule or syrup or elixir.Orally administered composition can be prepared according to any known method for preparing Pharmaceutical composition in this field, such composition can contain one or more ingredients selected from the following: sweetener, corrigent, colorant and preservative, to provide pleasing and palatable pharmaceutical formulation.Tablet contains active constituent and the suitable nontoxic pharmaceutical excipient for preparing tablet for mixing.

Water slurry contains active material and the suitable excipient for preparing water slurry for mixing.Aqueous suspension can also contain one or more preservatives such as ethylparaben or nipalgin n-propyl, one or more colorants, one or more corrigents and one or more sweeteners.

Oil suspension can be formulated by being suspended in active constituent in vegetable oil.Oil suspension can contain thickener.Above-mentioned sweetener and corrigent can be added, to provide palatable preparation.

The dispersible powder for being suitable for preparing aqueous suspension and particle can be made to provide active constituent and for mixed dispersing agent or wetting agent, suspending agent or one or more preservatives by the way that water is added.Suitable dispersing agent or wetting agent and suspending agent can illustrate above-mentioned example.Other excipient such as sweetener, corrigent and colorant can also be added.These compositions are saved by the way that antioxidant such as ascorbic acid is added.

Pharmaceutical composition of the invention is also possible to the form of oil in water emulsion.

Pharmaceutical composition can be sterile injectable aqueous form.The acceptable solvent or solvent that can be used have water, ringer's solution and isotonic sodium chlorrde solution.Aseptic injection preparation can be the aseptic injection oil-in-water microemulsion that wherein active constituent is dissolved in oily phase.Such as active constituent is dissolved in the mixture of soybean oil and lecithin.Then oil solution is added to processing in the mixture of water and glycerol form micro emulsion.Can be by a large amount of injections in part, it will be in injection or the blood flow of micro emulsion injection patient.Alternatively, preferably giving solution and micro emulsion in the way of it can keep the compounds of this invention constant circulating concentration.To keep this constant density, continuous intravenous delivery device can be used.The example of this device is Deltec CADD-PLUS.TM.5400 type Iv pump.

Pharmaceutical composition can be for intramuscular and the aseptic injection water of subcutaneous administration or the form of oil suspension.Can be by known technology, the dispersing agent or wetting agent and suspending agent for being suitable for those described above prepare the suspension.Aseptic injection preparation is also possible to the aseptic injectable solution or suspension prepared in the acceptable non-toxic diluent of parenteral or solvent.Furthermore, it is convenient to use sterile fixed oil as solvent or suspension media.

The compounds of this invention can be given by the suppository form for rectally.Can by by drug be at normal temperatures solid but be in the rectum liquid, thus can dissolve in the rectum and discharge the suitable nonirritant excipient mixing of drug to prepare these pharmaceutical compositions.Substance of this kind includes the mixture of the aliphatic ester of cocoa butter, glycerin gelatine, hydrogenated vegetable oil, the polyethylene glycol of various molecular weight and polyethylene glycol.

As known to those skilled in the art, the dosage of drug depends on many factors, including but be not limited to following factor: the activity of particular compound used, the age of patient, the weight of patient, the health status of patient, the row quilt of patient, the diet of patient, administration time, administration mode, the rate of excretion, the combination of drug etc.；In addition, optimal therapeutic modality can be verified such as mode, the consumption per day of general formula compound (I) or the type of pharmaceutical salt for the treatment of according to traditional therapeutic scheme.

Detailed description of the invention

Unless stated to the contrary, the term used in the specification and in the claims has following meanings.

Term " alkyl " refers to saturated aliphatic hydrocarbons group, is the linear chain or branched chain group comprising 1 to 20 carbon atom, preferably comprises the alkyl of 1 to 12 carbon atom, the more preferably alkyl containing 1 to 6 carbon atom.Non-limiting example includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1, 1- dimethyl propyl, 1, 2- dimethyl propyl, 2, 2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1, 1, 2- thmethylpropyl, 1, 1- dimethylbutyl, 1, 2- dimethylbutyl, 2, 2- dimethylbutyl, 1, 3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2, 3- dimethylbutyl, n-heptyl, 2- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2, 3- dimethyl amyl group, 2, 4- dimethyl amyl group, 2, 2- bis- Methyl amyl, 3, 3- dimethyl amyl group, 2- ethylpentyl, 3- ethylpentyl, n-octyl, 2, 3- dimethylhexanyl, 2, 4- dimethylhexanyl, 2, 5- dimethylhexanyl, 2, 2- dimethylhexanyl, 3, 3- dimethylhexanyl, 4, 4- dimethylhexanyl, 2- ethylhexyl, 3- ethylhexyl, 4- ethylhexyl, 2- methyl -2- ethylpentyl, 2- methyl -3- ethylpentyl, n-nonyl, 2- methyl -2- ethylhexyl, 2- methyl -3- ethylhexyl, 2, 2- diethyl amyl group, positive decyl, 3, 3- diethylhexyl, 2, 2- diethylhexyl, and its various branched isomers etc..Low alkyl group more preferably containing 1 to 6 carbon atom, non-limiting embodiment includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1, 1- dimethyl propyl, 1, 2- dimethyl propyl, 2, 2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1, 1, 2- thmethylpropyl, 1, 1- dimethylbutyl, 1, 2- dimethylbutyl, 2, 2- dimethylbutyl, 1, 3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2, 3- dimethylbutyl etc..Alkyl can be substituted or non-substituted, when substituted, substituent group can be substituted on any workable tie point, the substituent group be preferably independently optionally chosen from H atom, D atom, halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl, replaced one or more substituent groups in heteroaryl.

Term " alkoxy " refers to-O- (alkyl) and-O- (non-substituted naphthenic base), and wherein alkyl is as defined above.The non-limiting example of alkoxy includes: methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy.Alkoxy can be optionally replacing or non-substituted, when substituted, substituent group is preferably one or more following groups, independently selected from replaced one or more substituent groups in H atom, D atom, halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl, heteroaryl.

Term " naphthenic base " refers to that the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, cycloalkyl ring include 3 to 20 carbon atoms, preferably comprises 3 to 12 carbon atoms, preferably comprises 3 to 10 carbon atoms, more preferably includes 3 to 6 carbon atoms.The non-limiting example of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc.；Polycyclic naphthene base includes the naphthenic base of loop coil, condensed ring and bridged ring.Naphthenic base can be substituted or non-substituted, when substituted, substituent group can be substituted on any workable tie point, the substituent group be preferably independently optionally chosen from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl, replaced one or more substituent groups in heteroaryl.

Term " heterocycle " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, and it includes 3 to 20 annular atoms, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O) _mThe hetero atom of (wherein m is integer 0 to 2), but do not include the loop section of-O-O- ,-O-S- or-S-S-, remaining annular atom is carbon.3 to 12 annular atoms are preferably comprised, wherein 1~4 is hetero atom；It include more preferably 3 to 10 annular atoms, wherein 1-4 is hetero atom；It more preferably include 5 to 6 annular atoms；Wherein 1-3 are hetero atoms.The non-limiting example of monocyclic heterocycles base includes pyrrolidinyl, THP trtrahydropyranyl, 1,2.3.6- tetrahydro pyridyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, high piperazine base etc..Multiring heterocyclic includes the heterocycle of loop coil, condensed ring and bridged ring.

The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein the ring to link together with precursor structure is heterocycle, non-limiting example includes:

Heterocycle can be substituted or non-substituted, when substituted, substituent group can be substituted on any workable tie point, the substituent group be preferably independently optionally chosen from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl, replaced one or more substituent groups in heteroaryl.

Term " aryl " refers to 6 to 14 yuan of full carbon monocycles or fused polycycle (rings of namely shared adjacent carbon atoms pair) group, it is polycyclic (i.e. its ring for the having phase adjacency pair carbon atom) group of the pi-electron system with conjugation, preferably 6 to 10 yuan, such as phenyl and naphthalene.The aryl rings can be condensed on heteroaryl, heterocycle or cycloalkyl ring, wherein the ring to link together with precursor structure is aryl rings, non-limiting example includes:

Aryl can be substituted or non-substituted, when substituted, substituent group can be substituted on any workable tie point, the substituent group be preferably independently optionally chosen from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl, replaced one or more substituent groups in heteroaryl.

Term " heteroaryl " refers to the heteroaromatic system comprising 1 to 4 hetero atom, 5 to 14 annular atoms, and wherein hetero atom is selected from oxygen, sulphur and nitrogen.Heteroaryl is preferably 5 to 10 yuan, more preferably 5- or 6-membered, such as furyl, thienyl, pyridyl group, pyrrole radicals, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, pyrazolyl, tetrazole radical etc..The heteroaryl ring can be condensed on aryl, heterocycle or cycloalkyl ring, wherein the ring to link together with precursor structure is heteroaryl ring, non-limiting example includes:

Heteroaryl can be substituted or non-substituted, when substituted, substituent group can be substituted on any workable tie point, the substituent group be preferably independently optionally chosen from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl, replaced one or more substituent groups in heteroaryl.

Term " halogenated alkyl " refers to that alkyl is replaced by one or more halogens, and wherein alkyl is as defined above.

Term " deuteroalkyl " refers to that alkyl is replaced by one or more D-atoms, and wherein alkyl is as defined above.

Term " hydroxyl " refers to-OH group.

Term " hydroxyalkyl " refers to the alkyl being optionally substituted by a hydroxyl group, and wherein alkyl is as defined above.

Term " halogen " refers to fluorine, chlorine, bromine or iodine.

Term " hydroxyl " refers to-OH group.

Term " amino " refers to-NH ₂。

Term " cyano " refers to-CN.

Term " nitro " refers to-NO ₂。

Term " carbonyl " refers to C=O.

Term " carboxyl " refers to-C (O) OH.

Term " carboxylate " refers to-C (O) O (alkyl) or-C (O) O (naphthenic base), and wherein alkyl, naphthenic base are as defined above.

Term " carboxylic acid halides " refers to the compound containing-C (O)-halogen group.

The invention also includes the formula of various deuterated forms (I) compounds.The each available hydrogen atom connecting with carbon atom can be replaced independently by D-atom.Those skilled in the art can be with reference to formula (I) compound of pertinent literature synthesis deuterated form.Commercially available deuterated initial substance can be used in formula (I) compound for preparing deuterated forms, or routine techniques can be used to synthesize using deuterated reagent for they, deuterated reagent includes but is not limited to deuterated borine, three deuterated borine tetrahydrofuran solutions, deuterated lithium aluminium hydride, deuterated iodoethane and deuterated iodomethane etc..

" optional " or " optionally " mean event or environment described later can with but need not occur, which includes that the event or environment occur or not spot occasion.For example, mean " optionally by alkyl-substituted heterocyclic group " alkyl can with but necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.

" substituted " refers to that one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom are replaced by the substituent group of respective number independently of one another.Self-evident, substituent group is only in their possible chemistry position, and those skilled in the art can determine in the case where not paying and excessively making great efforts and (pass through experiment or theory) possible or impossible substitution.It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key.

" pharmaceutical composition " indicates mixture and other components such as physiology/pharmaceutical carrier and excipient containing one or more compounds described herein or its physiologically/pharmaceutical salt or pro-drug and other chemical constituents.The purpose of pharmaceutical composition is the administration promoted to organism, plays bioactivity in turn conducive to the absorption of active constituent.

" officinal salt " refers to the salt of the compounds of this invention, has safety and validity when this kind of salt is used in the mammalian body, and have due bioactivity.

The synthetic method of the compounds of this invention

In order to complete the purpose of the present invention, the present invention adopts the following technical scheme:

Scheme one

The present invention lead to formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt preparation method, comprising the following steps:

The first step, in the presence of a catalyst under alkaline condition, reaction obtains the compound of general formula (I-A) to the compound and boric acid or boric acid ester compound of general formula (A)；

In the presence of a catalyst under alkaline condition, reaction obtains the compound of logical formula (I) to the compound of second step, the compound of general formula (I-A) and general formula (I-B)；

The reagent for providing alkaline condition includes organic base and inorganic base, the organic bases include but is not limited to triethylamine, N, N- diisopropylethylamine, n-BuLi, lithium diisopropylamine, lithium hexamethyldisilazide, potassium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and n-butanol sodium, the inorganic base include but is 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 chloride, palladium acetate, bis- (two Asia Benzyl benzylacetones) palladiums, chlorine (2- dicyclohexyl phosphino- -2', 4', 6'- triisopropyl -1,1'- xenyl) [2- (2'- amino -1,1'- biphenyl)] palladium, [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride, 1,1 '-bis- (dibenzyl phosphorus) dichloro diamyl iron palladiums or tris(dibenzylideneacetone) dipalladium, preferably [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride；

Above-mentioned reaction preferably carries out in a solvent, solvent for use includes but is not limited to: acetic acid, methanol, ethyl alcohol, n-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4- dioxane, glycol dimethyl ether, water or n,N-Dimethylformamide and its mixture；

Wherein:

X is halogen；

M is

Ring A, G ¹~G ⁴、R ¹~R ⁴, r, q and n be as defined in logical formula (I).

Scheme two

General formula (Iaa) compound represented of the present invention or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt preparation method, comprising the following steps:

The first step, in the presence of a catalyst, under alkaline condition, reaction obtains the compound of general formula (Iaa-1) to the compound and boric acid or boric acid ester compound of general formula (Iaa-2)；

In the presence of a catalyst under alkaline condition, reaction obtains the compound of general formula (Iaa) to the compound of second step, the compound of general formula (Iaa-1) and general formula (I-B)；

Wherein:

X is halogen；

M is

Ring A, G ¹、G ²、R ¹、R ³、R ⁴, r and n be as defined in logical formula (I).

The reagent for providing alkaline condition includes organic base and inorganic base, the organic bases include but is not limited to triethylamine, N, N- diisopropylethylamine, n-BuLi, lithium diisopropylamine, lithium hexamethyldisilazide, potassium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and n-butanol sodium, the inorganic base include but is 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 chloride, palladium acetate, bis- (two Asia Benzyl benzylacetones) palladiums, chlorine (2- dicyclohexyl phosphino- -2', 4', 6'- triisopropyl -1,1'- xenyl) [2- (2'- amino -1,1'- biphenyl)] palladium, [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride, 1,1 '-bis- (dibenzyl phosphorus) dichloro diamyl iron palladiums or tris(dibenzylideneacetone) dipalladium, preferably [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride.

Above-mentioned reaction preferably carries out in a solvent, solvent for use includes but is not limited to: acetic acid, methanol, ethyl alcohol, n-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4- dioxane, glycol dimethyl ether, water or n,N-Dimethylformamide and its mixture.

Scheme three

General formula (Ibb) compound represented of the present invention or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt preparation method, comprising the following steps:

The first step, in the presence of a catalyst, under alkaline condition, reaction obtains the compound of general formula (Ibb-1) to the compound and boric acid or boric acid ester compound of general formula (Ibb-2)；

In the presence of a catalyst under alkaline condition, reaction obtains the compound of general formula (Ibb) to the compound of second step, the compound of general formula (Ibb-1) and general formula (I-B)；

Wherein:

X is halogen；

M is

Ring A, G ¹、G ²、R ¹、R ³、R ⁴, r and n be as defined in logical formula (I).

The reagent for providing alkaline condition includes organic base and inorganic base, the organic bases include but is not limited to triethylamine, N, N- diisopropylethylamine, n-BuLi, lithium diisopropylamine, lithium hexamethyldisilazide, potassium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and n-butanol sodium, the inorganic base include but is 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 chloride, palladium acetate, bis- (two Asia Benzyl benzylacetones) palladiums, chlorine (2- dicyclohexyl phosphino- -2', 4', 6'- triisopropyl -1,1'- xenyl) [2- (2'- amino -1,1'- biphenyl)] palladium, [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride, 1,1 '-bis- (dibenzyl phosphorus) dichloro diamyl iron palladiums or tris(dibenzylideneacetone) dipalladium, preferably [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride.

Above-mentioned reaction preferably carries out in a solvent, solvent for use includes but is not limited to: acetic acid, methanol, ethyl alcohol, n-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4- dioxane, glycol dimethyl ether, water or n,N-Dimethylformamide and its mixture.

Scheme four

The present invention lead to formula (II) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt preparation method, comprising the following steps:

The first step, in the presence of a catalyst under alkaline condition, reaction obtains the compound of general formula (II-A) to the compound and boric acid or boric acid ester compound of general formula (B)；

In the presence of a catalyst under alkaline condition, reaction obtains the compound of logical formula (II) to the compound of second step, the compound of general formula (II-A) and general formula (I-B)；

The reagent for providing alkaline condition includes organic base and inorganic base, the organic bases include but is not limited to triethylamine, N, N- diisopropylethylamine, n-BuLi, lithium diisopropylamine, lithium hexamethyldisilazide, potassium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and n-butanol sodium, the inorganic base include but is 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 chloride, palladium acetate, bis- (two Asia Benzyl benzylacetones) palladiums, chlorine (2- dicyclohexyl phosphino- -2', 4', 6'- triisopropyl -1,1'- xenyl) [2- (2'- amino -1,1'- biphenyl)] palladium, [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride, 1,1 '-bis- (dibenzyl phosphorus) dichloro diamyl iron palladiums or tris(dibenzylideneacetone) dipalladium, preferably [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride；

Above-mentioned reaction preferably carries out in a solvent, solvent for use includes but is not limited to: acetic acid, methanol, ethyl alcohol, n-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4- dioxane, glycol dimethyl ether, water or n,N-Dimethylformamide and its mixture；

Wherein:

X is halogen；

M is

Ring A, R ¹、R ³、R ⁴, r and n be as defined in logical formula (I).

Scheme five

The present invention lead to formula (III) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt preparation method, comprising the following steps:

The first step, in the presence of a catalyst under alkaline condition, reaction obtains the compound of general formula (II-A) to the compound and boric acid or boric acid ester compound of general formula (B)；

In the presence of a catalyst under alkaline condition, reaction obtains the compound of logical formula (III) to the compound of second step, the compound of general formula (II-A) and general formula (III-B)；

The reagent for providing alkaline condition includes organic base and inorganic base, the organic bases include but is not limited to triethylamine, N, N- diisopropylethylamine, n-BuLi, lithium diisopropylamine, lithium hexamethyldisilazide, potassium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and n-butanol sodium, the inorganic base include but is 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 chloride, palladium acetate, bis- (two Asia Benzyl benzylacetones) palladiums, chlorine (2- dicyclohexyl phosphino- -2', 4', 6'- triisopropyl -1,1'- xenyl) [2- (2'- amino -1,1'- biphenyl)] palladium, [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride, 1,1 '-bis- (dibenzyl phosphorus) dichloro diamyl iron palladiums or tris(dibenzylideneacetone) dipalladium, preferably [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride；

Above-mentioned reaction preferably carries out in a solvent, solvent for use includes but is not limited to: acetic acid, methanol, ethyl alcohol, n-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4- dioxane, glycol dimethyl ether, water or n,N-Dimethylformamide and its mixture；

Wherein:

X is halogen；

M is

R ¹、R ³、R ⁴, r and n be as defined in logical formula (I).

Specific embodiment

With reference to embodiments for further describing the present invention, but these embodiments not limit the scope of the present invention.

Embodiment

The structure of compound is by nuclear magnetic resonance (NMR) or/and mass spectrum (MS) come what is determined.NMR is displaced (δ) with 10 ^-6(ppm) unit provides.The measurement of NMR is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometer, and measurement solvent is deuterated dimethyl sulfoxide (DMSO-d ₆), deuterated chloroform (CDCl ₃), deuterated methanol (CD ₃OD), inside it is designated as tetramethylsilane (TMS).

The measurement of MS is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

High performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.

Chiral HPLC measurement uses Agilent 1260DAD high performance liquid chromatograph.

Efficient liquid phase preparation uses Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 preparative scale chromatography instrument.

Chirality preparation uses Shimadzu LC-20AP preparative scale chromatography instrument.

The quick preparing instrument of CombiFlash uses Combiflash Rf200 (TELEDYNE ISCO).

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and the specification that the silica gel plate that thin-layered chromatography (TLC) uses uses is 0.15mm~0.2mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm.

It is carrier that silica gel column chromatography, which generally uses 200~300 mesh silica gel of Yantai Huanghai Sea silica gel,.

Chiral preparatory column chromatography uses Prep Star SD-1 (Varian Instruments Inc.) or SFC-multigram (Berger Instruments Inc.).

Kinases average inhibition and IC ₅₀The measurement of value is with NovoStar microplate reader (German BMG company).

Known starting material of the invention can be used or be synthesized according to methods known in the art, or it is commercially available from ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, splendid remote chemistry scientific and technological (Accela ChemBio Inc) reach the companies such as auspicious chemicals.

Without specified otherwise in embodiment, reaction can be carried out under argon atmospher or nitrogen atmosphere.

Argon atmospher or nitrogen atmosphere refer to that reaction flask connects the argon gas or nitrogen balloon of an about 1L volume.

Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 1L volume.

Pressure hydration reaction hydrogenates instrument using Parr 3916EKX type hydrogenation instrument and clear indigo plant QL-500 type hydrogen generator or HC2-SS type.

Hydrogenation usually vacuumizes, and is filled with hydrogen, operates 3 times repeatedly.

Microwave reaction uses 908860 type microwave reactor of CEM Discover-S.

Without specified otherwise in embodiment, solution refers to aqueous solution.

Without specified otherwise in embodiment, it is 20 DEG C~30 DEG C that the temperature of reaction, which is room temperature,.

The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC), solvent used in reacting, the system of eluant, eluent and the solvent system of thin-layered chromatography for the column chromatography that purifying compound uses include: 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 solvent is different according to the polarity of compound and is adjusted, and the alkalinity such as a small amount of triethylamine and acetic acid can also be added or acid reagent is adjusted.

Embodiment 1

6- (8- methylquinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine

The first step

8- methyl -6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) quinoline 1b

The bromo- 8- methylquinoline 1a (444mg of 6- is sequentially added under an argon, 2.00mmol, using well known method " Journal of Organic Chemistry; 2014; 79 (11); 5379-5385 " is prepared), bis- (pinacol combined) two boron (508mg, 2.00mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (292mg, 0.40mmol) and potassium acetate (588mg, it 6.00mmol) is dissolved in 10mL ethylene glycol dimethyl ether solution, is heated to 80 DEG C, stir 12 hours.Stop reaction, it is cooled to room temperature, filters, 20mL ethyl acetate is added in filtrate, successively washed with water (10mL), saturated sodium chloride solution (10mL) washing, is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, residue thin-layered chromatography obtains title product 1b (320mg), yield: 59.5% with solvent system B purifying.

MS m/z(ESI):270.1[M+1]。

Second step

6- (8- methylquinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 1

1b (54mg is sequentially added under an argon, 0.20mmol), the bromo- 5- phenyl -1 of 6-, 2,4- triazine -3- ammonia 1c (50mg, 0.20mmol, using well known method " Journal of Medicinal Chemistry; 2012,55 (5), 1898-1903 " are prepared), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (29mg, 0.04mmol) it is dissolved in the mixed solution of 12mL Isosorbide-5-Nitrae-dioxane and water (V/V=5:1) with potassium carbonate (82mg, 0.60mmol), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filters, filtrate decompression concentration, 20mL ethyl acetate is added in residue, is successively washed with water (10mL), saturated sodium chloride solution (10mL) washing, it is dry with anhydrous sodium sulfate, filtering, filtrate decompression concentration, residue high performance liquid chromatography is with solvent system A purifying, obtain title product 1 (20mg), yield: 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)。

Embodiment 2

6- (8- fluorine quinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 2

The first step

The fluoro- 6- of 8- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) quinoline 2b

The bromo- 8- fluorine quinoline 2a (226mg of 6- is sequentially added under an argon, 1.00mmol), bis- (pinacol combined) two boron (305mg, 1.20mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (146mg, 0.20mmol) and potassium acetate (294mg, it 3.00mmol) is dissolved in 10mL ethylene glycol dimethyl ether solution, is heated to 80 DEG C, stir 12 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression distillation, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 2b (220mg), yield: 80.1% are obtained.

MS m/z(ESI):274.1[M+1]。

Second step

6- (8- fluorine quinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 2

2b (109mg is sequentially added under an argon, 0.40mmol), 1c (100mg, 0.40mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (58mg, 0.08mmol) it is dissolved in the mixed solution of 12mL Isosorbide-5-Nitrae-dioxane and water (V/V=5:1) with potassium carbonate (156mg, 1.20mmol), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 2 (20mg), yield: 15.9% are obtained.

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)。

Embodiment 3

5- phenyl -6- (quinoline -6- base) -1,2,4- triazine -3- amine

The first step

6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) quinoline 3b

6- bromoquinoline 3a (1.0g is sequentially added under an argon, 4.80mmol, it is splendid remote), bis- (pinacol combined) two boron (1.46g, 5.76mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (0.7g, 0.96mmol) and potassium acetate (1.4g, 14.40mmol) be dissolved in 20mL ethylene glycol dimethyl ether solution, 80 DEG C are heated to, is stirred 12 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression distillation, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 3b (1.2g), yield: 98.4% are obtained.

MS m/z(ESI):256.1[M+1]。

Second step

5- phenyl -6- (quinoline -6- base) -1,2,4- triazine -3- amine 3

3b (203mg is sequentially added under an argon, 0.80mmol), 1c (200mg, 0.80mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (116mg, 0.16mmol) it is dissolved in the mixed solution of 24mL Isosorbide-5-Nitrae-dioxane and water (V/V=5:1) with potassium carbonate (330mg, 2.40mmol), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 3 (100mg), yield: 42.0% are obtained.

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)。

Embodiment 4

6- (8- chloroquinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine

The first step

The chloro- 6- of 8- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) quinoline 4b

The bromo- 8- chloroquinoline 4a (300mg of 6- is sequentially added under an argon, 1.24mmol), bis- (pinacol combined) two boron (378mg, 1.49mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (181mg, 0.25mmol) and potassium acetate (364mg, it 3.72mmol) is dissolved in 50mL ethylene glycol dimethyl ether solution, is heated to 80 DEG C, stir 12 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression distillation, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 4b (260mg), yield: 72.6% are obtained.

MS m/z(ESI):290.5[M+1]。

Second step

6- (8- chloroquinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 4

4b (127mg is sequentially added under an argon, 0.44mmol), 1c (100mg, 0.40mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (58mg, 0.08mmol) it is dissolved in the mixed solution of 12mL Isosorbide-5-Nitrae-dioxane and water (V/V=5:1) with potassium carbonate (165mg, 1.20mmol), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, it is cooled to room temperature, 20mL ethyl acetate is added, it is washed with saturated sodium chloride solution (10mL), is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 4 (30mg), yield: 20.5% are obtained.

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)。

Embodiment 5

5- (5- methylfuran -2- base) -6- (8- methylquinoline -6- base) -1,2,4- triazine -3- amine

The first step

The bromo- 5- of 6- (5- methylfuran -2- base) -1,2,4- triazine -3- amine 5c

By 6- bromo- 1,2,4- triazine -3- ammonia 5a (1.0g, 5.72mmol, using well known method " Journal of the American Chemical Society; 2015; 137 (26), 8388-8391 " are prepared), 6mL trifluoroacetic acid and 6mL methylene chloride be added in reaction flask, 2- methylfuran 5b (567 μ L are added, 6.29mmol), it is stirred at room temperature 17 hours.Stop reaction, saturated sodium bicarbonate solution is added dropwise and adjusts pH > 7, the potassium hydroxide (962mg, 17.14mmol) of prefabricated 30mL and the aqueous solution of Hexacyanoferrate potassium (5.65g, 17.14mmol) is added, is stirred at room temperature 1 hour.Stop reaction, reaction solution is extracted with ethyl acetate (150mL × 3), merges organic phase, silica gel is added, is concentrated under reduced pressure, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system C, obtain title product 5c (450mg), yield: 30.9%.

MS m/z(ESI):257.3[M+1]。

Second step

5- (5- methylfuran -2- base) -6- (8- methylquinoline -6- base) -1,2,4- triazine -3- amine 5

5c (80mg is sequentially added under an argon, 0.31mmol), 1b (127mg, 0.47mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (23mg, 0.031mmol) it is dissolved in the mixed solution of 12mL Isosorbide-5-Nitrae-dioxane and water (V/V=5:1) with potassium carbonate (173mg, 1.25mmol), 90 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, 50mL water is added, it is extracted with ethyl acetate (30mL × 3), merges organic phase, be concentrated under reduced pressure, residue thin-layered chromatography obtains title product 5 (33mg), yield: 33.0% with solvent system B purifying.

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)。

Embodiment 6

5- (furans -2- base) -6- (8- methylquinoline -6- base) -1,2,4- triazine -3- amine

The first step

The bromo- 5- of 6- (5- methylfuran -2- base) -1,2,4- triazine -3- amine 6a

5a (1.0g, 5.72mmol), 6mL trifluoroacetic acid and 6mL methylene chloride are added in reaction flask, is added furans (457 μ L, 6.29mmol), is stirred at room temperature 17 hours.Stop reaction, saturated sodium bicarbonate solution is added dropwise and adjusts pH > 7, the potassium hydroxide (962mg, 17.14mmol) of prefabricated 20mL and the aqueous solution of Hexacyanoferrate potassium (5.65g, 17.14mmol) is added, is stirred at room temperature 1 hour.Stop reaction, reaction solution is extracted with dichloromethane (100mL × 4), merges organic phase, silica gel is added, is concentrated under reduced pressure, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system C, obtain title product 6a (222mg), yield: 16.1%.

MS m/z(ESI):243.3[M+1]。

Second step

5- (furans -2- base) -6- (8- methylquinoline -6- base) -1,2,4- triazine -3- amine 6

6a (70mg is sequentially added under an argon, 0.29mmol), 1b (86mg, 0.32mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (21mg, 0.029mmol) it is dissolved in the mixed solution of 12mL Isosorbide-5-Nitrae-dioxane and water (V/V=5:1) with potassium carbonate (160mg, 1.16mmol), 90 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, 50mL water is added, it is extracted with ethyl acetate (30mL × 3), merges organic phase, be concentrated under reduced pressure, residue thin-layered chromatography obtains title product 6 (35mg), yield: 39.8% with solvent system B purifying.

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)。

Embodiment 7

6- (8- methylquinoline -6- base) -5- (thiophene -2- base) -1,2,4- triazine -3- amine

The first step

The bromo- 5- of 6- (thiophene -2- base) -1,2,4- triazine -3- amine 7a

5a (1.0g, 5.72mmol), 6mL trifluoroacetic acid and 6mL methylene chloride are added in reaction flask, is added thiophene (503 μ L, 6.29mmol), is stirred at room temperature 17 hours.Stop reaction, saturated sodium bicarbonate solution is added dropwise and adjusts pH > 7, the potassium hydroxide (962mg, 17.14mmol) of prefabricated 30mL and the aqueous solution of Hexacyanoferrate potassium (5.65g, 17.14mmol) is added, is stirred at room temperature 2 hours.Stop reaction, reaction solution is extracted with ethyl acetate (50mL × 3), merges organic phase, silica gel is added, is concentrated under reduced pressure, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system C, obtain title product 7a (400mg), yield: 27.2%.

MS m/z(ESI):259.2[M+1]。

Second step

6- (8- methylquinoline -6- base) -5- (thiophene -2- base) -1,2,4- triazine -3- amine 7

7a (70mg is sequentially added under an argon, 0.27mmol), 1b (81mg, 0.30mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (20mg, 0.027mmol) it is dissolved in the mixed solution of 12mL Isosorbide-5-Nitrae-dioxane and water (V/V=5:1) with potassium carbonate (150mg, 1.09mmol), 90 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, 50mL water is added, it is extracted with ethyl acetate (50mL × 3), merges organic phase, be concentrated under reduced pressure, residue thin-layered chromatography obtains title product 7 (40mg), yield: 46.0% with solvent system B purifying.

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)。

Embodiment 8

5- (4- fluorophenyl) -6- (8- methylquinoline -6- base) -1,2,4- triazine -3- amine

The first step

5- (4- fluorophenyl) -6- (8- methylquinoline -6- base) -1,2,4- triazine -3- amine 8

1b (100mg is sequentially added under an argon, 0.37mmol), the bromo- 5- of 6- (4- fluorophenyl) -1, 2, 4- triazine -3- amine 8a (100mg, 0.37mmol, using well known method " Journal of Medicinal Chemistry, 2012, 55 (5), 1898-1903 " is prepared), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (54mg, 0.074mmol) and potassium carbonate (154mg, 1.12mmol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V/V=5:1), it is heated to 80 DEG C, stirring 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 8 (15mg), yield: 12.2% are obtained.

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)。

Embodiment 9

5- phenyl -6- (8- (trifluoromethyl) quinoline -6- base) -1,2,4- triazine -3- amine 9

The first step

6- bromo- 8- (trifluoromethyl) quinoline 9b

By 2- amino -5- 5 bromine benzotrifluoride 9a (1.1g, 4.58mmol), 1,2,3- propane triols (1.69g, 18.3mmol) and ferric sulfate (II) heptahydrate (204mg, 0.73mmol) it is added in reaction flask, it is cooled to 0 DEG C, 0.8mL sulfuric acid is added dropwise, is added dropwise, 120 DEG C are heated to, is stirred 4 hours.Stop reaction, be cooled to room temperature, 20mL water is added, it is extracted with ethyl acetate (30mL × 3), merges organic phase, be concentrated under reduced pressure, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 9b (0.9g), yield: 71.4% are obtained.

MS m/z(ESI):210.6[M+1]。

Second step

6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) -8- (trifluoromethyl) quinoline 9c

9b (276mg is sequentially added under an argon, 1.00mmol), bis- (pinacol combined) two boron (381mg, 1.50mmol) and [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (146mg, 0.20mmol) and potassium acetate (294mg, it 3.00mmol) is dissolved in 15mL ethylene glycol dimethyl ether solution, is heated to 80 DEG C, stir 12 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 9c (250mg), yield: 77.4% are obtained.

MS m/z(ESI):324.1[M+1]。

Third step

5- phenyl -6- (8- (trifluoromethyl) quinoline -6- base) -1,2,4- triazine -3- amine 9

9c (129mg is sequentially added under an argon, 0.40mmol), the bromo- 5- phenyl -1 of 6-, 2,4- triazine -3- amine 1c (100mg, 0.40mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (58mg, 0.08mmol) it is dissolved in the mixed solution of 12mL Isosorbide-5-Nitrae-dioxane and water (V/V=5:1) with potassium carbonate (156mg, 1.20mmol), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, it is cooled to room temperature, filters, filtrate decompression concentration, 20mL ethyl acetate is added in residue, it is washed with saturated sodium chloride solution (10mL), is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 9 (50mg), yield: 34.2% are obtained.

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)。

Embodiment 10

6- (8- isopropyl quinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 10

The first step

The bromo- 8- isopropyl quinoline 10b of 6-

By the bromo- 2- isopropyl aniline 10a of 4- (1.0g, 4.70mmol, using well known method " Synthesis; 2013,45 (17), 2474-2480 " are prepared), 1,2,3- propane triols (2.1g, 23.40mmol) and ferric sulfate (II) heptahydrate (0.2g, 0.75mmol) it is added in reaction flask, it is cooled to 0 DEG C, 0.9mL sulfuric acid is added dropwise, is added dropwise, 120 DEG C are heated to, is stirred 3 hours.Stop reaction, it is cooled to room temperature, 20mL water is added, (30mL × 3) are extracted with ethyl acetate, merge organic phase, it is washed with saturated sodium chloride solution (20mL), is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 10b (0.6g), yield: 51.7% are obtained.

MS m/z(ESI):251.1[M+1]。

Second step

8- isopropyl -6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) quinoline 10c

10b (600mg is sequentially added under an argon, 2.40mmol), bis- (pinacol combined) two boron (731mg, 2.88mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (350mg, 0.48mmol) and potassium acetate (705mg, it 7.20mmol) is dissolved in 40mL ethylene glycol dimethyl ether solution, is heated to 80 DEG C, stir 4 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 10c (450mg), yield: 63.1% are obtained.

MS m/z(ESI):298.2[M+1]。

Third step

6- (8- isopropyl quinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 10

10c (118mg is sequentially added under an argon, 0.40mmol), the bromo- 5- phenyl -1 of 6-, 2,4- triazine -3- ammonia 1c (100mg, 0.40mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (58mg, 0.08mmol) it is dissolved in the mixed solution of 24mL Isosorbide-5-Nitrae-dioxane and water (V/V=5:1) with potassium carbonate (165mg, 1.20mmol), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 10 (40mg), yield: 29.3% are obtained.

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)。

Embodiment 11

6- (8- ethyl quinolinium -6- base) -5- phenyl -1,2,4- triazine -3- amine 11

The first step

The bromo- 8- ethyl quinolinium 11b of 6-

By the bromo- 2- ethyl aniline 11a (1.0g of 4-, 5.00mmol, Alfa), 1,2,3- propane triol (2.3g, it 25.00mmol) is added in reaction flask with ferric sulfate (II) heptahydrate (0.22g, 0.80mmol), is cooled to 0 DEG C, 0.9mL sulfuric acid is added dropwise, it is added dropwise, is heated to 120 DEG C, stir 2 hours.Stop reaction, it is cooled to room temperature, 20mL water is added, (30mL × 3) are extracted with ethyl acetate, merge organic phase, it is washed with saturated sodium chloride solution (20mL), is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 11b (0.9g), yield: 76.3% are obtained.

MS m/z(ESI):237.1[M+1]。

Second step

8- ethyl -6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) quinoline 11c

11b (472mg is sequentially added under an argon, 2.00mmol), bis- (pinacol combined) two boron (610mg, 2.40mmol) and [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (292mg, 0.40mmol) and potassium acetate (588mg, it 6.00mmol) is dissolved in 30mL ethylene glycol dimethyl ether solution, is heated to 80 DEG C, stir 3 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue silica gel column chromatography obtains title product 11c (400mg), yield: 70.7% with eluant, eluent system B purifying.

MS m/z(ESI):284.1[M+1]。

Third step

6- (8- ethyl quinolinium -6- base) -5- phenyl -1,2,4- triazine -3- amine 11

11c (113mg is sequentially added under an argon, 0.40mmol), the bromo- 5- phenyl -1 of 6-, 2,4- triazine -3- amine 1c (100mg, 0.40mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (58mg, 0.08mmol) it is dissolved in the mixed solution of 24mL Isosorbide-5-Nitrae-dioxane and water (V/V=5:1) with potassium carbonate (165mg, 1.20mmol), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 11 (20mg), yield: 15.3% are obtained.

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)。

Embodiment 12

6- (8- cyclopropyl quinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 12

The first step

The bromo- 2- cyclopropyl aniline 12b of 4-

By 2- cyclopropyl aniline 12a (1.0g, 7.52mmol, it is prepared using method disclosed in patent application " WO201314997 ") it is added in 100mL acetonitrile solvent, N-bromosuccinimide (1.4g is added, 7.89mmol) and ammonium acetate (58mg, 0.075mmol), it stirs 2 hours, stops reaction.60mL water is added, (100mL × 3) are extracted with ethyl acetate, merge organic phase, it is washed with saturated sodium chloride solution (50mL), is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 12b (0.85g), yield: 53.5% are obtained.

MS m/z(ESI):213.1[M+1]。

Second step

The bromo- 8- cyclopropyl quinoline 12c of 6-

By the bromo- 2- ethyl aniline 12b (500mg of 4-, 2.36mmol), 1,2,3- propane triols (1.08g, 11.80mmol) and ferric sulfate (II) heptahydrate (105mg, 0.38mmol) it is added in reaction flask, it is cooled to 0 DEG C, 0.5mL sulfuric acid is added dropwise, is added dropwise, 120 DEG C are heated to, is stirred 2 hours.Stop reaction, it is cooled to room temperature, 50mL water is added, (50mL × 3) are extracted with ethyl acetate, merge organic phase, it is washed with saturated sodium chloride solution (50mL), is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 12c (0.4g), yield: 68.5% are obtained.

MS m/z(ESI):249.1[M+1]。

Third step

8- cyclopropyl -6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) quinoline 12d

12c (100mg is sequentially added under an argon, 0.40mmol), bis- (pinacol combined) two boron (123mg, 0.48mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (59mg, 0.08mmol) and potassium acetate (118mg, it 1.20mmol) is dissolved in 10mL ethylene glycol dimethyl ether solution, is heated to 80 DEG C, stir 4 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 12d (94mg), yield: 79.0% are obtained.

MS m/z(ESI):296.2[M+1]。

4th step

6- (8- cyclopropyl quinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 12

12d (94mg is sequentially added under an argon, 0.32mmol), the bromo- 5- phenyl -1 of 6-, 2,4- triazine -3- amine 1c (80mg, 0.32mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (47mg, 0.064mmol) it is dissolved in the mixed solution of 12mL Isosorbide-5-Nitrae-dioxane and water (V/V=5:1) with potassium carbonate (132mg, 0.96mmol), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 12 (10mg), yield: 9.2% are obtained.

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)。

Embodiment 13 (comparative example 1)

6- (naphthalene -2- base) -5- phenyl -1,2,4- triazine -3- amine

6- (naphthalene -2- base) -5- phenyl -1,2,4- triazine -3- amine 13

2- naphthalene boronic acids 13a (55mg is sequentially added under an argon, 0.32mmol), the bromo- 5- phenyl -1 of 6-, 2,4- triazine -3- amine 1c (80mg, 0.32mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (47mg, 0.064mmol) it is dissolved in the mixed solution of 12mL Isosorbide-5-Nitrae-dioxane and water (V/V=5:1) with potassium carbonate (132mg, 0.96mmol), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 13 (20mg), yield: 21.3% are obtained.

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)。

Embodiment 14

6- (4- methylquinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 14

The first step

4- methyl -6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) quinoline 14b

Under an argon, sequentially add the bromo- 4- methylquinoline 14a (444mg of 6-, 2mmol, using well known method " Tetrahedron; 2003; 59 (6); 813-819 " is prepared), bis- (pinacol combined) two boron (762mg, 3mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (292mg, 0.4mmol) and potassium acetate (588mg, 6mmol) be dissolved in 20mL dimethyl ether solution, 80 DEG C are heated to, is stirred 12 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 14b (460mg), yield: 85.5% are obtained.

MS m/z(ESI):270.4[M+1]。

Second step

6- (4- methylquinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 14

Under an argon, sequentially add compound 14b (107mg, 0.4mmol), compound 1c (100mg, 0.4mmol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (58mg, 0.08mmol) and potassium carbonate (165mg, 1.2mmol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V/V=5:1), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 14 (15mg), yield: 12% are obtained.

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)。

Embodiment 15

6- (4- methylquinazolin -6- base) -5- phenyl -1,2,4- triazine -3- amine 15

The first step

The bromo- 4- methylquinazolin 15b of 6-

By 1- (2- amino -5- bromophenyl) ethyl ketone 15a (1g, 4.67mmol, using well known method " Journal of Medicinal Chemistry, 2015,58 (14); 5522-5537 " is prepared), triethyl orthoformate (1.04g, 7.01mmol) and ammonium acetate (540.15mg, 7.01mmol) are added in reaction flask, at 110 DEG C, stir 2 hours.Stop reaction, is cooled to room temperature, reaction solution is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 15b (500mg), yield: 47.98% are obtained.

MS m/z(ESI):223.1[M+1]。

Second step

4- methyl -6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) quinazoline 15c

Compound 15b (360mg is sequentially added under an argon, 1.61mmol), bis- (pinacol combined) two boron (409.82mg, 1.61mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (236.17mg, 322.77 μm of ol) and potassium acetate (475.16mg, it 4.84mmol) is dissolved in 20mL dimethyl ether solution, is heated to 80 DEG C, stir 4 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 15c (330mg), yield: 75.7% are obtained.MS m/z(ESI):271.1[M+1].

Third step

6- (4- methylquinazolin -6- base) -5- phenyl -1,2,4- triazine -3- amine 15

Under an argon, sequentially add compound 15c (108mg, 399.80 μm of ol), compound 1c (100.38mg, 399.80 μm of mol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (58.51mg, 79.96 μm of ol) and potassium carbonate (165mg, 1.2mmol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V/V=4:1), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 15 (52mg), yield: 41.38% are obtained.

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)。

Embodiment 16

6- (the fluoro- 4- methylquinoline -6- base of 8-) -5- phenyl -1,2,4- triazine -3- amine 16

The first step

The fluoro- 4- methylquinoline 16c of the bromo- 8- of 6-

By the fluoro- aniline 16b (9.99g of the bromo- 2- of 4-, 52.58mmol, using well known method " Tetrahedron Letters, 2015,56 (41); 5646-5650 " is prepared) be dissolved in 300mL 1, in 4- dioxane, 5mL sulfuric acid is added dropwise, is heated to flow back, 20mL butyl- 3- alkene -2- ketone 16a (7.37g is slowly added dropwise again, 105.15mmol, using well known method " Tetrahedron Letters, 2006; 47 (37); 6635-6636 " is prepared) Isosorbide-5-Nitrae-dioxane solution, be added dropwise 1.5 hours, it is added dropwise, flows back 2 hours.Reaction solution is cooled to room temperature, and reaction solution is concentrated under reduced pressure.Add water in residue, it is 10 that saturated sodium bicarbonate to pH of mixed, which is added dropwise, ethyl acetate extracts three times, merges organic phase, and saturated sodium chloride solution washed once, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, residue are purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, obtain title compound 16c (3.5g), yield: 27.73%.

MS m/z(ESI):240.0[M+1]。

Second step

The fluoro- 4- methyl -6- of 8- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) quinoline 16d

Under an argon, by compound 16c (480mg, 2.00mmol), bis- (pinacol combined) two boron (761.59mg, 3.00mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (292.60mg, 399.88 μm of ol) and potassium acetate (588.68mg, 6.00mmol) be added in 20mL dimethyl ether, 80 DEG C are heated to, is stirred to react 3 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 16d (460mg), yield: 80.12% are obtained.

MS m/z(ESI):288.1[M+1]。

Third step

6- (the fluoro- 4- methylquinoline -6- base of 8-) -5- phenyl -1,2,4- triazine -3- amine 16

Under an argon, successively by compound 16d (110mg, 383.09 μm of ol), compound 1c (96mg, 383.09 μm of ol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (56mg, 76.62 μm of ol) and potassium carbonate (158.60mg, 1.15mmol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V/V=5:1), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 16 (18mg), yield: 14.2% are obtained.

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)。

Embodiment 17

5- (2- fluorophenyl) -6- (4- methylquinoline -6- base) -1,2,4- triazine -3- amine 17

Under an argon, successively by compound 14b (100mg, 371.55 μm of ol), the bromo- 5- of 6- (2- fluorophenyl) -1,2,4- triazine -3- amine 17a (99.97mg, 371.55 μm of ol, be prepared using the method " WO2016102672A2 " of patent application publication), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (54mg, 74.35 μm of ol) and potassium carbonate (153.82mg, 1.11mmol) be dissolved in the mixed solution of 12mL Isosorbide-5-Nitrae-dioxane and water (V/V=5:1), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 17 (50mg), yield: 40.6% are obtained.

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)。

Embodiment 18

5- (4- fluorophenyl) -6- (4- methylquinoline -6- base) -1,2,4- triazine -3- amine 18

Under an argon, successively by compound 14b (100mg, 371.55 μm of ol), compound 8a (99.97mg, 371.55 μm of ol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (54.37mg, 74.31 μm of ol) and potassium carbonate (153.82mg, 1.11mmol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V/V=5:1), 80 DEG C are heated to, is stirred to react 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 18 (15mg), yield: 12.18% are obtained.

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)。

Embodiment 19

5- (4- fluorophenyl) -6- (4- methylquinazolin -6- base) -1,2,4- triazine -3- amine 19

Under argon atmospher, by compound 15c (100mg, 370.19 μm of ol), compound 8a (99.61mg, 370.19 μm of ol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (54.17mg, 74.04 μm of ol) and potassium carbonate (153.26mg, 1.11mmol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V/V=5:1), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 19 (50mg), yield: 40.64% are obtained.

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)。

Embodiment 20

6- (the fluoro- 4- methylquinoline -6- base of 8-) -5- (4- fluorophenyl) -1,2,4- triazine -3- amine 20

Under argon atmospher, by compound 8a (100mg, 371.65 μm of ol), compound 16d (106.71mg, 371.65 μm of ol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (54.39mg, 74.33 μm of ol) and potassium carbonate (153.86mg, 1.11mmol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V/V=5:1), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 20 (50mg), yield: 38.51% are obtained.

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)。

Embodiment 21

5- (2,4 difluorobenzene base) -6- (4- methylquinoline -6- base) -1,2,4- triazine -3- amine 21

Under argon atmospher, by compound 14b (68mg, 252.65 μm ol), the bromo- 5- (2 of 6-, 4- difluorophenyl) -1,2,4- triazine -3- amine 21a (72.53mg, 252.65 μm of ol, it is prepared using method disclosed in patent application " WO2011095625A1 "), [1,1 '-bis- (diphenylphosphino) ferrocene] palladium chloride (36.97mg, 50.53 μm of ol) and potassium carbonate (104.60mg, 757.95 μm of ol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V/V=5:1), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 21 (40mg), yield: 50.99% are obtained.

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)。

Embodiment 22

5- (4- fluorophenyl) -6- [4- (three deuterated methyl) -6- quinolyl] -1,2,4- triazine -3- amine 22

The first step

The bromo- 4- of 6- (three deuterated methyl) quinoline 22a

Compound 14a (222mg, 999.64 μm of ol) and benzoic acid (12.21mg, 99.96 μm of ol) are dissolved in 1mL heavy water, at 100 DEG C, are stirred to react overnight.Saturated sodium bicarbonate solution is added, it is extracted with ethyl acetate three times, merge organic phase, anhydrous sodium sulfate is dry, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, by after purification solid and benzoic acid (12.21mg, 99.96 μm of ol) sequentially add in 1mL heavy water, at 100 DEG C, it is stirred to react overnight.Saturated sodium bicarbonate solution is added, is extracted with ethyl acetate three times, merges organic phase, anhydrous sodium sulfate is dry, and residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, obtains title compound 22a (100mg), yield: 44.44%.

MS m/z(ESI):225.0[M+1]。

Second step

6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) -4- (three deuterated methyl) quinoline 22b

Under an argon, by compound 22a (100mg, 444.25 μm of ol), bis- (pinacol combined) two boron (169.22mg, 666.37 μm of ol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (65.01mg, 88.85 μm of ol) and potassium acetate (130.80mg, 1.33mmol) be added 10mL Isosorbide-5-Nitrae-dioxane in, 80 DEG C are heated to, is stirred 4 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 22b (70mg), yield: 57.9% are obtained.

MS m/z(ESI):273.1[M+1]。

Third step

5- (4- fluorophenyl) -6- [4- (three deuterated methyl) -6- quinolyl] -1,2,4- triazine -3- amine 22

Under argon atmospher, by compound 22b (70mg, 257.20 μm of ol), compound 8a (69.20mg, 257.20 μm of ol), [1,1 '-bis- (diphenylphosphino) ferrocene] palladium chloride (37.64mg, 51.44 μm of ol) and potassium carbonate (106.48mg, 771.59 μm of ol) be dissolved in the mixed solution of 12mL Isosorbide-5-Nitrae-dioxane and water (V/V=5:1), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filters, filtrate decompression concentration, cooling, filtering, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, gained crude product thin-layered chromatography obtains title compound 22 (29mg), yield: 29.07% with solvent system A purifying.

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)。

Embodiment 23

6- (4- methoxy quinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 23

Under argon atmospher, by 4- methoxyl group -6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) quinoline 23a (114mg, 0.4mmol, it is prepared using method disclosed in patent application " WO2011084402A1 ") and compound 1c (100mg, 0.4mmol), [1,1 '-bis- (diphenylphosphino) ferrocene] palladium chloride (58mg, 0.08mmol) it is dissolved in the mixed solution of 12mL Isosorbide-5-Nitrae-dioxane and water (V/V=5:1) with potassium carbonate (165mg, 1.2mmol), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 23 (20mg), yield: 15.3% are obtained.

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)。

Embodiment 24

6- (3- fluorine quinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 24

The first step

3- fluorine quinoline -6- base triflate 24b

By 3- fluorine quinoline -6- alcohol 24a (489mg, 3mmol, using well known method " Synlett, 2014,25 (6); 858-862 " is prepared) and pyridine (474mg, it 6mmol) is dissolved in 10mL methylene chloride, under the conditions of 0 DEG C, trifluoro formic anhydride (0.55mL is added dropwise, 3.3mmol), it is stirred to react 2 hours.Water is added in reaction solution, (20mL × 3) are extracted with dichloromethane, merge organic phase, (20mL) is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, residue residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 24b (520mg), yield: 58.7% are obtained.

MS m/z(ESI):296.4[M+1]。

Second step

The fluoro- 6- of 3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) quinoline 24c

Under an argon, successively by compound 24b (100mg, 0.34mmol), bis- (pinacol combined) two boron (103mg, 0.4mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (50mg, 0.068mmol) and potassium acetate (100mg, 1mmol) be dissolved in 20mL dimethyl ether solution, 80 DEG C are heated to, is stirred 4 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 24c (70mg), yield: 76% are obtained.

MS m/z(ESI):274.4[M+1]。

Third step

6- (3- fluorine quinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 24

Under an argon, sequentially add compound 24c (70mg, 0.26mmol), compound 1c (64mg, 0.26mmol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (37mg, 0.05mmol) and potassium carbonate (106mg, 0.77mmol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V/V=5:1), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 24 (20mg), yield: 25% are obtained.

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)。

Embodiment 25

6- (8- methoxy quinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 25

The first step

8- methoxyl group -6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) quinoline 25b

Under an argon, successively by the bromo- 8- methoxy quinoline 25a (530mg of 6-, 2.2mmol, using well known method " Journal of the American Chemical Society; 2005; 127 (1); 74-75 " is prepared), bis- (pinacol combined) two boron (845mg, 3.3mmol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (162mg, 0.22mmol) and potassium acetate (652mg, 6.65mmol) it is dissolved in 10mL 1, in 4 dioxane, 80 DEG C are heated to, is stirred 3 hours.Stop reaction, be cooled to room temperature, diatomite filtering, filter cake is washed with ethyl acetate, and filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, obtains title product 25b (410mg), yield: 65%.

MS m/z(ESI):286.1[M+1]。

Second step

6- (8- methoxy quinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 25

Under an argon, sequentially add compound 25b (100mg, 0.37mmol), compound 1c (93mg, 0.37mmol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (27mg, 0.037mmol) and potassium carbonate (10mg, 0.074mmol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V/V=5:1), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, is cooled to room temperature, water is added in reaction solution, ethyl acetate extracts three times, merges organic phase, and organic phase is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, residue efficient liquid phase prepares (Waters 2767-SQ Detecor2, eluent system: ammonium hydrogen carbonate, water, acetonitrile) purifying, obtain title product 25 (25mg), yield: 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)。

Embodiment 26

5- (3- fluorophenyl) -6- (8- fluorine quinoline -6- base) -1,2,4- triazine -3- amine 26

Under an argon, sequentially add compound 2b (101.50mg, 371.65 μm ol), the bromo- 5- of 6- (3- fluorophenyl) -1, 2, 4- triazine -3- amine 26a (100mg, 71.65 μm ol, using well known method " Journal of Medicinal Chemistry, 2012, 55 (5), 1898-1903 " is prepared), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (54.39mg, 74.33 μm ol) and potassium carbonate (153.86mg, 1.11mmol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V/V=5:1), it is heated to 80 DEG C, stirring 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 26 (45mg), yield: 36.11% are obtained.

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)。

Embodiment 27

6- (4- chloroquinoline -6- base) -5- (4- fluorophenyl) -1,2,4- triazine -3- amine 27

Under an argon, sequentially add the chloro- 6- (4 of 4-, 4, 5, 5- tetramethyl -1, 3, 2- dioxaborolan -2- base) quinoline 27a (200mg, 690.69 μm of ol, using well known method " Journal of Medicinal Chemistry, 2011, 54 (13), 4735-4751 " is prepared), compound 8a (123.90mg, 460.46 μm ol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (67.38mg, 92.09 μm ol) and potassium carbonate (190.63mg, 1.38mmol) it is dissolved in 12mL 1, 4- dioxane and water (V/V=5:1) In mixed solution, 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 27 (25mg), yield: 15.43% are obtained.

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)。

Embodiment 28

6- (3- methylquinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 28

The first step

3- methyl -6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) quinoline 28b

Under an argon, sequentially add the bromo- 3- methylquinoline 28a (250mg of 6-, 1.13mmol, be prepared using the method " WO2006132739A2 " of patent application publication), bis- (pinacol combined) two boron (429mg, 1.69mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (165mg, 0.225mmol) and potassium acetate (331mg, it 3.38mmol) is dissolved in 20mL dimethyl ether solution, 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 28b (240mg), yield: 79.2% are obtained.

MS m/z(ESI):270.1[M+1]。

Second step

6- (3- methylquinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 28

Under an argon, sequentially add compound 28b (107mg, 0.4mmol), compound 1c (100mg, 0.4mmol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (58mg, 0.08mmol) and potassium carbonate (165mg, 1.2mmol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V/V=5:1), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 28 (50mg), yield: 40% are obtained.

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)。

Embodiment 29

5- phenyl -6- (quinazoline -6- base) -1,2,4- triazine -3- amine 29

The first step

6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) quinazoline 29b

Under an argon, sequentially add 6- bromine quinazoline 29a (418mg, 2mmol, using well known method " Science of Synthesis; 2004; 16; 573-749 " is prepared), bis- (pinacol combined) two boron (609mg, 7.4mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (292mg, 0.4mmol) and potassium acetate (588mg, 6mmol) be dissolved in 20mL dimethyl ether solution, 80 DEG C are heated to, is stirred 4 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 29b (450mg), yield: 87.9% are obtained.

MS m/z(ESI):257.1[M+1]。

Second step

5- phenyl -6- (quinazoline -6- base) -1,2,4- triazine -3- amine 29

Under an argon, successively by compound 29b (81mg, 0.32mmol), compound 1c (80mg, 0.32mmol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (47mg, 0.064mmol) and potassium carbonate (132mg, 0.96mmol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V/V=5:1), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 29 (10mg), yield: 5.1% are obtained.

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)。

Embodiment 30

5- (4- fluorophenyl) -6- (quinoline -6- base) -1,2,4- triazine -3- amine 30

Under an argon, by compound 3b (94.81mg, 371.65 μm of ol), compound 8a (100mg, 371.65 μm of ol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (54.39mg, 74.33 μm of ol) and potassium carbonate (153.86mg, 1.11mmol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V/V=5:1), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 30 (5mg), yield: 4.24% are obtained.

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)。

Embodiment 31

6- (the fluoro- 4- methylquinoline -6- base of 8-) -5- (2- fluorophenyl) -1,2,4- triazine -3- amine 31

Under an argon, by compound 17a (100mg, 371.65 μm of ol), compound 16d (106.71mg, 371.65 μm of ol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (54.39mg, 74.33 μm of ol) and potassium carbonate (153.86mg, 1.11mmol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V/V=5:1), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 31 (50mg), yield: 38.51% are obtained.

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)。

Embodiment 32

5- (4- fluorophenyl) -6- (8- fluorine quinoline -6- base) -1,2,4- triazine -3- amine 32

Under an argon, by compound 8a (100mg, 371.65 μm of ol), compound 2b (101.50mg, 371.65 μm of ol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (54.39mg, 74.33 μm of ol) and potassium carbonate (153.86mg, 1.11mmol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V/V=5:1), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filters, filtrate decompression concentration, residue are purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and gained crude product thin-layered chromatography is with solvent system D purifying, obtain title product 32 (20mg), yield: 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)。

Embodiment 33

5- (2,4 difluorobenzene base) -6- (4- methylquinazolin -6- base) -1,2,4- triazine -3- amine 33

Under an argon, by compound 21a (100mg, 349.56 μm of ol), compound 15c (94.43mg, 349.56 μm of ol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (51.16mg, 69.91 μm of ol) and potassium carbonate (144.72mg, 1.05mmol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V/V=5:1), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 33 (55mg), yield: 44.91% are obtained.

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)。

Embodiment 34

6- (3- methoxy quinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 34

The first step

3- methoxyl group -6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- base) quinoline 34b

Under an argon, sequentially add the bromo- 3- methoxy quinoline 34a (120mg of 6-, 0.5mmol, be prepared using the method " WO2012009194A1 " of patent application publication), bis- (pinacol combined) two boron (192mg, 0.76mmol), [1, bis- (diphenylphosphino) ferrocene of 1'-] palladium chloride (74mg, 0.1mmol) and potassium acetate (148mg, it 1.5mmol) is dissolved in 15mL dimethyl ether solution, 80 DEG C are heated to, is stirred 4 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 34b (90mg), yield: 62.9% are obtained.

MS m/z(ESI):286.1[M+1]。

Second step

6- (3- methoxy quinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 34

Under an argon, sequentially add compound 34b (79mg, 0.279mmol), compound 1c (70mg, 0.279mmol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (41mg, 0.056mmol) and potassium carbonate (115mg, 0.84mmol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V/V=5:1), 80 DEG C are heated to, is stirred 2 hours.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 34 (30mg), yield: 33% are obtained.

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)。

Embodiment 35

5- (2- fluorophenyl) -6- (8- fluorine quinoline -6- base) -1,2,4- triazine -3- amine 35

Using the synthetic route of embodiment 32, first step raw material compound 8a is replaced with into compound 17a, title product 35 (61mg) is made.

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)。

Embodiment 36

5- phenyl -6- (quinoxalin-6-yl) -1,2,4- triazine -3- amine 36

Using the synthetic route of embodiment 23, first step raw material compound 23a is replaced with into 6- (4,4,5,5- tetramethyls -1,3,2- dioxaborolan -2- base) and quinoxaline 36a (the well known method of use " Organic Letters, 2009,11 (13); 2860-2863 " is prepared), title product 36 (20mg) is made.

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)。

Embodiment 37

6- (2- methylquinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 37

Using the synthetic route of embodiment 23, first step raw material compound 23a is replaced with into 2- methyl -6- (4,4,5,5- tetramethyls -1,3,2- dioxaborolan -2- base) and quinoline 37a (the well known method of use " Journal of the American Chemical Society, 2015,137 (4); 1593-1600 " is prepared), title product 37 (20mg) is made.

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)。

Embodiment 38

6- (3- amino-5-phenyl -1,2,4- triazine -6- base) quinoline -8- formonitrile HCN 38

The first step

6- bromoquinoline -8- formamide 38b

6- bromoquinoline -8- methyl formate 38a (400mg, 1.5mmol are prepared using the method " WO2011020193A1 " of patent application publication) is dissolved in 15mL methanol, 40% ammonium hydroxide of 5mL is added dropwise, is stirred to react overnight.Water, ethyl acetate extraction are added in reaction solution three times, merges organic phase, saturated sodium chloride solution washing, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, residue silica gel column chromatography obtains title compound 38b (280mg), yield: 74% with eluant, eluent system B purifying

MS m/z(ESI):251.0[M+1]。

Second step

6- bromoquinoline -8- formonitrile HCN 38c

Compound 38b (190mg, 0.76mmol) is dissolved in 20mL methylene chloride, triethylamine (115mg, 1.14mmol) and trifluoroacetic anhydride (238mg, 1.14mmol) are sequentially added, is stirred to react 2 hours.Water is added, methylene chloride extracts three times, merges organic phase, organic phase is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and filtrate decompression concentration, residue is beaten with methanol, filtering collects filter cake, obtains title compound (180mg), yield: 100%.

MS m/z(ESI):232.9[M+1]。

Using embodiment 11 similar to synthetic route, second step raw material compound 11b is replaced with into 38c, title product 38 (25mg) is made.

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)。

Embodiment 39

6- (3- morpholine quinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 39

The first step

4- (6- chloroquinoline -3- base) morpholine 39b

Under argon atmospher, by the bromo- 6- chloroquinoline 39a (266mg of 3-, 1.1mmol, using well known method " Journal of Heterocyclic Chemistry; 2015; 52 (4); 1019-1025 " is prepared), morpholine (87mg, 1mmol), palladium acetate (12mg, 0.05mmol), (±) -2,2'- is bis--(diphenyl phosphine) -1,1'- dinaphthalene (31mg, 0.05mmol) and cesium carbonate (652mg, 2mmol) are dissolved in 10mL tetrahydrofuran, 70 DEG C are heated to, is stirred to react overnight.Stop reaction, be cooled to room temperature, filter, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 39b (180mg), yield: 66.2% are obtained

MS m/z(ESI):249.7[M+1]。

Using embodiment 11 similar to synthetic route, second step raw material compound 11b is replaced with into 39b, title product 39 (25mg) is made.

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)。

Embodiment 40

6- (4- (morpholine methyl) quinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 40

The first step

(6- bromoquinoline -4- base) methanol 40b

By lithium aluminium hydride reduction (150.76mg, it 3.97mmol) adds in 50mL tetrahydrofuran, at 0 DEG C, be added portionwise 6- bromoquinoline -4- carboxylic acid 40a (1.0g, 3.97mmol, using well known method " Chinese Chemical Letters; 2010; 21 (1), 35-38 " are prepared), continue stirring 2 hours.Add 5mL water, filtered with diatomite, ethyl acetate washs filter cake, filtrate decompression concentration, and residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, obtains title product 40b (250mg), yield: 26.5%.

Second step

6- bromo- 4- (chloromethyl) quinoline 40c

By compound 40b (250mg, it 1.05mmol) adds in 10mL methylene chloride, 2mL thionyl chloride is added, it is stirred to react 3 hours, reaction solution is concentrated under reduced pressure, and is spin-dried for, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, obtain title product 40c (180mg), yield: 66.8%.

Using embodiment 39 similar to synthetic route, first step raw material compound 39a is replaced with into compound 40c, title product 40 (5mg) is made.

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)。

Embodiment 41

6- (3- (morpholine methyl) quinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 41

Using embodiment 40 similar to synthetic route, second step raw material compound 40b is replaced with into compound 28a, title product 41 (5mg) is made.

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)。

Embodiment 42

6- (3- amino-5-phenyl -1,2,4- triazine -6- base) quinoline -8- formamide 42

Using 14 synthetic route of embodiment, first step raw material compound 14a is replaced with into compound 38b, title product 42 (14mg) is made.

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)。

Embodiment 43

6- (4- morpholine quinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 43

Using embodiment 39 similar to synthetic route, first step raw material compound 39a is replaced with into the bromo- 4- chloroquinoline 43a of 6- (using well known method " Journal of Medicinal Chemistry; 2015; 58 (14); 5522-5537 " is prepared), title compound 43 (50mg) is made.

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)。

Embodiment 44

6- (4- ethyl quinolinium -6- base) -5- (4- fluorophenyl) -1,2,4- triazine -3- amine 44

The first step

The bromo- 4- ethyl quinolinium 44a of 6-

By compound 14a (500mg, it 2.25mmol) is dissolved in 50mL tetrahydrofuran, at -78 DEG C, it is added dropwise lithium diisopropyl amido (723.54mg, 6.75mmol), is stirred to react 1 hour, iodomethane (3.20g is added, 22.51mmol), it is gradually warmed up room temperature, is stirred overnight.Saturated aqueous ammonium chloride is added, it is extracted with ethyl acetate three times, merge organic phase, it is washed once with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, it is concentrated under reduced pressure, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 44a (480mg), yield: 90.3% are obtained.

Using embodiment 25 similar to synthetic route, first step raw material compound 25a is replaced with into compound 44a, second step raw material compound 1c replaces with compound 8a, and title compound 44 (40mg) is made.

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)。

Embodiment 45

6- (the fluoro- 4- methylquinazolin -6- base of 8-) -5- phenyl -1,2,4- triazine -3- amine 45

The first step

The bromo- 3- fluorobenzonitrile 45b of 2- amino -5-

2- amino -3- fluorobenzonitrile 45a (1g, 7.35mmol, Shanghai Bepharm Science & Technology Co., Ltd.) is dissolved in 50mL methylene chloride, is added N- bromo-succinimide (1.37g, 7.71mmol), is stirred to react 16 hours.Add water, (50mL × 3) are extracted with dichloromethane, merge organic phase, (20mL) is washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, obtain title product 45b (1.25g), yield: 79.13%.

MS m/z(ESI):215.0[M+1]。

Second step

1- (2- amino -5- bromine-3-fluorophenyl) ethane -1- ketone 45c

By compound 45b (1g, it 4.65mmol) is dissolved in 60mL tetrahydrofuran, at -10 DEG C, methyl-magnesium-bromide (2.77g is added dropwise, 23.25mmol), reaction solution stirs 4 hours, add water, be extracted with ethyl acetate (20mL × 3), merges organic phase, (20mL) is washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, obtain title product 45c (900mg), yield: 83.41%.

Third step

The bromo- 8- fluorine 4- methylquinazolin 45d of 6-

By compound 45c (0.9g, 3.88mmol), triethyl orthoformate (862mg, 5.82mmol) and ammonium acetate (448mg, 5.82mmol) are added in 250mL single port bottle, at 110 DEG C, are stirred 2 hours.Cooling, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, obtains title product 45d (300mg), yield: 32.09%.

MS m/z(ESI):241.0[M+1]。

Using the synthetic route of embodiment 34, first step raw material compound 34a is replaced with into compound 45d, title product 45 (40mg) is made.Yield: 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)。

Embodiment 46

5- (4- chlorphenyl) -6- (4- methylquinazolin -6- base) -1,2,4- triazine -3- amine 46

Using the synthetic route of embodiment 15, third step raw material compound 1c is replaced with into the bromo- 5- of 6- (4- chlorphenyl) -1,2,4- triazine -3- amine 46a (is prepared) using the method " WO201195625A1 " of patent application publication, title product 46 (42mg), yield: 34.38% is made.

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)。

Embodiment 47

6- (4- ethyl -8- fluorine quinoline -6- base) -5- phenyl -1,2,4- triazine -3- amine 47

The first step

The bromo- 4- ethyl -8- fluorine quinoline 47a of 6-

Under argon atmospher, compound 16c (480mg, 2.00mmol) is dissolved in 10mL tetrahydrofuran, at -78 DEG C, it is added dropwise lithium diisopropylamine (257.02mg, 2.40mmol), stirs 1 hour, it adds iodomethane (297.98mg, 2.10mmol), stirs 2 hours.Add water, (30mL × 3) are extracted with ethyl acetate, merge organic phase, (20mL) is washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 47a (120mg), yield: 23.6% are obtained.

Using the synthetic route of embodiment 14, first step raw material compound 14a is replaced with into compound 47a, title product is made by 47 (30mg).Yield: 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)。

Embodiment 48

5- (2- picoline -4- base) -6- (4- methylquinoline -6- base) -1,2,4- triazine -3- amine 48

The first step

2- (2- picoline -4- base) -2- oxoacetaldehyde 48b

By 1- (2- picoline -4- base) ethyl -1- ketone 48a (4.29g, 31.74mmol, using well known method " Journal of Medicinal Chemistry; 2015; 58 (12); 5028-5037 " is prepared) be dissolved in 35mL dimethyl sulfoxide, add 35mL hydrobromic acid, 55 DEG C of reactions are overnight.Reaction solution is directly used in next step.

Second step

5- (2- picoline -4- base) -3- methyl mercapto -1,2,4- triazine 48c

By the different sulphur semicarbazides hydriodate (8.87g of S- methyl, 38.06mmol) and sodium bicarbonate (28g, it 333.31mmol) is added in 300mL ethyl alcohol, is then slowly added into crude Compound 48b (4.73g, 31.71mmol) reaction solution.It finishes, under the conditions of 80 DEG C, is stirred to react 1 hour.It is concentrated under reduced pressure, add water, it is extracted with ethyl acetate (100mL × 2), merges organic phase, wash (80mL × 3), saturated sodium chloride solution washs (80mL), anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, obtain title product 48c (5.6g), yield: 80.90%.

MS m/z(ESI):219.4[M+1]。

Third step

5- (2- picoline -4- base) -3- mesyl -1,2,4- triazine 48d

Compound 48c (5.4g, 24.74mmol) is dissolved in 180mL methylene chloride, adds metachloroperbenzoic acid (8g, 46.36mmol).It is stirred to react 3 hours.Filtering, filtrate decompression concentration obtain crude title product 48d (8.5g), and product without further purification, is directly used in next step.

4th step

5- (2- picoline -4- base) -1,2,4- triazine -3- amine 48e

Crude Compound 48d (8.5g, 33.96mmol) is dissolved in 80mL dioxane, 20mL ammonium hydroxide is added, is stirred to react 1 hour.It is concentrated under reduced pressure, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 48e (1.6g), yield: 25.17% are obtained.

MS m/z(ESI):188.1[M+1]。

5th step

The bromo- 5- of 6- (2- picoline -4- base) -1,2,4- triazine -3- amine 48f

Compound 48e (1.6g, 8.55mmol) is added in 200mL acetonitrile, N- bromo-succinimide (3.80g, 21.37mmol) and trifluoroacetic acid (1.95g, 17.09mmol) are added, is stirred 64 hours.It is concentrated under reduced pressure, water is added, (100mL × 3) are extracted with ethyl acetate in water phase, merge organic phase, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, and title product 48f (1.87g), yield: 82.22% are obtained.

6th step

5- (2- picoline -4- base) -6- (4- methylquinoline -6- base) -1,2,4- triazine -3- amine 48

Under argon atmospher, by compound 14b (100mg, 375 μm of ol), compound 48f (101mg, 375 μm of ol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (55mg, 75 μm of ol) and potassium carbonate (155mg, 1.13mmol) it is dissolved in 12mL 1, in the mixed solution of 4- dioxane and water (V:V=5:1), under the conditions of 80 DEG C, stir 2 hours.Cooling, diatomite filtering, filtrate decompression is concentrated, and residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system A, obtains title product 48 (30mg), yield: 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)。

Embodiment 49

6- (4- cyclopropyl quinoline -6- base) -5- (4- fluorophenyl) -1,2,4- triazine -3- amine 49

The first step

The bromo- 4- iodine quinoline 49b of 6-

The Isosorbide-5-Nitrae of the 4M hydrogen chloride of 5mL-dioxane solution is added in the bromo- 4- chloroquinoline 49a (1g, 4.12mmol) of 6-, is stirred to react 10 minutes, reaction solution is concentrated under reduced pressure spare.60mL acetonitrile is added in the residue after above-mentioned concentration, adds sodium iodide (6.18g, 41.24mmol), under reflux, is stirred to react 16 hours.Reaction solution is cooled to room temperature, it is concentrated under reduced pressure, add saturated sodium bicarbonate solution, it is extracted with ethyl acetate (20mL × 3), merges organic phase, anhydrous sodium sulfate is dry, it is concentrated under reduced pressure, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 49b (850mg), yield: 61.72% are obtained.

MS m/z(ESI):333.9[M+1]。

Second step

The bromo- 4- cyclopropyl quinoline 49c of 6-

Under argon atmospher, by compound 49b (350mg, 1.05mmol), cyclopropylboronic acid (99mg, 1.15mmol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (153mg, 209 μm of ol) and potassium carbonate (433mg, 3.14mmol) it is added the 1 of 30mL, in 4- dioxane, under the conditions of 80 DEG C, stir 16 hours.It is cooling, it filters, is concentrated under reduced pressure, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 49c (110mg), yield: 42.30% are obtained.

MS m/z(ESI):250.1[M+1]。

Using the synthetic route of embodiment 22, second step raw material compound 22a is replaced with into compound 49c, title product 49 (40mg), yield: 27.53% is made.

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)。

Embodiment 50

6- (the fluoro- 4- methylquinazolin -6- base of 8-) 5- (4- fluorophenyl) -1,2,4- triazine -3- amine 50

Using the synthetic route of embodiment 22, second step raw material compound 22a is replaced with into compound 45d, title product 50 (54mg) is made.Yield: 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)。

Embodiment 51

6- (4- (difluoromethyl) quinoline -6- base) -5- (4- fluorophenyl) -1,2,4- triazine -3- amine 51

The first step

6- bromoquinoline -4- formaldehyde 51a

Compound 14a (1.0g, 4.50mmol) is dissolved in 20mL Isosorbide-5-Nitrae-dioxane, 2mL water is added, adds selenium dioxide (1.5g, 13.51mmol), under the conditions of 80 DEG C, is stirred to react 16 hours.Reaction solution is cooled to room temperature, saturated sodium bicarbonate solution is added, ethyl acetate extracts (30mL × 3), merges organic phase, and organic phase is washed with saturated sodium chloride solution, sodium sulphate is dry, filtering, filtrate decompression concentration, residue silica gel column chromatography is with solvent system B purifying, obtain title compound 51a (670mg), yield: 63.0%.

Second step

6- bromo- 4- (difluoromethyl) quinoline 51b

Compound 51a (670mg, 2.84mmol) is dissolved in 20mL methylene chloride, is added dropwise diethylaminosulfurtrifluoride (915mg, 5.68mmol), is stirred to react 16 hours.Saturated sodium bicarbonate solution is added, stirs 30 minutes.Methylene chloride extracts (20mL × 3), merge organic phase, organic phase is washed with saturated sodium chloride solution, sodium sulphate is dry, filtering, filtrate decompression concentration, residue silica gel column chromatography is with solvent system B purifying, obtain title compound 51b (630mg), yield: 86.0%.

Using embodiment 25 similar to synthetic route, first step raw material compound 25a is replaced with into compound 51b, second step raw material compound 1c replaces with compound 8a, and title compound 51 (55mg) is made.

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)。

Embodiment 52

5- (4- fluorophenyl) -6- (4- (methyl-d3) quinazoline -6- base) -1,2,4- triazole -3- amine 52

The first step

The bromo- 4- of 6- (methyl-d3) quinazoline 52a

Compound 15b (200mg, 0.90mmol) is suspended in 4mL heavy water, is added benzoic acid (10.95mg, 0.09mmol), at 100 DEG C, is stirred 48 hours.Saturated sodium bicarbonate solution is added, ethyl acetate extracts (20mL × 3), merges organic phase, and organic phase is washed with saturated sodium chloride solution, and sodium sulphate dries, filters, filtrate decompression concentration.Residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title compound 52a (150mg), yield: 74.0% are obtained.

Using embodiment 25 similar to synthetic route, first step raw material compound 25a is replaced with into compound 52a, second step raw material compound 1c replaces with compound 8a, and title compound 52 (18mg) is made.

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)。

Embodiment 53

6- (4- ethyl quinazoline -6- base) -5- (4- fluorophenyl) -1,2,4- triazine -3- amine 53

The first step

1- (2- amino -5- bromophenyl) propyl- 1- ketone 53b

By 2- amino -5- bromobenzylcyanide 53a (500mg, 2.54mmol, using well known method " European Journal of Medicinal Chemistry; 2014,76,341-343 " is prepared) be dissolved in 10mL tetrahydrofuran, ice bath is cooling, under argon atmospher, the 1.0M ethylmagnesium bromide of 12.69mL is added dropwise, stirs 2 hours.6M hydrochloric acid is added, stirs 2 hours.Saturated sodium carbonate solution is added, ethyl acetate extracts (50mL × 3), merge organic phase, organic phase is washed with saturated sodium chloride solution, and sodium sulphate dries, filters, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title compound 53b (440mg), yield: 76.02% are obtained.

Second step

The bromo- 4- ethyl quinazoline 53c of 6-

By compound 53b (440mg, 1.93mmol), triethyl orthoformate (857.68mg, 5.79mmol) and ammonium acetate (451.14mg, 5.79mmol) mixing are heated to 110 DEG C, are stirred to react 16 hours.Saturated sodium carbonate solution is added, ethyl acetate extracts (20mL × 3), merge organic phase, organic phase is washed with saturated sodium chloride solution, and sodium sulphate dries, filters, filtrate decompression concentration, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title compound 53c (280mg), yield: 61.22% are obtained.

Using embodiment 25 similar to synthetic route, first step raw material compound 25a is replaced with into compound 53c, second step raw material compound 1c replaces with compound 8a, and title compound 53 (45mg) is made.

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)。

Embodiment 54

5- (4- fluorophenyl) -6- [4- (trifluoromethyl) quinoline -6- base] -1,2,4- triazine -3- amine 54

The first step

Bromo- -2 (1H) the -one 54b of 4- Trifluoromethylquinocarboxylic of 6-

Trifluoroacetic ethyl acetoacetate (1.24g, 6.75mmol) and triethylamine (1.65g, 16.28mmol) are added in 20mL toluene, then the toluene solution of 3mL 2.7M dropwise addition 4- bromaniline 54a, under counterflow condition, stir 16 hours.Reaction solution is concentrated under reduced pressure, and adds 30mL methylene chloride to dissolve, is washed with water (20mL × 2), and saturated sodium chloride solution washs (20mL), and anhydrous sodium sulfate dries, filters, filtrate decompression concentration.6mL sulfuric acid is added in gained intermediate, under the conditions of 100 DEG C, stirs 4 hours, reaction solution is cooled to room temperature, saturated sodium bicarbonate tune pH is added dropwise and is greater than 10, is extracted with ethyl acetate (30mL × 3), merges organic phase, anhydrous sodium sulfate is dry, filtering, filtrate decompression concentration, residue are purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, obtain title product 54b (1.5g), yield: 63.70%.

MS m/z(ESI):291.9[M+1]。

Second step

The bromo- 2- of 6- chloro- 4- (trifluoromethyl) quinoline 54c

Phosphorus oxychloride (4.73g, 30.82mmol) is added in compound 54b (1.5g, 5.14mmol), under the conditions of 100 DEG C, stirs 5 hours.It is cooling, it is added in ice water, stirs 30 minutes, it is extracted with ethyl acetate (50mL × 3), merges organic phase, anhydrous sodium sulfate is dry, it is concentrated under reduced pressure, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 54c (1.3g) is obtained.Yield: 81.52%.

Third step

The bromo- 4- Trifluoromethylquinocarboxylic 54d of 6-

Compound 54c (500mg, 1.61mmol) is dissolved in 8mL trifluoroacetic acid, is added zinc powder (842mg, 12.88mmol), reaction solution stirs 16 hours.Filtering is concentrated under reduced pressure.1M sodium hydroxide is added dropwise and is greater than 10 to residue pH, is extracted with ethyl acetate (30mL × 3), merges organic phase, anhydrous sodium sulfate is dry, it is concentrated under reduced pressure, residue is purified with the quick preparing instrument of CombiFlash with eluant, eluent system B, and title product 54d (200mg) is obtained.Yield: 44.99%.

MS m/z(ESI):275.8[M+1]。

Using the synthetic route of embodiment 22, second step raw material compound 22a is replaced with into compound 54d, title product 54 (30mg) is made.

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)。

Embodiment 55

5- (4- fluorophenyl) -6- (4- methoxyquinazoline hydrochloride -6- base) -1,2,4- triazine -3- amine 55

The first step

The bromo- 4- methoxyquinazoline hydrochloride 55b of 6-

The bromo- 4- chloro-quinazoline 55a (1.0g, 4.10mmol) of 6- is dissolved in 80mL methanol, is added sodium methoxide (2.21g, 41.05mmol), is stirred to react 3 hours.It is spin-dried for, adds water, filter, filtration cakes torrefaction obtains product 55b (0.55g).Yield: 56.01%.

MS m/z(ESI):239.1[M+1]

Using the synthetic route of embodiment 22, second step raw material compound 22a is replaced with into compound 55b, title product 55 (40mg) is made.Yield: 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)。

Test case:

Biological assessment

Test case 1, the compounds of this invention are to adenosine A _2aReceptor (adenosine A _2aReceptor, A _2aR) cAMP signal path, adenosine A _2bReceptor (adenosine A _2bReceptor, A _2bR) cAMP signal path, adenosine A ₁Receptor (adenosine A ₁Receptor, A ₁R) cAMP signal path and adenosine A ₃Receptor (adenosine A ₃Receptor, A ₃R) the measurement of cAMP signal path inhibitory activity.

Following methods are used to measure the compounds of this invention to adenosine A _2aReceptor (adenosine A _2aReceptor, A _2aR) cAMP signal path, adenosine A _2bReceptor cAMP signal path, adenosine A ₁Receptor cAMP signal path and adenosine A ₃The inhibitory activity of receptor cAMP signal path.Experimental method is summarized as follows:

One, experimental material and instrument

1.CHO-K1/A _2aR cell (NM_000675.5) or CHO-K1/A _2bR cell (NM_000676.2) or CHO-K1/A ₁R cell (NM_000674.2) or CHO-K1/A ₃R cell (NM_000677.3)

2. fetal calf serum (Gibco, 10099-141)

3. bleomycin (Thermo, R25001) or G418 (ENZO, ALX-380-013-G005) or puromycin (Thermo, 10687-010)

4.DMEM/F12 culture medium (GE, SH30023.01)

5. cell dissociating buffer (Thermo Fisher, 13151014)

6.HEPES(Gibco,42360-099)

7. bovine serum albumin(BSA) (MP Biomedicals, 219989725)

8. rolipram (sigma, R6520-10MG)

9. adenosine deaminase (sigma, 10102105001)

10. forskolin (sigma, F6886)

11.2Cl-IB-MECA(Tocrics,1104/10)

12.N6- UK 80882 (Tocris, 1702/50)

13. balanced salt solution (Thermo, 14025-092)

14.cAMP 2 kits of dynamic (cAMP dynamic 2kit) (Cisbio, 62AM4PEB)

15.384 orifice plates (Corning, 4514) or (Nunc, 267462#)

16. ethyl carbazole (Torcis, 1691/10)

17.PHERAstar multi-function microplate reader (Cisbio, 62AM4PEB)

Two, experimental procedure

2.1 adenosine A _2aReceptor

CHO-K1/A _2aR cell is cultivated with the DMEM/F12 culture medium containing 10% fetal calf serum and 800 μ g/ml bleomycins.Cell dissociating buffer vitellophag is used when experiment, and with cell is resuspended containing the balanced salt solution of 20mM HEPES and 0.1% bovine serum albumin(BSA) and counts, cell density is adjusted to 10 ⁶A/ml.5 μ l cell suspensions are added in every hole in 384 orifice plates, and 2.5 μ l, which are used, contains 20mM HEPES, 0.1% bovine serum albumin(BSA), and the test-compound for 4 × concentration that the balanced salt solution of 54 μM of roliprams and 2.7U/ml adenosine deaminase is prepared is incubated at room temperature 30 minutes.Every hole adds 2.5 μ l and uses containing 20mM HEPES, 0.1% bovine serum albumin(BSA), and the ethyl carbazole of 4 × concentration of the balanced salt solution preparation of 54 μM of roliprams and 2.7U/ml adenosine deaminase is incubated at room temperature 30 minutes.Final compound concentration is: 10000,2000,400,80,16,3.2,0.64,0.128,0.0256,0.00512,0.001024nM, ethyl carbazole final concentration is 20nM.Intracellular cAMP concentration is detected using cAMP 2 kits of dynamic.CAMP-d2 and anti-cAMP-Eu- cryptate (Anti-cAMP-Eu-Cryptate) are diluted respectively in the ratio of 1:4 with cAMP lysis buffer.The cAMP-d2 after 5 μ l dilution is added in every hole, and the anti-cAMP-Eu- cryptate after adding 5 μ l dilution, room temperature is protected from light incubation 1 hour.HTRF signal value is read using PHERAstar multi-function microplate reader.The IC of compound inhibitory activity is calculated with Graphpad Prism software ₅₀Value, is shown in Table 1.

2.2 adenosine A _2bReceptor

CHO-K1/A _2bR is cultivated with the DMEM/F12 culture medium containing 10% fetal calf serum and 1mg/ml G418.Cell dissociating buffer vitellophag is used when experiment, and with cell is resuspended containing the balanced salt solution of 20mM HEPES and 0.1% bovine serum albumin(BSA) and counts, cell density is adjusted to 10 ⁶A/ml.5 μ l cell suspensions are added in every hole in 384 orifice plates, and 2.5 μ l, which are used, contains 20mM HEPES, 0.1% bovine serum albumin(BSA), and the test-compound for 4 × concentration that the balanced salt solution of 54 μM of roliprams and 2.7U/ml adenosine deaminase is prepared is incubated at room temperature 30 minutes.Every hole, which adds 2.5 μ l and uses, contains 20mM HEPES, 0.1% bovine serum albumin(BSA), the ethyl carbazole (Torcis, 1691/10) for 4 × concentration that the balanced salt solution of 54 μM of roliprams and 2.7U/ml adenosine deaminase is prepared is incubated at room temperature 30 minutes.Final compound concentration is: 100000,10000,1000,100,10,1,0.1 and 0nM, and ethyl carbazole final concentration is 1 μM.Intracellular cAMP concentration is detected using cAMP 2 kits of dynamic.CAMP-d2 and anti-cAMP-Eu- cryptate are diluted respectively in the ratio of 1:4 with cAMP lysis buffer.The cAMP-d2 after 5 μ l dilution is added in every hole, and the anti-cAMP-Eu- cryptate after adding 5 μ l dilution, room temperature is protected from light incubation 1 hour.HTRF signal value is read using PHERAstar multi-function microplate reader.The IC of compound inhibitory activity is calculated with Graphpad Prism software ₅₀Value, is shown in Table 2.

2.3 adenosine A ₁Receptor

CHO-K1/A ₁R is cultivated with the DMEM/F12 culture medium containing 10% fetal calf serum and 1mg/mlG418.Cell dissociating buffer vitellophag is used when experiment, and then with cell is resuspended containing the balanced salt solution of 20mM HEPES and 0.1% bovine serum albumin(BSA) and counts, cell density is adjusted to 5 × 10 ⁵A/ml.12.5 μ l cell suspensions are added in every hole in 384 orifice plates, 6.25 μ l, which are used, contains 20mM HEPES, the test-compound for 4 × concentration that the balanced salt solution of 0.1% bovine serum albumin(BSA), 54 μM of roliprams and 2.7U/ml adenosine deaminase is prepared is incubated at room temperature 30 minutes.Every hole adds 6.25 μ l and uses containing 20mM HEPES, 0.1% bovine serum albumin(BSA), and the forskolin and n6-cyclopentyl adenosine of 4 × concentration of the balanced salt solution preparation of 54 μM of roliprams and 2.7U/ml adenosine deaminase are incubated at room temperature 30 minutes.Final compound concentration is: 100000,10000,1000,100,10,1,0.1 and 0nM, and the final concentration of forskolin is 10 μM, and the final concentration of CPA is 10nM.Intracellular cAMP concentration is detected using cAMP 2 kits of dynamic.CAMP-d2 and anti-cAMP-Eu- cryptate are diluted respectively according to the ratio of 1:4 with cAMP lysis buffer.The cAMP-d2 after 12.5 μ l dilution is added in every hole, and the anti-cAMP-Eu- cryptate after adding 12.5 μ l dilution, room temperature is protected from light incubation 1 hour.HTRF signal value is read using PHERAstar multi-function microplate reader.The IC of compound inhibitory activity is calculated with Graphpad Prism software ₅₀Value, is shown in Table 3.

2.4 adenosine A ₃Receptor

CHO-K1/A ₃R is cultivated with the DMEM/F12 culture medium containing 10% fetal calf serum and 10 μ g/ml puromycins.Cell dissociating buffer vitellophag is used when experiment, and with cell is resuspended containing the balanced salt solution of 20mM HEPES and 0.1% bovine serum albumin(BSA) and counts, cell density is adjusted to 5 × 10 ⁵/ml.12.5 μ l cell suspensions are added in every hole in 384 orifice plates, 6.25 μ l, which are used, contains 20mM HEPES, the test-compound for 4 × concentration that the balanced salt solution of 0.1% bovine serum albumin(BSA), 54 μM of roliprams and 2.7U/ml adenosine deaminase is prepared is incubated at room temperature 30 minutes.Every hole adds 6.25 μ l and uses containing 20mM HEPES, 0.1% bovine serum albumin(BSA), and the forskolin and 2Cl-IB-MECA of 4 × concentration of the balanced salt solution preparation of 54 μM of roliprams and 2.7U/ml adenosine deaminase are incubated at room temperature 30 minutes.Final compound concentration is: 100000,10000,1000,100,10,1,0.1 and 0nM, and the final concentration of forskolin is 10 μM, and the final concentration of 2Cl-IB-MECA is 5nM.Intracellular cAMP concentration is detected using cAMP 2 kits of dynamic.CAMP-d2 and anti-cAMP-Eu- cryptate are diluted respectively according to the ratio of 1:4 with cAMP lysis buffer.The cAMP-d2 after 12.5 μ l dilution is added in every hole, and the anti-cAMP-Eu- cryptate after adding 12.5 μ l dilution, room temperature is protected from light incubation 1 hour.HTRF signal value is read using PHERAstar multi-function microplate reader.The IC of compound inhibitory activity is calculated with Graphpad Prism software ₅₀Value, is shown in Table 3.

1 the compounds of this invention of table is to adenosine A _2aReceptor (adenosine A _2aReceptor, A _2aR) the IC of cAMP signal path inhibitory activity ₅₀Value.

Conclusion: the compounds of this invention is to adenosine A _2aReceptor has apparent inhibitory activity, nitrogen-atoms is introduced in the thick aryl moiety of parent nucleus compared with comparative example 1, so that the compounds of this invention is to adenosine A _2aThe inhibiting effect of receptor achieves unexpected effect, and comparative example 1 is compared with embodiment 3, and the two architectural difference is only that embodiment 3 introduces nitrogen-atoms on 5 of the naphthalene of comparative example 1, to adenosine A _2aThe inhibitory activity of receptor differs 225 times.

2 the compounds of this invention of table is to adenosine A _2bReceptor (adenosine A _2bReceptor, A _2bR) the IC of cAMP signal path inhibitory activity ₅₀Value.

Embodiment number	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

Conclusion: the compounds of this invention is to adenosine A _2bReceptor has preferable inhibitory activity.

3 the compounds of this invention of table is to adenosine A ₁Receptor (adenosine A ₁Receptor, A ₁R) cAMP signal path and adenosine A ₃The IC of receptor cAMP signal path inhibitory activity ₅₀Value.

Conclusion: the compounds of this invention is to adenosine A ₁Receptor and adenosine A ₃Receptor inhibiting activity effect is weaker, illustrates the compounds of this invention to adenosine A _2aReceptor and adenosine A _2bReceptor has selectivity, especially to adenosine A _2aReceptor.

Pharmacokinetic Evaluation

The mouse pharmacokinetics test of test case 2, the compounds of this invention

1, it makes a summary

Using mouse as animal subject, intragastric administration on mice is determined using LC/MS/MS method and gives drug concentration after 2 compound of embodiment, 3 compound of embodiment, 17 compound of embodiment, 18 compound of embodiment, 19 compound of embodiment, 20 compound of embodiment, 31 compound of embodiment and embodiment 44 in different moments blood plasma.The compounds of this invention is studied in the intracorporal pharmacokinetics behavior of mouse, evaluates its characteristics of pharmacokinetics.

2, testing program

2.1 test drug

2 compound of embodiment, 3 compound of embodiment, 17 compound of embodiment, 18 compound of embodiment, 19 compound of embodiment, 20 compound of embodiment, 31 compound of embodiment and embodiment 44.

2.2 experimental animal

C57 mouse 72, female is divided into 8 groups, every group 9, is purchased from Shanghai Jie Sijie experimental animal Co., Ltd, animal productiong licensing number: SCXK (Shanghai) 2013-0006.

2.3 drugs are prepared

A certain amount of drug is weighed, the DMSO of 5% volume, the tween80 of 5% volume and 90% physiological saline is added to be configured to 0.1mg/ml achromaticity and clarification transparency liquid.

2.4 administration

Gastric infusion after C57 mouse overnight fasting, dosage are 2.0mg/kg, and administered volume is 0.2ml/10g.

3, it operates

2 compound of embodiment, 3 compound of embodiment, 17 compound of embodiment, 18 compound of embodiment, 19 compound of embodiment, 20 compound of embodiment, 31 compound of embodiment and embodiment 44 is administered in intragastric administration on mice, before administration and 0.5,1.0,2.0 after administration, 4.0,6.0,8.0,11.0,24.0 hours blood sampling 0.1ml, it is placed in heparinised tubes, 3500 revs/min of centrifugations, 10 minutes separated plasmas, is saved in -20 DEG C.

Untested compound content after the drug gastric infusion of measurement various concentration in mice plasma: the 25 μ l of mice plasma at each moment after medicine is drawn, 50 μ l (100ng/mL) of inner mark solution camptothecine is added, 200 μ l of acetonitrile, vortex mixed 5 minutes, 10 minutes (4000 revs/min) are centrifuged, plasma sample takes 5 μ l of supernatant to carry out LC/MS/MS analysis.

4, pharmacokinetic parameter result

The pharmacokinetic parameter of the compounds of this invention is as follows:

Conclusion: in the medicine generation of the compounds of this invention, absorbs preferably, has pharmacokinetic advantage.

Claims (18)

1. A kind of logical formula (I) compound represented:

   Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt,

   Wherein:

   Ring A is aryl or heteroaryl；

   G ¹、G ²、G ³And G ⁴It is identical or different, and it is each independently selected from C, CH or N；

   R ¹Selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-OR ⁵、-C(O)R ⁵、-S(O) _mR ⁵、NH ₂S(O) _mR ⁵、-NR ⁶R ⁷、S(O) _mNR ⁶R ⁷With-C (O) NR ⁶R ⁷；Wherein alkyl, alkoxy, halogenated alkyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl and heteroaryl；

   R ²It is identical or different, and it is each independently selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-OR ⁵、-C(O)R ⁵、-S(O) _mR ⁵、NH ₂S(O) _mR ⁵、-NR ⁶R ⁷、S(O) _mNR ⁶R ⁷With-C (O) NR ⁶R ⁷；Wherein alkyl, alkoxy, halogenated alkyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl and heteroaryl；

   R ³It is identical or different, and it is each independently selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, deuteroalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-OR ⁵、-C(O)R ⁵、-S(O) _mR ⁵、NH ₂S(O) _mR ⁵、-NR ⁶R ⁷、S(O) _mNR ⁶R ⁷With-C (O) NR ⁶R ⁷；Wherein alkyl, alkoxy, halogenated alkyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in halogen, D-atom, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl and heteroaryl；

   R ⁴It is identical or different, and it is each independently selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl, heteroaryl ,-OR ⁵、-C(O)R ⁵、-S(O) _mR ⁵、NH ₂S(O) _mR ⁵、-NR ⁶R ⁷、S(O) _mNR ⁶R ⁷With-C (O) NR ⁶R ⁷；Wherein alkyl, alkoxy, halogenated alkyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in halogen, alkyl, alkoxy, halogenated alkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, naphthenic base, heterocycle, aryl and heteroaryl；

   R ⁵Selected from hydrogen atom, alkyl, halogenated alkyl, amino, hydroxyl, naphthenic base, heterocycle, aryl and heteroaryl；

   R ⁶And R ⁷It is each independently selected from hydrogen atom, alkyl, halogenated alkyl, naphthenic base, heterocycle, aryl and heteroaryl；Wherein alkyl, naphthenic base, heterocycle, aryl and the heteroaryl are each independently optionally replaced one or more substituent groups in alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

   Alternatively, the R ⁶And R ⁷Heterocycle is formed together with the nitrogen-atoms being connected, wherein in the heterocycle containing 1~2 identical or different hetero atom selected from N, O and S, and the heterocycle is optionally replaced one or more substituent groups in alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, naphthenic base, heterocycle, aryl and heteroaryl；

   M is 0,1 or 2；

   R is 0,1,2 or 3；

   Q is 0,1 or 2；And

   N is 0,1,2,3,4 or 5.
2. Logical formula (I) compound represented according to claim 1 is general formula (Iaa) compound represented:

   Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt,

   Wherein

   Ring A, G ¹、G ²、R ¹、R ³、R ⁴, r and n it is as defined in claim 1.
3. Logical formula (I) compound represented according to claim 1 or 2, to lead to formula (II) compound represented:

   Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt,

   Its middle ring A, R ¹、R ³、R ⁴, r and n it is as defined in claim 1.
4. Logical formula (I) compound represented described in any one of claim 1 to 3, wherein the ring A is selected from phenyl, pyridyl group, thienyl and furyl.
5. Logical formula (I) compound represented according to any one of claims 1 to 4, to lead to formula (III) compound represented:

   Or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt,

   Wherein R ¹、R ³、R ⁴, r and n it is as defined in claim 1.
6. Logical formula (I) compound represented according to any one of claims 1 to 5, wherein the R ¹Selected from hydrogen atom, halogen, alkyl, alkoxy, cyano, naphthenic base, halogenated alkyl, heterocycle and-C (O) NR ⁶R ⁷；R ⁶And R ⁷As defined in claim 1.
7. Logical formula (I) compound represented described according to claim 1~any one of 6, wherein the R ³It is identical or different, and it is each independently selected from hydrogen atom, halogen, alkyl, halogenated alkyl, deuteroalkyl, alkoxy, cyano, naphthenic base heterocycle, wherein the alkyl and alkoxy are each independently optionally replaced one or more substituent groups in halogen, D-atom, hydroxyl, cyano, amino, nitro, naphthenic base and heterocycle.
8. Logical formula (I) compound represented according to any one of claims 1 to 7, wherein the R ⁴It is identical or different, and it is each independently selected from hydrogen atom, alkyl and halogen.
9. According to claim 1, logical formula (I) compound represented described in~any one of 8, be selected from:
10. A method of logical formula (I) compound represented according to claim 1 is prepared, this method comprises:

    Coupling reaction occurs for the compound of general formula (I-A) and the compound of general formula (I-B), obtains the compound of logical formula (I),

    Wherein:

    X is halogen；

    M is

    Ring A, G ¹~G ⁴、R ¹~R ⁴, r, q and n it is as defined in claim 1.
11. A method of general formula according to claim 2 (Iaa) compound represented is prepared, this method comprises:

    Coupling reaction occurs for the compound of general formula (Iaa-1) and the compound of general formula (I-B), obtains the compound of general formula (Iaa),

    Wherein:

    X is halogen；

    M is

    Ring A, G ¹、G ²、R ¹、R ³、R ⁴, r and n it is as defined in claim 1.
12. A kind of pharmaceutical composition, described pharmaceutical composition contain therapeutically effective amount according to claim 1~any one of 9 described in logical formula (I) compound represented or its tautomer, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt and one or more pharmaceutically acceptable carriers, diluent or excipient.
13. Logical formula (I) compound represented or its tautomer described according to claim 1~any one of 9, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt or pharmaceutical composition according to claim 12 in preparation for treating by A _2aThe inhibition of receptor and the purposes in the drug of the improved patient's condition or illness.
14. Logical formula (I) compound represented or its tautomer described according to claim 1~any one of 9, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt or pharmaceutical composition according to claim 12 in preparation for treating by A _2bThe inhibition of receptor and the purposes in the drug of the improved patient's condition or illness.
15. Purposes described in 3 or 14 according to claim 1, wherein the patient's condition or illness is selected from the outer syndrome of cancer, depression, cognitive function illness, Neurodegenerative conditions, attention associated disease, cone, abnormal movement disorders, cirrhosis, liver fibrosis, fatty liver, fibrosis of skin, sleep disturbance, apoplexy, cerebral injury, neuroinflamation and Addictive Behaviors；Preferably cancer.
16. Purposes according to claim 15, wherein the cancer is selected from melanoma, brain tumor, the cancer of the esophagus, gastric cancer, liver cancer, cancer of pancreas, colorectal cancer, lung cancer, kidney, breast cancer, oophoroma, prostate cancer, cutaneum carcinoma, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, orchioncus, uterine cancer, H/N tumors, Huppert's disease, malignant lymphoma, polycythemia vera, leukaemia, thyroid tumors, tumor of ureter, bladder cancer, gallbladder cancer, cholangiocarcinoma, chorioepithelioma and pediatric tumors；Preferably lung cancer.
17. Logical formula (I) compound represented or its tautomer described according to claim 1~any one of 9, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt or pharmaceutical composition according to claim 12 in preparation for inhibiting A _2aPurposes in the drug of receptor.
18. Logical formula (I) compound represented or its tautomer described according to claim 1~any one of 9, mesomer, racemic modification, enantiomter, diastereoisomer, or mixtures thereof form or its pharmaceutical salt or pharmaceutical composition according to claim 12 in preparation for inhibiting A _2bPurposes in the drug of receptor.