CN104341416B - Protein tyrosine kinase inhibitor and its application - Google Patents
Protein tyrosine kinase inhibitor and its application Download PDFInfo
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- CN104341416B CN104341416B CN201310329248.8A CN201310329248A CN104341416B CN 104341416 B CN104341416 B CN 104341416B CN 201310329248 A CN201310329248 A CN 201310329248A CN 104341416 B CN104341416 B CN 104341416B
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- JOXGDNSTOGOWKM-UHFFFAOYSA-N CCCN(C)CCNCc(c(C(F)(F)F)c1)ccc1NC(c1cc(C#CC2=C(C)[n]3nc(N(C)C)nc3CC2)c(C)cc1)=O Chemical compound CCCN(C)CCNCc(c(C(F)(F)F)c1)ccc1NC(c1cc(C#CC2=C(C)[n]3nc(N(C)C)nc3CC2)c(C)cc1)=O JOXGDNSTOGOWKM-UHFFFAOYSA-N 0.000 description 1
- RASZUSKDUKICSI-UHFFFAOYSA-N Cc(c(C#Cc1ccc[n]2nc(NC)nc12)c1)ccc1C(Nc1ccc(CN2CCN(C)CC2)c(C(F)(F)F)c1)=O Chemical compound Cc(c(C#Cc1ccc[n]2nc(NC)nc12)c1)ccc1C(Nc1ccc(CN2CCN(C)CC2)c(C(F)(F)F)c1)=O RASZUSKDUKICSI-UHFFFAOYSA-N 0.000 description 1
- DBYMNQDLOULLJR-UHFFFAOYSA-N Cc(ccc(C(CNc1ccc(CN2CCN(C)CC2)c(C(F)(F)F)c1)=O)c1)c1C#C Chemical compound Cc(ccc(C(CNc1ccc(CN2CCN(C)CC2)c(C(F)(F)F)c1)=O)c1)c1C#C DBYMNQDLOULLJR-UHFFFAOYSA-N 0.000 description 1
- VPJPOLAKEXJROI-UHFFFAOYSA-N Cc(ccc(C(Nc1cc(C(F)(F)F)c(CCC2=CCCN(C)CC2)cc1)=O)c1)c1C#Cc1c[n]2nc(N)nc2cc1C Chemical compound Cc(ccc(C(Nc1cc(C(F)(F)F)c(CCC2=CCCN(C)CC2)cc1)=O)c1)c1C#Cc1c[n]2nc(N)nc2cc1C VPJPOLAKEXJROI-UHFFFAOYSA-N 0.000 description 1
- CMTDGUODVOOAOG-UHFFFAOYSA-N Cc(ccc(C(Nc1cc(C(F)(F)F)c(CN2CCN(C)CC2)cc1)=O)c1)c1C#Cc1c(C(F)(F)F)[n]2nc(NC)nc2cc1 Chemical compound Cc(ccc(C(Nc1cc(C(F)(F)F)c(CN2CCN(C)CC2)cc1)=O)c1)c1C#Cc1c(C(F)(F)F)[n]2nc(NC)nc2cc1 CMTDGUODVOOAOG-UHFFFAOYSA-N 0.000 description 1
- UHNMOAIINYVSKV-UHFFFAOYSA-N Cc(ccc(C(Nc1cc(C(F)(F)F)c(CN2CCN(C)CC2)cc1)=O)c1)c1C#Cc1c[n]2nc(N)nc2cc1C Chemical compound Cc(ccc(C(Nc1cc(C(F)(F)F)c(CN2CCN(C)CC2)cc1)=O)c1)c1C#Cc1c[n]2nc(N)nc2cc1C UHNMOAIINYVSKV-UHFFFAOYSA-N 0.000 description 1
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention belongs to chemical medicine, there is provided a class has the compound of protein tyrosine kinase inhibitory activity or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug.The present invention also provides the preparation method of the compounds of this invention, the pharmaceutical composition of the compound containing the present invention or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, and the compound and composition of the present invention is for the application in the medicine for the treatment of or prevention of tumor.
Description
Technical field
The invention belongs to chemical medicine, and in particular to a class has the compound of protein tyrosine kinase inhibitory activity
Or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, and the pharmaceutical composition containing these compounds
With the application of these compounds or composition in medicine preparation.
Background technology
Protein tyrosine kinase(PTKs)It is that a class can be catalyzed γ-phosphoric acid on ATP and be transferred on protein-tyrosine residue
Kinases, by be catalyzed multiple protein tyrosine residue on phenolic hydroxyl group occur phosphorylation, and then activate functional protein effect
Protein enzyme system.Protein tyrosine kinase(PTKs)In occupation of highly important status in signal transduction pathway in the cell,
Adjust a series of physiological and biochemical procedures such as cell growth, differentiation, death.The unconventionality expression of protein tyrosine kinase can cause carefully
Born of the same parents' propagation regulation gets muddled, and then leads oncogenic generation.Additionally, the unconventionality expression of protein tyrosine kinase also with tumour
Invasion and attack and transfer, tumor neovasculature generation, the chemotherapy resistance to the action of a drug of tumour are closely related.Tyrosine kinase inhibitor can conduct
Atriphos(ATP)The competitive inhibitor combined with EGFR-TK, competitive binding EGFR-TK block tyrosine
The activity of kinases, suppresses cell propagation, has had several tyrosine protein kinase inhibitors to be successfully obtained exploitation.
Chronic myelocytic leukemia(CML)Chromosome translocation in patient forms BCR-ABL fusions, the BCR- of expression
ABL protein tyrosine kinases are played an important role in cell signalling and conversion, are acted on by phosphorylation etc., are promoted
The unlimited hyperplasia of CML maturation granulocytes.BCR-ABL is not expressed in normal cell, has become the ideal medicament for the treatment of CML
Target.
Imatinib is the protein tyrosine kinase inhibitor of first molecular targeted therapy, Reverse transcriptase Adenosine triphosphate
Glycosides (ATP) and thymidine kinase(TK)Acceptor(Such as KIT)Binding site, block TK phosphorylations, so as to suppress signal transduction, and can
Suppress the KIT of the KIT mutation relevant with kinases and wild type, there is therapeutic effect to various types of cancers.Imatinib exists
Inside and outside can suppress BCR-ABL EGFR-TKs on a cellular level, Selective depression BCR-ABL positive cell lines cell with
And Philadelphia Chromosome Positive(Ph+)Chronic myelogenous leukemia(CML)With the fresh white blood of ALL patient
The propagation of sick cell, induces its apoptosis.Additionally, Imatinib can also suppress platelet derived growth factor(PDGF)Acceptor
The receptor tyrosine kinase c-Kit of EGFR-TK and stem cell factor (SCF), so as to suppress by PDGF and stem cell factor
The cell behavior of mediation.Clinically it is mainly used in treating chronic myelocytic leukemia (CML) CML-BC, accelerated period or alpha-interferon
Chronic phase patient after Endodontic failure, it is unable to surgery excision or the malignant gastrointestinal mesenchymal neoplasm of transfer occurs(GIST)Patient;
It is also used for treating the positive patients with gastrointestinal stromal tumors (GIST) of CD117.
The exploitation of Imatinib and Clinical practice open the New Times of tumor cells targeting.But long-term taking she horse replace
Buddhist nun, can produce drug resistance, cause disease relapse.With Imatinib extensive application clinically, resistance problems become increasingly conspicuous.
The point mutation for being primarily due to BCR-ABL of acquired tolerance causes Imatinib be combined with BCR-ABL and be produced
's.And, it has been found that hundreds of BCR-ABL point mutation is related to imatinib-resistant, wherein 15~20% imatinib resistant
There is T315I mutation in patient.
The appearance of imatinib-resistant, has evoked the research and development upsurge of tyrosine kinase inhibitor of new generation, to exploitation
Go out more excellent for treating leukaemia, such as new medicine of each phase CML, Ph+ALL of resistance or non-resistance.
The content of the invention
It is an object of the invention to provide a class of formula I has the compound or its medicine of the BCR-ABL inhibitions of wide spectrum
Acceptable salt, isomers, solvate, crystallization or prodrug are learned,
Wherein:
R1Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R2Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R3Selected from hydrogen, alkyl, haloalkyl, halogen, aminoacyl, alkyl monosubstituted amino acyl group, double alkylaminoacyls and
Cyano group;
X is selected from N and C (R4), wherein R4Selected from hydrogen, amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl acyl ammonia
Base, acrylamido, heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino,
Or R4Connected carbon atom forms C (=O), described amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl
Acylamino-, acrylamido, heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl sulphonyl
Amino can be replaced by one or more halogens, alkyl, amino, cyano group;
Y is selected from N, NH and C (R5), wherein R5Selected from hydrogen, amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl acyl
Amino, acrylamido, heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl sulphonyl ammonia
Base, described amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroaryl acyl ammonia
Base, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino can be by one or more halogens, alkane
Base, amino, cyano group replace;
Singly-bound or double bond are represented, when X is C (=O),Represent singly-bound;
It is not following compound that condition is the compound:
3- ((2- amino-[1,2,4] triazole simultaneously [1,5-a] pyridin-7-yl) acetenyl) -4- methyl-N- [4- ((4- first
Base piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide;
3- ((2- methylaminos-[1,2,4] triazole simultaneously [1,5-a] pyridin-7-yl) acetenyl) -4- methyl-N- [4- ((4-
Methylpiperazine-1-yl) methyl) -3- trifluoromethyls] benzamide;
3- ((2- dimethylaminos-[1,2,4] triazole simultaneously [1,5-a] pyridin-7-yl) acetenyl) -4- methyl-N- [4-
((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide.
It is a further object to provide the compounds of formula I or its pharmaceutically acceptable salt of the preparation present invention,
The method of isomers, solvate, crystallization or prodrug.
It is also another object of the present invention to provide comprising the present invention compounds of formula I or its pharmaceutically acceptable salt,
The composition of isomers, solvate, crystallization or prodrug and pharmaceutically acceptable carrier, and the formula I comprising the present invention
Compound or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug and another kind of or multiple protein tyrosine-kinase
The composition of enzyme inhibitor.
The present invention's a further object is the compounds of formula I or its pharmaceutically acceptable salt, isomery for providing the present invention
The treatment of body, solvate, crystallization or prodrug and/or the method for prevention of tumor, and the compounds of formula I or its medicine of the present invention
Learn acceptable salt, isomers, solvate, crystallization or prodrug prepare for treatment and/or prevention of tumor medicine in
Using.
For above-mentioned purpose, the present invention provides technical scheme below:
In a first aspect, the present invention provides compounds of formula I or its pharmaceutically acceptable salt, isomers, solvate, knot
Brilliant or prodrug,
Wherein:
R1Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R2Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R3Selected from hydrogen, alkyl, haloalkyl, halogen, aminoacyl, alkyl monosubstituted amino acyl group, double alkylaminoacyls and
Cyano group;
X is selected from N and C (R4), wherein R4Selected from hydrogen, amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl acyl ammonia
Base, acrylamido, heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino,
Or R4Connected carbon atom forms C (=O), described amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl
Acylamino-, acrylamido, heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl sulphonyl
Amino can be replaced by one or more halogens, alkyl, amino, cyano group;
Y is selected from N, NH and C (R5), wherein R5Selected from hydrogen, amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl acyl
Amino, acrylamido, heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl sulphonyl ammonia
Base, described amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroaryl acyl ammonia
Base, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino can be by one or more halogens, alkane
Base, amino, cyano group replace;
Singly-bound or double bond are represented, when X is C (=O),Represent singly-bound;
It is not following compound that condition is the compound:
3- ((2- amino-[1,2,4] triazole simultaneously [1,5-a] pyridin-7-yl) acetenyl) -4- methyl-N- [4- ((4- first
Base piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide;
3- ((2- methylaminos-[1,2,4] triazole simultaneously [1,5-a] pyridin-7-yl) acetenyl) -4- methyl-N- [4- ((4-
Methylpiperazine-1-yl) methyl) -3- trifluoromethyls] benzamide;
3- ((2- dimethylaminos-[1,2,4] triazole simultaneously [1,5-a] pyridin-7-yl) acetenyl) -4- methyl-N- [4-
((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide.
In the embodiment of some compound of Formula I, X is N, and Y is N,Represent double bond.
In the embodiment of some compound of Formula I, X is N, and Y is C (R5),Represent double bond, R5Selected from hydrogen, ammonia
Base, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroarylamido, sulfonamido,
Alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino, described amino, alkyl monosubstituted amino, double alkyl aminos, acyl
It is amino, alkyl amido, acrylamido, heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, miscellaneous
Arenesulfonyl amino can be replaced by one or more halogens, alkyl, amino, cyano group.
In the embodiment of some compound of Formula I, X is C (R4), Y is N,Represent double bond, described R4Choosing
From hydrogen, amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroarylamido, sulphur
Acylamino-, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino, described amino, alkyl monosubstituted amino, double alkyl
Amino, acylamino-, alkyl amido, acrylamido, heteroarylamido, sulfonamido, alkyl sulfonyl amino, arylsulfonyl
Amino, heteroaryl ylsulfonylamino can be replaced by one or more halogens, alkyl, amino, cyano group.
In the embodiment of some compound of Formula I, X is C (=O), and Y is NH,Represent singly-bound.
In the embodiment of some compound of Formula I, X is C (R4), Y is C (R5),Double bond is represented, it is described
R4、R5Separately selected from hydrogen, amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido,
Heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino, described amino, list
Alkyl amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroarylamido, sulfonamido, alkyl sulphur
Acylamino-, Arenesulfonyl amino, heteroaryl ylsulfonylamino can be replaced by one or more halogens, alkyl, amino, cyano group.
In the embodiment of some preferred compound of Formula I, R1Selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl, halo
C1-6Alkyl, halo C1-6Alkoxyl ,-OH ,-NH2, halogen and CN;R2Selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkane
Base, halo C1-6Alkoxyl ,-OH ,-NH2, halogen and CN;R3Selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, halogen, aminoacyl,
Single C1-6Alkylaminoacyl, double C1-6Alkylaminoacyl and cyano group.
In the embodiment of some preferred compound of Formula I, R1Selected from hydrogen, C1-4Alkyl, C1-4Alkoxyl, halo
C1-4Alkyl, halo C1-4Alkoxyl ,-OH ,-NH2, halogen and CN;R2Selected from hydrogen, C1-4Alkyl, C1-4Alkoxyl, halo C1-4Alkane
Base, halo C1-4Alkoxyl ,-OH ,-NH2, halogen and CN;R3Selected from hydrogen, C1-4Alkyl, halo C1-4Alkyl, halogen, aminoacyl,
Single C1-4Alkylaminoacyl, double C1-4Alkylaminoacyl and cyano group.
It is highly preferred that in the embodiment of compound of Formula I, R1Selected from hydrogen, C1-3Alkyl, C1-3Alkoxyl, halo C1-3
Alkyl, halo C1-3Alkoxyl ,-OH ,-NH2, halogen and CN;R2Selected from hydrogen, C1-3Alkyl, C1-3Alkoxyl, halo C1-3Alkyl, halogen
For C1-3Alkoxyl ,-OH ,-NH2, halogen and CN;R3Selected from hydrogen, C1-3Alkyl, halo C1-3Alkyl, halogen, aminoacyl, list C1-3
Alkylaminoacyl, double C1-3Alkylaminoacyl and cyano group.
Preferably, the present invention provides the compound or its pharmaceutically acceptable salt, isomers, solvate, knot of formula Ia
Brilliant or prodrug,
Wherein:
R1Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R2Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R3Selected from hydrogen, alkyl, haloalkyl, halogen, aminoacyl, alkyl monosubstituted amino acyl group, double alkylaminoacyls and
Cyano group;
X is selected from N and C (R4), wherein R4Selected from hydrogen, amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl acyl ammonia
Base, acrylamido, heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino,
Or R4Connected carbon atom forms C (=O), described amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl
Acylamino-, acrylamido, heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl sulphonyl
Amino can be replaced by one or more halogens, alkyl, amino, cyano group;
Y is selected from N, NH and C (R5), wherein R5Selected from hydrogen, amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl acyl
Amino, acrylamido, heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl sulphonyl ammonia
Base, described amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroaryl acyl ammonia
Base, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino can be by one or more halogens, alkane
Base, amino, cyano group replace;Singly-bound or double bond are represented, when X is C (=O),Represent singly-bound;
When X is N, Y is C (R5), and the acetenyl are connected by the pyridine ring that condensed with which of the ring containing X, Y and pyridine ring
Together constitute [1,2,4]-triazole simultaneously [1,5-a] pyridine -7- ethynyl groups when, R5Selected from hydrogen, acylamino-, alkyl acyl ammonia
Base, acrylamido, heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino,
Described acylamino-, alkyl amido, acrylamido, heteroarylamido, sulfonamido, alkyl sulfonyl amino, aryl sulphur
Acylamino-, heteroaryl ylsulfonylamino can be replaced by one or more halogens, alkyl, amino, cyano group.
In the embodiment of some formulas Ia compounds, X is N, and Y is N,Show double bond.
In the embodiment of some formulas Ia compounds, X is N, and Y is C (R5),Double bond is represented, and contains X, Y
The pyridine ring that condensed with which of ring and the acetenyl that is connected of pyridine ring together with constitute [1,2,4]-triazole simultaneously [1,5-a] pyrrole
During pyridine -7- ethynyl groups, R5Selected from hydrogen, acylamino-, alkyl amido, acrylamido, heteroarylamido, sulphonyl ammonia
Base, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino, described acylamino-, alkyl amido, aryl acyl ammonia
Base, heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino can by one or
Multiple halogens, alkyl, amino, cyano group replace.
In the embodiment of some formulas Ia compounds, X is N, and Y is C (R5),Double bond is represented, and contains X, Y
The pyridine ring that condensed with which of ring and the acetenyl that is connected of pyridine ring together with constitute [1,2,4]-triazole simultaneously [1,5-a] pyrrole
During pyridine -6- ethynyl groups, R5Selected from hydrogen, amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, aryl
Acylamino-, heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino, it is described
Amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroarylamido, sulphonyl ammonia
Base, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino can be by one or more halogens, alkyl, amino, cyanogen
Base replaces.
In the embodiment of some formulas Ia compounds, X is C (R4), Y is N,Represent double bond, described R4Choosing
From hydrogen, amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroarylamido, sulphur
Acylamino-, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino, described amino, alkyl monosubstituted amino, double alkyl
Amino, acylamino-, alkyl amido, acrylamido, heteroarylamido, sulfonamido, alkyl sulfonyl amino, arylsulfonyl
Amino, heteroaryl ylsulfonylamino can be replaced by one or more halogens, alkyl, amino, cyano group.
In the embodiment of some formulas Ia compounds, X is C (=O), and Y is NH,Represent singly-bound.
In the embodiment of some formulas Ia compounds, X is C (R4), Y is C (R5),Double bond is represented, it is described
R4、R5Separately selected from hydrogen, amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido,
Heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino, described amino, list
Alkyl amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroarylamido, sulfonamido, alkyl sulphur
Acylamino-, Arenesulfonyl amino, heteroaryl ylsulfonylamino can be replaced by one or more halogens, alkyl, amino, cyano group.
In the embodiment of some preferred formula Ia compounds, R1Selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl, halo
C1-6Alkyl, halo C1-6Alkoxyl ,-OH ,-NH2, halogen and CN;R2Selected from hydrogen, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkane
Base, halo C1-6Alkoxyl ,-OH ,-NH2, halogen and CN;R3Selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, halogen, aminoacyl,
Single C1-6Alkylaminoacyl, double C1-6Alkylaminoacyl and cyano group.
In the embodiment of some preferred formula Ia compounds, R1Selected from hydrogen, C1-3Alkyl, C1-3Alkoxyl, halo
C1-3Alkyl, halo C1-3Alkoxyl ,-OH ,-NH2, halogen and CN;R2Selected from hydrogen, C1-3Alkyl, C1-3Alkoxyl, halo C1-3Alkane
Base, halo C1-3Alkoxyl ,-OH ,-NH2, halogen and CN;R3Selected from hydrogen, C1-3Alkyl, halo C1-3Alkyl, halogen, aminoacyl,
Single C1-3Alkylaminoacyl, double C1-3Alkylaminoacyl and cyano group.
It is further preferred that the present invention provides the compound or its pharmaceutically acceptable salt, isomers, solvent of formula I-a
Compound, crystallization or prodrug,
Wherein:
R1Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R2Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R3Selected from hydrogen, alkyl, haloalkyl, halogen, aminoacyl, alkyl monosubstituted amino acyl group, double alkylaminoacyls and
Cyano group;
R5Selected from hydrogen, amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroaryl
Base acylamino-, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino, described amino, monoalkyl
Amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroarylamido, sulfonamido, alkylsulfonylamino group
Base, Arenesulfonyl amino, heteroaryl ylsulfonylamino can be replaced by one or more halogens, alkyl, amino, cyano group;
It is not following compound that condition is the compound:
3- ((2- amino-[1,2,4] triazole simultaneously [1,5-a] pyridin-7-yl) acetenyl) -4- methyl-N- [4- ((4- first
Base piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide;
3- ((2- methylaminos-[1,2,4] triazole simultaneously [1,5-a] pyridin-7-yl) acetenyl) -4- methyl-N- [4- ((4-
Methylpiperazine-1-yl) methyl) -3- trifluoromethyls] benzamide;
3- ((2- dimethylaminos-[1,2,4] triazole simultaneously [1,5-a] pyridin-7-yl) acetenyl) -4- methyl-N- [4-
((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide.
It is further preferred that the compound or its pharmaceutically acceptable salt, isomers, solvent of this offer formula I-b are closed
Thing, crystallization or prodrug,
Wherein:
R1Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R2Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R3Selected from hydrogen, alkyl, haloalkyl, halogen, aminoacyl, alkyl monosubstituted amino acyl group, double alkylaminoacyls and
Cyano group;
Y is selected from N and NH;
R4Selected from hydrogen, amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroaryl
Base acylamino-, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino, or R4With the carbon being connected
Atom forms C (=O), described amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido,
Heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino can be by one or many
Individual halogen, alkyl, amino, cyano group replace;
Singly-bound or double bond are represented, works as R4When connected carbon atom forms C (O),Singly-bound is represented, Y is
NH。
It is further preferred that the present invention provides the compound or its pharmaceutically acceptable salt, isomers, solvent of formula Ia-a
Compound, crystallization or prodrug,
Wherein:
R1Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R2Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R3Selected from hydrogen, alkyl, haloalkyl, halogen, aminoacyl, alkyl monosubstituted amino acyl group, double alkylaminoacyls and
Cyano group;
R5Selected from hydrogen, amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroaryl
Base acylamino-, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino, described amino, monoalkyl
Amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroarylamido, sulfonamido, alkylsulfonylamino group
Base, Arenesulfonyl amino, heteroaryl ylsulfonylamino can be replaced by one or more halogens, alkyl, amino, cyano group.
When [1,2,4]-triazole constitute together with the be connected acetenyl of pyridine ring and pyridine ring for being condensed [1,2,4]-
Triazole simultaneously [1,5-a] pyridine -7- ethynyl groups when, described R5Selected from hydrogen, acylamino-, alkyl amido, aryl acyl ammonia
Base, heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino, described acyl ammonia
Base, alkyl amido, acrylamido, heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl
Ylsulfonylamino can be replaced by one or more halogens, alkyl, amino, cyano group.
It is further preferred that the present invention provides the compound or its pharmaceutically acceptable salt of formula I-a ', isomers, molten
Agent compound, crystallization or prodrug,
Wherein:
R1Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R2Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R3Selected from hydrogen, alkyl, haloalkyl, halogen, aminoacyl, alkyl monosubstituted amino acyl group, double alkylaminoacyls and
Cyano group;
R5Selected from hydrogen, amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroaryl
Base acylamino-, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino, described amino, monoalkyl
Amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroarylamido, sulfonamido, alkylsulfonylamino group
Base, Arenesulfonyl amino, heteroaryl ylsulfonylamino can be replaced by one or more halogens, alkyl, amino, cyano group.
It is further preferred that the present invention provides formula I-a " compound or its pharmaceutically acceptable salt, isomers, molten
Agent compound, crystallization or prodrug,
Wherein:
R1Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R2Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R3Selected from hydrogen, alkyl, haloalkyl, halogen, aminoacyl, alkyl monosubstituted amino acyl group, double alkylaminoacyls and
Cyano group;
R5Selected from hydrogen, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroaryl acyl
Amino, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino, described acylamino-, alkyl acyl ammonia
Base, acrylamido, heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino
Can be replaced by one or more halogens, alkyl, amino, cyano group;
It is not following compound that condition is the compound:
3- ((2- methylaminos-[1,2,4] triazole simultaneously [1,5-a] pyridin-7-yl) acetenyl) -4- methyl-N- [4- ((4-
Methylpiperazine-1-yl) methyl) -3- trifluoromethyls] benzamide;
3- ((2- dimethylaminos-[1,2,4] triazole simultaneously [1,5-a] pyridin-7-yl) acetenyl) -4- methyl-N- [4-
((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide..
It is further preferred that the present invention provides the compound or its pharmaceutically acceptable salt of formula I-b ', isomers, molten
Agent compound, crystallization or prodrug,
Wherein:
R1Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R2Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R3Selected from hydrogen, alkyl, haloalkyl, halogen, aminoacyl, alkyl monosubstituted amino acyl group, double alkylaminoacyls and
Cyano group;
Y is selected from N and NH;
R4Selected from hydrogen, amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroaryl
Base acylamino-, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino, or R4It is connected with which
Carbon atom forms C (=O), described amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, aryl acyl ammonia
Base, heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino can by one or
Multiple halogens, alkyl, amino, cyano group replace;
Singly-bound or double bond are represented, works as R4When the carbon atom being connected with which forms C (=O),Represent singly-bound,
Y is NH.
It is further preferred that the present invention provides formula I-b " compound or its pharmaceutically acceptable salt, isomers, molten
Agent compound, crystallization or prodrug,
Wherein:
R1Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R2Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R3Selected from hydrogen, alkyl, haloalkyl, halogen, aminoacyl, alkyl monosubstituted amino acyl group, double alkylaminoacyls and
Cyano group;
Y is selected from N and NH;
R4Selected from hydrogen, amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, acrylamido, heteroaryl
Base acylamino-, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino, or R4It is connected with which
Carbon atom forms C (=O), described amino, alkyl monosubstituted amino, double alkyl aminos, acylamino-, alkyl amido, aryl acyl ammonia
Base, heteroarylamido, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino can by one or
Multiple halogens, alkyl, amino, cyano group replace;
Singly-bound or double bond are represented, works as R4When the carbon atom being connected with which forms C (=O),Represent singly-bound,
Y is NH.
It is further preferred that the present invention provide formula Ia-a ' compound or its pharmaceutically acceptable salt, isomers,
Solvate, crystallization or prodrug,
Wherein:
R1Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R2Selected from hydrogen, alkyl, alkoxyl, haloalkyl, halogenated alkoxy ,-OH ,-NH2, halogen and CN;
R3Selected from hydrogen, alkyl, haloalkyl, halogen, aminoacyl, alkyl monosubstituted amino acyl group, double alkylaminoacyls and
Cyano group;
R5Selected from hydrogen, acylamino-, alkyl amido, acrylamido, heteroarylamido, sulfonamido, alkyl sulfonyl
Amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino, described acylamino-, alkyl amido, acrylamido, heteroaryl acyl
Amino, sulfonamido, alkyl sulfonyl amino, Arenesulfonyl amino, heteroaryl ylsulfonylamino can be by one or more halogens, alkane
Base, amino, cyano group replace.
In a preferred embodiment of the present invention, R1Selected from hydrogen, alkyl, haloalkyl, halogen and CN.
In further preferred embodiment of the present invention, R1Selected from methyl and trifluoromethyl.
In a preferred embodiment of the present invention, R2Selected from hydrogen, alkyl, haloalkyl, halogen and CN.
In further preferred embodiment of the present invention, R2Selected from methyl, ethyl, propyl group and isopropyl.
In a preferred embodiment of the present invention, R3Selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, halogen, aminoacyl,
Single C1-6Alkylaminoacyl, double C1-6Alkylaminoacyl and cyano group.
In further preferred embodiment of the present invention, R3Selected from hydrogen, methyl, ethyl, propyl group, isopropyl, trifluoromethyl, three
Fluoro ethyl, halogen and methylamino acyl group.
In a preferred embodiment of the present invention, R4Selected from amino, list C1-6Alkyl amino, double C1-6Alkyl amino, formyl
Amino, acetylamino, propionamido, benzoyl amino, trifluoroacetamido, methanesulfonamido, second sulfonamido, benzene fulfonic amide
Base, or R4C (=O) is formed with the carbon atom being connected.
In further preferred embodiment of the present invention, R4Selected from amino, methylamino, ethylamino, the third amino, isopropylamino,
Dimethylamino, lignocaine, dipropyl amino, methylethylamine, methylpropylamino, ethylpropylamino, formamido group, second
Acylamino-, propionamido, trifluoroacetamido, methanesulfonamido, second sulfonamido, or R4Formed with the carbon atom being connected
C(=O)。
In a preferred embodiment of the present invention, R5Selected from amino, list C1-6Alkyl amino, double C1-6Alkyl amino, formyl
Amino, acetylamino, propionamido, benzoyl amino, trifluoroacetamido, methanesulfonamido, second sulfonamido, benzene fulfonic amide
Base.
In further preferred embodiment of the present invention, R5Selected from amino, methylamino, ethylamino, the third amino, isopropylamino,
Dimethylamino, lignocaine, dipropyl amino, methylethylamine, methylpropylamino, ethylpropylamino, formamido group, second
Acylamino-, propionamido, trifluoroacetamido, methanesulfonamido, second sulfonamido.
The invention provides compound in detail below:
On the other hand, the present invention provides the preparation method of the general formula compound of the present invention.The preparation side of compounds of formula I
Method comprises the steps:
(1) preparation of the intermediate of formula 5:
A) compound of formula 1 reacts the intermediate for obtaining formula 3 with the compound of formula 2;
B) intermediate of formula 3 reacts the intermediate for obtaining formula 4 with trimethylsilyl acetylene;
C) intermediate of formula 4 sloughs the intermediate that TMS obtains formula 5;
(2) preparation of compounds of formula I:
D) intermediate of formula 5 obtains compounds of formula I with the intermediate reaction of formula 6.
Wherein, R1、R2、R3、R5, X, Y there is implication in formula I, M is selected from chlorine, bromine, iodine.
Similarly, those skilled in the art can refer to the preparation method of compounds of formula I of the present invention, prepare the present invention logical
Formulas I, formula Ia, formula I-a, formula I-b, formula Ia-a, formula I-a ', formula I-a ", formula I-b ', formula I-b " and formula
The compound of Ia-a '.
Specifically, the preparation method of the compound of formula I-a comprises the steps:
(1)The preparation of the intermediate of formula 9:
E) compound of formula 7 reacts the intermediate for obtaining formula 8 with different sulphur cyanato- Ethyl formate;
F) intermediate of formula 8 reacts the intermediate for obtaining formula 9 with hydroxylamine hydrochloride;
(2)The synthesis of the intermediate of formula 10
G) intermediate of formula 9 is obtained formula 10 through conventional alkylated reaction, acylation reaction or sulfonylating reaction
Intermediate;
(3)The preparation of the compound of formula I-a:
Or
H) intermediate of the intermediate of formula 9 or formula 10 obtains formula I-a compounds with the intermediate reaction of formula 5;
Wherein, R1、R2、R3And R5With the implication in formula I-a, M is selected from chlorine, bromine, iodine.
Specifically, wherein R4Connected carbon atom forms C (=O), preparation sides of the Y for the compound of the formula I-b of NH
Method comprises the steps:
(1)The preparation of the intermediate of formula 13
I) intermediate of formula 11 and hydration hydrazine reaction obtain the intermediate of formula 12;
J) intermediate of formula 12 reacts the intermediate for obtaining formula 13 with triphosgene;
(2)The preparation of the target compound of Formulas I-b
K) intermediate of formula 13 obtains wherein R with the intermediate reaction of formula 54Connected carbon atom forms C (=O), Y
For the compound of the formula I-b of NH;
Wherein, R1、R2、R3With the implication in formula I-b, M is selected from chlorine, bromine, iodine.
The third aspect, the present invention provide pharmaceutical composition, its include the present invention compound or its pharmaceutically acceptable salt,
Isomers, solvate, crystallization or prodrug.
In some embodiments, the present invention provides pharmaceutical composition, and which includes the compound of the present invention, isomers, molten
Agent compound, crystallization or prodrug, also comprising one or more selected from following composition:Tyrosine protein enzyme inhibitor, EGFR suppress
Agent, VEGFR inhibitor, BCR-ABL inhibitor, c-kit inhibitor, c-Met inhibitor, Raf inhibitor, mek inhibitor, group egg
White deacetylase inhibitor, VEGF antibody, EGF antibody, HIV kinases inhibitors, HMG-CoA reductase inhibitor etc..
Can by the compound of the present invention, isomers, solvate, crystallization or prodrug and pharmaceutically acceptable carrier,
Diluent or excipient are prepared by mixing into pharmaceutical preparation, to be suitable for oral or parenteral.Medication includes, but does not limit
In intracutaneous, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and peroral route.The preparation can be applied by any approach, example
Such as by being transfused or injecting, applied by the approach that transepithelial or mucocutaneous (such as oral mucosa or rectum etc.) absorb.Give
Medicine can be whole body or local.The example of oral administration preparation includes solid or liquid dosage form, specifically, including piece
Agent, pill, granula, pulvis, capsule, syrup, emulsion, supensoid agent etc..The preparation can pass through methods known in the art system
It is standby, and include the conventional use of carrier of field of pharmaceutical preparations, diluent or excipient.
Fourth aspect, the present invention provide compound, isomers, solvate, crystallization or prodrug or the present invention of the present invention
Medicine composite for curing or prevention of tumor method and prepare prevention or tumor in application, including to tumour
Easily send out crowd or tumor patient applies compound, isomers, solvate, crystallization or the prodrug of the present invention or comprising the present invention
Compound, isomers, solvate, the pharmaceutical composition of crystallization or prodrug, effectively to reduce Tumor incidence, extend tumour
Patient vitals.
Term explanation
" alkyl " of the present invention refers to the saturated hydrocarbyl of straight or branched, preferably C1-6Alkyl, more preferably C1-3
Alkyl, suitable C1-3Alkyl is methyl, ethyl, propyl group, isopropyl.
" alkoxyl " of the present invention refers to alkyl-O-, preferably C1-6Alkyl-O-, more preferably C1-3Alkyl-O-,
Suitable C1-3Alkyl-O- is methoxyl group, ethyoxyl, propoxyl group, isopropoxy.
" halogen " of the present invention refers to fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine.
" haloalkyl " of the present invention is referred at least by the alkyl of a halogen substiuted, preferably halo C1-6Alkyl, enters one
Step is preferably halo C1-3Alkyl, suitable halo C1-3Alkyl is chloromethyl, methyl fluoride, dichloromethyl, difluoromethyl, three chloromethanes
Base, trifluoromethyl, chloroethyl, fluoro ethyl, Dichloroethyl, two fluoro ethyls, trichloroethyl, trifluoroethyl.
" halogenated alkoxy " of the present invention is referred at least by the alkoxyl of a halogen substiuted, preferably at least by a halogen
The C that element replaces1-6Alkoxyl, more preferably halo C1-3Alkoxyl, suitable halo C1-3Alkoxyl is chloromethane epoxide, fluorine
Methoxyl group, dichloro methoxyl group, difluoro-methoxy, trichloromethoxy, trifluoromethoxy;Two chloroethoxies, difluoroethoxy, trichlorine
Ethyoxyl, trifluoro ethoxy.
" acylamino- " of the present invention refers to HC (O)-NH-.
" alkyl amido " of the present invention refers to alkyl-C (O)-NH-, preferably C1-6Alkyl-C (O)-NH-, it is further excellent
Elect C as1-3Alkyl-C (O)-NH-.
" acrylamido " of the present invention refers to aryl-C (O)-NH-.
" heteroarylamido " of the present invention refers to heteroaryl-C (O)-NH-.
" sulfonamido " of the present invention refers to HS (O)2-NH-。
" the alkyl sulfonyl amino " of the present invention refers to alkyl-S (O)2- NH-, preferably C1-6Alkyl-S (O)2- NH-, enters one
Step is preferably C1-3Alkyl-S (O)2-NH-。
" Arenesulfonyl amino " of the present invention refers to aryl-S (O)2-NH-。
" the heteroaryl ylsulfonylamino " of the present invention refers to heteroaryl-S (O)2-NH-。
" aryl " of the present invention refers to the aromatic hydrocarbon group containing one or more phenyl ring.Suitable aryl includes phenyl, naphthalene
Base.
" heteroaryl " of the present invention refers to the aromatic radical that at least one carbon atom is substituted by hetero atom in aryl.Institute
The hetero atom stated is O, S, N.
" solvate " of the present invention refers to solute in a conventional sense(Such as reactive compound, the salt of reactive compound)With
Solvent(Such as water)The compound that combination is formed.Solvent refers to the solvent of known to those of skill in the art or easy determination.Such as
Fruit is water, then solvate is commonly referred to as hydrate, such as monohydrate, dihydrate, trihydrate etc..
" crystallization " of the present invention refers to the various solid forms that compound of the present invention is formed, including crystal formation, nothing are determined
Shape.
" isomers " of the present invention refers to the isomers of the cis or trans configuration of compound.Therefore, the present invention includes often
Plant cis-isomer or transisomer and be substantially free of the mixture of other isomers and these isomers.
" prodrug " of the present invention refer under the physiological condition of organism, due to the reaction such as enzyme, hydrochloric acid in gastric juice and conversion cost
The compound of the compound of invention, i.e., the compound of the compound invented by conversion costs such as the oxidation of enzyme, reduction, hydrolysis
And/or the compound of the compound of the conversion cost such as the hydrolysis by hydrochloric acid in gastric juice etc. invention.
" the pharmaceutically acceptable salt " of the present invention refers to the pharmaceutically acceptable salt that the compound of the present invention is formed with acid,
Described acid include but is not limited to phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, butanedioic acid,
Fumaric acid, acetic acid, lactic acid, nitric acid etc..
The present invention " pharmaceutical composition " refer to comprising any compound as herein described, including isomers, prodrug,
Solvate, pharmaceutically acceptable salt or its chemical forms of protection, and one or more pharmaceutically acceptable carrier is mixed
Compound.
The present invention " pharmaceutically acceptable carrier " refer to organism is not caused obvious irritation and do not disturb to
Give the carrier of the biologically active and property of compound, comprising solvent, diluent or other excipient, dispersant, surfactant,
Isotonic agent, thickener or emulsifying agent, preservative, solid binder, lubricant etc..Unless any conventional carrier medium and the present invention
Compound is incompatible.Carbohydrate, such as lactose, Portugal can be included, but are not limited to as some examples of pharmaceutically acceptable carrier
Grape sugar and sucrose;Starch, such as cornstarch and farina;Cellulose and its derivates, such as sodium carboxymethylcellulose and
Cellulose and cellulose acetate;Malt, gelatin etc..
" excipient " of the present invention refers to and is added in Pharmaceutical composition further to promote to give the inert substance of compound.
Excipient can include calcium carbonate, calcium phosphate, various saccharides and polytype starch, cellulose derivative, gelatin, plant
Oil, polyethylene glycol.
" application in the medicine for treatment or prevention of tumor is prepared " of the present invention refers to the life that can suppress tumour
Long, development and/or transfer, mainly give the compound for controlling the present invention for giving treatment effective dose to press down to required human or animal
System, the growth for slowing down or reversing subject's tumour, development or expanding.
The compound of the present invention refers to all of general formula compound of the invention, including formula I, formula Ia, formula I-a, logical
Change described in Formulas I-b, formula Ia-a, formula I-a ', formula I-a ", formula I-b ', formula I-b " and the arbitrary formulas of formula Ia-a '
Compound and particular compound.
Specific embodiment
Representational embodiment is in order to the present invention is better described, not for the protection model for limiting the present invention below
Enclose.
Embodiment 13- ((2- methylamino -7- methyl-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4-
Methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of step 11- (4- methyl -5- bromopyridine -2- bases) -3- ethoxycarbonylthioureas
In 50mL round-bottomed flasks, under condition of ice bath, addition 2- amino -4- methyl -5- bromopyridines (1.87g,
10mmol), dichloromethane (DCM, 20mL) is added, different sulphur cyanato- Ethyl formate is added(EtOC (O) NCS, 1.4g,
10.6mmol), 5 DEG C of reaction 15min, under normal temperature, then react 2h.40 DEG C of concentrations, add 50ml petroleum ethers(PE), have substantial amounts of solid
Body is separated out, and is filtered, and filter cake PE is washed 3 times, is dried, is obtained title compound.
ESI-MS m/z:[M+H]+=317.9。
The preparation of step 22- amino -6- bromine-7-methyls-[1,2,4] triazole simultaneously [1,5-a] pyridine
In 100mL eggplant-shape bottles, addition 1- (4- methyl -5- bromopyridine -2- bases) -3- ethoxycarbonylthioureas (1.21mg,
4mmol), hydroxylamine hydrochloride (1.38g, 20mmol) and DIPEA(DIEA, 1.65mL), add 40ml methyl alcohol and
The mixed solution of ethanol(V:V=1:1), 1h is stirred at room temperature, 70 DEG C of reaction 4h are warming up to.After reaction 4h, stop heating, be spin-dried for, plus
Enter 20ml frozen water, filter, be dried, obtain title compound.
1H NMR(300MHz,DMSO-d6)δ:8.88(s,1H),7.36(s,1H),6.04(s,2H),2.37(s,3H)。
ESI-MS m/z:[M+H]+=227.1。
The preparation of -6 bromine-7-methyl of step 32- methylamino-[1,2,4] triazole simultaneously [1,5-a] pyridine
In dry two mouthfuls of flasks of 100ml, compound 2- amino -6- bromine-7-methyls-[1,2,4] triazole is added simultaneously
[1,5-a] pyridine (200mg, 0.88mmol), paraformaldehyde (264mg, 8.8mmol), sodium methoxide(190mg, 3.52mmol)With
Methyl alcohol(5ml), nitrogen protection it is lower 80 DEG C reaction 2h, be cooled to room temperature, by sodium borohydride(167.2mg,4.4mmol)It is in batches careful
It is added in reaction system, is heated to after 80 DEG C of stirring 2h under condition of ice bath, adds acetone that excessive sodium borohydride is quenched, it is dense
Contracting.Add water(20ml), ethyl acetate(EA, 50ml)Extraction three times, merges organic phase concentration, is dried, filter, column chromatography purifying
Obtain title compound.
ESI-MS m/z:[M+H]+=241.1。
Step 4:The iodo- 4- methyl-N- of 3- [4- (4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide
Preparation
4- (4- methylpiperazine-1-yl methyl) -3- 5-trifluoromethylanilines are added in the reactor(2.27g, 8.3mmol)、
The iodo- 4- methyl benzoyl chlorides of 3-(10mmol), 15ml tetrahydrofurans, 10ml triethylamines, be stirred at room temperature 4 hours.Reaction terminates, and uses
Saturation NaHCO3Solution is washed, ethyl acetate/water extraction, the washing of saturation NaCl solution, anhydrous Na2SO4It is dried, vacuum distillation is removed
Solvent, silica column purification is gone to obtain title compound.
1H NMR(500MHz,CDCl3)δ:8.39(s,1H,N-H),8.29(s,1H,Ar-H),7.88(d,1H,Ar-H),
7.86(s,1H,Ar-H),7.75(d,1H,Ar-H),7.73(d,1H,Ar-H),7.28(d,1H,Ar-H),3.62(s,2H,
PhCH2),2.60(b,8H,4×-CH2),2.47(s,3H,-CH3),2.31(s,3H,-CH3)。
Step 5:3- Trimethylsilanylethynyl -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoros
Aminomethyl phenyl] benzamide preparation
By 3- iodo- 4- methyl-N- [4- (4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide
(3.1g, 6.1mmol)、Pd(PPh3)2Cl2(426mg, 0.61mmol)、CuI(231mg, 1.21mmol)It is placed in reactor, plus
Enter toluene 30ml and make solvent, triethylamine 1ml maintains alkaline environment.Under inert gas shielding, trimethyl is added in the mixture
Silane ethyl-acetylene(3.0g, 30.3mmol), 58 DEG C are stirred 24 hours.Reaction terminates, and in reactant mixture adds ethyl acetate
Extracted with water, merge organic layer, washed with saturation NaCl solution, added anhydrous Na2SO4It is dried.Reduced pressure concentration, residue
Jing silica column purifications obtain title compound.
1H NMR(500MHz,CDCl3)δ:8.30(s,1H,N-H),7.86(s,1H,Ar-H),7.83(d,1H,Ar-H),
7.72(s,1H,Ar-H),7.55(d,1H,Ar-H),7.41(d,1H,Ar-H),7.24(d,1H,Ar-H),3.60(s,2H,
PhCH2),2.48(b,8H,4×-CH2),2.45(s,3H,-CH3),2.28(s,3H,-CH3),0.26(s,9H,3×-CH3)。
Step 6:3- acetenyl -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzene
The preparation of formamide
Step 5 is reacted into gains (1.59g, 3.3mmol), potassium carbonate (1.82g, 13.2mmol), the mixing of 20ml methyl alcohol
In reactor, under inert gas shielding, 3 hours are stirred at room temperature.Reaction terminates, and methyl alcohol is removed on Rotary Evaporators, adds second
Acetoacetic ester and water are extracted, and are merged organic layer, are washed with saturation NaCl solution, add anhydrous Na2SO4It is dried.Then this is had
Machine solution is concentrated on a rotary evaporator, and residue Jing silica column purifications obtain title compound.
1H NMR(500MHz,CDCl3)δ:10.47(s,1H,N-H),8.19(s,1H,Ar-H),8.08(s,1H,Ar-H),
8.04(d,1H,Ar-H),7.91(d,1H,Ar-H),7.70(d,1H,Ar-H),7.47(d,1H,Ar-H),4.50(s,1H,≡
CH),3.56(s,2H,PhCH2),2.50(s,3H,-CH3),2.36(b,8H,-4×CH2),2.15(s,3H,-CH3)。
Step 73- ((2- methylamino -7- methyl-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- first
The preparation of base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
Weigh 3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzoyl
Amine(126mg, 0.3mmol), 2- methylamino -6- bromine-7-methyls-[1,2,4] triazole simultaneously [1,5-a] pyridine(60mg,
0.3mmol), Pd (Pph3)2Cl2(22mg, 0.03mmol), three hexamethylene phosphines(Pcy3,16mg, 0.06mmol), CuI(6mg,
0.03mmol), cesium carbonate(100mg, 0.3mmol), in adding tube sealing.Then in tube sealing 6 are added to drip diisopropyl ethyl amine
(DIPEA)And 6mL DMF.Logical argon gas deoxygenation was sealed after 5 minutes, and 80 DEG C are stirred overnight.During each reactant adds 10mL tube sealings,
Plus DMF is to half volume, lead to argon gas deoxygenation 5 minutes, sealing, 80 DEG C are stirred overnight.Next day reactant liquor ammonia scrubbing 2 times, second
Acetoacetic ester is extracted 3 times, uses saturated common salt water washing several times after merging organic layer, adds anhydrous sodium sulfate drying, purifying to obtain
Target compound.
1H NMR(300MHz,DMSO-d6)δ:10.54(s,1H),8.92(s,1H),8.20(s,1H),8.14(s,1H),
8.05(d,1H),7.92(d,1H),7.70(d,1H),7.52(d,1H),7.34(s,1H),6.58(q,1H),3.57(s,2H),
2.82(s,3H),2.57(s,3H),2.53(s,3H),2.38(m,8H),2.16(s,3H)。
ESI-MS m/z:[M+H]+=576.3。
Embodiment 23- ((2- amino -5- trifluoromethyls-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -
4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of bromo- [1,2,4] triazoles of step 12- amino -5- trifluoromethyl -6- simultaneously [1,5-a] pyridine
With the bromo- 6- trifluoromethyl pyridines of 2- amino -5- as raw material, title compound is prepared by 1 step 1 of embodiment and step 2
Thing.
1H NMR(300MHz,DMSO-d6)δ:7.77(d,1H),7.59(d,1H),6.48(s,2H)。
Step 23- ((2- amino -5- trifluoromethyls-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4-
The preparation of methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With bromo- [1,2,4] triazoles of 2- amino -5- trifluoromethyl -6- simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl -
N- [4- (4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide is raw material, according to the side of 1 step 7 of embodiment
Legal system obtains target compound.
1H NMR(300MHz,DMSO-d6)δ:10.52(s,1H),8.20(s,1H),8.16(s,1H),8.07(d,1H),
8.04(d,1H),7.76(d,1H),7.74(d,1H),7.71(d,1H),7.54(d,1H),6.61(s,2H),3.57(s,2H),
2.73(s,3H),2.40(m,8H),2.18(s,3H)。
ESI-MS m/z:[M+H]+=616.4。
Embodiment 33- ((2- amino -7- methyl-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- first
Base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of step 12- amino -6- bromine-7-methyls-[1,2,4] triazole simultaneously [1,5-a] pyridine
With 2- amino -4- methyl -5- bromopyridines as raw material, title compound is obtained by 1 step 1 of embodiment and step 2.
1H NMR(300MHz,DMSO-d6)δ:8.88(s,1H),7.36(s,1H),6.04(s,2H),2.37(s,3H)。
ESI-MS m/z:[M+H]+=227.1。
Step 23- ((2- amino -7- methyl-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- first
The preparation of base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With 2- amino -6- bromine-7-methyls-[1,2,4] triazole simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl-N-
[4- (4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide is raw material, according to the method for 1 step 7 of embodiment
Prepared target compound.
1H NMR(300MHz,DMSO-d6)δ:10.54(s,1H),8.86(s,1H),8.21(s,1H),8.15(s,1H),
8.06(d,1H),7.92(d,1H),7.71(d,1H),7.52(d,1H),7.33(s,1H),6.13(s,2H),3.58(s,2H),
2.58(s,6H),2.40(m,8H),2.19(s,3H)。
ESI-MS m/z:[M+H]+=562.4。
Embodiment 43- ((2- amino -8- methyl-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- first
Base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of the bromo- 8- methyl of step 12- amino -6--[1,2,4] triazole simultaneously [1,5-a] pyridine
With 2- amino -3- methyl -5- bromopyridines as raw material, title compound is obtained by 1 step 1 of embodiment and step 2.
Step 23- ((2- amino -8- methyl-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- first
The preparation of base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With the bromo- 8- methyl of 2- amino -6--[1,2,4] triazole simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl-N-
[4- (4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide is raw material, according to the method for 1 step 7 of embodiment
Prepare target compound.
1H NMR(300MHz,DMSO-d6)δ:10.52(s,1H),8.76(s,1H),8.21(s,1H),8.15(s,1H),
8.06(d,1H),7.91(d,1H),7.70(d,1H),7.51(d,1H),7.42(s,1H),6.16(s,2H),3.58(s,2H),
3.26(s,6H),2.42(m,8H),2.20(s,3H)。
ESI-MS m/z:[M+H]+=562.3。
Embodiment 53- ((2- amino -5- methyl-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- first
Base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of bromo- [1,2,4] triazoles of step 12- amino -5- methyl -6- simultaneously [1,5-a] pyridine
With 2- amino -6- methyl -5- bromopyridines as raw material, title compound is obtained by 1 step 1 of embodiment and step 2.
Step 23- ((2- amino -5- methyl-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- first
The preparation of base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With bromo- [1,2,4] triazoles of 2- amino -5- methyl -6- simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl-N-
[4- (4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide is raw material, according to the method for 1 step 7 of embodiment
Prepare target compound.
1H NMR(300MHz,DMSO-d6)δ:10.52(s,1H),8.21(s,1H),8.17(s,1H),8.06(d,1H),
7.91(d,1H),7.71(d,1H),7.58(d,1H),7.52(s,1H),7.29(s,1H),6.21(s,2H),3.58(s,2H),
2.85(s,3H),2.58(s,3H),2.40(m,8H),2.19(s,3H)。
ESI-MS m/z:[M+H]+=562.5。
Embodiment 63- ((2- dimethylamino -5- methyl-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -
4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of bromo- [1,2,4] triazoles of step 12- amino -5- methyl -6- simultaneously [1,5-a] pyridine
With 2- amino -6- methyl -5- bromopyridines as raw material, it is obtained by the method for 1 step 1 of embodiment and step 2 titled
Compound.
The preparation of bromo- [1,2,4] triazoles of step 22- dimethylamino -5- methyl -6- simultaneously [1,5-a] pyridine
In 50mL eggplant-shape bottles, under condition of ice bath, add bromo- [1,2, the 4] triazoles of 2- amino -5- methyl -6- simultaneously [1,
5-a] pyridine (1.06mg, 5mmol), be dried THF20ml, add sodium hydride(240mg, 10mmol), 15min is stirred, then
Add 2ml iodomethane, normal-temperature reaction 4h.It is spin-dried for, adds 50ml water, ethyl acetate extraction(30ml*3), column chromatography purifying obtain
Title compound.
Step 33- ((2- dimethylamino -5- methyl-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4-
The preparation of methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With bromo- [1,2,4] triazoles of 2- dimethylamino -5- methyl -6- simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl -
N- [4- (4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide is raw material, according to the side of 1 step 7 of embodiment
Method prepares target compound.
1H NMR(300MHz,DMSO-d6)δ:10.53(s,1H),8.21(s,1H),8.17(s,1H),8.06(d,1H),
7.92(d,1H),7.71(d,1H),7.64(d,1H),7.53(d,1H),7.37(s,1H),3.57(s,2H),3.31(s,3H),
3.08(s,3H),2.88(s,3H),2.58(s,3H),2.39(m,8H),2.18(s,3H)。
ESI-MS m/z:[M+H]+=590.3。
Embodiment 73- ((2- dimethylamino -8- methyl-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -
4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of bromo- [1,2,4] triazoles of step 12- dimethylamino -8- methyl -6- simultaneously [1,5-a] pyridine
With 2- amino -3- methyl -5- bromopyridines as raw material, title is prepared according to the method for 6 step 1 of embodiment and step 2
Compound.Step 23- ((2- dimethylamino -8- methyl-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4-
The preparation of methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With -6 bromo- [1,2,4] triazole of 2- dimethylamino -8- methyl simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl -
N- [4- (4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide is raw material, according to the side of 1 step 7 of embodiment
Method prepares target compound.
1H NMR(300MHz,DMSO-d6)δ:10.52(s,1H),8.87(s,1H),8.22(s,1H),8.16(s,1H),
8.07(d,1H),7.92(d,1H),7.72(d,1H),7.53(d,1H),7.48(s,1H),3.58(s,2H),3.31(s,3H),
3.08(s,3H),2.88(s,3H),2.58(s,3H),2.37(m,8H),2.18(s,3H)。
ESI-MS m/z:[M+H]+=590.3。
Embodiment 83- ((2- methylamino -8- methyl-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4-
Methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of bromo- [1,2,4] triazoles of step 12- methylamino -8- methyl -6- simultaneously [1,5-a] pyridine
With 2- amino -3- methyl -5- bromopyridines as raw material, title compound is prepared according to the method for 1 step 1-3 of embodiment
Thing.
1H NMR(300MHz,DMSO-d6)δ:8.83-8.79(m,1H),7.43(s,1H),6.53-6.52(m,1H),
3.32(s,3H),2.39(s,3H)。
ESI-MS m/z:[M+H]+=241.0。
Step 23- ((2- methylamino -8- methyl-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- first
The preparation of base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With bromo- [1,2,4] triazoles of 2- methylamino -8- methyl -6- simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl-N-
[4- (4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide is raw material, according to the method for 1 step 7 of embodiment
Prepare target compound.
1H NMR(300MHz,DMSO-d6)δ:10.52(s,1H),8.82(s,1H),8.21(s,1H),8.14(s,1H),
8.06(d,1H),7.91(d,1H),7.70(d,1H),7.51(d,1H),7.44(s,1H),6.62(q,1H),3.57(s,2H),
3.26(s,3H),2.84(d,3H),2.56(d,3H),2.41(m,8H),2.18(s,3H)。
ESI-MS m/z:[M+H]+=576.3。
Embodiment 93- ((fluoro- [1,2,4] triazoles of 2- amino -8- simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- first
Base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of fluoro- [1,2,4] triazoles of the bromo- 8- of step 12- amino -6- simultaneously [1,5-a] pyridine
With the fluoro- 5- bromopyridines of 2- amino -3- as raw material, title is prepared according to the method for 1 step 1 of embodiment and step 2
Compound.
1H NMR(300MHz,DMSO-d6)δ:8.30(s,1H),7.27(dd,1H),4.58(m,2H)。
Step 23- ((fluoro- [1,2,4] triazoles of 2- amino -8- simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- methyl -
The preparation of N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With fluoro- [1,2,4] triazoles of the bromo- 8- of 2- amino -6- simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl-N- [4-
(4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide be raw material, according to the method system of 1 step 7 of embodiment
It is standby go out target compound.
1H NMR(300MHz,DMSO-d6)δ:10.56(s,1H),8.88(s,1H),8.19(s,1H),8.14(s,1H),
8.05(d,1H),7.91(d,1H),7.69(d,1H),7.64(d,1H),7.51(d,1H),6.44(s,2H),3.57(s,2H),
2.73(s,3H),2.40(m,8H),2.25(s,3H)。
ESI-MS m/z:[M+H]+=566.4。
Embodiment 103- ((2- methylamino -5- trifluoromethyls-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetylene
Base) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of bromo- [1,2,4] triazoles of step 12- methylamino -5- trifluoromethyl -6- simultaneously [1,5-a] pyridine
With the bromo- 6- trifluoromethyl pyridines of 2- amino -5- as raw material, title is prepared according to the method for 1 step 1-3 of embodiment
Product.
1H NMR(500MHz,DMSO-d6)δ:7.79-7.77(m,1H),7.63-7.61(m,1H),6.91(s,1H),
2.85(s,3H)。
ESI-MS m/z:[M+H]+=296.0。
Step 23- ((2- methylamino -5- trifluoromethyls-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -
The preparation of 4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With 2- methylamino -5- trifluoromethyls -6- bromines [1,2,4] triazole simultaneously [1,5-a] pyridine and 3- acetenyl -4- first
Base-N- [4- (4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide is raw material, according to 1 step 7 of embodiment
Method prepare target compound.
1H NMR(300MHz,DMSO-d6)δ:10.54(s,1H),8.20(d,1H),8.16(d,1H),8.05(d,1H),
7.96(dd,1H),7.77(dd,2H),7.71(d,1H),7.54(d,1H),7.02(q,1H),3.58(s,2H),2.87(d,
3H),2.55(s,3H),2.41(m,8H),2.21(s,3H)。
ESI-MS m/z:[M+H]+=630.3。
Embodiment 113- ((2- amino -8- methyl-carbamoyls [1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetylene
Base) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of bromo- 8- methyl-carbamoyls [1,2,4] triazoles of step 12- amino -6- simultaneously [1,5-a] pyridine
With the bromo- N- methylnicotinamides of 2- amino -5- as raw material, prepare according to the method for 1 step 1 of embodiment and step 2
Title compound.
Step 23- ((2- amino -8- methyl-carbamoyls [1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetylene
Base) -4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide preparation
With bromo- 8- methyl-carbamoyls [1,2,4] triazoles of 2- amino -6- simultaneously [1,5-a] pyridine] pyridine and 3- acetylene
Base -4- methyl-N- [4- (4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide is raw material, according to embodiment
The method of 1 step 7 prepares target compound.
1H NMR(300MHz,DMSO-d6)δ:10.51(s,1H),9.17(d,2H),8.20(s,2H),8.14(s,1H),
8.06(d,1H),7.93(d,1H),7.71(d,1H),7.52(d,1H),6.63(s,2H),3.57(s,2H),2.95(d,3H),
2.58(s,3H),2.40(m,8H),2.17(s,3H)。
ESI-MS m/z:[M+H]+=605.5。
Embodiment 123- ((chloro- [1,2,4] triazoles of 2- amino -7- simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- first
Base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of chloro- [1,2,4] triazoles of the bromo- 7- of step 12- amino -6- simultaneously [1,5-a] pyridine
With the chloro- 5- bromines of 2- amino -4- as raw material, title compound is prepared according to the method for 1 step 1 of embodiment and step 2
Thing.
1H NMR(300MHz,DMSO-d6)δ:7.25(t,2H),7.17(d,2H)。
Step 23- ((chloro- [1,2,4] triazoles of 2- amino -7- simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- methyl -
The preparation of N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With chloro- [1,2,4] triazoles of the bromo- 7- of 2- amino -6- simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl-N- [4-
(4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide be raw material, according to the method system of 1 step 7 of embodiment
It is standby go out target compound.
1H NMR(300MHz,DMSO-d6)δ:10.55(s,1H),9.09(s,1H),8.20(d,1H),8.16(s,1H),
8.06(d,1H),7.94(d,1H),7.72(s,1H),7.71(s,1H),7.53(d,1H),6.36(s,2H),3.57(s,2H),
2.58(s,3H),2.35(s,3H),2.31(m,8H)。
ESI-MS m/z:[M+H]+=582.2。
Embodiment 133- ((2- methylamino -5- methyl-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -
4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of bromo- [1,2,4] triazoles of step 12- methylamino -5- methyl -6- simultaneously [1,5-a] pyridine
With the bromo- 6- methyl of 2- amino -5- as raw material, according to the method synthesis title product of 1 step 1-3 of embodiment.
ESI-MS m/z:[M+H]+=241.6。
Step 23- ((2- methylamino -5- methyl-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- first
The preparation of base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With bromo- [1,2,4] triazoles of 2- methylamino -5- methyl -6- simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl-N-
[4- (4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide is raw material, according to the method for 1 step 7 of embodiment
Prepare target compound.
1H NMR(300MHz,DMSO-d6)δ:10.56(s,1H),8.21(s,1H),8.18(s,1H),8.07(d,1H),
7.92(d,1H),7.71(d,1H),7.61(d,1H),7.53(d,1H),7.33(d,1H),6.69(m,1H),3.58(s,2H),
2.87(m,6H),2.58(s,3H),2.42(m,8H),2.22(s,3H)。
ESI-MS m/z:[M+H]+=576.3。
Embodiment 143- ((chloro- [1,2,4] triazoles of 2- amino -8- simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- first
Base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of chloro- [1,2,4] triazoles of the bromo- 8- of step 12- amino -6- simultaneously [1,5-a] pyridine
With the chloro- 5- bromopyridines of 2- amino -3- as raw material, title is prepared according to the method for 1 step 1 of embodiment and step 2
Compound.
1H NMR(300MHz,DMSO-d6)δ:8.38(s,1H),7.59(s,1H),4.67(m,2H)。
Step 23- ((chloro- [1,2,4] triazoles of 2- amino -8- simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- methyl -
The preparation of N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With chloro- [1,2,4] triazoles of the bromo- 8- of 2- amino -6- simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl-N- [4-
(4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide be raw material, according to the method system of 1 step 7 of embodiment
It is standby go out target compound.
1H NMR(300MHz,DMSO-d6)δ:10.54(s,1H),8.96(s,1H),8.21(s,1H),8.16(d,1H),
8.08(d,1H),7.93(d,1H),7.84(d,1H),7.71(d,1H),7.52(d,1H),6.45(s,2H),3.62(s,2H),
2.57(s,3H),2.45(m,8H),1.75(s,3H)。
ESI-MS m/z:[M+H]+=582.1。
Embodiment 153- ((fluoro- [1,2,4] triazoles of 2- dimethylamino -8- simultaneously [1,5-a] pyridine -6- bases) acetenyl) -
4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of fluoro- [1,2,4] triazoles of the bromo- 8- of step 12- amino -6- simultaneously [1,5-a] pyridine
With the fluoro- 5- bromopyridines of 2- amino -3- as raw material, title compound is prepared according to the method for 1-2 the step of embodiment 1
Thing.
The preparation of fluoro- [1,2,4] triazoles of the bromo- 8- of step 22- dimethylamino -6- simultaneously [1,5-a] pyridine
In dry two mouthfuls of flasks of 100ml, add fluoro- [1,2, the 4] triazoles of the bromo- 8- of compound 2- amino -6- simultaneously [1,
5-a] pyridine (160mg, 0.69mmol), sodium hydride(138mg,3.47mmol)And tetrahydrofuran(10mL).Reaction system is in nitrogen
0 DEG C under the conditions of gas shielded, react 30 minutes.Then, iodomethane(199mg,1.38mmol)It is dissolved in tetrahydrofuran(10mL)In batches
It is added drop-wise in above-mentioned reactant liquor, 12h is stirred at room temperature.TLC is detected.Under condition of ice bath, add methyl alcohol that excessive sodium hydride is quenched, it is dense
Contracting.Add water(20ml), pH to 7, ethyl acetate are adjusted with 1N watery hydrochloric acid(50ml)Three times, concentration is dried, and filters, column chromatography
Purifying obtains title compound.
1H NMR(500MHz,DMSO-d6)δ8.95(s,1H),7.78(d,1H),3.04(s,6H).
Step 33- ((fluoro- [1,2,4] triazoles of 2- dimethylamino -8- simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- first
The preparation of base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With fluoro- [1,2,4] triazoles of the bromo- 8- of 2- dimethylamino -6- simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl-N-
[4- (4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide is raw material, according to the method for 1 step 7 of embodiment
Prepare target compound.
1H NMR(300MHz,DMSO-d6)δ:10.52(s,1H),8.97(s,1H),8.20(s,1H),8.15(d,1H),
8.05(d,1H),7.93(d,1H),7.70(d,1H),7.68(d,1H),7.52(d,1H),3.57(s,2H),3.25(s,3H),
3.08(s,3H),2.56(s,3H),2.40(m,8H),2.18(s,3H)。
ESI-MS m/z:[M+H]+=594.3。
Embodiment 163- ((2- methylaminos-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- methyl -
N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of bromo- [1,2,4] triazoles of step 12- methylamino -6- simultaneously [1,5-a] pyridine
With 2- amino -5- bromopyridines as raw material, title compound is prepared according to the method for 1 step 1-3 of embodiment.
1H NMR(300MHz,DMSO-d6)δ:8.95(d,1H),7.56(dd,1H),7.34(d,1H),6.54(d,1H),
2.81(d,3H)。
ESI-MS m/z:[M+H]+=227.2。
Step 23- ((2- methylaminos-[1,2,4] triazole simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- methyl-N-
The preparation of [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With bromo- [1,2,4] triazoles of 2- methylamino -6- simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl-N- [4- (4-
Methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide be raw material, prepare according to the method for 1 step 7 of embodiment
Target compound.
1H NMR(300MHz,DMSO-d6)δ:10.52(s,1H),8.99(s,1H),8.21(s,1H),8.16(d,1H),
8.06(d,1H),7.92(d,1H),7.71(d,1H),7.60(d,1H),7.52(d,1H),7.42(d,1H),6.64(m,1H),
3.57(s,2H),2.86(dd,3H),2.56(s,3H),2.37(m,8H),2.16(s,3H)。
ESI-MS m/z:[M+H]+=562.2。
Embodiment 173- ((chloro- [1,2,4] triazoles of 2- methylamino -8- simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4-
Methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of chloro- [1,2,4] triazoles of the bromo- 8- of step 12- methylamino -6- simultaneously [1,5-a] pyridine
With the chloro- 5- bromopyridines of 2- amino -3- as raw material, title compound is prepared according to the method for 1 step 3 of embodiment.
1H NMR(300MHz,DMSO-d6)δ:9.00(s,1H),7.88(s,1H),6.81(s,1H),2.82(d,3H)。
ESI-MS m/z:[M+H]+=260.9。
Step 23- ((chloro- [1,2,4] triazoles of 2- methylamino -8- simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- first
The preparation of base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With chloro- [1,2,4] triazoles of the bromo- 8- of 2- methylamino -6- simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl-N-
[4- (4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide is raw material, according to the method for 1 step 7 of embodiment
Prepare target compound.
1H NMR(300MHz,DMSO-d6)δ:10.54(s,1H),8.20(s,1H),8.15(s,1H),8.06(d,1H),
7.93(d,1H),7.73(d,1H),7.68(d,1H),7.62(d,1H),7.52(d,1H),6.94(m,1H),3.57(s,2H),
2.86(s,3H),2.73(s,3H),2.37(m,8H),2.18(s,3H)。
ESI-MS m/z:[M+H]+=596.2。
Embodiment 183- ((fluoro- [1,2,4] triazoles of 2- methylamino -8- simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4-
Methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of fluoro- [1,2,4] triazoles of the bromo- 8- of step 12- methylamino -6- simultaneously [1,5-a] pyridine
With the fluoro- 5- bromopyridines of 2- amino -3- as raw material, title compound is prepared according to the method for implementing 1 step 1-3.
1H NMR(300MHz,DMSO-d6)δ:8.34 (s, 1H), 7.37-7.35 (m, 1H), 3.49 (s, 1H), 3.06 (s,
3H)。
ESI-MS m/z:[M+H]+=245.0。
Step 23- ((fluoro- [1,2,4] triazoles of 2- methylamino -8- simultaneously [1,5-a] pyridine -6- bases) acetenyl) -4- first
Base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With fluoro- [1,2,4] triazoles of the bromo- 8- of 2- methylamino -6- simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl-N-
[4- (4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide is raw material, according to the method for 1 step 7 of embodiment
Prepare target compound.
1H NMR(300MHz,DMSO-d6)δ:10.54(s,1H),8.94(s,1H),8.20(s,1H),8.16(d,1H),
8.06(d,1H),7.93(d,1H),7.71(d,1H),7.66(d,1H),7.52(d,1H),6.87(m,1H),3.57(s,2H),
2.85(d,3H),2.56(s,3H),2.40(m,8H),2.19(s,3H)。
ESI-MS m/z:[M+H]+=580.2。
Embodiment 193- ((2- isopropylaminos-[1,2,4] triazole simultaneously [1,5-a] pyridin-7-yl) acetenyl) -4- first
Base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of bromo- [1,2,4] triazoles of step 12- amino -7- simultaneously [1,5-a] pyridine
With 2- amino -4- bromopyridines as raw material, title compound is prepared according to the method for implementing 1 step 1 and step 2.
The preparation of bromo- [1,2,4] triazoles of step 22- isopropylamino -7- simultaneously [1,5-a] pyridine
In dry two mouthfuls of flasks of 50ml, bromo- [1,2, the 4] triazoles of 2- amino -7- simultaneously [1,5-a] pyridine is added
(300mg, 1.4mmol), sodium hydrogen(280mg, 7.0mmol, mass fraction 60%)And DMF(5ml).Reaction system is protected in nitrogen
Under the conditions of 10 DEG C, react 1 hour.Then, isopropyl bromide(512mg,4.2mmol)It is added drop-wise in above-mentioned reactant liquor in batches, room temperature
Stirring 2h.TLC is detected.Reactant liquor is poured in frozen water, ethyl acetate extraction(50ml)Three times, concentration is dried, and filters, post layer
Analysis purifying obtains title compound.
1H NMR(300MHz,DMSO-d6)δ:8.53(d,1H),7.67(d,1H),7.01(dd,1H),6.53(d,1H),
3.82-3.73(m,1H),1.16(d,6H)。
ESI-MS m/z:[M+H]+=255.0。
Step 33- ((2- isopropylaminos-[1,2,4] triazole simultaneously [1,5-a] pyridin-7-yl) acetenyl) -4- methyl -
The preparation of N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With bromo- [1,2,4] triazoles of 2- isopropylamino -7- simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl-N- [4-
(4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide be raw material, according to the method system of 1 step 7 of embodiment
It is standby go out target compound.
1H NMR(300MHz,DMSO-d6)δ:10.54(s,1H),8.63(d,1H),8.20(s,2H),8.06(d,1H),
7.94(d,1H),7.71(d,1H),7.62(s,1H),7.53(d,1H),7.01(d,1H),6.57(d,1H),3.85(m,1H),
3.57(s,2H),2.57(s,3H),2.39(m,8H),2.17(s,3H),1.18(s,6H)。
ESI-MS m/z:[M+H]+=590.2。
Embodiment 203- ((2- methylaminos-[1,2,4] triazole simultaneously [1,5-a] pyridine -5- bases) acetenyl) -4- methyl -
N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of bromo- [1,2,4] triazoles of step 12- methylamino -5- simultaneously [1,5-a] pyridine
With 2- amino -6- bromopyridines as raw material, title compound is prepared according to the method for implementing 1 step 1-3.
ESI-MS m/z:[M+H]+=227.0。
Step 23- ((2- methylaminos-[1,2,4] triazole simultaneously [1,5-a] pyridine -5- bases) acetenyl) -4- methyl-N-
The preparation of [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With bromo- [1,2,4] triazoles of 2- methylamino -5- simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl-N- [4- (4-
Methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide be raw material, prepare according to the method for 1 step 7 of embodiment
Target compound.
1H NMR(300MHz,DMSO-d6)δ:10.58(s,1H),8.25(s,1H),8.21(d,1H),8.06(d,1H),
8.02(d,1H),7.72(d,1H),7.58(d,1H),7.48(d,2H),7.27(d,1H),6.61(m,1H),3.58(s,2H),
2.88(dd,3H),2.68(s,3H),2.40(m,8H),2.19(s,3H)。
ESI-MS m/z:[M+H]+=562.3。
Embodiment 213- ((2- methylaminos-[1,2,4] triazole simultaneously [1,5-a] pyridine -8- bases) acetenyl) -4- methyl -
N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of bromo- [1,2,4] triazoles of step 12- methylamino -8- simultaneously [1,5-a] pyridine
With 2- amino -3- bromopyridines as raw material, title compound is prepared according to the method for implementing 1 step 1 to step 3.
1H NMR(300MHz,DMSO-d6)δ:8.62(d,1H),7.73(d,1H),6.82-6.77(m,1H),6.69-
6.67(m,1H),2.82(d,3H)。
ESI-MS m/z:[M+H]+=227.0。
Step 23- ((2- methylaminos-[1,2,4] triazole simultaneously [1,5-a] pyridine -8- bases) acetenyl) -4- methyl-N-
The preparation of [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With bromo- [1,2,4] triazoles of 2- methylamino -8- simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl-N- [4- (4-
Methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide be raw material, prepare according to the method for 1 step 7 of embodiment
Target compound.
1H NMR(300MHz,DMSO-d6)δ:10.56(s,1H),8.68(d,1H),8.21(s,1H),8.18(d,1H),
8.06(d,1H),7.94(d,1H),7.73(s,1H),7.70(s,1H),7.54(d,1H),6.93(d,1H),6.68(m,1H),
3.57(s,2H),2.85(d,3H),2.61(s,3H),2.40(m,8H),2.19(s,3H)。
ESI-MS m/z:[M+H]+=562.3。
Embodiment 223- ((2- (2,2,2- trifluoroacetamidos) imidazo [1,2-a] pyridin-7-yl) acetenyl) -4- first
Base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of step 12- tolysulfonyl amino -4- bromopyridines
2- amino -4- bromopyridines (1.72g, 10mmol), pyridine (5mL), ice bath are added in a 50mL round-bottomed flask
Under be slowly added dropwise paratoluensulfonyl chloride(2.29g,12mmol), 90 DEG C are warming up to, 6h is reacted, water, ethyl acetate extraction, silicon is added
Plastic column chromatography obtains title compound.
The preparation of step 22- (bromo- -1 (the 2H)-yls of 2 tolysulfonyl imines yl pyridines of 4-) acetamide
2- tolysulfonyl amino -4- bromopyridines (327mg, 1.0mmol), DMF are added in 25mL round-bottomed flasks
(5Ml), 2- acetbromamides(152mg,1.1mmol)And diisopropyl ethyl amine(142mg,1.1mmol), room temperature reaction 24h.
Water, ethyl acetate is added to extract, anhydrous sodium sulfate drying, silica gel column chromatography obtain title compound.
Step 32- (2,2,2- trifluoroacetamidos) -7- bromo- imidazo [1,2-a] pyridines
2- is added in 25mL round-bottomed flasks(Bromo- -1 (the 2H)-bases of 2 tolysulfonyl imines yl pyridines of 4-)Acetamide
(385mg, 1.0mmol), TFAA (2.10g, 10mmol), and dichloromethane(5mL), flow back 2h, TLC monitoring reactions
Finish, under ice bath, add water, dichloromethane to extract 3 times, merge organic phase, saturated sodium bicarbonate solution and saturated common salt washing
Wash, anhydrous sodium sulfate drying, silica gel column chromatography obtain title compound.
1H NMR(300MHz,DMSO-d6)δ:12.51(s,1H),8.57(d,1H),8.28(s,1H),7.85(s,1H),
7.14(dd,1H)。
ESI-MS m/z:[M+H]+=329.9。
Step 43- ((2- (2,2,2- trifluoroacetamide amino) imidazo [1,2-a] pyrazine -7- bases) acetenyl) -4- first
Base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With the 2- bromo- imidazos of (2,2,2- trifluoroacetamidos) -7- [1,2-a] pyridines and 3- acetenyl -4- methyl-N-
[4- (4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide is raw material, according to the method for 1 step 7 of embodiment
Prepare target compound.
1H NMR(300MHz,DMSO-d6)δ:10.50(s,1H),8.63(d,1H),8.31(s,1H),8.17(s,2H),
8.03(d,1H),7.91(d,1H),7.78(d,1H),7.69(s,1H),7.67(s,1H),7.50(d,1H),7.07(d,1H),
3.54(s,2H),2.55(s,3H),2.36(m,8H),2.16(s,3H)。
ESI-MS m/z:[M+H]+=643.3。
Embodiment 233- ((2- acetylaminohydroxyphenylarsonic acids [1,2,4] triazole simultaneously [1,5-a] pyridin-7-yl) acetenyl) -4- first
Base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of bromo- [1,2,4] triazoles of step 12- amino -7- simultaneously [1,5-a] pyridine
With 2- amino -4- bromopyridines as raw material, title compound is prepared according to the method for 1 step 1 of embodiment and step 2
Thing.
The preparation of bromo- [1,2,4] triazoles of step 22- acetylaminohydroxyphenylarsonic acid 7- simultaneously [1,5-a] pyridine
In dry two mouthfuls of flasks of 50ml, bromo- [1,2, the 4] triazoles of compound 2- amino -7- simultaneously [1,5-a] pyrrole is added
Pyridine (213mg, 1mmol) and acetic anhydride(10ml), it is subsequently added into pyridine (118mg, 1.5mmol).85 DEG C of backflows of reaction system, instead
Should overnight.TLC detects that reactant liquor concentration, ethyl acetate/water extraction, organic layer are dried, and column chromatography purifying obtains title compound
Thing.
ESI-MS m/z:[M+H]+=255.0。
Step 33- ((2- acetylaminohydroxyphenylarsonic acids [1,2,4] triazole simultaneously [1,5-a] pyridin-7-yl) acetenyl) -4- methyl-N-
The preparation of [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With bromo- [1,2,4] triazoles of 2- acetylaminohydroxyphenylarsonic acid 7- simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl-N- [4-
(4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide be raw material, according to the method system of 1 step 7 of embodiment
It is standby go out target compound.
1H NMR(300MHz,DMSO-d6)δ:10.84(s,1H),10.54(s,1H),8.90(d,1H),8.22(d,
1H),8.21(d,1H),8.07(d,1H),7.98(d,1H),7.97(s,1H),7.71(d,1H),7.55(s,1H),7.27
(dd,1H),3.58(s,2H),2.60(s,3H),2.41(m,8H),2.19(s,3H),2.16(s,3H)。
ESI-MS m/z:[M+H]+=590.3。
Embodiment 243- ((2- methanesulfonamidos-[1,2,4] triazole simultaneously [1,5-a] pyridin-7-yl) acetenyl) -4- first
Base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of bromo- [1,2,4] triazoles of step 12- amino -7- simultaneously [1,5-a] pyridine
With 2- amino -4- bromopyridines as raw material, title compound is prepared according to the method for 1 step 1 of embodiment and step 2
Thing.
The preparation of bromo- [1,2,4] triazoles of step 22- methanesulfonamido -7- simultaneously [1,5-a] pyridine
In dry two mouthfuls of flasks of 100mL, be initially charged THF (5mL), be subsequently adding compound 2- amino -7- it is bromo- [1,
2,4] triazole simultaneously [1,5-a] pyridine (213mg, 100mmol), mesyl chloride(3ml), pyridine(5mL).Room temperature reaction 24 is little
When.TLC detection raw materials disappear.Add water(10ml), dichloromethane(20ml)Extraction three times, concentration are dried, and filter, column chromatography
Purify to obtain title compound.
1H NMR(300MHz,DMSO-d6)δ:9.01(d,1H),8.35(s,1H),7.58(dd,1H),3.68(s,3H)。
Step 33- ((2- methanesulfonamidos-[1,2,4] triazole simultaneously [1,5-a] pyridin-7-yl) acetenyl) -4- methyl -
The preparation of N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With bromo- [1,2,4] triazoles of 2- methanesulfonamido -7- simultaneously [1,5-a] pyridine and 3- acetenyl -4- methyl-N- [4-
(4- methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide be raw material, according to the method system of 1 step 7 of embodiment
It is standby go out target compound.
1H NMR(300MHz,DMSO-d6)δ:10.53(s,1H),8.81(d,1H),8.21(d,2H),8.06(d,1H),
7.95(d,1H),7.88(s,1H),7.71(d,1H),7.54(d,1H),7.21(d,1H),3.58(s,2H),3.26(s,3H),
2.96(b,1H),2.59(s,3H),2.42(m,8H),2.22(s,3H)。
ESI-MS m/z:[M+H]+=626.2。
Embodiment 253- ((3- oxo -2,3- dihydros-[1,2,4] triazole simultaneously [4,3-a] pyridine -8- bases) acetenyl) -
4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of step 12- diazanyl -3- bromopyridines
Add the fluoro- 3- bromopyridines (3.52g, 20mmol) of 2- in 250ml round-bottomed flask, hydrazine hydrate (200mmol) and
THF (25mL), it is 30% 6h. to be stirred at room temperature and is concentrated into volume, and cooling crystallization under ice bath is filtered, and collects crystal, and vacuum drying is obtained
To title compound.
The preparation of bromo- [1,2,4] triazole of step 28- simultaneously [4,3-a] pyridine -3 (2H) -one
In dry two mouthfuls of flasks of 100ml, triphosgene (888mg, 300mmol), tetrahydrofuran solution 100mL. are added
It is dividedly in some parts compound 2- diazanyl -3- bromopyridines(188mg, 100mmol), reacting 3 hours, TLC points board raw material disappears.In ice bath
Under be slowly added to 100mL water.Vacuum distillation removes 70% solvent.Then stand slowly precipitation solid filtration to drain,
Forced air drying obtains title compound in 8 hours.
Step 33- ((3- oxo -2,3- dihydros-[1,2,4] triazole simultaneously [4,3-a] pyridine -8- bases) acetenyl) -4- first
The preparation of base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With bromo- [1,2,4] triazoles of 8- simultaneously -3 (2H) -one of [4,3-a] pyridine and 3- acetenyl -4- methyl-N- [4- (4-
Methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide be raw material, prepare according to the method for 1 step 7 of embodiment
Target compound.
1H NMR(300MHz,DMSO-d6)δ:12.67(s,1H),10.58(s,1H),8.21(s,1H),8.18(s,
1H),8.07(d,1H),7.95(d,1H),7.91(d,1H),7.71(d,1H),7.55(d,1H),7.54(s,1H),6.65(t,
1H),3.58(s,2H),2.59(s,3H),2.42(m,8H),2.22(s,3H)。
ESI-MS m/z:[M+H]+=549.3。
Embodiment 263- ((3- oxo -2,3- dihydros-[1,2,4] triazole simultaneously [4,3-a] pyridin-7-yl) acetenyl) -
4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of bromo- [1,2,4] triazole of step 17- simultaneously [4,3-a] pyridine -3 (2H) -one
With the fluoro- 4- bromopyridines of 2- as raw material, title compound is prepared with the method for 25 step 1 of embodiment and step 2.
ESI-MS m/z:[M+H]+=214.0。
Step 23- ((3- oxo -2,3- dihydros-[1,2,4] triazole simultaneously [4,3-a] pyridin-7-yl) acetenyl) -4- first
The preparation of base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With bromo- [1,2,4] triazoles of 7- simultaneously -3 (2H) -one of [4,3-a] pyridine and 3- acetenyl -4- methyl-N- [4- (4-
Methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide be raw material, prepare according to the method for 1 step 7 of embodiment
Target compound.
1H NMR(300MHz,DMSO-d6)δ:12.66(s,1H),10.52(s,1H),8.19(d,2H),8.06(d,
1H),7.95(d,1H),7.85(d,1H),7.71(d,1H),7.54(t,2H),6.62(d,1H),3.58(s,2H),2.56(s,
3H),2.42(m,8H),2.36(s,3H)。
ESI-MS m/z:[M+H]+=549.2。
Embodiment 273- ((3- oxo -2,3- dihydros-[1,2,4] triazole simultaneously [4,3-a] pyridine -5- bases) acetenyl) -
4- methyl-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
The preparation of bromo- [1,2,4] triazole of step 15- simultaneously [4,3-a] pyridine -3 (2H) -one
With the fluoro- 6- bromopyridines of 2- as raw material, title compound is prepared with the method for 25 step 1 of embodiment and step 2.
ESI-MS m/z:[M+H]+=214.0。
Step 23- ((3- oxo -2,3- dihydros-[1,2,4] triazole simultaneously [4,3-a] pyridine -5- bases) acetenyl) -4- first
The preparation of base-N- [4- ((4- methylpiperazine-1-yls) methyl) -3- trifluoromethyls] benzamide
With bromo- [1,2,4] triazoles of 5- simultaneously -3 (2H) -one of [4,3-a] pyridine and 3- acetenyl -4- methyl-N- [4- (4-
Methylpiperazine-1-yl methyl) -3- trifluoromethyls] benzamide be raw material, prepare according to the method for 1 step 7 of embodiment
Target compound.
1H NMR(300MHz,DMSO-d6)δ:12.68(s,1H),10.59(s,1H),8.22(s,1H),8.18(s,
1H),8.08(d,1H),7.96(d,1H),7.91(d,1H),7.71(d,1H),7.55(d,1H),7.54(d,1H),6.65(t,
1H),3.61(s,2H),2.59(s,3H),2.42(m,8H),2.22(s,3H)。
ESI-MS m/z:[M+H]+=549.3。
Embodiment 283- ((2- methylamino imidazo [1,2-a] pyridin-7-yls) acetenyl) -4- methyl-N- [4- ((4- first
Base piperazine -1- bases) methyl) -3- trifluoromethyls] benzamide
The preparation of step 12- methylamino -7- bromo- imidazo [1,2-a] pyridines
2- (2,2,2- trifluoroacetamidos) -7- bromo- imidazo [1,2-a] pyridines are added in 100mL round-bottomed flasks
(308mg, 1.0mmol), iodomethane (170mg, 1.2mmol), potassium carbonate (414mg, 3.0mmol) and acetone (5mL), room temperature
Stirring 14h.Water is added in system(5mL), flow back 2h, and removal of solvent under reduced pressure adds water, is extracted with ethyl acetate, anhydrous sulphur
Sour sodium is dried, and silica gel column chromatography obtains target product.
1H NMR(300MHz,DMSO-d6)δ:8.71(d,1H),8.34(s,1H),8.30(s,1H),7.54(dd,1H),
3.76(s,3H),2.67(b,1H)。
ESI-MS m/z:[M+H]+=226.0。
Step 23- ((2- methylamino imidazo [1,2-a] pyridin-7-yls) acetenyl) -4- methyl-N- [4- ((4- methyl
Piperazine -1- bases) methyl) -3- trifluoromethyls] and benzamide preparation
With bromo- imidazo [1,2-a] pyridines of 2- methylamino -7- and 3- acetenyl -4- methyl-N- [4- (4- methyl piperazines -
1- ylmethyls) -3- trifluoromethyls] benzamide be raw material, prepare target chemical combination according to the method for 1 step 7 of embodiment
Thing.
1H NMR(300MHz,DMSO-d6)δ:10.56(s,1H),8.82(d,1H),8.39(s,1H),8.23(d,2H),
8.22(s,1H),8.07(d,1H),7.98(d,1H),7.72(d,1H),7.57(d,1H),7.49(d,1H),4.03(q,1H),
3.83(s,3H),3.58(s,2H),2.62(s,3H),2.40(m,8H),2.17(s,3H)。
ESI-MS m/z:[M+H]+=561.4。
The Compound ira vitro cytoactive of 1 present invention of experimental example is evaluated
1. test material
1.1 compound
The compound of the present invention prepared by above example, each compound DMSO is dissolved to after 10mM, with training completely
Foster base is diluted to 50 μM, then with containing 0.1%DMSO complete medium be diluted to 10 μM after, successively 10 times dilution, totally 10 it is dense
Degree.
1.2 cell
K562 leukaemia:Purchased from ATCC companies of the U.S.
1.3 reagent
Dimethyl sulfoxide (DMSO)(Dimethyl sulfoxide, DMSO), it is purchased from Sigma Co., USA;
Luminescence method cell viability detection kit Luminescent Cell Viability
Assay Kit), it is purchased from Promega companies of the U.S.;
IMEM culture mediums(IMEM medium), it is purchased from Gibco companies of the U.S.;
Penicillin/streptomycin(Pen/Strep), it is purchased from Gibco companies of the U.S.;
Hyclone(Fatal bovine serun, FBS), it is purchased from Gibco companies of the U.S.;
0.25% pancreatin containing EDTA(0.25%Trypsin-EDTA), it is purchased from Gibco companies of the U.S.;
10cm Tissue Culture Dish(10cm cell culture dish), it is purchased from Corning companies of the U.S.;
50mL centrifuge tubes(50mL centrifuge tube), it is purchased from Corning companies of the U.S.;
The flat printing opacity blank in 384 holes(384Well Flat Clear Bottom White), it is purchased from U.S. Corning public
Department;
Phosphate buffer(Phosphate Buffered Saline, PBS), prepare weekly.
1.4 instrument
Automatic confocal fluorescence multi-function microplate reader(PHERAstar Plus), it is purchased from German BMG Labtech companies.
2. experimental technique:
1) logarithmic phase cell, adjustment concentration of cell suspension to 1 × 10 are collected5Individual/ml, 384 orifice plates add 40 μ L thin per hole
Born of the same parents' suspension, is 4 × 10 per hole cell number3Individual/hole.Edge hole is filled with aseptic PBS;
2) add the compound of the present invention of the concentrations above gradient of 10 μ L.Each compound each concentration is in triplicate.
Blank adds the DMSO of 10 μ L comparable sodiums;
3) cell is in 37 DEG C/5%CO2It is incubated in incubator;
4) 30 μ L luminescence method cell viability detection reagent mixed liquors are added after dosing 72h;
5)37℃/5%CO210min is incubated in incubator;Determine chemical on PHERAstar ELIASAs after slow-speed of revolution centrifugation
Luminous value;
6) cell viability(Cell Viability)=(RLUSample/RLUIt is negative)× 100%, wherein RLUSampleFor medicine feeding hole RLU
(Relative light unit)Value, RLUIt is negativeFor not medicine feeding hole RLU values(That is the cell controls of comparable sodium DMSO process), adopt
Four parameter logistic fit module of Graphpad Prism4.0 data processing softwares carries out processing data and calculates IC50。IC50Value is represented
With not plus compared with compound treatment group, compound suppresses the corresponding compound concentration of 50% cell growth.IC50The results are shown in Table 1.
Table 1
"-" is represented does not test.
IC of the compound of the present invention to leukaemia be can be seen that from above experimental result50Value has in nM levels
Strong inhibitory activity.Jia H-Y etc.(Jia H-Y,et al.ZD6474inhibits Src kinase leading to
apoptosis of imatinib-resistant K562cells.Leuk Res(2009),doi:10.1016/
j.leukres.2009.03.033)Research shows IC of the Imatinib to K562 cells50It is worth for 280nM, H Luo etc.(H Luo,
et al.HH-GV-678,a novel selective inhibitor of Bcr-Abl,outperforms imatinib
and effectively overrides imatinib resistance.Leukemia (2010)24,1807–1809;
doi:10.1038/leu.2010.169;Published online12August2010)Experiment proves Imatinib to K562
The IC of cell50It is worth for 296nM.As can be seen here, for the leukaemia of not resistance, compound and the Imatinib of the present invention have
Have quite, even more excellent effect.
Experimental example 2ABL1 (T315I) tyrosine kinase activity evaluation
The suppression of compound prepared by this experiment test embodiment of the present invention to ABL (T315I) kinase activity, using her horse
For Buddhist nun as control.Imatinib is obtained with reference to the method described in Chinese patent CN1043531C and is reflected by hydrogen spectrum and mass spectrum
It is fixed.
Using commercially available people source ABL T315I mutant enzymes(Human ABL1 (T315I), active, catalog number (Cat.No.) #14-522,
Millipore companies, the U.S.)Test ABL (T315I) tyrosine kinase activity.Kinase activity measure is carried out by manufacturers instruction.
Peptide substrates(Peptide substrate)For Abltide (EAIYAAPFAKKK), Millipore companies of the U.S. are purchased from.Ion is handed over
Change chromatography filter paper P81(ion exchange filter paper)It is purchased from Whatman companies of Britain.[γ -33P] ATP is purchased from
Perkin Elmer companies.
The compound and Imatinib of the present invention starts respectively 3 times of serial dilutions from 1 μM, totally 10 concentration (50.8pM,
152.0pM, 457.0pM, 1.37nM, 4.12nM, 12.3nM, 37.0nM, 111.0nM, 333.0nM and 1.0 μM).Add per hole
5.0 μM of Abltide, are subsequently adding people source T315I mutant enzymes.Add under room temperature [γ-33P] ATP, final concentration of 1.0 μM, reaction
120 minutes.20 μ l aliquots are transferred on P81 ion-exchange chromatography paper.Then chromatographic paper is abundant with 0.75% phosphoric acid solution
Washing 3 times, then washed once with acetone.Finally, carry out γ-33P radioactivity determinations.Experimental result is shown in Table 2.
Table 2
Above test result indicate that, the IC of the compound to T315I mutant enzymes of the present invention50Imatinib is significantly better than, is had
There is the ability of potent suppression T315I mutant enzymes.
Can draw from the experimental result of the present invention, the compound of the present invention is not only to having the leukaemia being mutated tool
There is extraordinary effect, and T315I mutant enzymes can be significantly inhibited, therefore be the BCR-ABL inhibitor of wide spectrum.For to junket
Histidine kinase inhibitor(TKI)Treatment resistance or the tumor patients in heilongjiang of opposing, such as chronic myelocytic leukemia (CML) are chronic
Phase, CML-BC, accelerated period patient and Philadelphia Chromosome Positive(Ph+)Chronic myelocytic leukemia and acute lymphoblastic it is white
The prospect that blood patient should have.
Although being below described in detail to the present invention, however it is understood by skilled practitioners that without departing from this
Various modifications and changes can be carried out to the present invention on the premise of bright spirit and scope.The interest field of the present invention is not limited to
The detailed description made above, and claims should be belonged to.
Claims (3)
1. a kind of compound or its pharmaceutically acceptable salt, wherein the compound is selected from following compound:
2. a kind of pharmaceutical composition, which includes the compound described in claim 1 or its pharmaceutically acceptable salt and pharmaceutically acceptable load
Body.
3. the pharmaceutical composition described in compound described in claim 1 or its pharmaceutically acceptable salt or claim 2 is in system
The application being ready for use in the medicine for the treatment of or prevention of tumor.
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