CN106831776A - 5,10 dihydro pyrido pyrazine triazin compounds and its application - Google Patents
5,10 dihydro pyrido pyrazine triazin compounds and its application Download PDFInfo
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- CN106831776A CN106831776A CN201710158925.2A CN201710158925A CN106831776A CN 106831776 A CN106831776 A CN 106831776A CN 201710158925 A CN201710158925 A CN 201710158925A CN 106831776 A CN106831776 A CN 106831776A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Abstract
The present invention relates to 5,10 dihydro pyridos [2 ', 3 ' shown in formula I:5,6] pyrazine simultaneously [2,3 e] [1,2,4] compound in triazine class, and its optically active body or raceme or its pharmaceutically acceptable salt, hydrate or solvate, wherein substituent R1、R2There is the implication for being given in the description with A.The invention further relates to the purposes of the compound in the medicine for the treatment of and/or pre- anti-cancer and other proliferative diseases is prepared of formula I.The general structure I of such compound is as follows：
Description
Technical field
The present invention relates to new 5,10- dihydro pyridos [2 ', 3 ':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazines
Compound, and its optically active body or raceme or pharmaceutically acceptable salt, hydrate or solvate, their preparation method with
And the pharmaceutical composition containing the compound.The invention further relates to 5,10- dihydro pyridos [2 ', 3 ':5,6] pyrazine simultaneously [2,3-
E] purposes of [1,2,4] compound in triazine class for preparation treatment and/or pre- anti-cancer in the medicine with other proliferative diseases.
Background technology
After Tumor dormancy typically refers to clinically primary tumo(u)r radical excision, there is Tumorlet stove or micro in patient's body
Tumour cell, is not both removed in the range of certain hour by body, does not also breed growth, but these tumour cells still have
Proliferation potential, can breed again, lead oncogenic recurrence or transfer.Evidence show immunosupress, new vessels are generated and outer
The factors such as section's operation can make Tumor dormancy cell-stimulating.However, because the tumour cell being in hibernation does not occur active proliferation,
Therefore traditional Radiotherapy chemotherapy can not be by its effective removing, so as to the thorough healing to tumour causes very big difficulty.This phenomenon
It is to cause malignant tumour to be difficult to the first cause for effecting a radical cure, is also the main mechanism of tumor escape treatment.
Recent years, the adoptive immunity cell therapy of cancer was developed rapidly, and 2013 by the U.S.《Science》Magazine is chosen
It is one of ten big sciences breakthrough.The immunotherapy of cancer can drive the tumour cell of the mankind to enter permanent park mode, so may be used
Body itself is defendd from cancer to suppress tumour growth.It is high to glycometabolism using cell mitochondrial in addition to immunotherapy
The characteristics of degree is sensitive, the kill Tumor dormancy cell of selectivity has become the new focus of tumor research, wherein important target spot
There are the LKB-AMPK-p53 approach and PI3K-Akt- of HIF, TNF-α and the NF- κ B and low sugar state that act on tumor hypoxia state
MTOR approach, and oxidative phosphorylation (OXPHOS) approach.Antitumor activity is wherein played by mitochondria dysfunction approach
Compound mainly have：Elesclomol (Elesclomol), diacetyl diphenolisatin (NSC 59687), 6-OHDA, parithenolide
(Parthenolide), CR108, HMJ-38, honokiol (Honokiol) etc..
This is primarily due in the case of high glucose, thin with normal for the very big proliferating cancer cells of ATP demands
Born of the same parents can provide energy by two approach, and one is that mitochondrial oxidative phosphorylation produces ATP；Another is hypoxia inducible
The glycolysis that the α of the factor -1 (HIF-1 α) is produced.VLX600 can make initiation mitochondria dysfunction so that mitochondria can not be aoxidized
Phosphorylation produces ATP.For proliferating cancer cells, because a large amount of ATP required for only passing through glycolytic pathway can not be expired
Foot, therefore there is autophagy in tumour cell.And normal human cell is less due to required ATP, therefore only carried by glycolytic pathway
Just can meet needs for ATP, autophagy will not occur.Dormancy tumour cell under LG environment is in default of HIF-1
α, unlikely that mitochondrial function defect is compensated by glycolytic pathway, after mitochondria is suppressed, the ATP needed for cell is tight
Lacking again causes dormancy tumour cell that autophagy occurs.
Research has shown that, there is the mechanism of action of autophagy and ferric ion (Fe in above-mentioned dormancy tumour cell3+) close phase
Close, it plays important role during the growth and breeding of tumour.Tumor cell proliferation and DNA are closed compared with normal cell
Into speed accelerate, it is necessary to more Fe3+Participation.Have confirmed that can play tumor cytotoxicity by following approach makees at present
With：(1) suppress ribonucleotide reductase, break the duplication and reparation of DNA in garland cells；(2) one in influence cell cycle process
The expression of a little important cyclins, the arresting cell cycle G1/S phases, prevents cell growth；(3) p53 is used as suppression cancer
Gene, can be with inducing cell cycle arrest or Apoptosis, Fe3+Chelating agent is capable of the level of the α of the activation-inducing anoxic factor -1, makes
Tumor suppressor protein p53 stabilizations are expressed；(4) by redox reaction, reactive oxygen species is produced, plays killing functions of immunocytes.
The iron chelator with antitumor activity in recent years containing fragrant hydrazone structure fragment be constantly reported as PIH,
PKIH, 2-NPE-PIH, 311 etc., report to act on and mitochondrial contain aryl hydrazone structure micromolecular compound VLX- for 2014
600, its colon cancer cell that can kill dormancy by tumour cell autophagy in experiments in vivo and isolated experiment, and
Toxic and side effect (Zhang, X. are nearly free to normal competent cell；M.；Hernlund,E.；Fayad,W.；De
Milito,A.；Olofsson,M.H.；Gogvadze,V.；Dang,L.；S.；Schughart,L.A.K.；
Rickardson,L.；D′Arcy,P.；Gullbo,J.；Nygren,P.；Larsson,R.；Linder,S.,Induction of
mitochondrial dysfunction as a strategy for targeting tumour cells in
metabolically compromised microenvironments.Nat Commun, 2014,5.)。
WO 2014/046589 discloses a series of substituted and the like, and such compound is capable of the effect of selectivity
In Tumor dormancy cell, and being capable of Induces Autophagy.Such compound can suppress the growth of malignant proliferating cell, moreover it is possible to hinder
The diffusion of disconnected abnormal cell.
On the basis of bibliography, design has synthesized a series of 5,10- dihydro pyridos [2 ', 3 ' to the present invention:5,6] pyrrole
Piperazine simultaneously [2,3-e] [1,2,4] compound in triazine class, through carrying out antitumor activity screening to various tumor cell strains in vitro, as a result
Show with antitumor activity.
On the basis of bibliography, design has synthesized a series of 5,10- dihydro pyridos [2 ', 3 ' to the present invention:5,6] pyrrole
Piperazine simultaneously [2,3-e] [1,2,4] compound in triazine class, through carrying out antitumor activity screening to various tumor cell strains in vitro, as a result
Show with antitumor activity.
The content of the invention
The present invention relates to the 5,10- dihydro pyridos [2 ', 3 ' shown in formula I:5,6] pyrazine simultaneously [2,3-e] [1,2,4] three
Piperazine class compound, and its optically active body or raceme or its pharmaceutically acceptable salt, hydrate or solvate,
Wherein：
R1It is H, C1-C6Alkyl；R2It is H, C1-C6Alkyl；
A is aryl, aryl C1-C4Alkyl, C3-C6Cycloalkyl, C3-C6Cycloalkyl C1-C4Alkyl, 5-10 unit's heteroaryls, 5-10
Unit's heteroaryl C1-C4Alkyl, 5-10 unit saturation or fractional saturation heterocyclic radical, 5-10 unit saturation or fractional saturation heterocyclic radical
C1-C4Alkyl；The heteroaryl or heterocyclic radical contain the 1-3 hetero atom selected from O, N or S, and the optional 1-3 R of A3Substitution；
R3It is halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, azido, nitro, cyano group, sulfydryl, (C1-
C4) alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, (C1-C4) alkoxy, (C1-C4) alkylthio group, hydroxyl (C1-C4) alkyl, amino
(C1-C4) alkyl, pi-allyl, (2- methyl) pi-allyl, (C1-C4) alkylamidoalkyl, (C1-C4) alkyl sulphinyl, (C1-C4)
Alkyl sulphonyl, (C1-C4) alkoxy methyl, (C1-C4) alkyl acyl, carbamoyl, N- (C1-C4) alkyl carbamoyl
The base, (C of N, N- bis-1-C4) alkyl-carbamoyl, amino-sulfonyl, N- (C1-C4) the alkyl amino sulfonyl, (C of N, N- bis-1-C4)
Alkyl amino sulfonyl, or (C1-C3) alkylenedioxy group,
Or R3For-NR4R5；
R4、R5It is identical or different, separately select C1-C6Alkyl, C3-C6Cycloalkyl, they can by 1-3 it is identical or
Different R6It is optionally substituted；Or R4、R55-10 units saturated heterocyclyl is formed together with the nitrogen-atoms being connected with them, it is described full
With heterocyclic radical except with R4And R5Outside the nitrogen-atoms of connection, can be containing the 1-3 hetero atom selected from O, N or S, optionally by 1~3
Individual identical or different R6Substitution；
R6It is C1-C4Alkyl.
The compound of the formula I present invention is preferably related to be defined as follows, and its optically active body or raceme or its pharmacy
Upper acceptable salt, hydrate or solvate,
Wherein, R1It is H, C1-C4Alkyl；R2It is H, C1-C4Alkyl；
A is aryl, aryl C1-C4Alkyl, 5-10 unit's heteroaryls, the heteroaryl contains the 1-3 miscellaneous original selected from O, N and S
Son, and the optional 1-3 R of A3Substitution；
R3It is halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, azido, nitro, cyano group, sulfydryl, (C1-
C4) alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, (C1-C4) alkoxy, (C1-C4) alkylthio group, hydroxyl (C1-C4) alkyl, amino
(C1-C4) alkyl, pi-allyl, (2- methyl) pi-allyl, (C1-C4) alkyl amido, (C1-C4) alkyl sulphinyl, (C1-C4)
Alkyl sulphonyl, (C1-C4) alkoxy methyl, (C1-C4) alkyl acyl, carbamoyl, N- (C1-C4) alkyl carbamoyl
The base, (C of N, N- bis-1-C4) alkyl-carbamoyl, amino-sulfonyl, N- (C1-C4) the alkyl amino sulfonyl, (C of N, N- bis-1-C4)
Alkyl amino sulfonyl, or (C1-C3) alkylenedioxy group,
Or R3For-NR4R5；
R4、R5It is identical or different, separately select C1-C6Alkyl, C3-C6Cycloalkyl, they can by 1-3 it is identical or
Different R6It is optionally substituted；Or R4、R55-10 units saturated heterocyclyl is formed together with the nitrogen-atoms being connected with them, it is described full
With heterocyclic radical except with R4And R5Outside the nitrogen-atoms of connection, can be containing the 1-3 hetero atom selected from O, N or S, optionally by 1~3
Individual identical or different R6Substitution；
R6It is C1-C4Alkyl.
The compound of the formula I present invention is preferably related to be defined as follows, and its optically active body or raceme or its pharmacy
Upper acceptable salt, hydrate or solvate,
Wherein
A is phenyl, pyridine radicals, thienyl, furyl, pyrrole radicals, naphthyl, quinolyl, isoquinolyl, imidazole radicals, pyrazoles
Base, thiazolyl , oxazolyl , isoxazolyls, triazol radical, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzyl, or
Phenethyl, and the optional 1-3 R of A3Substitution；
R3It is halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, azido, nitro, cyano group, sulfydryl, (C1-
C4) alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, (C1-C4) alkoxy, (C1-C4) alkylthio group, hydroxyl (C1-C4) alkyl, amino
(C1-C4) alkyl, pi-allyl, (2- methyl) pi-allyl, (C1-C4) alkyl amido, (C1-C4) alkyl sulphinyl, (C1-C4)
Alkyl sulphonyl, (C1-C4) alkoxy methyl, (C1-C4) alkyl acyl, carbamoyl, N- (C1-C4) alkyl carbamoyl
The base, (C of N, N- bis-1-C4) alkyl-carbamoyl, amino-sulfonyl, N- (C1-C4) the alkyl amino sulfonyl, (C of N, N- bis-1-C4)
Alkyl amino sulfonyl, or (C1-C3) alkylenedioxy group.
The present invention is also preferably relate to the compound of the formula I being defined as follows, and its optically active body or raceme or its medicine
Acceptable salt, hydrate or solvate on,
Wherein
R1It is H, C1-C4Alkyl；
R2It is H；
A is phenyl, pyridine radicals, thienyl, furyl, pyrrole radicals, naphthyl, quinolyl, isoquinolyl, imidazole radicals, pyrazoles
Base, thiazolyl , oxazolyl , isoxazolyls, triazol radical, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzyl, or
Phenethyl, and the optional 1-3 R of A3Substitution；
R3It is halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, azido, nitro, cyano group, sulfydryl, (C1-
C4) alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, (C1-C4) alkoxy, (C1-C4) alkylthio group, hydroxyl (C1-C4) alkyl, amino
(C1-C4) alkyl, pi-allyl, (2- methyl) pi-allyl, (C1-C4) alkyl amido, (C1-C4) alkyl sulphinyl, (C1-C4)
Alkyl sulphonyl, (C1-C4) alkoxy methyl, (C1-C4) alkyl acyl, carbamoyl, N- (C1-C4) alkyl carbamoyl
The base, (C of N, N- bis-1-C4) alkyl-carbamoyl, amino-sulfonyl, N- (C1-C4) the alkyl amino sulfonyl, (C of N, N- bis-1-C4)
Alkyl amino sulfonyl, or (C1-C3) alkylenedioxy group,
Or R3For-NR4R5；
R4、R5It is identical or different, separately select C1-C6Alkyl, C3-C6Cycloalkyl, they can by 1-3 it is identical or
Different R6It is optionally substituted；Or R4And R5Formed together with the nitrogen-atoms being connected with them morpholinyl, pyrrolidinyl, piperazinyl,
4- methyl piperazines base, piperidyl, imidazolidinyl or pyrazolidinyl；
The generalformulaⅰcompound being defined as follows specifically preferred according to the invention, and its optically active body or raceme or its pharmaceutically
Acceptable salt, hydrate or solvate,
Wherein,
R1It is H ,-CH3；R2It is H；
A is phenyl, pyridine radicals, thienyl, furyl, pyrrole radicals, naphthyl, quinolyl, isoquinolyl, imidazole radicals, pyrazoles
Base, thiazolyl , oxazolyl , isoxazolyls, triazol radical, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzyl, or
Phenethyl, and the optional 1-3 R of A3Substitution；
R3It is halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, azido, nitro, cyano group, sulfydryl, (C1-
C4) alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, (C1-C4) alkoxy, (C1-C4) alkylthio group, hydroxyl (C1-C4) alkyl, amino
(C1-C4) alkyl, pi-allyl, (2- methyl) pi-allyl, (C1-C4) alkyl amido, (C1-C4) alkyl sulphinyl, (C1-C4)
Alkyl sulphonyl, (C1-C4) alkoxy methyl, (C1-C4) alkyl acyl, carbamoyl, N- (C1-C4) alkyl carbamoyl
The base, (C of N, N- bis-1-C4) alkyl-carbamoyl, amino-sulfonyl, N- (C1-C4) the alkyl amino sulfonyl, (C of N, N- bis-1-C4)
Alkyl amino sulfonyl, or (C1-C3) alkylenedioxy group,
Or R3For-NR4R5；
R4、R5It is identical or different, separately select C1-C6Alkyl, C3-C6Cycloalkyl, they can by 1-3 it is identical or
Different R6It is optionally substituted；Or R4And R5Formed together with the nitrogen-atoms being connected with them morpholinyl, pyrrolidinyl, piperazinyl,
4- methyl piperazines base, piperidyl, imidazolidinyl or pyrazolidinyl；
The present invention it is also particularly that the generalformulaⅰcompound being defined as follows, and its optically active body or raceme or its pharmacy
Upper acceptable salt, hydrate or solvate,
Wherein,
R1It is H ,-CH3；R2It is H；
A is phenyl, and the optional 1-3 R of A3Substitution；
R3It is halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, azido, nitro, cyano group, sulfydryl, (C1-
C4) alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, (C1-C4) alkoxy, (C1-C4) alkylthio group, hydroxyl (C1-C4) alkyl, amino
(C1-C4) alkyl, pi-allyl, (2- methyl) pi-allyl, (C1-C4) alkyl amido, (C1-C4) alkyl sulphinyl, (C1-C4)
Alkyl sulphonyl, (C1-C4) alkoxy methyl, (C1-C4) alkyl acyl, carbamoyl, N- (C1-C4) alkyl carbamoyl
The base, (C of N, N- bis-1-C4) alkyl-carbamoyl, amino-sulfonyl, N- (C1-C4) the alkyl amino sulfonyl, (C of N, N- bis-1-C4)
Alkyl amino sulfonyl, or (C1-C3) alkylenedioxy group,
Or R3For-NR4R5；
Compound of Formula I of the present invention, and its optically active body or raceme or its pharmaceutically acceptable salt, hydrate or
Solvate preferably following compound, but these compounds are not meant to any limitation of the invention：
5- methyl -3- [2- (1- benzylidenes) diazanyl] -5,10- dihydro pyridos [2', 3':5,6] pyrazine is simultaneously [2,3-e]
[1,2,4] triazine；
5- methyl -3- { 2- [1- (3- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrrole
Piperazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (4- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrrole
Piperazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- [2- (1- phenylethylenes) diazanyl] -5,10- dihydro pyridos [2', 3':5,6] pyrazine is simultaneously [2,3-e]
[1,2,4] triazine；
5- methyl -3- { 2- [1- (pyridine -2- bases) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrazine
And [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (pyridine -2- bases) ethylidene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrazine
And [2,3-e] [1,2,4] triazine；
5,8- dimethyl -3- { 2- [1- (3,4,5- trimethoxyphenyls) ethylidene] diazanyl } -5,10- dihydro pyridos
[2',3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (3- trifluoromethyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,
6] pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5- cyclopropyl -3- { 2- [1- (4- trifluoromethyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':
5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (2,4- Dimethoxyphenyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':
5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (2- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrrole
Piperazine simultaneously [2,3-e] [1,2,4] triazine；
5,8- dimethyl -3- { 2- [1- (2- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,
6] pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (2 hydroxy naphthalene base) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrrole
Piperazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (4- hydroxy 3-methoxybenzenes base) methylene] diazanyl } -5,10- dihydro pyridos [2',
3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (4- Trifluoromethoxyphen-ls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':
5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (indol-3-yl) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrazine
And [2,3-e] [1,2,4] triazine；
5,8- dimethyl -3- { 2- [1- (indol-3-yl) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6]
Pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (3- pi-allyl -2- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyridos [2',
3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5,8- dimethyl -3- { 2- [1- (3- pi-allyl -2- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyridos
[2',3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (2,3,4- trimethoxyphenyls) methylene] diazanyl } -5,10- dihydro pyridos [2',
3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (pyrroles -2- bases) ethylidene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrazine
And [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (4- fluorophenyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrazine
And [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (4- nitrobenzophenones) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrrole
Piperazine simultaneously [2,3-e] [1,2,4] triazine；
5,8- dimethyl -3- { 2- [1- (the 3- pi-allyl -5- tert-butyl group -2- hydroxy phenyls) methylene] diazanyl } -5,10- two
Pyridinium hydroxide simultaneously [2', 3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine.
And, according to some usual methods of the art, 5, the 10- dihydro pyridos of formula I above in the present invention
[2’,3’:5,6] simultaneously [2,3-e] [1,2,4] compound in triazine class can be with acid generation pharmaceutically acceptable salt for pyrazine.Can medicine
Include inorganic acid or organic acid addition salt with addition salts, the salt with following sour addition is particularly preferred：Hydrochloric acid, hydrobromic acid, sulphur
Acid, phosphoric acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, Malaysia
Acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid etc..
Additionally, present invention additionally comprises the prodrug of the compounds of this invention.The prodrug of the compounds of this invention is the chemical combination of formula I
Thing, their own may have weaker activity even without activity, but upon administration, (for example pass through in physiological conditions
Metabolism, solvolysis or other mode) it is converted to corresponding biologically active form.
" halogen " refers to fluorine, chlorine, bromine or iodine etc. in the present invention；" alkyl " refers to the alkyl of straight or branched；" alkylidene "
It refer to the alkylidene of straight or branched；" cycloalkyl " refers to substituted or unsubstituted cycloalkyl；" aryl " refers to unsubstituted or company
The phenyl of substituted base；" heteroaryl " refers to be selected from the heteroatomic monocyclic or polycyclic ring bodies of N, O or S containing one or more
System, ring-type system is armaticity, such as imidazole radicals, pyridine radicals, pyrazolyl, (1,2,3)-and (1,2,4)-triazolyl, furyl, thiophene
Fen base, pyrrole radicals, thiazolyl, benzothiazolyl , oxazolyl , isoxazolyls, naphthyl, quinolyl, isoquinolyl, benzimidazolyl,
Benzoxazolyl etc.；" heterocyclic radical of saturation or fractional saturation " refers to be selected from the heteroatomic monocyclic of N, O or S containing one or more
Or polycyclic ring-type system, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidyl, pyrazolidinyl, imidazolidinyl or thiazolinyl.
The present invention can be containing formula I above 5,10- dihydro pyridos [2 ', 3 ':5,6] pyrazine simultaneously [2,3-e] [1,2,4] three
Piperazine class compound, and its pharmaceutically acceptable salt, hydrate or solvate are used as active ingredient, it is and pharmaceutically acceptable
Carrier or excipients are prepared by mixing into composition, and are prepared into clinically acceptable formulation, above-mentioned pharmaceutically acceptable tax
Type agent refers to any diluent that can be used for pharmaceutical field, adjuvant and/or carrier.Compound of the invention can be with other work
Sexual element is applied in combination, as long as they do not produce other unfavorable effects, such as allergic reaction.
Pharmaceutical composition of the invention can be configured to several formulation, wherein containing some conventional figurations in drug field
Agent.Several formulation as described above can be using injection, tablet, capsule, aerosol, suppository, film, pill, outer
With drug forms such as liniment, ointments.
Carrier for pharmaceutical composition of the present invention is available common type in drug field, including：Adhesive, profit
Lubrication prescription, disintegrant, cosolvent, diluent, stabilizer, suspending agent, non-pigment, flavouring, preservative, solubilizer and matrix etc..
Pharmaceutical preparation can by oral administration or parenteral (such as intravenous, subcutaneous, intraperitoneal or local) administration, if some drugses
It is unstable under the conditions of stomach, enteric coated tablets can be configured to.
Tested by anti tumor activity in vitro, it is found that the compounds of this invention has antitumor activity, therefore chemical combination of the present invention
Thing can be used for preparing treatment and/or prevent the medicine of various cancers, such as mammary gland, lung, liver, kidney, colon, rectum, stomach, preceding
Row gland, bladder, uterus, pancreas, marrow, testis, ovary, lymph, soft tissue, neck, thyroid gland, the cancer of esophagus or leukaemia,
Neuroblastoma etc..It is used in particular for the medicine for preparing treatment and/or prevention lung cancer or colon cancer.
Reactive compound of the invention or its officinal salt and its solvate can be independent as unique antineoplastic
Use, or can be with antineoplastic (such as platinum medicine cis-platinum, camptothecine Irinotecan, the Changchun for having listed
Flower bases medicine NVB, deoxidation born of the same parents' former times class medicine gemcitabine, etoposide, taxol etc.) it is used in combination.Therapeutic alliance is led to
Cross each therapeutic component simultaneously, order or separate administration and realize.
Examples provided hereinafter and preparation example further elucidate and illustrate the compounds of this invention and its preparation side
Method.It should be appreciated that the scope of following examples and preparation example limits the scope of the present invention never in any form.
Following synthetic route describes the preparation of compound of Formula I of the invention, and all of raw material is all by following
Mode described in flow, prepared by organic chemistry filed method well-known to the ordinarily skilled artisan or it is commercially available.This hair
Bright whole final compounds are prepared by the method described in below scheme or by similar method, these
Method is organic chemistry filed well-known to the ordinarily skilled artisan.The whole variable factor following articles applied in these exemplary flows
Definition in definition or such as claim.
Compound B is initiation material, in the basic conditions, substitution reaction is carried out with excessive substitution amine, and compound is obtained
C, then with hydrazine hydrate occur reduction reaction after with oxalic acid cyclization, obtain compound D.In POCl3, there is chlorination in D
Intermediate E is obtained, F is obtained after then there is cyclization with thiosemicarbazides, be obtained what G, compound G and A replaced through hydrazine hydrate substitution
Aldehydes or ketones are condensed, and obtain chemical compounds I.
Specific embodiment：
Embodiment is intended to illustrate rather than limitation the scope of the present invention.The proton nmr spectra BrukerARX- of compound
500 are determined, and mass spectrum is determined with Agilent 1100LC/MSD；It is pure or chemical pure that agents useful for same is analysis.
Embodiment 1：5- methyl -3- [2- (1- benzylidenes) diazanyl] -5,10- dihydro pyridos [2', 3':5,6] pyrazine
And [2,3-e] [1,2,4] triazine
Step A：The preparation of N- methyl-3-nitros-PA
24mL methylamines, 39.5mL triethylamines are added in 240mL dichloromethane, 30g is slowly dividedly in some parts at room temperature
The chloro- 3- nitropyridines of (0.18mol) 2-, charging is finished, and 5h is reacted at room temperature.After completion of the reaction, reaction solution is washed with water three times, plus
Enter anhydrous sodium sulfate water removal, suction filtration, revolving obtains yellow crystalline solid product 44.8g (yield is 95.76%).
MS[MH+](m/z):153.1；
Step B：N2The preparation of-methyl -2,3 diamino pyridine
N- methyl-3-nitros-PA 1g (4mmol), hydrazine hydrate 1.57mL and ferric trichloride 0.33g is added
In 448mL ethanol, a small amount of activated carbon is added, flowed back 5h at 80 DEG C, and suction filtration, filtrate is rotated while hot, obtain deep dark green solid and produce
Thing 0.8g (yield is 91.04%).
MS[MH+](m/z):123.5；
Step C：4- methyl isophthalic acids, the preparation of 4- dihydropyridines [2,3-b] piperazine -2,3- diketone
0.8g (3.6mmol) N- methyl -2,3- diamino-pyridines, 0.9mL hydrochloric acid and 1mL water are added in single-necked flask,
0.5g oxalic acid is slowly dividedly in some parts at room temperature.After charging is finished, flow back 3h at 110 DEG C.Standing is cooled to room temperature, and suction filtration is dried,
Obtain celadon solid product 0.3g (yield 30.03%).
MS[MH+](m/z):178.8；
Step D：The preparation of 2- chloromethyl -1,4- dihydropyridine [2,3-b] piperazine -3 (2H) -one
2.0g (7.4mmol) 4- methyl isophthalic acids, 4- dihydropyridines [2,3-b] piperazine -2,3- diketone are added to 20mL acetonitriles
In, 6.0mL POCl3s are slowly added dropwise at room temperature.After completion of dropping, flow back 8h at 80 DEG C, after completion of the reaction, reaction solution is revolved
Steam to thick, pour into trash ice, stir 0.5h.Extracted with dichloromethane, add anhydrous sodium sulfate water removal drying.Suction filtration, will
Filtrate rotates, and obtains red solid product 1.4g (yield 65.42%).
MS[MH+](m/z):197.1；
Step E：5- methyl -5,10- dihydropyridines [2', 3':5,6] piperazine [2,3-e] [1,2,4] triazine -3- sulfydryls
Prepare
0.16g thiosemicarbazides, 0.36g potassium carbonate, 5mL absolute ethyl alcohols and 5mL water are added sequentially in round-bottomed flask, together
Shi Kaiqi agitating heatings, in this case by 0.5g (1.7mmol) 2- chloromethyls-Isosorbide-5-Nitrae-dihydropyridine [2,3-b] piperazine -3
(2H) -one is dividedly in some parts in reaction solution.Flow back 6h at 80 DEG C, after stopping reaction, suction filtration while hot.Filtrate pH is adjusted with glacial acetic acid
It is 7, separates out solid, suction filtration is dried, and obtains brown solid 0.5g (yield 89%).
MS[MH+](m/z):233.3；
Step F：5- methyl -3- diazanyl -5,10- dihydropyridines [2', 3':5,6] piperazine [2,3-e] [1,2,4] triazine
Prepare
By 0.5g (1.5mmol) 5- methyl -5,10- dihydropyridines [2', 3':5,6] piperazine [2,3-e] [1,2,4] triazine-
3- sulfydryls and 2.5mL hydrazine hydrates are added in 5mL absolute ethyl alcohols, and flow back 6h at 80 DEG C.Reaction is finished, and is cooled down under agitation, cold
But a small amount of water is added during.Suction filtration, dries, and obtains brown solid 0.2g (yield 40%).
MS[MH+](m/z):231.3；
Step G：5- methyl -3- [2- (1- benzylidenes) diazanyl] -5,10- dihydro pyridos [2', 3':5,6] pyrazine is simultaneously
The preparation of [2,3-e] [1,2,4] triazine
By 0.2g (0.46mmol) 5- methyl -3- diazanyl -5,10- dihydropyridines [2', 3':5,6] piperazine [2,3-e] [1,
2,4] triazine is added in 6mL isopropanols, and lower dropwise addition 0.3mL benzaldehydes are stirred at room temperature.After completion of dropping, reacted at 80 DEG C
3.5h, is stood overnight, and suction filtration, filter cake is washed with isopropanol, is dried, and obtains product as light yellow solid 0.2g (yield 75.87%).
MS[MH+](m/z):319.2；1H NMR(DMSO-d6):δ3.62(s,3H),3.72(s,6H),4.71(s,1H),
6.51(d,1H),6.58(s,2H),7.17(s,2H),7.54(s,1H),7.93(s,1H),8.20(d,1H)。
According to the method for embodiment 1, first with the chloro- 3- nitropyridines of 2- or the chloro- 3- nitropyridines of substituted 2- and it is adapted to
Alkylamine, prepare N- substitutions -3- nitros-PA derivative；Sent out with hydrazine hydrate and palladium carbon again afterwards
Raw reduction reaction obtains pyrido [2,3-b] pyrazine -2 with oxalic acid cyclization again, and 3- diketone derivatives occur chlorine with POCl3
There is cyclization with thiosemicarbazides again after generation reaction, finally with suitable aryl aldehyde or aryl reactive ketone, embodiment 2- is obtained respectively
25 compounds.
Embodiment 2：5- methyl -3- { 2- [1- (3- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyridos [2',
3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 3：5- methyl -3- { 2- [1- (4- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyridos [2',
3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 4：5- methyl -3- [2- (1- phenylethylenes) diazanyl] -5,10- dihydro pyridos [2', 3':5,6] pyrazine
And [2,3-e] [1,2,4] triazine
MS[MH+](m/z):333.4。
Embodiment 5：5- methyl -3- { 2- [1- (pyridine -2- bases) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':
5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):320.4。
Embodiment 6：5- methyl -3- { 2- [1- (pyridine -2- bases) ethylidene] diazanyl } -5,10- dihydro pyridos [2', 3':
5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):333.5。
Embodiment 7：5,8- dimethyl -3- { 2- [1- (3,4,5- trimethoxyphenyls) ethylidene] diazanyl } -5,10- dihydros
Pyrido [2', 3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 8：5- methyl -3- { 2- [1- (3- trifluoromethyls) methylene] diazanyl } -5,10- dihydro pyridos
[2',3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 9：5- cyclopropyl -3- { 2- [1- (4- trifluoromethyls) methylene] diazanyl } -5,10- dihydro pyridos
[2',3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 10：5- methyl -3- { 2- [1- (2,4- Dimethoxyphenyls) methylene] diazanyl } -5,10- dihydropyridines
And [2', 3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 11：5- methyl -3- { 2- [1- (2- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyridos [2',
3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 12：5,8- dimethyl -3- { 2- [1- (2- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyridos
[2',3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 13：5- methyl -3- { 2- [1- (2 hydroxy naphthalene base) methylene] diazanyl } -5,10- dihydro pyridos [2',
3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 14：5,8- dimethyl -3- { 2- [1- (2- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyridos
[2',3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 15：5- methyl -3- { 2- [1- (4- hydroxy 3-methoxybenzenes base) methylene] diazanyl } -5,10- dihydro pyrroles
Pyridine simultaneously [2', 3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 16：5- methyl -3- { 2- [1- (4- Trifluoromethoxyphen-ls) methylene] diazanyl } -5,10- dihydropyridines
And [2', 3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 17：5- methyl -3- { 2- [1- (indol-3-yl) methylene] diazanyl } -5,10- dihydro pyridos [2',
3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 18：5,8- dimethyl -3- { 2- [1- (indol-3-yl) methylene] diazanyl } -5,10- dihydro pyridos
[2',3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 19：5- methyl -3- { 2- [1- (3- pi-allyl -2- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyrroles
Pyridine simultaneously [2', 3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 20：5,8- dimethyl -3- { 2- [1- (3- pi-allyl -2- hydroxy phenyls) methylene] diazanyl } -5,10- two
Pyridinium hydroxide simultaneously [2', 3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 21：5- methyl -3- { 2- [1- (2,3,4- trimethoxyphenyls) methylene] diazanyl } -5,10- dihydro pyrroles
Pyridine simultaneously [2', 3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 22：5- methyl -3- { 2- [1- (pyrroles -2- bases) ethylidene] diazanyl } -5,10- dihydro pyridos [2',
3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 23：5- methyl -3- { 2- [1- (4- fluorophenyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':
5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 24：5- methyl -3- { 2- [1- (4- nitrobenzophenones) methylene] diazanyl } -5,10- dihydro pyridos [2',
3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
Embodiment 25：5,8- dimethyl -3- { 2- [1- (the 3- pi-allyl -5- tert-butyl group -2- hydroxy phenyls) methylene] hydrazines
Base } -5,10- dihydro pyridos [2', 3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine
MS[MH+](m/z):414.8。
The antitumor activity of product of the present invention
To the 5,10- dihydro pyridos [2 ', 3 ' according to above formula of the invention I:5,6] pyrazine simultaneously [2,3-e] [1,2,4] three
Piperazine class compound has carried out external suppression people human breast carcinoma MDA-MB-231 cells, colon cancer HCT116 cells, HT29 cells
With typeⅡ pneumocyte screening active ingredients, reference substance 6- methyl -3- { 2- [1- (pyridine -2- bases) ethylidene] diazanyl } -5H- [1,
2,4] simultaneously [5,6-b] indoles (VLX600) is prepared triazine according to the methods describeds of patent WO 2014/046589.
(1) cell recovery and pass on 2-3 times stabilization after, it is disappeared from blake bottle bottom with trypsin solution (0.25%)
Change is got off.After cell dissociation buffer is poured into centrifuge tube, nutrient solution is added to terminate digestion afterwards.By centrifuge tube in 800r/min
Lower centrifugation 10min, adds 5mL nutrient solutions after abandoning supernatant, piping and druming mixes cell, draws 10 μ L cell suspensions and adds cell
Counted in tally, adjustment cell concentration is 104Individual/hole.Except A1 holes for blank well is not added with extracellular in 96 orifice plates, remaining all adds
Enter 100 μ L cell suspensions.96 orifice plates are put into incubator and cultivate 24h.
(2) with 50 μ L dmso solution given the test agent, appropriate nutrient solution is subsequently adding, sample is dissolved into 2mg/mL
Liquid, then in 24 orifice plates by Sample Dilution be 20,4,0.8,0.16,0.032 μ g/mL.
Each concentration add 3 holes, wherein around the row cell growing way of two row two it is affected by environment larger, only and be blanc cell
Hole uses.96 orifice plates are put into incubator and cultivate 72h.
(3) band medicine nutrient solution in 96 orifice plates is discarded, is rinsed cell twice with phosphate buffer solution (PBS), in every hole
The middle μ L of addition MTT (tetrazole) (0.5mg/mL) 100 are put into incubator after 4h, discard MTT solution, add dimethyl sulfoxide (DMSO)
100μL.Vibration makes survivaling cell fully be dissolved with MTT product formazans on magnetic force oscillator, is put into measure in ELIASA
As a result.Medicine IC can be obtained by Bliss methods50Value.
The suppression human breast carcinoma MDA-MB-231 cells of compound, colon cancer HCT116 cells, HT29 cells and human lung cancer
A549 cytoactives the results are shown in Table 1.
The compound of the formula I of the present invention of table 1 suppresses tumor cell viability result of the test
From above-mentioned result of the test it can be clearly seen that the compound of claimed formula I of the invention, with good
Anti tumor activity in vitro, part of compounds is suitable with the compound VLX600 activity of document report or better than compound VLX600.
The compound of formula of of the present invention I can be used alone, but typically be given with pharmaceutical carrier mixture, described medicinal
The selection of carrier will be according to required route of administration and standard pharmaceutical practice, separately below with the various medicine agent of such compound
Type, such as tablet, capsule, injection, aerosol, suppository, film, pill, the preparation method of externally-applied liniment and ointment,
Illustrate its new opplication in pharmaceutical field.
Embodiment 26：Tablet
With compound (by taking the compound of the embodiment 12 as an example) 10g containing compound in claim 1, according to pharmacy one
As after pressed disc method adds auxiliary material 20g to mix, be pressed into 100, every weight 300mg.
Embodiment 27：Capsule
With compound (by taking the compound of the embodiment 16 as an example) 10g containing compound in claim 1, according to pharmacy glue
After the requirement of wafer mixes auxiliary material 20g, load Capsules, each capsule weight 300mg.
Embodiment 28：Injection
It is normal according to pharmacy with compound (by taking the compound of the embodiment 1 as an example) 10g containing compound in claim 1
Rule method, carries out charcoal absorption, through 0.65 μm of filtering with microporous membrane after, insert nitrogen pot and be made hydro-acupuncture preparation, every dress
2mL, altogether filling 100 bottles.
Embodiment 29：Aerosol
With compound (by taking the compound of the embodiment 2 as an example) 10g containing compound in claim 1, appropriate propane diols is used
After dissolving, after adding distilled water and other spoke material, the settled solution for being made 500mL is obtained final product.
Embodiment 30：Suppository
With compound (by taking the compound of the embodiment 9 as an example) 10g containing compound in claim 1, by finely ground addition
Appropriate glycerine, adds the glycerin gelatine for having melted after grinding well, grinding is uniform, is poured into the model for having applied lubricant, and suppository is obtained
50
Embodiment 31：Film
With compound (by taking the compound of the embodiment 18 as an example) 10g containing compound in claim 1, by polyvinyl alcohol,
Heating for dissolving after the stirring expansion such as medicinal glycerin, water, 80 mesh sieve net filtrations, then the compound of embodiment 18 is added in filtrate stirs
Mix dissolving, film applicator masking 100.
Embodiment 32：Pill
With compound (by taking the compound of the embodiment 7 as an example) 10g containing compound in claim 1, with the matrix such as gelatin
After 50g heating fusings are mixed, instill in cryogenic liquid paraffin, the ball of dripping pill 1000 is obtained altogether.
Embodiment 33：Externally-applied liniment
With compound (by taking the compound of the embodiment 21 as an example) 10g containing compound in claim 1, according to conventional dose
The auxiliary material 2.5g mixed grindings such as method and emulsifying agent, then add distilled water prepared to 200mL.
Embodiment 34：Ointment
With compound (by taking the compound of the embodiment 17 as an example) 10g containing compound in claim 1, it is finely ground after with all scholars
The oleaginous base such as woods 500g grinds well prepared.
Although describing the present invention by particular, modification and equivalent variations are for being proficient in this field
Be will be apparent from for technical staff, and they are included within the scope of the invention.
Claims (10)
1. the compound of formula I, and its optically active body or raceme or its pharmaceutically acceptable salt, hydrate or solvation
Thing,
Wherein：
R1It is H, C1-C6Alkyl；
R2It is H, C1-C6Alkyl；
X is halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, azido, nitro, cyano group, sulfydryl, (C1-C4) alkane
Base, (C1-C4) alkenyl, (C1-C4) alkynyl, (C1-C4) alkoxy, (C1-C4) alkylthio group, hydroxyl (C1-C4) alkyl, amino (C1-
C4) alkyl, pi-allyl, (2- methyl) pi-allyl, (C1-C4) alkylamidoalkyl, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl
Sulfonyl, (C1-C4) alkoxy methyl, (C1-C4) alkyl acyl, carbamoyl, N- (C1-C4) alkyl-carbamoyl, N,
(the C of N- bis-1-C4) alkyl-carbamoyl, amino-sulfonyl, N- (C1-C4) the alkyl amino sulfonyl, (C of N, N- bis-1-C4) alkyl
Amino-sulfonyl, or (C1-C3) alkylenedioxy group；
A is aryl, aryl C1-C4Alkyl, C3-C6Cycloalkyl, C3-C6Cycloalkyl C1-C4Alkyl, 5-10 unit's heteroaryls, 5-10 units are miscellaneous
Aryl C1-C4Alkyl, 5-10 unit saturation or fractional saturation heterocyclic radical, 5-10 unit saturation or fractional saturation heterocyclic radical C1-C4
Alkyl；The heteroaryl or heterocyclic radical contain the 1-3 hetero atom selected from O, N or S, and the optional 1-3 R of A3Substitution；
R3It is halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, azido, nitro, cyano group, sulfydryl, (C1-C4)
Alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, (C1-C4) alkoxy, (C1-C4) alkylthio group, hydroxyl (C1-C4) alkyl, amino (C1-
C4) alkyl, pi-allyl, (2- methyl) pi-allyl, (C1-C4) alkylamidoalkyl, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl
Sulfonyl, (C1-C4) alkoxy methyl, (C1-C4) alkyl acyl, carbamoyl, N- (C1-C4) alkyl-carbamoyl, N,
(the C of N- bis-1-C4) alkyl-carbamoyl, amino-sulfonyl, N- (C1-C4) the alkyl amino sulfonyl, (C of N, N- bis-1-C4) alkyl
Amino-sulfonyl, or (C1-C3) alkylenedioxy group,
Or R3For-NR4R5；
R4、R5It is identical or different, separately select C1-C6Alkyl, C3-C6Cycloalkyl, they can be identical or different by 1-3
R6It is optionally substituted；Or R4、R55-10 units saturated heterocyclyl is formed together with the nitrogen-atoms being connected with them, the saturation is miscellaneous
Ring group except with R4And R5Outside the nitrogen-atoms of connection, can be containing the 1-3 hetero atom selected from O, N or S, optionally by 1~3 phase
Same or different R6Substitution；
R6It is C1-C4Alkyl.
2. the compound of claim 1 formula I, and its optically active body or raceme or its pharmaceutically acceptable salt, hydration
Thing or solvate, wherein
R1It is H, C1-C4Alkyl；
R2It is H, C1-C4Alkyl；
X is halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, azido, nitro, cyano group, sulfydryl, (C1-C4) alkane
Base, (C1-C4) alkenyl, (C1-C4) alkynyl, (C1-C4) alkoxy, (C1-C4) alkylthio group, hydroxyl (C1-C4) alkyl, amino (C1-
C4) alkyl, pi-allyl, (2- methyl) pi-allyl, (C1-C4) alkylamidoalkyl, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl
Sulfonyl, (C1-C4) alkoxy methyl, (C1-C4) alkyl acyl, carbamoyl, N- (C1-C4) alkyl-carbamoyl, N,
(the C of N- bis-1-C4) alkyl-carbamoyl, amino-sulfonyl, N- (C1-C4) the alkyl amino sulfonyl, (C of N, N- bis-1-C4) alkyl
Amino-sulfonyl, or (C1-C3) alkylenedioxy group；
A is aryl, aryl C1-C4Alkyl, 5-10 unit's heteroaryls；The heteroaryl contains the 1-3 hetero atom selected from O, N or S,
And the optional 1-3 R of A3Substitution；
R3It is halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, azido, nitro, cyano group, sulfydryl, (C1-C4)
Alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, (C1-C4) alkoxy, (C1-C4) alkylthio group, hydroxyl (C1-C4) alkyl, amino (C1-
C4) alkyl, pi-allyl, (2- methyl) pi-allyl, (C1-C4) alkyl amido, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl
Sulfonyl, (C1-C4) alkoxy methyl, (C1-C4) alkyl acyl, carbamoyl, N- (C1-C4) alkyl-carbamoyl, N,
(the C of N- bis-1-C4) alkyl-carbamoyl, amino-sulfonyl, N- (C1-C4) the alkyl amino sulfonyl, (C of N, N- bis-1-C4) alkyl
Amino-sulfonyl, or (C1-C3) alkylenedioxy group,
Or R3For-NR4R5；
R4、R5It is identical or different, separately select C1-C6Alkyl, C3-C6Cycloalkyl, they can be identical or different by 1-3
R6It is optionally substituted；Or R4、R55-10 units saturated heterocyclyl is formed together with the nitrogen-atoms being connected with them, the saturation is miscellaneous
Ring group except with R4And R5Outside the nitrogen-atoms of connection, can be containing the 1-3 hetero atom selected from O, N or S, optionally by 1~3 phase
Same or different R6Substitution；
R6It is C1-C4Alkyl.
3. the compound of claim 2 formula I, and its optically active body or raceme or its pharmaceutically acceptable salt, hydration
Thing or solvate, wherein,
R1It is H, C1-C4Alkyl；
R2It is H；
X is halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, azido, nitro, cyano group, sulfydryl, (C1-C4) alkane
Base, (C1-C4) alkenyl, (C1-C4) alkynyl, (C1-C4) alkoxy, (C1-C4) alkylthio group, hydroxyl (C1-C4) alkyl, amino (C1-
C4) alkyl, pi-allyl, (2- methyl) pi-allyl, (C1-C4) alkylamidoalkyl, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl
Sulfonyl, (C1-C4) alkoxy methyl, (C1-C4) alkyl acyl, carbamoyl, N- (C1-C4) alkyl-carbamoyl, N,
(the C of N- bis-1-C4) alkyl-carbamoyl, amino-sulfonyl, N- (C1-C4) the alkyl amino sulfonyl, (C of N, N- bis-1-C4) alkyl
Amino-sulfonyl, or (C1-C3) alkylenedioxy group；
A is phenyl, pyridine radicals, thienyl, furyl, pyrrole radicals, naphthyl, quinolyl, isoquinolyl, imidazole radicals, pyrazolyl, thiophene
Oxazolyl , oxazolyl , isoxazolyls, triazol radical, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzyl, or benzene second
Base, and the optional 1-3 R of A3Substitution；
R3It is halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, amino, azido, nitro, cyano group, sulfydryl, (C1-C4)
Alkyl, (C1-C4) alkenyl, (C1-C4) alkynyl, (C1-C4) alkoxy, (C1-C4) alkylthio group, hydroxyl (C1-C4) alkyl, amino (C1-
C4) alkyl, pi-allyl, (2- methyl) pi-allyl, (C1-C4) alkyl amido, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl
Sulfonyl, (C1-C4) alkoxy methyl, (C1-C4) alkyl acyl, carbamoyl, N- (C1-C4) alkyl-carbamoyl, N,
(the C of N- bis-1-C4) alkyl-carbamoyl, amino-sulfonyl, N- (C1-C4) the alkyl amino sulfonyl, (C of N, N- bis-1-C4) alkyl
Amino-sulfonyl, or (C1-C3) alkylenedioxy group,
Or R3For-NR4R5；
R4、R5It is identical or different, separately select C1-C6Alkyl, C3-C6Cycloalkyl, they can be identical or different by 1-3
R6It is optionally substituted；Or R4、R5Morpholinyl, pyrrolidinyl, piperazinyl, 4- first are formed together with the nitrogen-atoms being connected with them
Base piperazinyl, piperidyl, imidazolidinyl or pyrazolidinyl.
4. the compound of claim 3 formula I, and its optically active body or raceme or its pharmaceutically acceptable salt, hydration
Thing or solvate, wherein,
R1It is H ,-CH3；R2It is H.
5. the compound of claim 4 formula I, and its optically active body or raceme or its pharmaceutically acceptable salt, hydration
Thing or solvate, wherein,
A is phenyl, and the optional 1-3 R of A3Substitution.
6. the compound of general formula I, and its optically active body or raceme or its pharmaceutically acceptable salt, hydrate or molten
Agent compound：
5- methyl -3- [2- (1- benzylidenes) diazanyl] -5,10- dihydro pyridos [2', 3':5,6] pyrazine simultaneously [2,3-e] [1,
2,4] triazine；
5- methyl -3- { 2- [1- (3- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrazine is simultaneously
[2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (4- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrazine is simultaneously
[2,3-e] [1,2,4] triazine；
5- methyl -3- [2- (1- phenylethylenes) diazanyl] -5,10- dihydro pyridos [2', 3':5,6] pyrazine simultaneously [2,3-e] [1,
2,4] triazine；
5- methyl -3- { 2- [1- (pyridine -2- bases) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrazine is simultaneously
[2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (pyridine -2- bases) ethylidene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrazine is simultaneously
[2,3-e] [1,2,4] triazine；
5,8- dimethyl -3- { 2- [1- (3,4,5- trimethoxyphenyls) ethylidene] diazanyl } -5,10- dihydro pyridos [2',
3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (3- trifluoromethyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrrole
Piperazine simultaneously [2,3-e] [1,2,4] triazine；
5- cyclopropyl -3- { 2- [1- (4- trifluoromethyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6]
Pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (2,4- Dimethoxyphenyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6]
Pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (2- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrazine is simultaneously
[2,3-e] [1,2,4] triazine；
5,8- dimethyl -3- { 2- [1- (2- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrrole
Piperazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (2 hydroxy naphthalene base) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrazine is simultaneously
[2,3-e] [1,2,4] triazine；
5,8- dimethyl -3- { 2- [1- (2- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrrole
Piperazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (4- hydroxy 3-methoxybenzenes base) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,
6] pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (4- Trifluoromethoxyphen-ls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6]
Pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (indol-3-yl) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrazine is simultaneously
[2,3-e] [1,2,4] triazine；
5,8- dimethyl -3- { 2- [1- (indol-3-yl) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrazine
And [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (3- pi-allyl -2- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,
6] pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5,8- dimethyl -3- { 2- [1- (3- pi-allyl -2- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyridos [2',
3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (2,3,4- trimethoxyphenyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,
6] pyrazine simultaneously [2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (pyrroles -2- bases) ethylidene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrazine is simultaneously
[2,3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (4- fluorophenyls) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrazine simultaneously [2,
3-e] [1,2,4] triazine；
5- methyl -3- { 2- [1- (4- nitrobenzophenones) methylene] diazanyl } -5,10- dihydro pyridos [2', 3':5,6] pyrazine is simultaneously
[2,3-e] [1,2,4] triazine；
5,8- dimethyl -3- { 2- [1- (the 3- pi-allyl -5- tert-butyl group -2- hydroxy phenyls) methylene] diazanyl } -5,10- dihydro pyrroles
Pyridine simultaneously [2', 3':5,6] pyrazine simultaneously [2,3-e] [1,2,4] triazine.
7. a kind of Pharmaceutical composition, the compound comprising any one in claim 1-6, and its optically active body or raceme
Or its pharmaceutically acceptable salt, hydrate or solvate are used as active component and pharmaceutically acceptable excipients.
8. in claim 1-6 any one compound, and its optically active body or raceme or its is pharmaceutically acceptable
Salt, hydrate or solvate are preparing treatment and/or are preventing the medicine of various unregulated cell growths or abnormal cell disseminated disease
Application in thing.
9. in claim 1-6 any one compound, and its optically active body or raceme or its is pharmaceutically acceptable
The application of salt, hydrate or solvate in the medicine for preparing treatment and/or preventing various Cancerous diseases.
10. in claim 9 any one compound, and its optically active body or raceme or its is pharmaceutically acceptable
Salt, hydrate or solvate prepare treatment and/or prevent colon cancer, the application in the medicine of lung cancer or breast cancer.
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