CN103539784A - Heterocyclic benzamide compounds, pharmaceutical compositions as well as application thereof - Google Patents

Heterocyclic benzamide compounds, pharmaceutical compositions as well as application thereof Download PDF

Info

Publication number
CN103539784A
CN103539784A CN201210236713.9A CN201210236713A CN103539784A CN 103539784 A CN103539784 A CN 103539784A CN 201210236713 A CN201210236713 A CN 201210236713A CN 103539784 A CN103539784 A CN 103539784A
Authority
CN
China
Prior art keywords
replaces
methyl
benzamide
trifluoromethyl
pyrimidine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201210236713.9A
Other languages
Chinese (zh)
Other versions
CN103539784B (en
Inventor
丁克
李宇鹏
沈梦婕
龙活尤
张章
冷芳
陆小云
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangzhou Institute of Biomedicine and Health of CAS
Original Assignee
Guangzhou Institute of Biomedicine and Health of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangzhou Institute of Biomedicine and Health of CAS filed Critical Guangzhou Institute of Biomedicine and Health of CAS
Priority to CN201210236713.9A priority Critical patent/CN103539784B/en
Publication of CN103539784A publication Critical patent/CN103539784A/en
Application granted granted Critical
Publication of CN103539784B publication Critical patent/CN103539784B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses heterocyclic benzamide compounds with structural characteristics of formula (1) or pharmaceutically acceptable salts or steric isomers or prodrug molecules thereof. The heterocyclic benzamide compounds as well as pharmaceutically acceptable salts thereof can effectively restrain growth of a plurality of tumor cells, can generate inhibiting effect to proteases such as BCR-ABL, c-Kit and PDGFR, can be used for preparing anti-tumor drugs and can be used for overcoming existing drug (Gleevec)-induced drug resistance.

Description

Heterocycle benzamide compound, medicinal compositions and application thereof
Technical field
The invention belongs to chemical field of medicaments, particularly relate to a kind of heterocycle benzamide compound, medicinal compositions and application thereof.
Background technology
Tumour is the No.1 killer of current human health and life, and its sickness rate is only second to cardiovascular disease.And along with the impact of environmental pollution or other factors, the sickness rate of malignant tumour is fast rise trend.The data of announcing for 2003 according to the World Health Organization, the total malignant tumor patient 1,000 ten thousand in the whole world in 2000, because mortality of malignant tumors person is up to 6,200,000, accounts for the 12%-25% of total death toll.Anticipate the year two thousand twenty, the annual new cases in the whole world will reach 1,500 ten thousand.In recent years, though there is the exploitation listing of some novel target new drugs such as tyrosine protein inhibitor, but still cannot meet the sick human needs of growing clinical cancer far away.Antitumor drug research and development are also still the important research direction of current medicament research and development circle.
Tumour molecular targeted therapy is based on the closely-related key molecule of tumor growth being passed through to a kind of methods for the treatment of of chemistry or biological means selective killing tumour cell.The feature of targeted therapy is: specificity is high, and selectivity is strong, and toxic side effect is lighter; During combined utilization, it can strengthen the curative effect of traditional chemotherapy, radiotherapy, reduces postoperative recurrence.With Gleevec(STI571, imatinib, commodity are called imatinib mesylate) for the targeted drug of representative be that chemotherapy of tumors has been started a New Times.Neoplasm targeted therapy has obtained developing rapidly in recent years.The appearance of neoplasm targeted therapy forms impact to traditional administration idea and pattern, and for example, because toxic side effect is little, targeted drug often cannot reach dose-limiting toxicity and maximum tolerated dose in I clinical trial phase; While using target therapeutic agent, without reaching satisfactory effect with maximum tolerated dose.Neoplasm targeted therapy is focus and the development trend of oncotherapy.
Protein tyrosine kinase (PTKs) is the phenolic hydroxyl group generation phosphorylation of a class on can the tyrosine residues of the multiple key protein of catalysis, and then the protease of the function of mobilizing function albumen system.In 520 multiple protein kinases in human body nearly half be Tyrosylprotein kinase (PTKs).They have occupied very consequence in intracellular signal transduction pathway, are regulating a series of physiology processes such as cell growth in vivo, differentiation, death.Protein tyrosine kinase functional disorder can cause a series of diseases in organism.Research shows, proto-oncogene more than half is all relevant to protein tyrosine kinase with the activation of oncogene.The unconventionality expression of protein tyrosine kinase can cause cell proliferation adjusting to get muddled, and then causes tumour to occur.In addition, the unconventionality expression of Tyrosylprotein kinase also with invasion and attack and the transfer of tumour, tumor neovasculature generation, the chemotherapy resistance of tumour is closely related.The Tyrosylprotein kinase of take becomes as target spot carries out antitumor drug research and development the emphasis that the research of an international focus ，Ye Shi various countries drug development mechanism drops into.
So far, existing tens of kinds of protein tyrosine kinase micromolecular inhibitors and antibody enter clinical trial, the listing having, and obtained good result for the treatment of.As: be used for the treatment of the be positive Bcr-Abl inhibitor Gleevec of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs) of Philadelphia chromosome; Be used for the treatment of the EGFR inhibitor Iressa of nonsmall-cell lung cancer and Tarceva etc.Gleevec is first appropriate design exploitation after the cause of disease of understanding cancer, and has obtained the anti-tumor medicine of remarkable effect, and its success is a milestone of cancer therapy.This significant achievement Ye Bei U.S. < < science > > magazine is listed calendar year 2001 degree ten large science and technology news in.
The immense success obtaining in clinical cancer therapy for the specificity small molecules inhibition of protein tyrosine kinase has further confirmed that protein tyrosine kinase is critical treatment target spot, and its importance in tumour occurs is also described simultaneously.There is the sudden change of conclusive evidence proof protein tyrosine kinase encoding gene to cause that tumorigenic example comprises: Bcr-Abl and chronic myelocytic leukemia (chronic myeloid leukemia, CML); C-Kit and gastrointestinal stromal tumors (GISTs) (GIST), systemic mastocytosis (systemic mastocytosis, SM); PDGFR and chronic myelomonocytic leukemia (chronic myelomonocytic leukemia), dermatofibrosarcoma protuberans (dermatofibrosarcoma protuberan), hypereosinophilic syndrome; Flt3 and part acute myeloblastic leukemia; B-Raf and melanoma (melanoma); RET and thyroid carcinoma etc.In addition, c-Kit and small cell lung cancer have substantial connection.
Calendar year 2001 U.S. FDA approval in order to first target therapeutic agent Gleevec Main Function for the treatment of chronic myelocytic leukemia (CML) in Bcr-Abl, c-Kit, PDGFR etc.Gleevec single therapy can make 98% patient CML obtain the alleviation of clinical hematology clinically, and 53% obtains cytogenetics alleviates.
Yet along with STI571 widespread use clinically, resistance problem becomes increasingly conspicuous: part cancer patient is to STI571 natural tolerance (primary resistance); Another part patient responds while starting medication, but in medication therapeutic process, engenders acquired tolerance (secondary resistance).The patient of long-term taking easily produces tolerance.Tolerance refers to that chronic phase patient does not occur that after STI571 treatment complete hematology reaction or acceleration period and acute transformation phase patient fail to return to chronic phase after STI571 treatment.Clinically, acute lymphoblastic leukemia (the Acute lymphoblastic leukemia of the chronic myelocytic leukemia (CML) of acute transformation phase (blast-crisis), the Bcr-Abl positive, ALL) patient is more general to STI571 tolerance, and this two classes patient of approximately 70% occurred STI571 resistance at medication 3-6 month.Once and there is resistance, the state of an illness is often made progress rapidly.Acquired tolerance is considered to tumour cell for escaping a kind of defence killing and wounding, and it is multiple that its mechanism has, and comprising: 1. target gene (Bcr-Abl, c-Kit, PDGFR) amplification; 2. mutant target gene; 3. target gene dependent/non-dependent tumour clone's formation; 4. the overexpression of the generation of α-1 acid glycoprotein and multidrug-resisting gene M DR1.But generally acknowledged main mechanism is the secondary mutation (secondary mutation) in target gene (Bcr-Abl, c-Kit, PDGFR) expression product kinases territory at present.Research shows that the common point mutation site of the target gene clear and definite with STI571 Tolerance comprises E255K, E255V, T315I and the D276G of Bcr-Abl, the D816V of c-Kit etc.The patient who carries these sudden changes is easily recurred, and prognosis is bad.There is report to point out only to have 50% transitivity gastrointestinal stromal tumors (GISTs) (GIST) patient to react STI571, reliable for effect, and this part patient carries c-Kit and faces film territory V560G sudden change.In addition, still there is 50% transitivity patient GIST to lack reaction to STI571.The point mutation of c-Kit tyrosine kinase domain (as D816V, T315I) tolerates STI571 very much.Experiment in vitro shows that STI571 can not suppress to carry the propagation of D816V c-Kit and T315I Mutant Cells; The systemic mastocytosis patient who carries D816V c-Kit does not react STI571 yet.
How to overcome the important topic that STI571 resistivity is current tumour medical science.Find novel Tyrosylprotein kinase small molecules inhibition and be overcome STI571 resistivity important channel.For example, the Tyrosylprotein kinase small molecules inhibition Nilotinib (AMN107, nilotinib), the Dasatinib(BMS-354825 that go on the market recently, Dasatinib) effective to part (rather than all) STI571 resistivity Bcr-Abl point mutation case.AMN107 is identical with STI571 in conjunction with the kinase whose position of Abl, be also competitive binding to the Abl kinases of disactivation configuration, but stronger than STI571 with the avidity of Abl, drug effect be approximately the latter 10-50 doubly.AMN107 has obvious restraining effect to 15 kinds of point mutation cells except T315I, and IC50 is at 10-1000nM.Different from STI571 and AMN107, BMS-354825 combination simultaneously and the Bcr-Abl that suppresses not activation and activated.BMS-354825 has obvious restraining effect to 15 kinds of point mutation cells except T315I, and IC50 is at 10-125nM.But AMN107 and BMS-354825 are to Bcr-Abl(T315I) invalid, and AMN107 and STI571 invalid to c-Kit D816V point mutation cell.Therefore, develop novel, can effectively kill and wound STI571 resistivity c-KIT point mutation (D816V) and Bcr-Abl point mutation and carry (comprising T315I) micromolecular compound of cell and all seem very necessary and urgent in global oncotherapy scientific circles and industrial community.
In fact, current protein tyrosine kinase inhibitor series antineoplastic medicament exists the sudden change of drug-induced drug resistance gene mostly, and be faced with the clinical scope of application narrower and etc. problem.Therefore, exploitation s-generation protein tyrosine kinase inhibitor, to overcome existing drug resistance and to improve clinical effectiveness, is significant.
Summary of the invention
Based on this, the object of this invention is to provide a kind of heterocycle benzamide compound.
Concrete technical scheme is as follows:
Heterocycle benzamide compound or its pharmacy acceptable salt or steric isomer or the prodrugs with formula I constitutional features:
Figure BDA00001866829800031
Wherein, A ring is five-membered ring, can be connected arbitrarily with both sides fragment as upper/lower positions, certainly optional:
1) triazole
Figure BDA00001866829800032
2) oxadiazoles
Figure BDA00001866829800033
R 1certainly optional:
1) 2-substituted pyrimidyl
Figure BDA00001866829800041
2) and heterocyclic radical
Figure BDA00001866829800042
3) and heterocyclic radical
3) R 7substituted-phenyl
Figure BDA00001866829800044
R 2certainly optional:
1）H；
2) halogen;
3) C1-C5 alkyl;
4) C3-C6 cycloalkyl;
R 4for H, R 3certainly optional:
1)H；
2)(CH 2) nNR 5R 6；
3)(CH 2) n–Het 1；
Or R 3for H, R 4certainly optional:
1)H；
2)Het 2；
Wherein, X, Y, Z, is optionally N, CH, five yuan or the hexa-member heterocycle of C ring for containing 1-3 nitrogen-atoms; N is 0 or 1, Het 1for the nonaromatic heterocycles base that contains 1-3 N, Het 2for containing heteroatoms N, the 5-membered aromatic heterocycle base of O and/or S, the described non-aromatic and arbitrary C atom of aromatic heterocycle or N atom can substituted position can be by alkyl, cycloalkyl, or NR 5r 6replace;
R 5, R 6certainly optional:
1）H；
2) C1-C3 alkyl;
3) C1-C3 is containing fluoroalkyl;
4) C3-C6 cycloalkyl;
Or R 5and R 6by C, O, N, S atom forms five yuan, hexa-atomic, seven yuan or octatomic ring shape structure.
R 7certainly optional:
1）H，
2）OH；
3)NH 2。
Therein in some embodiment, R 1certainly optional:
1) 2-substituted pyrimidyl
Figure BDA00001866829800051
2) and heterocyclic radical
Figure BDA00001866829800052
3) and heterocyclic radical
Figure BDA00001866829800053
R 2certainly optional:
1）H；
2) halogen;
3) C1-C5 alkyl;
4) C3-C6 cycloalkyl;
R 4for H, R 3certainly optional:
1)H；
2)(CH 2) nNR 5R 6；
3)(CH 2) n–Het 1；
Or R 3for H, R 4certainly optional:
1)H；
2)Het 2；
Wherein, Y, Z, is optionally N, CH, five yuan or the hexa-member heterocycle of C ring for containing 1-3 nitrogen-atoms; N is 0 or 1, Het 1for the nonaromatic heterocycles base that contains 1-3 N, Het 2for containing heteroatoms N, the 5-membered aromatic heterocycle base of O and/or S, the described non-aromatic and arbitrary C atom of aromatic heterocycle or N atom can substituted position can be by alkyl, cycloalkyl, or NR 5r 6replace;
R 5, R 6certainly optional:
1）H；
2) C1-C3 alkyl;
3) C1-C3 is containing fluoroalkyl;
4) C3-C6 cycloalkyl;
Or R 5and R 6by C, O, N, S atom forms five yuan, hexa-atomic, seven yuan or octatomic ring shape structure.
In some embodiment, the selected 2-substituted uracil of described R1 is one of following structure therein:
Figure BDA00001866829800061
Therein in some embodiment, described R 1selected five yuan and hexa-member heterocycle are one of following structure:
Figure BDA00001866829800062
Therein in some embodiment, described R 2optionally from following structure:
1）H;
2）CH 3，CH 2CH 3;
3）
Figure BDA00001866829800063
4）F,Cl,Br,I；
6）CF 3。
Therein in some embodiment, the described R that works as 4for H, R 3certainly optional:
1)H；
2)CH 2NR 5R 6；
3)(CH 2) n–Het 1；
Or R 3for H, R 4certainly optional:
1)H；
2)Het 2；
R 5, R 6definition identical with claim 1, n is 1, Het 1be selected from following structure:
Het 2be selected from following structure:
Figure BDA00001866829800065
Therein in some embodiment, R 1certainly optional:
Figure BDA00001866829800071
R 2certainly optional:
1）H;
2）CH 3，CH 2CH 3;
3）
Figure BDA00001866829800072
4）F,Cl,Br；
Work as R 4for H, R 3certainly optional:
1)H；
2)CH 2NR 5R 6；
3)(CH 2) n–Het 1；
Or R 3for H, R 4certainly optional:
1)H；
2)Het 2；
R 5, R 6definition identical with claim 1, n is 1, Het 1be selected from following structure:
Figure BDA00001866829800073
Het 2be selected from following structure:
Figure BDA00001866829800074
Another object of the present invention is to provide a kind of medicinal compositions for the treatment of tumour.
Concrete technical scheme is as follows:
Treat a medicinal compositions for tumour, by above-mentioned heterocycle benzamide compound and pharmacy acceptable salt thereof or steric isomer or its prodrugs and pharmaceutically acceptable carrier, formed.
Another object of the present invention is to provide the application of above-mentioned heterocycle benzamide compound in the medicine of preparation treatment tumour.
Concrete technical scheme is as follows:
The application in the medicine of preparation treatment tumour of above-mentioned heterocycle benzamide compound and pharmacy acceptable salt thereof or steric isomer or its prodrugs.
In some embodiment, described tumour is any in leukemia, gastrointestinal stromal tumors (GISTs), histocyte lymphatic cancer, nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, carcinoma of the pancreas, mammary cancer, prostate cancer, liver cancer, skin carcinoma, cell carcinoma, nasopharyngeal carcinoma etc. therein.
In some embodiment, described leukemia is the CML for the BCR-ABL positive therein, AML leukemia and to imatinib, dasatinib, the leukemia of nilotinib resistance; In described drug-resistant leukemia, the intractable drug-resistant leukemia that particularly sudden change causes for BCR-ABL kinases territory T315I.
In some embodiment, described leukemia is chronic myelocytic leukemia and the acute leukemia of BCR-ABL high expression level therein.
Abl(Abelson TK) gene and Bcr(break point cluster region) gene fusion to express Bcr-abl Tyrosylprotein kinase be chronic myelocytic leukemia (CML), the main mechanism of the leukemogenesis such as acute lymphoblastic leukemia (ALL).For Bcr-Abl Tyrosylprotein kinase design targeting micromolecular inhibitor, obtained significant success, wherein representative example is exactly in the medicine Gleevec of calendar year 2001 approval listing by U.S. FDA.Yet along with the widespread use of Gleevec in clinical, its clinical drug-resistant phenomenon is more and more outstanding.In numerous reasons that cause Gleevec resistance, Bcr-abl kinases territory sudden change (mutations in the Bcr-Abl kinase domain) accounts for 35-45%.。And wherein, T315I sudden change accounts for 12% of gross mutation.The sudden change causing for Gleevec resistance, Bcr-Abl inhibitor nilotinib of new generation (nilotinib) and dasatinib (Dasatinib) be successfully listing.Although these two molecules have the inhibition activity that overcomes numerous mutant strains, still feel simply helpless for the resistance due to T315I.Therefore, solve approximately 12% patient that Gleeve resistance, especially T315I resistance cause in clinical treatment without medicine can with problem there is scientific research, clinical and marketable value.
In compound of the present invention, for example, as any variable (R 1, R 2deng) in any component, occur surpassing once, its each definition occurring is independent of other each definition occurring.Equally, allow the combination of substituting group and variable, as long as this combination makes stability of compounds.Be appreciated that this area, those of ordinary skill can be selected the substituting group of the compounds of this invention and substitution pattern and provide chemically stable, and can from the raw material that can easily obtain, be easy to synthetic compound by the method for art technology and following proposition.If substituting group self is exceeded a group, replace, should understand these groups can be in identical carbon atoms or on different carbon atom, as long as make Stability Analysis of Structures.
Term used herein " alkyl " means to comprise saturated fatty alkyl side chain and straight chain with particular carbon atom number.For example, " C 1-C 5alkyl " in " C 1-C 5" definition comprise the group with 1,2,3,4 or 5 carbon atom of arranging with straight or branched.For example, " C 1-C 5alkyl " specifically comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group.Term " cycloalkyl " refers to have the monocycle saturated fatty alkyl of particular carbon atom number.For example " cycloalkyl " comprises cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl etc.
Term used " heterocycle " or " heterocyclic radical " refer to and contain 1-4 heteroatomic 5 yuan of-6 yuan of aromaticity or nonaro-maticity heterocycle that is selected from O, N and S herein, and comprise bicyclic radicals." heterocyclic radical " comprises heteroaryl, also comprises its dihydro and tetrahydro-analogue." heterocyclic radical " further example includes but not limited to: imidazolyl, indyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl (oxetanyl), pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, quinoxalinyl, tetrazyl, thiadiazolyl group, thiazolyl, thienyl, triazolyl, l, 4-alkyl dioxin, pyrrolidyl, glyoxalidine base, dihydro-isoxazole base, dihydro isothiazolyl, Er Qing oxadiazolyl, dihydro-oxazole base, dihydro pyrazinyl, pyrazoline base, dihydropyridine base, dihydro-pyrimidin base, pyrrolin base, dihydro tetrazyl, thiodiazoline base, dihydro-thiazolyl, dihydro-thiophene base, dihydro triazolyl, dihydro azetidinyl, tetrahydrofuran base and tetrahydro-thienyl, and N-oxide compound.The connection of heterocyclic substituent can realize by carbon atom or by heteroatoms.
In one embodiment, heterocycle is selected from imidazolyl, pyridyl, 1-pyrrolidone, 2-piperidone, 2-pyrimidone, 2-Pyrrolidone, thienyl, oxazolyl, triazol radical, isoxazolyl.
As understood by one of ordinary skill in the art, " halogen " used (" halo ") or " halogen " mean to comprise chlorine, fluorine, bromine and iodine herein.
Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical substituting group can be unsubstituted or replacement.For example, C 1-C 6alkyl can be replaced by one, substituting group that two or three are selected from OH, halogen, alkoxyl group, dialkyl amido or heterocyclic radical such as morpholinyl, piperidyl etc.
In some example, definition Het, makes it jointly form 4-7 unit monocycle with the nitrogen that is connected them or each ring is the bicyclic heterocycle of 4-7 unit, and optionally contains and denitrogenate that one or two is selected from the other heteroatoms of N, O and S outward.
The present invention includes the free form of formula I compound, also comprise its pharmacy acceptable salt and steric isomer.
Therefore, the pharmacy acceptable salt of the compounds of this invention comprises by the compounds of this invention and conventional the non-toxic salt inorganic or the compounds of this invention that organic acid reaction forms.For example, conventional non-toxic salt comprises the salt that derives from mineral acid such as hydrochloric acid, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid, nitric acid etc., also comprises from organic acid such as acetic acid, propionic acid, succsinic acid, oxyacetic acid, stearic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, flutters the salt of the preparations such as acid, toxilic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, Sulphanilic Acid, 2-acetoxyl group-phenylformic acid, fumaric acid, toluenesulphonic acids, methylsulfonic acid, ethane disulfonic acid, oxalic acid, hydroxyethylsulfonic acid, trifluoroacetic acid.
Berg etc. are at Pharmaceutical Salts, and J.Pharm.Sci.1977, describes the preparation of pharmacy acceptable salt mentioned above and other typical pharmacy acceptable salt in detail in 66:1-19.
Heterocycle benzamide compound and the pharmacy acceptable salt thereof that the present invention relates to, can effectively suppress the growth of kinds of tumor cells, and to BcrAbl, c-Kit, the protease-producing restraining effect such as PDGF, can be used for preparing antitumor drug, and can overcome the resistance that existing medicine (Gleevec) brings out.As understood by those skilled in the art, related compound and the pharmacologically acceptable salts thereof of the application can be used for the excess proliferative diseases such as the preparation treatment mankind and other mammiferous tumour.
Embodiment
Except standard method known or illustration in experimental arrangement in the literature, can adopt the reaction as shown in following scheme to prepare the compounds of this invention.Therefore, following illustrative approach is the object for illustrating rather than is confined to listed compound or any specific substituting group.The substituting group number showing in scheme must not meet number used in claim, and for clarity sake, shows that monosubstituted base is connected under the definition of formula (I) hereinbefore to allow on the compound of multi-substituent.
scheme
Compound R in formula as shown in option A (I) 1the transformation of part can be that starting raw material is walked and reacted synthetic by 4-5 by 3-amino-methyl 4 methylbenzoate.
option A
Compound R in formula as shown in option b (I) 3it is synthetic that the transformation of part can be that starting raw material passes through 5 steps reactions by 4-methyl-3-(trifluoromethyl) aniline.
option b
Figure BDA00001866829800102
Compound R in formula (I) as shown in scheme C 4it is synthetic that the transformation of part can be that starting raw material passes through 3 steps reactions by the bromo-5-of 3-(trifluoromethyl) aniline.
scheme C
Compound R in formula (I) as shown in scheme D 2it is synthetic that the transformation 3-Methyl anthranilate that can be replaced by 4-of part is that starting raw material passes through 3 steps reactions.
scheme D
Figure BDA00001866829800112
As shown in scheme E in formula (I) salt of compound can be that starting raw material passes through 1 step reaction by former compound synthetic.
scheme E
Figure BDA00001866829800113
Because the synthetic method of the A ring except triazole is different, cannot be organized into general formula, will in specific embodiment, illustrate.
The application provides compound and the pharmacologically acceptable salts thereof that a kind of utilization has formula (I) to treat excess proliferative disease or the symptoms such as people or other mammal tumor.
The compound that the application is designed and pharmacologically acceptable salts thereof can be used for the treatment of or control the excess proliferative diseases such as gastrointestinal stromal tumors (GISTs), histocyte lymphatic cancer, nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, carcinoma of the pancreas, mammary cancer, prostate cancer, liver cancer, skin carcinoma, cell carcinoma, prostate cancer, nasopharyngeal carcinoma, leukemia.
The compound that the application is designed and pharmacologically acceptable salts thereof can with estrogenic agents current application or that just locating the development phase, androgen receptor modifier, retinoid-like receptor modulators, cytotoxin/cytostatics, antiproliferative, protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV kinases inhibitor, reverse transcriptase inhibitors, angiogenesis inhibitor, cell proliferation and survival signaling inhibitor, medicine and the cell death inducer at the interference cell cycle outpost of the tax office, cytotoxic drug, tyrosine protein inhibitor, EGFR inhibitor, VEGFR inhibitor, serine/threonine protein inhibitor, Bcr-Abl inhibitor, c-Kit inhibitor, Met inhibitor, Raf inhibitor, mek inhibitor, MMP inhibitor, topoisomerase enzyme inhibitor, Histone deacetylase inhibitor, proteasome inhibitor, CDK inhibitor, Bcl-2 family protein inhibitor, MDM2 family protein inhibitor, IAP family protein inhibitor, STAT family protein inhibitor, PI3K inhibitor, AKT inhibitor, integrin retarding agent, interferon-' alpha ', IL-12, cox 2 inhibitor, p53, p53 activator, VEGF antibody, the medication combined medications such as EGF antibody increase its clinical effectiveness.
The compound that the application is related and pharmacologically acceptable salts thereof can be used for the treatment of according to method below following disease and the Other diseases of not listing below:
1) a kind of utilization comprises the application's method related, that have the compound of formula (I) structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other mammiferous mammary cancer.Including, but not limited to aggressive duct carcinoma, aggressive lobular carcinoma, DCIS and LCIS.
2) a kind of utilization comprises the application's method related, that have the compound of formula (I) structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other mammiferous respiratory cancer.Including, but not limited to minicell & nonsmall-cell lung cancer and bronchial adenoma and pleura pulmonary blastoma.
3) a kind of utilization comprises the application's method related, that have the compound of formula (I) structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other mammiferous cancer of the brain.Including, but not limited to brain stem and neurospongioma, cerebellum and large cerebral astrocytoma, ependymoma and neuroderm and pine nut knurl body now.
4) a kind of utilization comprises the application's method related, that have the compound of formula (I) structure and the medicinal compositions of pharmacologically acceptable salts thereof treatment people or other mammiferous hero, female reproductive organ's tumour.The tumour of male reproductive organ includes but not limited to prostate gland and carcinoma of testis.Female reproductive organ's tumour includes but not limited to carcinoma of endometrium, cervical cancer, ovarian cancer, carcinoma of vagina and carcinoma vulvae and intrauterine knurl.
5) a kind of utilization comprises the application's method related, that have the compound of formula (I) structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other mammiferous gastral tumour.Include but not limited to anus cancer, colorectal carcinoma, colon straight way cancer, esophagus cancer, cancer of the stomach, the carcinoma of the pancreas rectum cancer, carcinoma of small intestine or glandula cancer.
6) a kind of utilization comprises the application's method related, that have the tumour of the compound of formula (I) structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other mammiferous urethra.Include but not limited to bladder cancer, penile cancer, kidney, carcinoma of renal pelvis, carcinoma of ureter or urethral carcinoma.
7) a kind of utilization comprises the application's method related, that have the compound of formula (I) structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other mammiferous cancer eye.Include but not limited to intraocular melanoma and retinocytoma.
8) a kind of utilization comprises the application's method related, that have the compound of formula (I) structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other Mammals liver cancer.Include but not limited to hepatoma (thering is or do not have the stem cell cancer that fiberboard changes), cholangiocarcinoma (intrahepatic cholangiocarcinoma) and the Hepatocellular cholangiocarcinoma mixing.
9) a kind of utilization comprises the application's method related, that have the compound of formula (I) structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other mammal skin cancer.Include but not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merck Schwann Cells skin carcinoma and non-melanoma cells cancer.
10) a kind of utilization comprises the application's method related, that have the compound of formula (I) structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other Mammals head and neck cancer.Include but not limited to larynx, hypopharynx, nasopharynx, oropharynx cancer and lip and oral carcinoma.
11) a kind of utilization comprise the application related, there is the compound of formula (I) structure and the medicinal compositions of pharmacologically acceptable salts thereof treatment people or the lymphadenomatous method of other Mammals.Include but not limited to AIDS associated lymphoma, non Hodgkin lymphoma, cutaneous T cell lymphoma, He Jiesen disease and central nervous system lymphoma.
12) a kind of utilization comprises the application's method related, that have the compound of formula (I) structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other Mammals sarcoma.Include but not limited to that soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, woods are sarcoma and rhabdosarcoma.
13) a kind of utilization comprise the application related, there is the compound of formula (I) structure and the medicinal compositions of pharmacologically acceptable salts thereof treatment people or the leukemic method of other Mammals.Include but not limited to acute myeloid leukemia, acute woods chronic myeloid leukemia, chronic lymphocyte leukemia, chronic lymphocytic leukemia and hairy cell leukemia.
Take mode and dosage range
According to standard pharmaceutical technology, the compounds of this invention can give Mammals with pharmaceutically acceptable acceptor, auxiliary material or thinner combination separately or in medicinal compositions, preferably people.Can be oral or subcutaneous, intramuscular injection, intraperitoneal, vein, rectum and part, eyes, lung, nasal cavity, parenteral give compound.
When utilizing formula (I) compounds for treating or controlling the patients such as cancer, taking dose scope is in oral 0.1-500 mg/day/kg body weight.Suitable administering mode is single dose administration or every twice-daily, three times, four inferior multiple dosings or utilize slow release method administration every day.For multiple large mammal, its preferred dosage range is 0.1-1500 mg/day/kg body weight, is preferable over 0.5-100 mg/day/kg body weight.For mean body weight, be the patient of 70 kilograms, its every per daily dose is 1-500 milligram.For some special high-activity compounds, the every per daily dose of adult patient can lowly reach 0.1 mg/day.
Drug metabolite and prodrug
The compound that the application is related and the meta-bolites of pharmacologically acceptable salts thereof, and the prodrug that can change in vivo the structure of the related compound of the application and pharmacologically acceptable salts thereof into, be also contained in the application's protection domain.
Drug combination
Formula I compound can or improve the other medicines coupling of similar symptom to known treatment.During Combined Preparation, originally the administering mode of medicine and dosage remain unchanged, and simultaneously or take subsequently formula I compound.When formula I compound and other one or more medicines are taken simultaneously, preferably use contains the medicinal compositions of one or more known drugs and formula I compound simultaneously.Drug combination is also included within the overlapping time period and takes formula I compound and other one or more known drugs.When formula I compound and other one or more medicines carry out drug combination, the dosage when dosage of formula I compound or known drug may be than their independent medications is lower.
Medicine or the activeconstituents that can carry out drug combination with formula I compound comprise but are not limited to:
Estrogenic agents, androgen receptor modifier, retinoid-like receptor modulators, cytotoxin/cytostatics, antiproliferative, protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV kinases inhibitor, reverse transcriptase inhibitors, angiogenesis inhibitor, cell proliferation and survival signaling inhibitor, medicine and the cell death inducer at the interference cell cycle outpost of the tax office, cytotoxic drug, tyrosine protein inhibitor, EGFR inhibitor, VEGFR inhibitor, serine/threonine protein inhibitor, Bcr-Abl inhibitor, c-Kit inhibitor, Met inhibitor, Raf inhibitor, mek inhibitor, MMP inhibitor, topoisomerase enzyme inhibitor, Histone deacetylase inhibitor, proteasome inhibitor, CDK inhibitor, Bcl-2 family protein inhibitor, MDM2 family protein inhibitor, IAP family protein inhibitor, STAT family protein inhibitor, PI3K inhibitor, AKT inhibitor, integrin retarding agent, interferon-' alpha ', IL-12, cox 2 inhibitor, p53, p53 activator, VEGF antibody, EGF antibody etc.
Medicine or the activeconstituents that can carry out drug combination with formula I compound comprise but are not limited to: rIL-2, clinic effect of alendronate, Interferon, rabbit, Ah Qu Nuoying, allopurinol, epidermal growth factor, Palonosetron hydrochloride, altretamine, amino glutethimide, amifostine, amrubicin, SN-11841, anastrozole, dolasetron, aranesp, arglabin, white arsenic, Arnold is new, U-18496, azathioprine, bacille Calmette-Guerin vaccine or tice bacille Calmette-Guerin vaccine, bestatin, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan, thyrocalcitonin, A Laizuo monoclonal antibody injection, capecitabine, carboplatin, Kang Shi get, cefesone, celmoleukin, daunorubicin, Chlorambucil, cis-platinum, CldAdo, CldAdo, chlorine is bent phosphoric acid, endoxan, arabinose born of the same parents former times, Dacarbazine, dactinomycin, daunorubicin liposome, dexamethasone, Wymesone, Estradiol Valerate, denileukin diftitox, Di Bomei, deslorelin, ground La Zuosheng, stilboestrol, Fluconazole, docetaxel, doxifluridine, Zorubicin, dronabinol, admire-166-chitosan complexes, eligard, rasburicase, epirubicin hydrochloride, aprepitant, pidorubicin, Epoetin Alfa, erythropoietin, eptalatin, Ergamisole, estradiol preparation, 17-β-estradiol, estramustine phosphate sodium, ethinylestradiol, amifostine, hydroxyl phosphoric acid, Etopophos, etoposide, fadrozole, tamoxifen preparation, filgrastim, Tamsulosin, Fei Leisi replaces, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5 FU 5 fluorouracil, Fluoxymesterone, flutamide, formestane, 1-β-D-R furanose born of the same parents thialdine-5 '-stearyl phosphoric acid ester, fotemustine, fulvestrant, gamma-globulin, gemcitabine, WAY-CMA 676, imatinib mesylate, Gliadel, goserelin, Graniseeron Hydrochloride, histrelin, new with U.S., hydrocortisone, erythro-hydroxyl nonyl VITAMIN B4, hydroxyurea, replace not monoclonal antibody of smooth different shellfish, idarubicin, ifosfamide, interferon alpha, interferon-' alpha ' 2, interferon α-2 A, interferon α-2 B, Interferon α-nl, Alferon N, interferon beta, interferon-gamma-la, interleukin II, intron A, Iressa, Rinotecan, Kytril, sulfuric acid lentinan, letrozole, formyl tetrahydrofolic acid, Leuprolide, leuprolide acetate, L-tetramisole, levo leucovorin calcium salt, levothyroxine sodium, levothyroxine sodium preparation, lomustine, lonidamine, dronabinol, mustargen, mecobalamin, medroxyprogesterone acetate, Magace, melphalan, esterified estriol, 6-coloured glaze base purine, mesna, methotrexate, amino-laevulic acid methyl esters, miltefosine, Minomycin, ametycin, mitotane, rice holder green onion quinone, Win-24540, citric acid Evacet, S 254, Pegylation filgrastim, oprelvekin, neupogen, Nilutamide, tamoxifen, NSC-631570, recombination human interleukins-11-β, Sostatin, Ondansetron Hydrochloride, dehydrohydro-cortisone oral solution, oxaliplatin, taxol, Pediapred, pegaspargase, Pai Luoxin, pentostatin, Picibanil, hydrochloric acid pilocarpine, adjoin the soft star that compares, Plicamycin, porfimer sodium, prednimustine, prednisolone steaglate, prednisone, premarin, the third kappa navel, epoetin, Raltitrexed, Libiee, etidronic acid rhenium-186, Mabthera, Redoxon-A, romurtide, Salagen, Sostatin, sargramostim, semustine, sizofiran, sobuzoxane, bluff sodium prednisolone, Paphos acid, stem-cell therapy, streptozocin, Metastron, levothyroxine sodium, tamoxifen, YM-617, Ta Suonaming, tastolactone, taxotere, Ro 23-6019, Temozolomide, teniposide, testosterone propionate, Synrotabs, Tioguanine, thio-tepa, thyrotropic hormone, tiludronic acid, topotecan, toremifene, tositumomab, Herceptin, Treosulfan, tretinoin, Rheumatrex tablet, trimethylammonium melamine, trimetrexate, acetic acid triptorelin, triptorelin pamoate, Youfuding, uridine, valrubicin, vesnarinone, vinealeucoblastine(VLB), vincristine(VCR), vindesine, vinorelbine, virulizin, ADR-529, Zinostatin stimalamer, Zudan, taxol protein stabilization formulations, acolbifene, Interferon, rabbit r-lb, affinitak, aminopterin-induced syndrome, arzoxifene, asoprisnil, Atamestane, atrasentan, BAY43-9006, Avastin, CCI-779, CDC-501, celecoxib, Cetuximab, crisnatol, cyproterone acetate, Decitabine, DN-101, Zorubicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, Exatecan, fenretinide, histamine dihydrochloric acid, histrelin hydrogel implant, holmium-166DOTMP, Ibandronic acid, interferon-gamma, intron-PEG, ixabepilone, keyhole shape hemocyanin, L-651582, lanretide, Lasofoxifene, libra, lonafamib, Miproxifene, minot is bent acid esters, MS-209, liposome MTP-PE, MX-6, nafarelin, Nemorubicin, Neovastat, Nola Qu Te, Ao Limosen, onco-TCS, osidem, taxol polyglutamic acid esters, pamidronate disodium injection, PN-401, QS-21, overstate the West, R-1549, raloxifene, ranpirnase, isotretinoin, Satraplatin, seocalcitol, T-138067, tarceva, docosahexenoic acid taxol, extrasin alpha l, loud, high-pitched sound azoles furan woods, tipifarnib, Win-59075, TLK-286, toremifene, trans MID-lo7R, valspodar, vapreotide, vatalanib, Visudyne, Vinflunine, Z-100 and Zoledronic acid or their combination.
The present invention will be further described for following examples, but this embodiment is not for limiting the scope of the invention.
Embodiment 1
3-(4-(2-(hexamethylene is amino) pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide (D1174)
Figure BDA00001866829800161
Step 1. is synthesized the bromo-N-cyclohexyl pyrimidine-2-of 5-amine
In tube sealing, add the bromo-2-chloropyrimide of 5-(1.93g, 10.0mmol) and hexahydroaniline (2.29mL, 20mmol), with ethanol (15.0mL), dissolve, be heated to 80 ° of C.Stirring is spent the night, cool to room temperature.Decompression is spin-dried for solvent and obtains white solid, adds EtOAc and water extraction, organic phase anhydrous Na 2sO 4dry, decompression is spin-dried for, and the white solid of gained is target product (2.4g, productive rate: 94%).
1H?NMR(400MHz,CDCl 3),δ8.24(s,2H),5.06(d,J=5.6Hz,1H),3.78-3.69(m,1H),2.03-1.99(m,2H),1.77-1.71(m,2H),1.66-1.62(m,1H),1.46-1.35(m,2H),1.27-1.16(m,3H);
Step 2. is synthesized N-cyclohexyl-5-ethynyl pyrimidine-2-amine
Figure BDA00001866829800163
In tube sealing, add the bromo-N-cyclohexyl pyrimidine-2-amine of 5-(1.28g, 5.0mmol), CuI (0.048g, 0.25mmol), Pd (PPh 3) 2cl 2(0.18g, 0.25mmol), uses argon replaces three times.With syringe, add acetonitrile (15.0mL), Et 3n (2.1mL, 15.0mmol) and trimethylsilyl acetylene (2.1mL, 15.0mmol), sealing post-heating to 100 ° C, reacts 24 hours, by reacting liquid filtering, is spin-dried for.In oily matter after being spin-dried for, add methyl alcohol (20.0mL) and K 2cO 3(1.4g, 10.0mmol).Stirring at normal temperature half an hour, reacting liquid filtering, is spin-dried for, and silica gel column chromatography is separated, and the yellow solid of gained is target product (0.9g, productive rate: 89%).
1H?NMR(400MHz,CDCl 3),δ8.36(s,2H),5.24(d,J=6.2Hz,1H),3.87-3.78(m,1H),3.16(s,1H),2.04-2.00(m,2H),1.77-1.72(m,2H),1.66-1.61(m,1H),1.47-1.36(m,2H),1.27-1.18(m,3H);
Step 3. is synthesized 3-azido--methyl 4 methylbenzoate
Figure BDA00001866829800171
At room temperature, 3-amino-4 benzoic acid methyl esters (8.4g, 0.05mol) is dissolved in HCl (6.0mol/L, 40.0mL, 0.24mol).After cooling to 0 ° of C, add NaNO 2(3.57g is dissolved in 8.4mL H to the aqueous solution 2o, 0.05mol), under-5 ° of C ~ 0 ° C, reaction solution was stirred after 10 minutes, (3.97g is dissolved in 12.6mL H slowly to add sodium azide aqueous solution 2o, 0.06mol), react 2 hours.After having reacted, reaction solution adds EtOAc and adds water extraction, saturated common salt washing, anhydrous Na 2sO 4dry, decompression is spin-dried for, and the yellow oil of gained is target product (9.7g, productive rate: 99%).
1H?NMR(400MHz,CDCl 3),δ7.70(d,J=1.2Hz,1H),7.63(dd,J=7.6Hz,1.2Hz,1H),7.15(d,J=8.0Hz,1H),3.85(s,3H),2.18(s,3H).
Step 4. is synthesized 3-azido--4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide
Figure BDA00001866829800172
Under-20 ° of C, by 3-azido--methyl 4 methylbenzoate (9.6g, 0.5mol) and 4-((4-methylpiperazine-1-replace) methyl)-3-(trifluoromethyl) aniline (13.7g, 0.5mol) be dissolved in the tetrahydrofuran (THF) (50.0mL) after heavily steaming, slowly drip the heavily steaming tetrahydrofuran solution (50.0mL) of potassium tert.-butoxide (16.8g, 0.15mol), react after 1 hour, naturally be warmed up to room temperature, then react 8 hours.After having reacted, be spin-dried for solvent, add EtOAc and water extraction, organic phase is washed with saturated common salt, anhydrous Na 2sO 4dry, the separating obtained red solid of silica gel column chromatography is target product (13.5g, productive rate: 61%).
1H?NMR(400MHz,CDCl 3),δ7.81-7.77(m,3H),7.73(d,J=8.0Hz,1H),7.62(d,J=1.2Hz,1H),7.39(dd,J=7.8Hz,1.4Hz,1H),7.21(d,J=8.3Hz,1H),3.57(s,3H),2.45(br,8H),2.23(s,3H),2.21(s,3H).MS(ESI),m/z:433(M ++H +).
Step 5. is synthesized 3-(4-(2-(hexamethylene is amino) pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide (D1174)
By N-cyclohexyl-5-ethynyl pyrimidine-2-amine (0.20g, 1.0mmol), 3-azido--4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide (0.43g, 1.0mmol), CuSO 4(16mg, 0.1mmol) and sodium ascorbate (40mg, 0.2mmol) are dissolved in the mixing solutions of the trimethyl carbinol and water (1:1,4.0mL), 90 ° of C reactions, spend the night.After having reacted, be cooled to room temperature, with EtOAc extraction 3 times, saturated common salt washing, anhydrous Na 2sO 4dry, silica gel column chromatography is separated, and the white solid of gained is target product (0.31g, productive rate: 50%).
1H?NMR(400MHz,CDCl 3),δ8.71(s,2H),8.41(s,1H),7.95-7.88(m,5H),7.78(d,J=8.8Hz,1H),7.51(d,J=7.6Hz,1H),5.21(d,J=7.6Hz,1H),3.88-3.86(m,1H),3.63(s,2H),2.50(br,8H),2.35(s,3H),2.30(s,3H),2.07-2.04(m,2H),1.75(m,2H),1.67-1.64(m,1H),1.48-1.39(m,2H),1.29-1.24(m,3H). 13C?NMR(125MHz,CDCl 3),δ164.30,161.45,155.66,143.58,137.99,136.47,136.37,134.12,133.53,132.24,131.40,129.27(J=32.2Hz),128.57,125.08,124.71,123.36,122.90,119.75,117.69,113.39,57.77,55.23,53.14,49.83,46.05,33.13,25.68,24.80,18.22.MS(ESI),m/z:634(M ++H +).
Following examples 2-21 synthetic method is as embodiment 1.
Embodiment 2
3-(4-(2-isopropylamine base pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1161)
Figure BDA00001866829800181
1H?NMR(400MHz,CDCl 3),δ8.74(s,2H),8.23(s,1H),7.95-7.87(m,5H),7.79(d,J=8.8Hz,1H),7.53(d,J=7.6Hz,1H),5.13(d,J=8.0Hz,1H),4.22-4.17(m,1H),3.63(s,2H),2.51(br,8H),2.37(s,3H),2.30(s,3H),1.28(d,J=6.2Hz,6H). 13C?NMR(125MHz,CDCl 3),δ164.09,161.49,155.69,143.61,138.06,136.59,136.29,134.19,133.53,132.29,131.44,129.32(J=30.0Hz),128.42,124.73,124.00(J=275.0Hz),123.33,119.74,117.68,113.52,57.77,55.23,53.15,46.06,43.09,22.83,18.26.MS(ESI),m/z:594(M ++H +).
Embodiment 3
3-(4-(2-benzamido group pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1162)
1H?NMR(400MHz,CDCl 3),δ8.76(s,2H),8.30(s,1H),7.95-7.87(m,5H),7.78(d,J=8.8Hz,1H),7.52(d,J=8.0Hz,1H),7.37-7.33(m,4H),7.30-7.28(m,1H),5.68(t,J=5.6Hz,1H),4.70(d,J=5.6Hz,2H),3.63(s,2H),2.51(br,8H),2.36(s,3H),2.30(s,3H). 13C?NMR(125MHz,CDCl 3),δ164.12,162.01,155.72,143.43,138.74,138.03,136.52,136.31,134.17,133.54,132.28,131.43,129.30(J=30.0Hz),128.67,128.49,127.47,127.39,124.73,124.00(J=273.8Hz),123.35,119.90,117.68,114.20,57.77,55.23,53.14,46.05,45.58,18.23.MS(ESI),m/z:642(M ++H +).
Embodiment 4
3-(4-(2-amine pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1168)
Figure BDA00001866829800191
1H?NMR(400MHz,CDCl 3),δ8.77(s,2H),8.36(s,1H),7.98-7.87(m,5H),7.78(d,J=8.8Hz,1H),7.52(d,J=8.0Hz,1H),5.25(s,2H),3.63(s,2H),2.51(br,8H),2.36(s,3H),2.30(s,3H). 13C?NMR(125MHz,CDCl 3),δ164.14,162.67,155.87,143.12,138.00,136.45,136.31,134.19,133.56,132.28,131.43,129.30(J=30.0Hz),128.55,124.75,124.00(J=272.5Hz),123.36,120.16,117.72,115.03,57.77,55.22,53.14,46.05,18.22.MS(ESI),m/z:552(M ++H +).
Embodiment 5
3-(4-(2-methylamino pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1171)
Figure BDA00001866829800192
1H?NMR(400MHz,CDCl 3),δ8.77(s,2H),8.18(s,1H),7.95-7.92(m,3H),7.88-7.87(m,2H),7.79(d,J=9.2Hz,1H),7.54(d,J=7.6Hz,1H),5.28(q,J=4.8Hz,1H),3.63(s,2H),3.07(d,J=5.2Hz,3H),2.51(br,8H),2.37(s,3H),2.30(s,3H). 13C?NMR(125MHz,CDCl 3),δ164.07,162.67,155.66,143.53,138.09,136.61,136.28,134.21,133.53,132.30,131.45,129.34(J=30.0Hz),128.40,124.74,124.00(J=272.5Hz),123.32,119.81,117.68,113.74,57.79,55.24,53.16,46.07,28.52,18.27.MS(ESI),m/z:566(M ++H +).
Embodiment 6
3-(4-(2-ethylamino-pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1172)
Figure BDA00001866829800201
1H?NMR(400MHz,CDCl 3),δ8.71(s,2H),8.55(s,1H),7.95-7.88(m,5H),7.76(d,J=8.8Hz,1H),7.50(d,J=8.0Hz,1H),5.30(t,J=5.2Hz,1H),3.62(s,2H),3.50(m,2H),2.50(br,8H),2.34(s,3H),2.30(s,3H),1.27(t,J=7.2Hz,3H). 13C?NMR(125MHz,CDCl 3),δ164.24,162.00,155.62,143.51,137.95,136.41,134.06,133.52,132.23,131.38,129.24(J=28.8Hz),128.62,124.71,124.00(J=272.5Hz),123.38,119.86,117.74,113.58,57.76,55.20,53.09,46.01,36.43,18.20,14.84.MS(ESI),m/z:580(M ++H +).
Embodiment 7
3-(4-(2-cyclopropyl amino pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1173)
Figure BDA00001866829800202
1H?NMR(400MHz,CDCl 3),δ8.77(s,2H),8.65(s,1H),7.96-7.88(m,5H),7.76(d,J=9.2Hz,1H),7.49(d,J=8.0Hz,1H),5.61(d,J=2.0Hz,1H),3.62(s,2H),2.85-2.79(m,1H),2.50(br,8H),2.34(s,3H),2.29(s,3H),0.90-0.85(m,2H),0.61-0.57(m,2H). 13C?NMR(125MHz,CDCl 3),δ164.27,162.98,155.60,143.31,137.89,136.44,136.35,134.02,133.54,132.22,131.37,129.23(J=32.5Hz),128.66,124.73,123.97(J=272.5Hz),123.38,120.02,117.71,114.35,57.75,55.18,53.07,45.99,23.97,18.19,7.43.MS(ESI),m/z:592(M ++H +).
Embodiment 8
4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl)-3-(4-(2-(piperidines-1-replaces) pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces) benzamide (D1175)
1H?NMR(400MHz,CDCl 3),δ8.74(s,2H),8.32(s,1H),7.95-7.88(m,5H),7.78(d,J=8.0Hz,1H),7.52(d,J=7.2Hz,1H),3.85(s,4H),3.63(s,2H),2.51(br,8H),2.36(s,3H),2.30(s,3H),1.70(br,2H),1.64(br,4H). 13C?NMR(125MHz,CDCl 3),δ164.16,161.28,155.30,143.81,138.03,136.56,136.36,134.10,133.50,132.26,131.41,129.29(J=30.0Hz),128.48,124.70,124.00(J=272.5Hz),123.34,119.59,117.70,111.97,57.78,55.22,53.12,46.04,44.99,25.77,24.82,18.26.MS(ESI),m/z:620(M ++H +).
Embodiment 9
4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl)-3-(4-(2-(anilino) pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces) benzamide (D1181)
Figure BDA00001866829800211
1H?NMR(400MHz,DMSO),δ10.60(s,1H),9.91(s,1H),9.04(s,1H),9.02(s,2H),8.18(d,J=4.0Hz,2H),8.10(dd,J=31.2,8.0Hz,2H),7.76(dd,J=35.4,7.8Hz,4H),7.32(d,J=6.8Hz,1H),7.30(d,J=7.6Hz,1H),6.98(t,J=6.8Hz,1H),3.56(s,2H),2.38(br,8H),2.34(s,3H),2.15(s,3H). 13C?NMR(125MHz,CDCl 3),δ164.02,159.45,154.88,142.12,140.11,137.95,137.14,136.04,133.12,132.26,131.81,131.23,131.23,129.10,128.49,127.38(J=29.8Hz),125.04,124.27(J=272.7Hz),123.53,122.38,121.69,119.02,117.30,115.44,57.41,54.68,52.66,45.68,17.67.MS(ESI),m/z:628(M ++H +).
Embodiment 10
3-(4-(imidazo [1,2-b] pyridazine-3-replacement)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide (D1280)
Figure BDA00001866829800212
1H?NMR(400MHz,DMSO),δ10.60(s,1H),9.12(s,1H),8.75(t,1H),8.21-8.19(m,2H),8.10(dd,J=33.6,8.0Hz,2H),7.72(d,J=8.0Hz,2H),7.40(s,1H),3.57(s,2H),2.39(br,8H),2.33(s,3H),2.19(s,3H). 13C?NMR(125MHz,CDCl 3),δ164.08,144.59,137.95,137.56,135.89,133.04,132.23,131.73,131.24,129.23,127.37(J=29.8Hz),125.28,124.26(J=272.5Hz),123.53,123.25,117.29,57.39,54.61,52.63,17.62.MS(ESI),m/z:576(M ++H +).
Embodiment 11
4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-6-replacement)-1H-1,2,3-triazol radical-1-replaces) benzamide (D1167)
Figure BDA00001866829800221
1H?NMR(400MHz,CDCl 3),δ9.50(t,J=0.8Hz,1H),8.92(d,J=2.0Hz,1H),8.29(s,1H),8.19(d,J=2.2Hz,1H),8.17(s,1H),7.97-7.87(m,4H),7.78(d,J=8.8Hz,1H),7.54(d,J=7.6Hz,1H),6.77(t,J=1.2Hz,1H),3.62(s,2H),2.50(br,4H),2.46(br,4H),2.38(s,3H),2.29(s,3H). 13C?NMR(125MHz,CDCl 3),δ164.02,147.97,147.47,146.00,141.96,137.98,136.36,136.25,134.26,133.69,132.36,131.63,131.46,129.33(J=30.3Hz),128.56,124.85,123.98(J=273.0Hz),123.38,121.33,117.75,117.70,112.27,97.57,57.76,55.21,53.12,46.03,18.26.MS(ESI),m/z:576(M ++H +).
Embodiment 12
3-(4-(2-(dimethylamino) pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide (D1166)
Figure BDA00001866829800222
1H?NMR(400MHz,CDCl 3),δ8.77(s,2H),8.67(s,1H),8.03(s,1H),7.98-7.93(m,4H),7.69(d,J=8.2Hz,1H),7.51(d,J=8.2Hz,1H),3.64(s,2H),3.24(s,6H),2.61(br,8H),2.43(s,3H),2.37(s,3H). 13C?NMR(125MHz,CDCl 3),δ164.27,161.87,155.16,143.76,137.94,136.55,136.45,133.89,133.49,132.22,131.38,129.24(J=30.1Hz),128.64,124.26(J=212.7Hz),124.70,123.41,119.73,117.81,111.94,57.75,55.09,52.86,45.82,37.21,18.23.MS(ESI),m/z:580(M ++H +).
Embodiment 13
3-(4-(2-amido quinazoline-6-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(piperazine-1-substituent methyl)-3-(trifluoromethyl) phenyl) benzamide (D1169)
Figure BDA00001866829800231
1H?NMR(400MHz,CDCl 3),δ9.07(s,1H),8.37(br,1H),8.24(s,1H),8.14(dd,J=8.6,1.8Hz,1H),8.05(s,1H),7.97-7.89(m,4H),7.78(d,J=9.2Hz,1H),7.64(d,J=8.8Hz,1H),7.52(d,J=8.2Hz,1H),5.30(s,2H),3.62(s,2H),2.50(br,4H),2.46(br,4H),2.37(s,3H),2.29(s,3H). 13C?NMR(125MHz,CDCl 3),δ164.06,162.57,160.98,151.73,146.24,137.95,137.16,136.14,133.08,132.25,131.79,131.65,131.24,129.06,127.35(J=39.2Hz),125.33,127.27(J=271.6Hz),123.85,123.80,123.53,122.91,119.47,117.30,57.40,54.68,52.65,45.66,17.68.MS(ESI),m/z:602(M ++H +).
Embodiment 14
3-(4-(1H-indoles-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide (D1170)
Figure BDA00001866829800232
1H?NMR(400MHz,DMSO),δ11.22(s,1H),10.59(s,1H),8.94(s,1H),8.20(s,2H),8.16(s,1H),8.10(d,J=8.2,22.2Hz,2H),7.72-7.69(m,3H),7.50(d,J=8.2Hz,1H),7.40(s,1H),6.51(s,1H),3.56(s,2H)2.35(br,8H),2.35(s,3H),2.15(s,3H). 13C?NMR(125MHz,CDCl 3),δ164.10,148.31,137.99,137.15,136.35,135.85,133.03,132.24,131.74,131.23,128.90,127.91,127.41(J=28.2Hz),126.20,125.03,124.31(J=268.1Hz),123.53,121.79,121.24,119.15,117.29,117.10,111.83,101.44,57.42,54.69,52.67,45.68,17.73.MS(ESI),m/z:574(M ++H +).
Embodiment 15
4-methyl-3-(4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridine-5-replacement)-1H-1,2,3 triazol radicals-1-replaces)-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide (D1182)
Figure BDA00001866829800233
1H?NMR(400MHz,CDCl 3),δ12.40(br,1H),9.11(s,1H),8.86(s,1H),8.50(s,1H),8.01-7.92(m,5H),7.73(d,J=6.8Hz,1H),7.44(d,J=6.0Hz,1H),3.59(s,2H),2.59(s,3H),2.48(br,8H),2.28(s,6H). 13C?NMR(125MHz,CDCl 3),δ164.05,146.66,144.93,141.47,137.95,137.11,136.10,133.12,132.26,131.83,131.24,129.07,127.38(J=29.7Hz),125.71,125.02,124.27(J=272.2Hz),123.53,122.86,118.88,117.30,113.88.MS(ESI),m/z:590(M ++H +).
Embodiment 16
(4-([1 for 3-, 2,4] triazole [1,5-a] pyrimidine-6-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide (D1281)
1H?NMR(400MHz,CDCl 3),δ9.48(d,J=2.0Hz,1H),9.21(d,J=2.0Hz,1H),8.61(s,1H),8.56(s,1H),8.27(s,1H),8.06(s,1H),8.02(d,J=8.0Hz,1H),7.92-7.90(m,2H),7.77(d,J=9.2Hz,1H),7.56(d,J=8.0Hz,1H),3.62(s,2H),2.50(br,8H)2.37(s,3H),2.30(s,3H). 13C?NMR(125MHz,CDCl 3),δ163.97,156.90,154.73,152.93,140.67,137.95,136.32,136.19,134.25,133.78,132.43,132.39,131.47,129.33(J=30.7Hz),128.81,124.98,123.99(J=272.2Hz),123.46,121.87,117.84,117.79,115.29,57.77,55.19,53.08,46.00,18.24.MS(ESI),m/z:577(M ++H +).
Embodiment 17
3-(4-(1H-indazole-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide (D1305)
1H?NMR(400MHz,DMSO),δ10.59(s1H),9.04(s,1H),8.36(s,1H),8.19-8.12(m,4H),8.02(dd,J=16.8,8.2Hz,2H),7.71(d,J=8.0Hz,1H),7.67(d,J=8.2Hz,1H),3.56(s,1H),3.56(s,2H),2.38(br,8H),2.35(s,3H),2.15(s,3H). 13C?NMR(125MHz,DMSO),δ164.10,147.33,139.68,137.98,137.18,136.24,133.96,133.07,132.26,131.78,131.26,129.01,127.41(J=29.7Hz),125.38,125.07,124.24,123.55,123.19,122.73,122.46,117.32,117.28,117.13,110.75,57.41,54.68,52.64,45.65,17.72.MS(ESI),m/z:575(M ++H +).
Embodiment 18
4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-3-replacement)-1H-1,2,3-triazol radical-1-replaces) benzamide (D1306)
Figure BDA00001866829800251
1H?NMR(400MHz,DMSO),δ10.58(s,1H),9.24(dd,J=7.0,1.2Hz,1H),8.82(s,1H),8.76(s,1H),8.69(dd,J=4.0,1.6Hz,1H),8.18(s,2H),8.08(dd,J=16.4,8.2Hz,2H),7.17(t,J=7.2Hz,2H),7.17(dd,J=6.8,4.0Hz,1H),3.56(s,2H),2.38(br,8H),2.33(s,3H),2.15(s,3H). 13C?NMR(125MHz,DMSO),δ164.61,151.20,144.50,142.528,139.26,138.45,137.86,136.94,136.58,133.47,132.71,132.20,131.72,129.51,127.86(J=29.9Hz),125.58,124.75(J=273.2Hz),124.03,122.54,117.79,117.74,109.59,101.58,57.88,55.15,53.13,46.14,18.18.MS(ESI),m/z:576(M ++H +).
Embodiment 19
3-(4-(imidazo [1,2-a] pyrimidine-3-replacement)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide (D1307)
Figure BDA00001866829800252
1H?NMR(400MHz,DMSO),δ10.61(s,1H),9.63(d,J=6.2Hz,1H),9.21(s,1H),8.67(s,1H),8.26(s,1H),8.21(d,J=12.0Hz,2H),8.17(d,J=8.0Hz,1H),8.07(d,J=8.0Hz,1H),7.73(t,J=7.0Hz,2H),7.29(s,1H),3.57(s,2H),2.38(br,8H)2.36(s,3H),2.16(s,3H). 13C?NMR(125MHz,CDCl 3),δ164.02,150.26,148.44,137.94,137.36,137.29,135.82,134.47,133.61,133.16,132.27,131.84,131.25,129.25,127.39(J=25.6Hz),125.21,124.26(J=272.7Hz),123.56,117.30,117.25,114.38,109.73,57.39,54.65,52.61,48.54,45.63,17.65.MS(ESI),m/z:575(M ++H +).
Embodiment 20
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1163)
Figure BDA00001866829800261
1H?NMR(400MHz,d-DMSO),δ13.81(s,1H),10.60(s,1H),9.15(d,J=9.6Hz,2H),8.77(s,1H),8.26(s,1H),8.19(d,J=5.2Hz,2H),8.14(d,J=6.2Hz,1H),8.06(d,J=6.8Hz,1H),7.72(dd,J=6.2Hz,2.8Hz,2H),3.56(s,2H),2.36(br,10H),2.15(s,3H). 13C?NMR(125MHz,d-DMSO),δ164.04,146.89,144.77,137.95,137.15,136.09,133.65,133.11,132.26,131.81,131.24,129.10,127.38(J=30Hz),126.15,125.36,125.07,123.53,123.18,123.01,119.70,117.27,114.36,57.40,54.68,52.66,45.68,17.70.MS(ESI),m/z:576(M ++H +).
Embodiment 21
3-(4-(4-hydroxyphenyl)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1309)
Figure BDA00001866829800262
1H?NMR(400MHz,CDCl 3),δ10.58(s,1H),9.67(s,1H),8.86(s,1H),8.17(d,J=12.0Hz,2H),8.09(dd,J=16.2,8.2Hz,2H),7.76(d,J=8.2Hz,2H),7.70(d,J=8.0Hz,2H),6.88(d,J=8.2Hz,2H),3.56(s,2H),2.38(br,8H),2.32(s,3H),2.15(s,3H). 13C?NMR(125MHz,DMSO),δ164.09,157.54,146.98,137.96,137.18,136.25,133.03,132.25,131.73,131.25,128.94,127.39(J=30.0Hz),126.80,125.03,124.28(J=272.9Hz),123.54,123.19,121.70,121.20,117.31,117.26,115.71,57.41,54.69,52.66,45.68,17.67.MS(ESI),m/z:551(M ++H +).
Embodiment 22
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl isophthalic acid, 4-phenodiazine Zhuo-1-replaces) methyl-3-trifluoromethyl) benzamide (D1286)
Figure BDA00001866829800271
Step 1. is synthesized 4-methyl-3-(trifluoromethyl) anilino t-butyl formate
Figure BDA00001866829800272
By 4-methyl-3-(trifluoromethyl) aniline (25.0g, 0.14mol), be dissolved in dioxane (50.0mL), add sodium carbonate (22.3g, the 0.21mol) aqueous solution (50.0mL) and (Boc) 2o (39.0mL, 0.17mol).Stirring is spent the night, and adds EtOAc dilution, saturated common salt washing, anhydrous Na 2sO 4dry, the red oil that is spin-dried for gained is target product (39.0g, productive rate: 99%).
1H?NMR(400MHz,CDCl 3),δ7.61(d,J=2.0Hz,1H),7.42(d,J=7.6Hz,1H),7.18(d,J=8.2Hz,1H),6.53(br,1H),2.41(d,J=1.6Hz,3H),1.52(s,9H).
Step 2. is synthesized 4-(brooethyl)-3-(trifluoromethyl) anilino t-butyl formate
Figure BDA00001866829800273
By 4-methyl-3-(trifluoromethyl) anilino t-butyl formate (18.3g, 0.066mol), NBS (23.6g, 0.133mol) and AIBN (1.1g, 6.6mmol) are dissolved in CCl 4(50.0mL), condensing reflux spends the night.After having reacted, filter saturated common salt washing, anhydrous Na 2sO 4dry, the red oil that is spin-dried for gained is target product (23.0g, productive rate: 98%).
1H?NMR(400MHz,CDCl 3),δ7.68(d,J=1.6Hz,1H),7.54(d,J=8.8Hz,1H),7.48(d,J=8.2Hz,1H),6.80(br,1H),4.59(s,2H),2.76(s,9H).
Step 3. is synthesized 4-((4-methyl isophthalic acid, 4-phenodiazine Zhuo-1-replaces) methyl)-3-(trifluoromethyl) anilino t-butyl formate
By 4-(brooethyl)-3-(trifluoromethyl) anilino t-butyl formate (1.8g, 5.0mmol), N-methyl homopiperazine (1.5mL, 12.0mmol) and Et 3n (2.1mL, 15.0mmol) is dissolved in the THF (10.0mL) after heavily steaming.Under 50 ° of C, stir and spend the night.After having reacted, be spin-dried for solvent, add EtOAc dilution, saturated common salt washing, anhydrous Na 2sO 4dry, be spin-dried for, the yellow oil of silica gel column chromatography gained is target product (1.75g, productive rate: 88%).
1H?NMR(400MHz,CDCl 3),δ7.71(d,J=8.2Hz,1H),7.63(d,J=2.0Hz,1H),7.49(d,J=8.0Hz,1H),6.75(s,1H),3.70(s,2H),2.71-2.66(m,6H),2.63-2.60(m,2H),2.37(s,3H),1.86-1.80(m,2H),1.51(s,9H).
Step 4. is synthesized 3-azido--4-methyl-N-(4-((4-methyl isophthalic acid, 4-phenodiazine Zhuo-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide
Figure BDA00001866829800281
By 4-((4-methyl isophthalic acid, 4-phenodiazine Zhuo-1-replacement) methyl)-3-(trifluoromethyl) anilino t-butyl formate (1.75g, 4.5mmol) is dissolved in the mixed solvent of DCM (5.0mL) and TFA (5.0mL). stirring at room 1 hour.After having reacted, be spin-dried for solvent, NaHCO 3neutralization, adds EtOAc extraction, saturated common salt washing, anhydrous Na 2sO 4dry, be spin-dried for to obtain yellow oil (1.3g, quantitative).Then, add 3-azido--methyl 4 methylbenzoate (1.03g, 5.4mmol), with anhydrous tetrahydro furan (5.0mL), dissolve, be cooled to-20 ℃, slowly drip potassium tert.-butoxide (1.5g, anhydrous tetrahydro furan 12.6mmol) (15.0mL), react after 1 hour, naturally rise to room temperature, reaction is spent the night.After having reacted, be spin-dried for solvent, add EtOAc dilution, saturated common salt washing, anhydrous Na 2sO 4dry, be spin-dried for, the yellow oil of silica gel column chromatography gained is target product (1.5g, productive rate: 74%).
1H?NMR(400MHz,CDCl 3),δ8.65(s,1H),7.95(s,1H),7.92(d,J=8.8Hz,1H),7.73(d,J=1.2Hz,1H),7.67(d,J=8.2Hz,1H),7.53(dd,J=8.0Hz,1.2Hz,1H),7.25(d,overlap,1H),3.76(s,2H),3.16-3.14(m,2H),3.03-3.01(m,2H),2.81-2.78(m,2H),2.62(s,3H),2.06-2.00(m,4H).
Step 5. is synthesized 3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl isophthalic acid, 4-phenodiazine Zhuo-1-replaces) methyl-3-trifluoromethyl) benzamide (D1286)
Figure BDA00001866829800282
By 5-ethynyl-1H-pyrazolo [3,4-b] pyrimidine (0.30g, 2.1mmol), 3-azido--4-methyl-N-(4-((4-methyl isophthalic acid, 4-phenodiazine Zhuo-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide (0.3g, 0.7mmol), CuSO 4(11mg, 0.07mmol) and sodium ascorbate (28mg, 0.14mmol) are dissolved in the mixing solutions of the trimethyl carbinol and water (1:1,5.0mL), 90 ° of C reactions, spend the night.After having reacted, be cooled to room temperature, with EtOAc extraction 3 times, saturated common salt washing, anhydrous Na 2sO 4dry, silica gel column chromatography is separated, and the white solid of gained is target product (0.31g, productive rate: 50%).
1H?NMR(400MHz,d-DMSO),δ13.84(s,1H),10.60(s,1H),9.16(s,1H),9.14(d,J=1.2Hz,1H),8.77(d,J=1.2Hz,1H),8.26(s,1H),8.20(s,1H),8.17(s,1H),8.14(d,J=6.2Hz,1H),8.06(d,J=6.2Hz,1H),7.76(d,J=6.8Hz,1H),7.71(d,J=6.2Hz,1H),3.69(s,2H),2.64-2.60(m,4H),2.58-2.55(m,2H),2.52(m,2H),2.35(s,3H),2.24(s,3H),1.72-1.70(m,2H). 13C?NMR(100MHz,d-DMSO),δ163.94,151.46,146.78,144.67,137.70,136.98,136.00,133.39,133.09,131.61,130.96,128.88,127.14(J=31.0Hz),126.04,125.55,124.93,123.45,122.80,119.62,117.26,114.24,57.25,57.15,55.92,54.19,53.81,46.14,26.79,17.46.MS(ESI),m/z:590(M ++H +).
Following examples 23-31 synthetic method is as embodiment 22.
Embodiment 23
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(piperidines-1-replaces) methyl-3-trifluoromethyl) benzamide (D1183)
Figure BDA00001866829800291
1H?NMR(400MHz,d-DMSO),δ13.80(s,1H),10.59(s,1H),9.16(s,1H),9.14(d,J=2.0Hz,1H),8.77(d,J=2.0Hz,1H),8.26(s,1H),8.20(d,J=1.6Hz,1H),8.18(d,J=2.0Hz,1H),8.15(dd,J=8.0Hz,1.6Hz,1H),8.06(dd,J=8.8Hz,1.6Hz,1H),7.74(d,J=5.6Hz,1H),7.72(d,J=5.2Hz,1H),3.52(s,2H),2.36(br,7H),1.52-1.50(m,4H),1.41-1.40(m,2H). 13C?NMR(125MHz,d-DMSO),δ164.02,151.44,146.86,144.76,137.81,137.14,136.09,133.72,133.13,132.80,131.81,131.06,129.09,127.27(J=30.0Hz),126.15,125.07,124.29(J=272.5Hz),123.55,123.01,119.70,117.22,114.38,58.12,54.05,25.56,23.85,17.68.MS(ESI),m/z:576(M ++H +).
Embodiment 24
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(morpholine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1184)
Figure BDA00001866829800292
1H?NMR(400MHz,d-DMSO),δ13.81(s,1H),10.61(s,1H),9.16(s,1H),9.14(s,1H),8.77(s,1H),8.26(s,1H),8.20(s,2H),8.14(d,J=7.6Hz,1H),8.08(d,J=8.2Hz,1H),7.74(d,J=8.0Hz,1H),7.72(d,J=7.2Hz,1H),3.58(s,6H),2.36(br,7H). 13C?NMR(125MHz,d-DMSO),δ164.08,151.45,146.90,144.79,138.07,137.18,136.11,133.74,133.12,131.84,131.75,131.39,129.12,127.52(J=28.8Hz),126.18,125.09,124.27(J=272.5Hz),123.52,123.03,119.72,117.34,114.40,66.20,57.83,53.26,17.71.MS(ESI),m/z:563(M ++H +).
Embodiment 25
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(pyrroles-1-replaces) methyl-3-trifluoromethyl) benzamide (D1185)
Figure BDA00001866829800301
1H?NMR(400MHz,d-DMSO),δ13.81(s,1H),10.59(s,1H),9.16(s,1H),9.14(d,J=2.0Hz,1H),8.77(d,J=1.6Hz,1H),8.26(s,1H),8.21(d,J=1.2Hz,1H),8.18(d,J=1.8Hz,1H),8.15(dd,J=8.2Hz,1.6Hz,1H),8.06(dd,J=8.2Hz,1.6Hz,1H),7.73(d,J=8.2Hz,1H),7.72(d,J=8.0Hz,1H),3.70(s,2H),2.47(m,4H),2.36(s,3H),1.72(m,4H). 13C?NMR(125MHz,d-DMSO),δ164.03,151.45,146.88,144.78,137.79,137.16,136.10,133.73,133.26,133.13,131.82,131.10,129.11,126.82(J=27.5Hz),126.16,125.08,124.32(J=272.5Hz),123.58,123.02,119.71,117.16,114.39,55.04,53.57,23.18,17.70.MS(ESI),m/z:547(M ++H +).
Embodiment 26
(S)-3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replaces)-N-(4-(3-dimethylamino pyrroles-1-replaces) methyl-3-trifluoromethyl)-4-methyl benzamide (D1351)
Figure BDA00001866829800302
1H?NMR(400MHz,d-DMSO),δ13.82(s,1H),10.59(s,1H),9.16(s,1H),9.14(s,1H),8.77(s,1H),8.26-8.06(m,5H),7.71(br,2H),3.72-3.61(m,2H),2.72-2.56(m,3H),2.36(br,4H),2.07(s,6H),1.84(br,1H),1.62(m,1H). 13C?NMR(125MHz,d-DMSO),δ164.04,151.52,146.90,144.79,137.86,137.15,136.10,133.62,133.14,132.89,131.82,131.05,129.10,126.90(J=30.0Hz),126.16,125.08,124.30(J=272.5Hz),123.57,123.01,119.71,117.25,114.38,64.82,57.65,55.25,53.02,43.18,28.31,17.70.MS(ESI),m/z:590(M ++H +).
Embodiment 27
(R)-3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replaces)-N-(4-(3-dimethylamino pyrroles-1-replaces) methyl-3-trifluoromethyl)-4-methyl benzamide (D1187)
Figure BDA00001866829800311
1H?NMR(400MHz,d-DMSO),δ13.82(s,1H),10.60(s,1H),9.17(s,1H),9.14(d,J=2.0Hz,1H),8.77(d,J=2.0Hz,1H),8.27(s,1H),8.21(d,J=1.2Hz,1H),8.19(d,J=2.0Hz,1H),8.15(dd,J=8.0Hz,1.6Hz,1H),8.07(d,J=8.2Hz,1H),7.73(d,J=8.2Hz,1H),7.71(d,J=8.2Hz,1H),3.68(q,J=14.2Hz,2H),2.77-2.70(m,1H),2.67-2.62(m,1H),2.60-2.56(m,1H),2.48-2.46(m,1H),2.36(s,3H),2.34-2.32(m,1H),2.08(s,6H),1.90-1.82(m,1H),1.67-1.59(m,1H). 13C?NMR(125MHz,d-DMSO),δ164.05,151.50,146.90,144.78,137.85,137.16,136.10,133.66,133.13,132.90,131.83,131.07,129.11,126.90(J=30.0Hz),126.17,125.08,124.32(J=271.2Hz),123.58,123.02,119.71,117.25,114.37,64.82,57.65,55.25,53.03,43.20,28.31,17.70.MS(ESI),m/z:590(M ++H +).
Embodiment 28
4-methyl-3-(4-(pyrazoles [1,5-a] pyrimidine-6-replaces)-1H-1,2,3-triazol radical-1-replaces)-N-(4-(pyrroles-1-replaces) methyl-3-trifluoromethyl) benzamide (D1188)
Figure BDA00001866829800312
1H?NMR(400MHz,CDCl 3),δ9.15(s,1H),9.02(s,1H),8.83(s,1H),8.19(s,1H),8.15(s,1H),7.95-7.84(m,4H),7.71(d,J=8.2Hz,1H),7.39(d,J=8.0Hz,1H),6.71(s,1H),3.71(s,2H),2.52(s,4H),2.27(s,3H),1.78(s,4H). 13C?NMR(125MHz,CDCl 3),δ164.39,147.79,147.39,145.88,141.75,137.65,136.19,136.00,135.07,133.63,132.11,131.45,131.12,128.86,128.44(J=32.5Hz),124.74,124.02(J=273.8Hz),123.51,121.57,117.69,112.16,97.46,55.43,54.14,23.60,18.07.MS(ESI),m/z:590(M ++H +).
Embodiment 29
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-4-((4-(4-methylpiperazine-1-replaces) piperidines-1-replaces) methyl-3-trifluoromethyl) benzamide (D1288)
1H?NMR(500MHz,d-DMSO),δ13.82(s,1H),10.60(s,1H),9.15(s,1H),9.13(d,J=1.2Hz,1H),8.77(d,J=1.2Hz,1H),8.26(s,1H),8.19(s,1H),8.18(s,1H),8.14(d,J=6.2Hz,1H),8.05(d,J=6.2Hz,1H),7.72(d,J=6.2Hz,2H),3.52(s,2H),2.80(d,J=8.8Hz,2H),2.44(br,4H),2.35(s,3H),2.27(br,4H),2.15-2.08(m,4H),1.95(t,J=8.8Hz,2H),1.70(d,J=9.2Hz,2H),1.54(q,J=8.2Hz,2H). 13C?NMR(125MHz,d-DMSO),δ164.13,151.56,146.96,144.83,137.90,137.23,136.15,133.71,133.18,132.81,131.89,131.13,129.16,127.32(J=31.2Hz),126.27,125.13,124.34(J=277.5Hz),123.65,123.06,119.76,117.28,114.44,60.98,57.47,55.16,52.77,48.54,45.74,28.03,17.74.MS(ESI),m/z:659(M ++H +).
Embodiment 30
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-N-(4-(4-dimethylamino piperidine-1-replaces) methyl-3-trifluoromethyl)-4-methyl benzamide (D1289)
Figure BDA00001866829800322
1H?NMR(400MHz,d-DMSO),δ13.81(s,1H),10.59(s,1H),9.16(s,1H),9.14(s,1H),8.77(s,1H),8.26(s,1H),8.20(s,1H),8.19(s,1H),8.15(d,J=7.6Hz,1H),8.06(d,J=8.0Hz,1H),7.73(d,J=8.2Hz,1H),7.72(d,J=7.6Hz,1H),3.54(s,2H),2.81(d,J=10.8Hz,2H),2.36(s,3H),2.17(s,6H),2.08(s,1H),1.97(t,J=10.8Hz,2H),1.71(d,J=11.2Hz,2H),1.39(q,J=10.0Hz,2H). 13C?NMR(125MHz,d-DMSO),δ164.04,151.50,146.90,144.77,137.86,137.16,136.10,133.65,133.13,132.74,131.82,131.06,129.11,127.26(J=27.5Hz),126.16,125.08,124.32(J=272.5Hz),123.60,123.02,119.70,117.24,114.37,61.49,57.39,52.54,41.41,28.02,17.69.MS(ESI),m/z:604(M ++H +).
Embodiment 31
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-((3aR, 6aS)-5-methyl hexahydropyrrolo [3,4-c] pyrroles-2 (1H)-replacement) methyl-3-trifluoromethyl) benzamide (D1297)
Figure BDA00001866829800331
1H?NMR(500MHz,d-DMSO),δ13.81(s,1H),10.60(s,1H),9.16(s,1H),9.14(d,J=1.2Hz,1H),8.77(d,J=1.2Hz,1H),8.26(s,1H),8.20(s,1H),8.17(s,1H),8.14(d,J=6.2Hz,1H),8.06(d,J=6.2Hz,1H),7.72(d,J=6.2Hz,1H),7.70(d,J=6.8Hz,1H),3.64(s,2H),2.58-2.56(m,4H),2.47-2.46(m,2H),2.36(s,3H),2.26-2.25(m,2H),2.20-2.18(m,5H). 13C?NMR(125MHz,d-DMSO),δ164.05,151.51,146.89,144.78,137.84,137.14,136.09,133.62,133.15,133.01,131.82,131.06,129.09,126.93(J=30.0Hz),126.16,125.08,124.30(J=272.5Hz),123.54,123.01,119.70,117.26,114.37,61.54,59.20,54.46,42.12,41.36,17.69.MS(ESI),m/z:636(M ++H +).
Embodiment 32
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(3-(4-methyl isophthalic acid H-imidazoles-1-replaces)-5-trifluoromethyl) benzamide (D1285)
Figure BDA00001866829800332
Step 1. is synthesized 3-(4-methyl isophthalic acid H-imidazoles-1-replaces)-5-(trifluoromethyl) aniline
Figure BDA00001866829800333
By CuI (190mg, 1mmol), 4-methyl isophthalic acid H-imidazoles (1.64g, 20mmol), Cs 2cO 3(3.25g, 10mmol), 3-bromo-5-(trifluoromethyl) aniline (2.40g, 10mmol); 1-(5,6,7,8-tetrahydroquinoline-8-replaces) ethyl ketone (350mg; 2mmol) be dissolved in DMF (30mL), with argon shield, be heated to 130 ° of C, react 24 hours.After having reacted, cool to room temperature, is spin-dried for, and silica gel column chromatography is separated, and the white solid of recrystallization gained is target product (1.7g, productive rate: 71%).
1H?NMR(400MHz,d-DMSO),δ8.06(s,1H),7.35(s,1H),6.97(s,1H),6.93(s,1H),6.81(s,1H),5.87(br,2H),2.15,(s,3H).MS(ESI),m/z:242(M ++H +).
Step 2. is synthesized 3-azido--4-methyl-N-(3-(4-methyl isophthalic acid H-imidazoles-1-replaces)-5-(trifluoromethyl) phenyl) benzamide
Figure BDA00001866829800341
By 3-azido--methyl 4 methylbenzoate (0.19g, 1.0mmol) and 3-(4-methyl isophthalic acid H-imidazoles-1-replace)-5-(trifluoromethyl) aniline (0.24g, 1.0mmol), be dissolved in anhydrous tetrahydro furan (2.0mL), be cooled to-20 ° of C, slowly drip potassium tert.-butoxide (0.34g, anhydrous tetrahydro furan 3.0mmol) (5.0mL), react after 1 hour, naturally rise to room temperature, reaction is spent the night.After having reacted, be spin-dried for solvent, add EtOAc dilution, saturated common salt washing, anhydrous Na 2sO 4dry, be spin-dried for, the white solid of silica gel column chromatography gained is target product (0.37g, productive rate: 92%).
1H?NMR(400MHz,d-DMSO),δ10.71(s,1H),8.28(s,1H),8.21(s,1H),8.12(s,1H),7.81(s,1H),7.75-7.74(m,2H),7.49(s,1H),7.44(d,J=8.0Hz,1H),2.24(s,3H),2.18(s,3H).MS(ESI),m/z:401(M ++H +).
Step 3. is synthesized 3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(3-(4-methyl isophthalic acid H-imidazoles-1-replaces)-5-trifluoromethyl) benzamide (D1285)
Figure BDA00001866829800342
By 5-ethynyl-1H-pyrazolo [3,4-b] pyrimidine (0.24g, 1.7mmol), 3-azido--4-methyl-N-(3-(4-methyl isophthalic acid H-pyrimidine-1-replaces)-5-(trifluoromethyl) phenyl) benzamide (0.22g, 0.55mmol), CuSO 4(8.8mg, 0.55mmol) and sodium ascorbate (22mg, 1.1mmol) are dissolved in the mixing solutions of the trimethyl carbinol and water (1:1,5.0mL), 90 ° of C reactions, spend the night.After having reacted, be cooled to room temperature, with EtOAc extraction three times, saturated common salt washing, anhydrous Na 2sO 4dry, silica gel column chromatography is separated, and the yellow solid of gained is target product (0.21g, productive rate: 70%).
1H?NMR(400MHz,d-DMSO),δ13.81(s,1H),10.84(s,1H),9.18(s,1H),9.14(s,1H),8.77(s,1H),8.50(s,1H),8.36(s,1H),8.26(s,1H),8.24(s,1H),8.17(s,2H),7.79(s,1H),7.76(d,J=7.6Hz,1H),7.60(s,1H),2.37(s,3H),2.21(s,3H). 13C?NMR(125MHz,d-DMSO),δ164.82,151.90,147.32,145.27,141.52,138.01,137.76,136.61,135.30,134.19,133.15,132.43,131.32(J=27.5Hz),129.64,126.63,125.59,123.96(J=271.2Hz),123.48,120.13,115.87,115.29,114.84,112.76,18.18,9.02.MS(ESI),m/z:578(M -+Cl -).
Following examples 33-34 synthetic method is as embodiment 32.
Embodiment 33
N-(3-(1H-1,2,4-triazole-1-replaces)-5-trifluoromethyl)-3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl benzamide (D1287)
Figure BDA00001866829800351
1H?NMR(400MHz,d-DMSO),δ13.81(s,1H),10.88(s,1H),9.47(s,1H),9.17(s,1H),9.14(s,1H),8.77(s,1H),8.69(s,1H),8.31-8.26(m,4H),8.19(s,1H),8.06(s,1H),7.75(d,J=7.6Hz,1H),2.37(s,3H). 13C?NMR(125MHz,d-DMSO),δ164.86,153.13,151.91,147.34,145.25,143.37,141.63,138.13,138.00,136.60,134.19,133.17,132.39,131.14(J=33.8Hz),129.69,126.63,125.64,124.00(J=268.8Hz),123.49,120.14,115.64,114.83,111.14,18.18.MS(ESI),m/z:565(M -+Cl -).
Embodiment 34
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(3-(3-methyl isophthalic acid H-1,2,4-triazole-1-replaces)-5-trifluoromethyl) benzamide (D1290)
1H?NMR(400MHz,d-DMSO),δ13.80(s,1H),10.84(s,1H),9.32(s,1H),9.17(s,1H),9.14(d,J=1.6Hz,1H),8.77(d,J=2.0Hz,1H),8.63(s,1H),8.26(s,3H),8.18(d,J=8.0Hz,1H),8.01(s,1H),7.75(d,J=8.0Hz,1H),2.38(s,3H),2.37(s,3H). 13C?NMR(125MHz,d-DMSO),δ164.82,161.82,151.92,147.36,145.27,143.54,141.60,138.14,138.00,136.61,134.20,133.18,132.40,131.12(J=33.8Hz),129.70,126.65,125.63,124.04(J=271.2Hz),123.49,120.16,115.14,114.85,114.41,110.59,18.19,14.08.MS(ESI),m/z:565(M -+Cl -).
Embodiment 35
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4 cyclopropyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1301)
Figure BDA00001866829800353
Step 1. synthesizing methyl 4-cyclopropyl-3-nitrobenzoyl acid esters
Figure BDA00001866829800361
By methyl 4-cyclopropyl-3-nitrobenzoyl acid esters (1.0g, 3.9mmol), cyclopropylboronic acid (0.34g, 3.9mmol) is dissolved in dioxane (10.0mL), then adds Pd (dppf) Cl 2-DCM (64mg, 0.078mmol) and K 3pO 4(2.08g, 7.8mmol).Nitrogen replacement three times stirs and spends the night under 90 ° of C.After having reacted, filter, be spin-dried for solvent, add EtOAc dilution, saturated common salt washing, anhydrous Na 2sO 4dry, be spin-dried for, obtain target product, directly throw next step.
Step 2. synthesizing methyl 3-amino-4-cyclopropyl-phenyl manthanoate
Figure BDA00001866829800362
Methyl 3-amino-4-cyclopropyl-phenyl manthanoate (20g, 91mmol) is dissolved in to THF/water (1:1) (200mL), adds CF 3cOOH (4.38g, 73mmol) and NH 4cl (0.48g, 9.1mmol).After reflux, gradation adds iron powder (20.5g, 364mmol).Continue to stir 3 hours.After having reacted, filter saturated common salt washing, anhydrous Na 2sO 4dry, be spin-dried for, silica gel column chromatography, the yellow oil of gained is target product (16.5g, productive rate: 95%).
1H?NMR(400MHz,d-DMSO),δ7.25(d,J=2.0Hz,1H),7.06(dd,J=8.0Hz,2.0Hz,1H),6.87(d,J=8.0Hz,1H),5.27(s,2H),3.78(s,3H),1.75-1.71(m,1H),0.92-0.88(m,2H),0.56-0.52(m,2H).
Step 3. synthesizing methyl 3-azido--4-cyclopropyl-phenyl manthanoate
Figure BDA00001866829800363
Synthetic method and the identical (productive rate: 95%) of methyl 3-azido--4-methyl benzoic acid ester.
1H?NMR(400MHz,CDCl 3),δ7.78(d,J=2.0Hz,1H),7.70(dd,J=8.0Hz,1.6Hz,1H),6.86(d,J=8.0Hz,1H),3.92(s,3H),2.16-2.11(m,1H),1.06-1.02(m,2H),0.75-0.71(m,2H).
Step 4. is synthesized 3-azido--4-cyclopropyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide
Figure BDA00001866829800364
Synthetic method and 3-azido--4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) identical (productive rate: 15%) of benzamide.
m/z:459(M ++H +).
Step 5. is synthesized 3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-cyclopropyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide
Figure BDA00001866829800371
Synthetic method and 3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) identical (productive rate: 25%) of benzamide.
1H?NMR(400MHz,d-DMSO),δ9.16(s,1H),9.13(d,J=1.6Hz,1H),8.76(d,J=1.6Hz,1H),8.25(s,1H),8.18(s,2H),8.14(d,J=8.0Hz,1H),8.05(d,J=8.0Hz,1H),7.70(d,J=8.2Hz,1H),7.37(d,J=8.2Hz,1H),3.56(s,2H),2.38(br,4H),2.33(br,4H),2.15(s,3H),1.82-1.75(m,1H),1.01-0.99(m,2H),0.85-0.84(m,2H). 13C?NMR(125MHz,d-DMSO),δ163.97,151.82,146.74,144.84,143.22,138.10,136.42,133.50,132.24,132.17,131.23,129.60,127.43(J=30.0Hz),126.09,125.71,125.29,124.29(J=272.5Hz),123.56,123.52,119.53,117.30,114.38,57.42,55.99,54.69,52.66,45.68,18.51,11.07,9.74.MS(ESI),m/z:602(M ++H +).
The methyl benzoate that following examples 36-47 can directly replace from the 3-amino-4-buying obtains target product.Synthetic method is as embodiment 35.
Embodiment 36
The chloro-N-of 4-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-6-replaces)-1H-1,2,3-triazol radical-1-replaces) benzamide (D1291)
Figure BDA00001866829800372
1H?NMR(400MHz,d-DMSO),δ10.74(s,1H),9.65(s,1H),9.29(s,1H),9.16(s,1H),8.40(s,1H),8.32(s,1H),8.26(d,J=9.2Hz,1H),8.18(s,1H),8.05(d,J=8.8Hz,1H),7.73(d,J=8.8Hz,1H),6.85(s,1H),3.57(s,2H),2.38(br,4H),2.33(br,4H),2.15(s,3H). 13C?NMR(125MHz,d-DMSO),δ163.23,147.64,147.34,145.73,141.28,137.73,134.43,134.15,132.57,131.82,131.78,131.32,131.09,131.00,129.62,127.30,124.31,123.63,117.38,112.18,96.79,57.41,54.69,52.67,45.69.MS(ESI),m/z:596(M ++H +).
Embodiment 37
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces) the chloro-N-of-4-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1292)
Figure BDA00001866829800381
1H?NMR(400MHz,d-DMSO),δ13.83(s,1H),10.73(s,1H),9.24(s,1H),9.13(s,1H),8.78(s,1H),8.41(s,1H),8.27(s,1H),8.24(m,1H),8.18(s,1H),8.05-8.03(m,2H),7.73(d,J=8.2Hz,1H),3.57(s,2H),2.38(br,4H),2.33(br,4H),2.15(s,3H). 13C?NMR(125MHz,d-DMSO),δ163.28,151.59,146.89,144.85,137.75,134.36,133.77,132.57,131.99,131.33,131.04,130.91,129.74(J=28.8Hz),127.47(J=275.0Hz),127.32,126.37,123.64,123.52,123.17,119.44,117.38,114.39,57.41,54.69,52.66,45.68.MS(ESI),m/z:596(M ++H +).
Embodiment 38
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces) the bromo-N-of-4-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1302)
Figure BDA00001866829800382
1H?NMR(400MHz,d-DMSO),δ13.82(s,1H),10.71(s,1H),9.22(s,1H),9.13(d,J=1.6Hz,1H),8.78(d,J=1.6Hz,1H),8.36(s,1H),8.27(s,1H),8.17(s,3H),8.05(d,J=8.2Hz,1H),7.72(d,J=8.2Hz,1H),3.56(s,2H),2.38(br,4H),2.33(br,4H),2.15(s,3H). 13C?NMR(125MHz,d-DMSO),δ163.34,151.53,146.84,144.77,137.74,136.13,134.84,134.12,133.70,132.55,131.30,131.09,127.43(J=30.0Hz),127.46,126.27,124.24(J=272.5Hz),123.61,123.50,122.72,119.47,117.35,114.39,57.41,55.99,54.69,52.67,45.68,18.51.MS(ESI),m/z:640(M ++H +).
Embodiment 39
The bromo-N-of 4-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-6-replaces)-1H-1,2,3-triazol radical-1-replaces) benzamide (D1378)
Figure BDA00001866829800383
1H?NMR(400MHz,d-DMSO),δ10.72(s,1H),9.65(d,J=1.6Hz,1H),9.26(s,1H),9.15(d,J=2.0Hz,1H),8.35(s,1H),8.31(d,J=6.2Hz,1H),8.18-8.17(m,3H),8.04(d,J=8.2Hz,1H),7.72(d,J=8.2Hz,1H),6.84(d,J=2.0Hz,1H),3.56(s,2H),2.38(br,4H),2.33(br,4H),2.15(s,3H). 13C?NMR(125MHz,d-DMSO),δ163.32,147.60,147.35,145.72,141.21,137.73,135.92,134.92,134.19,132.57,131.70,131.31,131.20,127.46(J=28.8Hz),127.47,124.26(J=272.5Hz),124.29,123.61,122.54,117.36,112.23,96.80,57.41,56.00,54.69,52.66,45.68,18.51.MS(ESI),m/z:640(M ++H +).
Embodiment 40
4-cyclopropyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-6-replaces)-1H-1,2,3-triazol radical-1-replaces) benzamide (D1380)
Figure BDA00001866829800391
1H?NMR(400MHz,d-DMSO),δ10.59(s,1H),9.64(s,1H),9.21(s,1H),9.16(d,J=1.6Hz,1H),8.30(d,J=2.0Hz,1H),8.18(m,2H),8.15(d,J=8.2Hz,1H),8.05(d,J=8.2Hz,1H),7.70(d,J=8.2Hz,1H),7.38(d,J=8.2Hz,1H),6.83(d,J=1.6Hz,1H),3.55(s,2H),2.38(br,4H),2.33(br,4H),2.14(s,3H),1.81-1.74(m,1H),1.02-1.00(m,2H),0.85-0.84(m,2H). 13C?NMR(125MHz,d-DMSO),δ163.91,147.69,147.30,145.63,143.10,141.17,137.98,136.22,132.26,132.23,131.64,131.22,129.69,127.38(J=28.8Hz),125.78,125.25,124.39,124.27(J=272.5Hz),123.51,117.26,112.48,96.72,57.41,54.68,52.66,45.68,11.08,9.78.
Embodiment 41
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1304)
Figure BDA00001866829800392
1H?NMR(400MHz,d-DMSO),δ9.53(s,1H),9.12(d,J=2.0Hz,1H),8.76(d,J=2.0Hz,1H),8.57(s,1H),8.26(s,1H),8.23(d,J=2.0Hz,1H),8.20(dd,J=8.0Hz,1.6Hz,1H),8.12(d,J=8.0Hz,1H),8.08(dd,J=8.2Hz,1.6Hz,1H),7.84(t,J=8.0Hz,1H),7.73(d,J=8.2Hz,1H),3.57(s,2H),2.40(br,4H),2.34(br,4H),2.16(s,3H). 13C?NMR(125MHz,d-DMSO),δ164.56,151.56,146.83,145.62,137.97,136.67,136.19,133.64,132.37,131.27,130.28,127.83,127.44(J=30.0Hz),126.19,124.29(J=272.5Hz),123.60,123.08,119.72,119.55,119.27,117.34,114.37,57.43,55.99,54.70,52.68,45.69,18.50.MS(ESI),m/z:562(M ++H +).
Embodiment 42
N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-6-replaces)-1H-1,2,3-triazol radical-1-replaces) benzamide (D1377)
Figure BDA00001866829800401
1H?NMR(400MHz,d-DMSO),δ10.77(s,1H),9.59(d,J=1.2Hz,1H),9.57(s,1H),9.13(d,J=2.0Hz,1H),8.53(s,1H),8.31(d,J=2.2Hz,1H),8.22(d,J=1.6Hz,1H),8.17(dd,J=8.0Hz,1.2Hz,1H),8.14(d,J=8.0Hz,1H),8.08(d,J=8.2Hz,1H),7.85(t,J=8.0Hz,1H),7.73(d,J=8.2Hz,1H),6.83(d,J=2.0Hz,1H),3.57(s,2H),2.39(br,4H),2.34(br,4H),2.15(s,3H). 13C?NMR(125MHz,d-DMSO),δ164.45,147.57,147.31,145.69,141.98,137.94,136.49,136.21,132.37,131.58,131.25,130.35,127.98,127.41(J=30.0Hz),124.28(J=272.5Hz),123.60,123.11,120.62,119.33,117.34,112.34,96.76,57.41,54.70,52.67,45.69.MS(ESI),m/z:562(M ++H +).
Embodiment 43
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces) the fluoro-N-of-4-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1303)
Figure BDA00001866829800402
1H?NMR(400MHz,d-DMSO),δ13.82(s,1H),10.72(s,1H),9.29(d,J=1.2Hz,1H),9.15(d,J=2.0Hz,1H),8.79(d,J=2.0Hz,1H),8.58(dd,J=6.8Hz,2.0Hz,1H),8.26-8.24(m,2H),8.19(d,J=1.6Hz,1H),8.06(d,J=8.2Hz,1H),7.83(t,J=9.6Hz,1H),7.73(d,J=8.2Hz,1H),3.57(s,2H),2.39(br,4H),2.33(br,4H),2.15(s,3H). 13C?NMR(125MHz,d-DMSO),δ163.37,156.60,154.56,146.92,145.28,137.85,133.69,132.08(J=90.0Hz),131.26,130.96(J=8.8Hz),127.42(J=28.8Hz),126.44,125.35,124.60(J=10.0Hz),123.61,123.18,122.69,119.33,117.64(J=20.0Hz),117.34,114.36,57.41,54.69,52.66,45.67.MS(ESI),m/z:580(M ++H +).
Embodiment 44
The fluoro-N-of 4-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-6-replaces)-1H-1,2,3-triazol radical-1-replaces) benzamide (D1379)
Figure BDA00001866829800411
1H?NMR(400MHz,d-DMSO),δ10.73(s,1H),9.66(s,1H),9.34(s,1H),9.16(d,J=2.0Hz,1H),8.58(dd,J=7.2Hz,2.0Hz,1H),8.30(d,J=2.0Hz,1H),8.28-8.25(m,1H),8.19(d,J=1.2Hz,1H),8.05(d,J=8.2Hz,1H),7.84(t,J=9.6Hz,1H),7.72(d,J=8.2Hz,1H),6.83(d,J=1.6Hz,1H),3.56(s,2H),2.39(br,4H),2.33(br,4H),2.15(s,3H). 13C?NMR(125MHz,d-DMSO),δ163.38,156.50,154.46,147.69,147.36,145.75,141.76,137.85,132.14(J=86.2Hz),131.60(J=77.5Hz),131.08,127.44(J=30.0Hz),124.29(J=272.5Hz),125.26,124.46,123.66,123.53,123.49,117.72(J=21.2Hz),117.40,112.14,96.78,57.44,54.71,52.68,45.70.MS(ESI),m/z:580(M ++H +).
Embodiment 45
The chloro-3-of 4-(4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3 triazol radicals-1-replaces)-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1374)
Figure BDA00001866829800412
1H?NMR(400MHz,d-DMSO),δ13.38(s,1H),10.72(s,1H),9.22(s,1H),9.09(d,J=2.0Hz,1H),8.75(d,J=1.6Hz,1H),8.41(d,J=1.6Hz,1H),8.25(dd,J=8.2Hz,2.0Hz,1H),8.18(d,J=1.6Hz,1H),8.06-8.02(m,2H),7.73(d,J=8.2Hz,1H),3.57(s,2H),2.57(s,3H),2.39(br,4H),2.33(br,4H),2.15(s,3H). 13C?NMR(125MHz,d-DMSO),δ163.24,152.17,146.64,145.00,141.46,137.74,134.35,132.54,131.88,131.29,131.02,130.85,127.42(J=28.8Hz),127.25,125.89,124.24(J=272.5Hz),123.61,123.34,118.60,117.35,113.89,57.40,54.68,52.66,45.68,12.19.
Embodiment 46
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-ethyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1375)
Figure BDA00001866829800421
1H?NMR(400MHz,d-DMSO),δ13.81(s,1H),10.59(s,1H),9.15-9.14(m,2H),8.77(d,J=1.6Hz,1H),8.26(s,1H),8.19-8.17(m,3H),8.06(d,J=8.2Hz,1H),7.75(d,J=8.0Hz,1H),7.71(d,J=8.2Hz,1H),3.56(s,2H),2.63(q,J=7.6Hz,2H),2.38(br,4H),2.33(br,4H),2.15(s,3H),1.12(t,J=7.6Hz,3H). 13C?NMR(125MHz,d-DMSO),δ164.06,151.51,146.90,144.80,143.27,137.97,135.56,133.64,133.10,132.26,131.26,130.32,129.55,127.40(J=28.8Hz),126.17,125.55,124.27(J=272.5Hz),123.51,123.30,119.68,117.26,114.38,57.41,54.67,52.63,45.65,23.93,14.63.MS(ESI),m/z:590(M ++H +).
Embodiment 47
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-sec.-propyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1376)
Figure BDA00001866829800422
1H?NMR(400MHz,d-DMSO),δ13.82(s,1H),10.61(s,1H),9.15-9.14(m,2H),8.77(d,J=2.0Hz,1H),8.26(s,1H),8.23(dd,J=8.0Hz,1.6Hz,1H),8.19(d,J=1.6Hz,1H),8.14(d,J=1.6Hz,1H),8.06(d,J=8.2Hz,1H),7.84(d,J=8.0Hz,1H),7.71(d,J=8.2Hz,1H),3.56(s,2H),2.84-2.78(m,1H),2.38(br,8H),2.15(s,3H),1.22(d,J=6.8Hz,6H). 13C?NMR(125MHz,d-DMSO),δ164.04,151.52,148.10,146.89,144.78,137.98,134.82,133.62,132.88,132.23,131.24,129.92,127.40(J=30.0Hz),127.46,126.16,125.79,124.27(J=272.5Hz),123.65,123.49,119.66,117.24,114.37,57.39,54.64,52.59,45.61and45.60,27.89,23.28.MS(ESI),m/z:604(M ++H +).
Embodiment 48
3-(4-(1H-pyrazoles [3,4-b] pyridine-5-replaces)-1H-1,2,3-triazol radical-5-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1298)
Figure BDA00001866829800423
By 3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement) ethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide (synthetic method is shown in WO2012/000304 and CN201010216603.7) (0.27g, 0.5mmol) and sodium azide (0.16g, 2.5mmol) be dissolved in the DMF (2.0mL) heavily steaming, in tube sealing, be heated to 200 ° of C, stir 24 hours.After having reacted, cool to room temperature.EtOAc dilution, saturated common salt washing, anhydrous Na 2sO 4dry, be spin-dried for, silica gel column chromatography, the yellow solid of gained is target product (73g, productive rate: 25%).
1H?NMR(400MHz,d-DMSO),δ13.76(s,1H),10.48(s,1H),8.54(s,1H),8.19(s,1H),8.15-8.14(m,2H),8.02-8.01(m,3H),7.67(d,J=7.6Hz,1H),7.54(d,J=6.8Hz,1H),3.54(s,2H),2.37(br,8H),2.14(s,3H),2.06(s,3H). 13C?NMR(125MHz,d-DMSO),δ164.91,151.15,147.24,141.13,140.35,139.65,138.12,133.69,132.19,132.09,131.22,130.78,130.46,129.63,128.52,127.41,127.40(J=30.0Hz),125.58,124.34(J=273.8Hz),119.95,117.34,114.21,57.45,54.70,52.66,45.68,19.59.MS(ESI),m/z:576(M ++H +).
Embodiment 49
3-(5-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1,3,4-oxadiazole-2-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide (D1300)
Figure BDA00001866829800431
Step 1. synthesizing methyl 1H-pyrazoles [3,4-b] pyrimidine-5-carboxylic acid ester
Figure BDA00001866829800432
By bromo-1H-pyrazoles [3, the 4-b] pyrimidine of 5-(5.0g, 25mmol), Pd (OAc) 2(0.28g, 1.25mmol), dppf (1.4g, 2.5mmol), methyl alcohol (5.0mL, 125mmol) and Et 3n (7.0mL, 50mmol) is added in 100mL round-bottomed flask, dissolves, with CO displacement three times with DMF (15.0mL).100 ° of C reactions 12 hours.After having reacted, be cooled to room temperature, filter, be spin-dried for, silica gel column chromatography is separated, and the yellow solid of gained is target product (2.0g, productive rate: 46%).
1H?NMR(400MHz,d-DMSO),δ14.04(s,1H),9.03(s,1H),8.83(s,1H),8.31(s,1H),3.90(d,J=2.0Hz,3H).MS(ESI),m/z:178(M ++H +).
Step 2. is synthesized 1H-pyrazoles [3,4-b] pyrimidine-5-carbonyl hydrazides
Figure BDA00001866829800441
Methyl 1H-pyrazoles [3,4-b] pyrimidine-5-carboxylic acid ester (0.53g, 3.0mmol) is dissolved in to ethanol (2.0mL), then adds hydrazine hydrate (2.0mL), backflow 1H.After having reacted, be cooled to room temperature, filter, with EtOAc dilution, wash twice, saturated common salt is washed once, anhydrous Na 2sO 4dry, silica gel column chromatography is separated, and the white solid of gained is target product (0.35g, productive rate: 66%).
1H?NMR(400MHz,d-DMSO),δ13.87(s,1H),9.91(s,1H),8.94(d,J=2.0Hz,1H),8.65(d,J=2.0Hz,1H),8.27(s,1H),4.62(br,2H).
Step 3. is synthesized 3-(2-(1H-pyrazoles [3,4-b] pyrimidine-5-carbonyl) carbonyl hydrazides)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide
Figure BDA00001866829800442
By 1H-pyrazoles [3,4-b] pyrimidine-5-carbonyl hydrazide (44mg, 0.25mmol), the iodo-4-methyl-N-of 3-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide (129mg, 0.25mmol), Pd (OAc) 2(2.8mg, 0.0125mmol), PPh 3(3.3mg, 0.0125mmol), Et 3n (70 μ L, 0.5mmol) is dissolved in DMF (1.0mL), with CO displacement three times.120 ° of C reactions, spend the night.After having reacted, be cooled to room temperature, filter, be spin-dried for, silica gel column chromatography is separated, and the yellow solid of gained is target product (0.13g, productive rate: 50%).
1H?NMR(400MHz,d-DMSO),δ13.99(s,1H),10.76(s,1H),10.60(s,1H),10.41(s,1H),9.06(s,1H),8.82(s,1H),8.35(s,1H),8.22(s,1H),8.08(s,1H),8.06(m,1H),8.03(d,J=8.0Hz,1H),7.72(d,J=8.8Hz,1H),7.50(d,J=7.6Hz,1H),3.58(s,2H),2.54(s,3H),2.40(br,8H),2.19(s,3H).MS(ESI),m/z:595(M ++H +).
Step 4. is synthesized 3-(5-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1,3,4-oxadiazoles-2-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1300)
Figure BDA00001866829800443
By 3-(5-(1H-pyrazoles [3,4-b] pyrimidine-5-carbonyl) carbonyl hydrazides)-4-methyl-N-(4-((4-methylpiperazine-1-replace) methyl)-3-(trifluoromethyl) phenyl) benzamide (0.19g, 0.32mmol) is dissolved in POCl 3(2.0mL), reflux 2 hours.After having reacted, be cooled to room temperature, use saturated NaHCO 3neutralization, EtOAc extracting twice, saturated common salt washing, anhydrous Na 2sO 4dry, silica gel column chromatography is separated, ethyl alcohol recrystallization, and the white solid of gained is target product (60mg, productive rate: 33%).
1H?NMR(400MHz,d-DMSO),δ14.12(s,1H),10.66(s,1H),9.27(d,J=1.9Hz,1H),9.03(d,J=1.9Hz,1H),8.68(d,J=1.2Hz,1H),8.38(s,1H),8.24(d,J=1.6Hz,1H),8.12(dd,J=7.8Hz,1.2Hz,1H),8.06(d,J=8.2Hz,1H),7.72(d,J=8.5Hz,1H),7.67(d,J=8.1Hz,1H),3.57(s,2H),2.81(s,3H),2.40(br,4H),2.34(br,4H),2.16(s,3H). 13C?NMR(125MHz,d-DMSO),δ165.55,163.69,162.97,152.34,147.03,141.62,138.01,134.75,132.66,132.21,131.99,131.19,130.30,129.51,128.24,127.36(J=30.0Hz),124.34(J=271.2Hz),123.60,122.63,117.32,114.10,113.03,57.40,54.67,52.65,45.66,21.59.MS(ESI),m/z:577(M ++H +).
Embodiment 50
3-(5-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1,2,4-oxadiazole-2-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1344)
Figure BDA00001866829800451
Step 1. is synthesized 1H-pyrazoles [3,4-b] pyrimidine-5-carboxylic acid
Figure BDA00001866829800452
Methyl 1H-pyrazoles [3,4-b] pyrimidine-5-carboxylic acid ester (0.18g, 1.0mmol) and lithium hydroxide (0.13g, 3.0mmol) are dissolved in to methyl alcohol-THF-water (1:1:1) (3.0mL), in stirred overnight at room temperature.After having reacted, be spin-dried for, with 1N HCl acidifying, filter, filtration cakes torrefaction, the yellow solid of gained is target product (0.11g, productive rate: 69%).
1H?NMR(400MHz,d-DMSO),δ13.96(s,1H),13.25(s,1H),9.03(s,1H),8.79(s,1H),8.30(s,1H).
Step 2. is synthesized 3-cyano group-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide
Figure BDA00001866829800461
By the iodo-4-methyl-N-of 3-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide (2.1g, 4.0mmol), CuCN (0.36g, 4.0mmol), Pd 2(dba) 3(92mg, 0.1mmol), dppf (111mg, 0.2mmol) is added in tube sealing, with DMF (5.0mL), dissolves.By argon replaces three times, 120 ° of C reactions, spend the night.After having reacted, be cooled to room temperature, filter, be spin-dried for, silica gel column chromatography is separated, and the gray solid of gained is target product (1.53g, productive rate: 92%).
1H?NMR(400MHz,CDCl 3),δ8.15(s,1H),8.03-8.01(m,2H),7.89-7.86(m,2H),7.79(d,J=8.0Hz,1H),7.48(d,J=8.0Hz,1H),3.64(s,2H),2.64(s,3H),2.51(br,8H),2.31(s,3H).MS(ESI),m/z:417(M ++H +).
Step 3. is synthesized (E)-3-(N'-hydroxyl amidino groups)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide
Figure BDA00001866829800462
By 3-cyano group-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide (1.53g, 3.7mmol), NaHCO 3(1.55g, 18.4mmol) is dissolved in ethanol (15.0mL), then adds oxammonium hydrochloride (1.28g, 18.4mmol).80 ° of C reactions 5 hours.Be spin-dried for rear direct throwing next step.
Step 4. is synthesized (Z)-3-(N'-(1H-pyrazoles [3,4-b] pyrimidine-5-carbonyl oxygen base) carboxamide imines)-4-1H-1,2,3-triazol radical-1-replaces)-4-cyclopropyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide
Figure BDA00001866829800463
By (E)-3-(N'-hydroxyl amidino groups)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide (0.96g, 2.1mmol), PyBOP (1.09g, 2.1mmol), Et 3n (0.35mL, 2.5mmol) is dissolved in DMF (5.0mL), uses argon replaces three times, at room temperature reaction, spends the night.After having reacted, be spin-dried for, silica gel column chromatography is separated, and the yellow solid of gained is target product (0.39g, productive rate: 31%).
1H?NMR(400MHz,d-DMSO),δ14.04(s,1H),10.55(s,1H),9.27(d,J=2.0Hz,1H),9.12(d,J=2.0Hz,1H),8.34(s,1H),8.22(d,J=2.0Hz,1H),8.11-8.08(m,2H),8.03(dd,J=8.0Hz,1.8Hz,1H),7.71(d,J=8.8Hz,1H),7.51(d,J=8.0Hz,1H),7.20(br,2H),3.57(s,2H),2.51(s,3H),2.42(br,8H),2.22(s,3H).MS(ESI),m/z:595(M ++H +).
Step 5. is synthesized 3-(5-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1,2,4-oxadiazoles-2-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide (D1344)
Figure BDA00001866829800471
By (Z)-3-(N'-(1H-pyrazoles [3,4-b] pyrimidine-5-oxygen carbonyl) carboxamide imines)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide (59mg, 0.1mmol) be dissolved in the toluene (1.0mL) heavily steaming, THF solution (the 0.12mL that adds again 1N TBAF, 0.12mmol), 110 ° of C reactions 1 hour.After having reacted, be cooled to room temperature, be spin-dried for, silica gel column chromatography is separated, ethyl alcohol recrystallization, and the yellow solid of gained is target product (50mg, productive rate: 87%).
1H?NMR(400MHz,d-DMSO),δ14.20(s,1H),10.66(s,1H),9.32(s,1H),9.15(s,1H),8.66(s,1H),8.40(s,1H),8.23(s,1H),8.12(d,J=7.6Hz,1H),8.07(d,J=8.2Hz,1H),7.72(d,J=8.2Hz,1H),7.64(d,J=8.0Hz,1H),3.57(s,2H),2.72(s,3H),2.40(br,4H),2.34(br,4H),2.16(s,3H). 13C?NMR(125MHz,d-DMSO),δ173.92,168.40,164.85,152.73,148.02,141.77,138.12,135.22,132.50,132.18,131.74,131.30,131.25,129.92,129.34,127.44(J=26.2Hz),125.73,124.35(J=272.5Hz),123.62,117.34,114.21,113.09,57.45,54.72,52.69,45.70,21.70.MS(ESI),m/z:577(M ++H +).
Embodiment 51
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide dimethanesulfonate (D1163 tetramethyl sulfonate)
Figure BDA00001866829800472
By 575mg D1163(1mmol) be placed in 100mL single port bottle, add 30mL dehydrated alcohol, stir the lower 384mg methylsulfonic acid (4mmol) that drips, be heated to boil, system becomes to be clarified, backflow 4h, be cooled to room temperature, adularescent solid is separated out, and filters, filter residue is washed three times with ethanol, and vacuum-drying obtains light yellow solid 1.34g(90%).
1H?NMR(400MHz,DMSO),δ10.70(s,1H),9.17(s,1H),9.14(d,J=2.0Hz,1H),8.78(d,J=2.0Hz,1H),8.27(s,1H),8.25(d,J=1.6Hz,1H),8.20(s,1H),8.18-8.14(m,2H),7.76(dd,J=20.0,8.4Hz,2H),3.95(br,2H),3.50(br,2H),3.15(br,4H),2.84(s,3H),2.70(br,2H),2.39(s,12H),2.36(s,3H).MS(ESI),m/z:576(M ++H +).
Embodiment 52
4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-6-replacement)-1H-1,2,3-triazol radical-1-replaces) benzamide mesylate (D1167 tri-mesylates)
Figure BDA00001866829800481
By 575mg D1167(1mmol) be placed in 100mL single port bottle, add 30mL dehydrated alcohol, stir the lower 384mg methylsulfonic acid (4mmol) that drips, be heated to boil, system becomes to be clarified, backflow 4h, be cooled to room temperature, adularescent solid is separated out, and filters, filter residue is washed three times with ethanol, and vacuum-drying obtains light yellow solid 1.35g(91%).
1H?NMR(400MHz,DMSO),δ10.74(s,1H),9.18(s,1H),9.14(d,J=2.0Hz,1H),8.78(d,J=2.0Hz,3H),8.28-8.27(m,2H),8.21(s,1H),8.18-8.15(m,3H),7.82(d,J=8.4Hz,1H),7.73(d,J=8.0Hz,1H),4.09(br,2H),3.56(d,J=6.8Hz,2H),3.23(br,8H),2.86(s,5H),2.42(s,9H),2.36(s,3H).MS(ESI),m/z:576(M ++H +).
Embodiment 53
3-(4-(imidazo [1,2-b] pyridazine-3-replacement)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide hydrochloride salt (D1280 hydrochloride)
Figure BDA00001866829800482
By 575mg D1280(1mmol) be placed in 100mL there-necked flask, add 30mL dehydrated alcohol, stir the lower 6N of dropping aqueous hydrochloric acid, treat that raw material all dissolves, be spin-dried for to obtain light yellow solid 501mg(82%).
1H?NMR(400MHz,DMSO),δ11.19(s,1H),9.37(s,1H),9.15(s,1H),8.28(s,3H),8.21(d,J=7.6Hz,1H),7.94(s,1H),7.70(d,J=8.0Hz,1H),4.50(s,2H),3.66-3.56(m,8H),2.82(s,3H),2.30(s,3H).MS(ESI),m/z:576(M ++H +).
Embodiment 54
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces) the chloro-N-of-4-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide hydrochloride salt (D1292 hydrochloride)
Figure BDA00001866829800483
Synthetic method is with embodiment 53.
1H?NMR(400MHz,d-DMSO),δ13.83(s,1H),10.73(s,1H),9.24(s,1H),9.13(s,1H),8.78(s,1H),8.41(s,1H),8.27(s,1H),8.24(m,1H),8.18(s,1H),8.05-8.03(m,2H),7.73(d,J=8.2Hz,1H),3.57(s,2H),2.38(br,4H),2.33(br,4H),2.15(s,3H).
Embodiment 55
3-(5-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1,2,4-oxadiazoles-2-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide hydrochloride salt (D1344 hydrochloride)
Synthetic method is with embodiment 53.
1H?NMR(400MHz,d-DMSO),δ14.20(s,1H),10.66(s,1H),9.32(s,1H),9.15(s,1H),8.66(s,1H),8.40(s,1H),8.23(s,1H),8.12(d,J=7.6Hz,1H),8.07(d,J=8.2Hz,1H),7.72(d,J=8.2Hz,1H),7.64(d,J=8.0Hz,1H),3.57(s,2H),2.72(s,3H),2.40(br,4H),2.34(br,4H),2.16(s,3H).
Embodiment 56
Vitro kinase activity detects
Kinase activity detects the fluorescence polarization immunoassay (FPIA) method that adopts.Medicine carries out gradient dilution (since 3 times of dilutions of 10 μ M), and add kinases (the about 0.1-0.01U/mL of Abl or the about 0.1-0.01U/mL of ABl (T315I)) and substrate (approximately 50 μ M-800 μ M) in the reaction system of 25ul, phosphorylation reaction 2 hours; Add again with fluorescently-labeled MALDI-PSD and identification MALDI-PSD antibody in reaction system, the about 4-24 hour of balance then detects in microplate reader.This medicine FP value of gained, through Graphpad Prism5.0 Fitting Analysis, obtains the IC of sieved medicine 50.Each compound is to the kinase whose half-inhibition concentration (IC of Abl 50) value describes as table 1.Compound used therefor is selected from respectively the prepared compound into embodiment 1-55, in table 1, with Drug No. label, represents.
The IC of table 1. part of compounds to Abl kinase activity 50(nM)
Figure BDA00001866829800492
Figure BDA00001866829800501
(ND：Not?Detected)
Above-mentioned Abl kinases is normal tyrosine protein kinase, Abl(T315I) is mutant strain, it is characterized in that the 315th, Abl kinases territory Threonine is sported Isoleucine.
Chemical structure and the given vitro kinase activity data of embodiment 56 of the prepared compound of 1-55, can analyze and obtain heterocycle benzamide compound to ABL kinases and ABL(T315I in conjunction with the embodiments) kinases has remarkable structure activity relationship.Its feature is as follows: 1) work as R 1during for 2-substituted pyrimidyl, R 5or R 6while having at least one to be H, activity is better than other molecules; 2) work as R 1for 2-substituted pyrimidyl, R 5or R 6while having at least one to be H, another substituent size affects the activity of compound, and universal law is that compound substituent is larger, and activity is poorer; 3) work as R 1when middle B ring is five yuan or hexa-member heterocycle, the compound activity that X is N is significantly higher than the similar compound of other atoms; 4) R 1when middle C ring is five yuan or hexa-member heterocycle, the position of containing a NH and NH in C ring encircle with B in N atom when adjacent, compound activity is better than other congeneric elements; 5) when B ring N atom and C ring NH exist simultaneously, the activity of this quasi-molecule is more excellent, and is better than 2-substituted pyrimidines compounds; 6) R 2substituent size affects the activity of compound, and universal law is that substituting group is H, during F, active in methyl, Cl and Br, and substituting group is too large, as sec.-propyl, makes too activity decreased.
D0101 chemical structure is:
Figure BDA00001866829800511
D0102 chemical structure is:
Figure BDA00001866829800512
D0103 chemical structure is:
D0104 chemical structure is:
Figure BDA00001866829800514
Embodiment 57
Cell in vitro is active to be detected
The cell growth inhibiting activity of heterocycle benzamide compound is used the method for describing in CCK-8 test kit to assess.Cell (3000-10000/hole) is inoculated in to 96 porocyte culture plates after upper 24 hour, the compound solution of 100 μ L different concns joins in each culture hole, hatch 72 hours, 10 μ L CCK-8 solution join in each culture hole, hatch again 2-3 hour, by microplate reader, measure the light absorption value of 450nm and 650nm.In EXCELL form, process raw data, obtain respectively processing the cell survival rate in hole.Then use survival rate data on GraphPad Prism software, to use nonlinear regression model (NLRM) to calculate IC 50value.Found that, heterocycle benzamide compound can significantly suppress Ba/F3Bcr/Abl-T315I, K562, and K562R, the propagation of KU812, its half-inhibition concentration (IC50, table 2) becomes positive correlation with drug level.Compound used therefor is respectively the prepared compound of embodiment 1-55, in table 2, with Drug No. label, represents.
The IC of table 2. part of compounds to different tumour cells 50(nM)
Figure BDA00001866829800515
(ND:Not?Detected)
Prepared compound chemical structure and the given cell in vitro activity data of embodiment 57 of 1-55 in conjunction with the embodiments, can analyze that to obtain heterocycle benzamide compound basically identical to the structure activity relationship of cell in vitro activity and embodiment 57.
K562(is human chronic polymorpho nuclear leukemia cells system) and KU812(be the strain of human peripheral basophil) be a kind of representative in Leukemia Cell Lines.In embodiment 1-55, compound has stronger inhibition activity to it more.And the K562R persister that to be imatinib induction obtain (this persister builds screening acquisition by the present patent application people by ordinary method, and can provide to the public), imatinib is had to strong drug-resistant effect, but compound in embodiment 1-55 is shown to stronger susceptibility.BaF3(T315I) clone (build screening by present inventor by ordinary method and obtain, and can provide to the public) be a kind of can stably express Bcr-Abl(T315I) BaF3 clone.It can react micromolecular inhibitor and Bcr-Abl(T315I relatively single-mindedly) site interaction.The good molecule of activity as cited in embodiment 57, as D1163, has the activity of very strong inhibition cell in vitro T315I sudden change.Especially with three marketed drug Imatinib, Dasatinib and Nilotinib compare, and this compounds is suppressing to have clear superiority aspect T315I sudden change.
Embodiment 58
External mutant clone is active to be detected
The cell growth inhibiting activity of heterocycle benzamide compound is used the method for describing in CCK-8 test kit to assess.Cell (3000-10000/hole) is inoculated in to 96 porocyte culture plates after upper 24 hour, the compound solution of 100 μ L different concns joins in each culture hole, hatch 72 hours, 10 μ L CCK-8 solution join in each culture hole, hatch again 2-3 hour, by microplate reader, measure the light absorption value of 450nm and 650nm.In EXCELL form, process raw data, obtain respectively processing the cell survival rate in hole.Then use survival rate data on GraphPad Prism software, to use nonlinear regression model (NLRM) to calculate IC 50value.Found that, heterocycle benzamide compound can significantly suppress various Abl kinases territory mutant clone (as M351T, F486S, Q252H, Y253H, E355G, M244V, T315I, H396P, E255K, G250E) propagation, its half-inhibition concentration (IC 50, table 3) and become positive correlation with drug level.Compound used therefor is selected from the prepared compound of embodiment 1-55, in table 3, with Drug No. label, represents.
The IC of table 3. part of compounds to different mutant strains 50(nM)
In table 3, the Mutant Cells system such as cited M351T, F486S, Q252H, Y253H, E355G, M244V, T315I, H396P, E255K, G250E utilizes the Abl kinases ATP that the method artificial screening of induced mutation builds to cause the external model of the resistances such as imatinib in conjunction with territory (being catalytic site) single amino acids site mutation.These mutant strains are the inhibition of compound of reaction to clinical drug resistance cases such as imatinib relatively preferably.
As can be seen from Table 3, Compound D 1163, D1292, D1302 all shows strong inhibition to most imatinib and the active not high mutant strain of nilotinib inhibition; Compound D 1163, D1292, D1302 all shows that to the mutant strain except T315I similar inhibition is active with dasatinib, but for T315I mutant strain, dasatinib is weaker than D1163, D1292, D1302 far away to its inhibition activity.
Associative list 1, the data of table 2 and table 3, we think that the described compound of embodiment 1-55 has the leukemia to the various Bcr-Abl positives, especially has potential result for the treatment of to the leukemia of clinical medicine imatinib, nilotinib and dasatinib resistance.Compound in vitro kinase activity test and cytoactive test comprise various mutant strain active testings all demonstrate good inhibition Bcr-Abl kinases with and the activity of various saltant types.And contrast imatinib, nilotinib and dasatinib, the described compound of embodiment 1-55 also has outstanding advantage.This invention for solve current clinical drug-resistant patient without medicine can with miserable present situation brought dawn.
The above embodiment has only expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but can not therefore be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.

Claims (13)

1. heterocycle benzamide compound or its pharmacy acceptable salt or steric isomer or the prodrugs with formula I constitutional features:
Figure FDA00001866829700011
Wherein, A ring is five-membered ring, can be connected arbitrarily with both sides fragment as upper/lower positions, certainly optional:
1) triazole
Figure FDA00001866829700012
2) oxadiazoles
Figure FDA00001866829700013
R 1certainly optional:
1) 2-substituted pyrimidyl
Figure FDA00001866829700014
2) and heterocyclic radical
Figure FDA00001866829700015
3) and heterocyclic radical
Figure FDA00001866829700016
3) R 7substituted-phenyl
R 2certainly optional:
1）H；
2) halogen;
3) C1-C5 alkyl;
4) C3-C6 cycloalkyl;
R 4for H, R 3certainly optional:
1)H；
2)(CH 2) nNR 5R 6；
3)(CH 2) n–Het 1；
Or R 3for H, R 4certainly optional:
1)H；
2)Het 2；
Wherein, X, Y, Z, is optionally N, CH, five yuan or the hexa-member heterocycle of C ring for containing 1-3 nitrogen-atoms; N is 0 or 1, Het 1for the nonaromatic heterocycles base that contains 1-3 N, Het 2for containing heteroatoms N, the 5-membered aromatic heterocycle base of O and/or S, the described non-aromatic and arbitrary C atom of aromatic heterocycle or N atom can substituted position can be by alkyl, cycloalkyl, or NR 5r 6replace;
R 5, R 6certainly optional:
1）H；
2) C1-C3 alkyl;
3) C1-C3 is containing fluoroalkyl;
4) C3-C6 cycloalkyl;
Or R 5and R 6by C, O, N, S atom forms five yuan, hexa-atomic, seven yuan or octatomic ring shape structure.
R 7certainly optional:
1）H，
2）OH；
3)NH 2。
2. heterocycle benzamide compound according to claim 1 or its pharmacy acceptable salt or steric isomer or prodrugs, is characterized in that, wherein
R 1certainly optional:
1) 2-substituted pyrimidyl
Figure FDA00001866829700021
2) and heterocyclic radical
Figure FDA00001866829700022
3) and heterocyclic radical
Figure FDA00001866829700023
R 2certainly optional:
1）H；
2) halogen;
3) C1-C5 alkyl;
4) C3-C6 cycloalkyl;
R 4for H, R 3certainly optional:
1)H；
2)(CH 2) nNR 5R 6；
3)(CH 2) n–Het 1；
Or R 3for H, R 4certainly optional:
1)H；
2)Het 2；
Wherein, Y, Z, is optionally N, CH, five yuan or the hexa-member heterocycle of C ring for containing 1-3 nitrogen-atoms; N is 0 or 1, Het 1for the nonaromatic heterocycles base that contains 1-3 N, Het 2for containing heteroatoms N, the 5-membered aromatic heterocycle base of O and/or S, the described non-aromatic and arbitrary C atom of aromatic heterocycle or N atom can substituted position can be by alkyl, cycloalkyl, or NR 5r 6replace;
R 5, R 6certainly optional:
1）H；
2) C1-C3 alkyl;
3) C1-C3 is containing fluoroalkyl;
4) C3-C6 cycloalkyl;
Or R 5and R 6by C, O, N, S atom forms five yuan, hexa-atomic, seven yuan or octatomic ring shape structure.
3. heterocycle benzamide compound according to claim 1 and 2 or its pharmacy acceptable salt or steric isomer or prodrugs, is characterized in that, described R 1selected 2-substituted uracil is one of following structure:
4. heterocycle benzamide compound according to claim 1 and 2 or its pharmacy acceptable salt or steric isomer or prodrugs, is characterized in that, described R 1selected five yuan and hexa-member heterocycle are one of following structure:
Figure FDA00001866829700032
5. heterocycle benzamide compound according to claim 1 and 2 or its pharmacy acceptable salt or steric isomer or prodrugs, is characterized in that, wherein
R 2optionally from following structure:
1）H;
2）CH 3，CH 2CH 3;
3）
Figure FDA00001866829700041
4）F,Cl,Br,I；
5）CF 3。
6. heterocycle benzamide compound according to claim 1 and 2 or its pharmacy acceptable salt or steric isomer or prodrugs, is characterized in that, wherein
Work as R 4for H, R 3certainly optional:
1)H；
2)CH 2NR 5R 6；
3)(CH 2) n–Het 1；
Or R 3for H, R 4certainly optional:
1)H；
2)Het 2；
R 5, R 6definition identical with claim 1, n is 1, Het 1be selected from following structure:
Figure FDA00001866829700042
Het 2be selected from following structure:
Figure FDA00001866829700043
7. heterocycle benzamide compound according to claim 1 and 2 or its pharmacy acceptable salt or steric isomer or prodrugs, is characterized in that,
R 1certainly optional:
Figure FDA00001866829700044
R 2certainly optional:
1）H;
2）CH 3，CH 2CH 3;
3）
Figure FDA00001866829700051
4）F,Cl,Br；
Work as R 4for H, R 3certainly optional:
1)H；
2)CH 2NR 5R 6；
3)(CH 2) n–Het 1；
Or R 3for H, R 4certainly optional:
1)H；
2)Het 2；
R 5, R 6definition identical with claim 1, n is 1, Het 1be selected from following structure:
Figure FDA00001866829700052
Het 2be selected from following structure:
Figure FDA00001866829700053
8. heterocycle benzamide compound according to claim 1 or its pharmacy acceptable salt or steric isomer or prodrugs, is characterized in that, described heterocycle benzamide compound is selected from following compound:
3-(4-(2-(hexamethylene is amino) pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide;
3-(4-(2-isopropylamine base pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide;
3-(4-(2-benzamido group pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide;
3-(4-(2-amine pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide;
3-(4-(2-methylamino pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide;
3-(4-(2-ethylamino-pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide;
3-(4-(2-cyclopropyl amino pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide;
4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl)-3-(4-(2-(piperidines-1-replaces) pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces) benzamide;
4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl)-3-(4-(2-(anilino) pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces) benzamide;
3-(4-(imidazo [1,2-b] pyridazine-3-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide;
4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-6-replaces)-1H-1,2,3-triazol radical-1-replaces) benzamide;
3-(4-(2-(dimethylamino) pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide;
3-(4-(2-amido quinazoline-6-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(piperazine-1-substituent methyl)-3-(trifluoromethyl) phenyl) benzamide;
3-(4-(1H-indoles-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide;
4-methyl-3-(4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridine-5-replacement)-1H-1,2,3-triazol radical-1-replaces)-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide;
(4-([1 for 3-, 2,4] triazole [1,5-a] pyrimidine-6-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide;
3-(4-(1H-indazole-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide;
4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-3-replaces)-1H-1,2,3-triazol radical-1-replaces) benzamide;
3-(4-(imidazo [1,2-a] pyrimidine-3-replaces)-1H-1,2,3 triazol radicals-1-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide;
3-(4-(4-hydroxyphenyl)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl isophthalic acid, 4-phenodiazine Zhuo-1-replaces) methyl-3-trifluoromethyl) benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(piperidines-1-replaces) methyl-3-trifluoromethyl) benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(morpholine-1-replaces) methyl-3-trifluoromethyl) benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(pyrroles-1-replaces) methyl-3-trifluoromethyl) benzamide;
(S)-3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-N-(4-(3-dimethylamino pyrroles-1-replaces) methyl-3-trifluoromethyl)-4-methyl benzamide;
(R)-3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-N-(4-(3-dimethylamino pyrroles-1-replaces) methyl-3-trifluoromethyl)-4-methyl benzamide;
4-methyl-3-(4-(pyrazoles [1,5-a] pyrimidine-6-replaces)-1H-1,2,3-triazol radical-1-replaces)-N-(4-(pyrroles-1-replaces) methyl-3-trifluoromethyl) benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H1,2,3-triazol radical-1-replaces)-4-methyl-N-4-((4-(4-methylpiperazine-1-replaces) piperidines-1-replaces) methyl-3-trifluoromethyl) benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-N-(4-(4-dimethylamino piperidine-1-replaces) methyl-3-trifluoromethyl)-4-methyl benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-((3aR, 6aS)-5-methyl hexahydropyrrolo [3,4-c] pyrroles-2 (1H)-replacement) methyl-3-trifluoromethyl) benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(3-(4-methyl isophthalic acid H-imidazoles-1-replaces)-5-trifluoromethyl) benzamide;
N-(3-(1H-1,2,4-triazole-1-replaces)-5-trifluoromethyl)-3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(3-(3-methyl isophthalic acid H-1,2,4-triazole-1-replaces)-5-trifluoromethyl) benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-cyclopropyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide;
The chloro-N-of 4-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-6-replaces)-1H-1,2,3-triazol radical-1-replaces) benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces) the chloro-N-of-4-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces) the bromo-N-of-4-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide;
The bromo-N-of 4-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-6-replaces)-1H-1,2,3-triazol radical-1-replaces) benzamide;
4-cyclopropyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-6-replaces)-1H-1,2,3-triazol radical-1-replaces) benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide;
N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-6-replaces)-1H-1,2,3-triazol radical-1-replaces) benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces) the fluoro-N-of-4-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide;
The fluoro-N-of 4-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-6-replaces)-1H-1,2,3-triazol radical-1-replaces) benzamide;
The chloro-3-of 4-(4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-ethyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-sec.-propyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyridine-5-replaces)-1H-1,2,3-triazol radical-5-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide;
3-(5-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1,3,4-oxadiazole-2-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide;
3-(5-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1,2,4-oxadiazole-2-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide dimethanesulfonate;
4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-6-replaces)-1H-1,2,3-triazol radical-1-replaces) benzamide mesylate;
3-(4-(imidazo [1,2-b] pyridazine-3-replaces)-1H-1,2,3-triazol radical-1-replaces)-4-methyl-N-(4-((4-methylpiperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide hydrochloride salt;
3-(5-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1,2,4-oxadiazoles-2-replaces)-4-methyl-N-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide hydrochloride salt;
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replaces)-1H-1,2,3-triazol radical-1-replaces) the chloro-N-of-4-(4-(4-methyl piperidine-1-replaces) methyl-3-trifluoromethyl) benzamide hydrochloride salt.
9. treat a medicinal compositions for tumour, by heterocycle benzamide compound described in claim 1-8 any one and pharmacy acceptable salt thereof or steric isomer or its prodrugs and pharmaceutically acceptable carrier, formed.
10. heterocycle benzamide compound and pharmacy acceptable salt thereof or steric isomer or its prodrugs application in the medicine of preparation treatment tumour described in claim 1-8 any one.
11. application according to claim 10, it is characterized in that, described tumour is any in leukemia, gastrointestinal stromal tumors (GISTs), histocyte lymphatic cancer, nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, carcinoma of the pancreas, mammary cancer, prostate cancer, liver cancer, skin carcinoma, cell carcinoma, nasopharyngeal carcinoma etc.
12. application according to claim 11, is characterized in that, described leukemia is the CML for the BCR-ABL positive, AML leukemia and to imatinib, dasatinib, the leukemia of nilotinib resistance.
13. application according to claim 11, is characterized in that, described leukemia is chronic myelocytic leukemia and the acute leukemia of BCR-ABL high expression level.
CN201210236713.9A 2012-07-09 2012-07-09 Heterocycle benzamide compound, Pharmaceutical composition and application thereof Active CN103539784B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201210236713.9A CN103539784B (en) 2012-07-09 2012-07-09 Heterocycle benzamide compound, Pharmaceutical composition and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201210236713.9A CN103539784B (en) 2012-07-09 2012-07-09 Heterocycle benzamide compound, Pharmaceutical composition and application thereof

Publications (2)

Publication Number Publication Date
CN103539784A true CN103539784A (en) 2014-01-29
CN103539784B CN103539784B (en) 2016-08-17

Family

ID=49963687

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201210236713.9A Active CN103539784B (en) 2012-07-09 2012-07-09 Heterocycle benzamide compound, Pharmaceutical composition and application thereof

Country Status (1)

Country Link
CN (1) CN103539784B (en)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106580993A (en) * 2016-07-25 2017-04-26 广州顺健生物医药科技有限公司 Novel application of icotinib and salt acceptable pharmaceutically in disease treatment
CN109336829A (en) * 2017-08-23 2019-02-15 沈阳药科大学 Aryl methanamide compounds of the triazole structure containing 1,2,3- and application thereof
CN111249282A (en) * 2018-12-03 2020-06-09 苏州亚盛药业有限公司 Cancer therapy
CN111592533A (en) * 2020-06-16 2020-08-28 浙江工业大学 1,2, 4-oxadiazole bipyridyl substituted benzamide compound and preparation method and application thereof
CN112442014A (en) * 2019-08-29 2021-03-05 中国科学院合肥物质科学研究院 PDGFR kinase inhibitors and uses thereof
CN112898271A (en) * 2021-01-29 2021-06-04 中国医科大学 N- (pyridine-3-yl) pyrrolidine-2-formamide compound and preparation method and application thereof
CN113292556A (en) * 2020-02-21 2021-08-24 苏州亚盛药业有限公司 Preparation method and intermediate of alkynyl-containing compound
WO2022002177A1 (en) * 2020-07-02 2022-01-06 广州顺健生物医药科技有限公司 Crystals of alkynyl-containing compound, salt and solvate thereof, preparation method, and applications
WO2022105836A1 (en) * 2020-11-19 2022-05-27 Guangzhou Healthquest Pharma Co., Ltd. Combination therapies for treating cancer
WO2022129915A1 (en) 2020-12-16 2022-06-23 Benevolentai Bio Limited Pyrazole derivatives as c-abl inhibitors
WO2022188792A1 (en) * 2021-03-12 2022-09-15 四川科伦博泰生物医药股份有限公司 Heterocyclic compound having protein kinase inhibitory activity, pharmaceutical composition comprising same, preparation method therefor, and use thereof
RU2816314C1 (en) * 2020-11-19 2024-03-28 Гуанчжоу Хэлсквест Фарма Ко., Лтд. Types of combination therapy for treating cancer

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101298427A (en) * 2008-06-26 2008-11-05 中国科学院广州生物医药与健康研究院 Diaryl urea compound and use thereof
CN101537001A (en) * 2008-03-19 2009-09-23 中国科学院广州生物医药与健康研究院 Application of compound as JAK-STAT3 signal passage inhibitor
CN101796045A (en) * 2007-07-02 2010-08-04 贝林格尔.英格海姆国际有限公司 New chemical compounds
US20100240657A1 (en) * 2007-07-02 2010-09-23 Boehringer Ingelheim International Gmbh Chemical compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101796045A (en) * 2007-07-02 2010-08-04 贝林格尔.英格海姆国际有限公司 New chemical compounds
US20100240657A1 (en) * 2007-07-02 2010-09-23 Boehringer Ingelheim International Gmbh Chemical compounds
CN101537001A (en) * 2008-03-19 2009-09-23 中国科学院广州生物医药与健康研究院 Application of compound as JAK-STAT3 signal passage inhibitor
CN101298427A (en) * 2008-06-26 2008-11-05 中国科学院广州生物医药与健康研究院 Diaryl urea compound and use thereof

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018018950A1 (en) * 2016-07-25 2018-02-01 广州顺健生物医药科技有限公司 Novel application of gzd824 and pharmaceutically acceptable salts thereof in treating diseases
CN106580993B (en) * 2016-07-25 2018-11-30 广州顺健生物医药科技有限公司 New application of the Nike for Buddhist nun and its pharmaceutically acceptable salt in treatment disease
JP2019522019A (en) * 2016-07-25 2019-08-08 ヘルスクエスト ファーマ インク． Novel use of nexinib and its pharmaceutically acceptable salts in the treatment of disease
CN106580993A (en) * 2016-07-25 2017-04-26 广州顺健生物医药科技有限公司 Novel application of icotinib and salt acceptable pharmaceutically in disease treatment
CN109336829A (en) * 2017-08-23 2019-02-15 沈阳药科大学 Aryl methanamide compounds of the triazole structure containing 1,2,3- and application thereof
CN109336829B (en) * 2017-08-23 2022-03-01 沈阳药科大学 Aryl formamide compound containing 1,2, 3-triazole structure and application thereof
CN111249282A (en) * 2018-12-03 2020-06-09 苏州亚盛药业有限公司 Cancer therapy
CN111249282B (en) * 2018-12-03 2023-08-29 苏州亚盛药业有限公司 cancer therapy
EP3713576A4 (en) * 2018-12-03 2021-01-13 Ascentage Pharma (Suzhou) Co., Ltd. Methods for cancer therapy
CN112442014B (en) * 2019-08-29 2021-10-08 中国科学院合肥物质科学研究院 PDGFR kinase inhibitors and uses thereof
CN112442014A (en) * 2019-08-29 2021-03-05 中国科学院合肥物质科学研究院 PDGFR kinase inhibitors and uses thereof
CN113292556A (en) * 2020-02-21 2021-08-24 苏州亚盛药业有限公司 Preparation method and intermediate of alkynyl-containing compound
CN113292556B (en) * 2020-02-21 2022-08-23 苏州亚盛药业有限公司 Preparation method and intermediate of alkynyl-containing compound
CN111592533B (en) * 2020-06-16 2021-08-24 浙江工业大学 1,2, 4-oxadiazole bipyridyl substituted benzamide compound and preparation method and application thereof
CN111592533A (en) * 2020-06-16 2020-08-28 浙江工业大学 1,2, 4-oxadiazole bipyridyl substituted benzamide compound and preparation method and application thereof
WO2022002177A1 (en) * 2020-07-02 2022-01-06 广州顺健生物医药科技有限公司 Crystals of alkynyl-containing compound, salt and solvate thereof, preparation method, and applications
WO2022105836A1 (en) * 2020-11-19 2022-05-27 Guangzhou Healthquest Pharma Co., Ltd. Combination therapies for treating cancer
RU2816314C1 (en) * 2020-11-19 2024-03-28 Гуанчжоу Хэлсквест Фарма Ко., Лтд. Types of combination therapy for treating cancer
WO2022129915A1 (en) 2020-12-16 2022-06-23 Benevolentai Bio Limited Pyrazole derivatives as c-abl inhibitors
CN112898271A (en) * 2021-01-29 2021-06-04 中国医科大学 N- (pyridine-3-yl) pyrrolidine-2-formamide compound and preparation method and application thereof
CN112898271B (en) * 2021-01-29 2022-03-25 中国医科大学 N- (pyridine-3-yl) pyrrolidine-2-formamide compound and preparation method and application thereof
WO2022188792A1 (en) * 2021-03-12 2022-09-15 四川科伦博泰生物医药股份有限公司 Heterocyclic compound having protein kinase inhibitory activity, pharmaceutical composition comprising same, preparation method therefor, and use thereof

Also Published As

Publication number Publication date
CN103539784B (en) 2016-08-17

Similar Documents

Publication Publication Date Title
CN103124730B (en) Heterocyclic alkynyl benzene compounds and medical compositions and uses thereof
CN103539784B (en) Heterocycle benzamide compound, Pharmaceutical composition and application thereof
CN103012399B (en) 7-oxopyridinopyrimidine compound as well as medicinal composition and application thereof
AU2015353210B2 (en) 2-aminopyrimidine compound and pharmaceutical composition and use thereof
CN102816162B (en) Pyrimido-pyrimidine ketone compounds and medicinal compositions thereof and application
CN106467541A (en) Substituted quinolone analog derivative or its pharmaceutically acceptable salt or stereoisomer and its Pharmaceutical composition and application
US8846671B2 (en) Heterocyclic alkynyl benzene compounds and medical compositions and uses thereof
ES2842230T3 (en) Therapeutic compounds as orexin-1 receptor inhibitors
CN105555786A (en) Substituted dihydropyrido[3,4-b]pyrazinones as dual inhibitors of bet proteins and polo-like kinases
AU2015206652A1 (en) Heteroaryls and uses thereof
CN107206004A (en) Target micromolecular inhibitor of discoidin domain receptor 1 and application thereof
TW201217359A (en) Novel compounds and compositions for the inhibition of NAMPT
CN101537001A (en) Application of compound as JAK-STAT3 signal passage inhibitor
JP2014520860A (en) 4-oxo-3,5,7,8-tetrahydro-4H-pyrano {4,3-d} pyrminidinyl compounds for use as tankyrase inhibitors
CN101747330A (en) Pyridyl thiazole amines compound, as well as medical composite and application thereof
WO2020119739A1 (en) 2-aminopyrimidine compound and application therefor
WO2021041976A1 (en) Perk inhibiting indolinyl compounds
CN108530444A (en) A kind of novel NAMPT and IDO double inhibitors and preparation method thereof and medical usage
CN103374000B (en) Kui Linpyrimido quinoline Diazepines and medicinal compositions thereof and application
CN109689657A (en) Deuterated 3- (4,5- substituted-amino pyrimidine) phenyl derivatives and its application
CN112313213B (en) 3-amino pyrazole compound and application thereof
CN103570731B (en) Pyrimido three encircles or pyrimido Fourth Ring compounds and Pharmaceutical composition and application
WO2021180008A1 (en) Tri-aromatic ring compound containing urea structure and use thereof
CN101298427A (en) Diaryl urea compound and use thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant