CN105585565B - - 4- thiazole the pyridine derivative of anilino- containing 2- and its preparation method and pharmaceutical composition and purposes - Google Patents

- 4- thiazole the pyridine derivative of anilino- containing 2- and its preparation method and pharmaceutical composition and purposes Download PDF

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CN105585565B
CN105585565B CN201410571559.XA CN201410571559A CN105585565B CN 105585565 B CN105585565 B CN 105585565B CN 201410571559 A CN201410571559 A CN 201410571559A CN 105585565 B CN105585565 B CN 105585565B
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base
pyridine
methylthiazol
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anilino
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CN105585565A (en
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冯志强
陈晓光
李燕
张莉婧
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Institute of Materia Medica of CAMS
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Abstract

The present invention relates to 2- anilino- -4- thiazole pyridine derivative shown in Formulas I, officinal salt, and preparation method thereof, the purposes of composition and such compound containing this one or more compound in terms for the treatment of tumor disease.

Description

- 4- thiazole the pyridine derivative of anilino- containing 2- and its preparation method and pharmaceutical composition with Purposes
Invention field
The present invention relates to 2- anilino- -4- thiazole pyridine derivative, officinal salt, and its preparation sides shown in Formulas I Method, the purposes of composition and such compound containing this one or more compound in terms for the treatment of tumor disease.
Background of invention
Recent years greatly promotees due to the raising of the understanding to enzyme and some other biomolecule relevant to disease Into the discovery or development of the new drug for the treatment of disease, protein kinase is exactly a kind of important one kind studied extensively, it is one Large family, it is related with the intracellular control of various signal transduction processes.Due to they structure and catalysis conservative it Be considered evolving from a common ancestral gene.Nearly all kinases all contains a similar 250-300 ammonia Base acid catalysis domain.These protein kinases are divided into multiple families, such as protein tyrosine kinase, egg according to the difference of phosphorylated substrate White serine/threonine kinase, lipoid etc..Generally, protein kinase is turned by influencing a phosphoryl from a ribonucleoside triphosphote It moves on to a protein receptor relevant to signal transduction pathway and carrys out signal transduction in mediated cell.These phosphorylated events, which are used as, divides Sub switch adjusts the biological function of target protein, is finally excited and reacts to various extracellular and other stimulations.Kinases exists In multilayer signal transduction path, receptor tyrosine kinase is located at the upstream of Tumor Angiongesis Signal transduction pathway.Serine/ Serineprotein kinase is located at the downstream of the Signal transduction pathway of tumour and Tumor Angiongesis cell.
Aurora A is a kind of novel one Serineprotein kinase of serine, participate in adjusting mitotic center body and The function of micro-pipe, to influence cell cycle progression.It is currently known in human cell that there are 3 kinds of structure and functions are highly relevant Aurora A hypotype: Aurora A, B and C.Although their amino acid sequence and three-dimensional structure have very big similitude, It is made a big difference in subcellular positioning and function.Aurora A is from the mitotic S end of term to next division cycle The G phase start to be positioned at around centerbody and the both ends of spindle, influence centerbody separation and mature and the two poles of the earth spindle Forming process, over-express the division of matter capable of inhibiting cell, prevent cell from leaving the M phase, so as to cause the expansion of centerbody Increase.Aurora B is referred to as " chromosome passenger protein ", is positioned at core, is transferred to silk in mitotic early period to mid-term Grain, into people's mitosis anaphase after be gradually positioned at centerbody until cytokinesis complete.Aurora B, which has, adjusts kinetochore Function, adjustable chromosome carries out being correctly oriented arrangement and separation, and influences spindle detecting functions and cytokinesis；? During mitosis, it is compound quaternary can be formed with another 3 kinds of chromosome passenger proteins INCENP, Survivin and Borealin The positioning regulatory function of object, the compound can be such that it is accurately positioned on intracellular centerbody and spindle.At present to Aurora The research of C is less, and having report to point out Aumra C also in recent years is chromosome passenger protein, in vitro can directly with INCENP and Suvivin is combined, and in mammalian cells, Aurora-C-INCENP can make endogenous phosphorylated histone H3.
Aurora A is often overexpressed in human tumor, and important function is played during mitosis, different Often expression can cause cell transformation at potential cancer.Genetic abnormality based on human cancer is more and more common, in cell transformation The protein of the middle integrality for maintaining chromosome separation may also play an important role.Aurora A is that a kind of kinases of key is compiled Code gene, is located in 20q13.2, the area generally existing amplification in human malignancies, such as colon cancer, oophoroma, gastric cancer, cream The .Aurora such as gland cancer and cancer of the esophagus B is positioned at chromosome 17q13.1, which expands in human malignancies without typical Increase.However, in many human cancers, including glioblastoma multiforme, malignant mesothelioma and hematologic malignancies, It was found that the overexpression of Aurora B.People are less to the carcinogenesis research of Aurora C, and some research discovery Aurora C exist It is overexpressed in colon cancer, breast cancer and prostate cancer.In short, Aurora A A, B, C are overexpressed in many human cancers, And it is all related with the unstability of chromosome, carcinogenic transformation, tumor proliferation and chemoresistance, therefore Aurora A may be at For one of promising target spot in anticancer drug development.
Vascular endothelial growth factor receptor (vascular endothelial growth factor receptor, VEGFR) family includes 3 kinds of hypotypes, it may be assumed that VEGFR-1 (while Flt-1 can also be write), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt 1), in addition, there are also neuropilin (neuropilin) l and 2 two cooperative expert systems.Wherein VEGFR-1 It is mainly distributed on vascular endothelial cell, candidate stem cell, macrophage and monocyte, it can be with VEGF-A, VEGF-B and P1GF In conjunction with mainly related with the growth regulating of candidate stem cell.VEGFR-2 is mainly distributed on vascular endothelial cell and lymphatic endothelia is thin It, can be in conjunction with VEGF-A, VEGF-C, VEGF-D, VEGF-E in born of the same parents.VEGF stimulating endothelial cell proliferation increases vascular permeability Property and new vascular generation effect mainly by conjunction with activation VEGFR-2 come realize compared with VEGFR-2, VEGFR-l with The affinity of VEGF is 10 times high, but the activity for adjusting endothelial cell is much lower, it may be possible to have negative regulation to VEGFR-2 activity Effect.VEGFR-3 is mainly expressed in lymphatic endothelial cells, can regulate and control lymphatic endothelium in conjunction with VEGF-C and VEGF-D Growth.
Research shows that: when diameter of tumor is greater than 2mm, it is useless to provide nutriment and excretion metabolism to need new vessels Object.VEGF/VEGFR signal path serve in tumor vascular generation it is key, can be by blocking or interfering VEGF/ VEGFR signal path inhibits the new life of blood vessel, to reach the curative effect of the growth of control tumour.With traditional cytotoxic drug phase Than having very big advantage under normal physiological conditions by the anti-tumor drug of target of VEGF/VEGFR-2, angiogenesis only exists It works in the physiological activities such as wound healing and menstrual cycle, so tumour is treated using anti-angiogenic medicaments, to human body poison Property effect it is small, vascular endothelial cell is directly contacted with blood, so that drug is more easier arrival action site, therefore with VEGF/ VEGFR-2 is also one of promising target spot in anticancer drug development.
Platelet derived growth factor (platelet.derived growth factor, PDGF) is induction and promotion blood Pipe formation effect most one of strong, most single-minded angiogenesis factor.PDGF mainly by with pdgf receptor (PDGFR) combine, into And activated protein kinase signal transduction pathway and play a role.PDGFR is made of two kinds of subunits of α and β, shares 3 kinds of dimers (PDGFR- α α, α β, β β), wherein β β dimerization receptor body (PDGFR- β) is mostly important, and molecular weight is about 180~190ku, belongs to In tyrosine kinase receptor (receptor tyrosine kinase, RTK) family.PDGFR is in tumour formation and development process In also play an important role.
The overexpression of PDGFR- β or overactivity can stimulate intratumoral vasculature to generate, and promote tumour growth.
PDGFR- β is one of molecular marker of tumor vascular endothelial cell, the high table in endothelial cells in tumor neogenetic blood vessels It reaches, and closely related with the growth, transfer and prognosis of certain tumours.So PDGFR- β is an ideal cancer target Therapeutic targets.
Many diseases are associated with abnormal cell effect of protein kinase mediated event initiation.These disease packets It includes, but is not limited to, tumour, inflammation disease, immunological diseases, bone disease, metabolic disease, neurological disease, cardiovascular and cerebrovascular disease, hormone Relevant disease etc..Consequently found that being very important with searching kinases inhibitor as therapeutic agent.In addition, existing card According to display, most of tumour is not dominated by single signal conduction path, carries out inhibiting to obtain for multiple target point bigger Curative effect.Although many inventions have made very big contribution to this field, to improve medication effect, this field still is continuing to grind Study carefully.
Summary of the invention
The purpose of the present invention is to provide 2- anilino- -4- thiazole pyridine derivatives shown in general formula I and its pharmaceutically acceptable Salt.
Another object of the present invention is to provide the preparations of 2- anilino- -4- thiazole pyridine derivative shown in general formula I Method.
It is pyridine derived containing 2- anilino- -4- thiazolyl shown in general formula I that a further object of the present invention is to provide one kind The pharmaceutical composition of object.
Another object of the present invention is to provide purposes of such compound in anticancer drug.
In order to complete the purpose of the present invention, following technical solution can be used:
The present invention is related to having structure 2- anilino- -4- thiazole pyridine derivative shown in general formula I and its can Pharmaceutical salts；
In formula:
R1Selected from hydrogen, halogen, cyano, nitro, carboxyl, mesyl, sulfamoyl, methylphosphine acyl group, C1-C6 alkyl, take C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, amino, the C1-C6 alkylamino radical, substituted C1-C6 in generation Alkylamino radical, C1-C6 heterocycle, substituted C1-C6 heterocycle, C1-C6 alkyl amide, substituted C1-C6 alkyl amide, C2-C6 Unsaturated alkyl amide, substituted C2-C6 unsaturation alkyl amide, C3-C6 cycloalkanes amide groups, substituted C3-C6 cycloalkanes amide Base, C1-C6 heterocycleamide base, substituted C1-C6 heterocycleamide base, wherein substituent group is selected from: halogen, hydroxyl, cyano, C1-C6 Alkyl, benzoyl, two C1-C6 alkyl aminos, methoxyl group, trifluoromethyl, trifluoromethoxy, mesyl；
N is selected from 1,2,3,4,5；
R2And R3It is independently selected from hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 naphthenic base, substituted C3- C6 naphthenic base, C1-C8 alkanoyl, substituted C1-C8 alkanoyl, C2-C8 unsaturation alkanoyl, substituted C2-C8 unsaturation alkane Acyl group, C3-C6 cycloalkanes formoxyl, substituted C3-C6 cycloalkanes formoxyl, C1-C6 heterocycle formyl, substituted C1-C6 heterocycle first Acyl group, C6-C10 aromatic ring formoxyl, substituted C6-C10 aromatic ring formoxyl, C6-C12 aromatic ring alkanoyl, substituted C6-C12 virtue Cycloalkanoyl, wherein substituent group is selected from: halogen, hydroxyl, cyano, C1-C6 alkyl, benzoyl, two C1-C6 alkyl aminos, first Oxygroup, trifluoromethyl, trifluoromethoxy, mesyl；
R1More preferably from hydrogen, fluorine, chlorine, bromine, cyano, nitro, carboxyl, mesyl, sulfamoyl, C1-C6 alkyl, substitution C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, amino, C1-C6 alkylamino radical, substituted C1-C6 alkane Amido, C1-C6 heterocycle, substituted C1-C6 heterocycle, C1-C6 alkyl amide, substituted C1-C6 alkyl amide, C2-C6 are not Be saturated alkyl amide, substituted C2-C6 unsaturation alkyl amide, C3-C6 cycloalkanes amide groups, substituted C3-C6 cycloalkanes amide groups, C1-C6 heterocycleamide base, replace C1-C6 heterocycleamide base, wherein substituent group is selected from: halogen, hydroxyl, cyano, methyl, second Base, isopropyl, tert-butyl, benzoyl, dimethylamino, methoxyl group, trifluoromethyl, trifluoromethoxy, mesyl；
N is selected from 1,2,3,4；
R2And R3It is more excellent to be independently selected from hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 naphthenic base, replace C3-C6 naphthenic base, C1-C8 alkanoyl, substituted C1-C8 alkanoyl, C2-C8 unsaturation alkanoyl, substituted C2-C8 insatiable hunger It is miscellaneous with alkanoyl, C3-C6 cycloalkanes formoxyl, substituted C3-C6 cycloalkanes formoxyl, C1-C6 heterocycle formyl, substituted C1-C6 Ring formoxyl, benzoyl, substituted benzoyl, phenyl C1-C6 alkanoyl, substituted phenyl C1-C6 alkanoyl, wherein taking Dai Ji is selected from: fluorine, chlorine, bromine, hydroxyl, cyano, methyl, ethyl, isopropyl, tert-butyl, benzoyl, dimethylamino, diethylamino Base, methoxyl group, trifluoromethyl, trifluoromethoxy, mesyl；
R1More preferably from hydrogen, fluorine, chlorine, bromine, cyano, nitro, carboxyl, mesyl, sulfamoyl, methyl, ethyl, isopropyl Base, tert-butyl, trifluoromethyl, dimethylamino methyl, methylol, hydroxyl, methoxyl group, isopropoxy, trifluoromethoxy, methoxy second Oxygroup, amino, methylamino, dimethylamino, lignocaine, hydroxyethylamine, morpholinyl, piperazinyl, piperidyl, N methyl piperazine Base, formamido, acetamido, propionamido-, Isopropamide base, amide-based small, isobutyl amide, pivaloyl amido, valeryl Amido, isovaleryl amido, 2,2- amide dimethyl butyrate base, trifluoroacetyl amido, hydroxyl acetamido, methoxyacetyl amido, diformazan Base glycyl amido, allyl amide groups, 3,3- dimethallyl amide groups, butene-2-amide groups, propine amide groups, butine- 2- amide groups, cyclopropyl carboxamide base, cyclobutylmethyl amide groups, cyclopenta formamido, cyclohexyl formamido, 2- piperidines first Amide groups, 4- piperidine formyl amido, methyl piperidine formamido, isopropyl piperidine formyl amido；
N is selected from 1,2,3,4；
R2And R3It is more excellent to be independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, ethoxy, dimethylamine Ethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopenta, formoxyl, acetyl group, propiono, iso-propionyl, bytyry, isobutyl Acyl group, valeryl, valeryl, isovaleryl, caproyl, 2,2- dimethylbutanoyl, trifluoroacetyl group, 2- difluoro propionyl Acyl, glycolyl, ammonia acetyl group, methoxyacetyl, Dimethyl Glycyl, allyl acyl group, butene-2-acyl group, butylene-3- Acyl group, 3,3- dimethallyl acyl group, hexadiene -2,4- acyl group, propine acyl group, 3- isopropyl propine acyl group, 3- tert-butyl third Alkynes acyl group, crotonylene-acyl group, cyclopropyl formoxyl, cyclobutylmethyl acyl group, cyclopenta formoxyl, cyclohexyl formoxyl, 2- piperidines Formoxyl, 4- piperidine formyl base, methyl piperidine formoxyl, isopropyl piperidine formyl base, benzoyl, fluoro benzoyl, Chlorobenzene formacyl, to fluoro benzoyl, to chlorobenzene formacyl, fluorine to chlorobenzene formacyl, adjacent fluoro benzoyl, to methylbenzene first Acyl group, to cyanobenzoyl, to dimethylamino benzoyl, para hydroxybenzene formoxyl, to methoxybenzoyl base, to hydroxyl Meta-methoxy benzoyl, m-trifluoromethyl benzoyl, to trifluoromethylbenzoyl, cyanobenzoyl, phenylacetyl Base, fluorobenzene acetyl group, chloro acetyl, between fluorobenzene acetyl group chlorine, cyano phenylacetyl group,；
R1Particularly preferably from hydrogen, fluorine, chlorine, bromine, cyano, carboxyl, mesyl, methyl, ethyl, isopropyl, tert-butyl, trifluoro Methyl, dimethylamino methyl, methylol, hydroxyl, methoxyl group, isopropoxy, trifluoromethoxy, methoxyethoxy, amino, methylamine Base, dimethylamino, lignocaine, hydroxyethylamine, morpholinyl, piperazinyl, piperidyl, N methyl piperazine base, formamido, second Amide groups, propionamido-, Isopropamide base, amide-based small, isobutyl amide, pivaloyl amido, valeryl amido, isovaleramide Base, 2,2- amide dimethyl butyrate base, trifluoroacetyl amido, hydroxyl acetamido, methoxyacetyl amido, dimethylamino acetamide Base, allyl amide groups, 3,3- dimethallyl amide groups, butene-2-amide groups, propine amide groups, crotonylene-amide groups, ring Cyclopropylmethylamide base, cyclobutylmethyl amide groups, cyclopenta formamido, cyclohexyl formamido, 4- piperidine formyl amido, methyl Piperidine formyl amido, isopropyl piperidine formyl amido；
N is selected from 1,2,3,4；
R2And R3Spy is excellent to be independently selected from hydrogen, methyl, ethyl, isopropyl, ethoxy, decil, methoxy second Base, cyclopropyl, cyclobutyl, formoxyl, acetyl group, propiono, iso-propionyl, bytyry, isobutyryl, valeryl, valeryl Base, isovaleryl, caproyl, 2,2- dimethylbutanoyl, trifluoroacetyl group, 2- difluoro propionyl acyl, glycolyl, ammonia acetyl Base, methoxyacetyl, Dimethyl Glycyl, allyl acyl group, butene-2-acyl group, butylene-3- acyl group, 3,3- dimethyl alkene Propiono, hexadiene -2,4- acyl group, propine acyl group, 3- isopropyl propine acyl group, 3- tert-butyl propine acyl group, crotonylene-acyl Base, cyclopropyl formoxyl, cyclobutylmethyl acyl group, cyclopenta formoxyl, cyclohexyl formoxyl, 2- piperidine formyl base, 4- piperidines first Acyl group, methyl piperidine formoxyl, isopropyl piperidine formyl base, benzoyl, fluoro benzoyl, chlorobenzene formacyl, to fluorine Benzoyl, to chlorobenzene formacyl, fluorine to chlorobenzene formacyl, adjacent fluoro benzoyl, to methyl benzoyl, to cyano benzene first Acyl group, to dimethylamino benzoyl, para hydroxybenzene formoxyl, to methoxybenzoyl base, to hydroxyl meta-methoxy benzoyl Base, m-trifluoromethyl benzoyl, to trifluoromethylbenzoyl, cyanobenzoyl, phenylacetyl group, fluorobenzene acetyl Base, chloro acetyl, between fluorobenzene acetyl group chlorine；
R1Most preferably from hydrogen, fluorine, chlorine, bromine, cyano, carboxyl, mesyl, methyl, isopropyl, tert-butyl, trifluoromethyl, Dimethylamino methyl, methylol, hydroxyl, methoxyl group, isopropoxy, trifluoromethoxy, methoxyethoxy, amino, methylamino, two Methylamino, lignocaine, hydroxyethylamine, morpholinyl, piperazinyl, piperidyl, N methyl piperazine base, formamido, acetamide Base, propionamido-, Isopropamide base, amide-based small, isobutyl amide, pivaloyl amido, valeryl amido, isovaleryl amido, 2, 2- amide dimethyl butyrate base, trifluoroacetyl amido, hydroxyl acetamido, methoxyacetyl amido, dimethylamino acetamide base, allyl Amide groups, 3,3- dimethallyl amide groups, butene-2-amide groups, propine amide groups, crotonylene-amide groups, cyclopropyl formyl Amido, cyclobutylmethyl amide groups, cyclopenta formamido, cyclohexyl formamido, 4- piperidine formyl amido, methyl piperidine formyl Amido, isopropyl piperidine formyl amido；
N is selected from 1,2,3,4；
R2And R3It is optimal to be independently selected from hydrogen, methyl, ethyl, isopropyl, ethoxy, decil, methoxy second Base, cyclopropyl, cyclobutyl, formoxyl, acetyl group, propiono, iso-propionyl, bytyry, isobutyryl, valeryl, valeryl Base, isovaleryl, caproyl, 2,2- dimethylbutanoyl, trifluoroacetyl group, 2- difluoro propiono, glycolyl, ammonia acetyl Base, methoxyacetyl, Dimethyl Glycyl, allyl acyl group, butene-2-acyl group, butylene-3- acyl group, 3,3- dimethyl alkene Propiono, hexadiene -2,4- acyl group, propine acyl group, 3- isopropyl propine acyl group, crotonylene-acyl group, cyclopropyl formoxyl, ring Butyl formoxyl, cyclopenta formoxyl, cyclohexyl formoxyl, 2- piperidine formyl base, 4- piperidine formyl base, methyl piperidine formyl Base, isopropyl piperidine formyl base, benzoyl, fluoro benzoyl, chlorobenzene formacyl, to fluoro benzoyl, to chlorobenzene first Acyl group, fluorine to chlorobenzene formacyl, adjacent fluoro benzoyl, nicotinoyl base, 6- amino nicotinoyl base, to methyl benzoyl, to cyano Benzoyl, to dimethylamino benzoyl, para hydroxybenzene formoxyl, to methoxybenzoyl base, to hydroxyl meta-methoxy benzene Formoxyl, m-trifluoromethyl benzoyl, to trifluoromethylbenzoyl, cyanobenzoyl, phenylacetyl group, fluorophenethyl Acyl group, chloro acetyl, between fluorobenzene acetyl group chlorine；
The most preferred compound of the present invention is selected from following group:
2- (3-Aminotrifluorotoluene base) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (the chloro- 6- toluidine of 2-) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (2- fluoroanilino) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (2,4- difluorobenzene amido) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (the bromo- 4- fluoroanilino of 2-) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (2- methoxyl group -4-N- methyl piperazine anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (4- morpholine anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (4- (cyclopropyl formamido) anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (3,4,5- trimethoxy-benzene amido) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (4- dimethylamino anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (3- cyclopropyl formamido anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (4- (N methyl piperazine base) anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (m-nitro amido) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (m-aminophenyl amido) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (propionamido anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (isophthalic acetyl amino phenyl amido) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (3- trifluoroacetamido anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (3- nitrobenzene amido) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- acrylamido -4- methylthiazol -5- base) pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- (3- dimethyl allene acyl) amino -4- methylthiazol -5- base) pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- (hexadiene -2,4- acylamino-) -4- methylthiazol -5- base) pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- propionamido -4- methylthiazol -5- base) pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- (3- methylbutyrylamino) -4- methylthiazol -5- base) pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- valeryl amino -4- methylthiazol -5- base) pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- cyclopropylcarboxamido -4- methylthiazol -5- base) pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- cyclobutylmethyl acylamino- -4- methylthiazol -5- base) pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- cyclopenta formamido group -4- methylthiazol -5- base) pyridine
2- (3- trifluoromethylbenzene amido) -4- (chIorobenzoyIamino -4- methylthiazol -5- base between 2-) pyridine
2- (3- trifluoromethylbenzene amido) -4- (fluorobenzene acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base between 2-) pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- m-fluoroaniline formamido group -4- methylthiazol -5- base) pyridine
2- (adjacent fluoroanilino) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine
2- (2,4- dichloroanilino) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine
2- (p-dimethylamino aniline base) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine
2- (3,4,5- trimethoxy-benzene amido) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine
2- (4- cyclopropyl formamido group anilino-) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine
2- (3- cyclopropyl formamido group anilino-) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine
2- (adjacent fluoroanilino) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (2,4- difluorobenzene amido) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (p-dimethylamino aniline base) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (3,4,5- trimethoxy-benzene amido) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (to morpholinyl anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (adjacent fluoroanilino) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (2,4- dichloroanilino) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (p-dimethylamino aniline base) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (3,4,5- trimethoxy-benzene amido) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (to cyclopropyl formamido group anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (to morpholinyl anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (cyclopropyl formamido group anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (cyclopropyl formamido group anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (m-acetamidoaniline base) -4- (acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (propionamido anilino-) -4- (2- propionamido -4- methylthiazol -5- base) pyridine
2- (3- isopropyl formamido group anilino-) -4- (2- isopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (the tertiary fourth formamido group anilino- of 3-) -4- (the tertiary fourth formamido group -4- methylthiazol -5- base of 2-) pyridine
2- (3- (3- methyl butene -2- acylamino-) anilino-) -4- (2- (3- methyl butene -2- acylamino-) -4- methyl thiazolium Azoles -5- base) pyridine
2- (3- ring fourth formamido group anilino-) -4- (2- ring fourth formamido group -4- methylthiazol -5- base) pyridine
2- (3- cyclopropyl formamido group anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (3- cyclopropyl formamido group anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (3- cyclopropyl formamido group anilino-) -4- (2- isobutyl formamido group -4- methylthiazol -5- base) pyridine
2- (3- cyclopropyl formamido group anilino-) -4- (2- (3- methyl butene -2- acylamino-) -4- methylthiazol -5- base) Pyridine
2- (3- cyclopropyl formamido group anilino-) -4- (2- cyclopenta formamido group -4- methylthiazol -5- base) pyridine
2- (3- cyclopropyl formamido group anilino-) -4- (2- is to toluyl amino -4- methylthiazol -5- base) pyridine
2- (3- cyclopropyl formamido group anilino-) -4- (2- phenylacetylamino -4- methylthiazol -5- base) pyridine
2- (3- nitrobenzene amido) -4- (2- trifluoroacetyl amido -4- methylthiazol -5- base) pyridine
2- (3- nitrobenzene amido) -4- (2- cyclopropyl formamido -4- methylthiazol -5- base) pyridine
2- (3- nitrobenzene amido) -4- (2- isopropyl formamido -4- methylthiazol -5- base) pyridine
2- (3- aminobenzene amido) -4- (2- cyclopropyl formamido -4- methylthiazol -5- base) pyridine
2- (3- aminobenzene amido) -4- (2- isopropyl formamido -4- methylthiazol -5- base) pyridine
2- (3- trifluoroacetamido anilino-) -4- (2- trifluoroacetamido -4- methylthiazol -5- base) pyridine
2- (3- trifluoroacetamido anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (3- trifluoroacetamido anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (3- ring fourth formamido group anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (3- trifluoroacetamido anilino-) -4- (2- ring fourth formamido group -4- methylthiazol -5- base) pyridine
2- (3- ring fourth formamido group anilino-) -4- (2- isopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (3- cyclopropyl formamido group anilino-) -4- (2- trifluoroacetamido -4- methylthiazol -5- base) pyridine
Second aspect of the present invention additionally provides the method for preparing the compounds of this invention, includes the following steps:
Route 1
It with the bromo- 4- thiazole pyridine derivative 1 of 2- is raw material in step (a), under acidic environment, the aniline that replaces with R1 Nucleophilic substitution occurs and forms compound 2；
In step (b), the amine on thiazole ring in compound 2 is alkylated or is acylated with common methods, such as and alkane The substitution reaction of base halide R2X or R3X are dehydrated by condensing agent with acid, or generate target compound I with acyl chloride reaction；
Route 2
It with the bromo- 4- thiazole pyridine derivative 1 of 2- is raw material in step (a), with common methods to the amine on its thiazole ring It is alkylated or is acylated, such as the substitution reaction with alkyl halide R2X or R3X, be dehydrated with acid by condensing agent, or and acyl Chlorine reaction generates midbody compound 3；
In step (b), under acidic environment, the aniline and compound 3 that R1 replaces occur nucleophilic substitution and generate target Compound I；
In addition, the starting material and intermediate in above-mentioned reaction are easy to get, or to those skilled in the art It can be easy to synthesize with the conventional method in organic synthesis.
2- anilino- -4- thiazole pyridine derivative described in Formulas I can exist in the form of solvate or non-solvent compound, Crystallization, which is carried out, using different solvents is likely to be obtained different solvates.Pharmaceutically acceptable salt described in Formulas I includes difference Acid-addition salts, such as acid-addition salts of following inorganic acid or organic acid: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, to toluene sulphur Acid, trifluoroacetic acid, fructus lycii acid, maleic acid, tartaric acid, fumaric acid, citric acid, lactic acid.Within the scope of the present invention all these Conventional method preparation all can be used in salt.In the 2- anilino- -4- thiazole pyridine derivative and its solvate and its salt Preparation process in, different crystallization conditions are likely to occur polycrystalline or eutectic.
Third aspect present invention further relates to the pharmaceutical composition using the compounds of this invention as active ingredient.The pharmaceutical composition Object can be prepared according to method well known in the art.Can by by the compounds of this invention with it is one or more pharmaceutically acceptable solid Body or liquid excipient and/or adjuvant combine, and any dosage form used suitable for human or animal is made.The compounds of this invention is in its medicine Content in compositions is usually 0.1-95 weight %.
The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and administration route can be enteron aisle Or non-bowel, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, Vagina, rectum etc..
Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be solution (including True solution and colloidal solution), emulsion (including o/w type, w/o type and emulsion), suspension, injection (including liquid drugs injection, powder-injection And infusion), eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets, lozenge, Dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard capsule, soft capsule, capsulae enterosolubilis), granule, dissipate Agent, pellet, dripping pill, suppository, film, patch, the agent of gas (powder) mist, spray etc.；Semisolid dosage form can be ointment, gel Agent, paste etc..
It is sustained release preparation, controlled release preparation, targeting preparation and various that the compounds of this invention, which can be made ordinary preparation, also be made, Particulate delivery system.
In order to which tablet is made in the compounds of this invention, various excipient well known in the art can be widely used, including dilute Release agent, binder, wetting agent, disintegrating agent, lubricant, glidant.Diluent can be starch, dextrin, sucrose, glucose, cream Sugar, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, second Alcohol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, Arabic gum Slurry, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, card Wave nurse, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrating agent can be dried starch, microcrystalline cellulose, low substituted hydroxy-propyl fiber Element, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxy second Alkene sorbitan fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be talcum powder, silica, tristearin Hydrochlorate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets or double Synusia and multilayer tablet.
In order to which capsule is made in administration unit, effective component the compounds of this invention and diluent, glidant can be mixed It closes, mixture is placed directly in hard capsule or soft capsule.It can also effective component the compounds of this invention is first and diluent, bonding Particle or pellet is made in agent, disintegrating agent, then is placed in hard capsule or soft capsule.It is used to prepare each dilute of the compounds of this invention tablet Release agent, binder, wetting agent, disintegrating agent, glidant kind can also be used for preparing the capsule of the compounds of this invention.
For injection is made in the compounds of this invention, water, ethyl alcohol, isopropanol, propylene glycol or their mixture can be used Make solvent and appropriate solubilizer commonly used in the art, cosolvent, pH adjustment agent, osmotic pressure regulator is added.Solubilizer or hydrotropy Agent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjustment agent can be phosphate, acetate, hydrochloric acid, hydrogen Sodium oxide molybdena etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..Such as prepare freeze-dried powder Mannitol, glucose etc. can be also added as proppant in injection.
In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation Agent.
To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well known can be given with any The administration of prescription method.
The dosage of the compounds of this invention pharmaceutical composition is according to the property and serious journey to be prevented or be treated disease The individual instances of degree, patient or animal, administration route and dosage form etc. can have large-scale variation.In general, of the present inventionization The daily Suitable dosage ranges for closing object are 0.001-150mg/Kg weight, preferably 0.01-100mg/Kg weight.Above-mentioned dosage With a dosage unit or several dosage unit administrations can be divided into, this depends on the clinical experience of doctor and including with other The dosage regimen for the treatment of means.
The compound of the present invention or composition can individually be taken, or merge use with other treatment drug or symptomatic drugs. When the compound of the present invention and other therapeutic agents, which exist, to act synergistically, its dosage should be adjusted according to the actual situation.
The compounds of this invention is multiple target point kinases inhibitor or its precursor, these protein kinases are according to phosphorylated substrate Difference be divided into multiple families, such as protein tyrosine kinase, Protein Serine/threonine kinase, lipoid etc..Generally, albumen Kinases is transferred to a protein receptor relevant to signal transduction pathway from a ribonucleoside triphosphote by influencing a phosphoryl Carry out signal transduction in mediated cell.These phosphorylated events adjust the biological function of target protein as molecular switch, are finally swashed Hair reacts to various extracellular and other stimulations.Kinases is present in multilayer signal transduction path, receptor tyrosine kinase Positioned at the upstream of Tumor Angiongesis Signal transduction pathway and the upstream of tumour cell Signal transduction pathway.Serine/threonine Protein kinase is located at the downstream of the Signal transduction pathway of tumour and Tumor Angiongesis cell.Research shows that by blocking in upstream VEGFR and pdgf receptor inhibit Aurora A in downstream, can reduce the angiogenesis of tumour simultaneously and inhibit tumour cell Duplication, to hinder the growth of tumour.The compounds of this invention bioavilability with higher, can be used for a variety of human malignants The treatment of tumour is liver cancer, gastric cancer, kidney, lung cancer, cancer of pancreas, colorectal cancer, bladder cancer and cream including the tumor disease Gland cancer, oophoroma, squamous cell carcinoma, glioma, leukaemia, head-neck carcinoma.
Specific embodiment
Invention is described further below with reference to embodiment, but is not limit the scope of the invention.
Determining instrument: NMR spectrum Vaariaan Mercury300 or 400 type Nuclear Magnetic Resonance.Mass spectrum is used ZAD-2F and VG300 mass spectrograph.
Embodiment 1.2- (3-Aminotrifluorotoluene base) -4- (2- amino -4- methylthiazol -5- base) pyridine
The bromo- 4- of 2- (2- amino -4- methylthiazol -5- base) pyridine (270mg, 1mmol) is added to 10ml mixed solvent (1N HCl/H2O/Dioxane=2/4/1 in), it is heated to 80 DEG C under stirring, 3-Aminotrifluorotoluene is added after to be dissolved (242mg, 1.5mmol), and heat up, it is back to fully reacting.It is cooled to room temperature, reaction solution is poured into saturated sodium bicarbonate water In solution, solid is collected in filtering, and column chromatographic purifying obtains product 2- (3-Aminotrifluorotoluene base) -4- (2- amino -4- methyl thiazolium Azoles -5- base) pyridine.1H-NMR(400MHz,DMSO-d6):δ(ppm):9.43(s,1H,-NH-),9.23(s,1H,ArH), 8.14(d,1H,ArH),7.86(d,1H,ArH),7.47(t,1H,ArH),7.26(s,2H,-NH2 ),7.18(d,1H,ArH), 6.81(s,1H,ArH),6.77(d,1H,ArH),2.32(s,3H,-CH3 )；m/z351.0[M+H]+.
Embodiment 2.2- (the chloro- 6- toluidine of 2-) -4- (2- amino -4- methylthiazol -5- base) pyridine
3-Aminotrifluorotoluene is replaced with the chloro- 6- methylaniline of 2-, the operating process of reference implementation example 1 obtains 2- (2- Chloro- 6- toluidine) -4- (2- amino -4- methylthiazol -5- base) pyridine1H-NMR(300MHz,DMSO-d6):δ (ppm):8.30(s,1H,-NH-),7.89(d,1H,ArH),7.36-7.34(d,1H,ArH),7.26-7.24(d,1H,ArH), 7.19-7.14(m,3H,ArH,-NH2 ),6.60-6.58(dd,1H,ArH),6.37(s,1H,ArH),2.23(s,3H,-CH3 ), 2.18(s,3H,-CH3 )；m/z331.0[M+H]+.
Embodiment 3.2- (2- fluoroanilino) -4- (2- amino -4- methylthiazol -5- base) pyridine
3-Aminotrifluorotoluene is replaced with 2- fluoroaniline, the operating process of reference implementation example 1 obtains 2- (2- fluoroaniline Base) -4- (2- amino -4- methylthiazol -5- base) pyridine1H-NMR(300MHz,DMSO-d6):δ(ppm):8.71(s,1H,- NH-),8.26-8.20(m,1H,ArH),8.05(d,1H,ArH),7.22-7.09(m,4H,-NH2 ,ArH),6.99-6.93(m, 2H,ArH),6.73-6.70(m,1H,ArH),2.30(s,3H,-CH3 )；m/z301.0[M+H]+.
Embodiment 4.2- (2,4- difluorobenzene amido) -4- (2- amino -4- methylthiazol -5- base) pyridine
3-Aminotrifluorotoluene is replaced with 2,4- difluoroaniline, the operating process of reference implementation example 1 obtains 2- (2,4- bis- Fluoroanilino) -4- (2- amino -4- methylthiazol -5- base) pyridine
1H-NMR(300MHz,DMSO-d6):δ(ppm):8.66(s,1H,-NH-),8.16-8.08(m,1H,ArH), 8.01(d,1H,ArH),7.29-7.21(m,3H,ArH,-NH2 ),7.04-6.98(m,1H,ArH),6.87(s,1H,ArH), 6.70-6.68(m,1H,ArH),2.28(s,3H,-CH3 )；m/z319.0[M+H]+.
Embodiment 5.2- (the bromo- 4- fluoroanilino of 2-) -4- (2- amino -4- methylthiazol -5- base) pyridine
3-Aminotrifluorotoluene is replaced with the bromo- 4- fluoroaniline of 2-, the operating process of reference implementation example 1, obtaining 2-, (2- is bromo- 4- fluoroanilino) -4- (2- amino -4- methylthiazol -5- base) pyridine
1H-NMR(300MHz,DMSO-d6):δ(ppm):8.34(s,1H,-NH-),7.97(d,1H,ArH),7.82- 7.77(m,1H,ArH),7.60-7.56(m,1H,ArH),7.25-7.21(m,3H,ArH,-NH2 ),6.79(s,1H,ArH), 6.70-6.68(m,1H,ArH),2.28(s,3H,-CH3 )；m/z379.0[M+H]+.
Embodiment 6.2- (2- methoxyl group -4-N- methyl piperazine anilino-) -4- (2- amino -4- methylthiazol -5- base) pyrrole Pyridine
3-Aminotrifluorotoluene is replaced with 2- methoxyl group -4-N- methyl piperazine aniline, the operating process of reference implementation example 1, Obtain 2- (2- methoxyl group -4-N- methyl piperazine anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
1H-NMR(300MHz,DMSO-d6):δ(ppm):7.95(d,1H,ArH),7.90(s,1H,-NH-),7.71(d, 1H,ArH),7.17(s,2H,-NH2 ),6.69(s,1H,ArH),6.61(d,1H,ArH),6.57-6.55(dd,1H,ArH), 6.47-6.43(dd,1H,ArH),3.80(s,3H,-OCH3 ),3.11(brs,4H,-CH2 CH2-),2.49(brs,4H,- CH2 CH2-),2.25(brs,6H,-CH3 )；m/z411.2[M+H]+.
Embodiment 7.2- (4- morpholine anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
3-Aminotrifluorotoluene is replaced with 4- morpholinyl phenylamine, the operating process of reference implementation example 1 obtains 2- (4- morpholine Anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
1H-NMR(300MHz,DMSO-d6):δ(ppm):8.75(s,1H,-NH-),8.01(d,1H,ArH),7.50(d, 2H,ArH),7.18(s,2H,-NH2 ),6.88(d,2H,ArH),6.66(s,1H,ArH),6.61(d,1H,ArH),3.74 (brs,4H,-CH2 CH2-),3.02(brs,4H,-CH2 CH2-),2.28(s,3H,-CH3 )；m/z368.1[M+H]+.
Embodiment 8.2- (4- (cyclopropyl formamido) anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
3-Aminotrifluorotoluene is replaced with 4- (cyclopropyl formamido) aniline, the operating process of reference implementation example 1 obtains 2- (4- (cyclopropyl formamido) anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
1H-NMR(400MHz,DMSO-d6):δ(ppm):10.01(s,1H,-NH),8.93(s,1H,-NH),8.05- 8.04(d,1H,ArH),7.57(d,2H,ArH),7.47(d,2H,ArH),7.20(s,2H,-NH2 ),6.66(d,1H,ArH), 6.69(d,1H,ArH),2.30(s,3H,-CH3 ),1.74(m,1H,-CH2CHCH2-),0.78-0.75(m,4H,- CH2 CHCH2 -)；m/z366.1[M+H]+.
Embodiment 9.2- (3,4,5- trimethoxy-benzene amido) -4- (2- amino -4- methylthiazol -5- base) pyridine
3-Aminotrifluorotoluene is replaced with 3,4,5- trimethoxy-anilines, the operating process of reference implementation example 1 obtains 2- (3,4,5- trimethoxy-benzene amido) -4- (2- amino -4- methylthiazol -5- base) pyridine
1H-NMR(300MHz,DMSO-d6):δ(ppm):8.93(s,1H,-NH-),8.06(d,1H,ArH),7.21(s, 2H,ArH),7.04(s,2H,-NH2 ),6.74(s,1H,ArH),6.66(d,1H,ArH),3.72(s,6H,-OCH3 ),3.60(s, 3H,-OCH3 ),2.29(s,3H,-CH3 )；m/z373.1[M+H]+.
Embodiment 10.2- (4- dimethylamino anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
3-Aminotrifluorotoluene is replaced with 4- dimethylamino aniline, the operating process of reference implementation example 1 obtains 2- (4- bis- Methylamino anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
1H-NMR(300MHz,DMSO-d6):δ(ppm):8.60(s,1H,-NH-),7.98(d,1H,ArH),7.41(d, 2H,ArH),7.17(s,2H,-NH2 ),6.71(d,2H,ArH),6.62(s,1H,ArH),6.57(d,1H,ArH),2.83(s, 6H,-NCH3 ),2.27(s,3H,-CH3 )；m/z326.1[M+H]+.
Embodiment 11.2- (3- cyclopropyl formamido anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
3-Aminotrifluorotoluene is replaced with 3- cyclopropyl formamido aniline, the operating process of reference implementation example 1 obtains 2- (3- cyclopropyl formamido anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
1H-NMR(300MHz,DMSO-d6):δ(ppm):10.09(s,1H,-NH),9.03(s,1H,-NH),8.08(d, 1H,ArH),7.92(s,1H,ArH),7.40(m,1H,ArH), 7.22~7.13 (m, 4H, ArH,-NH2 ),6.80(s,1H, ArH),6.69(d,1H,ArH),2.30(s,3H,-CH3 ),1.81(m,1H,-CH2CHCH2-),0.79-0.77(m,4H,- CH2 CHCH2 -)；m/z366.1[M+H]+.
Embodiment 12.2- (4- (N methyl piperazine base) anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
3-Aminotrifluorotoluene is replaced with 4- (N methyl piperazine base) aniline, the operating process of reference implementation example 1 obtains 2- (4- (N methyl piperazine base) anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
1H-NMR(400MHz,DMSO-d6):δ(ppm):8.72(s,1H,-NH-),8.00(d,1H,ArH),7.47(d, 2H,ArH),7.18(s,2H,-NH2 ),6.87(d,2H,ArH),6.66(s,1H,ArH),6.60(d,1H,ArH),3.04 (brs,4H,-CH2 CH2-),2.46(brs,4H,-CH2 CH2-),2.28(s,3H,-CH3 ),2.22(s,3H,-CH3 )；m/ z381.1[M+H]+.
Embodiment 13.2- (m-nitro amido) -4- (2- amino -4- methylthiazol -5- base) pyridine
3-Aminotrifluorotoluene is replaced with meta nitro aniline, the operating process of reference implementation example 1 obtains 2- (m-nitro Amido) -4- (2- amino -4- methylthiazol -5- base) pyridine
1H NMR(300MHz,DMSO-d6):δ9.65(s,1H,-NH-),8.83(s,1H,ArH),8.17-8.15(d,1H, ArH),7.97-7.94(d,1H,ArH),7.71-7.68(d,1H,ArH),7.54-7.48(t,1H,ArH),7.27(s,2H,- NH 2),6.82-6.78(m,2H,ArH),2.31(s,3H,-CH 3).MS(FAB)(M++ 1=328).
Embodiment 14.2- (m-aminophenyl amido) -4- (2- amino -4- methylthiazol -5- base) pyridine
3-Aminotrifluorotoluene is replaced with m-aminophenyl amine, the operating process of reference implementation example 1 obtains 2- (m-aminophenyl Amido) -4- (2- amino -4- methylthiazol -5- base) pyridine
1H NMR(300MHz,DMSO-d6):δ8.69(s,1H,-NH-),8.04-8.02(d,1H,ArH),7.19(s, 2H,-NH 2),6.94(s,1H,ArH),6.90-6.85(t,1H,ArH),6.76(s,2H,ArH),6.64-6.62(d,1H, ArH),6.14-6.11(d,1H,ArH),4.99(br s,2H,-NH 2),2.29(s,3H,-CH 3).MS(FAB)(M++ 1= 298)。
Embodiment 15.2- (propionamido anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
3-Aminotrifluorotoluene is replaced with propionamido aniline, and the operating process of reference implementation example 1 obtains 2- (third Acylamino- anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
1H NMR(300MHz,DMSO-d6):δ9.76(s,1H,-NH-),9.02(s,1H,-NH-),8.07-8.05(d, 1H,ArH),7.91(s,1H,ArH),7.41-7.39(d,1H,ArH),7.21(s,2H,-NH2 ),7.16-7.11(m,2H, ArH),6.79(s,1H,ArH),6.68-6.66(d,1H,ArH),2.34-2.26(m,5H,-CH 2,-CH 3),1.09-1.04(t, 3H,-CH 3).MS(FAB)(M++ 1=354).
Embodiment 16.2- (isophthalic acetyl amino phenyl amido) -4- (2- amino -4- methylthiazol -5- base) pyridine
Replace 3-Aminotrifluorotoluene with isophthalic acetylaminoaniline, the operating process of reference implementation example 1, obtain 2- ( Phenylacetylamino anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
1H NMR(300MHz,DMSO-d6):δ10.08(s,1H,-NH-),9.04(s,1H,-NH-),8.08(s,1H, ArH),7.94(s,1H,ArH),7.40-7.14(m,10H,ArH,-NH2 ),6.79(s,1H,ArH),6.69(s,1H,ArH), 3.64(s,2H,-CH 2-),2.29(s,3H,-CH 3).MS(FAB)(M++ 1=416).
Embodiment 17.2- (3- trifluoroacetamido anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
3-Aminotrifluorotoluene is replaced with trifluoroacetamido aniline, the operating process of reference implementation example 1 obtains 2- (3- Trifluoroacetamido anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
1H-NMR(400MHz,DMSO-d6):δ(ppm):11.19(s,1H,-NH-),9.19(s,1H,-NH-),8.10- 8.07(m,2H,ArH),7.57-7.55(d,1H,ArH),7.29-7.25(m,3H,ArH),7.17-7.15(d,1H,ArH), 6.81(s,1H,ArH),6.73-6.71(d,1H,ArH),2.31(s,3H,-CH3)；m/z394.[M+H]+.
Embodiment 18.2- (3- nitrobenzene amido) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
1) by the bromo- 4- of 2- (2- amino -4- methylthiazol -5- base) pyridine (270mg, 1mmol) be added to 10ml mix it is molten Agent (1N HCl/H2O/Dioxane=2/4/1 in), it is heated to 80 DEG C under stirring, meta nitro aniline is added after to be dissolved (207mg, 1.5mmol), and heat up, it is back to fully reacting.It is cooled to room temperature, reaction solution is poured into saturated sodium bicarbonate water In solution, solid is collected in filtering, and column chromatographic purifying obtains product 2- (3- nitrobenzene amido) -4- (2- amino -4- methylthiazol -5- Base) pyridine1H NMR(300MHz,DMSO-d6):δ9.65(s,1H,-NH-),8.83(s,1H,ArH),8.17-8.15(d,1H, ArH),7.97-7.94(d,1H,ArH),7.71-7.68(d,1H,ArH),7.54-7.48(t,1H,ArH),7.27(s,2H,- NH 2),6.82-6.78(m,2H,ArH),2.31(s,3H,-CH 3).MS(FAB)(M++ 1=328).
2) 2- (3- nitrobenzene amido) -4- (2- amino -4- methylthiazol -5- base) pyridine (1mmol) is dissolved in a small amount of DMA In, DMAP is added, is added dropwise chloroacetic chloride (1.2mmol), 70 DEG C of reactions are warming up to after being added dropwise to complete, are cooled to room temperature, to Saturated sodium bicarbonate aqueous solution is added in reaction solution, there is solid precipitation, filters, column chromatographic purifying is up to product.1H NMR (300MHz,DMSO-d6):δ12.26(s,1H,-NH-),9.70(s,1H,-NH-),8.85(s,1H,ArH),8.27-8.26 (d,1H,ArH),7.99-7.97(d,1H,ArH),7.74-7.72(d,1H,ArH),7.57-7.54(t,1H,ArH),6.98 (s,2H,ArH),2.47(br s,3H,-CH 3),2.17(s,3H,-CH 3).MS(FAB)(M++ 1=370).
Embodiment 19.2- (3- trifluoromethylbenzene amido) -4- (2- acrylamido -4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with 3- 5-trifluoromethylaniline, acryloyl chloride replaces chloroacetic chloride, the operation of reference implementation example 18 Process obtains 2- (3- trifluoromethylbenzene amido) -4- (2- acrylamido -4- methylthiazol -5- base) pyridine1H-NMR (300MHz,DMSO-d6):δ(ppm):12.53(s,1H,-NH-),9.55(s,1H,-NH-),8.26(s,2H,ArH),7.90- 7.87(d,1H,ArH),7.52-7.47(t,1H,ArH),7.22-7.20(d,1H,ArH),6.98(s,1H,ArH),6.95- 6.93(d,1H,ArH), 6.52-6.49 (d, 1H ,=CH), 6.45-6.39 (d, 1H ,=CH), 5.95-5.92 (d, 1H ,= CH),2.48(s,3H,-CH 3).MS(FAB)(M++ 1=405).
Embodiment 20.2- (3- trifluoromethylbenzene amido) -4- (2- (3- dimethyl allene acyl) amino -4- methylthiazol -5- Base) pyridine
3- nitroaniline is replaced with 3- 5-trifluoromethylaniline, 3- dimethyl acryloyl chloride replaces chloroacetic chloride, reference implementation example 18 operating process obtains 2- (3- trifluoromethylbenzene amido) -4- (2- (3- dimethyl allene acyl) amino -4- methylthiazol -5- Base) pyridine
1H-NMR(300MHz,DMSO-d6):δ(ppm):12.17(s,1H,-NH-),9.52(s,1H,-NH-),8.24 (s,2H,ArH),7.89-7.87(d,1H,ArH),7.51-7.48(t,1H,ArH),7.22-7.20(d,1H,ArH),6.98 (s,1H,ArH),6.93(s,1H,ArH), 5.99 (s, 1H ,=CH),2.47(s,3H,-CH3 ),2.22(s,3H,-CH3 ),1.91 (s,3H,-CH3 ).MS(FAB)(M++ 1=433).
Embodiment 21.2- (3- trifluoromethylbenzene amido) -4- (2- (hexadiene -2,4- acylamino-) -4- methylthiazol -5- Base) pyridine
3- nitroaniline is replaced with 3- 5-trifluoromethylaniline, hexadiene -2,4- acyl chlorides replaces chloroacetic chloride, reference implementation example 18 Operating process, obtain 2- (3- trifluoromethylbenzene amido) -4- (2- (hexadiene -2,4- acylamino-) -4- methylthiazol -5- base) Pyridine.1H-NMR(300MHz,DMSO-d6):δ(ppm):12.38(s,1H,-NH-),9.54(s,1H,-NH-),8.25(s, 2H,ArH),7.87(brs,1H,ArH),7.49(brs,1H,ArH), 7.31 (brs, 1H ,=CH),7.22(s,1H,ArH), 6.97-6.93(m,2H,ArH), 6.31-6.16 (m, 3H ,=CH),2.48(s,3H,-CH3 ),1.85(s,3H,-CH3 ).MS (FAB)(M++ 1=445).
Embodiment 22.2- (3- trifluoromethylbenzene amido) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with 3- 5-trifluoromethylaniline, the operating process of reference implementation example 18 obtains 2- (3- fluoroform Base anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,DMSO-d6):δ(ppm): 12.28(s,1H,-NH-),9.55(s,1H,-NH-),8.28-8.25(m,2H,ArH),7.91-7.89(d,1H,ArH), 7.54-7.50(t,1H,ArH),7.24-7.22(d,1H,ArH),6.99(s,1H,ArH),6.96-6.94(d,1H,ArH), 2.49(s,3H,-CH3 ),2.19(s,3H,-CH3 ).MS(FAB)(M++ 1=393).
Embodiment 23.2- (3- trifluoromethylbenzene amido) -4- (2- propionamido -4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with 3- 5-trifluoromethylaniline, propionyl chloride replaces chloroacetic chloride, the operation of reference implementation example 18 Journey obtains 2- (3- trifluoromethylbenzene amido) -4- (2- propionamido -4- methylthiazol -5- base) pyridine.
1H-NMR(300MHz,DMSO-d6):δ(ppm):12.22(s,1H,-NH-),9.53(s,1H,-NH-),8.25- 8.23(m,2H,ArH),7.90-7.87(d,1H,ArH),7.52-7.47(t,1H,ArH),7.22-7.20(d,1H,ArH), 6.97(s,1H,ArH),6.93-6.91(d,1H,ArH),2.47-2.42(m,5H,-CH3 ,-CH2 -),1.13-1.08(t,3H,- CH3 ).MS(FAB)(M++ 1=407).
Embodiment 24.2- (3- trifluoromethylbenzene amido) -4- (2- (3- methylbutyrylamino) -4- methylthiazol -5- base) Pyridine
3- nitroaniline is replaced with 3- 5-trifluoromethylaniline, 3-Methylbutanoyl chloride replaces chloroacetic chloride, reference implementation example 18 Operating process obtains 2- (3- trifluoromethylbenzene amido) -4- (2- (3- methylbutyrylamino) -4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,DMSO-d6):δ(ppm):12.24(s,1H,-NH-),9.52(s,1H,-NH-),8.25-8.23(m, 2H,ArH),7.89-7.87(d,1H,ArH),7.52-7.48(t,1H,ArH),7.22-7.20(d,1H,ArH),6.97(s, 1H,ArH),6.93-6.92(d,1H,ArH),2.47(s,3H,-CH3 ),2.34-2.32(d,2H,-CH2 -),2.12-2.08(m, 1H,-CH-),0.94-0.92(d,6H,-CH(CH 3)2).MS(FAB)(M++ 1=435).
Embodiment 25.2- (3- trifluoromethylbenzene amido) -4- (2- valeryl amino -4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with 3- 5-trifluoromethylaniline, valeric chloride replaces chloroacetic chloride, the operation of reference implementation example 18 Journey obtains 2- (3- trifluoromethylbenzene amido) -4- (2- valeryl amino -4- methylthiazol -5- base) pyridine.
1H-NMR(300MHz,CDCl3):δ(ppm):10.04(s,1H,-NH-),8.25-8.23(d,1H,ArH),7.69 (s,1H,ArH),7.58-7.54(d,1H,ArH),7.48-7.43(t,1H,ArH),7.38(s,1H,-NH-),7.31-7.29 (d,1H,ArH),6.90-6.88(m,2H,ArH),2.50-2.45(m,5H,-CH3 ,-CH2 -),1.78-1.68(m,2H,- CH2 -),1.44-1.36(m,2H,-CH2 -),0.96-0.91(t,3H,-CH2CH 3).MS(FAB)(M++ 1=435).
Embodiment 26.2- (3- trifluoromethylbenzene amido) -4- (2- cyclopropylcarboxamido -4- methylthiazol -5- base) pyrrole Pyridine
3- nitroaniline is replaced with 3- 5-trifluoromethylaniline, Cyclopropyl carbonyl chloride replaces chloroacetic chloride, reference implementation example 18 Operating process obtains 2- (3- trifluoromethylbenzene amido) -4- (2- cyclopropylcarboxamido -4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,CDCl3):δ(ppm):10.89(s,1H,-NH-),8.24-8.22(d,1H,ArH),7.69(s,1H, ArH),7.57-7.54(d,1H,ArH),7.48-7.43(t,1H,ArH),7.39(s,1H,-NH-),7.32-7.29(d,1H, ArH),6.91-6.87(m,2H,ArH),2.47(s,3H,-CH3 ),1.64(m,1H,-CH-),1.25-1.22(m,2H,- CH2 -),1.01-0.99(m,2H,-CH2 -).MS(FAB)(M++ 1=419).
Embodiment 27.2- (3- trifluoromethylbenzene amido) -4- (2- cyclobutylmethyl acylamino- -4- methylthiazol -5- base) pyrrole Pyridine
3- nitroaniline is replaced with 3- 5-trifluoromethylaniline, cyclobutylmethyl acyl chlorides replaces chloroacetic chloride, reference implementation example 18 Operating process obtains 2- (3- trifluoromethylbenzene amido) -4- (2- cyclobutylmethyl acylamino- -4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,DMSO-d6):δ(ppm):12.11(s,1H,-NH-),9.52(s,1H,-NH-),8.23(s,2H, ArH),7.85(brs,1H,ArH),7.48(brs,1H,ArH),7.21(brs,1H,ArH),6.95-6.91(d,2H,ArH), 3.32(m,1H,-CH-),2.45(s,3H,-CH3 ),2.23-2.15(m,4H,-CH2 -),1.96(m,1H,-CH-),1.83(m, 1H,-CH-).MS(FAB)(M++ 1=433).
Embodiment 28.2- (3- trifluoromethylbenzene amido) -4- (2- cyclopenta formamido group -4- methylthiazol -5- base) pyrrole Pyridine
3- nitroaniline is replaced with 3- 5-trifluoromethylaniline, cyclopenta formyl chloride replaces chloroacetic chloride, reference implementation example 18 Operating process obtains 2- (3- trifluoromethylbenzene amido) -4- (2- cyclopenta formamido group -4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,DMSO-d6):δ(ppm):12.23(s,1H,-NH-),9.51(s,1H,-NH-),8.23(s,2H, ArH),7.88-7.85(d,1H,ArH),7.51-7.46(t,1H,ArH),7.21-7.18(d,1H,ArH),6.95(s,1H, ArH),6.91-6.89(d,1H,ArH),2.91(m,1H,-CH-),2.45(s,3H,-CH3 ),1.86(m,2H,-CH2 -), 1.68-1.56(m,6H,-CH 2-).MS(FAB)(M++ 1=447).
Embodiment 29.2- (3- trifluoromethylbenzene amido) -4- (chIorobenzoyIamino -4- methylthiazol -5- base between 2-) pyrrole Pyridine
3- nitroaniline is replaced with 3- 5-trifluoromethylaniline, m-chlorobenzoyl chloride replaces chloroacetic chloride, reference implementation example 18 Operating process obtains 2- (3- trifluoromethylbenzene amido) -4- (chIorobenzoyIamino -4- methylthiazol -5- base between 2-) pyridine.1H-NMR(300MHz,DMSO-d6):δ(ppm):12.95(s,1H,-NH-),9.54(s,1H,-NH-),8.24(brs,2H, ArH),8.16(s,1H,ArH),8.06-8.04(d,1H,ArH),7.89-7.86(d,1H,ArH),7.71-7.69(d,1H, ArH),7.60-7.55(t,1H,ArH),7.51-7.46(t,1H,ArH),7.21-7.18(d,1H,ArH),6.90(s,1H, ArH),6.96-6.94(d,1H,ArH),2.48(s,3H,-CH3 ).MS(FAB)(M++ 1=490).
Embodiment 30.2- (3- trifluoromethylbenzene amido) -4- (fluorobenzene acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base between 2-) pyrrole Pyridine
3- nitroaniline is replaced with 3- 5-trifluoromethylaniline, fluorophenylacetyl chloride replaces chloroacetic chloride, reference implementation example 18 Operating process obtains 2- (3- trifluoromethylbenzene amido) -4- (fluorobenzene acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base between 2-) pyridine.1H-NMR(300MHz,DMSO-d6):δ(ppm):12.53(s,1H,-NH-),9.51(s,1H,-NH-),8.23-8.21(d, 2H,ArH),7.87-7.85(d,1H,ArH),7.50-7.45(t,1H,ArH),7.41-7.34(m,1H,ArH),7.20-7.07 (m,4H,ArH),6.94(s,1H,ArH),6.90-6.88(m,1H,ArH),3.82(s,2H,-CH 2),2.46(s,3H,-CH3 ) .MS(FAB)(M++ 1=487).
Embodiment 31.2- (3- trifluoromethylbenzene amido) -4- (2- m-fluoroaniline formamido group -4- methylthiazol -5- base) Pyridine
3- nitroaniline is replaced with 3- 5-trifluoromethylaniline, m-fluoroaniline formyl chloride replaces chloroacetic chloride, reference implementation example 18 Operating process, obtain 2- (3- trifluoromethylbenzene amido) -4- (2- m-fluoroaniline formamido group -4- methylthiazol -5- base) pyrrole Pyridine.1H-NMR(300MHz,DMSO-d6):δ(ppm):10.78(s,1H,-NH-),9.53(s,1H,-NH-),9.26(s,1H,- NH-),8.25-8.23(m,2H,ArH),7.90-7.87(d,1H,ArH),7.53-7.47(m,2H,ArH),7.39-7.31(m, 1H,ArH),7.22-7.20(m,2H,ArH),6.97-6.87(m,3H,ArH),2.45(s,3H,-CH3 ).MS(FAB)(M++ 1= 488)。
Embodiment 32.2- (adjacent fluoroanilino) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with adjacent fluoroaniline, acryloyl chloride replaces chloroacetic chloride, and the operating process of reference implementation example 18 obtains To 2- (adjacent fluoroanilino) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,DMSO-d6): δ(ppm):12.49(s,1H,-NH-),8.82(s,1H,-NH-),8.25-8.19(t,1H,ArH),8.15-8.13(d,1H, ArH),7.24-7.17(t,1H,ArH),7.15-7.10(m,2H,ArH),7.00-6.94(m,1H,ArH),6.88-6.86(d, 1H,ArH), 6.56-6.37 (m, 2H ,=CH), 5.93-5.89 (d, 1H ,=CH),2.45(s,3H,-CH3 ).MS(FAB)(M++1 =355).
Embodiment 33.2- (2,4- dichloroanilino) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with 2,4- dichloroaniline, acryloyl chloride replaces chloroacetic chloride, the operation of reference implementation example 18 Journey obtains 2- (2,4- dichloroanilino) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine.
1H-NMR(300MHz,DMSO-d6):δ(ppm):12.50(s,1H,-NH-),8.62(s,1H,-NH-),8.19- 8.13(m,2H,ArH),7.58-7.57(d,1H,ArH),7.36-7.33(dd,1H,ArH),7.22(s,1H,ArH),6.94- 6.92(dd,1H,ArH), 6.56-6.37 (m, 2H ,=CH), 5.94-5.90 (m, 1H ,=CH),2.46(s,3H,-CH3 ).MS (FAB)(M++ 1=406).
Embodiment 34.2- (p-dimethylamino aniline base) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with p-dimethylamino aniline, acryloyl chloride replaces chloroacetic chloride, the operation of reference implementation example 18 Process obtains 2- (p-dimethylamino aniline base) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine.1H-NMR (300MHz,DMSO-d6):δ(ppm):12.47(s,1H,-NH-),8.71(s,1H,-NH-),8.08-8.06(d,1H,ArH), 7.43-7.40(d,2H,ArH),6.76-6.70(m,4H,ArH), 6.56-6.37 (m, 2H ,=CH),5.93-5.89(m,1H, =CH),2.83(s,6H,-CH3 ),2.43(s,3H,-CH3 ).MS(FAB)(M++ 1=380).
Embodiment 35.2- (3,4,5- trimethoxy-benzene amido) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyrrole Pyridine
3- nitroaniline is replaced with 3,4,5- trimethoxy-anilines, acryloyl chloride replaces chloroacetic chloride, reference implementation example 18 Operating process obtains 2- (3,4,5- trimethoxy-benzene amido) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,DMSO-d6):δ(ppm):12.50(s,1H,-NH-),9.06(s,1H,-NH-),8.17-8.15(d, 1H,ArH),7.05(s,2H,ArH),6.90(s,1H,ArH),6.83-6.81(dd,1H,ArH), 6.56-6.37 (m, 2H ,= CH), 5.94-5.90 (m, 1H ,=CH),3.76(s,6H,-OCH3 ),3.61(s,3H,-OCH3 ),2.46(s,3H,-CH3 ).MS (FAB)(M++ 1=427).
Embodiment 36.2- (4- cyclopropyl formamido group anilino-) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyrrole Pyridine
3- nitroaniline is replaced with 4- cyclopropyl formamido group aniline, acryloyl chloride replaces chloroacetic chloride, reference implementation example 18 Operating process obtains 2- (4- cyclopropyl formamido group anilino-) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,DMSO-d6):δ(ppm):10.03(s,1H,-NH-),9.04(s,1H,-NH-),8.14-8.12(d, 1H,ArH),7.59-7.56(d,2H,ArH),7.48-7.45(d,2H,ArH),6.87(s,1H,ArH),6.81-6.79(d, 1H,ArH), 6.56-6.36 (m, 2H ,=CH), 5.92-5.99 (m, 1H ,=CH),2.45(s,3H,-CH3 ),1.74(m,1H,- CH),0.76-0.73(m,4H,-CH2 CH2 -).MS(FAB)(M++ 1=420).
Embodiment 37.2- (3- cyclopropyl formamido group anilino-) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyrrole Pyridine
3- nitroaniline is replaced with 3- cyclopropyl formamido group aniline, acryloyl chloride replaces chloroacetic chloride, reference implementation example 18 Operating process obtains 2- (3- cyclopropyl formamido group anilino-) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,DMSO-d6):δ(ppm):12.49(s,1H,-NH-),10.11(s,1H,-NH-),9.13(s,1H,- NH-),8.17-8.15(d,1H,ArH),7.92(s,1H,ArH),7.44-7.41(m,1H,ArH),7.21-7.13(m,2H, ArH),6.95(s,1H,ArH),6.84-6.82(dd,1H,ArH), 6.56-6.37 (m, 2H ,=CH),5.94-5.90(dd, 1H,ArH),2.45(s,3H,-CH3 ),1.61(m,1H,-CH),0.78-0.75(m,4H,-CH2 CH2 -).MS(FAB)(M++ 1= 420)。
Embodiment 38.2- (adjacent fluoroanilino) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with adjacent fluoroaniline, cyclopropyl formyl chloride replaces chloroacetic chloride, the operating process of reference implementation example 18, Obtain 2- (adjacent fluoroanilino) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,DMSO- d6):δ(ppm):12.52(s,1H,-NH-),8.81(s,1H,-NH-),8.26-8.20(m,1H,ArH),8.15-8.13(d, 1H,ArH),7.25-7.11(m,3H,ArH),7.01-6.95(m,1H,ArH),6.87-6.84(m,1H,ArH),2.45(s, 3H,-CH3 ),1.96-1.92(m,1H,-CH-),0.94-0.91(m,4H,-CH 2CH2 -).MS(FAB)(M++ 1=369).
Embodiment 39.2- (2,4- dichloroanilino) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with 2,4- dichloroaniline, cyclopropyl formyl chloride replaces chloroacetic chloride, the operation of reference implementation example 18 Process obtains 2- (2,4- dichloroanilino) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine.1H-NMR (300MHz,DMSO-d6):δ(ppm):12.53(s,1H,-NH-),8.61(s,1H,-NH-),8.20-8.13(m,2H,ArH), 7.60-7.59(d,1H,ArH),7.38-7.34(dd,1H,ArH),7.21(s,1H,ArH),6.92-6.90(d,1H,ArH), 2.46(s,3H,-CH3 ),1.95(m,1H,-CH-),0.94-0.92(m,4H,-CH 2CH2 -).MS(FAB)(M++ 1=420).
Embodiment 40.2- (p-dimethylamino aniline base) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with p-dimethylamino aniline, cyclopropyl formyl chloride replaces chloroacetic chloride, the behaviour of reference implementation example 18 Make process, obtains 2- (p-dimethylamino aniline base) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine.1H-NMR (300MHz,DMSO-d6):δ(ppm):12.48(s,1H,-NH-),8.68(s,1H,-NH-),8.06-8.04(d,1H,ArH), 7.42-7.39(d,2H,ArH),6.73-6.67(m,4H,ArH),2.82(s,6H,-NCH3 ),2.41(s,3H,-CH3 ),1.92 (m,1H,-CH-),0.90(brs,4H,-CH 2CH2 -).MS(FAB)(M++ 1=394).
Embodiment 41.2- (3,4,5- trimethoxy-benzene amido) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) Pyridine
3- nitroaniline is replaced with 3,4,5- trimethoxy-anilines, cyclopropyl formyl chloride replaces chloroacetic chloride, reference implementation example 18 Operating process, obtain 2- (3,4,5- trimethoxy-benzene amido) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyrrole Pyridine.1H-NMR(300MHz,DMSO-d6):δ(ppm):12.52(s,1H,-NH-),9.04(s,1H,-NH-),8.17-8.15 (d,1H,ArH),7.06(s,2H,ArH),6.89(s,1H,ArH),6.81-6.79(d,1H,ArH),3.77(s,6H,- OCH3 ),3.62(s,3H,-OCH3 ),2.46(s,3H,-CH3 ),1.95(m,1H,-CH-),0.92(brs,4H,-CH 2CH2 -).MS (FAB)(M++ 1=441).
Embodiment 42.2- (to morpholinyl anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with to morpholinyl phenylamine, cyclopropyl formyl chloride replaces chloroacetic chloride, the operation of reference implementation example 18 Process obtains 2- (to morpholinyl anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine.1H-NMR (300MHz,DMSO-d6):δ(ppm):12.50(s,1H,-NH-),8.84(s,1H,-NH-),8.10-8.08(d,1H,ArH), 7.52-7.49(d,2H,ArH),6.91-6.88(d,2H,ArH),6.80(s,1H,ArH),6.74-6.72(d,1H,ArH), 3.74(brs,4H,-CH 2CH2 -),3.03(brs,4H,-CH 2CH2 -),2.43(s,3H,-CH3 ),1.94(m,1H,-CH-), 0.91(brs,4H,-CH 2CH2 -).MS(FAB)(M++ 1=436).
Embodiment 43.2- (adjacent fluoroanilino) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with adjacent fluoroaniline, the operating process of reference implementation example 18 obtains 2- (adjacent fluoroanilino) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,DMSO-d6):δ(ppm):12.21(s,1H,- NH-),8.80(s,1H,-NH-),8.26-8.21(m,1H,ArH),8.14-8.12(d,1H,ArH),7.23-7.17(m,1H, ArH),7.17-7.09(m,2H,ArH),6.99-6.93(m,1H,ArH),6.87-6.81(m,1H,ArH),2.33(s,3H,- CH3 ),2.15(s,3H,-CH3 ).MS(FAB)(M++ 1=343).
Embodiment 44.2- (2,4- dichloroanilino) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with 2,4- dichloroaniline, the operating process of reference implementation example 18 obtains 2- (2,4- dichloro-benzenes Amido) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,CDCl3):δ(ppm):9.95(s, 1H,-NH-),8.27-8.25(d,1H,ArH),8.15-8.12(d,1H,ArH),7.41(d,1H,ArH),7.22(d,1H, ArH),6.98(s,1H,ArH),6.92-6.90(d,1H,ArH),6.82(s,1H,-NH-),2.46(s,3H,-CH3 ),2.28 (s,3H,-CH3 ).MS(FAB)(M++ 1=394).
Embodiment 45.2- (p-dimethylamino aniline base) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with p-dimethylamino aniline, the operating process of reference implementation example 18 obtains 2- (to diformazan ammonia Base anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,CDCl3):δ(ppm):10.54 (s,1H,-NH-),8.13-8.11(d,1H,ArH),7.18-7.16(m,3H,ArH,-NH-),6.76-6.73(d,2H,ArH), 6.70-6.68(d,1H,ArH),6.65(s,1H,ArH),2.95(s,6H,-CH3 ),2.36(s,3H,-CH3 ),2.26(s,3H,- CH3 ).MS(FAB)(M++ 1=368).
Embodiment 46.2- (3,4,5- trimethoxy-benzene amido) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
With 3,4,5- trimethoxy-anilines replace 3- nitroaniline, the operating process of reference implementation example 18, obtain 2- (3,4, 5- trimethoxy-benzene amido) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,CDCl3):δ (ppm):10.69(s,1H,-NH-),8.19-8.17(d,1H,ArH),7.44(s,1H,-NH-),6.88(s,1H,ArH), 6.82-6.80(d,1H,ArH),6.60(s,2H,ArH),2.43(s,3H,-CH3 ),2.28(s,3H,-CH3 ).MS(FAB)(M++ 1=415).
Embodiment 47.2- (to cyclopropyl formamido group anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with to cyclopropyl formamido group aniline, the operating process of reference implementation example 18 obtains 2- (to ring Third formamido group anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,DMSO-d6):δ (ppm):12.11(s,1H,-NH-),10.04(s,1H,-NH-),9.02(s,1H,-NH-),8.13-8.11(d,1H,ArH), 7.60-7.57(d,2H,ArH),7.50-7.47(d,2H,ArH),6.87(s,1H,ArH),6.80-6.78(d,1H,ArH), 2.43(s,3H,-CH3 ),2.14(s,3H,-CH3 ),1.75(brs,1H,-CH-),0.77(brs,4H,-CH 2CH2 -).MS (FAB)(M++ 1=408).
Embodiment 48.2- (to morpholinyl anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with to morpholinyl phenylamine, the operating process of reference implementation example 18 obtains 2- (to morpholinyl benzene Amido) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,CDCl3):δ(ppm):10.85(s, 1H,-NH-),8.15-8.13(d,1H,ArH),7.37(s,1H,-NH-),7.25-7.22(d,2H,ArH),6.94-6.91(d, 2H,ArH),6.74-6.72(d,2H,ArH),3.89-3.86(t,4H,-CH2 CH2 -),3.17-3.14(t,4H,-CH2 CH2 -), 2.37(s,3H,-CH3 ),2.28(s,3H,-CH3 ).MS(FAB)(M++ 1=410).
Embodiment 49.2- (cyclopropyl formamido group anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) Pyridine
By the bromo- 4- of 2- (2- amino -4- methylthiazol -5- base) pyridine (270mg, 1mmol) (542mg, 2.0mmol) positive fourth In alcohol (5ml), m-phenylene diamine (MPD) (4.0mmol) and concentrated hydrochloric acid (0.33ml, 4.0mmol), 160 DEG C of microwave reactions are then added 15min is cooled to room temperature, and reaction solution is poured into saturated aqueous sodium carbonate, and ethyl acetate extraction takes organic layer with anhydrous sulphur Sour sodium is dry, concentration, and column chromatographs to obtain phenalgin amido -4- (2- amino -4- methylthiazol -5- base) pyridine between 2-.1H NMR (300MHz,DMSO-d6):δ8.69(s,1H,-NH-),8.04-8.02(d,1H,ArH),7.19(s,2H,-NH 2),6.94(s, 1H,ArH),6.90-6.85(t,1H,ArH),6.76(s,2H,ArH),6.64-6.62(d,1H,ArH),6.14-6.11(d, 1H,ArH),4.99(br s,2H,-NH 2),2.29(s,3H,-CH 3).MS(FAB)(M++ 1=298)
Phenalgin amido -4- between 2- (2- amino -4- methylthiazol -5- base) pyridine (1equiv) is dissolved in a small amount of DMA, is added Enter DMAP (3equiv), be added dropwise cyclopropyl formyl chloride (2.2equiv), 70 DEG C of reactions are warming up to after being added dropwise to complete, when cooling Saturated sodium bicarbonate aqueous solution is added into reaction solution for room temperature, there is solid precipitation, filtering, and column chromatography both obtains product 2- (cyclopropyl Formamido group anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,DMSO- d6):δ(ppm):12.48(s,1H,-NH-),10.10(s,1H,-NH-),9.11(s,1H,-NH-),8.16-8.14(d,1H, ArH),7.92(s,1H,ArH),7.42(brs,1H,ArH),7.14(brs,2H,ArH),6.93(s,1H,ArH),6.81- 6.79(d,1H,ArH),2.44(s,3H,-CH3 ),1.93(brs,1H,-CH-),1.81(brs,1H,-CH-),0.91(brs, 4H,-CH 2CH2 -),0.78(brs,4H,-CH 2CH2 -).MS(FAB)(M++ 1=434).
Embodiment 50.2- (to cyclopropyl formamido group anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) Pyridine
3- nitroaniline is replaced with to cyclopropyl formamido group aniline, Cyclopropyl carbonyl chloride replaces chloroacetic chloride, reference implementation example 18 operating process obtains 2- (to cyclopropyl formamido group anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) Pyridine.1H-NMR(300MHz,DMSO-d6):δ(ppm):12.51(s,1H,-NH-),10.03(s,1H,-NH-),9.02(s, 1H,-NH-),8.14-8.12(d,1H,ArH),7.59-7.56(d,2H,ArH),7.50-7.47(d,2H,ArH),6.86(s, 1H,ArH),6.79-6.77(d,1H,ArH),2.45(s,3H,-CH3 ),1.94(m,1H,-CH-),1.75(m,1H,-CH-), 0.92(brs,4H,-CH 2CH2-),0.77-0.75(m,4H,-CH 2CH2 -).MS(FAB)(M++ 1=434).
Embodiment 51.2- (cyclopropyl formamido group anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
By the bromo- 4- of 2- (2- amino -4- methylthiazol -5- base) pyridine (270mg, 1mmol) (542mg, 2.0mmol) positive fourth In alcohol (5ml), m-phenylene diamine (MPD) (4.0mmol) and concentrated hydrochloric acid (0.33ml, 4.0mmol), 160 DEG C of microwave reactions are then added 15min is cooled to room temperature, and reaction solution is poured into saturated aqueous sodium carbonate, and ethyl acetate extraction takes organic layer with anhydrous sulphur Sour sodium is dry, concentration, and column chromatographs to obtain phenalgin amido -4- (2- amino -4- methylthiazol -5- base) pyridine between 2-.1H NMR (300MHz,DMSO-d6):δ8.69(s,1H,-NH-),8.04-8.02(d,1H,ArH),7.19(s,2H,-NH 2),6.94(s, 1H,ArH),6.90-6.85(t,1H,ArH),6.76(s,2H,ArH),6.64-6.62(d,1H,ArH),6.14-6.11(d, 1H,ArH),4.99(br s,2H,-NH 2),2.29(s,3H,-CH 3).MS(FAB)(M++ 1=298)
Phenalgin amido -4- between 2- (2- amino -4- methylthiazol -5- base) pyridine (1equiv) is dissolved in a small amount of DMA, is added Enter DMAP (3equiv), be added dropwise cyclopropyl formyl chloride (1.1equiv), 70 DEG C of reactions are warming up to after being added dropwise to complete, when cooling Saturated sodium bicarbonate aqueous solution is added into reaction solution for room temperature, there is solid precipitation, filtering, and column chromatography both obtains 2- (cyclopropyl formyl Aminobenzene amido) -4- (2- amino -4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,DMSO-d6):δ(ppm): 10.09(s,1H,-NH),9.03(s,1H,-NH),8.08(d,1H,ArH),7.92(s,1H,ArH),7.40(m,1H,ArH), 7.22~7.13 (m, 4H, ArH,-NH2 ),6.80(s,1H,ArH),6.69(d,1H,ArH),2.30(s,3H,-CH3 ),1.81 (m,1H,-CH2CHCH2-),0.79-0.77(m,4H,-CH2 CHCH2 -)；m/z366.1[M+H]+.
2- (cyclopropyl formamido group anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine (1equiv) is dissolved in It in a small amount of DMA, is added DMAP (3equiv), is added dropwise chloroacetic chloride (1.1equiv), 70 DEG C are warming up to after being added dropwise and is reacted to complete Entirely, room temperature when cooling, saturated sodium bicarbonate aqueous solution is added into reaction solution, there is solid precipitation, and filtering both obtains product 2- (ring Third formamido group anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine.1H-NMR(300MHz,DMSO-d6):δ (ppm):12.23(s,1H,-NH-),10.11(s,1H,-NH-),9.12(s,1H,-NH-),8.17(s,1H,ArH),7.93 (s,1H,ArH),7.43(s,1H,ArH),7.15(s,2H,ArH),6.95(s,1H,ArH),6.84(s,1H,ArH),2.45 (s,3H,-CH3 ),2.16(s,3H,-CH3 ),1.82(brs,1H,-CH-),0.79(brs,4H,-CH 2CH2 -).MS(FAB)(M++ 1=408).
Embodiment 52.2- (m-acetamidoaniline base) -4- (acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with m-acetamidoaniline, the operating process of reference implementation example 18 obtains 2- (acetyl ammonia Base anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine.1H NMR(300MHz,DMSO-d6):δ12.23(s, 1H,-NH-),9.86(s,1H,-NH-),9.14(s,1H,-NH-),8.16-8.15(d,1H,ArH),7.93(s,1H,ArH), 7.48-7.46(d,1H,ArH),7.19-7.09(m,2H,ArH),6.96(s,1H,ArH),6.84-6.83(d,1H,ArH), 2.45(s,3H,-CH 3),2.16(s,3H,-CH3 ),2.04(s,3H,-CH3 ).MS(FAB)(M++ 1=382).
Embodiment 53.2- (propionamido anilino-) -4- (2- propionamido -4- methylthiazol -5- base) pyridine
By the bromo- 4- of 2- (2- amino -4- methylthiazol -5- base) pyridine (270mg, 1mmol) (542mg, 2.0mmol) positive fourth In alcohol (5ml), m-phenylene diamine (MPD) (4.0mmol) and concentrated hydrochloric acid (0.33ml, 4.0mmol), 160 DEG C of microwave reactions are then added 15min is cooled to room temperature, and reaction solution is poured into saturated aqueous sodium carbonate, and ethyl acetate extraction takes organic layer with anhydrous sulphur Sour sodium is dry, concentration, and column chromatographs to obtain phenalgin amido -4- (2- amino -4- methylthiazol -5- base) pyridine between 2-.1H NMR (300MHz,DMSO-d6):δ8.69(s,1H,-NH-),8.04-8.02(d,1H,ArH),7.19(s,2H,-NH 2),6.94(s, 1H,ArH),6.90-6.85(t,1H,ArH),6.76(s,2H,ArH),6.64-6.62(d,1H,ArH),6.14-6.11(d, 1H,ArH),4.99(br s,2H,-NH 2),2.29(s,3H,-CH 3).MS(FAB)(M++ 1=298)
Phenalgin amido -4- between 2- (2- amino -4- methylthiazol -5- base) pyridine (1equiv) is dissolved in a small amount of DMA, is added Enter DMAP (3equiv), be added dropwise propionyl chloride (2.2equiv), 70 DEG C of reactions are warming up to after being added dropwise to complete, room when cooling Saturated sodium bicarbonate aqueous solution is added into reaction solution for temperature, there is solid precipitation, filtering, and column chromatography both obtains product 2- (propionyl ammonia Base anilino-) -4- (2- propionamido -4- methylthiazol -5- base) pyridine.1H NMR(300MHz,DMSO-d6):δ12.18(s, 1H,-NH-),9.78(s,1H,-NH-),9.12(s,1H,-NH-),8.16-8.14(d,1H,ArH),7.92(s,1H,ArH), 7.44-7.42(d,1H,ArH),7.17-7.12(m,2H,ArH),6.94(s,1H,ArH),6.82-6.80(d,1H,ArH), 2.45-2.40(m,5H,-CH 2,-CH 3),2.34-2.27(q,2H,-CH2 ),1.11-1.04(m,6H,-CH3 ).MS(FAB)(M++ 1=410).
Embodiment 54.2- (3- isopropyl formamido group anilino-) -4- (2- isopropyl formamido group -4- methylthiazol -5- base) Pyridine
3- nitroaniline is replaced with 3- isopropyl formamido group aniline, isopropyl formyl chloride replaces chloroacetic chloride, reference implementation example 18 Operating process, obtain 2- (3- isopropyl formamido group anilino-) -4- (2- isopropyl formamido group -4- methylthiazol -5- base) pyrrole Pyridine.1H NMR(300MHz,DMSO-d6):δ12.19(s,1H,-NH-),9.75(s,1H,-NH-),9.12(s,1H,-NH-), 8.18-8.16(d,1H,ArH),7.95(s,1H,ArH),7.44-7.43(d,1H,ArH),7.17-7.15(d,2H,ArH), 6.95(s,1H,ArH),6.83-6.81(d,1H,ArH),2.77-2.69(p,1H,-CH-),2.64-2.59(p,1H,-CH-), 2.45(s,3H,-CH 3),1.14-1.09(t,12H,-CH3 ).MS(FAB)(M++ 1=438).
Embodiment 55.2- (the tertiary fourth formamido group anilino- of 3-) -4- (the tertiary fourth formamido group -4- methylthiazol -5- base of 2-) Pyridine
3- nitroaniline is replaced with the tertiary fourth formamido group aniline of 3-, tertiary fourth formyl chloride replaces chloroacetic chloride, reference implementation example 18 Operating process, obtain the tertiary fourth formamido group anilino- of 2-3-) -4- (the tertiary fourth formamido group -4- methylthiazol -5- base of 2-) pyrrole Pyridine.1H NMR(300MHz,DMSO-d6):δ11.95(s,1H,-NH-),9.13(s,1H,-NH-),9.10(s,1H,-NH-), 8.18-8.16(d,1H,ArH),7.92(s,1H,ArH),7.51-7.49(d,1H,ArH),7.17-7.13(m,2H,ArH), 6.95(s,1H,ArH),6.83-6.81(d,1H,ArH),2.77-2.69(p,1H,-CH-),2.64-2.59(p,1H,-CH-), 2.46(s,3H,-CH 3),1.23(br s,18H,-CH3 ).MS(FAB)(M++ 1=466).
Embodiment 56.2- (3- (3- methyl butene -2- acylamino-) anilino-) -4- (2- (3- methyl butene -2- acyl ammonia Base) -4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with 3- (3- methyl butene -2- acylamino-) aniline, 3- methyl butene -2- acyl chlorides replaces acetyl Chlorine, the operating process of reference implementation example 18 obtain 2- (3- (3- methyl butene -2- acylamino-) anilino-) -4- (2- (3- methyl Butene-2-acylamino-)-4- methylthiazol-5- base) pyridine.1H NMR(400MHz,DMSO-d6):δ12.14(s,1H,-NH-), 9.75(s,1H,-NH-),9.12(s,1H,-NH-),8.16-8.15(d,1H,ArH),7.95(s,1H,ArH),7.51-7.49 (d,1H,ArH),7.14(s,2H,ArH),6.97(s,1H,ArH),6.84(s,1H,ArH), 5.98-5.91 (d, 2H ,=CH), 2.46(s,3H,-CH 3),2.21(s,3H,-CH3 ),2.16(s,3H,-CH3 ),1.91(s,3H,-CH3 ),1.86(s,3H,- CH3 ).MS(FAB)(M++ 1=462).
Embodiment 57.2- (3- ring fourth formamido group anilino-) -4- (2- ring fourth formamido group -4- methylthiazol -5- base) Pyridine
3- nitroaniline is replaced with 3- ring fourth formamido group aniline, ring fourth formyl chloride replaces chloroacetic chloride, reference implementation example 18 Operating process, obtain 2- (3- ring fourth formamido group anilino-) -4- (2- ring fourth formamido group -4- methylthiazol -5- base) pyrrole Pyridine.1H NMR(300MHz,DMSO-d6):δ12.10(s,1H,-NH-),9.65(s,1H,-NH-),9.13(s,1H,-NH-), 8.18-8.15(m,1H,ArH),7.95(s,1H,ArH),7.44-7.43(d,1H,ArH),7.15(s,2H,ArH),6.95(s, 1H,ArH),6.83-6.82(d,1H,ArH),3.39-3.32(m,1H,-CH-),3.28-3.22(m,1H,-CH-),2.44(br s,3H,-CH 3),2.32-2.12(m,8H,-CH2 -),2.00-1.81(m,4H,-CH2 -).MS(FAB)(M++ 1=462).
Embodiment 58.2- (3- cyclopropyl formamido group anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with 3- cyclopropyl formamido group aniline, the operating process of reference implementation example 18 obtains 2- (3- ring Third formamido group anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine.1H NMR(300MHz,DMSO-d6):δ 12.23(s,1H,-NH-),10.11(s,1H,-NH-),9.13(s,1H,-NH-),8.17-8.15(d,1H,ArH),7.94(s, 1H,ArH),7.43(s,1H,ArH),7.15(s,2H,ArH),6.95(s,1H,ArH),6.84-6.82(d,1H,ArH),2.45 (s,3H,-CH 3),2.16(s,3H,-CH 3),1.82(s,1H,-CH-),0.79(br s,4H,-CH 2CH2 -).MS(FAB)(M++1 =408).
Embodiment 59.2- (3- cyclopropyl formamido group anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) Pyridine
3- nitroaniline is replaced with 3- cyclopropyl formamido group aniline, cyclopropyl formyl chloride replaces chloroacetic chloride, reference implementation example 18 Operating process, obtain 2- (3- cyclopropyl formamido group anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyrrole Pyridine.1H NMR(300MHz,DMSO-d6):δ12.51(s,1H,-NH-),10.11(s,1H,-NH-),9.12(s,1H,-NH-), 8.15(s,1H,ArH),7.93(s,1H,ArH),7.42(s,1H,ArH),7.14(s,2H,ArH),6.94(s,1H,ArH), 6.81(s,1H,ArH),2.45(s,3H,-CH 3),1.94(s,1H,-CH-),1.81(s,1H,-CH-),1.82(m,1H,- CH-),0.92(br s,4H,-CH 2CH2 -),0.79(br s,4H,-CH 2CH2 -).MS(FAB)(M++ 1=434).
Embodiment 60.2- (3- cyclopropyl formamido group anilino-) -4- (2- isobutyl formamido group -4- methylthiazol -5- base) Pyridine
3- nitroaniline is replaced with 3- cyclopropyl formamido group aniline, isobutyl formyl chloride replaces chloroacetic chloride, reference implementation example 18 Operating process, obtain 2- (3- cyclopropyl formamido group anilino-) -4- (2- isobutyl formamido group -4- methylthiazol -5- base) pyrrole Pyridine.1H NMR(300MHz,DMSO-d6):δ12.21(s,1H,-NH-),10.11(s,1H,-NH-),9.12(s,1H,-NH-), 8.17-8.15(d,1H,ArH),7.93(s,1H,ArH),7.42(s,1H,ArH),7.14(s,2H,ArH),6.95(s,1H, ArH),6.84-6.82(d,1H,ArH),2.45(s,3H,-CH 3),2.34-2.31(d,2H,-CH2 -),2.11-2.07(m, 1H,-CH-),1.82(m,1H,-CH-),0.93-0.91(d,6H,-CH 3),0.79(br s,4H,-CH 2CH2 -).MS(FAB)(M++ 1=450).
Embodiment 61.2- (3- cyclopropyl formamido group anilino-) -4- (2- (3- methyl butene -2- acylamino-) -4- methyl thiazolium Azoles -5- base) pyridine
3- nitroaniline is replaced with 3- cyclopropyl formamido group aniline, 3- methyl butene -2- acyl chlorides replaces chloroacetic chloride, with reference to reality The operating process for applying example 18 obtains 2- (3- cyclopropyl formamido group anilino-) -4- (2- (3- methyl butene -2- acylamino-) -4- first Base thiazole -5- base) pyridine.1H NMR(300MHz,DMSO-d6):δ12.21(s,1H,-NH-),10.11(s,1H,-NH-), 9.12(s,1H,-NH-),8.17-8.15(d,1H,ArH),7.93(s,1H,ArH),7.42(br s,1H,ArH),7.16- 7.14(m,2H,ArH),6.97(s,1H,ArH),6.84-6.83(d,1H,ArH), 5.98 (s, 1H ,=CH),2.45(s,3H,- CH 3),2.21(s,3H,-CH3 ),1.91(s,3H,-CH 3),1.82(m,1H,-CH-),0.79(m,4H,-CH 2CH2 -).MS (FAB)(M++ 1=448).
Embodiment 62.2- (3- cyclopropyl formamido group anilino-) -4- (2- cyclopenta formamido group -4- methylthiazol -5- Base) pyridine
3- nitroaniline is replaced with 3- cyclopropyl formamido group aniline, cyclopenta formyl chloride replaces chloroacetic chloride, reference implementation example 18 operating process obtains 2- (3- cyclopropyl formamido group anilino-) -4- (2- cyclopenta formamido group -4- methylthiazol -5- Base) pyridine.1H NMR(400MHz,DMSO-d6):δ12.21(s,1H,-NH-),10.11(s,1H,-NH-),9.12(s,1H,- NH-),8.17(s,1H,ArH),7.93(s,1H,ArH),7.43(s,1H,ArH),7.15(s,2H,ArH),6.95(s,1H, ArH),6.82(s,1H,ArH),2.92(m,1H,-CH-),2.45(s,3H,-CH3 ),1.87-1.57(m,9H,-CH2 -,- CH-),0.79(br s,4H,-CH 2CH2 -).MS(FAB)(M++ 1=462).
(2- is to toluyl amino -4- methylthiazol -5- by embodiment 63.2- (3- cyclopropyl formamido group anilino-) -4- Base) pyridine
3- nitroaniline is replaced with 3- cyclopropyl formamido group aniline, Butyltriphenylphosphonium chloride replaces chloroacetic chloride, reference implementation example 18 operating process, obtaining 2- (3- cyclopropyl formamido group anilino-) -4-, (2- is to toluyl amino -4- methylthiazol -5- Base) pyridine.1H NMR(400MHz,DMSO-d6):δ12.71(s,1H,-NH-),10.12(s,1H,-NH-),9.15(s,1H,- NH-),8.19-8.18(d,1H,ArH),8.04-8.02(d,2H,ArH),7.95(s,1H,ArH),7.45-7.44(d,1H, ArH),7.37-7.35(d,2H,ArH),7.16(s,2H,ArH),7.00(s,1H,ArH),6.88-6.87(d,1H,ArH), 2.51(s,3H,-CH 3),2.40(s,3H,-CH 3),1.83(br s,1H,-CH-),0.79-0.77(m,4H,-CH 2CH2 -).MS (FAB)(M++ 1=484).
Embodiment 64.2- (3- cyclopropyl formamido group anilino-) -4- (2- phenylacetylamino -4- methylthiazol -5- base) pyrrole Pyridine
3- nitroaniline is replaced with 3- cyclopropyl formamido group aniline, phenyllacetyl chloride replaces chloroacetic chloride, reference implementation example 18 Operating process obtains 2- (3- cyclopropyl formamido group anilino-) -4- (2- phenylacetylamino -4- methylthiazol -5- base) pyridine.1H NMR(400MHz,DMSO-d6):δ12.51(s,1H,-NH-),10.11(s,1H,-NH-),9.13(s,1H,-NH-),8.15 (s,1H,ArH),7.93(s,1H,ArH),7.42-7.14(m,8H,ArH),6.94(s,1H,ArH),6.80(s,1H,ArH), 3.78(s,2H,-CH2 -),2.45(s,3H,-CH3 ),1.81(br s,1H,-CH-),0.79(br s,4H,-CH 2CH2 -).MS (FAB)(M++ 1=484).
Embodiment 65.2- (3- nitrobenzene amido) -4- (2- trifluoroacetyl amido -4- methylthiazol -5- base) pyridine
Chloroacetic chloride is replaced with trifluoro-acetyl chloride, the operating process of reference implementation example 18 obtains 2- (3- nitrobenzene amido) -4- (2- trifluoroacetyl amido -4- methylthiazol -5- base) pyridine.1H-NMR(400MHz,DMSO-d6):δ(ppm):9.77(s, 1H,-NH),8.85(s,1H,ArH),8.32-8.31(d,1H,ArH),7.99-7.97(d,1H,ArH),7.75-7.73(d, 1H,ArH),7.58-7.54(t,1H,ArH),7.00-6.99(m,2H,ArH),2.47(s,3H,-CH3 ).MS(FAB)(M++ 1= 424)。
Embodiment 66.2- (3- nitrobenzene amido) -4- (2- cyclopropyl formamido -4- methylthiazol -5- base) pyridine
Chloroacetic chloride is replaced with Cyclopropyl carbonyl chloride, the operating process of reference implementation example 18 obtains 2- (3- nitrobenzene amido)- 4- (2- cyclopropyl formamido -4- methylthiazol -5- base) pyridine.1H-NMR(400MHz,DMSO-d6):δ(ppm):9.65(s, 1H,-NH),8.85(s,1H,ArH),8.20-8.19(d,1H,ArH),7.99-7.97(d,1H,ArH),7.72-7.70(d, 1H,ArH),7.55-7.51(t,1H,ArH),6.93(s,1H,ArH),6.90-6.89(d,1H,ArH),2.43(s,3H,- CH3 ),1.78(br s,1H,-CH2CHCH2-),0.82-0.77(m,4H,-CH2 CHCH2 -).MS(FAB)(M++ 1=396).
Embodiment 67.2- (3- nitrobenzene amido) -4- (2- isopropyl formamido -4- methylthiazol -5- base) pyridine
Chloroacetic chloride is replaced with isopropyl formyl chloride, the operating process of reference implementation example 18 obtains 2- (3- nitrobenzene amido)- 4- (2- isopropyl formamido -4- methylthiazol -5- base) pyridine.1H-NMR(400MHz,DMSO-d6):δ(ppm):12.23(s, 1H,-NH),9.71(s,1H,-NH),8.85(s,1H,ArH),8.28-8.27(d,1H,ArH),8.00-7.98(d,1H, ArH),7.74-7.72(d,1H,ArH),7.57-7.53(t,1H,ArH),6.98(s,1H,ArH),6.96-6.95(d,1H, ArH),2.78-2.73(m,1H,-CH-),2.47(s,3H,-CH3 ),1.14(br s,6H,CH3 CHCH3 ).MS(FAB)(M++1 =398).
Embodiment 68.2- (3- aminobenzene amido) -4- (2- cyclopropyl formamido -4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with 3- amino aniline, Cyclopropyl carbonyl chloride replaces chloroacetic chloride, the operation of reference implementation example 18 Process obtains 2- (3- aminobenzene amido) -4- (2- cyclopropyl formamido -4- methylthiazol -5- base) pyridine.
1H-NMR(400MHz,DMSO-d6):δ(ppm):12.50(s,1H,-NH),9.79(s,1H,-NH),8.85(s, 1H,ArH),8.13-8.12(d,1H,ArH),6.95(s,1H,ArH),6.91-6.87(m,2H,ArH),6.78-6.75(m, 2H,ArH),6.93(s,1H,ArH),6.16-6.14(d,1H,ArH),4.95(s,2H,-NH2 ),2.44(s,3H,-CH3 ), 1.95-1.92(m,1H,-CH2CHCH2-),0.93-0.89(m,4H,-CH2 CHCH2 -).MS(FAB)(M++ 1=366).
Embodiment 69.2- (3- aminobenzene amido) -4- (2- isopropyl formamido -4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with 3- amino aniline, isopropyl formyl chloride replaces chloroacetic chloride, the operation of reference implementation example 18 Process obtains 2- (3- aminobenzene amido) -4- (2- isopropyl formamido -4- methylthiazol -5- base) pyridine.
1H-NMR(400MHz,DMSO-d6):δ(ppm):12.18(s,1H,-NH),8.79(s,1H,-NH),8.13- 8.12(d,1H,ArH),6.95(s,1H,ArH),6.92-6.88(m,2H,ArH),6.79-6.77(m,2H,ArH),6.16- 6.14(d,1H,ArH),4.96(br s,2H,-NH2),2.75-2.72(m,1H,-CH-),2.44(s,3H,-CH3 ),1.14- 1.12(m,6H,CH3 CHCH3 ).MS(FAB)(M++ 1=368).
Embodiment 70.2- (3- trifluoroacetamido anilino-) -4- (2- trifluoroacetamido -4- methylthiazol -5- base) Pyridine
3- nitroaniline is replaced with 3- trifluoroacetamido aniline, trifluoro-acetyl chloride replaces chloroacetic chloride, reference implementation example 18 Operating process, obtain 2- (3- trifluoroacetamido anilino-) -4- (2- trifluoroacetamido -4- methylthiazol -5- base) pyrrole Pyridine.1H NMR(400MHz,DMSO-d6)δ11.26(s,1H,-NH-),9.52(s,1H,-NH-),8.26-8.24(d,1H, ArH),8.12(s,1H,ArH),7.62-7.60(d,1H,ArH),7.33-7.22(t,1H,ArH),7.24-7.22(d,1H, ArH),7.05(s,1H,ArH),6.93-6.92(d,1H,ArH),6.14-6.11(d,1H,ArH),2.29(s,3H,-CH3)； ESI-MS:[M+H]+490。
Embodiment 71.2- (3- trifluoroacetamido anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) Pyridine
3- nitroaniline is replaced with 3- trifluoroacetamido aniline, Cyclopropyl carbonyl chloride replaces chloroacetic chloride, reference implementation example 18 operating process obtains 2- (3- trifluoroacetamido anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) Pyridine.1H NMR(400MHz,DMSO-d6)δ12.53(s,1H,-NH-),11.21(s,1H,-NH-),9.28(s,1H,-NH-), 8.19-8.08(m,2H,ArH),8.09(s,1H,ArH),7.59(br s,1H,ArH),7.28(br s,1H,ArH),7.19 (br s,1H,ArH),6.95(s,1H,ArH),6.85(br s,1H,ArH),2.46(s,3H,-CH3),1.96(br s,1H,- CH-),0.92(s,4H,-CH2-)；ESI-MS:[M+H]+462。
Embodiment 72.2- (3- trifluoroacetamido anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
3- nitroaniline is replaced with 3- trifluoroacetamido aniline, the operating process of reference implementation example 18 obtains 2- (3- tri- Acetyl fluoride aminobenzene amido) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine.1H NMR(400MHz,DMSO-d6)δ 12.23(s,1H,-NH-),11.20(s,1H,-NH-),9.28(s,1H,-NH-),8.19-8.18(d,1H,ArH),8.09(s, 1H,ArH),7.60-7.58(d,1H,ArH),7.30-7.26(t,1H,ArH),7.19-7.17(d,1H,ArH),6.97(s, 1H,ArH),6.87-6.86(d,1H,ArH),2.46(s,3H,-CH3),2.16(s,3H,-CH3)；ESI-MS:[M+H]+436。
Embodiment 73.2- (3- ring fourth formamido group anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) Pyridine
By the bromo- 4- of 2- (2- amino -4- methylthiazol -5- base) pyridine (270mg, 1mmol) (542mg, 2.0mmol) positive fourth In alcohol (5ml), meta nitro aniline (4.0mmol) and concentrated hydrochloric acid (0.33ml, 4.0mmol), 160 DEG C of microwave reactions are then added 15min is cooled to room temperature, and reaction solution is poured into saturated aqueous sodium carbonate, and ethyl acetate extraction takes organic layer with anhydrous sulphur Sour sodium is dry, and concentration, column chromatographs to obtain 2- m-nitro amido -4- (2- amino -4- methylthiazol -5- base) pyridine.1H NMR (300MHz,DMSO-d6):δ9.65(s,1H,-NH-),8.83(s,1H,ArH),8.17-8.15(d,1H,ArH),7.97- 7.94(d,1H,ArH),7.71-7.68(d,1H,ArH),7.54-7.48(t,1H,ArH),7.27(s,2H,-NH 2),6.82- 6.78(m,2H,ArH),2.31(s,3H,-CH 3).ESI-MS:[M+H]+328
2- m-nitro amido -4- (2- amino -4- methylthiazol -5- base) pyridine (1equiv) is dissolved in a small amount of DMA, It is added DMAP (3equiv), is added dropwise cyclopropyl formyl chloride (1.1equiv), 70 DEG C of reactions are warming up to after being added dropwise to complete, cooling When room temperature, saturated sodium bicarbonate aqueous solution is added into reaction solution, there is a solid precipitation, filtering both product 2- meta nitro aniline Base -4- (2- cyclopropyl formamido -4- methylthiazol -5- base) pyridine.1H-NMR(400MHz,DMSO-d6):δ(ppm):9.65 (s,1H,-NH),8.85(s,1H,ArH),8.20-8.19(d,1H,ArH),7.99-7.97(d,1H,ArH),7.72-7.70 (d,1H,ArH),7.55-7.51(t,1H,ArH),6.93(s,1H,ArH),6.90-6.89(d,1H,ArH),2.43(s,3H,- CH3 ),1.78(br s,1H,-CH2CHCH2-),0.82-0.77(m,4H,-CH2 CHCH2 -).ESI-MS:[M+H]+396
Iron powder (5.0equiv) is placed in 2ml2N HCl solution and stirs 5min, 2- m-nitro amido -4- is then added The methanol solution of (2- cyclopropyl formamido -4- methylthiazol -5- base) pyridine (1.0equiv), temperature rising reflux to fully reacting, It is cooled to room temperature, saturated sodium bicarbonate aqueous solution neutralization reaction liquid is added, ethyl acetate extracts 3 times, merges organic layer, and drying is dense Contract to obtain 2- m-aminophenyl amido -4- (2- cyclopropyl formamido -4- methylthiazol -5- base) pyridine.1H-NMR(400MHz,DMSO- d6):δ(ppm):12.50(s,1H,-NH),9.79(s,1H,-NH),8.85(s,1H,ArH),8.13-8.12(d,1H,ArH), 6.95(s,1H,ArH),6.91-6.87(m,2H,ArH),6.78-6.75(m,2H,ArH),6.93(s,1H,ArH),6.16- 6.14(d,1H,ArH),4.95(s,2H,-NH2 ),2.44(s,3H,-CH3 ),1.95-1.92(m,1H,-CH2CHCH2-), 0.93-0.89(m,4H,-CH2 CHCH2 -).ESI-MS:[M+H]+366
2- m-aminophenyl amido -4- (2- cyclopropyl formamido -4- methylthiazol -5- base) pyridine (1.0equiv) is dissolved in It in a small amount of DMA, is added DMAP (3.0equiv), is added dropwise ring fourth formyl chloride (1.1equiv), 70 DEG C is warming up to after being added dropwise, instead It should be cooled to room temperature, saturated sodium bicarbonate aqueous solution is added into reaction solution, there is solid precipitation to complete, filter, column chromatographs 2- (3- ring fourth formamido group anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine.1H NMR (400MHz,DMSO-d6)δ12.51(s,1H,-NH-),9.64(s,1H,-NH-),9.11(s,1H,-NH-),8.16-8.15 (d,1H,ArH),7.94(s,1H,ArH),7.43-7.42(d,1H,ArH),7.14(br s,2H,ArH),6.94(s,1H, ArH),6.82-6.81(d,1H,ArH),3.26-3.22(m,1H,-CH-),2.45(s,3H,-CH3),2.25-2.18(m, 2H,-CH2-),2.11-2.08(m,2H,-CH2-),1.96-1.90(m,2H,-CH2-),1.82-1.79(m,1H,-CH-), 0.94-0.92(br s,4H,-CH2-)；ESI-MS:[M+H]+448。
Embodiment 74.2- (3- trifluoroacetamido anilino-) -4- (2- ring fourth formamido group -4- methylthiazol -5- base) Pyridine
3- nitroaniline is replaced with 3- trifluoroacetamido aniline, cyclobutylmethyl acyl chlorides replaces chloroacetic chloride, reference implementation example 18 operating process obtains 2- (3- trifluoroacetamido anilino-) -4- (2- ring fourth formamido group -4- methylthiazol -5- base) Pyridine.1H NMR(400MHz,DMSO-d6)δ12.11(s,1H,-NH-),11.20(s,1H,-NH-),9.28(s,1H,-NH-), 8.19-8.18(d,1H,ArH),8.09(s,1H,ArH),7.60-7.58(d,1H,ArH),7.30-7.26(t,1H,ArH), 7.19-7.17(d,1H,ArH),6.96(s,1H,ArH),6.87-6.86(d,1H,ArH),3.38-3.34(m,1H,-CH-), 2.45(s,3H,-CH3),2.26-2.14(m,4H,-CH2-),1.96-1.82(m,2H,-CH2-)；ESI-MS:[M+H]+476。
Embodiment 75.2- (3- ring fourth formamido group anilino-) -4- (2- isopropyl formamido group -4- methylthiazol -5- base) Pyridine
3- nitroaniline is replaced with 3- ring fourth formamido group aniline, isopropyl formyl chloride replaces chloroacetic chloride, reference implementation example 18 operating process obtains 2- (3- ring fourth formamido group anilino-) -4- (2- isopropyl formamido group -4- methylthiazol -5- base) Pyridine.1H NMR(400MHz,DMSO-d6)δ12.19(s,1H,-NH-),9.65(s,1H,-NH-),9.12(s,1H,-NH-), 8.17-8.16(d,1H,ArH),7.95(s,1H,ArH),7.43(s,1H,ArH),7.15(br s,2H,ArH),6.95(s, 1H,ArH),6.83(s,1H,ArH),3.26-3.22(m,1H,-CH-),2.75-2.72(m,1H,-CH-),2.45(s,3H,- CH3),2.25-2.20(m,2H,-CH2-),2.11(br s,2H,-CH2-),1.96-1.90(m,2H,-CH2-),1.14-1.12 (br s,6H,-CH3)；ESI-MS:[M+H]+450。
Embodiment 76.2- (3- cyclopropyl formamido group anilino-) -4- (2- trifluoroacetamido -4- methylthiazol -5- base) Pyridine
3- nitroaniline is replaced with 3- cyclopropyl formamido group aniline, trifluoro-acetyl chloride replaces chloroacetic chloride, reference implementation example 18 Operating process, obtain 2- (3- cyclopropyl formamido group anilino-) -4- (2- trifluoroacetamido -4- methylthiazol -5- base) pyrrole Pyridine.1H NMR(400MHz,DMSO-d6)δ10.13(s,1H,-NH-),9.27(s,1H,-NH-),8.22-8.20(d,1H, ArH),7.94(s,1H,ArH),7.43-7.41(d,1H,ArH),7.16(br s,2H,ArH),6.97(s,1H,ArH), 6.89-6.87(d,1H,ArH),2.46(s,3H,-CH3),1.82(m,1H,-CH-),0.79-0.77(m,4H,-CH2CH2-)； ESI-MS:[M+H]+462。
Pharmacological activity
External activity evaluation:
Mtt assay measures tumor cell survival
It is 0.8~2 × 10 that concentration is configured to after the cell of logarithmic growth phase is digested with pancreatin4Cell/ml cell liquid, 96 orifice plates are inoculated in by 1000/hole, every hole adds 100 μ l.Next day addition drug containing various concentration and coordinative solvent compare new Fresh culture medium, every hole add 100 μ l (DMSO final concentration < 0.5%), and every medicine sets 5~7 dosage groups, and every group at least sets three in parallel Supernatant is abandoned, every hole adds the serum-free of the MTT containing 0.5mg/ml of 100 μ l Fresh to train after 37 DEG C are continued to cultivate 120hr in hole Base is supported, continues to cultivate 4hr, abandons culture supernatant, every hole adds 200 μ l DMSO dissolution MTT first hairpin precipitating, vibrated with microoscillator It mixes, OD value (OD) is measured under the conditions of reference wavelength 450nm, Detection wavelength 570nm with MK3 type microplate reader, with solvent The tumour cell of control treatment is control group, calculates drug to the inhibiting rate of tumour cell with following formula, and press middle efficacious prescriptions journey Calculate IC50:
MTT the selection result

Claims (15)

1. 2- anilino- -4- thiazole pyridine derivative, officinal salt shown in Formulas I；
In formula:
R1Selected from hydrogen, halogen, cyano, nitro, carboxyl, mesyl, sulfamoyl, C1-C6 alkyl, substituted C1-C6 alkyl, Hydroxyl, C1-C6 alkoxy amino, C1-C6 alkylamino radical, C1-C6 heterocycle, C1-C6 alkyl amide, substituted C1-C6 alkane amide Base, C2-C6 unsaturation alkyl amide, substituted C2-C6 unsaturation alkyl amide, C3-C6 cycloalkanes amide groups, substituted C3-C6 Cycloalkanes amide groups, C1-C6 heterocycleamide base, substituted C1-C6 heterocycleamide base, wherein substituent group is selected from: halogen, hydroxyl, cyanogen Base, C1-C6 alkyl；
N is selected from 1,2,3；
R2And R3It is independently selected from hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 naphthenic base, substituted C3-C6 ring Alkyl, C1-C8 alkanoyl, substituted C1-C8 alkanoyl, C2-C8 unsaturation alkanoyl, substituted C2-C8 unsaturation alkanoyl, C3-C6 cycloalkanes formoxyl, substituted C3-C6 cycloalkanes formoxyl, C1-C6 heterocycle formyl, substituted C1-C6 heterocycle formyl, Wherein substituent group is selected from: halogen, hydroxyl, cyano, C1-C6 alkyl, benzoyl, two (C1-C6 alkyl) amino, methoxyl group, and three Methyl fluoride, trifluoromethoxy, mesyl.
2. compound according to claim 1 and its officinal salt, which is characterized in that
R1Selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, carboxyl, mesyl, sulfamoyl, C1-C6 alkyl, substituted C1-C6 alkane Base, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino radical, C1-C6 heterocycle, C1-C6 alkyl amide, substituted C1-C6 alkane Amide groups, C2-C6 unsaturation alkyl amide, C3-C6 cycloalkanes amide groups, substituted C3-C6 cycloalkanes amide groups, C1-C6 heterocycle acyl Amido, substituted C1-C6 heterocycleamide base, wherein substituent group is selected from: halogen, hydroxyl, cyano, methyl, ethyl, isopropyl, uncle Butyl；
N is selected from 1,2,3；
R2And R3It is independently selected from hydrogen, C1-C8 alkanoyl, substituted C1-C8 alkanoyl, C2-C8 unsaturation alkanoyl, takes The C2-C8 unsaturation alkanoyl in generation, C3-C6 cycloalkanes formoxyl, substituted C3-C6 cycloalkanes formoxyl, C1-C6 heterocycle formyl, Substituted C1-C6 heterocycle formyl, wherein substituent group is selected from: fluorine, chlorine, bromine, hydroxyl, cyano, methyl, ethyl, isopropyl, diformazan Amino, lignocaine, methoxyl group, trifluoromethyl.
3. compound according to claim 2 and its officinal salt, which is characterized in that
R1Selected from hydrogen, fluorine, chlorine, bromine, cyano, mesyl, sulfamoyl, methyl, ethyl, isopropyl, trifluoromethyl, diformazan ammonia Ylmethyl, methylol, hydroxyl, methoxyl group, isopropoxy, trifluoromethoxy, methylamino, dimethylamino, lignocaine, morpholine Base, piperazinyl, piperidyl, N methyl piperazine base, formamido, acetamido, propionamido-, Isopropamide base, amide-based small, Isobutyl amide, pivaloyl amido, valeryl amido, isovaleryl amido, 2,2- amide dimethyl butyrate base, trifluoroacetyl amido, hydroxyl Acetamido, methoxyacetyl amido, dimethylamino acetamide base, allyl amide groups, 3,3- dimethallyl amide groups, fourth Alkene -2- amide groups, propine amide groups, crotonylene-amide groups, cyclopropyl carboxamide base, cyclobutylmethyl amide groups, cyclopenta formyl Amido, cyclohexyl formamido, 2- piperidine formyl amido, 4- piperidine formyl amido, methyl piperidine formamido, isopropyl phenylpiperidines Formamido；
N is selected from 1,2,3；
R2And R3It is independently selected from hydrogen, formoxyl, acetyl group, propiono, iso-propionyl, bytyry, isobutyryl, new penta Acyl group, valeryl, isovaleryl, caproyl, 2,2- dimethylbutanoyl, trifluoroacetyl group, 2- difluoro propionyl acyl, hydroxyl acetyl Base, ammonia acetyl group, methoxyacetyl, Dimethyl Glycyl, allyl acyl group, butene-2-acyl group, butylene-3- acyl group, 3,3- Dimethallyl acyl group, hexadiene -2,4- acyl group, propine acyl group, 3- isopropyl propine acyl group, 3- tert-butyl propine acyl group, fourth Alkynes -2- acyl group, cyclopropyl formoxyl, cyclobutylmethyl acyl group, cyclopenta formoxyl, cyclohexyl formoxyl, 2- piperidine formyl base, 4- Piperidine formyl base, methyl piperidine formoxyl, isopropyl piperidine formyl base.
4. compound according to claim 3 and its officinal salt, which is characterized in that
R1Selected from hydrogen, fluorine, chlorine, bromine, cyano, mesyl, methyl, ethyl, isopropyl, trifluoromethyl, methoxyl group, isopropoxy, Trifluoromethoxy, dimethylamino, morpholinyl, piperazinyl, piperidyl, N methyl piperazine base, formamido, acetamido, third Amide groups, Isopropamide base, pivaloyl amido, 2,2- amide dimethyl butyrate base, trifluoroacetyl amido, hydroxyl acetamido, methoxy Acetamido, dimethylamino acetamide base, allyl amide groups, 3,3- dimethallyl amide groups, butene-2-amide groups, third Alkynyl amide base, crotonylene-amide groups, cyclopropyl carboxamide base, cyclobutylmethyl amide groups, cyclopenta formamido, cyclohexyl first Amide groups, 4- piperidine formyl amido, methyl piperidine formamido, isopropyl piperidine formyl amido；
N is selected from 1,2；
R2And R3It is independently selected from hydrogen, formoxyl, acetyl group, propiono, iso-propionyl, valeryl, 2,2- dimethyl butyrate Acyl group, trifluoroacetyl group, 2- difluoro propionyl acyl, glycolyl, ammonia acetyl group, methoxyacetyl, Dimethyl Glycyl, alkene Propiono, butene-2-acyl group, butylene-3- acyl group, 3,3- dimethallyl acyl group, hexadiene-2,4- acyl group, propine acyl group, fourth Alkynes -2- acyl group, cyclopropyl formoxyl, cyclobutylmethyl acyl group, cyclopenta formoxyl, cyclohexyl formoxyl, 2- piperidine formyl base, 4- Piperidine formyl base, methyl piperidine formoxyl, isopropyl piperidine formyl base.
5. compound according to claim 4 and its officinal salt, which is characterized in that
R1Selected from chlorine, bromine, trifluoromethyl, methoxyl group, dimethylamino, morpholinyl, N methyl piperazine base, formamido, acetamide Base, propionamido-, Isopropamide base, pivaloyl amido, 2,2- amide dimethyl butyrate base, trifluoroacetyl amido, hydroxyl acetamido, Methoxyacetyl amido, dimethylamino acetamide base, allyl amide groups, 3,3- dimethallyl amide groups, butene-2-amide Base, propine amide groups, crotonylene-amide groups, cyclopropyl carboxamide base, cyclobutylmethyl amide groups, cyclopenta formamido, hexamethylene Base formamido, 4- piperidine formyl amido, methyl piperidine formamido, isopropyl piperidine formyl amido；
N is selected from 1,2,3；
R2And R3It is independently selected from hydrogen, formoxyl, acetyl group, propiono, iso-propionyl, valeryl, 2,2- dimethyl butyrate Acyl group, trifluoroacetyl group, 2- difluoro propiono, glycolyl, ammonia acetyl group, allyl acyl group, 3,3- dimethallyl acyl group, third Alkynes acyl group, cyclopropyl formoxyl, cyclobutylmethyl acyl group, cyclopenta formoxyl, cyclohexyl formoxyl, 4- piperidine formyl base, methyl Piperidine formyl base, isopropyl piperidine formyl base.
6. compound according to claim 1 and its officinal salt, the compound is selected from following group:
2- (3-Aminotrifluorotoluene base) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (4- (cyclopropyl formamido) anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (3,4,5- trimethoxy-benzene amido) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (4- dimethylamino anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (3- cyclopropyl formamido anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (4- (N methyl piperazine base) anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (propionamido anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (3- trifluoroacetamido anilino-) -4- (2- amino -4- methylthiazol -5- base) pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- acrylamido -4- methylthiazol -5- base) pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- (hexadiene -2,4- acylamino-) -4- methylthiazol -5- base) Pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- propionamido -4- methylthiazol -5- base) pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- (3- methylbutyrylamino) -4- methylthiazol -5- base) pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- cyclopropylcarboxamido -4- methylthiazol -5- base) pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- cyclobutylmethyl acylamino- -4- methylthiazol -5- base) pyridine
2- (3- trifluoromethylbenzene amido) -4- (2- cyclopenta formamido group -4- methylthiazol -5- base) pyridine
2- (adjacent fluoroanilino) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine
2- (2,4- dichloroanilino) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine
2- (p-dimethylamino aniline base) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine
2- (3,4,5- trimethoxy-benzene amido) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine
2- (4- cyclopropyl formamido group anilino-) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine
2- (3- cyclopropyl formamido group anilino-) -4- (2- allyl acylamino- -4- methylthiazol -5- base) pyridine
2- (p-dimethylamino aniline base) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (3,4,5- trimethoxy-benzene amido) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (to morpholinyl anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (3,4,5- trimethoxy-benzene amido) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (to cyclopropyl formamido group anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (to morpholinyl anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (cyclopropyl formamido group anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (cyclopropyl formamido group anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (m-acetamidoaniline base) -4- (acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (propionamido anilino-) -4- (2- propionamido -4- methylthiazol -5- base) pyridine
2- (3- isopropyl formamido group anilino-) -4- (2- isopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (the tertiary fourth formamido group anilino- of 3-) -4- (the tertiary fourth formamido group -4- methylthiazol -5- base of 2-) pyridine
2- (3- (3- methyl butene -2- acylamino-) anilino-) -4- (2- (3- methyl butene -2- acylamino-) - 4- methylthiazol -5- base) pyridine
2- (3- ring fourth formamido group anilino-) -4- (2- ring fourth formamido group -4- methylthiazol -5- base) pyridine
2- (3- cyclopropyl formamido group anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (3- cyclopropyl formamido group anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (3- cyclopropyl formamido group anilino-) -4- (2- isobutyl formamido group -4- methylthiazol -5- base) pyridine
2- (3- cyclopropyl formamido group anilino-) -4- (2- (3- methyl butene -2- acylamino-) -4- methyl thiazolium Azoles -5- base) pyridine
2- (3- cyclopropyl formamido group anilino-) -4- (2- cyclopenta formamido group -4- methylthiazol -5- base) pyrrole Pyridine
2- (3- trifluoroacetamido anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (3- trifluoroacetamido anilino-) -4- (2- acetylaminohydroxyphenylarsonic acid 4- methylthiazol -5- base) pyridine
2- (3- ring fourth formamido group anilino-) -4- (2- cyclopropyl formamido group -4- methylthiazol -5- base) pyridine
2- (3- ring fourth formamido group anilino-) -4- (2- isopropyl formamido group -4- methylthiazol -5- base) pyridine
7. compound as claimed in one of claims 1-6 and its officinal salt, which is characterized in that the officinal salt, Its hydrochlorate includes: hydrochloride, hydrobromate, phosphate, sulfate, mesylate, tosilate, acetate, trifluoro second Hydrochlorate, salicylate, amino-acid salt, fructus lycii hydrochlorate, maleate, tartrate, fumarate, citrate, lactate, Alkali salt includes: sodium salt, sylvite, calcium salt, magnesium salts, lithium salts.
8. the method for preparing the compound and its officinal salt of any one of claim 1-7, including following route: route 1
Route 2
9. preparation method according to claim 8, which is characterized in that with the bromo- 4- thiazolyl pyrrole of 2- in the step a of the route 1 Piperidine derivatives 1 are raw material, under acidic environment, with R1Substituted aniline occurs nucleophilic substitution and forms compound 2；Step b In, the amine on thiazole ring in compound 2 is alkylated or is acylated, target compound I is generated.
10. preparation method according to claim 9, which is characterized in that in the step b, to the amine on thiazole ring in compound 2 Being alkylated or being acylated is and alkyl halide R2X or R3The substitution reaction of X is dehydrated with acid by condensing agent, or and acyl chlorides Reaction.
11. preparation method according to claim 8, which is characterized in that with the bromo- 4- thiazolyl pyrrole of 2- in the step a of the route 2 Piperidine derivatives 1 are raw material, and the amine on its thiazole ring is alkylated or is acylated, and generate midbody compound 3；In step b, Under acidic environment, R1Substituted aniline and compound 3 occurs nucleophilic substitution and generates target compound I.
12. preparation method according to claim 11, which is characterized in that in the step a, carry out alkane to the amine on its thiazole ring Base or acylation are and alkyl halide R2X or R3The substitution reaction of X is dehydrated with acid by condensing agent, or and acyl chloride reaction.
13. a kind of composition of drug, which is characterized in that the compound containing any one of claim 1-7 and its pharmaceutically acceptable Salt and the acceptable carrier of galenic pharmacy.
14. the compound and its officinal salt of any one of claim 1-7 prevent and treat tumour and tumor disease in preparation Application in related drug.
15. application according to claim 14, which is characterized in that the tumor disease is selected from liver cancer, kidney, lung cancer, pancreas Cancer, gastric cancer, colorectal cancer, bladder cancer, breast cancer, oophoroma, cutaneum carcinoma, thyroid cancer, leukemia, squamous cell carcinoma, neuroglia Matter tumor and head-neck carcinoma.
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