CN103539784B - Heterocycle benzamide compound, Pharmaceutical composition and application thereof - Google Patents

Heterocycle benzamide compound, Pharmaceutical composition and application thereof Download PDF

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CN103539784B
CN103539784B CN201210236713.9A CN201210236713A CN103539784B CN 103539784 B CN103539784 B CN 103539784B CN 201210236713 A CN201210236713 A CN 201210236713A CN 103539784 B CN103539784 B CN 103539784B
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replacement
methyl
trifluoromethyl
pyrimidine
benzoylamide
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CN103539784A (en
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丁克
李宇鹏
沈梦婕
龙活尤
张章
冷芳
陆小云
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Guangzhou Institute of Biomedicine and Health of CAS
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Guangzhou Institute of Biomedicine and Health of CAS
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    • 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

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a kind of heterocycle benzamide compound with formula I architectural feature or its pharmaceutically acceptable salt or stereoisomer or prodrugs.This heterocycle benzamide compound and pharmaceutically acceptable salt thereof, can effectively suppress the growth of kinds of tumor cells, and to BCR ABL, c Kit, the protease such as PDGFR produce inhibitory action, can be used for preparing antitumor drug, it is possible to overcome the drug resistance that existing medicine (Gleevec) induces.

Description

Heterocycle benzamide compound, Pharmaceutical composition and application thereof
Technical field
The invention belongs to chemical medicine, particularly relate to a kind of heterocycle benzamide compound, Pharmaceutical composition and answer With.
Background technology
Tumor is the number one killer of current human health and life, and its sickness rate is only second to cardiovascular disease.And along with ring Environment pollution or the impact of other factors, the sickness rate of malignant tumor is rapid increase trend.According to World Health Organization's public affairs in 2003 The data of cloth, the total malignant tumor patient 10,000,000 in the whole world in 2000, because of mortality of malignant tumors, person is up to 6,200,000, accounts for total dead The 12%-25% of number of dying.Anticipating the year two thousand twenty, the annual new cases in the whole world will reach 15,000,000.In recent years, though having The exploitation listing of the targeting new drugs such as novel tyrosine protein inhibitor, but still it is sick to meet far away growing clinical cancer Human needs.Antitumor drug research and development are also still the important research direction of current medicament research and development circle.
Tumor cells targeted therapy is to be selected by chemistry or biological means based on key molecule closely-related to tumor growth A kind of Therapeutic Method of property killing tumor cell.The feature of targeted therapy is: specificity is high, and selectivity is strong, and toxic and side effects is lighter； During use in conjunction, it can strengthen the curative effect of classic chemotherapy, radiotherapy, reduces postoperative recurrence.With Gleevec (STI571, her horse For Buddhist nun, trade name imatinib mesylate) be the targeted drug of representative be that chemotherapy of tumors has started a New Times.Neoplasm targeted therapy exists Developed rapidly in a few years.Convenient administration idea and pattern composition are impacted by going out of neoplasm targeted therapy, such as, Because toxic and side effects is little, targeted drug is often unable to reach dose-limiting toxicity and maximum tolerated dose in I clinical trial phase； When using target therapeutic agent, it is not necessary to i.e. can reach satisfactory effect with maximum tolerated dose.Neoplasm targeted therapy is the heat of oncotherapy Point and development trend.
Protein tyrosine kinase (PTKs) is that the phenolic hydroxyl group that a class can be catalyzed on the tyrosine residue of multiple key protein occurs Phosphorylation, and then activate the protease system of the function of functional protein.About half in 520 multiple protein kinases in human body It is tyrosine kinase (PTKs).They occupy highly important status in intracellular signal transduction pathway, regulate cell A series of physiology processes such as tumor growth, differentiation, death.Protein tyrosine kinase functional disorder can cause in organism one Series of disease.Research shows, proto-oncogene more than half is all relevant to protein tyrosine kinase with the activation of oncogene.Albumen The unconventionality expression of tyrosine kinase may result in cell proliferation regulation and gets muddled, and then causes tumor to occur.Additionally, tyrosine-kinase The unconventionality expression of enzyme also with invasion and attack and the transfer of tumor, tumor neovasculature generation, the chemotherapy Drug resistance of tumor is closely related. Carrying out antitumor drug research and development with tyrosine kinase for target spot and become an international focus, drug development mechanism of Ye Shi various countries grinds Study carefully the emphasis of input.
So far, existing tens of kinds of protein tyrosine kinase micromolecular inhibitors and antibody enter clinical trial, and have goes up City, and achieve preferable therapeutic effect.As: it is used for treating Philadelphia chromosome and is positive chronic myeloid leukemia (CML) and stomach The Bcr-Abl inhibitor Gleevec of intestinal mesenchymoma；For treat nonsmall-cell lung cancer EGFR inhibitor Iressa and Tarceva etc..Gleevec is first appropriate design exploitation after the cause of disease understanding cancer, and achieves the tumor of remarkable effect Medicine, its success is a milestone for the treatment of of cancer.This significant achievement is also listed in 2001 by the U.S.'s " science " magazine Annual ten big science and technology news.
The immense success obtained in clinical cancer therapy for the specific small molecule mortifier of protein tyrosine kinase is further Confirm that protein tyrosine kinase is critical therapy target, its importance in tumor occurs also is described simultaneously.Have definite Evidence proves that the sudden change of protein tyrosine kinase encoding gene causes tumorigenic example to include: Bcr-Abl and chronic granulocytic Leukemia (chronic myeloid leukemia, CML)；C-Kit increases with gastrointestinal stromal tumors (GISTs) (GIST), systematic mast cell Many diseases (systemic mastocytosis, SM)；PDGFR and chronic myelomonocytic leukemia (chronic Myelomonocytic leukemia), dermatofibrosarcoma protuberans (dermatofibrosarcoma protuberan), high Hypereosinophilic syndrome；Flt3 and part of Acute myelocytic leukemia；B-Raf and melanoma (melanoma)；RET with Thyroid carcinoma etc..Additionally, c-Kit and small cell lung cancer have substantial connection.
First target therapeutic agent in order to treat chronic myelocytic leukemia (CML) of calendar year 2001 U.S. FDA approval Gleevec mainly acts on Bcr-Abl, c-Kit, PDGFR etc..Gleevec single therapy can make the CML of 98% clinically Patient obtains the alleviation of clinical hematology, and 53% obtains cytogenetics alleviates.
However as STI571 extensive application clinically, resistance problems becomes increasingly conspicuous: part cancer patient was to STI571 days So tolerance (primary resistance)；Another part patient starts to respond during medication, but in medication therapeutic process gradually Acquired tolerance (secondary resistance) occurs.The patient of long-term taking is easily generated toleration.Toleration refers to chronic Phase patient does not occurs that after STI571 treats complete hematology reaction or accelerated period and acute transformation phase patient fail after STI571 treats Return to chronic phase.Clinically, the chronic myelocytic leukemia (CML) of acute transformation phase (blast-crisis), Bcr-Abl STI571 is tolerated by positive acute lymphoblastic leukemia (Acute lymphoblastic leukemia, ALL) patient Relatively universal, this two classes patient of about 70% occurred STI571 drug resistance at medication 3-6 month.And drug resistance, the state of an illness once occur Often progress is rapidly.Acquired tolerance be considered as tumor cell be to escape a kind of defence killed, its mechanism has multiple, including: 1. target gene (Bcr-Abl, c-Kit, PDGFR) amplification；2. mutant target gene；3. the formation of target gene dependent/non-dependent tumor colonies； 4. the generation of α-1 acidoglycoprotein and the overexpression of multidrug-resisting gene M DR1.But the main mechanism generally acknowledged at present is target base Secondary mutation (secondary mutation) because of (Bcr-Abl, c-Kit, PDGFR) expression product kinases territory.Research shows The common point mutation site of the target gene clear and definite with STI571 Tolerance includes E255K, E255V, T315I of Bcr-Abl And the D816V etc. of D276G, c-Kit.The patient carrying these sudden changes is easily recurred, and prognosis is bad.It is reported that only have STI571 is reacted by transitivity gastrointestinal stromal tumors (GISTs) (GIST) patient of 50%, reliable for effect, and this some patients carries c-Kit Face film territory V560G sudden change.Additionally, still there is transitivity patient GIST of 50% that STI571 is lacked reaction.C-Kit tyrosine-kinase STI571 is then tolerated by the point mutation (such as D816V, T315I) in enzyme territory very much.Experiment in vitro shows that STI571 can not suppress Carry D816V c-Kit and the propagation of T315I Mutant Cells；The systematic mast cell carrying D816V c-Kit increases Disease patient do not react STI571.
How overcoming STI571 repellence is the important topic of current medical oncology.Find the novel little molecule of tyrosine kinase to press down Thing processed be overcome STI571 repellence important channel.Such as, the tyrosine kinase little molecules in inhibiting thing of listing recently Nilotinib (AMN107, nilotinib), Dasatinib (BMS-354825, Dasatinib) are (rather than complete to part Portion) STI571 repellence Bcr-Abl point mutation case is effective.It is identical with STI571 that AMN107 combines the kinase whose position of Abl, Also it is the competitive binding Abl kinases to disactivation configuration, but more higher than STI571 with the affinity of Abl, and drug effect is approximately the latter 10-50 times.AMN107 has obvious inhibitory action, IC to 15 kinds of point mutation cells in addition to T315I50At 10-1000 nM.Different from STI571 and AMN107, BMS-354825 can be in combination with Bcr-Abl that is unactivated with suppression and that activated. BMS-354825 has obvious inhibitory action, IC to 15 kinds of point mutation cells in addition to T315I50At 10-125nM.But It is that AMN107 and BMS-354825 is invalid to Bcr-Abl (T315I), and AMN107 and STI571 is to c-Kit D816V Point mutation cell is invalid.Therefore, develop novel, can effectively kill STI571 repellence c-KIT point mutation (D816V) and Bcr-Abl point mutation carries (including T315I) micromolecular compound of cell in whole world oncotherapy scientific circles and industrial circle all Seem the most necessary and urgent.
Dash forward it is true that current protein tyrosine kinase inhibitor series antineoplastic medicament also exists drug-induced drug resistance gene mostly Become, and be faced with the clinical scope of application narrower and etc. problem.Therefore, exploitation second filial generation protein tyrosine kinase inhibitor is to overcome Existing drug resistance also improves clinical effectiveness, is significant.
Summary of the invention
Based on this, it is an object of the invention to provide a kind of heterocycle benzamide compound.
Concrete technical scheme is as follows:
There is the heterocycle benzamide compound of formula I architectural feature or its pharmaceutically acceptable salt or stereoisomer Or prodrugs:
Wherein, A ring is five-ring heterocycles, arbitrarily can be connected with both sides fragment in following location, the most certainly:
1) triazole
2) diazole
R1The most certainly:
1) 2-substituted pyrimidyl
2) and heterocyclic radical
3) and heterocyclic radical
3)R7Substituted-phenyl
R2The most certainly:
1)H；
2) halogen；
3) C1-C5 alkyl；
4) C3-C6 cycloalkyl；
R4For H, R3The most certainly:
1)H；
2)(CH2)nNR5R6；
3)(CH2)n–Het1；
Or R3For H, R4The most certainly:
1)H；
2)Het2；
Wherein, X, Y, Z, be optionally N, and CH, C ring is five yuan containing 1-3 nitrogen-atoms or hexa-member heterocycle；N be 0 or 1, Het1For the nonaromatic heterocycles base containing 1-3 N, Het2For the 5-membered aromatic heterocycle base containing hetero atom N, O and/or S, Described non-aromatic and aromatic heterocycle arbitrary C atom or atom N can be by alkyl in the position that can be replaced, cycloalkyl, or NR5R6 Replace；
R5, R6The most certainly:
1)H；
2) C1-C3 alkyl；
3) C1-C3 contains fluoroalkyl；
4) C3-C6 cycloalkyl；
Or R5And R6By C, O, N, S atom forms five yuan, hexa-atomic, seven yuan or octatomic ring shape structure.
R7The most certainly:
1) H,
2)OH；
3)NH2。
Wherein in some embodiments, R1The most certainly:
1) 2-substituted pyrimidyl
2) and heterocyclic radical
3) and heterocyclic radical
R2The most certainly:
1)H；
2) halogen；
3) C1-C5 alkyl；
4) C3-C6 cycloalkyl；
R4For H, R3The most certainly:
1)H；
2)(CH2)nNR5R6；
3)(CH2)n–Het1；
Or R3For H, R4The most certainly:
1)H；
2)Het2；
Wherein, Y, Z, be optionally N, and CH, C ring is five yuan containing 1-3 nitrogen-atoms or hexa-member heterocycle；N is 0 or 1, Het1For the nonaromatic heterocycles base containing 1-3 N, Het2For the 5-membered aromatic heterocycle base containing hetero atom N, O and/or S, institute Stating non-aromatic and aromatic heterocycle arbitrary C atom or atom N can be by alkyl in the position that can be replaced, cycloalkyl, or NR5R6 Replace；
R5, R6The most certainly:
1)H；
2) C1-C3 alkyl；
3) C1-C3 contains fluoroalkyl；
4) C3-C6 cycloalkyl；
Or R5And R6By C, O, N, S atom forms five yuan, hexa-atomic, seven yuan or octatomic ring shape structure.
Wherein in some embodiments, described R1Selected 2-substituted uracil, for one of following structure:
Wherein in some embodiments, described R1Selected five yuan and hexa-member heterocycle, for one of following structure:
Wherein in some embodiments, described R2Optionally from following structure:
1)H；
2)CH3, CH2CH3；
3)
4)F,Cl,Br,I；
5)CF3。
Wherein in some embodiments, described work as R4For H, R3The most certainly:
1)H；
2)CH2NR5R6；
3)(CH2)n–Het1；
Or R3For H, R4The most certainly:
1)H；
2)Het2；
R5、R6Definition identical with claim 1, n is 1, Het1Selected from following structure:
Het2Selected from following structure:
Wherein in some embodiments, R1The most certainly:
R2The most certainly:
1)H；
2)CH3, CH2CH3；
3)
4)F,Cl,Br；
Work as R4For H, R3The most certainly:
1)H；
2)CH2NR5R6；
3)(CH2)n–Het1；
Or R3For H, R4The most certainly:
1)H；
2)Het2；
R5、R6Definition identical with claim 1, n is 1, Het1Selected from following structure:
Het2Selected from following structure:
It is a further object of the present invention to provide a kind of Pharmaceutical composition treating tumor.
Concrete technical scheme is as follows:
A kind of Pharmaceutical composition treating tumor, by above-mentioned heterocycle benzamide compound and pharmaceutically acceptable salt thereof or vertical Body isomer or its prodrugs form with pharmaceutically acceptable carrier.
It is a further object of the present invention to provide the application in the medicine of preparation treatment tumor of the above-mentioned heterocycle benzamide compound.
Concrete technical scheme is as follows:
Above-mentioned heterocycle benzamide compound and pharmaceutically acceptable salt thereof or stereoisomer or its prodrugs are controlled in preparation Treat the application in the medicine of tumor.
Wherein in some embodiments, described tumor is leukemia, gastrointestinal stromal tumors (GISTs), histiocytic lymphatic cancer, non-small cell Pulmonary carcinoma, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, breast carcinoma, carcinoma of prostate, hepatocarcinoma, skin carcinoma, epithelium are thin Any one in born of the same parents' cancer, nasopharyngeal carcinoma etc..
Wherein in some embodiments, described leukemia is CML, the AML leukemia positive for BCR-ABL and right The leukemia of imatinib, dasatinib, nilotinib drug resistance；In described drug-resistant leukemia, especially for BCR-ABL The intractable drug-resistant leukemia that T315I sudden change in kinases territory is caused.
Wherein in some embodiments, described leukemia is chronic myelocytic leukemia and the acute leukemia of BCR-ABL high expressed.
Abl (Abelson TK) gene and Bcr (break point cluster region) gene fusion also express Bcr-abl The leukemogenesis such as tyrosine kinase is chronic myelocytic leukemia (CML), acute lymphoblastic leukemia (ALL) Main mechanism.Achieve significant success for Bcr-Abl tyrosine kinase design targeting micromolecular inhibitor, wherein represent Property example be exactly by U.S. FDA in calendar year 2001 approval listing medicine Gleevec.However as wide in clinic of Gleevec General application, its clinical drug-resistant phenomenon is more and more prominent.In numerous reasons causing Gleevec drug 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 total The 12% of body sudden change.The sudden change caused for Gleevec drug resistance, a new generation Bcr-Abl inhibitor nilotinib (nilotinib) Have been successfully listed with dasatinib (Dasatinib).Although the two molecule has the inhibitory activity overcoming numerous mutant, But the drug resistance caused by T315I is still felt simply helpless.Therefore, solving Gleeve drug resistance, especially T315I drug resistance is led Cause about 12% patient in clinical treatment without medicine can problem there is scientific research, clinic and market value.
In compound of the present invention, as any variable (such as R1、R2Deng) occur more than once in any component, then its The definition that the definition every time occurred occurs independent of other every time.Equally, it is allowed to substituent group and the combination of variable, if this group Conjunction makes stability of compounds.Be appreciated that this area, those of ordinary skill may select the substituent group of the compounds of this invention and substitution pattern and There is provided the most stable, and can be readily synthesized from readily available raw material by the method for art technology and following proposition Compound.It is exceeded group if instead of base self to replace, it should be understood that these groups can be in identical carbon atoms or different On carbon atom, as long as making Stability Analysis of Structures.
The side chain that terms used herein " alkyl " means to include to have particular carbon atom number and the saturated fat alkyl of straight chain. Such as, " C1-C5Alkyl " in " C1-C5" definition include with straight or branched arrangement there are 1,2,3,4 or 5 carbon The group of atom.Such as, " C1-C5Alkyl " specifically include methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, Isobutyl group, amyl group.Term " cycloalkyl " refers to the monocycle saturated fat alkyl with particular carbon atom number.Such as " cycloalkyl " Including cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyI-cyclopentyl, cyclohexyl etc..
Term used herein " heterocycle " or " heterocyclic radical " refer to be selected from the heteroatomic of O, N and S containing 1-4 5 yuan of-6 yuan of armaticity or non-aromatic heterocyclic rings, and include bicyclic radicals." heterocyclic radical " includes heteroaryl, also include its two Hydrogenation and tetrahydro analog." heterocyclic radical " further example includes but not limited to: imidazole radicals, indyl, isothiazolyl, Isoxazolyl, di azoly, oxazolyl, oxetanyl (oxetanyl), pyranose, pyrazinyl, pyrazolyl, pyridazine Base, pyridine radicals, pyrimidine radicals, pyrrole radicals, quinolyl, tetrazole radical, thiadiazolyl group, thiazolyl, thienyl, triazolyl, l, 4- Dialkyl group, pyrrolidinyl, glyoxalidine base, dihydro isoxazolyl, dihydro isothiazolyl, dihydrooxadiazole base, dihydro Oxazolyl, dihydro pyrazinyl, pyrazoline base, dihydropyridine base, dihydro-pyrimidin base, pyrrolin base, dihydro tetrazole radical, two Thiodiazoline base, dihydro-thiazolyl, dihydro-thiophene base, dihydro triazolyl, dihydro azetidinyl, tetrahydrofuran base and four Hydrogen thienyl, and N-oxide.The connection of heterocyclic substituent can realize by carbon atom or by hetero atom.
In one embodiment, heterocycle is selected from imidazole radicals, pyridine radicals, 1-ketopyrrolidine, 2-piperidones, 2-pyrimidone, 2- Ketopyrrolidine, thienyl, oxazolyl, triazol radical, isoxazolyl.
As will be appreciated by a person skilled in the art, used herein to " halogen " to (" halo ") or " halogen " mean to include chlorine, Fluorine, bromine and iodine.
Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituent can be unsubstituted or substituted. Such as, C1-C6Alkyl can by one, two or three selected from OH, halogen, alkoxyl, dialkyl amido or heterocyclic radical such as The substituent group of morpholinyl, piperidyl etc. replaces.
In some example, define Het so that it is 4-7 unit monocycle can be collectively forming with the nitrogen being connected them or each ring is 4-7 The bicyclic heterocycle of unit, and optionally containing denitrogenate outer one or two selected from the other hetero atom of N, O and S.
The present invention includes the free form of compound of formula I, also includes its pharmaceutically acceptable salt and stereoisomer.
Therefore, the pharmaceutically acceptable salt of the compounds of this invention includes by the compounds of this invention and inorganic or organic acid reaction shape The conventional non-toxic salts of the compounds of this invention become.Such as, conventional nontoxic salts include deriving from mineral acid such as hydrochloric acid, hydrobromic acid, The salt of sulphuric acid, sulfamic acid, phosphoric acid, nitric acid etc., also include from organic acid such as acetic acid, propanoic acid, succinic acid, glycolic, Stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, flutter acid, maleic acid, hydroxymaleic acid, phenylacetic acid, Glutamic acid, benzoic acid, salicylic acid, p-aminobenzene sulfonic acid, 2-acetoxy-benzoic, fumaric acid, toluenesulfonic acid, methanesulfonic acid, The salt of the preparation such as ethane disulfonic acid, oxalic acid, hydroxyethylsulfonic acid., trifluoroacetic acid.
Berg etc., at Pharmaceutical Salts, describe in detail above in J.Pharm.Sci.1977,66:1-19 Described pharmaceutically acceptable salt and the preparation of other typical pharmaceutically acceptable salt.
The heterocycle benzamide compound that the present invention relates to and pharmaceutically acceptable salt thereof, can effectively suppress kinds of tumors thin The growth of born of the same parents, and to protease generation inhibitory action such as Bcr-Abl, c-Kit, PDGF, can be used for preparing antitumor drug, and The drug resistance that existing medicine (Gleevec) induces can be overcome.As understood by those skilled in the art, the change involved by the application Compound and pharmaceutically acceptable salt thereof can be used for the excess proliferative diseases such as the tumor of the preparation treatment mankind and other mammal.
Detailed description of the invention
Except known in the literature or in addition to the standard method of illustration, the reaction as shown in following scheme can be used in experimental arrangement Prepare the compounds of this invention.Therefore, following illustrative approach is for descriptive purpose rather than to be confined to listed compound or any Specific substituent group.In scheme, the substituent group number of display not necessarily meets number used in claim, and for understand See, show that monosubstituted base is connected to allow under the definition of hereinbefore formula (I) on the compound of multi-substituent.
Scheme
Compound R in formula (I) as shown in option A1The transformation of part can be initial by 3-amino-methyl 4 methylbenzoate Raw material is synthesized by 4-5 step.
Option A
Compound R in formula (I) as shown in option b3The transformation of part can be initial by 4-methyl-3-(trifluoromethyl) aniline Raw material is synthesized by 5 steps.
Option b
Compound R in formula (I) as shown in scheme C4The transformation of part can be initial by 3-bromo-5-(trifluoromethyl) aniline Raw material is synthesized by 3 steps.
Scheme C
Compound R in formula (I) as shown in scheme D2The transformation of part can be by 4-substituted 3-Methyl anthranilate Beginning raw material is synthesized by 3 steps.
Scheme D
In formula (I) as shown in scheme E, the salt of compound can be that initiation material is synthesized by 1 step by former compound.
Scheme E
Owing to the synthetic method of the A ring in addition to triazole is different, it is impossible to be organized into formula, will illustrate in a particular embodiment.
This application provides a kind of utilization and there is the compound of formula (I) and pharmaceutically acceptable salts for treating people thereof or other suckling is moved Excess proliferative disease or the symptoms such as thing tumor.
Compound and pharmaceutically acceptable salt thereof designed by the application may be used for treatment or controls gastrointestinal stromal tumors (GISTs), histiocyte Property lymphatic cancer, nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, breast carcinoma, carcinoma of prostate, liver The excess proliferative diseases such as cancer, skin carcinoma, cell carcinoma, carcinoma of prostate, nasopharyngeal carcinoma, leukemia.
Compound designed by the application and pharmaceutically acceptable salt thereof can with application at present or female swashing of just locating the development phase Element receptor modulators, androgen receptor modifier, retinoid-like receptor modulators, cytotoxin/cytostatics, antiproliferative, Protein transferase inhibitor, HMG-CoA reductase inhibitor, HIV kinases inhibitor, reverse transcriptase inhibitors, blood vessel are raw Become inhibitor, cell proliferation and survival signaling inhibitor, the medicine of interference cell cycle check and cell death inducer, cell Poison class medicine, 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, topology is different Structure enzyme inhibitor, Histone deacetylase inhibitor, proteasome inhibitor, CDK inhibitor, Bcl-2 family protein suppresses Agent, MDM2 family protein inhibitor, IAP family protein inhibitor, STAT family protein inhibitor, PI3K inhibitor, AKT Inhibitor, integrin blocker, interferon-' alpha ', IL-12, cox 2 inhibitor, p53, p53 activator, VEGF The combination therapies such as antibody, EGF antibody increase its clinical effectiveness.
Compound involved by the application and pharmaceutically acceptable salt thereof can according to method below for treat following disease with And the Other diseases do not listed below:
1) a kind of utilization comprises compound involved by the application, that have formula (I) structure and pharmaceutically acceptable salt thereof The method of the breast carcinoma of Pharmaceutical composition treatment people or other mammal.Including, but not limited to aggressive conduit Cancer, aggressive lobular carcinoma, DCIS and LCIS.
2) a kind of utilization comprises compound involved by the application, that have formula (I) structure and pharmaceutically acceptable salt thereof The method of the respiratory cancer of Pharmaceutical composition treatment people or other mammal.Including, but not limited to minicell & Nonsmall-cell lung cancer and bronchial adenoma and pleuropulinonary blastoma.
3) a kind of utilization comprises compound involved by the application, that have formula (I) structure and pharmaceutically acceptable salt thereof The method of the brain cancer of Pharmaceutical composition treatment people or other mammal.Including, but not limited to brain stem and now god Through glioma, cerebellum and cerebral astrocytoma, ependymoma and neuroderm and strobile tumor body.
4) a kind of utilization comprises compound involved by the application, that have formula (I) structure and pharmaceutically acceptable salt thereof Pharmaceutical composition treatment people or the hero of other mammal, the method for tumor of female reproductive organ.Arrenotoky The tumor of organ includes but not limited to prostate and carcinoma of testis.The tumor of female reproductive organ includes but not limited to son Endometrial carcinoma, cervical cancer, ovarian cancer, cancer of vagina and carcinoma vulvae and intrauterine tumor.
5) a kind of utilization comprises compound involved by the application, that have formula (I) structure and pharmaceutically acceptable salt thereof The method of the gastral tumor of Pharmaceutical composition treatment people or other mammal.Include but not limited to anus cancer, Colon cancer, colon straight way cancer, esophageal carcinoma, gastric cancer, cancer of pancreas rectal cancer, carcinoma of small intestine or glandula cancer.
6) a kind of utilization comprises compound involved by the application, that have formula (I) structure and pharmaceutically acceptable salt thereof The method of the tumor of the urethra of Pharmaceutical composition treatment people or other mammal.Include but not limited to bladder cancer, Carcinoma of penis, renal carcinoma, carcinoma of renal pelvis, carcinoma of ureter or carcinoma of urethra.
7) a kind of utilization comprises compound involved by the application, that have formula (I) structure and pharmaceutically acceptable salt thereof The method of the cancer eye of Pharmaceutical composition treatment people or other mammal.Include but not limited to intraocular melanoma and regard Retinulae tumor.
8) a kind of utilization comprises compound involved by the application, that have formula (I) structure and pharmaceutically acceptable salt thereof Pharmaceutical composition treatment people or the method for other mammalian hepatoma.Include but not limited to hepatoma (have or Do not have fibre board change stem cell cancer), cancer of biliary duct (intrahepatic cholangiocarcinoma) and mixing Hepatocellular gallbladder Pipe cancer.
9) a kind of utilization comprises compound involved by the application, that have formula (I) structure and pharmaceutically acceptable salt thereof Pharmaceutical composition treatment people or the method for other mammal skin cancer.Include but not limited to squamous cell carcinoma, card Ripple Ji sarcoma, malignant melanoma, Merck Schwann Cells skin carcinoma and non-melanoma cell carcinoma.
10) a kind of utilization comprises compound involved by the application, that have formula (I) structure and pharmaceutically acceptable salt thereof Pharmaceutical composition treatment people or the method for other mammal head and neck cancer.Include but not limited to larynx, hypopharynx, nasopharynx, Oropharynx cancer and lip and oral cancer.
11) a kind of utilization comprises compound involved by the application, that have formula (I) structure and pharmaceutically acceptable salt thereof Pharmaceutical composition treatment people or the method for other mammalian lymphoma.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 compound involved by the application, that have formula (I) structure and pharmaceutically acceptable salt thereof Pharmaceutical composition treatment people or the method for other mammal sarcoma.Include but not limited to soft tissue sarcoma, kindred Tumor, malignant fibrous histiocytoma, woods are sarcoma and rhabdomyosarcoma.
13) a kind of utilization comprises compound involved by the application, that have formula (I) structure and pharmaceutically acceptable salt thereof Pharmaceutical composition treatment people or the method for other mammalian leukemia.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 techniques, the compounds of this invention can individually or in Pharmaceutical composition with pharmaceutically acceptable receptor, auxiliary Material or diluent combination give mammal, preferably people.Orally available or subcutaneous, intramuscular injection, intraperitoneal, vein, rectum and local, Eyes, pulmonary, nasal cavity, parenteral give compound.
When utilizing formula (I) compounds for treating or control the patient such as cancer, taking dose scope be oral 0.1-500 mg/day/ Kg body weight.Suitable administering mode be every day single dose be administered or every twice-daily, three times, four inferior multiple dosings or utilize slow Technology of releasing is administered.For multiple large mammal, its preferred dosage range is 0.1-1500 mg/day/kg body weight, excellent Select in 0.5-100 mg/day/kg body weight.For the patient that average weight is 70 kilograms, its daily dosage is 1-500 milligram. For some special high-activity compounds, adult patient's daily dosage low can reach 0.1 mg/day.
Drug metabolite and prodrug
Compound involved by the application and the metabolite of pharmaceutically acceptable salt thereof, and the application can be changed in vivo Involved compound and the prodrug of the structure of pharmaceutically acceptable salt thereof, be also contained in the protection domain of the application.
Drug combination
Compound of formula I can be to known treatment or the other medicines combination improving similar condition of illness.During administering drug combinations, originally medicine Administering mode and dosage keep constant, and subsequently or simultaneously take compound of formula I.When compound of formula I is a kind of or several with other When kind medicine is taken simultaneously, the Pharmaceutical composition that simultaneously contain one or more known drugs and compound of formula I is preferably used.Medicine Internet of Things takes compound of formula I and other one or more known drugs with the time period being also included within overlap.When compound of formula I with When other one or more medicines carry out drug combination, the dosage of compound of formula I or known drug may than they independent medications time Dosage relatively low.
The medicine of drug combination can be carried out with compound of formula I or active component includes but is 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 suppress Agent, angiogenesis inhibitor, cell proliferation and survival signaling inhibitor, the medicine of interference cell cycle check and apoptosis lure Lead agent, cytotoxic drug, tyrosine protein inhibitor, EGFR inhibitor, VEGFR inhibitor, serine/threonine egg White inhibitor, Bcr-Abl inhibitor, c-Kit inhibitor, Met inhibitor, Raf inhibitor, mek inhibitor, MMP presses down Preparation, 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 blocker, interferon-' alpha ', IL-12, cox 2 inhibitor, p53, p53 swash Agent, VEGF antibody, EGF antibody alive etc..
The medicine of drug combination can be carried out with compound of formula I or active component includes but is not limited to: aldesleukin, A Lun Phosphonic acids, interferon, Ah Qu Nuoying, allopurinol, allopurinol sodium, palonosetron hydrochlorate, altretamine, amino lattice Rumi Spy, amifostine, amrubicin, SN-11841, arimidex, dolasetron, aranesp, arglabin, arsenic trioxide, Arnold is new, U-18496, azathioprine, bacillus calmette-guerin vaccine or tice bacillus calmette-guerin vaccine, bestatin, betamethasone acetate, betamethasone Sodium phosphate preparation, bexarotene, Bleomycin Sulphate, broxuridine, bortezomib, busulfan, calcitonin, A Laizuo are mono- Anti-injection, capecitabine, carboplatin, Kang Shi get, cefesone, celmoleukin, daunorubicin, chlorambucil, suitable Platinum, cladribine, cladribine, chlorine bend phosphoric acid, cyclophosphamide, arabinose born of the same parents' former times, dacarbazine, actinomycin D, soft red Mycin liposome, dexamethasone, dexamethasone phosphate, estradiol valerate, denileukin diftitox, Di Bomei, deslorelin, Dilazep assistant life, diethylstilbestrol, Fluconazole, docetaxel, doxifluridine, amycin, dronabinol ,-166-chitosan of admiring Complex, eligard, rasburicase, epirubicin hydrochloride, aprepitant, epirubicin, Epoetin Alfa, erythrocyte Generate element, eptalatin, Ergamisole, estradiol preparation, 17-β-estradiol, estramustine phosphate sodium, ethinylestradiol, ammonia phosphorus Spit of fland, hydroxyl phosphoric acid, Etopophos, etoposide, fadrozole, tamoxifen preparation, filgrastim, Tamsulosin, Fei Leisi replace, Floxuridine, fluconazol, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, fluoxymesterone, fluorine His amine, formestane, 1-β-D-R furanose born of the same parents' thialdine-5 '-stearoyl phosphate ester, fotemustine, fulvestrant, Gamma globulin, gemcitabine, gemtuzumab Ozogamicin Mylotarg CDP 771, imatinib mesylate, Gliadel, goserelin, salt Acid granisetron, histrelin and U.S. are new, hydrocortisone, erythro-hydroxynonyl adenine, hydroxyurea, for smooth different shellfish Not monoclonal antibody, 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, easily Auspicious sand, Irinotecan, Kytril, sulphuric acid lentinan, letrozole, formyl tetrahydrofolic acid, leuprorelin, leuprorelin vinegar Hydrochlorate, L-tetramisole, levo leucovorin calcium salt, levothyroxine sodium, levothyroxine sodium preparation, lomustine, chlorine Buddhist nun Reach bright, dronabinol, chlormethine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estriol, 6- Coloured glaze base purine, mesna, methotrexate, amino-laevulic acid methyl ester, miltefosine, minocycline, ametycin, rice Tuo Tan, rice torr Herba Alii fistulosi quinone, trilostane, citric acid Evacet, nedaplatin, Pegfilgrastim, Ao Purui Interleukin, neupogen, nilutamide, tamoxifen, NSC-631570, recombination human interleukins-11-β, Austria Bent peptide, Ondansetron Hydrochloride, dehydrohydro-cortisone oral solution, oxaliplatin, paclitaxel, Pediapred, Pegaspargase, PEG-IFN alpha-2a, pentostatin, Picibanil, hydrochloric acid pilocarpine, adjoin soft than star, plicamycin, porphin nurse Sodium, prednimustine, prednisolone steaglate, prednisone, premarin, the third kappa umbilicus, epoetin, thunder For Qu Sai, Libiee, etidronic acid rhenium-186, Mabthera, Redoxon-A, romurtide, Salagen, Austria Bent peptide, sargramostim, semustine, sizofiran, sobuzoxane, bluff sodium prednisolone, Paphos acid, stem-cell therapy, chain Assistant star, Metastron, levothyroxine sodium, tamoxifen, YM-617, Ta Suonaming, tastolactone, Thailand Suo Di, teceleukin, temozolomide, teniposide, Testosterone Propionate, methyltestosterone, thioguanine, thio-tepa, thyrotrophic hormone(TH) Hormone, tiludronic acid, topotecan, toremifene, tositumomab, Herceptin, treosulfan, tretinoin, first Aminopterin tablet, trimethyl melamine, trimetrexate, acetic acid triptorelin, triptorelin pamoate, UFT, uridnine, Valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizin, ADR-529, Zinostatin stimalamer, ondansetron, Taxol-protein stabilization formulations, acolbifene, interferon r-lb, affinitak, Aminopterin-induced syndrome, arzoxifene, asoprisnil, atamestane, atrasentan, BAY 43-9006, Avastin, CCI-779, CDC-501, celecoxib, Cetuximab, crisnatol, cyproterone acetate, decitabine, DN-101, Amycin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, Exatecan, fenretinide, group Amine dihydrochloride, histrelin hydrogel implant, holmium-166DOTMP, ibandronic acid, interferon gamma, intron-PEG, Ixabepilone, keyhole shape hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafamib, Miproxifene, minot bend acid esters, MS-209, liposome MTP-PE, MX-6, nafarelin, Nemorubicin, new Cut down department he, Nola Qu Te, Ao Limosen, onco-TCS, osidem, paclitaxel 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 paclitaxel, extrasin alpha l, loud, high-pitched sound azoles furan woods, tipifarnib, replace La Zhaming, TLK-286, toremifene, trans MID-lo7R, valspodar, vapreotide, vatalanib, dimension are for pool Sweet smell, vinflunine, Z-100 and zoledronic acid or combinations thereof.
The present invention will be further described for following example, but this embodiment is not intended to limit protection scope of the present invention.
Embodiment 1
3-(4-(2-(Cyclohexylamino) pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-((4-first Base piperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) Benzoylamide (D1174)
Step 1. synthesizes 5-bromo-N-cyclohexyl pyrimidine-2-amine
In tube sealing, add 5-bromo-2-chloropyrimide (1.93g, 10.0mmol) and cyclohexylamine (2.29mL, 20mmol), use Ethanol (15.0mL) dissolves, and is heated to 80 DEG C.It is stirred overnight, is cooled to room temperature.Decompression is spin-dried for solvent and obtains white solid, adds EtOAc and water extraction, organic facies anhydrous Na2SO4Being dried, decompression is spin-dried for, and the white solid of gained is that (2.4g produces target product Rate: 94%).
1H NMR(400MHz,CDCl3), δ 8.24 (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. synthesizes N-cyclohexyl-5-acetenyl pyrimidine-2-amine
5-bromo-N-cyclohexyl pyrimidine-2-amine (1.28g, 5.0mmol), CuI (0.048g, 0.25mmol) is added in tube sealing, Pd(PPh3)2Cl2(0.18g, 0.25mmol), replaces three times with argon.Acetonitrile (15.0mL), Et is added with syringe3N (2.1mL, 15.0mmol) and trimethylsilyl acetylene (2.1mL, 15.0mmol), seal post-heating to 100 DEG C, reacts 24 Hour, by reacting liquid filtering, it is spin-dried for.Grease after being spin-dried for adds methanol (20.0mL) and K2CO3(1.4g,10.0 mmol).Stirring at normal temperature half an hour, reacting liquid filtering, it is spin-dried for, silica gel column chromatography separates, and the yellow solid of gained is target product (0.9g, productivity: 89%).
1H NMR(400MHz,CDCl3), δ 8.36 (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. synthesizes 3-azido-methyl 4 methylbenzoate
At room temperature, 3-amino-4 benzoic acid methyl ester (8.4g, 0.05mol) is dissolved in HCl (6.0mol/L, 40.0mL, In 0.24mol).NaNO is added after cooling to 0 DEG C2(3.57g is dissolved in 8.4mL H to aqueous solution2O, 0.05mol) ,-5 DEG C～0 DEG C at, reactant liquor was stirred after 10 minutes, (3.97g is dissolved in 12.6mL H to be slowly added to sodium azide aqueous solution2O,0.06 Mol), reaction 2 hours.After having reacted, reactant liquor adds EtOAc and adds water extraction, and saturated common salt is washed, anhydrous Na2SO4Dry Dry, decompression is spin-dried for, and the yellow oil of gained is target product (9.7g, productivity: 99%).
1H NMR(400MHz,CDCl3), δ 7.70 (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. synthesizes 3-azido-4-methyl-N-(4-((4-methyl piperazine-1-replacement) methyl)-3-(trifluoromethyl) phenyl) benzene first Amide
At-20 DEG C, by 3-azido-methyl 4 methylbenzoate (9.6g, 0.5mol) and 4-((4-methyl piperazine-1-replacement) Methyl)-3-(trifluoromethyl) aniline (13.7g, 0.5mol) be dissolved in heavily steam after oxolane (50.0mL) in, be slowly added dropwise Heavily steaming tetrahydrofuran solution (50.0mL) of potassium tert-butoxide (16.8g, 0.15mol), after reacting 1 hour, is warmed up to naturally Room temperature, then react 8 hours.After having reacted, being spin-dried for solvent, add EtOAc and water extraction, organic facies saturated common salt is washed, Anhydrous Na2SO4Being dried, the separating obtained red solid of silica gel column chromatography is target product (13.5g, productivity: 61%).
1H NMR(400MHz,CDCl3), δ 7.81-7.77 (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. synthesizes 3-(4-(2-(Cyclohexylamino) pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl -N-(4-((4-methyl piperazine-1-replacement) methyl)-3-(trifluoromethyl) phenyl) Benzoylamide (D1174)
By N-cyclohexyl-5-acetenyl pyrimidine-2-amine (0.20g, 1.0mmol), 3-azido-4-methyl-N-(4-((4-first Base piperazine-1-replace) methyl)-3-(trifluoromethyl) phenyl) Benzoylamide (0.43g, 1.0mmol), CuSO4(16mg,0.1 And sodium ascorbate (40mg, 0.2mmol) is dissolved in (1:1,4.0mL) in the mixed solution of the tert-butyl alcohol and water, at 90 DEG C mmol) Reaction is overnight.After having reacted, being cooled to room temperature, extract 3 times with EtOAc, saturated common salt is washed, anhydrous Na2SO4It is dried, Silica gel column chromatography separates, and the white solid of gained is target product (0.31g, productivity: 50%).
1H NMR(400MHz,CDCl3),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, CDCl3),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+).
Example 2 below-21 synthetic method such as embodiment 1.
Embodiment 2
3-(4-(2-isopropylamine base pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-(4-methyl piperidine -1-replaces) methyl-3-trifluoromethyl) Benzoylamide (D1161)
1H NMR(400MHz,CDCl3),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,CDCl3),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), 123.33,119.74,117.68,113.52,57.77,55.23,53.15,46.06,43.0 9, 22.83,18.26.MS(ESI),m/z:594(M++H+).
Embodiment 3
3-(4-(2-benzamido group pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-(4-methyl piperidine-1- Replace) methyl-3-trifluoromethyl) Benzoylamide (D1162)
1H NMR(400MHz,CDCl3),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,CDCl3),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
((4-methyl piperazine-1-takes 4--4-methyl-N-3-(4-(2-amine pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement) Generation) methyl-3-trifluoromethyl) Benzoylamide (D1168)
1H NMR(400MHz,CDCl3),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,CDCl3),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-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-(4-methyl piperazine-1- Replace) methyl-3-trifluoromethyl) Benzoylamide (D1171)
1H NMR(400MHz,CDCl3),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,CDCl3),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-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-(4-methyl piperazine-1- Replace) methyl-3-trifluoromethyl) Benzoylamide (D1172)
1H NMR(400MHz,CDCl3),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,CDCl3),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-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-(4-methyl piperazine -1-replaces) methyl-3-trifluoromethyl) Benzoylamide (D1173)
1H NMR(400MHz,CDCl3),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,CDCl3),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-replacement) methyl-3-trifluoromethyl)-3-(4-(2-(piperidines-1-replacement) pyrimidine -5-replaces)-1H-1,2,3-triazol radical-1-replacement) Benzoylamide (D1175)
1H NMR(400MHz,CDCl3),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,CDCl3), 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-methyl piperazine-1-replacement) methyl)-3-(trifluoromethyl) phenyl)-3-(4-(2-(anilino-) pyrimidine-5- Replace)-1H-1,2,3-triazol radical-1-replacement) Benzoylamide (D1181)
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,CDCl3),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-replacement)-4-methyl-N-(4-((4-methyl Piperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) Benzoylamide (D1280)
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,CDCl3),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-methyl piperazine-1-replacement) methyl)-3-(trifluoromethyl) phenyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-6- Replace)-1H-1,2,3-triazol radical-1-replacement) Benzoylamide (D1167)
1H NMR(400MHz,CDCl3), δ 9.50 (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,CDCl3),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-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-((4-methyl piperazine Piperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) Benzoylamide (D1166)
1H NMR(400MHz,CDCl3),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,CDCl3),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
((piperazine-1-replaces first to 4-to-4-methyl-N-to 3-(4-(2-amido quinazoline-6-replacement)-1H-1,2,3-triazol radical-1-replacement) Base)-3-(trifluoromethyl) phenyl) Benzoylamide (D1169)
1H NMR(400MHz,CDCl3),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,CDCl3),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-indole-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-((4-methyl piperazine-1-replacement) Methyl)-3-(trifluoromethyl) phenyl) Benzoylamide (D1170)
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,CDCl3),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-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridine-5-replacement)-1H-1,2,3-triazol radical-1-takes 4-methyl-3- Generation)-N-(4-((4-methyl piperazine-1-replacement) methyl)-3-(trifluoromethyl) phenyl) Benzoylamide (D1182)
1H NMR(400MHz,CDCl3),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,CDCl3),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
3-(4-([1,2,4] triazole [1,5-a] pyrimidine-6-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl -N-(4-((4-methyl piperazine-1-replacement) methyl)-3-(trifluoromethyl) phenyl) Benzoylamide (D1281)
1H NMR(400MHz,CDCl3), δ 9.48 (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,CDCl3),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-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-((4-methyl piperazine-1-replacement) Methyl)-3-(trifluoromethyl) phenyl) Benzoylamide (D1305)
1H NMR(400MHz,DMSO),δ10.59(s 1H),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-methyl piperazine-1-replacement) methyl)-3-(trifluoromethyl) phenyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-3- Replace)-1H-1,2,3-triazol radical-1-replacement) Benzoylamide (D1306)
1H NMR (400MHz, DMSO), δ 10.58 (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-replacement)-4-methyl-N-(4-((4-methyl piperazine Piperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) Benzoylamide (D1307)
1H NMR (400MHz, DMSO), δ 10.61 (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,CDCl3),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-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-(4-methyl piperazine Piperazine-1-replaces) methyl-3-trifluoromethyl) Benzoylamide (D1163)
1H NMR (400MHz, d-DMSO), δ 13.81 (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-replacement)-4-methyl-N-(4-(4-methyl piperidine-1-replacement) methyl-3- Trifluoromethyl) Benzoylamide (D1309)
1H NMR(400MHz,CDCl3),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-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-(4-methyl -1,4-phenodiazine Zhuo-1-replaces) methyl-3-trifluoromethyl) Benzoylamide (D1286)
Step 1. synthesizes 4-methyl-3-(trifluoromethyl) anilino-t-butyl formate
By 4-methyl-3-(trifluoromethyl) aniline (25.0g, 0.14mol), it is dissolved in dioxane (50.0mL), adds carbon Acid sodium (22.3g, 0.21mol) aqueous solution (50.0mL) and (Boc)2O(39.0mL,0.17mol).It is stirred overnight, adds EtOAc dilutes, and saturated common salt is washed, anhydrous Na2SO4Being dried, the red oil being spin-dried for gained is that (39.0g produces target product Rate: 99%).
1H NMR(400MHz,CDCl3), δ 7.61 (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. synthesizes 4-(bromomethyl)-3-(trifluoromethyl) anilino-t-butyl formate
By 4-methyl-3-(trifluoromethyl) anilino-t-butyl formate (18.3g, 0.066mol), NBS (23.6g, 0.133 And AIBN (1.1g, 6.6mmol) is dissolved in CCl mol)4(50.0mL), condensing reflux is overnight.After having reacted, filter, Saturated common salt is washed, anhydrous Na2SO4Being dried, the red oil being spin-dried for gained is target product (23.0g, productivity: 98%).
1H NMR(400MHz,CDCl3), δ 7.68 (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. synthesizes 4-((4-methyl isophthalic acid, 4-phenodiazine Zhuo-1-replaces) methyl)-3-(trifluoromethyl) anilino-t-butyl formate
By 4-(bromomethyl)-3-(trifluoromethyl) anilino-t-butyl formate (1.8g, 5.0mmol), N-methylhomopiperazin (1.5 ML, 12.0mmol) and Et3N (2.1mL, 15.0mmol) is dissolved in the THF (10.0mL) after heavily steaming.Stir at 50 DEG C Overnight.After having reacted, being spin-dried for solvent, add EtOAc dilution, saturated common salt is washed, anhydrous Na2SO4It is dried, is spin-dried for, silicon The yellow oil of plastic column chromatography gained is target product (1.75g, productivity: 88%).
1H NMR(400MHz,CDCl3), δ 7.71 (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. synthesizes 3-azido-4-methyl-N-(4-((4-methyl isophthalic acid, 4-phenodiazine Zhuo-1-replaces) methyl)-3-(trifluoromethyl) benzene Base) Benzoylamide
By 4-((4-methyl isophthalic acid, 4-phenodiazine Zhuo-1-replace) methyl)-3-(trifluoromethyl) anilino-t-butyl formate (1.75g, 4.5mmol) it is dissolved in DCM (5.0mL) and the mixed solvent of TFA (5.0mL). it is stirred at room temperature 1 hour.After having reacted, It is spin-dried for solvent, NaHCO3Neutralizing, add EtOAc extraction, saturated common salt is washed, anhydrous Na2SO4It is dried, is spin-dried for obtaining yellow oily Thing (1.3g, quantitative).Then, add 3-azido-methyl 4 methylbenzoate (1.03g, 5.4mmol), Dissolve with anhydrous tetrahydro furan (5.0mL), be cooled to-20 DEG C, be slowly added dropwise potassium tert-butoxide (1.5g, 12.6mmol) Anhydrous tetrahydro furan (15.0mL), after reacting 1 hour, is warmed to room temperature naturally, and reaction is overnight.After having reacted, it is spin-dried for solvent, Adding EtOAc dilution, saturated common salt is washed, anhydrous Na2SO4Being dried, be spin-dried for, the yellow oil of silica gel column chromatography gained is mesh Mark product (1.5g, productivity: 74%).
1H NMR(400MHz,CDCl3), δ 8.65 (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. synthesizes 3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl -N-(4-(4-methyl isophthalic acid, 4-phenodiazine Zhuo-1-replaces) methyl-3-trifluoromethyl) Benzoylamide (D1286)
By 5-acetenyl-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) Benzoylamide (0.3g, 0.7mmol), CuSO4(11 Mg, 0.07mmol) and sodium ascorbate (28mg, 0.14mmol) be dissolved in (1:1,5.0mL) in the mixed solution of the tert-butyl alcohol and water, 90 DEG C of reactions overnight.After having reacted, being cooled to room temperature, extract 3 times with EtOAc, saturated common salt is washed, anhydrous Na2SO4 Being dried, silica gel column chromatography separates, and the white solid of gained is target product (0.31g, productivity: 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+).
Example 2 below 3-31 synthetic method such as embodiment 22.
Embodiment 23
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-(piperidines-1- Replace) methyl-3-trifluoromethyl) Benzoylamide (D1183)
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-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-(morpholine-1- Replace) methyl-3-trifluoromethyl) Benzoylamide (D1184)
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-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-(pyrroles-1- Replace) methyl-3-trifluoromethyl) Benzoylamide (D1185)
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-replacement)-N-(4-(3-dimethylamino Pyrroles-1-replaces) methyl-3-trifluoromethyl)-4-methyl benzamide (D1351)
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-replacement)-N-(4-(3-dimethylamino Pyrroles-1-replaces) methyl-3-trifluoromethyl)-4-methyl benzamide (D1187)
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-replacement)-1H-1,2,3-triazol radical-1-replacement)-N-(4-(pyrroles-1-replacement) Methyl-3-trifluoromethyl) Benzoylamide (D1188)
1H NMR(400MHz,CDCl3),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,CDCl3),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), 123.51,121.57,117.69,112.16,97.46,55.43,54.14,23.60,18.0 7. 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-replacement)-4-methyl-N-4-((4-(4-first Base piperazine-1-replaces) piperidines-1-replacement) methyl-3-trifluoromethyl) Benzoylamide (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-replacement)-1H-1,2,3-triazol radical-1-replacement)-N-(4-(4-dimethylamino piperidine -1-replaces) methyl-3-trifluoromethyl)-4-methyl benzamide (D1289)
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-replacement)-4-methyl -N-(4-((3aR, 6aS)-5-methyl hexahydropyrrolo [3,4-c] pyrroles-2 (1H)-replacement) methyl-3-trifluoromethyl) benzoyl Amine (D1297)
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-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(3-(4-methyl -1H-imidazoles-1-replaces)-5-trifluoromethyl) Benzoylamide (D1285)
Step 1. synthesizes 3-(4-methyl isophthalic acid H-imidazoles-1-replacement)-5-(trifluoromethyl) aniline
By CuI (190mg, 1mmol), 4-methyl isophthalic acid H-imidazoles (1.64g, 20mmol), Cs2CO3(3.25g, 10mmol), 3-bromine -5-(trifluoromethyl) aniline (2.40g, 10mmol), 1-(5,6,7,8-tetrahydroquinoline-8-replacement) ethyl ketone (350mg, 2mmol) It is dissolved in DMF (30mL), with argon shield, is heated to 130 DEG C, react 24 hours.After having reacted, it is cooled to room temperature, Being spin-dried for, silica gel column chromatography separates, and the white solid of recrystallization gained is target product (1.7g, productivity: 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. synthesizes 3-azido-4-methyl-N-(3-(4-methyl isophthalic acid H-imidazoles-1-replacement)-5-(trifluoromethyl) phenyl) benzoyl Amine
By 3-azido-methyl 4 methylbenzoate (0.19g, 1.0mmol) and 3-(4-methyl isophthalic acid H-imidazoles-1-replacement)-5-(three Methyl fluoride) aniline (0.24g, 1.0mmol), it is dissolved in anhydrous tetrahydro furan (2.0mL), is cooled to-20 DEG C, is slowly added dropwise The anhydrous tetrahydro furan (5.0mL) of potassium tert-butoxide (0.34g, 3.0mmol), after reacting 1 hour, is warmed to room temperature, instead naturally Should be overnight.After having reacted, being spin-dried for solvent, add EtOAc dilution, saturated common salt is washed, anhydrous Na2SO4It is dried, is spin-dried for, The white solid of silica gel column chromatography gained is target product (0.37g, productivity: 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. synthesizes 3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl -N-(3-(4-methyl isophthalic acid H-imidazoles-1-replacement)-5-trifluoromethyl) Benzoylamide (D1285)
By 5-acetenyl-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) Benzoylamide (0.22g, 0.55mmol), CuSO4(8.8mg, 0.55mmol) it is dissolved in (1:1,5.0mL) in the mixed solution of the tert-butyl alcohol and water, 90 with sodium ascorbate (22mg, 1.1mmol) DEG C reaction overnight.After having reacted, being cooled to room temperature, extract three times with EtOAc, saturated common salt is washed, anhydrous Na2SO4Dry Dry, silica gel column chromatography separates, and the yellow solid of gained is target product (0.21g, productivity: 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-).
Example 3 below 3-34 synthetic method such as embodiment 32.
Embodiment 33
((1H-pyrazoles [3,4-b] pyrimidine-5-takes 4--3-N-(3-(1H-1,2,4-triazole-1-replacement)-5-trifluoromethyl) Generation)-1H-1,2,3-triazol radical-1-replacement)-4-methyl benzamide (D1287)
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-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(3-(3-methyl -1H-1,2,4-triazole-1-replaces)-5-trifluoromethyl) Benzoylamide (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-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-cyclopropyl-N-(4-(4-methyl Piperidines-1-replaces) methyl-3-trifluoromethyl) Benzoylamide (D1301)
Step 1. synthesizing methyl 4-cyclopropyl-3-nitrobenzoyl acid esters
By methyl 4-cyclopropyl-3-nitrobenzoyl acid esters (1.0g, 3.9mmol), cyclopropylboronic acid (0.34g, 3.9mmol) It is dissolved in dioxane (10.0mL), adds Pd (dppf) Cl2-DCM (64mg, 0.078mmol) and K3PO4(2.08g,7.8 mmol).Nitrogen is replaced three times, is stirred overnight at 90 DEG C.After having reacted, filter, be spin-dried for solvent, add EtOAc dilution, Saturated common salt is washed, anhydrous Na2SO4It is dried, is spin-dried for, obtains target product, directly throw next step.
Step 2. synthesizing methyl 3-amino-4-cyclopropyl-phenyl formic acid esters
Methyl 3-amino-4-cyclopropyl-phenyl formic acid esters (20g, 91mmol) is dissolved in THF/water (1:1) (200mL), adds CF3COOH (4.38g, 73mmol) and NH4Cl(0.48g,9.1mmol).After being heated to reflux, and gradation addition iron powder (20.5g, 364 mmol).Continue stirring 3 hours.After having reacted, filtering, saturated common salt is washed, anhydrous Na2SO4It is dried, is spin-dried for, silicon Plastic column chromatography, the yellow oil of gained is target product (16.5g, productivity: 95%).
1H NMR (400MHz, d-DMSO), δ 7.25 (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 formic acid esters
Synthetic method and methyl 3-azido-4-methyl benzoic acid ester identical (productivity: 95%).
1H NMR(400MHz,CDCl3), δ 7.78 (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. synthesizes 3-azido-4-cyclopropyl-N-(4-((4-methyl piperazine-1-replacement) methyl)-3-(trifluoromethyl) phenyl) benzene Methanamide
Synthetic method and 3-azido-4-methyl-N-(4-((4-methyl piperazine-1-replacement) methyl)-3-(trifluoromethyl) phenyl) benzene Methanamide identical (productivity: 15%).
m/z:459(M++H+).
Step 5. synthesizes 3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-cyclopropyl -N-(4-(4-methyl piperidine-1-replacement) methyl-3-trifluoromethyl) Benzoylamide
Synthetic method and 3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl -N-(4-(4-methyl piperidine-1-replacement) methyl-3-trifluoromethyl) Benzoylamide identical (productivity: 25%).
1H NMR (400MHz, d-DMSO), δ 9.16 (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+).
Example 3 below 6-47 directly can obtain target product from the 3-substituted essence of Niobe of amino-4-bought.Close One-tenth method such as embodiment 35.
Embodiment 36
((pyrazoles [1,5-a] pyrimidine-6-takes 4--3-the chloro-N-of 4-(4-(4-methyl piperazine-1-replacement) methyl-3-trifluoromethyl) Generation)-1H-1,2,3-triazol radical-1-replacement) Benzoylamide (D1291)
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-replacement)-1H-1,2,3-triazol radical-1-replacement) the chloro-N-of-4-(4-(4-methyl piperazine -1-replaces) methyl-3-trifluoromethyl) Benzoylamide (D1292)
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-replacement)-1H-1,2,3-triazol radical-1-replacement) the bromo-N-of-4-(4-(4-methyl piperazine -1-replaces) methyl-3-trifluoromethyl) Benzoylamide (D1302)
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
((pyrazoles [1,5-a] pyrimidine-6-takes 4--3-the bromo-N-of 4-(4-(4-methyl piperazine-1-replacement) methyl-3-trifluoromethyl) Generation)-1H-1,2,3-triazol radical-1-replacement) Benzoylamide (D1378)
1H NMR (400MHz, d-DMSO), δ 10.72 (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
((pyrazoles [1,5-a] pyrimidine-6-takes 4--3-4-cyclopropyl-N-(4-(4-methyl piperidine-1-replacement) methyl-3-trifluoromethyl) Generation)-1H-1,2,3-triazol radical-1-replacement) Benzoylamide (D1380)
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-replacement)-1H-1,2,3-triazol radical-1-replacement)-N-(4-(4-methyl piperazine-1- Replace) methyl-3-trifluoromethyl) Benzoylamide (D1304)
1H NMR (400MHz, d-DMSO), δ 9.53 (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), 123.60,123.08,119.72,119.55,119.27,117.34,114.37,57.43,5 5.99, 54.70,52.68,45.69,18.50.MS(ESI),m/z:562(M++H+).
Embodiment 42
((pyrazoles [1,5-a] pyrimidine-6-takes 4--3-N-(4-(4-methyl piperidine-1-replacement) methyl-3-trifluoromethyl) Generation)-1H-1,2,3-triazol radical-1-replacement) Benzoylamide (D1377)
1H NMR (400MHz, d-DMSO), δ 10.77 (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),δ 164.45,147.57,147.31,145.69,141.98,137.94,136.49,136.21,132.37,131.58, 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-replacement)-1H-1,2,3-triazol radical-1-replacement) the fluoro-N-of-4-(4-(4-methyl piperazine -1-replaces) methyl-3-trifluoromethyl) Benzoylamide (D1303)
1H NMR (400MHz, d-DMSO), δ 13.82 (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
((pyrazoles [1,5-a] pyrimidine-6-takes 4--3-the fluoro-N-of 4-(4-(4-methyl piperidine-1-replacement) methyl-3-trifluoromethyl) Generation)-1H-1,2,3-triazol radical-1-replacement) Benzoylamide (D1379)
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-replacement)-1H-1,2,3-triazol radical-1-replacement)-N-(4-(4- Methyl piperazine-1-replaces) methyl-3-trifluoromethyl) Benzoylamide (D1374)
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-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-ethyl-N-(4-(4-methyl piperazine Piperazine-1-replaces) methyl-3-trifluoromethyl) Benzoylamide (D1375)
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(125 MHz,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-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-isopropyl-N-(4-(4-methyl Piperidines-1-replaces) methyl-3-trifluoromethyl) Benzoylamide (D1376)
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, 57.39,54.64,52.59,45.61and 45.60,27.89,23.28.MS(ESI),m/z:604(M++H+).
Embodiment 48
3-(4-(1H-pyrazoles [3,4-b] pyridine-5-replacement)-1H-1,2,3-triazol radical-5-replace)-4-methyl-N-(4-(4-methyl piperazine Piperazine-1-replaces) methyl-3-trifluoromethyl) Benzoylamide (D1298)
By 3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement) acetenyl)-4-methyl-N-(4-((4-methyl piperazine-1-replacement) first Base)-3-(trifluoromethyl) phenyl) Benzoylamide (synthetic method is shown in WO2012/000304 and CN201010216603.7) (0.27g, 0.5mmol) it is dissolved in, with sodium azide (0.16g, 2.5mmol), the DMF (2.0mL) heavily steamed, tube sealing is heated to 200 DEG C, Stir 24 hours.After having reacted, it is cooled to room temperature.EtOAc dilutes, and saturated common salt is washed, anhydrous Na2SO4It is dried, is spin-dried for, Silica gel column chromatography, the yellow solid of gained is target product (73g, productivity: 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-replacement)-1,3,4-diazole-2-replacement)-4-methyl-N-(4-((4-methyl piperazine Piperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) Benzoylamide (D1300)
Step 1. synthesizing methyl 1H-pyrazoles [3,4-b] pyrimidine-5-carboxylic acid ester
By bromo-for 5-1H-pyrazoles [3,4-b] pyrimidine (5.0g, 25mmol), Pd (OAc)2(0.28g,1.25mmol),dppf(1.4 G, 2.5mmol), methanol (5.0mL, 125mmol) and Et3N (7.0mL, 50mmol) is added to 100mL round-bottomed flask In, dissolve with DMF (15.0mL), replace three times with CO.React 12 hours at 100 DEG C.After having reacted, it is cooled to room Temperature, filters, is spin-dried for, and silica gel column chromatography separates, and the yellow solid of gained is target product (2.0g, productivity: 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. synthesizes 1H-pyrazoles [3,4-b] pyrimidine-5-carbonyl hydrazides
Methyl 1H-pyrazoles [3,4-b] pyrimidine-5-carboxylic acid ester (0.53g, 3.0mmol) is dissolved in ethanol (2.0mL), then adds Entering hydrazine hydrate (2.0mL), reflux 1H.After having reacted, it is cooled to room temperature, filters, dilute with EtOAc, wash twice, Saturated common salt is washed once, anhydrous Na2SO4Be dried, silica gel column chromatography separate, the white solid of gained be target product (0.35g, Productivity: 66%).
1H NMR (400MHz, d-DMSO), δ 13.87 (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. synthesizes 3-(2-(1H-pyrazoles [3,4-b] pyrimidine-5-carbonyl) carbonyl hydrazides)-4-methyl-N-(4-((4-methyl piperazine-1- Replace) methyl)-3-(trifluoromethyl) phenyl) Benzoylamide
By 1H-pyrazoles [3,4-b] pyrimidine-5-carbonyl hydrazide (44mg, 0.25mmol), 3-iodo-4-methyl-N-(4-((4-methyl piperazine Piperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) Benzoylamide (129mg, 0.25mmol), Pd (OAc)2(2.8mg, 0.0125mmol),PPh3(3.3mg,0.0125mmol),Et3N (70 μ L, 0.5mmol) is dissolved in DMF (1.0mL), Replace three times with CO.120 DEG C of reactions overnight.After having reacted, being cooled to room temperature, filter, be spin-dried for, silica gel column chromatography divides From, the yellow solid of gained is target product (0.13g, productivity: 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. synthesizes 3-(5-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1,3,4-oxadiazoles-2-replacement)-4-methyl -N-(4-(4-methyl piperidine-1-replacement) methyl-3-trifluoromethyl) Benzoylamide (D1300)
By 3-(5-(1H-pyrazoles [3,4-b] pyrimidine-5-carbonyl) carbonyl hydrazides)-4-methyl-N-(4-((4-methyl piperazine-1-replacement) first Base)-3-(trifluoromethyl) phenyl) Benzoylamide (0.19g, 0.32mmol) is dissolved in POCl3(2.0mL), backflow 2 hours. After having reacted, it is cooled to room temperature, uses saturated NaHCO3Neutralizing, EtOAc is extracted twice, and saturated common salt is washed, anhydrous Na2SO4 Being dried, silica gel column chromatography separates, and ethyl alcohol recrystallization, the white solid of gained is target product (60mg, productivity: 33%).
1H NMR (400MHz, d-DMSO), δ 14.12 (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-replacement)-1,2,4-diazole-2-replacement)-4-methyl-N-(4-(4-methyl piperazine Pyridine-1-replaces) methyl-3-trifluoromethyl) Benzoylamide (D1344)
Step 1. synthesizes 1H-pyrazoles [3,4-b] pyrimidine-5-carboxylic acid
By methyl 1H-pyrazoles [3,4-b] pyrimidine-5-carboxylic acid ester (0.18g, 1.0mmol) and Lithium hydrate (0.13g, 3.0mmol) It is dissolved in methanol-THF-water (1:1:1) (3.0mL), is stirred at room temperature overnight.After having reacted, it is spin-dried for, with 1N HCl acid Changing, filter, filtration cakes torrefaction, the yellow solid of gained is target product (0.11g, productivity: 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. synthesizes 3-cyano group-4-methyl-N-(4-((4-methyl piperazine-1-replacement) methyl)-3-(trifluoromethyl) phenyl) benzoyl Amine
By iodo-for 3-4-methyl-N-(4-((4-methyl piperazine-1-replacement) methyl)-3-(trifluoromethyl) phenyl) Benzoylamide (2.1g, 4.0 mmol),CuCN(0.36g,4.0mmol),Pd2(dba)3(92mg,0.1mmol),dppf(111mg,0.2mmol) It is added in tube sealing, dissolves with DMF (5.0mL).Replace three times with argon, 120 DEG C of reactions overnight.After having reacted, cold But to room temperature, filtering, be spin-dried for, silica gel column chromatography separates, and the gray solid of gained is target product (1.53g, productivity: 92%).
1H NMR(400MHz,CDCl3),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. synthesizes (E)-3-(N'-hydroxyl amidino groups)-4-methyl-N-(4-((4-methyl piperazine-1-replacement) methyl)-3-(fluoroform Base) phenyl) Benzoylamide
By 3-cyano group-4-methyl-N-(4-((4-methyl piperazine-1-replacement) methyl)-3-(trifluoromethyl) phenyl) Benzoylamide (1.53g,3.7mmol),NaHCO3(1.55g, 18.4mmol) is dissolved in ethanol (15.0mL), adds oxammonium hydrochloride. (1.28 g,18.4mmol).React 5 hours at 80 DEG C.Next step is directly thrown after being spin-dried for.
Step 4. synthesizes (Z)-3-(N '-(1H-pyrazoles [3,4-b] pyrimidine-5-carbonyloxy group) carbamyl imines)-4-1H-1,2,3-triazole Base-1-replaces)-4-cyclopropyl-N-(4-(4-methyl piperidine-1-replacement) methyl-3-trifluoromethyl) Benzoylamide
By (E)-3-(N'-hydroxyl amidino groups)-4-methyl-N-(4-((4-methyl piperazine-1-replacement) methyl)-3-(trifluoromethyl) phenyl) Benzoylamide (0.96g, 2.1mmol), PyBOP (1.09g, 2.1mmol), Et3N (0.35mL, 2.5mmol) is molten In DMF (5.0mL), replace three times with argon, at room temperature reaction overnight.After having reacted, being spin-dried for, silica gel column chromatography separates, The yellow solid of gained is target product (0.39g, productivity: 31%).
1H NMR (400MHz, d-DMSO), δ 14.04 (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. synthesizes 3-(5-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1,2,4-oxadiazoles-2-replacement)-4-methyl -N-(4-(4-methyl piperidine-1-replacement) methyl-3-trifluoromethyl) Benzoylamide (D1344)
By (Z)-3-(N'-(1H-pyrazoles [3,4-b] pyrimidine-5-oxygen carbonyl) carbamyl imines)-4-methyl-N-(4-((4-methyl piperazine Piperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) Benzoylamide (59mg, 0.1mmol) is dissolved in the toluene (1.0mL) heavily steamed, Add the THF solution (0.12mL, 0.12mmol) of 1N TBAF, react 1 hour at 110 DEG C.After having reacted, cooling To room temperature, be spin-dried for, silica gel column chromatography separate, ethyl alcohol recrystallization, the yellow solid of gained be target product (50mg, productivity: 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),δ 173.92,168.40,164.85,152.73,148.02,141.77,138.12,135.22,132.50,132.18, 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-replacement)-4-methyl-N-(4-(4-methyl piperazine Piperazine-1-replaces) methyl-3-trifluoromethyl) Benzoylamide dimethanesulfonate (D1163 tetra-mesylate)
575mg D1163 (1mmol) is placed in 100mL single port bottle, adds 30mL dehydrated alcohol, the lower dropping of stirring 384mg methanesulfonic acid (4mmol), is heated to boiling, and system becomes clarification, and reflux 4h, is cooled to room temperature, has white solid to separate out, Filtering, filtering residue ethanol is washed three times, is vacuum dried to obtain light yellow solid 1.34g (90%).
1H NMR (400MHz, DMSO), δ 10.70 (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-methyl piperazine-1-replacement) methyl)-3-(trifluoromethyl) phenyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-6- Replace)-1H-1,2,3-triazol radical-1-replacement) benzamide methanesulfonate (D1167 tri-mesylate)
575mg D1167 (1mmol) is placed in 100mL single port bottle, adds 30mL dehydrated alcohol, the lower dropping of stirring 384mg methanesulfonic acid (4mmol), is heated to boiling, and system becomes clarification, and reflux 4h, is cooled to room temperature, has white solid to separate out, Filtering, filtering residue ethanol is washed three times, is vacuum dried to obtain light yellow solid 1.35g (91%).
1H NMR (400MHz, DMSO), δ 10.74 (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-replacement)-4-methyl-N-(4-((4-methyl Piperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) benzamide hydrochloride salt (D1280 hydrochlorate)
575mg D1280 (1mmol) is placed in 100mL there-necked flask, adds 30mL dehydrated alcohol, the lower dropping of stirring 6N aqueous hydrochloric acid solution, treats that raw material all dissolves, and is spin-dried for obtaining 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-replacement)-1H-1,2,3-triazol radical-1-replacement) the chloro-N-of-4-(4-(4-methyl piperazine -1-replaces) methyl-3-trifluoromethyl) benzamide hydrochloride salt (D1292 hydrochlorate)
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-replacement)-1,2,4-oxadiazoles-2-replacement)-4-methyl-N-(4-(4-methyl piperidine-1- Replace) methyl-3-trifluoromethyl) benzamide hydrochloride salt (D1344 hydrochlorate)
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 detection uses fluorescenee polarization immunoassay method.Medicine carries out gradient dilution (starting 3 times of dilutions from 10 μMs), And add kinases (Abl about 0.1-0.01U/mL or ABl (T315I) about 0.1-0.01U/mL) and substrate (about 50 μMs-800 μMs) In the reaction system of 25ul, phosphorylation reaction 2 hours；Add the fluorescently-labeled MALDI-PSD of band and identify that phosphorylation is many The antibody of peptide, in reaction system, balances about 4-24 hour, then detects in microplate reader.This medicine FP value of gained Through Graphpad Prism 5.0 Fitting Analysis, obtain the IC of sieved medicine50.Each compound half kinase whose to Abl suppresses Concentration (IC50) value is as described by table 1.Compound used therefor is respectively selected from the compound prepared by embodiment 1-55, at table 1 Middle Drug No. label represents.
Table 1. part of compounds IC to Abl kinase activity50(nM)
(ND:Not Detected)
Above-mentioned Abl kinases is normal tyrosine protein kinase, and Abl (T315I) is mutant, it is characterized in that Abl kinases territory 315th threonine is sported isoleucine.
The chemical constitution of the compound prepared by 1-55 and the vitro kinase activity data given by embodiment 56 in conjunction with the embodiments, Can analyze and obtain heterocycle benzamide compound ABL kinases and ABL (T315I) kinases are had notable structure activity relationship. Its feature is as follows: 1) work as R1During for 2-substituted pyrimidyl, R5Or R6At least one when being H, activity is better than other molecules； 2) R is worked as1For 2-substituted pyrimidyl, R5Or R6At least one when being H, the size of another substituent group affects compound Activity, universal law is that compound substituent is the biggest, and activity is the poorest；3) R is worked as1Middle B ring is five yuan or during hexa-member heterocycle, X is The compound activity of N is significantly higher than the similar compound of other atoms；4)R1Middle C ring is five yuan or during hexa-member heterocycle, in C ring When position containing NH and NH is adjacent with atom N in B ring, compound activity is better than other congeneric elements；5) when B ring In the presence of the while of atom N and C ring NH, the activity of this quasi-molecule is more excellent, and is better than 2-substituted pyrimidines compounds；6)R2Take The size of Dai Ji affects the activity of compound, universal law be substituent group be H, during F, activity not as methyl, Cl and Br, and Substituent group is too big, such as isopropyl, makes activity reduction too.
D0101 chemical constitution is:
D0102 chemical constitution is:
D0103 chemical constitution is:
D0104 chemical constitution is:
Embodiment 57
Cell in vitro Activity determination
The cell growth inhibiting activity of heterocycle benzamide compound uses the method described in CCK-8 test kit to be estimated. After cell (3000-10000/hole) was inoculated in 96 porocyte culture plate upper 24 hours, the chemical combination of 100 μ L variable concentrations Thing solution joins in each culture hole, hatches 72 hours, and 10 μ L CCK-8 solution join in each culture hole, then hatch 2-3 Hour, the light absorption value of 450nm and 650nm is measured by microplate reader.In EXCELL form, process initial data, obtain everywhere The cell survival rate in reason hole.Then survival rate data is used to use nonlinear regression model (NLRM) meter on GraphPad Prism software Calculate IC50Value.It was found that heterocycle benzamide compound can significantly inhibit Ba/F3-Bcr/Abl-T315I, K562, K562R, The propagation of KU812, its half-inhibition concentration (IC50, table 2) and become positive correlation with drug level.Compound used therefor is respectively to be implemented Compound prepared by example 1-55, represents with Drug No. label in table 2.
Table 2. part of compounds IC to different tumor cells50(nM)
(ND:Not Detected)
Compound chemical structure prepared by 1-55 and the cell in vitro activity data given by embodiment 57 in conjunction with the embodiments, can Heterocycle benzamide compound is obtained basically identical with embodiment 57 to the structure activity relationship of cell in vitro activity with analysis.
K562 (i.e. human chronic polymorpho nuclear leukemia cells system) and KU812 (i.e. human peripheral basophil strain) is white A kind of representative in disorders of blood cell line.In embodiment 1-55, compound has stronger inhibitory activity to it more.And K562R is (this persister is built screening by present invention applicant by conventional method and obtains the persister that imatinib induction obtains, and can be to The public provides), imatinib is had strong drug-resistant effect, but compound in embodiment 1-55 is shown stronger sensitivity. BaF3 (T315I) cell line (built screening by present inventor by conventional method to obtain, and can provide to the public) is one Plant the BaF3 cell line that can stably express Bcr-Abl (T315I).It can the most exclusively react micromolecular inhibitor with Bcr-Abl (T315I) site interacts.Activity as cited by embodiment 57 preferably molecule, such as D1163, has very The activity of strong suppression cell in vitro T315I sudden change.Especially with three marketed drug Imatinib, Dasatinib and Nilotinib compares, and this compounds has clear superiority in terms of suppression T315I sudden change.
Embodiment 58
External mutant clone Activity determination
The cell growth inhibiting activity of heterocycle benzamide compound uses the method described in CCK-8 test kit to be estimated. After cell (3000-10000/hole) was inoculated in 96 porocyte culture plate upper 24 hours, the chemical combination of 100 μ L variable concentrations Thing solution joins in each culture hole, hatches 72 hours, and 10 μ L CCK-8 solution join in each culture hole, then hatch 2-3 Hour, the light absorption value of 450nm and 650nm is measured by microplate reader.In EXCELL form, process initial data, obtain everywhere The cell survival rate in reason hole.Then survival rate data is used to use nonlinear regression model (NLRM) meter on GraphPad Prism software Calculate IC50Value.It was found that heterocycle benzamide compound can significantly inhibit various Abl kinases territories mutant clone (as M351T, F486S, Q252H, Y253H, E355G, M244V, T315I, H396P, E255K, G250E) propagation, the suppression of its half is dense Degree (IC50, table 3) and become positive correlation with drug level.Compound used therefor is selected from the compound prepared by embodiment 1-55, at table 3 Middle Drug No. label represents.
Table 3. part of compounds IC to different mutants50(nM)
M351T cited in table 3, F486S, Q252H, Y253H, E355G, M244V, T315I, H396P, E255K, The Mutant Cells systems such as G250E are that the Abl kinases ATP binding domain utilizing the method artificial screening of induced mutation to build (is i.e. catalyzed Site) single amino acids site mutation causes the external model of the drug resistances such as imatinib.These mutants can be the most anti- Answer the compound inhibition to clinical drug drug resistance cases such as imatinib.
As can be seen from Table 3, compound D1163, most imatinib and nilotinib suppression are lived by D1292, D1302 The mutant that property is the highest all shows strong inhibition；Compound D1163, D1292, D1302 and dasatinib are to except T315I Outside mutant all show similar inhibitory activity, but for T315I mutant, its suppression is lived by dasatinib Property is weaker than far away D1163, D1292, D1302.
In conjunction with table 1, table 2 and the data of table 3, it is believed that the compound described by embodiment 1-55 has various Bcr-Abl Positive leukemia, especially has latent to the leukemia of clinical medicine imatinib, nilotinib and dasatinib drug resistance Therapeutic effect.The test of compound kinase activity in vitro and cytoactive test include that various mutant active testing all shows Go out good suppression Bcr-Abl kinases and the activity of its various saltant types.And contrast imatinib, nilotinib and Dasatinib, the compound described by embodiment 1-55 also has prominent advantage.This invention is for solving current clinical drug-resistant Patient without medicine can miserable present situation bring dawn.
Embodiment described above only have expressed the several embodiments of the present invention, and it describes more concrete and in detail, but can not be because of This and 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, On the premise of present inventive concept, it is also possible to make some deformation and improvement, these broadly fall into protection scope of the present invention. Therefore, the protection domain of patent of the present invention should be as the criterion with claims.

Claims (6)

1. heterocycle benzamide compound or its pharmaceutically acceptable salt or stereoisomer, it is characterised in that described heterocycle Benzamide compound is selected from following compound:
3-(4-(2-amine pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-(4-methyl piperazine-1-replacement) methyl-3- Trifluoromethyl) Benzoylamide；
3-(4-(2-methylamino pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-(4-methyl piperazine-1-replacement) methyl -3-trifluoromethyl) Benzoylamide；
3-(4-(2-ethylamino-pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-(4-methyl piperazine-1-replacement) methyl -3-trifluoromethyl) Benzoylamide；
3-(4-(2-cyclopropyl amino pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-(4-methyl piperazine-1-replacement) first Base-3-trifluoromethyl) Benzoylamide；
((2-(anilino-) pyrimidine-5-takes 4--3-4-methyl-N-(4-((4-methyl piperazine-1-replacement) methyl)-3-(trifluoromethyl) phenyl) Generation)-1H-1,2,3-triazol radical-1-replacement) Benzoylamide；
3-(4-(2-amido quinazoline-6-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-(piperazine-1-substituent methyl)-3-(three Methyl fluoride) phenyl) Benzoylamide；
4-methyl-3-(4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyridine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-N-(4-((4-methyl piperazine Piperazine-1-replaces) methyl)-3-(trifluoromethyl) phenyl) Benzoylamide；
3-(4-([1,2,4] triazole [1,5-a] pyrimidine-6-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-((4-methyl piperazine -1-replaces) methyl)-3-(trifluoromethyl) phenyl) Benzoylamide；
3-(4-(1H-indazole-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-((4-methyl piperazine-1-replacement) first Base)-3-(trifluoromethyl) phenyl) Benzoylamide；
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-(4-methyl piperazine-1-replacement) Methyl-3-trifluoromethyl) Benzoylamide；
((4-methyl isophthalic acid, 4-phenodiazine is tall and erect for 4-for 3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N- -1-replaces) methyl-3-trifluoromethyl) Benzoylamide；
(S) ((3-dimethylamino pyrroles-1-takes 4--N--3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement) Generation) methyl-3-trifluoromethyl)-4-methyl benzamide；
(R) ((3-dimethylamino pyrroles-1-takes 4--N--3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement) Generation) methyl-3-trifluoromethyl)-4-methyl benzamide；
(((4-methyl piperazine-1-takes 4--4-methyl-N-4-3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement) Generation) piperidines-1-replacement) methyl-3-trifluoromethyl) Benzoylamide；
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-N-(4-(4-dimethylamino piperidine-1-replacement) first Base-3-trifluoromethyl)-4-methyl benzamide；
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-((3aR, 6aS)-5-methyl six Hydrogen pyrroles [3,4-c] pyrroles-2 (1H)-replacement) methyl-3-trifluoromethyl) Benzoylamide；
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(3-(4-methyl isophthalic acid H-imidazoles-1- Replace)-5-trifluoromethyl) Benzoylamide；
N-(3-(1H-1,2,4-triazole-1-replacement)-5-trifluoromethyl)-3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-three Nitrogen oxazolyl-1-replaces)-4-methyl benzamide；
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(3-(3-methyl isophthalic acid H-1,2,4-tri- Nitrogen azoles-1-replaces)-5-trifluoromethyl) Benzoylamide；
The chloro-N-of 4-(4-(4-methyl piperazine-1-replacement) methyl-3-trifluoromethyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-6-replacement)-1H-1,2,3- Triazol radical-1-replaces) Benzoylamide；
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement) the chloro-N-of-4-(4-(4-methyl piperazine-1-replacement) Methyl-3-trifluoromethyl) Benzoylamide；
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement) the bromo-N-of-4-(4-(4-methyl piperazine-1-replacement) Methyl-3-trifluoromethyl) Benzoylamide；
The bromo-N-of 4-(4-(4-methyl piperazine-1-replacement) methyl-3-trifluoromethyl)-3-(4-(pyrazoles [1,5-a] pyrimidine-6-replacement)-1H-1,2,3- Triazol radical-1-replaces) Benzoylamide；
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-N-(4-(4-methyl piperazine-1-replacement) methyl -3-trifluoromethyl) Benzoylamide；
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement) the fluoro-N-of-4-(4-(4-methyl piperazine-1-replacement) Methyl-3-trifluoromethyl) Benzoylamide；
The chloro-3-of 4-(4-(3-methyl isophthalic acid H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-N-(4-(4-methyl piperazine -1-replaces) methyl-3-trifluoromethyl) Benzoylamide；
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-ethyl-N-(4-(4-methyl piperazine-1-replacement) Methyl-3-trifluoromethyl) Benzoylamide；
3-(4-(1H-pyrazoles [3,4-b] pyridine-5-replacement)-1H-1,2,3-triazol radical-5-replace)-4-methyl-N-(4-(4-methyl piperazine-1-replacement) Methyl-3-trifluoromethyl) Benzoylamide；
3-(5-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1,3,4-diazole-2-replacement)-4-methyl-N-(4-((4-methyl piperazine-1-replacement) first Base)-3-(trifluoromethyl) phenyl) Benzoylamide；
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement)-4-methyl-N-(4-(4-methyl piperazine-1-replacement) Methyl-3-trifluoromethyl) Benzoylamide dimethanesulfonate；
((pyrazoles [1,5-a] pyrimidine-6-takes 4--3-4-methyl-N-(4-((4-methyl piperazine-1-replacement) methyl)-3-(trifluoromethyl) phenyl) Generation)-1H-1,2,3-triazol radical-1-replacement) benzamide methanesulfonate；
3-(4-(1H-pyrazoles [3,4-b] pyrimidine-5-replacement)-1H-1,2,3-triazol radical-1-replacement) the chloro-N-of-4-(4-(4-methyl piperazine-1-replacement) Methyl-3-trifluoromethyl) benzamide hydrochloride salt.
2. treat a Pharmaceutical composition for tumor, by heterocycle benzamide compound described in claim 1 and pharmaceutically acceptable Salt or stereoisomer and pharmaceutically acceptable carrier form.
3. heterocycle benzamide compound described in claim 1 and pharmaceutically acceptable salt or stereoisomer thereof swell in preparation treatment Application in the medicine of tumor.
Application the most according to claim 3, it is characterised in that described tumor is leukemia.
Application the most according to claim 4, it is characterised in that described leukemia is the CML, AML positive for BCR-ABL Leukemia and to imatinib, the leukemia of dasatinib, nilotinib drug resistance.
Application the most according to claim 4, it is characterised in that described leukemia is the chronic granulocyte of BCR-ABL high expressed Property leukemia and acute leukemia.
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