CN105585565A - 2-phenylamino-4-thiazolyl pyridine derivatives, preparing method thereof, pharmaceutical compositions of the derivatives and uses of the derivatives - Google Patents

2-phenylamino-4-thiazolyl pyridine derivatives, preparing method thereof, pharmaceutical compositions of the derivatives and uses of the derivatives Download PDF

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CN105585565A
CN105585565A CN201410571559.XA CN201410571559A CN105585565A CN 105585565 A CN105585565 A CN 105585565A CN 201410571559 A CN201410571559 A CN 201410571559A CN 105585565 A CN105585565 A CN 105585565A
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pyridine
group
methylthiazol
amido
formamido
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CN105585565B (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 invention relates to 2-phenylamino-4-thiazolyl pyridine derivatives shown as a formula I, pharmaceutical salts thereof, a preparing method of the derivatives and the pharmaceutical salts, compositions containing one or more compounds selected from the derivatives and the pharmaceutical salts, and uses of the derivatives and the pharmaceutical salts in the field of tumor disease treatment.

Description

Containing 2-anilino--4-thiazolyl pyridine derivate and method for making and pharmaceutical composition and purposes
Invention field
The present invention relates to the 2-anilino--4-thiazolyl pyridine derivate shown in formula I, its officinal salt, and systemPreparation Method, the composition that contains one or more these compounds, and this compounds is aspect treatment tumor diseasePurposes.
Background of invention
Recent years, due to raising with the understanding of the biomolecule of disease association to enzyme and some other, very bigGround has promoted discovery or the development of the new drug for the treatment of disease, and protein kinase is exactly important one of a kind of broad researchClass, it is extended familys, relevant with the control of various signal transduction processes in cell. Due to their structureThey are considered to evolve from a common ancestral gene with the conservative of catalysis. Nearly all kinasesAll contain a similar 250-300 amino acid catalytic domain. These protein kinases are not according to phosphorylated substrateWith being divided into multiple families, as protein tyrosine kinase, albumen serine/threonine kinase, lipoid etc. OneAs, protein kinase is transferred to one and signal transduction pathway by affecting a phosphoryl from a ribonucleoside triphosphoteRelevant protein receptor carrys out signal transduction in mediated cell. These phosphorylated events regulate target as molecular switchThe biological function of albumen, is finally excited and is reacted in various extracellulars and other stimulation. Kinases is present in manyIn layer signal transduction path, receptor tyrosine kinase is positioned at the upstream of tumor vessel generation Signal transduction pathway. SilkPropylhomoserin/Serineprotein kinase is positioned at the downstream of the Signal transduction pathway of tumour and tumor vessel cellulation.
Aurora A is a kind of novel serine one Serineprotein kinase, participates in regulating mitotic centerThe function of body and microtubule, thus cell cycle progression affected. In current known human cell, exist 3 kinds of structures andThe Aurora A hypotype of function height correlation: AuroraA, B and C. Although their amino acid sequence andThree-dimensional structure has very large similitude, but makes a big difference in subcellular location and function. AuroraAThe G phase from the mitotic S end of term to next division cycle starts to be positioned centerbody around and spindleTwo ends, affect the separation of centerbody and the forming process of maturation and the two poles of the earth spindle, its overexpression can press downMake cytoplasmic division, make cell can not leave the M phase, thereby cause the amplification of centerbody. AuroraB is claimedFor " chromosome passerby albumen ", be positioned core, transfer to centromere in mitotic early stage to mid-term, enterPeople is positioned centerbody gradually until cytokinesis completes after mitosis anaphase. It is moving that AuroraB has adjustingGrain function, adjustable chromosome carries out correct aligning and separating, and affect spindle measuring ability andCytokinesis; In mitosis process, its can with another 3 kinds of chromosome passerby protein I NCENP, SurvivinForm tetraplex with Borealin, the location regulatory function of this compound can make it accurately be positioned in cellOn centerbody and spindle. At present less to the research of AuroraC, in recent years there is report to point out that AumraC is alsoChromosome passerby albumen, can directly be combined with INCENP and Suvivin in vitro, in mammalian cell,Aurora-C-INCENP can make endogenous phosphorylated histone H3.
Aurora A is often crossed and is expressed in human tumor, brings into play important function in mitosis process,Its exception table Danone causes cell transformation to become potential cancer. Genetic abnormality based on human cancer is more and more general,The protein that maintains the integrality of chromosome separation in cell transformation may also be played an important role. AuroraABe a kind of kinases encoding gene of key, be positioned at 20q13.2, this district ubiquity in human malignanciesAmplification, as the .AuroraB such as colon cancer, oophoroma, cancer of the stomach, breast cancer and the cancer of the esophagus are positioned chromosome17q13.1, this region does not have typical case's amplification in human malignancies. But, in many human cancers,Comprise glioblastoma multiforme, malignant mesothelioma and hematologic malignancies, all find AuroraBCross express. People are less to the carcinogenesis research of AuroraC, and some researchs find that AuroraC is at colonIn cancer, breast cancer and prostate cancer, cross and express. In a word, Aurora A A, B, C are in many human cancersAll cross expression, and all relevant with chromosomal unstability, carcinogenic transformation, tumor proliferation and chemoresistance,Therefore Aurora A may become one of promising target spot in cancer therapy drug development.
Vascular endothelial growth factor receptor (vascularendothelialgrowthfactorreceptor,VEGFR) family includes 3 kinds of hypotypes, that is: VEGFR-1 (also can write Flt-1 simultaneously), VEGFR-2(KDR/Flk-1) and VEGFR-3 (Flt 1), in addition, also have neural pilin (neuropilin) l and 2 liangIndividual collaborative acceptor. Wherein VEGFR-1 is mainly distributed in vascular endothelial cell, candidate stem cell, macrophageAnd monocyte, can be combined with VEGF-A, VEGF-B and P1GF, growth main and candidate stem cell is adjustedSave relevant. VEGFR-2 is mainly distributed in vascular endothelial cell and lymph endothelial cell, can with VEGF-A,VEGF-C, VEGF-D, VEGF-E combination. VEGF stimulating endothelial cell propagation, increase vasopermeabilityMainly realize with activation VEGFR-2 by combination with the effect of new Angiogenesis. compared with VEGFR-2,The affinity of VEGFR-l and VEGF is high 10 times, but regulates the activity of endothelial cell much lower, may be rightVEGFR-2 activity has negative regulation effect. VEGFR-3 mainly expresses at lymphatic endothelial cells, can be withVEGF-C and VEGF-D combination, the growth of regulation and control lymph endothelial cell.
Research shows: in the time that diameter of tumor is greater than 2mm, need to have new vessels that nutriment and row are providedLet out metabolic waste. VEGF/VEGFR signal path plays key effect in tumor vascular generation, canWith by blocking or disturb VEGF/VEGFR signal path to suppress the new life of blood vessel, to reach control tumourThe curative effect of growth. Compared with traditional cytotoxic drug, anti-swollen taking VEGF/VEGFR-2 as targetTumor medicine has very large advantage. and under normal physiological conditions, angiogenesis is only in wound healing and menstrual cycle etc.In physiological activity, work, thus anti-angiogenic medicaments treatment tumour used, little to human toxicity effect, bloodEndothelial cell directly contacts with blood, makes medicine be more prone to arrive action site., therefore with VEGF/VEGFR-2 is also one of promising target spot in cancer therapy drug development.
Platelet derived growth factor (platelet.derivedgrowthfactor, PDGF) is induction and promotesVascularization effect the most by force, one of the most single-minded angiogenesis factor. PDGF mainly by with pdgf receptor(PDGFR) combination, and then activated protein kinase signal transduction pathway and playing a role. PDGFR is by α and β twoPlant subunit and form, have 3 kinds of dimers (PDGFR-α α, α β, β β), wherein β β dimer acceptor (PDGFR-β) important, its molecular weight is about 180～190ku, belongs to tyrosine kinase receptor (receptortyrosineKinase, RTK) family. PDGFR also plays an important role in tumour formation and development process.
The overexpression of PDGFR-β or overactivity all can stimulate intratumoral vasculature to generate, and promote tumor growth.
PDGFR-β is one of molecular marker of tumor vascular endothelial cell, high in endothelial cells in tumor neogenetic blood vesselsExpress, and closely related with growth, the Metastasis and prognosis of some tumour. So PDGFR-β be one comparativelyDesirable neoplasm targeted therapy target.
Numerous disease is that the abnormal cell effect causing with protein kinase mediated event is associated. ThisA little diseases include, but not limited to tumour, inflammation disease, immunological diseases, bone disease, metabolic disease, nerveDisease, cardiovascular and cerebrovascular disease, the disease that hormone is relevant etc. Therefore find and find kinases inhibitor conductMedicine is very important. In addition, existing evidence demonstration, most of tumour is not conducted by single signalPath is arranged, and suppresses to obtain larger curative effect for many target spots. Although many inventions are done this areaGone out very large contribution, but for improving medication effect, research is still being continued in this area.
Summary of the invention
The object of the present invention is to provide the 2-anilino--4-thiazolyl pyridine derivate shown in general formula I and canPharmaceutical salts.
Another object of the present invention is to provide 2-anilino--4-thiazolyl pyridine derivate shown in general formula IPreparation method.
A further object of the present invention is to provide a kind of 2-anilino--4-thiazolyl pyridine shown in general formula I that containsThe pharmaceutical composition of derivative.
Another object of the present invention is to provide the purposes of this compounds in cancer therapy drug.
In order to complete the present invention's object, can adopt following technical scheme:
The present invention relates to have the lower array structure 2-anilino--4-thiazolyl pyridine derivate shown in general formula I and canPharmaceutical salts;
In formula:
R1Be selected from hydrogen, halogen, cyano group, nitro, carboxyl, mesyl, sulfamoyl, methylphosphine acyl group, C1-C6The C1-C6 alkoxyl of the C1-C6 alkyl of alkyl, replacement, hydroxyl, C1-C6 alkoxyl, replacement, amino,The C1-C6 heterocyclic radical of the C1-C6 alkylamino radical of C1-C6 alkylamino radical, replacement, C1-C6 heterocyclic radical, replacement,The C2-C6 of the C1-C6 alkyl amide of C1-C6 alkyl amide, replacement, the unsaturated alkyl amide of C2-C6, replacementThe C3-C6 cycloalkanes amide groups of unsaturated alkyl amide, C3-C6 cycloalkanes amide groups, replacement, C1-C6 heterocycle acylThe C1-C6 heterocycleamide base of amido, replacement, wherein substituting group is selected from: halogen, hydroxyl, cyano group, C1-C6Alkyl, benzoyl, two C1-C6 alkyl aminos, methoxyl group, trifluoromethyl, trifluoromethoxy, first sulphurAcyl group;
N is selected from 1,2,3,4,5;
R2And R3Independently be selected from respectively hydrogen, C1-C6 alkyl, replacement C1-C6 alkyl, C3-C6 cycloalkyl,The C3-C6 cycloalkyl, C1-C8 alkanoyl, the C1-C8 alkanoyl of replacement, the unsaturated alkane of C2-C8 that replaceThe C3-C6 cycloalkanes first of the unsaturated alkanoyl of C2-C8 of acyl group, replacement, C3-C6 cycloalkanes formoxyl, replacementC1-C6 heterocycle formyl, the C6-C10 aromatic ring formoxyl of acyl group, C1-C6 heterocycle formyl, replacement, getThe C6-C12 aromatic ring alkanoyl of the C6-C10 aromatic ring formoxyl in generation, C6-C12 aromatic ring alkanoyl, replacement, itsMiddle substituting group is selected from: halogen, hydroxyl, cyano group, C1-C6 alkyl, benzoyl, two C1-C6 alkyl aminos,Methoxyl group, trifluoromethyl, trifluoromethoxy, mesyl;
R1More preferably from hydrogen, fluorine, chlorine, bromine, cyano group, nitro, carboxyl, mesyl, sulfamoyl, C1-C6The C1-C6 alkoxyl of the C1-C6 alkyl of alkyl, replacement, hydroxyl, C1-C6 alkoxyl, replacement, amino,The C1-C6 heterocyclic radical of the C1-C6 alkylamino radical of C1-C6 alkylamino radical, replacement, C1-C6 heterocyclic radical, replacement,The C2-C6 of the C1-C6 alkyl amide of C1-C6 alkyl amide, replacement, the unsaturated alkyl amide of C2-C6, replacementThe C3-C6 cycloalkanes amide groups of unsaturated alkyl amide, C3-C6 cycloalkanes amide groups, replacement, C1-C6 heterocycle acylAmido,, the C1-C6 heterocycleamide base that replaces, wherein substituting group is selected from: halogen, hydroxyl, cyano group, methyl,Ethyl, isopropyl, the tert-butyl group, benzoyl, dimethylamino, methoxyl group, trifluoromethyl, trifluoro methoxyBase, mesyl;
N is selected from 1,2,3,4;
R2And R3Independently be not selected from C1-C6 alkyl, the C3-C6 cycloalkanes of hydrogen, C1-C6 alkyl, replacement compared with optimal sortingThe C3-C6 cycloalkyl of base, replacement, C1-C8 alkanoyl, the C1-C8 alkanoyl of replacement, C2-C8 insatiable hungerC3-C6 ring with the unsaturated alkanoyl of C2-C8 of alkanoyl, replacement, C3-C6 cycloalkanes formoxyl, replacementThe benzene of the C1-C6 heterocycle formyl of alkane formoxyl, C1-C6 heterocycle formyl, replacement, benzoyl, replacementThe phenyl C1-C6 alkanoyl of formoxyl, phenyl C1-C6 alkanoyl, replacement, wherein substituting group is selected from: fluorine,Chlorine, bromine, hydroxyl, cyano group, methyl, ethyl, isopropyl, the tert-butyl group, benzoyl, dimethylamino, twoEthylamino, methoxyl group, trifluoromethyl, trifluoromethoxy, mesyl;
R1More preferably from hydrogen, fluorine, chlorine, bromine, cyano group, nitro, carboxyl, mesyl, sulfamoyl, methyl,Ethyl, isopropyl, the tert-butyl group, trifluoromethyl, dimethylamino methyl, methylol, hydroxyl, methoxyl group, differentPropoxyl group, trifluoromethoxy, methoxyethoxy, amino, methylamino, dimethylamino, lignocaine, hydroxylEthylamino-, morpholinyl, piperazinyl, piperidyl, N methyl piperazine base, formamido, acetamido, propionylAmido, Isopropamide base, amide-based small, isobutyl amide, pivaloyl amido, valeryl amido, isovaleramideBase, 2,2-amide dimethyl butyrate base, trifluoroacetyl amido, hydroxyl acetamido, methoxy acetamido, diformazanBase glycyl amido, acrylyl amido, 3,3-dimethyl acrylyl amido, butene-2-amide groups, propineAmide groups, crotonylene-amide groups, cyclopropyl carboxamide base, cyclobutylmethyl amide groups, cyclopenta formamido,Cyclohexyl formamido, 2-piperidine formyl amido, 4-piperidine formyl amido, methyl piperidine formamido, isopropylPhenylpiperidines formamido;
N is selected from 1,2,3,4;
R2And R3More optimal sorting be not independently selected from hydrogen, methyl, ethyl, propyl group, isopropyl, the tert-butyl group, ethoxy,Decil, methoxyethyl, cyclopropyl, cyclobutyl, cyclopenta, formoxyl, acetyl group, propiono,Isopropyl acyl group, bytyry, isobutyryl, valeryl, valeryl, isovaleryl, caproyl, 2,2-Dimethyl butyrate acyl group, trifluoroacetyl group, 2-difluoro propionyl acyl, glycolyl, ammonia acetyl group, methoxy acetyl group,Dimethylamino acetyl group, allyl acyl group, butene-2-acyl group, butylene-3-acyl group, 3,3-dimethyl acrylylBase, hexadiene-2,4-acyl group, propine acyl group, 3-isopropyl propine acyl group, 3-tert-butyl group propine acyl group, fourthAlkynes-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, benzoyl,Between fluoro benzoyl, a chlorobenzene formacyl, to fluoro benzoyl, to chlorobenzene formacyl, a fluorine to chlorobenzoylBase, adjacent fluoro benzoyl, to methyl benzoyl, to cyano group benzoyl, to dimethylamino benzoyl,Para hydroxybenzene formoxyl, to methoxybenzoyl base, to hydroxyl meta-methoxy benzoyl, m-trifluoromethyl benzeneFormoxyl, to trifluoromethyl benzoyl, a cyano group benzoyl, phenylacetyl group, a fluorophenethyl acyl group,Chloro acetyl, to fluorophenethyl acyl group between chlorine, a cyano group phenylacetyl group;
R1Particularly preferably from hydrogen, fluorine, chlorine, bromine, cyano group, carboxyl, mesyl, methyl, ethyl, isopropyl,The tert-butyl group, trifluoromethyl, dimethylamino methyl, methylol, hydroxyl, methoxyl group, isopropoxy, fluoroformOxygen base, methoxyethoxy, 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-dimethyl butyrateAmide groups, trifluoroacetyl amido, hydroxyl acetamido, methoxy acetamido, dimethylamino acetamido, alkenePropionamido-, 3,3-dimethyl acrylyl amido, butene-2-amide groups, propioloyl amido, crotonylene-acid amidesBase, cyclopropyl carboxamide base, cyclobutylmethyl amide groups, cyclopenta formamido, cyclohexyl formamido, 4-Piperidine formyl amido, methyl piperidine formamido, isopropyl piperidine formyl amido;
N is selected from 1,2,3,4;
R2And R3Special optimal sorting be not independently selected from hydrogen, methyl, ethyl, isopropyl, ethoxy, decil,Methoxyethyl, cyclopropyl, cyclobutyl, formoxyl, acetyl group, propiono, isopropyl acyl group, bytyry, differentBytyry, valeryl, valeryl, isovaleryl, caproyl, 2,2-dimethyl butyrate acyl group, trifluoro secondAcyl group, 2-difluoro propionyl acyl, glycolyl, ammonia acetyl group, methoxy acetyl group, dimethylamino acetyl group,Allyl acyl group, butene-2-acyl group, butylene-3-acyl group, 3,3-dimethyl allyl acyl group, hexadiene-2,4-acylBase, propine acyl group, 3-isopropyl propine acyl group, 3-tert-butyl group propine acyl group, crotonylene-acyl group, cyclopropyl firstAcyl group, cyclobutylmethyl acyl group, cyclopenta formoxyl, cyclohexyl formoxyl, 2-piperidine formyl base, 4-piperidines firstAcyl group, methyl piperidine formoxyl, isopropyl piperidine formyl base, benzoyl, a fluoro benzoyl, a chlorobenzeneFormoxyl, to fluoro benzoyl, to chlorobenzene formacyl, a fluorine to chlorobenzene formacyl, adjacent fluoro benzoyl, rightMethyl benzoyl, to cyano group benzoyl, to dimethylamino benzoyl, para hydroxybenzene formoxyl, to firstOxygen base benzoyl, to hydroxyl meta-methoxy benzoyl, m-trifluoromethyl benzoyl, to trifluoromethylbenzeneFormoxyl, a cyano group benzoyl, phenylacetyl group, a fluorophenethyl acyl group, a chloro acetyl, to fluorine between chlorinePhenylacetyl group;
R1Most preferably from hydrogen, fluorine, chlorine, bromine, cyano group, carboxyl, mesyl, methyl, isopropyl, the tert-butyl group,Trifluoromethyl, dimethylamino methyl, methylol, hydroxyl, methoxyl group, isopropoxy, trifluoromethoxy, firstOxygen ethyoxyl, amino, methylamino, dimethylamino, lignocaine, hydroxyethylamine, morpholinyl, piperazinyl,Piperidyl, N methyl piperazine base, formamido, acetamido, propionamido-, Isopropamide base, butyramideBase, isobutyl amide, pivaloyl amido, valeryl amido, isovaleryl amido, 2,2-amide dimethyl butyrate base,Trifluoroacetyl amido, hydroxyl acetamido, methoxy acetamido, dimethylamino acetamido, acrylyl amido,3,3-dimethyl acrylyl amido, butene-2-amide groups, propioloyl amido, crotonylene-amide groups, cyclopropylFormamido, cyclobutylmethyl amide groups, cyclopenta formamido, cyclohexyl formamido, 4-piperidine formamideBase, methyl piperidine formamido, isopropyl piperidine formyl amido;
N is selected from 1,2,3,4;
R2And R3Optimum be independently selected from respectively hydrogen, methyl, ethyl, isopropyl, ethoxy, decil,Methoxyethyl, cyclopropyl, cyclobutyl, formoxyl, acetyl group, propiono, isopropyl acyl group, bytyry, differentBytyry, valeryl, valeryl, isovaleryl, caproyl, 2,2-dimethyl butyrate acyl group, trifluoro secondAcyl group, 2-difluoro propiono, glycolyl, ammonia acetyl group, methoxy acetyl group, dimethylamino acetyl group,Allyl acyl group, butene-2-acyl group, butylene-3-acyl group, 3,3-dimethyl allyl acyl group, hexadiene-2,4-acylBase, propine acyl group, 3-isopropyl propine acyl group, crotonylene-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, benzoyl, a fluoro benzoyl, a chlorobenzene formacyl, to fluoro benzoyl,To chlorobenzene formacyl, a fluorine to chlorobenzene formacyl, adjacent fluoro benzoyl, nicotinoyl base, the amino nicotinoyl base of 6-, rightMethyl benzoyl, to cyano group benzoyl, to dimethylamino benzoyl, para hydroxybenzene formoxyl, to firstOxygen base benzoyl, to hydroxyl meta-methoxy benzoyl, m-trifluoromethyl benzoyl, to trifluoromethylbenzeneFormoxyl, a cyano group benzoyl, phenylacetyl group, a fluorophenethyl acyl group, a chloro acetyl, to fluorine between chlorinePhenylacetyl group;
The most preferred compound of the present invention is selected from following group:
2-(3-Aminotrifluorotoluene base)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(the chloro-6-toluidine of 2-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(2-fluoroanilino)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(2,4-difluorobenzene amido)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(the bromo-4-fluoroanilino of 2-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(2-methoxyl group-4-N-methyl piperazine anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(4-morpholine anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(4-(ring propyl formamide base) anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(3,4,5-trimethoxy-benzene amido)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(4-dimethylamino anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(3-ring propyl formamide base anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(4-(N methyl piperazine base) anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(m-nitro amido)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(m-aminophenyl amido)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(a propionamido anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(isophthalic acetyl amino phenyl amido)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(3-trifluoroacetamido anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(3-nitrobenzene amido)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-acrylamido-4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-(3-dimethyl allene acyl) amino-4-methylthiazol-5-yl) pyrrolePyridine
2-(3-trifluoromethylbenzene amido)-4-(2-(hexadiene-2,4-acylamino-)-4-methylthiazol-5-yl) pyrrolePyridine
2-(3-trifluoromethylbenzene amido)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-propionamido-4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-(3-methylbutyryl amino)-4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-valeryl amino-4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-cyclopropyl formamido group-4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-cyclobutylmethyl acylamino--4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-cyclopenta formamido group-4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-m-chloro benzamido-4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(fluorobenzene acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl between 2-) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-m-fluoroaniline formamido group-4-methylthiazol-5-yl) pyridine
2-(adjacent fluoroanilino)-4-(2-acrylyl amino-4-methylthiazol-5-yl) pyridine
2-(2,4-dichloroanilino)-4-(2-acrylyl amino-4-methylthiazol-5-yl) pyridine
2-(p-dimethylamino aniline base)-4-(2-acrylyl amino-4-methylthiazol-5-yl) pyridine
2-(3,4,5-trimethoxy-benzene amido)-4-(2-acrylyl amino-4-methylthiazol-5-yl) pyridine
2-(4-encircles the third formamido group anilino-)-4-(2-acrylyl amino-4-methylthiazol-5-yl) pyridine
2-(3-encircles the third formamido group anilino-)-4-(2-acrylyl amino-4-methylthiazol-5-yl) pyridine
2-(adjacent fluoroanilino)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
2-(2,4-difluorobenzene amido)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
2-(p-dimethylamino aniline base)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
2-(3,4,5-trimethoxy-benzene amido)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
2-(to morpholinyl anilino-)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
2-(adjacent fluoroanilino)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(2,4-dichloroanilino)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(p-dimethylamino aniline base)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(3,4,5-trimethoxy-benzene amido)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(to encircling the third formamido group anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(to morpholinyl anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(ring the third formamido group anilino-)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
2-(ring the third formamido group anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(m-acetamidoaniline base)-4-(acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(a propionamido anilino-)-4-(2-propionamido-4-methylthiazol-5-yl) pyridine
2-(3-isopropyl formamido group anilino-)-4-(2-isopropyl formamido group-4-methylthiazol-5-yl) pyridine
2-(the tertiary fourth formamido group of 3-anilino-)-4-(the tertiary fourth formamido group-4-of 2-methylthiazol-5-yl) pyridine
2-(3-(3-methyl butene-2-acylamino-) anilino-)-4-(2-(3-methyl butene-2-acylamino-)-4-methylthiazol-5-yl) pyridine
2-(3-ring fourth formamido group anilino-)-4-(2-ring fourth formamido group-4-methylthiazol-5-yl) pyridine
2-(3-encircles the third formamido group anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(3-encircles the third formamido group anilino-)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
2-(3-encircles the third formamido group anilino-)-4-(2-isobutyl formamido group-4-methylthiazol-5-yl) pyridine
2-(3-encircles the third formamido group anilino-)-4-(2-(3-methyl butene-2-acylamino-)-4-methylthiazol-5-yl)Pyridine
2-(3-encircles the third formamido group anilino-)-4-(2-cyclopenta formamido group-4-methylthiazol-5-yl) pyridine
2-(3-encircles the third formamido group anilino-)-4-(2-is to toluyl amino-4-methylthiazol-5-yl) pyridine
2-(3-encircles the third formamido group anilino-)-4-(2-phenylacetylamino-4-methylthiazol-5-yl) pyridine
2-(3-nitrobenzene amido)-4-(2-trifluoroacetyl amido-4-methylthiazol-5-yl) pyridine
2-(3-nitrobenzene amido)-4-(2-ring propyl formamide base-4-methylthiazol-5-yl) pyridine
2-(3-nitrobenzene amido)-4-(2-isopropyl formamido-4-methylthiazol-5-yl) pyridine
2-(3-aminobenzene amido)-4-(2-ring propyl formamide base-4-methylthiazol-5-yl) pyridine
2-(3-aminobenzene amido)-4-(2-isopropyl formamido-4-methylthiazol-5-yl) pyridine
2-(3-trifluoroacetamido anilino-)-4-(2-trifluoroacetamido-4-methylthiazol-5-yl) pyridine
2-(3-trifluoroacetamido anilino-)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
2-(3-trifluoroacetamido anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(3-ring fourth formamido group anilino-)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
2-(3-trifluoroacetamido anilino-)-4-(2-ring fourth formamido group-4-methylthiazol-5-yl) pyridine
2-(3-ring fourth formamido group anilino-)-4-(2-isopropyl formamido group-4-methylthiazol-5-yl) pyridine
2-(3-encircles the third formamido group anilino-)-4-(2-trifluoroacetamido-4-methylthiazol-5-yl) pyridine
Second aspect present invention also provides the method for preparing the compounds of this invention, comprises the steps:
Route 1
In step (a), taking the bromo-4-thiazolyl of 2-pyridine derivate 1 as raw material, under sour environment, replace with R1Aniline generation nucleophilic substitution form compound 2;
In step (b), the amine on thiazole ring in compound 2 is carried out to alkylation or acyl group by common methods, asWith the substitution reaction of alkyl halide R2X or R3X, dewater by condensing agent with acid, or raw with acyl chloride reactionBecome target compound I;
Route 2
In step (a) taking the bromo-4-thiazolyl of 2-pyridine derivate 1 as raw material, by common methods on its thiazole ringAmine carries out alkylation or acyl group, as with the substitution reaction of alkyl halide R2X or R3X, with acid by contractingMixture dehydration, or generate midbody compound 3 with acyl chloride reaction;
In step (b), under sour environment, there is nucleophilic substitution and generate in the aniline that R1 replaces and compound 3Target compound I;
In addition, initiation material and intermediate in above-mentioned reaction easily obtain, or to this area knack peopleMember can be easy to synthesize by the conventional method in organic synthesis.
Described in formula I, 2-anilino--4-thiazolyl pyridine derivate can solvate or the form of non-solvent compoundExist, utilize different solvents to carry out crystallization and may obtain different solvates. Described in formula I, pharmaceutically canThe salt of accepting comprises different acid-addition salts, as following inorganic acid or organic acid acid-addition salts: hydrochloric acid, hydrogen bromineAcid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, trifluoroacetic acid, matrimony vine acid, maleic acid, tartaric acid,Fumaric acid, citric acid, lactic acid. All these salt within the scope of the present invention all can adopt conventional method preparation.In the preparation process of described 2-anilino--4-thiazolyl pyridine derivate and solvate and its salt, noMay there is polycrystalline or eutectic in syncrystallization condition.
Third aspect present invention also relates to the pharmaceutical composition using the compounds of this invention as active ingredient. This medicineCompositions can be according to method preparation well known in the art. Can pass through the compounds of this invention and one or more medicinesAcceptable solid or liquid excipient and/or assistant agent combination on, make and be suitable for any of human or animal's useFormulation. The content of the compounds of this invention in its pharmaceutical composition is generally 0.1-95 % by weight.
The compounds of this invention or the pharmaceutical composition that contains it can unit dosage form administrations, and method of administration canFor enteron aisle or non-enteron aisle, as oral, intravenous injection, intramuscular injection, hypodermic 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 solutionAgent (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), supensoid agent, notePenetrate agent (comprising liquid drugs injection, powder-injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid formulationType can be that tablet (comprises that ordinary tablet, enteric coatel tablets, lozenge, dispersing tablet, chewable tablets, effervescent tablet, oral cavity collapseSeparate sheet), capsule (comprising hard shell capsules, soft capsule, capsulae enterosolubilis), granule, powder, micropill, dripping pill,Suppository, film, paster, the agent of gas (powder) mist, spray etc.; Semisolid dosage form can be ointment, gelAgent, paste etc.
The compounds of this invention can be made ordinary preparation, also make is sustained release preparation, controlled release preparation, target systemAgent and various particulate delivery system.
For the compounds of this invention is made to tablet, can be widely used various excipient well known in the art,Comprise diluent, binder, wetting agent, disintegrant, lubricant, glidant. Diluent can be starch,Dextrin, sucrose, glucose, lactose, sweet mellow wine, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate,Calcium monohydrogen phosphate, calcium carbonate etc.; Wetting agent can be water, ethanol, isopropyl alcohol etc.; Adhesive can be starch slurry,Dextrin, syrup, honey, glucose solution, microcrystalline cellulose, mucialga of arabic gummy, gelatine size, carboxymethyl fibreTie up plain sodium, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer,Polyvinylpyrrolidone, polyethylene glycol etc.; Disintegrant can be dried starch, microcrystalline cellulose, low-substituted hydroxypropylBase cellulose, PVPP, Ac-Di-Sol, sodium carboxymethyl starch, bicarbonateSodium and citric acid, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfate etc.; Lubricant and glidantCan be talcum powder, silica, stearate, tartaric acid, atoleine, polyethylene glycol etc.
Tablet further can also be made to coating tablet, for example sugar coated tablet, thin membrane coated tablet, enteric coatingSheet, or double-layer tablet and multilayer tablet.
For capsule is made in administration unit, can be by active ingredient the compounds of this invention and diluent, helpStream agent mixes, and mixture is directly placed in to hard shell capsules or soft capsule. Also can be by active ingredient the compounds of this inventionElder generation and diluent, binder, disintegrant granulation or micropill, then be placed in hard shell capsules or soft capsule. Be used forEach diluent, binder, wetting agent, disintegrant, the glidant kind of preparing the compounds of this invention tablet also canFor the preparation of the capsule of the compounds of this invention.
For the compounds of this invention is made to injection, can water, ethanol, isopropyl alcohol, propane diols or theyMixture as solvent and add the conventional solubilizer in appropriate this area, cosolvent, pH to adjust agent, osmotic pressureConditioning agent. Solubilizer or cosolvent can be poloxamer, lecithin, HP-β-CD etc.; PH adjustsAgent agent can be phosphate, acetate, hydrochloric acid, NaOH etc.; Osmotic pressure regulator can be sodium chloride,Sweet mellow wine, glucose, phosphate, acetate etc. As prepare freeze drying powder injection, also can add sweet mellow wine, PortugalGrape sugar waits as proppant.
In addition,, as needs, also can in pharmaceutical preparation, add colouring agent, anticorrisive agent, spices, flavouringOr other additive.
For reaching medication object, strengthen result for the treatment of, medicine of the present invention or pharmaceutical composition can be used any public affairsThe medication administration of knowing.
The dosage of the compounds of this invention pharmaceutical composition is according to preventing or treat the character of disease and tightHeavy degree, the individual instances of patient or animal, method of administration and formulation etc. can have large-scale variation. Generally, the suitable dose scope of the every day of the compounds of this invention is 0.001-150mg/Kg body weight, is preferably0.01-100mg/Kg body weight. Above-mentioned dosage can a dosage unit or is divided into several dosage unit administrations, thisDepend on doctor's clinical experience and comprise the dosage regimen of using other treatment means.
Compound of the present invention or composition can be taken separately, or merge with other treatment medicine or symptomatic drugsUse. In the time of compound of the present invention and other medicine existence synergy, should be according to actual conditions adjustmentIts dosage.
The compounds of this invention is many target point proteins inhibitors of kinases or its precursor, and these protein kinases are according to phosphoric acidThe difference of changing substrate is divided into multiple families, as protein tyrosine kinase, and albumen serine/threonine kinase,Lipoid etc. Generally, protein kinase is transferred to one and letter by affecting a phosphoryl from a ribonucleoside triphosphoteThe protein receptor that number transduction pathway is relevant carrys out signal transduction in mediated cell. These phosphorylated events are as moleculeSwitch regulates the biological function of target protein, is finally excited and is reacted in various extracellulars and other stimulation. SwashEnzyme is present in multilayer signal transduction path, and receptor tyrosine kinase is positioned at tumor vessel and generates Signal transduction pathwayUpstream and the upstream of tumour cell Signal transduction pathway. Serine/threonine protein kitase is positioned at tumour and swollenThe downstream of the Signal transduction pathway of knurl Angiogenesis cell. Research show by upstream retardance VEGFR andPdgf receptor, suppresses Aurora A in downstream, can reduce the Angiogenesis of tumour simultaneously and suppress swollenCopying of oncocyte, thereby the growth of obstruction tumour. The compounds of this invention has higher bioavilability, canFor the treatment of multiple human malignancies, comprise that described tumor disease is liver cancer, cancer of the stomach, kidney, lung cancer,Cancer of pancreas, colorectal cancer, carcinoma of urinary bladder and breast cancer, oophoroma, squamous cell carcinoma, glioma, white bloodDisease, Head and Neck cancer.
Detailed description of the invention
Below with reference to embodiment, invention is described further, but does not limit the scope of the invention.
Determining instrument: VaariaanMercury300 or 400 type NMRs for NMR spectrum. Mass spectrum is usedZAD-2F and VG300 mass spectrograph.
Embodiment 1.2-(3-Aminotrifluorotoluene base)-4-(2-amino-4-methylthiazol-5-yl) pyridine
Bromo-2-4-(2-amino-4-methylthiazol-5-yl) pyridine (270mg, 1mmol) is joined to 10ml to be mixed moltenAgent (1NHCl/H2O/Dioxane=2/4/1) in, under stirring, be heated to 80 DEG C, between adding after to be dissolved threeMethyl fluoride aniline (242mg, 1.5mmol), and heat up, be back to and react completely. Be cooled to room temperature, will be anti-Answer liquid impouring to saturated sodium bicarbonate aqueous solution, filter, collect solid, column chromatography purification obtain product 2-(Trifluoromethylbenzene amido)-4-(2-amino-4-methylthiazol-5-yl) 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,-NH 2 ),7.18(d,1H,ArH),6.81(s,1H,ArH),6.77(d,1H,ArH),2.32(s,3H,-CH 3 )；m/z351.0[M+H]+.
Embodiment 2.2-(the chloro-6-toluidine of 2-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
By the chloro-6-methylaniline replacement of 2-3-Aminotrifluorotoluene, the operating process of reference example 1, obtains 2-(2-Chloro-6-toluidine)-4-(2-amino-4-methylthiazol-5-yl) pyridine.1H-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,-NH 2 ),6.60-6.58(dd,1H,ArH),6.37(s,1H,ArH),2.23(s,3H,-CH 3 ),2.18(s,3H,-CH 3 )；m/z331.0[M+H]+.
Embodiment 3.2-(2-fluoroanilino)-4-(2-amino-4-methylthiazol-5-yl) pyridine
By 2-fluoroaniline replacement 3-Aminotrifluorotoluene, the operating process of reference example 1, obtains 2-(2-fluoroanilineBase)-4-(2-amino-4-methylthiazol-5-yl) pyridine.1H-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,-NH 2 ,ArH),6.99-6.93(m,2H,ArH),6.73-6.70(m,1H,ArH),2.30(s,3H,-CH 3 )；m/z301.0[M+H]+.
Embodiment 4.2-(2,4-difluorobenzene amido)-4-(2-amino-4-methylthiazol-5-yl) pyridine
With 2,4-difluoroaniline replace 3-Aminotrifluorotoluene, the operating process of reference example 1, obtain 2-(2,4-difluorobenzene amido)-4-(2-amino-4-methylthiazol-5-yl) 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,-NH 2 ),7.04-6.98(m,1H,ArH),6.87(s,1H,ArH),6.70-6.68(m,1H,ArH),2.28(s,3H,-CH 3 )；m/z319.0[M+H]+.
Embodiment 5.2-(the bromo-4-fluoroanilino of 2-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
By the bromo-4-fluoroaniline replacement of 2-3-Aminotrifluorotoluene, the operating process of reference example 1, obtains 2-(2-Bromo-4-fluoroanilino)-4-(2-amino-4-methylthiazol-5-yl) 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,-NH 2 ),6.79(s,1H,ArH),6.70-6.68(m,1H,ArH),2.28(s,3H,-CH 3 )；m/z379.0[M+H]+.
Embodiment 6.2-(2-methoxyl group-4-N-methyl piperazine anilino-)-4-(2-amino-4-methylthiazol-5-yl)Pyridine
With 2-methoxyl group-4-N-methyl piperazine aniline replacement 3-Aminotrifluorotoluene, the operating process of reference example 1,Obtain 2-(2-methoxyl group-4-N-methyl piperazine anilino-)-4-(2-amino-4-methylthiazol-5-yl) 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,-NH 2 ),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,-OCH 3 ),3.11(brs,4H,-CH 2 CH2-),2.49(brs,4H,-CH 2 CH2-),2.25(brs,6H,-CH 3 )；m/z411.2[M+H]+.
Embodiment 7.2-(4-morpholine anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
By 4-morpholinyl phenylamine replacement 3-Aminotrifluorotoluene, the operating process of reference example 1, obtains 2-(4-Morpholine anilino-)-4-(2-amino-4-methylthiazol-5-yl) 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,-NH 2 ),6.88(d,2H,ArH),6.66(s,1H,ArH),6.61(d,1H,ArH),3.74(brs,4H,-CH 2 CH2-),3.02(brs,4H,-CH 2 CH2-),2.28(s,3H,-CH 3 )；m/z368.1[M+H]+.
Embodiment 8.2-(4-(ring propyl formamide base) anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
With 4-(ring propyl formamide base) aniline replacement 3-Aminotrifluorotoluene, the operating process of reference example 1,To 2-(4-(ring propyl formamide base) anilino-)-4-(2-amino-4-methylthiazol-5-yl) 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,-NH 2 ),6.66(d,1H,ArH),6.69(d,1H,ArH),2.30(s,3H,-CH 3 ),1.74(m,1H,-CH2CHCH2-),0.78-0.75(m,4H,-CH 2 CHCH 2 -)；m/z366.1[M+H]+.
Embodiment 9.2-(3,4,5-trimethoxy-benzene amido)-4-(2-amino-4-methylthiazol-5-yl) pyridine
By 3,4,5-trimethoxy-aniline replacement 3-Aminotrifluorotoluene, the operating process of reference example 1, obtains2-(3,4,5-trimethoxy-benzene amido)-4-(2-amino-4-methylthiazol-5-yl) 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,-NH 2 ),6.74(s,1H,ArH),6.66(d,1H,ArH),3.72(s,6H,-OCH 3 ),3.60(s,3H,-OCH 3 ),2.29(s,3H,-CH 3 )；m/z373.1[M+H]+.
Embodiment 10.2-(4-dimethylamino anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
By 4-dimethylamino aniline replacement 3-Aminotrifluorotoluene, the operating process of reference example 1, obtains 2-(4-Dimethylamino anilino-)-4-(2-amino-4-methylthiazol-5-yl) 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,-NH 2 ),6.71(d,2H,ArH),6.62(s,1H,ArH),6.57(d,1H,ArH),2.83(s,6H,-NCH 3 ),2.27(s,3H,-CH 3 )；m/z326.1[M+H]+.
Embodiment 11.2-(3-ring propyl formamide base anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
By 3-ring propyl formamide base aniline replacement 3-Aminotrifluorotoluene, the operating process of reference example 1, obtains2-(3-ring propyl formamide base anilino-)-4-(2-amino-4-methylthiazol-5-yl) 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,-NH 2 ),6.80(s,1H,ArH),6.69(d,1H,ArH),2.30(s,3H,-CH 3 ),1.81(m,1H,-CH2CHCH2-),0.79-0.77(m,4H,-CH 2 CHCH 2 -)；m/z366.1[M+H]+.
Embodiment 12.2-(4-(N methyl piperazine base) anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyrrolePyridine
With 4-(N methyl piperazine base) aniline replacement 3-Aminotrifluorotoluene, the operating process of reference example 1,Obtain 2-(4-(N methyl piperazine base) anilino-)-4-(2-amino-4-methylthiazol-5-yl) 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,-NH 2 ),6.87(d,2H,ArH),6.66(s,1H,ArH),6.60(d,1H,ArH),3.04(brs,4H,-CH 2 CH2-),2.46(brs,4H,-CH 2 CH2-),2.28(s,3H,-CH 3 ),2.22(s,3H,-CH 3 )；m/z381.1[M+H]+.
Embodiment 13.2-(m-nitro amido)-4-(2-amino-4-methylthiazol-5-yl) pyridine
Replace 3-Aminotrifluorotoluene with meta nitro aniline, the operating process of reference example 1, obtains a 2-(nitroAnilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine.
1HNMR(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-yl) pyridine
By m-aminophenyl amine replacement 3-Aminotrifluorotoluene, the operating process of reference example 1, obtains a 2-(aminoAnilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine.
1HNMR(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(brs,2H,-NH 2),2.29(s,3H,-CH 3).MS(FAB)(M++1＝298)。
Embodiment 15.2-(a propionamido anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
Replace a 3-Aminotrifluorotoluene with propionamido aniline, the operating process of reference example 1, obtain 2-(Propionamido anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine.
1HNMR(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,-NH 2 ),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-yl) pyridine
By isophthalic acetylaminoaniline replacement 3-Aminotrifluorotoluene, the operating process of reference example 1, obtains 2-(isophthalic acetyl amino phenyl amido)-4-(2-amino-4-methylthiazol-5-yl) pyridine.
1HNMR(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,-NH 2 ),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-yl) pyridine
By trifluoroacetamido aniline replacement 3-Aminotrifluorotoluene, the operating process of reference example 1, obtains 2-(3-trifluoroacetamido anilino-)-4-(2-amino-4-methylthiazol-5-yl) 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-yl) pyridine
1) bromo-2-4-(2-amino-4-methylthiazol-5-yl) pyridine (270mg, 1mmol) being joined to 10ml mixesBonding solvent (1NHCl/H2O/Dioxane=2/4/1) in, under stirring, be heated to 80 DEG C, add after to be dissolvedMeta nitro aniline (207mg, 1.5mmol), and heat up, be back to and react completely. Be cooled to room temperature, will be anti-Answer liquid impouring to saturated sodium bicarbonate aqueous solution, filter, collect solid, column chromatography purification obtains product 2-(3-Nitrobenzene amido)-4-(2-amino-4-methylthiazol-5-yl) pyridine.1HNMR(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-yl) pyridine (1mmol) is dissolved in lessIn amount DMA, add DMAP, drip chloroacetic chloride (1.2mmol), after dropwising, be warming up to 70 DEG C insteadShould, to completely, be cooled to room temperature, in reactant liquor, add saturated sodium bicarbonate aqueous solution, have solid to separate out, mistakeFilter, column chromatography purification obtains product.1HNMR(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(brs,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-yl) pyridine
With 3-5-trifluoromethylaniline replacement 3-nitroaniline, acryloyl chloride replaces chloroacetic chloride, the behaviour of reference example 18Make process, obtain 2-(3-trifluoromethylbenzene amido)-4-(2-acrylamido-4-methylthiazol-5-yl) pyrrolePyridine.1H-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-methyl thiazoliumAzoles-5-yl) pyridine
With 3-5-trifluoromethylaniline replacement 3-nitroaniline, 3-dimethyl acryloyl chloride replaces chloroacetic chloride, reference example18 operating process, obtains 2-(3-trifluoromethylbenzene amido)-4-(2-(3-dimethyl allene acyl) amino-4-Methylthiazol-5-yl) 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,-CH 3 ),2.22(s,3H,-CH 3 ),1.91(s,3H,-CH 3 ).MS(FAB)(M++1＝433)。
Embodiment 21.2-(3-trifluoromethylbenzene amido)-4-(2-(hexadiene-2,4-acylamino-)-4-methylthiazol-5-yl) pyridine
With 3-5-trifluoromethylaniline replacement 3-nitroaniline, hexadiene-2,4-acyl chlorides replaces chloroacetic chloride, reference example18 operating process, obtains 2-(3-trifluoromethylbenzene amido)-4-(2-(hexadiene-2,4-acylamino-)-4-Methylthiazol-5-yl) 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,-CH 3 ),1.85(s,3H,-CH 3 ).MS(FAB)(M++1＝445)。
Embodiment 22.2-(3-trifluoromethylbenzene amido)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
With 3-5-trifluoromethylaniline replacement 3-nitroaniline, the operating process of reference example 18, obtains 2-(3-tri-Methyl fluoride anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) 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,-CH 3 ),2.19(s,3H,-CH 3 ).MS(FAB)(M++1＝393)。
Embodiment 23.2-(3-trifluoromethylbenzene amido)-4-(2-propionamido-4-methylthiazol-5-yl) pyridine
With 3-5-trifluoromethylaniline replacement 3-nitroaniline, propionyl chloride replaces chloroacetic chloride, the operation of reference example 18Process, obtains 2-(3-trifluoromethylbenzene amido)-4-(2-propionamido-4-methylthiazol-5-yl) 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,-CH 3 ,-CH 2 -),1.13-1.08(t,3H,-CH 3 ).MS(FAB)(M++1＝407)。
Embodiment 24.2-(3-trifluoromethylbenzene amido)-4-(2-(3-methylbutyryl amino)-4-methylthiazol-5-yl)Pyridine
With 3-5-trifluoromethylaniline replacement 3-nitroaniline, 3-Methylbutanoyl chloride replaces chloroacetic chloride, reference example 18Operating process, obtain 2-(3-trifluoromethylbenzene amido)-4-(2-(3-methylbutyryl amino)-4-methylthiazol-5-yl) 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,-CH 3 ), 2.34-2.32(d,2H,-CH 2 -),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-yl) pyridine
With 3-5-trifluoromethylaniline replacement 3-nitroaniline, valeric chloride replaces chloroacetic chloride, the operation of reference example 18Process, obtains 2-(3-trifluoromethylbenzene amido)-4-(2-valeryl amino-4-methylthiazol-5-yl) 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,-CH 3 ,-CH 2 -),1.78-1.68(m,2H,-CH 2 -),1.44-1.36(m,2H,-CH 2 -),0.96-0.91(t,3H,-CH2CH 3).MS(FAB)(M++1＝435)。
Embodiment 26.2-(3-trifluoromethylbenzene amido)-4-(2-cyclopropyl formamido group-4-methylthiazol-5-yl)Pyridine
With 3-5-trifluoromethylaniline replacement 3-nitroaniline, cyclopropyl formyl chloride replaces chloroacetic chloride, reference example 18Operating process, obtain 2-(3-trifluoromethylbenzene amido)-4-(2-cyclopropyl formamido group-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,-CH 3 ),1.64(m,1H, -CH-),1.25-1.22(m,2H,-CH 2 -),1.01-0.99(m,2H,-CH 2 -).MS(FAB)(M++1＝419)。
Embodiment 27.2-(3-trifluoromethylbenzene amido)-4-(2-cyclobutylmethyl acylamino--4-methylthiazol-5-yl)Pyridine
With 3-5-trifluoromethylaniline replacement 3-nitroaniline, cyclobutylmethyl acyl chlorides replaces chloroacetic chloride, reference example 18Operating process, obtain 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,-CH 3 ),2.23-2.15(m,4H,-CH 2 -),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-yl)Pyridine
With 3-5-trifluoromethylaniline replacement 3-nitroaniline, cyclopenta formyl chloride replaces chloroacetic chloride, reference example 18Operating process, obtain 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, -CH 3 ),1.86(m,2H,-CH 2 -),1.68-1.56(m,6H,-CH 2-).MS(FAB)(M++1＝447)。
Embodiment 29.2-(3-trifluoromethylbenzene amido)-4-(2-m-chloro benzamido-4-methylthiazol-5-yl)Pyridine
With 3-5-trifluoromethylaniline replacement 3-nitroaniline, m-chlorobenzoyl chloride replaces chloroacetic chloride, reference example 18Operating process, obtain 2-(3-trifluoromethylbenzene amido)-4-(2-m-chloro benzamido-4-methylthiazol-5-Base) 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,-CH 3 ).MS(FAB)(M++1＝490)。
Embodiment 30.2-(3-trifluoromethylbenzene amido)-4-(fluorobenzene acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl between 2-)Pyridine
With 3-5-trifluoromethylaniline replacement 3-nitroaniline, a fluorophenylacetyl chloride replaces chloroacetic chloride, reference example 18Operating process, obtain 2-(3-trifluoromethylbenzene amido)-4-(fluorobenzene acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-between 2-Base) 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,-CH 3 ).MS(FAB)(M++1＝487)。
Embodiment 31.2-(3-trifluoromethylbenzene amido)-4-(2-m-fluoroaniline formamido group-4-methylthiazol-5-yl)Pyridine
With 3-5-trifluoromethylaniline replacement 3-nitroaniline, m-fluoroaniline formyl chloride replaces chloroacetic chloride, reference example18 operating process, obtains 2-(3-trifluoromethylbenzene amido)-4-(2-m-fluoroaniline formamido group-4-methylThiazole-5-yl) 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,-CH 3 ).MS(FAB)(M++1＝488)。
Embodiment 32.2-(adjacent fluoroanilino)-4-(2-acrylyl amino-4-methylthiazol-5-yl) pyridine
With adjacent fluoroaniline replacement 3-nitroaniline, acryloyl chloride replaces chloroacetic chloride, the operating process of reference example 18,Obtain 2-(adjacent fluoroanilino)-4-(2-acrylyl amino-4-methylthiazol-5-yl) 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,-CH 3 ).MS(FAB)(M++1＝355)。
Embodiment 33.2-(2,4-dichloroanilino)-4-(2-acrylyl amino-4-methylthiazol-5-yl) pyridine
With 2,4-dichloroaniline replacement 3-nitroaniline, acryloyl chloride replaces chloroacetic chloride, the behaviour of reference example 18Make process, obtain 2-(2,4-dichloroanilino)-4-(2-acrylyl amino-4-methylthiazol-5-yl) 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,-CH 3 ).MS(FAB)(M++1＝406)。
Embodiment 34.2-(p-dimethylamino aniline base)-4-(2-acrylyl amino-4-methylthiazol-5-yl) pyridine
With p-dimethylamino aniline replacement 3-nitroaniline, acryloyl chloride replaces chloroacetic chloride, the behaviour of reference example 18Make process, obtain 2-(p-dimethylamino aniline base)-4-(2-acrylyl amino-4-methylthiazol-5-yl) pyrrolePyridine.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,-CH 3 ),2.43(s,3H,-CH 3 ).MS(FAB)(M++1＝380)。
Embodiment 35.2-(3,4,5-trimethoxy-benzene amido)-4-(2-acrylyl amino-4-methylthiazol-5-yl)Pyridine
With 3,4,5-trimethoxy-aniline replacement 3-nitroaniline, acryloyl chloride replaces chloroacetic chloride, reference example18 operating process, obtains 2-(3,4,5-trimethoxy-benzene amido)-4-(2-acrylyl amino-4-methylThiazole-5-yl) 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,-OCH 3 ),3.61(s,3H,-OCH 3 ),2.46(s,3H,-CH 3 ).MS(FAB)(M++1＝427)。
Embodiment 36.2-(4-encircles the third formamido group anilino-)-4-(2-acrylyl amino-4-methylthiazol-5-yl)Pyridine
Encircle the third formamido group aniline with 4-and replace 3-nitroaniline, acryloyl chloride replaces chloroacetic chloride, reference example 18Operating process, obtain 2-(4-encircles the third formamido group anilino-)-4-(2-acrylyl amino-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,-CH 3 ),1.74(m,1H,-CH),0.76-0.73(m,4H,-CH 2 CH 2 -).MS(FAB)(M++1＝420)。
Embodiment 37.2-(3-encircles the third formamido group anilino-)-4-(2-acrylyl amino-4-methylthiazol-5-yl)Pyridine
Encircle the third formamido group aniline with 3-and replace 3-nitroaniline, acryloyl chloride replaces chloroacetic chloride, reference example 18Operating process, obtain 2-(3-encircles the third formamido group anilino-)-4-(2-acrylyl amino-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,-CH 3 ),1.61(m,1H,-CH),0.78-0.75(m,4H,-CH 2 CH 2 -).MS(FAB)(M++1＝420)。
Embodiment 38.2-(adjacent fluoroanilino)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
With adjacent fluoroaniline replacement 3-nitroaniline, ring the third formyl chloride replaces chloroacetic chloride, the operation of reference example 18Journey, obtains 2-(adjacent fluoroanilino)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) 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,-CH 3 ),1.96-1.92(m,1H,-CH-),0.94-0.91(m,4H,-CH 2CH 2 -).MS(FAB)(M++1＝369)。
Embodiment 39.2-(2,4-dichloroanilino)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
With 2,4-dichloroaniline replacement 3-nitroaniline, ring the third formyl chloride replaces chloroacetic chloride, reference example 18Operating process, obtains 2-(2,4-dichloroanilino)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl)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,-CH 3 ),1.95(m,1H,-CH-),0.94-0.92(m,4H,-CH 2CH 2 -).MS(FAB)(M++1＝420)。
Embodiment 40.2-(p-dimethylamino aniline base)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyrrolePyridine
With p-dimethylamino aniline replacement 3-nitroaniline, ring the third formyl chloride replaces chloroacetic chloride, reference example 18Operating process, obtains 2-(p-dimethylamino aniline base)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl)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,-NCH 3 ),2.41(s,3H,-CH 3 ),1.92(m,1H,-CH-),0.90(brs,4H,-CH 2CH 2 -).MS(FAB)(M++1＝394)。
(2-encircles the third formamido group-4-methylthiazol-5-to embodiment 41.2-(3,4,5-trimethoxy-benzene amido)-4-Base) pyridine
With 3,4,5-trimethoxy-aniline replacement 3-nitroaniline, ring the third formyl chloride replaces chloroacetic chloride, reference implementationThe operating process of example 18, (2-encircles the third formamido group-4-to-4-to obtain 2-(3,4,5-trimethoxy-benzene amido)Methylthiazol-5-yl) 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,-OCH 3 ),3.62(s,3H,-OCH 3 ),2.46(s,3H,-CH 3 ),1.95(m,1H,-CH-),0.92(brs,4H,-CH 2CH 2 -).MS(FAB)(M++1＝441)。
Embodiment 42.2-(to morpholinyl anilino-)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
With morpholinyl phenylamine is replaced to 3-nitroaniline, ring the third formyl chloride replaces chloroacetic chloride, the behaviour of reference example 18Make process, obtain 2-(to morpholinyl anilino-)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyrrolePyridine.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 2CH 2 -),3.03(brs,4H,-CH 2CH 2 -),2.43(s,3H,-CH 3 ),1.94(m,1H,-CH-),0.91(brs,4H,-CH 2CH 2 -).MS(FAB)(M++1＝436)。
Embodiment 43.2-(adjacent fluoroanilino)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
With adjacent fluoroaniline replacement 3-nitroaniline, the operating process of reference example 18, obtains 2-(adjacent fluoroanilino)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) 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,-CH 3 ),2.15(s,3H,-CH 3 ).MS(FAB)(M++1＝343)。
Embodiment 44.2-(2,4-dichloroanilino)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
With 2,4-dichloroaniline replacement 3-nitroaniline, the operating process of reference example 18, obtains 2-(2,4-Dichloroanilino)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) 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,-CH 3 ),2.28(s,3H,-CH 3 ).MS(FAB)(M++1＝394)。
Embodiment 45.2-(p-dimethylamino aniline base)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
With p-dimethylamino aniline replacement 3-nitroaniline, the operating process of reference example 18, obtains 2-(to twoMethylamino anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) 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,-CH 3 ),2.36(s,3H,-CH 3 ),2.26(s,3H,-CH 3 ).MS(FAB)(M++1＝368)。
Embodiment 46.2-(3,4,5-trimethoxy-benzene amido)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl)Pyridine
With 3,4,5-trimethoxy-aniline replacement 3-nitroaniline, the operating process of reference example 18, obtains 2-(3,4,5-trimethoxy-benzene amido)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) 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,-CH 3 ),2.28(s,3H,-CH 3 ).MS(FAB)(M++1＝415)。
Embodiment 47.2-(to encircling the third formamido group anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyrrolePyridine
With replacing 3-nitroaniline to encircling the third formamido group aniline, the operating process of reference example 18, obtains 2-(rightEncircle the third formamido group anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) 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,-CH 3 ),2.14(s,3H,-CH 3 ),1.75(brs,1H, -CH-),0.77(brs,4H,-CH 2CH 2 -).MS(FAB)(M++1＝408)。
Embodiment 48.2-(to morpholinyl anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
With morpholinyl phenylamine is replaced to 3-nitroaniline, the operating process of reference example 18, obtains 2-(to morpholineBase anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) 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,-CH 2 CH 2 -),3.17-3.14(t,4H,-CH 2 CH 2 -),2.37(s,3H,-CH 3 ),2.28(s,3H,-CH 3 ).MS(FAB)(M++1＝410)。
Embodiment 49.2-(ring the third formamido group anilino-)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl)Pyridine
By bromo-2-4-(2-amino-4-methylthiazol-5-yl) pyridine (270mg, 1mmol) (542mg, 2.0Mmol), in n-butanol (5ml), then add m-phenylene diamine (MPD) (4.0mmol) and concentrated hydrochloric acid (0.33ml, 4.0Mmol), 160 DEG C of reaction 15min of microwave, are cooled to room temperature, pour reactant liquor into saturated aqueous sodium carbonateIn, ethyl acetate extraction, gets organic layer anhydrous sodium sulfate drying, and concentrated, column chromatography obtains phenalgin amido between 2--4-(2-amino-4-methylthiazol-5-yl) pyridine.1HNMR(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(brs, 2H,-NH 2),2.29(s,3H,-CH 3).MS(FAB)(M++1＝298)
Phenalgin amido-4-between 2-(2-amino-4-methylthiazol-5-yl) pyridine (1equiv) is dissolved in to a small amount of DMAIn, add DMAP (3equiv), drip ring the third formyl chloride (2.2equiv), after dropwising, be warming up to 70DEG C reaction is to completely, and room temperature when cooling adds saturated sodium bicarbonate aqueous solution in reactant liquor, has solid to separate out,Filter, column chromatography had both obtained product 2-(ring the third formamido group anilino-), and (2-encircles the third formamido group-4-first to-4-Base thiazole-5-yl) 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,-CH 3 ),1.93(brs,1H,-CH-),1.81(brs,1H,-CH-),0.91(brs,4H,-CH 2CH 2 -),0.78(brs,4H,-CH 2CH 2 -).MS(FAB)(M++1＝434)。
Embodiment 50.2-(to encircling the third formamido group anilino-)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl)Pyridine
With replacing 3-nitroaniline to encircling the third formamido group aniline, cyclopropyl formyl chloride replaces chloroacetic chloride, reference example18 operating process, (2-encircles the third formamido group-4-methyl to-4-to obtain 2-(to encircling the third formamido group anilino-)Thiazole-5-yl) 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,-CH 3 ),1.94(m,1H,-CH-),1.75(m,1H,-CH-),0.92(brs,4H,-CH 2CH2-),0.77-0.75(m,4H,-CH 2CH 2 -).MS(FAB)(M++1＝434)。
Embodiment 51.2-(ring the third formamido group anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyrrolePyridine
By bromo-2-4-(2-amino-4-methylthiazol-5-yl) pyridine (270mg, 1mmol) (542mg, 2.0Mmol), in n-butanol (5ml), then add m-phenylene diamine (MPD) (4.0mmol) and concentrated hydrochloric acid (0.33ml, 4.0Mmol), 160 DEG C of reaction 15min of microwave, are cooled to room temperature, pour reactant liquor into saturated aqueous sodium carbonateIn, ethyl acetate extraction, gets organic layer anhydrous sodium sulfate drying, and concentrated, column chromatography obtains phenalgin amido between 2--4-(2-amino-4-methylthiazol-5-yl) pyridine.1HNMR(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(brs,2H,-NH 2),2.29(s,3H,-CH 3).MS(FAB)(M++1＝298)
Phenalgin amido-4-between 2-(2-amino-4-methylthiazol-5-yl) pyridine (1equiv) is dissolved in to a small amount of DMAIn, add DMAP (3equiv), drip ring the third formyl chloride (1.1equiv), after dropwising, be warming up to 70DEG C reaction is to completely, and room temperature when cooling adds saturated sodium bicarbonate aqueous solution in reactant liquor, has solid to separate out,Filter, column chromatography had both obtained 2-(ring the third formamido group anilino-)-4-(2-amino-4-methylthiazol-5-yl)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,-NH 2 ),6.80(s,1H,ArH),6.69(d,1H,ArH),2.30(s,3H,-CH 3 ),1.81(m,1H,-CH2CHCH2-),0.79-0.77(m,4H,-CH 2 CHCH 2 -)；m/z366.1[M+H]+.
By 2-(ring the third formamido group anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine (1equiv)Be dissolved in a small amount of DMA, add DMAP (3equiv), drip chloroacetic chloride (1.1equiv), dropwiseAfter be warming up to 70 DEG C of reactions to completely, room temperature when cooling adds saturated sodium bicarbonate aqueous solution in reactant liquor,There is solid to separate out, filter and both obtain product 2-(ring the third formamido group anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-firstBase thiazole-5-yl) 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,-CH 3 ),2.16(s,3H,-CH 3 ),1.82(brs,1H,-CH-),0.79(brs,4H,-CH 2CH 2 -).MS(FAB)(M++1＝408)。
Embodiment 52.2-(m-acetamidoaniline base)-4-(acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
With m-acetamidoaniline replacement 3-nitroaniline, the operating process of reference example 18, obtains a 2-(secondAcylamino-anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine.1HNMR(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,-CH 3 ),2.04(s,3H,-CH 3 ).MS(FAB)(M++1＝382)。
Embodiment 53.2-(a propionamido anilino-)-4-(2-propionamido-4-methylthiazol-5-yl) pyridine
By bromo-2-4-(2-amino-4-methylthiazol-5-yl) pyridine (270mg, 1mmol) (542mg, 2.0Mmol), in n-butanol (5ml), then add m-phenylene diamine (MPD) (4.0mmol) and concentrated hydrochloric acid (0.33ml, 4.0Mmol), 160 DEG C of reaction 15min of microwave, are cooled to room temperature, pour reactant liquor into saturated aqueous sodium carbonateIn, ethyl acetate extraction, gets organic layer anhydrous sodium sulfate drying, and concentrated, column chromatography obtains phenalgin amido between 2--4-(2-amino-4-methylthiazol-5-yl) pyridine.1HNMR(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(brs,2H,-NH 2),2.29(s,3H,-CH 3).MS(FAB)(M++1＝298)
Phenalgin amido-4-between 2-(2-amino-4-methylthiazol-5-yl) pyridine (1equiv) is dissolved in to a small amount of DMAIn, add DMAP (3equiv), drip propionyl chloride (2.2equiv), after dropwising, be warming up to 70 DEG CReaction is to complete, and room temperature when cooling adds saturated sodium bicarbonate aqueous solution in reactant liquor, has solid to separate out,Filter, column chromatography had both obtained product 2-(a propionamido anilino-)-4-(2-propionamido-4-methylthiazol-5-Base) pyridine.1HNMR(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,-CH 2 ),1.11-1.04(m,6H,-CH 3 ).MS(FAB)(M++1＝410)。
Embodiment 54.2-(3-isopropyl formamido group anilino-)-4-(2-isopropyl formamido group-4-methylthiazol-5-yl)Pyridine
With 3-isopropyl formamido group aniline replacement 3-nitroaniline, isopropyl formyl chloride replaces chloroacetic chloride, reference example18 operating process, obtains 2-(3-isopropyl formamido group anilino-)-4-(2-isopropyl formamido group-4-methylThiazole-5-yl) pyridine.1HNMR(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,-CH 3 ).MS(FAB)(M++1＝438)。
Embodiment 55.2-(the tertiary fourth formamido group of 3-anilino-)-4-(the tertiary fourth formamido group-4-of 2-methylthiazol-5-yl)Pyridine
With the tertiary fourth formamido group of 3-aniline replacement 3-nitroaniline, tertiary fourth formyl chloride replaces chloroacetic chloride, reference example18 operating process, obtains the tertiary fourth formamido group of 2-3-anilino-)-4-(the tertiary fourth formamido group-4-of 2-methyl thiazoliumAzoles-5-yl) pyridine.1HNMR(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(brs,18H,-CH 3 ).MS(FAB)(M++1＝466)。
Embodiment 56.2-(3-(3-methyl butene-2-acylamino-) anilino-)-4-(2-(3-methyl butene-2-acylamino-)-4-Methylthiazol-5-yl) pyridine
With 3-(3-methyl butene-2-acylamino-) aniline replacement 3-nitroaniline, 3-methyl butene-2-acyl chlorides replaces chloroacetic chloride,The operating process of reference example 18, obtains 2-(3-(3-methyl butene-2-acylamino-) anilino-)-4-(2-(3-Methyl butene-2-acylamino-)-4-methylthiazol-5-yl) pyridine.1HNMR(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,-CH 3 ),2.16(s,3H,-CH 3 ),1.91(s,3H,-CH 3 ),1.86(s,3H,-CH 3 ).MS(FAB)(M++1＝462)。
Embodiment 57.2-(3-ring fourth formamido group anilino-)-4-(2-ring fourth formamido group-4-methylthiazol-5-yl)Pyridine
With 3-ring fourth formamido group aniline replacement 3-nitroaniline, ring fourth formyl chloride replaces chloroacetic chloride, reference example18 operating process, obtains 2-(3-ring fourth formamido group anilino-)-4-(2-ring fourth formamido group-4-methylThiazole-5-yl) pyridine.1HNMR(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(brs,3H,-CH 3),2.32-2.12(m,8H,-CH 2 -),2.00-1.81(m,4H,-CH 2 -).MS(FAB)(M++1＝462)。
Embodiment 58.2-(3-encircles the third formamido group anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyrrolePyridine
Encircle the third formamido group aniline with 3-and replace 3-nitroaniline, the operating process of reference example 18, obtains 2-(3-Encircle the third formamido group anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine.1HNMR(300MHz,DMSO-d6):δ12.23(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(brs,4H,-CH 2CH 2 -).MS(FAB)(M++1＝408)。
Embodiment 59.2-(3-encircles the third formamido group anilino-)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl)Pyridine
Encircle the third formamido group aniline with 3-and replace 3-nitroaniline, ring the third formyl chloride replaces chloroacetic chloride, reference example18 operating process, (2-encircles the third formamido group-4-methyl to obtain 2-(3-encircles the third formamido group anilino-)-4-Thiazole-5-yl) pyridine.1HNMR(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(brs,4H,-CH 2CH 2 -),0.79(brs,4H,-CH 2CH 2 -).MS(FAB)(M++1＝434)。
Embodiment 60.2-(3-encircles the third formamido group anilino-)-4-(2-isobutyl formamido group-4-methylthiazol-5-yl)Pyridine
Encircle the third formamido group aniline with 3-and replace 3-nitroaniline, isobutyl formyl chloride replaces chloroacetic chloride, reference example18 operating process, obtains 2-(3-encircles the third formamido group anilino-)-4-(2-isobutyl formamido group-4-methylThiazole-5-yl) pyridine.1HNMR(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,-CH 2 -),2.11-2.07(m,1H,-CH-),1.82(m,1H,-CH-),0.93-0.91(d,6H,-CH 3),0.79(brs,4H,-CH 2CH 2 -).MS(FAB)(M++1＝450)。
Embodiment 61.2-(3-encircles the third formamido group anilino-)-4-(2-(3-methyl butene-2-acylamino-)-4-methyl thiazoliumAzoles-5-yl) pyridine
Encircle the third formamido group aniline with 3-and replace 3-nitroaniline, 3-methyl butene-2-acyl chlorides replaces chloroacetic chloride, referenceThe operating process of embodiment 18, obtains 2-(3-encircles the third formamido group anilino-)-4-(2-(3-methyl butene-2-Acylamino-)-4-methylthiazol-5-yl) pyridine.1HNMR(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(brs,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,-CH 3 ),1.91(s,3H,-CH 3),1.82(m,1H,-CH-),0.79(m,4H,-CH 2CH 2 -).MS(FAB)(M++1＝448)。
Embodiment 62.2-(3-encircles the third formamido group anilino-)-4-(2-cyclopenta formamido group-4-methylthiazol-5-Base) pyridine
Encircle the third formamido group aniline with 3-and replace 3-nitroaniline, cyclopenta formyl chloride replaces chloroacetic chloride, reference implementationThe operating process of example 18, obtains 2-(3-encircles the third formamido group anilino-)-4-(2-cyclopenta formamido group-4-Methylthiazol-5-yl) pyridine.1HNMR(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,-CH 3 ),1.87-1.57(m,9H,-CH 2 -,-CH-),0.79(brs,4H,-CH 2CH 2 -).MS(FAB)(M++1＝462)。
(2-is to toluyl amino-4-methylthiazol-5-for embodiment 63.2-(3-encircles the third formamido group anilino-)-4-Base) pyridine
Encircle the third formamido group aniline with 3-and replace 3-nitroaniline, Butyltriphenylphosphonium chloride replaces chloroacetic chloride, reference implementationThe operating process of example 18, (2-is to toluyl amino-4-for-4-to obtain 2-(3-encircles the third formamido group anilino-)Methylthiazol-5-yl) pyridine.1HNMR(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(brs,1H,-CH-),0.79-0.77(m,4H,-CH 2CH 2 -).MS(FAB)(M++1＝484)。
Embodiment 64.2-(3-encircles the third formamido group anilino-)-4-(2-phenylacetylamino-4-methylthiazol-5-yl)Pyridine
Encircle the third formamido group aniline with 3-and replace 3-nitroaniline, phenyllacetyl chloride replaces chloroacetic chloride, reference example 18Operating process, obtain 2-(3-encircles the third formamido group anilino-)-4-(2-phenylacetylamino-4-methylthiazol-5-Base) pyridine.1HNMR(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,-CH 2 -),2.45(s,3H,-CH 3 ),1.81(brs,1H,-CH-),0.79(brs,4H,-CH 2CH 2 -).MS(FAB)(M++1＝484)。
Embodiment 65.2-(3-nitrobenzene amido)-4-(2-trifluoroacetyl amido-4-methylthiazol-5-yl) pyridine
Replace chloroacetic chloride with trifluoro-acetyl chloride, the operating process of reference example 18, obtains 2-(3-nitrobenzene amido)-4-(2-trifluoroacetyl amido-4-methylthiazol-5-yl) 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,-CH 3 ).MS(FAB)(M++1＝424)。
Embodiment 66.2-(3-nitrobenzene amido)-4-(2-ring propyl formamide base-4-methylthiazol-5-yl) pyridine
With cyclopropyl formyl chloride replacement chloroacetic chloride, the operating process of reference example 18, obtains 2-(3-nitroanilineBase)-4-(2-ring propyl formamide base-4-methylthiazol-5-yl) 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,-CH 3 ),1.78(brs,1H,-CH2CHCH2-),0.82-0.77(m,4H,-CH 2 CHCH 2 -).MS(FAB)(M++1＝396)。
Embodiment 67.2-(3-nitrobenzene amido)-4-(2-isopropyl formamido-4-methylthiazol-5-yl) pyridine
With isopropyl formyl chloride replacement chloroacetic chloride, the operating process of reference example 18, obtains 2-(3-nitroanilineBase)-4-(2-isopropyl formamido-4-methylthiazol-5-yl) 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,-CH 3 ),1.14(brs,6H,CH 3 CHCH 3 ).MS(FAB)(M++1＝398)。
Embodiment 68.2-(3-aminobenzene amido)-4-(2-ring propyl formamide base-4-methylthiazol-5-yl) pyridine
With 3-amino aniline replacement 3-nitroaniline, cyclopropyl formyl chloride replaces chloroacetic chloride, the behaviour of reference example 18Make process, obtain 2-(3-aminobenzene amido)-4-(2-ring propyl formamide base-4-methylthiazol-5-yl) 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,-NH 2 ),2.44(s,3H,-CH 3 ),1.95-1.92(m,1H,-CH2CHCH2-),0.93-0.89(m,4H,-CH 2 CHCH 2 -).MS(FAB)(M++1＝366)。
Embodiment 69.2-(3-aminobenzene amido)-4-(2-isopropyl formamido-4-methylthiazol-5-yl) pyridine
With 3-amino aniline replacement 3-nitroaniline, isopropyl formyl chloride replaces chloroacetic chloride, the behaviour of reference example 18Make process, obtain 2-(3-aminobenzene amido)-4-(2-isopropyl formamido-4-methylthiazol-5-yl) 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(brs,2H,-NH2),2.75-2.72(m,1H,-CH-),2.44(s,3H,-CH 3 ),1.14-1.12(m,6H,CH 3 CHCH 3 ).MS(FAB)(M++1＝368)。
Embodiment 70.2-(3-trifluoroacetamido anilino-)-4-(2-trifluoroacetamido-4-methylthiazol-5-yl)Pyridine
With 3-trifluoroacetamido aniline replacement 3-nitroaniline, trifluoro-acetyl chloride replaces chloroacetic chloride, reference example18 operating process, obtains 2-(3-trifluoroacetamido anilino-)-4-(2-trifluoroacetamido-4-methylThiazole-5-yl) pyridine.1HNMR(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-encircles the third formamido group-4-methylthiazol-5-yl)Pyridine
With 3-trifluoroacetamido aniline replacement 3-nitroaniline, cyclopropyl formyl chloride replaces chloroacetic chloride, reference implementationThe operating process of example 18, (2-encircles the third formamido group-4-first to obtain 2-(3-trifluoroacetamido anilino-)-4-Base thiazole-5-yl) pyridine.1HNMR(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(brs,1H,ArH),7.28(brs,1H,ArH),7.19(brs,1H,ArH),6.95(s,1H,ArH),6.85(brs,1H,ArH),2.46(s,3H,-CH3),1.96(brs,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-yl) pyrrolePyridine
With 3-trifluoroacetamido aniline replacement 3-nitroaniline, the operating process of reference example 18, obtains 2-(3-Trifluoroacetamido anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine.1HNMR(400MHz,DMSO-d6)δ12.23(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-encircles the third formamido group-4-methylthiazol-5-yl)Pyridine
By bromo-2-4-(2-amino-4-methylthiazol-5-yl) pyridine (270mg, 1mmol) (542mg, 2.0Mmol), in n-butanol (5ml), then add meta nitro aniline (4.0mmol) and concentrated hydrochloric acid (0.33ml, 4.0Mmol), 160 DEG C of reaction 15min of microwave, are cooled to room temperature, pour reactant liquor into saturated aqueous sodium carbonateIn, ethyl acetate extraction, gets organic layer anhydrous sodium sulfate drying, and concentrated, column chromatography obtains 2-meta nitro anilineBase-4-(2-amino-4-methylthiazol-5-yl) pyridine.1HNMR(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-yl) pyridine (1equiv) is dissolved on a small quantityIn DMA, add DMAP (3equiv), drip ring the third formyl chloride (1.1equiv), dropwise rear intensificationTo 70 DEG C of reactions to complete, room temperature when cooling adds saturated sodium bicarbonate aqueous solution in reactant liquor, has solidBody is separated out, and filters and both obtains product 2-m-nitro amido-4-(2-ring propyl formamide base-4-methylthiazol-5-yl)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,-CH 3 ),1.78(brs,1H,-CH2CHCH2-),0.82-0.77(m,4H,-CH 2 CHCH 2 -).ESI-MS:[M+H]+396
Iron powder (5.0equiv) is placed in to 2ml2NHCl solution and stirs 5min, then add 2-m-nitroThe methanol solution of amido-4-(2-ring propyl formamide base-4-methylthiazol-5-yl) pyridine (1.0equiv), heats up backFlow to and react completely, be cooled to room temperature, add saturated sodium bicarbonate aqueous solution neutralization reaction liquid, ethyl acetate extractionGet 3 times, merge organic layer, dry 2-m-aminophenyl amido-4-(2-ring propyl formamide base-4-methyl that concentrates to obtainThiazole-5-yl) 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,-NH 2 ),2.44(s,3H,-CH 3 ),1.95-1.92(m,1H,-CH2CHCH2-),0.93-0.89(m,4H,-CH 2 CHCH 2 -).ESI-MS:[M+H]+366
By 2-m-aminophenyl amido-4-(2-ring propyl formamide base-4-methylthiazol-5-yl) pyridine (1.0equiv)Be dissolved in a small amount of DMA, add DMAP (3.0equiv), drip ring fourth formyl chloride (1.1equiv), dripAfter finishing, be warming up to 70 DEG C, reaction, to completely, is cooled to room temperature, in reactant liquor, adds saturated sodium bicarbonate waterSolution, has solid to separate out, and filters, and column chromatography obtains 2-(3-ring fourth formamido group anilino-), and (2-encircles the third first to-4-Acylamino--4-methylthiazol-5-yl) pyridine.1HNMR(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(brs,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(brs,4H,-CH2-)；ESI-MS:[M+H]+448。
Embodiment 74.2-(3-trifluoroacetamido anilino-)-4-(2-ring fourth formamido group-4-methylthiazol-5-yl)Pyridine
With 3-trifluoroacetamido aniline replacement 3-nitroaniline, cyclobutylmethyl acyl chlorides replaces chloroacetic chloride, reference implementationThe operating process of example 18, obtains 2-(3-trifluoroacetamido anilino-)-4-(2-ring fourth formamido group-4-firstBase thiazole-5-yl) pyridine.1HNMR(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-yl)Pyridine
With 3-ring fourth formamido group aniline replacement 3-nitroaniline, isopropyl formyl chloride replaces chloroacetic chloride, reference implementationThe operating process of example 18, obtains 2-(3-ring fourth formamido group anilino-)-4-(2-isopropyl formamido group-4-firstBase thiazole-5-yl) pyridine.1HNMR(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(brs,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(brs,2H,-CH2-),1.96-1.90(m,2H,-CH2-),1.14-1.12(brs,6H,-CH3)；ESI-MS:[M+H]+450。
Embodiment 76.2-(3-encircles the third formamido group anilino-)-4-(2-trifluoroacetamido-4-methylthiazol-5-yl)Pyridine
Encircle the third formamido group aniline with 3-and replace 3-nitroaniline, trifluoro-acetyl chloride replaces chloroacetic chloride, reference example18 operating process, obtains 2-(3-encircles the third formamido group anilino-)-4-(2-trifluoroacetamido-4-methylThiazole-5-yl) pyridine.1HNMR(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(brs,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。
Pharmacologically active
External activity is evaluated:
Mtt assay is measured tumour cell survival rate
Be 0.8～2 × 10 by the cell of exponential phase with being mixed with concentration after trypsinization4Cell/ml's is thinCytosol, is inoculated in 96 orifice plates by 1000/hole, and every hole adds 100 μ l. Add next day containing variable concentrations medicineThe fresh culture of thing and coordinative solvent contrast, every hole adds 100 μ l (DMSO final concentration < 0.5%), everyMedicine is established 5～7 dosage groups, at least establishes three parallel holes for every group, cultivate after 120hr in 37 DEG C of continuation,Abandon supernatant, every hole adds the freshly prepared serum free medium containing 0.5mg/mlMTT of 100 μ l, continues trainingSupport 4hr, abandon culture supernatant, every hole adds 200 μ lDMSO and dissolves MTT first hairpin precipitation, uses micro-oscillatingDevice vibration mixes, and, detects under wavelength 570nm condition at reference wavelength 450nm with MK3 type ELIASAMeasure OD value (OD), taking the tumour cell of solvent control processing as control group, calculate with formula belowThe inhibiting rate of medicine to tumour cell, and calculate IC by middle efficacious prescriptions journey50：
MTT the selection result

Claims (13)

1. anilino--the 4-of the 2-shown in formula I thiazolyl pyridine derivate, its officinal salt;
In formula:
R1Be selected from hydrogen, halogen, cyano group, nitro, carboxyl, mesyl, sulfamoyl, methylphosphine acyl group, C1-C6The C1-C6 alkoxyl of the C1-C6 alkyl of alkyl, replacement, hydroxyl, C1-C6 alkoxyl, replacement, amino,The C1-C6 heterocyclic radical of the C1-C6 alkylamino radical of C1-C6 alkylamino radical, replacement, C1-C6 heterocyclic radical, replacement,The C2-C6 of the C1-C6 alkyl amide of C1-C6 alkyl amide, replacement, the unsaturated alkyl amide of C2-C6, replacementThe C3-C6 cycloalkanes amide groups of unsaturated alkyl amide, C3-C6 cycloalkanes amide groups, replacement, C1-C6 heterocycle acylThe C1-C6 heterocycleamide base of amido, replacement, wherein substituting group is selected from: halogen, hydroxyl, cyano group, C1-C6Alkyl, benzoyl, two (C1-C6 alkyl) amino, methoxyl group, trifluoromethyl, trifluoromethoxy, first sulphurAcyl group;
N is selected from 1,2,3,4,5;
R2And R3Independently be selected from respectively hydrogen, C1-C6 alkyl, replacement C1-C6 alkyl, C3-C6 cycloalkyl,The C3-C6 cycloalkyl, C1-C8 alkanoyl, the C1-C8 alkanoyl of replacement, the unsaturated alkane of C2-C8 that replaceThe C3-C6 cycloalkanes first of the unsaturated alkanoyl of C2-C8 of acyl group, replacement, C3-C6 cycloalkanes formoxyl, replacementThe C1-C6 heterocycle formyl of acyl group, C1-C6 heterocycle formyl, replacement, C5-C8 aromatic ring formoxyl, replacementC5-C8 aromatic ring formoxyl, C6-C12 aromatic ring alkanoyl, the C6-C12 aromatic ring alkanoyl of replacement, whereinSubstituting group is selected from: halogen, hydroxyl, cyano group, C1-C6 alkyl, benzoyl, two (C1-C6 alkyl) be amino,Methoxyl group, trifluoromethyl, trifluoromethoxy, mesyl.
2. according to the compound of claim 1 and officinal salt thereof, it is characterized in that,
R1Be selected from hydrogen, fluorine, chlorine, bromine, cyano group, nitro, carboxyl, mesyl, sulfamoyl, C1-C6 alkyl,The C1-C6 alkyl, hydroxyl, C1-C6 alkoxyl, the C1-C6 alkoxyl of replacement, amino, the C1-C6 that replaceThe C1-C6 alkylamino radical of alkylamino radical, replacement, C1-C6 heterocyclic radical, the C1-C6 heterocyclic radical of replacement, C1-C6The C2-C6 of the C1-C6 alkyl amide of alkyl amide, replacement, the unsaturated alkyl amide of C2-C6, replacement is notSaturated alkyl amide, C3-C6 cycloalkanes amide groups, the C3-C6 cycloalkanes amide groups of replacement, C1-C6 heterocycleamideBase,, the C1-C6 heterocycleamide base that replaces, wherein substituting group is selected from: halogen, hydroxyl, cyano group, methyl,Ethyl, isopropyl, the tert-butyl group, benzoyl, dimethylamino, methoxyl group, trifluoromethyl, trifluoro methoxyBase, mesyl;
N is selected from 1,2,3,4;
R2And R3Independently be selected from respectively hydrogen, C1-C6 alkyl, replacement C1-C6 alkyl, C3-C6 cycloalkyl,The C3-C6 cycloalkyl, C1-C8 alkanoyl, the C1-C8 alkanoyl of replacement, the unsaturated alkane of C2-C8 that replaceThe C3-C6 cycloalkanes first of the unsaturated alkanoyl of C2-C8 of acyl group, replacement, C3-C6 cycloalkanes formoxyl, replacementThe benzoyl of the C1-C6 heterocycle formyl of acyl group, C1-C6 heterocycle formyl, replacement, benzoyl, replacementThe phenyl C1-C6 alkanoyl of base, phenyl C1-C6 alkanoyl, replacement, wherein substituting group is selected from: fluorine, chlorine,Bromine, hydroxyl, cyano group, methyl, ethyl, isopropyl, the tert-butyl group, benzoyl, dimethylamino, diethylaminoBase, methoxyl group, trifluoromethyl, trifluoromethoxy, mesyl.
3. according to the compound of claim 2 and officinal salt thereof, it is characterized in that,
R1Be selected from hydrogen, fluorine, chlorine, bromine, cyano group, nitro, carboxyl, mesyl, sulfamoyl, methyl, secondBase, isopropyl, the tert-butyl group, trifluoromethyl, dimethylamino methyl, methylol, hydroxyl, methoxyl group, isopropylOxygen base, trifluoromethoxy, methoxyethoxy, amino, methylamino, dimethylamino, lignocaine, hydroxyl secondAmido, morpholinyl, piperazinyl, piperidyl, N methyl piperazine base, formamido, acetamido, propionamideBase, Isopropamide base, amide-based small, isobutyl amide, pivaloyl amido, valeryl amido, isovaleryl amido,2,2-amide dimethyl butyrate base, trifluoroacetyl amido, hydroxyl acetamido, methoxy acetamido, dimethylaminoYl acetamide base, acrylyl amido, 3,3-dimethyl acrylyl amido, butene-2-amide groups, propine acid amidesBase, crotonylene-amide groups, cyclopropyl carboxamide base, cyclobutylmethyl amide groups, cyclopenta formamido, ringHexyl formamido, 2-piperidine formyl amido, 4-piperidine formyl amido, methyl piperidine formamido, isopropylPiperidine formyl amido;
N is selected from 1,2,3,4;
R2And R3Independently be selected from respectively hydrogen, methyl, ethyl, propyl group, isopropyl, the tert-butyl group, ethoxy, twoMethylamine ethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopenta, formoxyl, acetyl group, propiono, differentPropiono, bytyry, isobutyryl, valeryl, valeryl, isovaleryl, caproyl, 2,2-bis-Methylbutyryl base, trifluoroacetyl group, 2-difluoro propionyl acyl, glycolyl, ammonia acetyl group, methoxy acetyl group,Dimethylamino acetyl group, allyl acyl group, butene-2-acyl group, butylene-3-acyl group, 3,3-dimethyl acrylylBase, hexadiene-2,4-acyl group, propine acyl group, 3-isopropyl propine acyl group, 3-tert-butyl group propine acyl group, fourthAlkynes-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, benzoyl,Between fluoro benzoyl, a chlorobenzene formacyl, to fluoro benzoyl, to chlorobenzene formacyl, a fluorine to chlorobenzoylBase, adjacent fluoro benzoyl, to methyl benzoyl, to cyano group benzoyl, to dimethylamino benzoyl,Para hydroxybenzene formoxyl, to methoxybenzoyl base, to hydroxyl meta-methoxy benzoyl, m-trifluoromethyl benzeneFormoxyl, to trifluoromethyl benzoyl, a cyano group benzoyl, phenylacetyl group, a fluorophenethyl acyl group,Chloro acetyl, to fluorophenethyl acyl group, a cyano group phenylacetyl group between chlorine.
4. according to the compound of claim 3 and officinal salt thereof, it is characterized in that,
R1Be selected from hydrogen, fluorine, chlorine, bromine, cyano group, carboxyl, mesyl, methyl, ethyl, isopropyl, tertiary fourthBase, trifluoromethyl, dimethylamino methyl, methylol, hydroxyl, methoxyl group, isopropoxy, trifluoromethoxy,Methoxyethoxy, amino, methylamino, dimethylamino, lignocaine, hydroxyethylamine, morpholinyl, piperazineBase, piperidyl, N methyl piperazine base, formamido, acetamido, propionamido-, Isopropamide base, fourthAmide groups, isobutyl amide, pivaloyl amido, valeryl amido, isovaleryl amido, 2,2-dimethyl butyrylAmido, trifluoroacetyl amido, hydroxyl acetamido, methoxy acetamido, dimethylamino acetamido, allylAmide groups, 3,3-dimethyl acrylyl amido, butene-2-amide groups, propioloyl amido, crotonylene-amide groups,Cyclopropyl carboxamide base, cyclobutylmethyl amide groups, cyclopenta formamido, cyclohexyl formamido, 4-piperidinesFormamido, methyl piperidine formamido, isopropyl piperidine formyl amido;
N is selected from 1,2,3,4;
R2And R3Independently be selected from respectively hydrogen, methyl, ethyl, isopropyl, ethoxy, decil, methoxyEthyl, cyclopropyl, cyclobutyl, formoxyl, acetyl group, propiono, isopropyl acyl group, bytyry, isobutyrylBase, valeryl, valeryl, isovaleryl, caproyl, 2,2-dimethyl butyrate acyl group, trifluoroacetyl group,2-difluoro propionyl acyl, glycolyl, ammonia acetyl group, methoxy acetyl group, dimethylamino acetyl group, acrylylBase, butene-2-acyl group, butylene-3-acyl group, 3,3-dimethyl allyl acyl group, hexadiene-2,4-acyl group, thirdAlkynes acyl group, 3-isopropyl propine acyl group, 3-tert-butyl group propine acyl group, crotonylene-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, benzoyl, a fluoro benzoyl, a chlorobenzene formacyl,To fluoro benzoyl, to chlorobenzene formacyl, a fluorine to chlorobenzene formacyl, adjacent fluoro benzoyl, to methylbenzene firstAcyl group, to cyano group benzoyl, to dimethylamino benzoyl, para hydroxybenzene formoxyl, to methoxybenzene firstAcyl group, to hydroxyl meta-methoxy benzoyl, m-trifluoromethyl benzoyl, to trifluoromethyl benzoyl,Between cyano group benzoyl, phenylacetyl group, a fluorophenethyl acyl group, a chloro acetyl, to fluorophenethyl acyl group between chlorine.
5. according to the compound of claim 4 and officinal salt thereof, it is characterized in that,
R1Be selected from hydrogen, fluorine, chlorine, bromine, cyano group, carboxyl, mesyl, methyl, isopropyl, the tert-butyl group, threeMethyl fluoride, dimethylamino methyl, methylol, hydroxyl, methoxyl group, isopropoxy, trifluoromethoxy, amino,Methylamino, dimethylamino, lignocaine, hydroxyethylamine, morpholinyl, piperazinyl, piperidyl, N-methylPiperazinyl, 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, methoxy acetamido, dimethylamino acetamido, acrylyl amido, 3,3-dimethylAcrylyl amido, butene-2-amide groups, propioloyl amido, crotonylene-amide groups, cyclopropyl carboxamide base,Cyclobutylmethyl amide groups, cyclopenta formamido, cyclohexyl formamido, 4-piperidine formyl amido, methyl piperazinePyridine formamido, isopropyl piperidine formyl amido;
N is selected from 1,2,3,4;
R2And R3Independently be selected from respectively hydrogen, methyl, ethyl, isopropyl, ethoxy, decil, methoxyEthyl, cyclopropyl, cyclobutyl, formoxyl, acetyl group, propiono, isopropyl acyl group, bytyry, isobutyrylBase, valeryl, valeryl, isovaleryl, caproyl, 2,2-dimethyl butyrate acyl group, trifluoroacetyl group,2-difluoro propiono, glycolyl, ammonia acetyl group, methoxy acetyl group, dimethylamino acetyl group, acrylylBase, butene-2-acyl group, butylene-3-acyl group, 3,3-dimethyl allyl acyl group, hexadiene-2,4-acyl group, thirdAlkynes acyl group, 3-isopropyl propine acyl group, crotonylene-acyl group, cyclopropyl formoxyl, cyclobutylmethyl acyl group, ring pentaBase formoxyl, cyclohexyl formoxyl, 2-piperidine formyl base, 4-piperidine formyl base, methyl piperidine formoxyl, differentPropyl group piperidine formyl base, benzoyl, a fluoro benzoyl, a chlorobenzene formacyl, to fluoro benzoyl, rightChlorobenzene formacyl, a fluorine are to chlorobenzene formacyl, adjacent fluoro benzoyl, to methyl benzoyl, to cyano group benzene firstAcyl group, to dimethylamino benzoyl, para hydroxybenzene formoxyl, to methoxybenzoyl base, to first between hydroxylOxygen base benzoyl, m-trifluoromethyl benzoyl, to trifluoromethyl benzoyl, a cyano group benzoyl,Phenylacetyl group, a fluorophenethyl acyl group, a chloro acetyl, to fluorophenethyl acyl group between chlorine.
6. according to compound and the officinal salt thereof of any one in claim 1-5, described compound is selected from as followsGroup:
2-(3-Aminotrifluorotoluene base)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(the chloro-6-toluidine of 2-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(2-fluoroanilino)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(2,4-difluorobenzene amido)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(the bromo-4-fluoroanilino of 2-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(2-methoxyl group-4-N-methyl piperazine anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(4-morpholine anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(4-(ring propyl formamide base) anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(3,4,5-trimethoxy-benzene amido)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(4-dimethylamino anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(3-ring propyl formamide base anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(4-(N methyl piperazine base) anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(m-nitro amido)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(m-aminophenyl amido)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(a propionamido anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(isophthalic acetyl amino phenyl amido)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(3-trifluoroacetamido anilino-)-4-(2-amino-4-methylthiazol-5-yl) pyridine
2-(3-nitrobenzene amido)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-acrylamido-4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-(3-dimethyl allene acyl) amino-4-methylthiazol-5-yl) pyrrolePyridine
2-(3-trifluoromethylbenzene amido)-4-(2-(hexadiene-2,4-acylamino-)-4-methylthiazol-5-yl) pyrrolePyridine
2-(3-trifluoromethylbenzene amido)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-propionamido-4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-(3-methylbutyryl amino)-4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-valeryl amino-4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-cyclopropyl formamido group-4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-cyclobutylmethyl acylamino--4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-cyclopenta formamido group-4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-m-chloro benzamido-4-methylthiazol-5-yl) pyridine
2-(3-trifluoromethylbenzene amido)-4-(fluorobenzene acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl between 2-) pyridine
2-(3-trifluoromethylbenzene amido)-4-(2-m-fluoroaniline formamido group-4-methylthiazol-5-yl) pyridine
2-(adjacent fluoroanilino)-4-(2-acrylyl amino-4-methylthiazol-5-yl) pyridine
2-(2,4-dichloroanilino)-4-(2-acrylyl amino-4-methylthiazol-5-yl) pyridine
2-(p-dimethylamino aniline base)-4-(2-acrylyl amino-4-methylthiazol-5-yl) pyridine
2-(3,4,5-trimethoxy-benzene amido)-4-(2-acrylyl amino-4-methylthiazol-5-yl) pyridine
2-(4-encircles the third formamido group anilino-)-4-(2-acrylyl amino-4-methylthiazol-5-yl) pyridine
2-(3-encircles the third formamido group anilino-)-4-(2-acrylyl amino-4-methylthiazol-5-yl) pyridine
2-(adjacent fluoroanilino)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
2-(2,4-difluorobenzene amido)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
2-(p-dimethylamino aniline base)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
2-(3,4,5-trimethoxy-benzene amido)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
2-(to morpholinyl anilino-)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
2-(adjacent fluoroanilino)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(2,4-dichloroanilino)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(p-dimethylamino aniline base)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(3,4,5-trimethoxy-benzene amido)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(to encircling the third formamido group anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(to morpholinyl anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(ring the third formamido group anilino-)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
2-(ring the third formamido group anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(m-acetamidoaniline base)-4-(acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(a propionamido anilino-)-4-(2-propionamido-4-methylthiazol-5-yl) pyridine
2-(3-isopropyl formamido group anilino-)-4-(2-isopropyl formamido group-4-methylthiazol-5-yl) pyridine
2-(the tertiary fourth formamido group of 3-anilino-)-4-(the tertiary fourth formamido group-4-of 2-methylthiazol-5-yl) pyridine
2-(3-(3-methyl butene-2-acylamino-) anilino-)-4-(2-(3-methyl butene-2-acylamino-)-4-methylthiazol-5-yl) pyridine
2-(3-ring fourth formamido group anilino-)-4-(2-ring fourth formamido group-4-methylthiazol-5-yl) pyridine
2-(3-encircles the third formamido group anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(3-encircles the third formamido group anilino-)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
2-(3-encircles the third formamido group anilino-)-4-(2-isobutyl formamido group-4-methylthiazol-5-yl) pyridine
2-(3-encircles the third formamido group anilino-)-4-(2-(3-methyl butene-2-acylamino-)-4-methylthiazol-5-yl)Pyridine
2-(3-encircles the third formamido group anilino-)-4-(2-cyclopenta formamido group-4-methylthiazol-5-yl) pyridine
2-(3-encircles the third formamido group anilino-)-4-(2-is to toluyl amino-4-methylthiazol-5-yl) pyridine
2-(3-encircles the third formamido group anilino-)-4-(2-phenylacetylamino-4-methylthiazol-5-yl) pyridine
2-(3-nitrobenzene amido)-4-(2-trifluoroacetyl amido-4-methylthiazol-5-yl) pyridine
2-(3-nitrobenzene amido)-4-(2-ring propyl formamide base-4-methylthiazol-5-yl) pyridine
2-(3-nitrobenzene amido)-4-(2-isopropyl formamido-4-methylthiazol-5-yl) pyridine
2-(3-aminobenzene amido)-4-(2-ring propyl formamide base-4-methylthiazol-5-yl) pyridine
2-(3-aminobenzene amido)-4-(2-isopropyl formamido-4-methylthiazol-5-yl) pyridine
2-(3-trifluoroacetamido anilino-)-4-(2-trifluoroacetamido-4-methylthiazol-5-yl) pyridine
2-(3-trifluoroacetamido anilino-)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
2-(3-trifluoroacetamido anilino-)-4-(2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-yl) pyridine
2-(3-ring fourth formamido group anilino-)-4-(2-encircles the third formamido group-4-methylthiazol-5-yl) pyridine
2-(3-trifluoroacetamido anilino-)-4-(2-ring fourth formamido group-4-methylthiazol-5-yl) pyridine
2-(3-ring fourth formamido group anilino-)-4-(2-isopropyl formamido group-4-methylthiazol-5-yl) pyridine
2-(3-encircles the third formamido group anilino-)-4-(2-trifluoroacetamido-4-methylthiazol-5-yl) pyridine
7. according to compound and the officinal salt thereof of any one in claim 1-6, it is characterized in that, described canPharmaceutical salts, its hydrochlorate comprises: hydrochloride, hydrobromate, phosphate, sulfate, mesylate, to tolueneSulfonate, acetate, trifluoroacetate, salicylate, amino-acid salt, matrimony vine hydrochlorate, maleate, wineStone hydrochlorate, fumarate, citrate, lactate, its alkali salt comprises: sodium salt, sylvite, calcium salt, magnesium salts,Lithium salts.
8. the compound of any one and the method for officinal salt thereof in preparation claim 1-7, comprises following route:Route 1
9. preparation method according to Claim 8, is characterized in that, in the step (a) of described route 1 with 2-Bromo-4-thiazolyl pyridine derivate 1 is raw material, under sour environment, gets with the aniline generation nucleophilic that R1 replacesGeneration reaction forms compound 2; In step (b), the amine on thiazole ring in compound 2 is entered by common methodsRow alkylation or acyl group, as with the substitution reaction of alkyl halide R2X or R3X, pass through condensing agent with acidDehydration, or generate target compound I with acyl chloride reaction.
10. preparation method according to Claim 8, is characterized in that, in the step (a) of described route 2 with 2-Bromo-4-thiazolyl pyridine derivate 1 is raw material, with common methods to the amine on its thiazole ring carry out alkylation orAcyl group, as with the substitution reaction of alkyl halide R2X or R3X, dewater by condensing agent with acid, or withAcyl chloride reaction generates midbody compound 3; In step (b), under sour environment, R1 replace aniline withThere is nucleophilic substitution and generate target compound I in compound 3.
The composition of 11. 1 kinds of medicines, is characterized in that, the compound that contains any one in claim 1-7 andOfficinal salt and galenic pharmacy acceptable carrier.
In 12. claim 1-7, the compound of any one and officinal salt thereof are in preparation prevention and treatment tumour and tumourApplication in the relevant medicine of disease.
13. according to the application of claim 12, it is characterized in that, described tumor disease is selected from liver cancer, kidney, lungCancer, cancer of pancreas, cancer of the stomach, colorectal cancer, carcinoma of urinary bladder, breast cancer, oophoroma, cutaneum carcinoma, thyroid cancer,Leukemia, squamous cell carcinoma, glioma and Head and Neck cancer.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017114500A1 (en) * 2015-12-31 2017-07-06 恩瑞生物医药科技（上海）有限公司 Acrylanilide derivative, preparation method therefor, and applications thereof in pharmacy
CN108239040A (en) * 2016-12-26 2018-07-03 中国医学科学院药物研究所 Nitric acid 2-（4- methylthiazol -5- bases）The preparation method of carbethoxy hydrochloride
CN111039941A (en) * 2018-10-12 2020-04-21 上海医药集团股份有限公司 Nitrogen-containing heterocyclic compound, preparation method and application thereof
US11174250B2 (en) 2016-03-01 2021-11-16 Propellon Therapeutics Inc. Substituted carboxamides as inhibitors of WDR5 protein-protein binding
US11319299B2 (en) 2016-03-01 2022-05-03 Propellon Therapeutics Inc. Substituted carboxamides as inhibitors of WDR5 protein-protein binding

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040097531A1 (en) * 2002-07-09 2004-05-20 Mark Ledeboer Inhibitors of c-Jun N-terminal kinases (JNK) and other protein kinases
CN1681810A (en) * 2002-09-18 2005-10-12 辉瑞产品公司 Novel oxazole and thiazole compounds as transforming growth factor (TGF) inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040097531A1 (en) * 2002-07-09 2004-05-20 Mark Ledeboer Inhibitors of c-Jun N-terminal kinases (JNK) and other protein kinases
CN1681810A (en) * 2002-09-18 2005-10-12 辉瑞产品公司 Novel oxazole and thiazole compounds as transforming growth factor (TGF) inhibitors

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017114500A1 (en) * 2015-12-31 2017-07-06 恩瑞生物医药科技（上海）有限公司 Acrylanilide derivative, preparation method therefor, and applications thereof in pharmacy
US10342796B2 (en) 2015-12-31 2019-07-09 Ancureall Pharmaceutical (Shanghai) Co., Ltd. Acrylanilide derivative, preparation method, and applications thereof in pharmacy
US11174250B2 (en) 2016-03-01 2021-11-16 Propellon Therapeutics Inc. Substituted carboxamides as inhibitors of WDR5 protein-protein binding
US11319299B2 (en) 2016-03-01 2022-05-03 Propellon Therapeutics Inc. Substituted carboxamides as inhibitors of WDR5 protein-protein binding
CN108239040A (en) * 2016-12-26 2018-07-03 中国医学科学院药物研究所 Nitric acid 2-（4- methylthiazol -5- bases）The preparation method of carbethoxy hydrochloride
CN111039941A (en) * 2018-10-12 2020-04-21 上海医药集团股份有限公司 Nitrogen-containing heterocyclic compound, preparation method and application thereof
CN111039941B (en) * 2018-10-12 2023-03-21 上海医药集团股份有限公司 Nitrogen-containing heterocyclic compound, preparation method and application thereof

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