CN105801584B - Novel aryl amide Raf kinase and its preparation method and application - Google Patents

Novel aryl amide Raf kinase and its preparation method and application Download PDF

Info

Publication number
CN105801584B
CN105801584B CN201610158137.9A CN201610158137A CN105801584B CN 105801584 B CN105801584 B CN 105801584B CN 201610158137 A CN201610158137 A CN 201610158137A CN 105801584 B CN105801584 B CN 105801584B
Authority
CN
China
Prior art keywords
methyl
phenyl
trifluoromethyl
base
pyrimidine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201610158137.9A
Other languages
Chinese (zh)
Other versions
CN105801584A (en
Inventor
唐伟方
王路
陆涛
韩伟
唐三植
陈亚东
周湘
刘海春
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
China Pharmaceutical University
Original Assignee
China Pharmaceutical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by China Pharmaceutical University filed Critical China Pharmaceutical University
Priority to CN201610158137.9A priority Critical patent/CN105801584B/en
Publication of CN105801584A publication Critical patent/CN105801584A/en
Application granted granted Critical
Publication of CN105801584B publication Critical patent/CN105801584B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems

Abstract

The present invention relates to a kind of novel aryl amide compound, their preparation method, the Pharmaceutical composition containing these compounds and their medical applications, especially as the purposes of Raf kinase.The noval chemical compound composition can be used alone or with for treat by protein kinase adjust disorders such as cancers at least one other drug combination.

Description

Novel aryl amide Raf kinase and its preparation method and application
Invention field
The present invention relates to a kind of aryl amide noval chemical compounds, their preparation method, medicinal group containing these compounds Object and their medical application are closed, especially as the purposes of Raf kinase.The noval chemical compound composition can individually make With or with for treating at least one other drug combination of the disorders such as cancers adjusted by protein kinase.
Background technique
Malignant tumour is to seriously threaten the common disease and frequently-occurring disease of human life, clinical treatment of the anti-tumor drug in tumour In play an important role.In recent years, further recognize with the development of Protocols in Molecular Biology and to Tumorigenesis, needle The targeted drug that improper signal conduction system in tumour cell is target is researched and developed, since its target spot is clear, Small side effects, is easy The features such as controlling and is orally available, achieves major progress.Signaling transduction networks and regulation the generation of tumour, development and recurrence, It plays an important role in transfer, has become for the targeted therapy of key molecule in tumor signal Signal Transduction Pathways and capture malignant tumour Effective means.As tyrosine kinase receptor monoclonal antibody Trastuzumab, active tyrosine enzyme inhibitor Imatinib, epidermis are raw Growth factor receptor body inhibitor Gefitinib and multiple target point new drug Sorafenib and Sunitinib etc. are successfully applied to clinic, The targeted therapy of tumour is advanced to a brand-new stage.
The phosphorylation and dephosphorylation of protein are as the signal transduction mechanism for transmitting various information, in the biology of cell It plays an important role in activity.A series of protein kinase and its phosphorylation constitute in the biology of signal transduction most The access of feature.Ras/Raf/MAPK signal path is to study one of access the most active, Ras/Raf/MAPK so far Access is the signal of interest conduction path for adjusting cell growth and proliferation.The activation of the signal transduction pathway can cause from cell A series of cascade reaction events in surface to nucleus, eventually lead to the activation of specific gene and cause cell Proliferation, apoptosis or The different cell behaviors such as differentiation.It has been confirmed that the somatic mutation of the pathway members or the change of expression are swollen with a variety of The morbidity of tumor is related.Crucial effect protein one of of the Raf kinases as the downstream Ras, is a kind of protein serine/threonine, is First molecule of MAPK cascade reaction, Raf play very important role in Ras/Raf/MAPK signal transduction pathway, It is activated in such a way that a kind of GTP is relied on by upstream Ras, and the Raf of activation can activate the mapk kinase (MEK1/2) in downstream, And then activate MAPK (ERK1/2), constitute MAPK cascade reaction, can enter after MAPK activation core activate a variety of nuclear factors and Kinases, and then influence genetic transcription, adjust cell function.Raf kinases includes 3 kinds of main hypotypes: A-Raf, B-Raf and C- Raf.Wherein, A-Raf and C-Raf is respectively necessary for the conservative serine of N-terminal and tyrosine phosphorylation to activate, but the N-terminal of B-Raf Serine can continue phosphorylation, therefore B-Raf is easier to be activated compared with A-Raf, C-Raf.In B-Raf, valine 599 and figured silk fabrics ammonia A part of 600 composition activation loop of acid.These usual amino acid residues are responsible for maintaining in the case where B-Raf is not phosphorylated The nonactive conformation of B-Raf, but V599K or V600E mutation keeps these interactions unstable, causes to activate and cause potential Downstream signal and cell growth it is out of control.By mutation, the Raf kinases of constitutive activation has the characteristics that oncogene, institute's table The kinases reached persistently stimulates ERK independent of Ras in vivo, and eventually leads to many physiological functions, and such as cell Proliferation is divided Change, the generation of angiogenesis, Apoptosis inhibitor and tumour.The most common B-Raf mutation occurs closing on conservative DFG motif 600 residues, i.e., glutamic acid is instead of valine (V600E).The somatic mutation rate after B-Raf is activated is had determined that at present 50-70% is up in melanoma, up to 35% in oophoroma, up to 41% in thyroid cancer, up to 10% in colon cancer. B- RafV600ECatalytic activity than wild type B-Raf (B-RafWT) activity is 500 times high, and B-RafV600EIt can be by stimulating blood The secretion of endothelial tube growth factor (VEGFR) is to promote the generation of tumour peripheral vessels.Therefore, B-RafV600EIt is anti-as exploitation The ideal targets of tumour medicine.
Ras/Raf/MAPK signal path is the most access of feature in cell biology, is risen in tumorigenesis Important role, so that the antitumor research for targeted drug provides multiple potential target spots.At present for Raf kinases Targeted drug research it is especially noticeable, using its as the chemotherapy compound of target include diarylurea derivative Sorafenib and Regorafenib and 7-azaindole derivatives Vemurafenib and pyrimidine derivatives Dabrafnib.
Summary of the invention
The present invention is taken by the crystal structure model of research Raf protein kinase using Computer-Aided Drug Design means The structure-activity relationship model and drug virtual screening model for having built Raf inhibitor, have designed and synthesized a series of base of brand news In purine and the isostructural aryl amide compound of pyrimidine, preliminary pharmacological tests the result shows that: the compound of the present invention have it is good Good Raf kinase inhibiting activity, so as to inhibit the growth of malignant tumour.
Technical scheme is as follows:
The compound or its pharmaceutically acceptable salt of logical formula (I):
Wherein Q be above formula shown in 7H- pyrrolo- [2,3-d] pyrimidine-4-yl, 6- substituted pyrimidines -4- base, 2- replace it is phonetic Pyridine -4- base, 9H- purine -6- base and 2- substituted pyridines -4- base；
Wherein R1、R2Each independently represent hydrogen, alkyl or R1、R2Connect the carbocyclic ring of the 3-6 carbon atom formed；
R3Indicate hydrogen, alkyl, halogen, cyano, alkyl oxy, alkyl sulfenyl；
R4、R5It is each independently selected from hydrogen, halogen, cyano, alkyl, aryl or Het1Substituent group, wherein the alkyl can be into One step is replaced one or more halogens, cyano, the Het1Selected from pyrazolyl, furyl, thienyl, pyridyl group, pyrazine Base, pyrimidine radicals；Or following aliphatic heterocycle: nafoxidine base, morpholinyl, morpholinyl alkyl, morpholinylalkoxy groups, morpholinyl Alkylamino, piperazinyl, piperazinyl alkyl, piperazinyl alkoxy, piperazinyl alkylamino, piperidyl, piperidinylalkyl group, piperidyl alkane Oxygroup, piperidyl alkylamino；
R6Selected from H ,-NHR ,-NH (CH2)1-6OR、-NH(CH2)1-6SR、-NH(CH2)1-6NHR、-NH(CH2)1-6NR2、 - NHCONHR、-CONHR、-NH(CH2)1-6CO2H、-NH(CH2)1-6Het2With-O (CH2)1-6OR.The R is selected from hydrogen or alkyl, institute State Het2Selected from piperidyl, pyrrole radicals, pyrazolyl, piperidyl, imidazole radicals, furyl, morpholinyl, thienyl, oxazolyl, different evil Oxazolyl, thiazolyl, isothiazolyl, pyridyl group, pyrimidine radicals, piperazinyl, substituted piperazinyl, the monocycle of pyrazinyl or pyridazinyl are miscellaneous Ring；Or it is selected from quinolyl, quinoxalinyl, indyl, benzimidazolyl, benzoxazolyl, benzo isoxazolyl, benzothiazole Base, benzisothia oxazolyl, benzofuranyl, benzothienyl, 2,3- dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxane or benzo The bicyclic heterocycle of [d] [1,3] dioxolanyl；Each monocycle or bicyclic heterocycle are optionally replaced by 1,2 or 3 substituent group, each to replace Base is independently selected from halogen, halogenated alkyl, hydroxyl, alkyl or alkoxy, or is selected from C3-C8Aliphatic carbocyclic ring or following fat Race's heterocycle: nafoxidine base, morpholinyl, alkoxy morpholinyl, piperazinyl, piperidyl, alkylamino piperidyl；
L each independently represents CONH, NHCO, NHCONH, NHSO2Or SO2The connexons such as NH；
Abovementioned alkyl is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom；It or is the ring with 3-6 carbon atom Shape saturated hydrocarbyl；Or to connect the ring-type with 3-6 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom Saturated hydrocarbyl；
Alkoxy is the linear chain or branched chain saturation oxyl with 1-6 carbon atom, or is the ring with 3-6 carbon atom Shape is saturated oxyl, or to connect the ring with 3-6 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom Shape is saturated oxyl；
Alkylthio group is the linear chain or branched chain saturation sulfenyl with 1-6 carbon atom, or is the ring with 3-6 carbon atom Shape is saturated sulfenyl；Or to connect the ring with 3-6 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom Shape is saturated sulfenyl；
Armaticity carbocyclic ring is the carbocyclic ring selected from phenyl, naphthalene, acenaphthenyl or tetralyl, is respectively optionally taken by 1,2 or 3 Replace for base, each substituent group is independently selected from hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkane sulphur Base, alkyl amino, alkoxyalkyl, aryl or Het, aryl alkyl or Het alkyl；
Halogen is selected from fluorine, chlorine, bromine or iodine.
Preferred embodiment of the invention is:
R1、R2Each independently represent alkyl；Or R1、R2Connect the carbocyclic ring of the 3-6 carbon atom formed；
R3Indicate alkyl, halogen；
R4、R5Each independently represent hydrogen, halogen, cyano, alkyl, aryl or Het1Substituted aryl, wherein the alkyl Can be further replaced one or more halogens, cyano, Het1Selected from aliphatic heterocycle: morpholinyl, alkyl morpholine base, alcoxyl Base morpholinyl, piperazinyl, alkylpiperazinyl, alkoxy piperazinyl, substituted piperazinyl, piperidyl, alkyl piperidine piperidinyl, alkoxy piperazine Piperidinyl；
R6Selected from H ,-NHR ,-NH (CH2)1-6OR、-NH(CH2)1-6NHR、-NH(CH2)1-6NR2、-NHCONHR、 - CONHR、-NH(CH2)1-6CO2H、-NH(CH2)1-6Het2Or-O (CH2)1-6OR, R indicate hydrogen, alkyl；The Het2Selected from following Aliphatic heterocycle: nafoxidine base, morpholinyl, alkoxy morpholinyl, piperazinyl, piperidyl, alkylamino piperidyl；
L each independently represents CONH, NHCO, NHCONH, NHSO2Or SO2The connexons such as NH.
It is of the invention another preference is that:
R1、R2Preferred methyl or R each independently1、R2Connect 3 yuan or five yuan of the carbocyclic ring formed；
R3Preferably methyl or halogen；
R4、R5Each independently be preferably hydrogen, halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, morpholinyl, Quinoline methyl, 2- (morpholine -1- base) ethyoxyl, 3- (morpholine -1- base) propoxyl group, piperidyl, piperidin-4-ylmethyl, 1- methyl piperazine Pyridine -4- base oxygroup, 1- methyl piperidine -4- ylmethoxy, piperazinyl, 4- methyl piperazine base or 4- methyl piperazine methyl；
R6Preferably methylamino, methoxyethylamino, dimethylaminopropylamino, hydroxyethylamino, 2- (nafoxidine -1- Base) ethylamino, 2- (nafoxidine -1- base) propylcarbamic, 2- (piperidin-1-yl) ethylamino, 1- methyl piperidine -4- base ammonia Base, 1- methyl piperidine -4- base methylamino, 2- (4- methylpiperazine-1-yl) ethylamino, 3- (morpholinyl -1- base) propylcarbamic, Carbamoyl or methyl-carbamoyl；
L each independently represents CONH, NHCO or NHCONH connexon.
The preferably following structural compounds of compounds of formula I:
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) cyclopropyl Alkane -1- formamido group] benzamide (I-1),
N- [3- [1- (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) cyclopropane -1- formamido group] -4- aminomethyl phenyl] -4- Chloro- 3- (trifluoromethyl) benzamide (I-2),
N- [5- [4- chloro- 3- (trifluoromethyl) phenyl urea groups] -2- aminomethyl phenyl] -1- (7H- pyrrolo- [2,3-d] pyrimidine - 4- yl) -1- cyclopropane carboxamide (I-3),
N- [4- morpholinyl -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) Cyclopropane -1- formamido group] benzamide (I-4),
N- [4- (4- methylpiperazine-1-yl) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (7H- pyrrolo- [2,3- D] pyrimidine-4-yl) cyclopropane -1- formamido group] benzamide (I-5),
N- [4- (1- methyl piperidine -4- base oxygroup) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) cyclopropane -1- formamido group] benzamide (I-6),
N- [4- [(1- methyl piperidine -4- base) methoxyl group] -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (7H- pyrroles And [2,3-d] pyrimidine-4-yl) cyclopropane -1- formamido group] benzamide (I-7),
N- [4- (morpholinyl propoxyl group) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (7H- pyrrolo- [2,3-d] Pyrimidine-4-yl) cyclopropane -1- formamido group] benzamide (I-8),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (6- methylaminopyrimidin -4- base) cyclopropane -1- first Acylamino-] benzamide (II-1),
N- [3- [1- [6- (methylamino) pyrimidine-4-yl] cyclopropane -1- formamido group] -4- aminomethyl phenyl] chloro- 3- of -4- (trifluoromethyl) benzamide (II -2),
N- [5- [3- [4- chloro- 3- (trifluoromethyl) phenyl] urea groups] -2- aminomethyl phenyl] -1- [6- (methylamino) pyrimidine -4- Base] cyclopropane -1- formamide (II-3),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [2- methyl -2- [6- (methylamino) pyrimidine-4-yl] third Acylamino-] benzamide (II -4),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (2- hydroxyethylamino) pyrimidine-4-yl] cyclopropyl Alkane -1- formamido group] benzamide (II-5),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- [2- (methoxyethylamino) pyrimidine-4-yl] Cyclopropane -1- formamido group] benzamide (II-6),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- [3- (dimethylaminopropylamino) pyrimidine -4- Base] cyclopropane -1- formamido group] benzamide (II-7),
N- [4- chloro- 3- (trifluoromethyl) phenyl] fluoro- 3- of -4- [1- [6- [1- (methyl piperidine -4- base) methylamino] pyrimidine - 4- yl] cyclopropane -1- formamido group] benzamide (II-8),
[[6- [2- (nafoxidine -1- base) ethylamino] is phonetic by 1- by N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- Pyridine -4- base] cyclopropane -1- formamido group] benzamide (II-9),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- [2- (piperidin-1-yl) ethylamino] pyrimidine -4- Base] cyclopropane -1- formamido group] benzamide (II-10),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (the third amino of morpholinyl) pyrimidine-4-yl] ring Propane -1- formamido group] benzamide (II-11),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (1- methyl piperidine -4- base amino) pyrimidine -4- Base] cyclopropane -1- formamido group] benzamide (II-12),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- [(1- methyl piperidine base -4- base) methylamino] Pyrimidine-4-yl] cyclopropane -1- formamido group] benzamide (II-13),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- [2- (4- methylpiperazine-1-yl) ethylamino] Pyrimidine-4-yl] cyclopropane -1- formamido group] benzamide (II-14),
N- [4- [1- (methyl piperidine -4- base) oxygroup] -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (first ammonia Base) pyrimidine-4-yl] cyclopropane -1- formamido group] benzamide (II-15),
N- [4- [(1- methyl piperidine -4- base) methoxyl group] -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (first ammonia Base) pyrimidine-4-yl] cyclopropane -1- formamido group] benzamide (II-16),
N- [4- (morpholinyl propoxyl group) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (methylamino) pyrimidine - 4- yl] cyclopropane -1- formamido group] benzamide (II-17),
N- [4- (morpholinyl methyl) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (methylamino) pyrimidine-4-yl] Cyclopropane -1- formamido group] benzamide (II-18),
N- [4- [(1- methyl piperidine -4- base) methoxyl group] -3- (trifluoromethyl) phenyl] -4- methyl -3- [2- methyl -2- [6- (methylamino) pyrimidine-4-yl] propionamido] benzamide (II-19),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [2- (methylamino) pyrimidine-4-yl] cyclopropane -1- Formamido group] benzamide (II-20),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [2- [the third amino of 3- (dimethylamino)] pyrimidine -4- Base] cyclopropane -1- formamido group] benzamide (II-21),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [2- [the third amino of 3- (morpholinyl)] pyrimidine-4-yl] Cyclopropane -1- formamido group] benzamide (II-22),
N- [4- (morpholinyl propoxyl group) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [2- (methylamino) pyrimidine - 4- yl] cyclopropane -1- formamido group] benzamide (II-23),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (methylamino) pyrimidine-4-yl] pentamethylene - 1- formamido group] benzamide (II-24),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (9H- purine -6- base) cyclopropane -1- formyl ammonia Base] benzamide (III-1),
N- (3- isopropyl phenyl) -4- methyl -3- [1- (9H- purine -6- base) cyclopropane -1- formamido group] benzamide (III-2),
N- [4- chloro- 3- (trifluoromethyl) phenyl] fluoro- 3- of -4- [1- (9H- purine -6- base) cyclopropane -1- formamido group] Benzamide (III-3),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [2- methyl -2- (9H- purine -6- base) propionamido] Benzamide (III-4),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (9H- purine -6- base) pentamethylene -1- formyl ammonia Base] benzamide (III-5),
N- [4- (morpholinyl methyl) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (9H- purine -6- base) cyclopropane - 1- formamido group] benzamide (III-6),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (2- carbamyl) pyrimidine-4-yl] cyclopropyl Alkane -1- formamido group] benzamide (IV-1),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (2- methyl-carbamoyl) pyrimidine-4-yl] ring Propane -1- formamido group] benzamide (IV-2).
According to the present invention, pharmaceutically acceptable salt includes compound of Formula I and the acid-addition salts that following acid is formed: salt Acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, naphthalene sulfonic acids, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, Maleic acid, benzene sulfonic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or tussol.It additionally include the acid salt of inorganic base, Such as: containing alkali metal cations, alkaline earth metal cation, ammonium cation salt.
The invention further relates to general formula I compound represented or its pharmaceutically acceptable salts or pharmaceutically acceptable Carrier.
The invention further relates to general formula I compound represented or its pharmaceutically acceptable salt or include its medicine group It closes object and is preparing the purposes in the drug for preventing or treating disease related with Raf kinase.
The invention further relates to general formula I compound represented or its pharmaceutically acceptable salt or include its medicine group Close purposes of the object in the drug of preparation treating cancer class disease, wherein the cancer be selected from melanoma, liver cancer, kidney, Acute leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, cutaneum carcinoma, colorectal cancer, cancer of pancreas, oophoroma, cream Gland cancer, myelodysplastic syndrome, the cancer of the esophagus, gastric cancer or celiothelioma etc..
Part of compounds of the invention the preparation method is as follows:
Method 1-1:
Method 1-2:
Method 1-3:
Method 1-4:
The compounds of this invention can be prepared with above-mentioned or similar above-mentioned preparation method, according to the difference of substituent group Corresponding raw material is selected with the difference of substituting group position.
RNH applied in method 1-1 to method 1-42Including bis-aryl amide aniline, double arylamine anilides, double virtues Base urea aniline and Het1Substituted bis-aryl amide aniline.The synthetic method of this 4 kinds of amine is as follows:
Method 1-5: the synthetic method of bis-aryl amide amino benzenes compounds:
Method 1-6: the synthetic method of double arylamine anilide compounds:
Method 1-7: the synthetic method of double aryl ureas amino benzenes compounds:
Method 1-8:Het1The synthetic method of substituted bis-aryl amide aniline:
Aminated compounds can be prepared with above-mentioned preparation method in the present invention, be selected according to the difference of substituent group Corresponding raw material.
Here is partial pharmacologic test and result:
(1) part of compounds is to RafV600EThe research of kinase inhibiting activity
Material
Instrument: Bole Westernblot electrophoresis apparatus (BIO-RAD company, the U.S.)；The black 384 orifice plate (U.S. of wall black matrix Corning company)；Plate shaker (light laboratory apparatus factory, Jiangsu Province).
Reagent: B-Raf (truncated) (U.S. Sigma)；Lck(truncated)；(the U.S. MEK1 unactive Sigma)；Assay Dilution Buffer1 (U.S. Sigma)；Magnesium/ATP Cocktail (U.S. Sigma)； Anti-phospho- MEK1 (Ser218/222)/MEK2 (U.S. Sigma)；Goat anti-rabbit HRP Conjugated lgG (U.S. Sigma)；DMSO (U.S. Sigma).
Method
It takes EP to manage (50 μ L), 20 μ L Magnesium/ATP Cocktail is added；1 μ L B-Raf is added；Medicine to be sieved is added 2 μ L (1.0 × 10 of object-5mol/mL)；0.84 μ L MEK1 unactive is added, adds 14.16 μ L Assay Dilution Buffer 1；After micro centrifuge centrifugation, 30 DEG C of 30min on shaking table；Add 40 μ L sample buffer, boiling water boiling 5min；Every 10 μ L, SDS-PAGE electrophoresis of hole, transferring film, tri-distilled water are washed twice of film；TBST closing containing 5% skimmed milk power, greenhouse 30min is gently shaken on shaking table；Primary antibody Anti-phospho-MEK1 (Ser218/222)/MEK2 is incubated, 4 DEG C overnight；Three steamings are incubated Goat anti-rabbit HRP conjugated lgG secondary antibody；Tri-distilled water is washed twice of film；It is washed with TBS-0.05%Tween-20 Film 3-5min；Tri-distilled water rinses film 4-5 times；Westernblot chemiluminescence detection.
Part preferred compound inhibits RafV600EExperimental result:
Number IC50(nM) Number IC50(nM) Number IC50(nM) Number IC50(nM)
I-1 3.46 II-3 18.5 II-13 14.3 II-23 144
I-2 2.28 II-4 192.4 II-14 13.9 II-24 154
I-3 2.07 II-5 31.5 II-15 59.1 III-1 1.91
I-4 13.4 II-6 35.8 II-16 23.1 III-2 4.56
I-5 34.5 II-7 18.7 II-17 36.5 III-3 285
I-6 15.8 II-8 43.3 II-18 29.1 III-4 9.67
I-7 13.4 II-9 19.5 II-19 30.5 III-5 230
I-8 7.4 II-10 23.4 II-20 166 III-6 3.49
II-1 2.78 II-11 18.3 II-21 84 IV-1 > 0.3uM
II-2 4.31 II-12 21.4 II-22 73.8 IV-2 > 0.3uM
(2) part of compounds is to RafV600EThe research of the highly expressed cancer cell suppression activity of kinases
Material:
Instrument: super-clean bench (upper marine net cleaning equipment Co., Ltd produces)；Electronic balance (METTLER TOLEDO AL104 Type)；Centrifuge (Anke/ flying pigeon TDL80-2B)；Inverted microscope (Leica DMI3000 B uses LAS V3.7 software)； CO2Incubator (Thermo)；Microplate reader (TECAN GENion).
Reagent: CellTiter-Glo (CTG) (Promega, production number: G7573)；Culture medium (DMEM, RPMI1640, EMEM, L-15 (100%air) and McCoy ' s 5a): (Gibco production)；(Gibco is produced FBS- fetal calf serum, and lot number is C2027050)；Pancreatin (Amresco production)；PBS, PH 7.2 (Gibco, production number: 10010-023)；DMSO (Sigma, product Number D2650)
Cell strain: human renal carcinoma cell strain A498；Human colon cancer cell strain HT-29；Human colon cancer cell strain COLO-205；People Maxicell lung cancer cell line NCI-H460；Human melanoma cell strain A375；HepG2 cell lines；Lung cancer cell line EBC-1；Human thyroid squamous cell carcinoma strain SW579；Acute leukemia cells strain MV4-11.
Positive control drug: Vemurafenib, Dabrafenib, Sorafenib tosylate, LY3009120
Method: CellTiter-Glo method test cell maximum inhibition and cell activity inhibit IC50Value
Plating cells: it collects the cell in exponential phase of growth and carries out living cells meter with Vi-Cell XR cell counter Number.Cell suspension is adjusted to concentration appropriate with culture medium, every hole adds 90 μ l cell suspensions in 96- porocyte culture plates.Paving Good cell is placed in 37 DEG C, 5%CO2Incubator culture 24 hours.
Compound processing: to compound processing board is set as, every plant of cell per well adds the corresponding 3 times of gradients of 10 μ l dilute respectively 10 × the compound solution (20 μM or 10 μM of final initial concentration) released, each each 3 multiple holes of drug concentration.
Read T3: after drug-treated 72 hours, every hole is added 50 μ l and melts in advance and equilibrate to the CTG solution of room temperature, and use is micro- Orifice plate oscillator mixes 2 minutes, is believed after ten minutes with Envision2104 plate reader measurement luminescence in being placed at room temperature for Number.
Data are analyzed and experimental result: the calculation formula of POC (percent of control: with the percentage compareed): Compound handles value/DMSO processing hole average value * 100% in hole, and wherein the value in compound processing hole is drug-treated hole T3 luminescence value, DMSO handle the T3 luminescence that the average value in hole handles hole for 6 DMSO on every block of plate The average value of value draws S type dosage-POC curve simultaneously using nonlinear regression model (NLRM) using 5.0 software of GraphPad Prism Calculate IC50Value.
(part of compounds tests IC to the result of cell activity test50Value):
(ND expression is not tested)
Pharmacology test result shows that compounds of formula I and its pharmaceutically acceptable salt have not external Raf kinases With the inhibiting effect of degree.Therefore, compound of Formula I and its pharmaceutically acceptable salt can be used for prevention or treatment and Raf The related clinical disease of kinase inhibitor.The disease related with Raf kinase can be melanoma, liver cancer, kidney Cancer, acute leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, cutaneum carcinoma, colorectal cancer, cancer of pancreas, oophoroma, Breast cancer, myelodysplastic syndrome, the cancer of the esophagus, gastric cancer or celiothelioma.
Specific embodiment
1H-NMR JEOL FX90Q type fourier transform NMR instrument, BRUKER ACF-300 type Nuclear Magnetic Resonance and BRUKER AM-500 type Nuclear Magnetic Resonance completes (TMS internal standard)；MS 2000 type Fourier transform mass spectrometer of Nicolet and The measurement of MAT-212 type mass spectrograph.
Embodiment 1
The chloro- 7- of 4- (4- Methyl benzenesulfonyl base) -7H- pyrrolo- [2,3-d] pyrimidine (I-a)
Chloro- 7H- pyrrolo- [2, the 3-d] pyrimidine (3.0g, 20mmol) of 4- and triethylamine are added in 250mL eggplant-shape bottle (6.1g, 60 mmol) add 100mL anhydrous methylene chloride stirring and dissolving, are added paratoluensulfonyl chloride (2.6g, 24mmol), room temperature 5h is stirred, TLC detects raw material point and disappears.Evaporating solvent under reduced pressure, column chromatographic isolation and purification obtain white solid I-a 4.85g, yield 79.2%.ESI-MS m/z:308 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 2.37 (3H, s, CH3), 6.96 (1H, D, ArH, J=4.0Hz), 7.48 (2H, d, ArH, J=8.1Hz), 8.05 (2H, d, ArH, J=8.1Hz), 8.12 (1H, d, ArH, J=4.0Hz), 8.82 (1H, s, ArH).
Embodiment 2
2- [7- (4- Methyl benzenesulfonyl base) -7H- pyrrolo- [2,3-d] pyrimidine-4-yl] diethyl malonate (I-b)
Diethyl malonate (5.3g, 33mmol) is added in 250mL eggplant-shape bottle, the anhydrous THF of 50mL dissolves, and delays under ice bath It is slow that sodium hydride (60%, 800mg, 33mmol) is added and stirs 5min, I-a (1.0g, 3.3mmol) is molten with the anhydrous THF of 20mL It is slowly added in reaction flask after solution, flow back 2.5h, and TLC detects raw material point and disappears.It is cooled to room temperature, pours into saturated ammonium chloride solution In 100mL, ethyl acetate extracts (50mL × 3), merges organic layer, and saturated sodium-chloride washs (30mL × 3), and anhydrous magnesium sulfate is dry It is dry overnight.Evaporating solvent under reduced pressure, column chromatographic purifying obtain colorless oil I-b 1.4g, yield 98.6%.ESI-MS m/z: 432[M+H]+。
Embodiment 3
2- [7- (4- Methyl benzenesulfonyl base) -7H- pyrrolo- [2,3-d] pyrimidine-4-yl] ethyl acetate (I-c)
I-b (850mg, 2mmol) is dissolved in dehydrated alcohol 50mL, is added sodium ethoxide (13mg, 0.2mmol), reflux 2.5h, TLC detect raw material point and disappear.It is cooled to room temperature, dilute hydrochloric acid (1mol/L) adjusts pH to neutrality, evaporating solvent under reduced pressure, column Chromatography purifies to obtain white solid I-c 530mg, yield 77.0%.ESI-MS m/z:360 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.19 (3H, t, CH2 CH 3, J=7.1Hz), 2.36 (3H, s, ArCH3), 4.08 (2H, q, CH 2CH3, J=7.1 Hz), 4.34 (2H, s, CH2CO), 7.03 (1H, d, ArH, J=4.0Hz), 7.46 (1H, d, ArH, J=8.2Hz), 7.99 (1H, D, ArH, J=4.0Hz), 8.04 (2H, d, ArH, J=8.2Hz), 8.87 (1H, s, ArH).
Embodiment 4
1- [7- (4- Methyl benzenesulfonyl base) -7H- pyrrolo- [2,3-d] pyrimidine-4-yl] cyclopropane -1- Ethyl formate (I- d)
I-c (1.0g 2.7mmol) is dissolved in anhydrous DMF 40mL, be slowly added under ice bath sodium hydroxide (334mg, 8.3 mmol), 1,2- Bromofume (2.8g, 14mmol) is added dropwise after stirring 5min, is warming up to and 5h is stirred at room temperature, TLC detection is former Shots disappear.Water 100mL is added, pH is adjusted to neutrality with dilute hydrochloric acid (1mol/L), ethyl acetate extracts (50mL × 3), merges Organic layer, saturated sodium-chloride wash (50mL × 3), and anhydrous magnesium sulfate is dry.Evaporating solvent under reduced pressure, column chromatographic isolation and purification obtain brown Yellow solid I-d 350mg, yield 33.0%.ESI-MS m/z:386 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.04 (3H, t, CH2CH 3, J=7.0Hz), 1.51~1.54 (2H, m, CH2CH2), 1.57~1.62 (2H, m, CH2CH2), 2.36 (3H, s, ArCH3), 4.06 (2H, t, CH 2CH3), 6.84 (1H, d, ArH, J=4.0Hz), 7.47 (2H, d, ArH, J= 8.1Hz), 7.98 (1H, d, ArH, J=4.0Hz), 8.06 (2H, d, ArH, J=8.1Hz), 8.86 (1H, s, ArH).
Embodiment 5
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [7- (4- Methyl benzenesulfonyl base) -7H- pyrrolo- [2,3-d] pyrimidine-4-yl] cyclopropane -1- formamido group] benzamide (I-e-1)
I-d (100mg, 0.26mmol) is added in 100mL three-necked bottle, N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- first Base -3- aminobenzamide (V-c-1,85mg, 0.26mmol), dry toluene 30mL dissolve, nitrogen protection, under ice bath slowly The toluene solution (2M, 0.39mL, 0.78mmol) of trimethyl aluminium is added, is to slowly warm up to 80 DEG C of stirrings 5h, TLC and detects raw material point It disappears.Extract reaction of going out with 1M dilute hydrochloric acid, ethyl acetate extracts (30mL × 3), and saturated sodium chloride solution washs (30mL × 3), nothing Water magnesium sulfate is dry.Evaporating solvent under reduced pressure obtains yellow solid I-e-1 93mg, and yield 53.7% directly casts single step reaction.
Embodiment 6
N- [4- methyl -3- [1- [7- (4- Methyl benzenesulfonyl base) -7H- pyrrolo- [2,3-d] pyrimidine-4-yl] cyclopropane - 1- formamido group] phenyl] -4- chloro- 3- (trifluoromethyl) benzamide (I-e-2)
With I-d (100mg, 0.26mmol), N- (4- methyl -3- aminophenyl) -4- chloro- 3- (trifluoromethyl) benzamide (VI-c, 85mg, 0.26mmol) is raw material, and the same I-e-1 of operating method obtains yellow solid I-e-2 87mg, yield 50.2%, Directly cast single step reaction.
Embodiment 7
N- [5- [4- chloro- 3- (trifluoromethyl) phenyl urea groups] -2- aminomethyl phenyl] -1- [7- (4- Methyl benzenesulfonyl base) - 7H- pyrrolo- [2,3-d] pyrimidine-4-yl] cyclopropane -1- formamide (I-e-3)
With I-d (100mg, 0.26mmol), N- (3- amino -4- aminomethyl phenyl)-N '-(the chloro- 3- trifluoromethyl of 4-) Urea (VII-b, 89 mg, 0.26mmol) is raw material, and the same I-e-1 of operating method obtains yellow solid I-e-3 97mg, yield 54.7%, directly cast single step reaction.
Embodiment 8
N- [4- morpholinyl -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [7- (4- Methyl benzenesulfonyl base) -7H- pyrroles And [2,3-d] pyrimidine-4-yl] cyclopropane -1- formamido group] benzamide (I-e-4)
With I-d (100mg, 0.26mmol), N- [4- morpholinyl -3- (trifluoromethyl) phenyl] -4- methyl -3- aminobenzoic Amide (VIII-d-1,65mg, 0.26mmol) is raw material, and the same I-e-1 of operating method obtains yellow solid I-e-4 89.5mg, is received Rate 47.9%, directly casts single step reaction.
Embodiment 9
N- [4- (4- methylpiperazine-1-yl) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [7- (4- Methyl benzenesulfonyl Base) -7H- pyrrolo- [2,3-d] pyrimidine-4-yl] cyclopropane -1- formamido group] benzamide (I-e-5)
With I-d (100mg, 0.26mmol), N- [4- (4- methylpiperazine-1-yl) -3- (trifluoromethyl) phenyl] -4- first Base -3-AB (VIII-d-2,56mg, 0.26mmol) is raw material, and the same I-e-1 of operating method obtains yellow solid I- E-5 106mg, yield 55.7%, directly casts single step reaction.
Embodiment 10
N- [4- (1- methyl piperidine -4- base oxygroup) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [7- (4- methylbenzene Sulfonyl) -7H- pyrrolo- [2,3-d] pyrimidine-4-yl] cyclopropane -1- formamido group] benzamide (I-e-6)
With I-d (100mg, 0.26mmol), N- [4- (1- methyl piperidine -4- base oxygroup) -3- (trifluoromethyl) phenyl] -4- Methyl -3-AB (VIII-h-1,56mg, 0.26mmol) is raw material, and the same I-e-1 of operating method obtains yellow solid I-e-5 113mg, yield 58.2%, directly casts single step reaction.
Embodiment 11
N- [4- [(1- methyl piperidine -4- base) methoxyl group] -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [7- (4- first Base benzenesulfonyl) -7H- pyrrolo- [2,3-d] pyrimidine-4-yl] cyclopropane -1- formamido group] benzamide (I-e-7)
With I-d (100mg, 0.26mmol), and N- [4- [(1- methyl piperidine -4- base) methoxyl group) -3- (trifluoromethyl) benzene Base] -4- methyl -3- aminobenzamide (VIII-h-2,56mg, 0.26mmol) is raw material, the same I-e-1 of operating method obtains yellow Color solid I-e-7 107.4mg, yield 54.3% directly cast single step reaction.
Embodiment 12
N- [4- (morpholinyl propoxyl group) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [7- (4- Methyl benzenesulfonyl Base) -7H- pyrrolo- [2,3-d] pyrimidine-4-yl] cyclopropane -1- formamido group] benzamide (I-e-8)
With I-d (100mg, 0.26mmol), N- [4- (morpholinyl propoxyl group) -3- (trifluoromethyl) phenyl] -4- methyl - ((VIII-h-3,56mg, 0.26mmol) is raw material to 3-AB, and the same I-e-1 of operating method obtains yellow solid I-e-8 119.6mg, yield 59.2%, directly casts single step reaction.
Embodiment 13
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) cyclopropyl Alkane -1- formamido group] benzamide (I-1)
I-e-1 (93mg, 0.14mmol) is added in 50mL eggplant-shape bottle, it is molten that 1M sodium hydroxide is added dropwise in ethyl alcohol 20mL dissolution 0.5 mL of liquid, is stirred at room temperature 1h, and TLC detects raw material point and disappears.It removes under reduced pressure.Column chromatographs (eluent: ethyl acetate: petroleum ether =1: 1) isolating and purifying to obtain yellow solid I-1 53mg, yield 74.4%.ESI-MS:m/z:513 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.68~1.71 (2H, m, CH2), 1.90~1.98 (2H, m, CH2), 2.27 (3H, s, ArCH3), 6.58 (1H, d, ArH, J=1.7Hz), 7.37 (1H, d, ArH, J=8.0Hz), 7.57 (1H, t, J=2.8Hz), 7.71 (2H, d, ArH, J=8.5 Hz), 8.08 (1H, s, ArH), 8.12 (1H, d, ArH, J=8.9Hz), 8.35 (1H, d, ArH, J=2.3Hz), 8.75 (1H, s, ArH), 10.10 (1H, s, CONH), 10.57 (1H, s, CONH), 12.18 (1H, s, NH)。
Embodiment 14
N- [3- [1- (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) cyclopropane -1- formamido group] -4- aminomethyl phenyl] -4- Chloro- 3- (trifluoromethyl) benzamide (I-2)
With I-e-2 (87mg, 0.13mmol) for raw material, the same I-1 of operating method obtains yellow solid 45mg, yield 67.3%. ESI-MS m/z:513 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.61~1.63 (2H, m, CH2), 1.65~1.67 (2H, m, CH2), 2.10 (3H, s, ArCH3), 6.58 (1H, s, ArH), 7.18 (1H, d, ArH, J=8.2Hz), 7.51~7.56 (2H, m, ArH), 7.90~7.95 (2H, m, ArH), 8.26 (1H, d, ArH, J=8.3Hz), 8.38 (1H, s, ArH), 8.74 (1H, s, ArH), 10.05 (1H, s, CONH), 10.50 (1H, s, CONH), 12.19 (1H, s, NH).
Embodiment 15
N- [5- [4- chloro- 3- (trifluoromethyl) phenyl urea groups] -2- aminomethyl phenyl] -1- (7H- pyrrolo- [2,3-d] pyrimidine - 4- yl) -1- cyclopropane carboxamide (I-3)
With I-e-3 (97mg, 0.14mmol) for raw material, the same I-1 of operating method obtains yellow solid 53mg, yield 70.6%. ESI-MS m/z:529 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.61~1.63 (2H, m, CH2), 1.69~1.71 (2H, m, CH2), 2.06 (3H, s, ArCH3), 7.07 (1H, d, ArH, J=8.2Hz), 7.20 (1H, d, ArH, J=7.8Hz), 7.56~7.69 (3H, m, ArH), 7.95 (1H, s, ArH), 8.11 (1H, s, ArH), 8.74 (1H, s, NHCONH), 8.84 (1H, s, ArH), 9.04 (1H, s, NHCONH), 10.00 (1H, s, CONH), 12.21 (1H, s, NH).
Embodiment 16
N- [4- morpholinyl -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) Cyclopropane -1- formamido group] benzamide (I-4)
With I-e-4 (86.3mg, 0.12mmol) for raw material, the same I-1 of operating method obtains yellow solid 56.6mg, yield 83.5%.ESI-MS m/z:565 [M+H]+。1H-NMR [300MHz, DMSO-d6]: δ 1.62 (2H, m, CH2), 1.69 (2H, M, CH2), 2.20 (3H, s, ArCH3), 2.84 (4H, s, CH2NCH2), 3.70 (4H, s, CH2OCH2), 6.59 (1H, m, ArH), 7.36 (1H, d, ArH, J=7.7Hz), 7.58~7.61 (2H, m, ArH), 7.70~7.73 (1H, d, ArH, J=7.9Hz), 8.06 (1H, s, ArH), 8.15 (1H, s, ArH), 8.75 (1H, s, ArH), 10.08 (1H, s, CONH), 10.42 (1H, s, CONH), 12.20 (1H, s, NH).
Embodiment 17
N- [4- (4- methylpiperazine-1-yl) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (7H- pyrrolo- [2,3- D] pyrimidine-4-yl) cyclopropane -1- formamido group] benzamide (I-5)
With I-e-5 (102.5mg, 0.14mmol) for raw material, the same I-e-1 of operating method obtains yellow solid 67.8mg, yield 83.9%.ESI-MS m/z:578 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.61 (2H, m, CH2), 1.68 (2H, m, CH2), 2.37 (3H, s, NCH3), 2.56 (3H, s, ArCH3), 2.84~2.88 (4H, m, CH2NCH2), 3.68~3.71 (4H, m, CH2NCH2), 6.57 (1H, d, ArH, J=3.6Hz), 7.20 (1H, d, ArH, J=6.0Hz), 7.25 (1H, d, ArH, J= 5.6Hz), 7.30 (1H, d, ArH, J=4.0Hz), 7.60 (2H, d, ArH, J=7.9Hz), 7.77 (1H, d, ArH, J= 8.5Hz), 7.94 (1H, d, ArH, J=2.1Hz), 8.45 (1H, m, ArH), 8.77 (1H, s, ArH), 8.83 (1H, s, CONH), 9.68 (1H, s, CONH), 11.75 (1H, s, NH).
Embodiment 18
N- [4- (1- methyl piperidine -4- base oxygroup) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) cyclopropane -1- formamido group] benzamide (I-6)
With I-e-6 (89.6mg, 0.12mmol) for raw material, the same I-1 of operating method obtains yellow solid 59.9mg, yield 84.2%.ESI-MS m/z:593 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.59~1.61 (2H, m, CH2), 1.68 ~1.71 (5H, m, CH2), 1.91~1.93 (3H, m), 2.20 (4H, m), 2.22 (3H, s, ArCH3), 2.34 (2H, m, NCH2), 2.58 (2H, m, NCH2), 3.99~4.06 (1H, m, OCH), 6.59 (1H, d, ArH, J=2.0Hz), 7.30~7.36 (2H, m, ArH), 7.56~7.58 (1H, m, ArH), 7.69~7.72 (1H, m, ArH), 7.98 (1H, d, ArH, J= 8.9Hz), 8.05~8.08 (2H, m, ArH), 8.75 (1H, s, ArH), 10.08 (1H, s, CONH), 10.30 (1H, s, CONH), 12.21 (1H, s, NH).
Embodiment 19
N- [4- [(1- methyl piperidine -4- base) methoxyl group] -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (7H- pyrroles And [2,3-d] pyrimidine-4-yl) cyclopropane -1- formamido group] benzamide (I-7)
With I-e-7 (91.3mg, 0.12mmol) for raw material, the same I-1 of operating method obtains yellow solid 61mg, yield 83.8%.ESI-MS m/z:607 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.39~1.43 (4H, m, CH 2CHCH 2), δ 1.61 (2H, m, CH2), 1.68 (2H, m, CH2), 1.76~1.80 (1H, m, CH), 2.19 (3H, s, NCH3), 2.35 (3H, s, ArCH3), 2.50 (4H, m, CH2NCH2), 3.96~3.97 (2H, m, OCH2), 6.58 (1H, d, ArH, J=2.0Hz), 7.26 (1H, d, ArH, J=9.0Hz), 7.35 (1H, d, ArH, J=8.1Hz), 7.57 (1H, m, ArH), 7.71 (2H, m, ArH, J= 8.0Hz), 8.00 (1H, d, ArH, J=8.7Hz), 8.05~8.08 (2H, m, ArH), 8.75 (1H, s, ArH), 10.00 (1H, S, CONH), 10.30 (1H, s, CONH), 12.21 (1H, s, NH).
Embodiment 20
N- [4- (morpholinyl propoxyl group) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (7H- pyrrolo- [2,3-d] Pyrimidine-4-yl) cyclopropane -1- formamido group] benzamide (I-8)
With I-e-8 (93.2mg, 0.12mmol) for raw material, the same I-1 of operating method obtains yellow solid 62.5mg, yield 83.6%.ESI-MS m/z:623 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.62 (2H, m, CH2), 1.68 (2H, m, CH2), 1.85~1.90 (2H, m, OCH2CH 2CH2N), 2.27 (3H, s, ArCH3), 2.34 (4H, m, CH2NCH2), 2.43 (2H, T, CH2N), 3.55~3.58 (4H, m, CH2OCH2), 4.11~4.15 (2H, m, OCH 2CH2), 6.59 (1H, d, ArH, J= 2.4Hz), 7.27 (1H, d, ArH, J=8.8Hz), 7.35 (1H, d, ArH, J=7.9Hz), 7.58 (1H, m, ArH), 7.69~ 7.72 (1H, d, ArH, J=7.7Hz), 7.99 (1H, d, ArH, J=9Hz), 8.05~8.08 (2H, m, ArH), 8.75 (1H, S, ArH), 10.00 (1H, s, CONH), 10.30 (1H, s, CONH), 12.21 (1H, s, NH).
Embodiment 21
(6- chlorine pyrimidine-4-yl) diethyl malonate (II-a-1)
With 4,6- dichloro pyrimidine 5.0g (33mmol) for raw material, preparation method same I-b, give light yellow oil II-a-1 9.0g, yield 98.3%.Product directly casts single step reaction without purifying.
Embodiment 22
(2- chlorine pyrimidine-4-yl) diethyl malonate (II-a-2)
With 2,4- dichloro pyrimidine 5.0g (33mmol) for raw material, preparation method same I-b, give light yellow oil II-a-2 8.8g, yield 95.6%.Product directly casts single step reaction without purifying.
Embodiment 23
(6- chlorine pyrimidine-4-yl) ethyl acetate (II-b-1)
With II-a-1 9g (33mmol) for raw material, the same I-c of preparation method obtains yellow oil II-b-1 5.7g, yield 86.6%.
Embodiment 24
(2- chlorine pyrimidine-4-yl) ethyl acetate (II-b-2)
With II-a-2 9.0g (33mmol) for raw material, the same I-c of preparation method obtains yellow oil II-b-2 5.9g, receives Rate 89.2%.
Embodiment 25
1- (6- chlorine pyrimidine-4-yl) cyclopropane -1- ethyl acetate (II-c-1)
With II-b-1 5.6g (28mmol) for raw material, the same I-d of preparation method obtains yellow oil product I I-c-1 5.5g, yield 87.3%.
Embodiment 26
2- (6- chlorine pyrimidine-4-yl) -2 Methylpropionic acid ethyl ester (II-c-2)
With II-b-1 2.0g (10mmol) and iodomethane 5.7g (40mmol) for raw material, the same I-d of preparation method obtains yellow Grease II-c-2 2.1g, yield 90.7%.
Embodiment 27
(2- chlorine pyrimidine-4-yl) cyclopropane -1- ethyl acetate (II-c-3)
With II-b-2 5.6g (28mmol) for raw material, the same I-d of preparation method obtains yellow oil product I I-c-3 5.5g, yield 87.3%.
Embodiment 28
1- (6- chlorine pyrimidine-4-yl) pentamethylene -1- ethyl acetate (II-c-4)
With II-b-1 2.0g (10mmol) and Isosorbide-5-Nitrae-dibromobutane 8.6g (40mmol) for raw material, the same I-d of preparation method, Obtain yellow oil product I I-c-4 2.1g, yield 82.3%.
Embodiment 29
1- (6- methylaminopyrimidin -4- base) cyclopropane -1- ethyl acetate (II-d-1)
II-c-1 5.7g (28mmol) is dissolved in isopropanol in the eggplant-shape bottle of 250mL, 33% methylamine is added dropwise under ice bath Alcoholic solution 24mL (170mmol).2h, evaporating solvent under reduced pressure is stirred at room temperature.Water 30mL washing, ethyl acetate 50mL are extracted, saturation Saline solution 30mL washing, anhydrous magnesium sulfate are dry.Column chromatographic isolation and purification obtains white solid II-d-1 3.3g, yield 87.9%. MS (LR-ESI): m/z:222.1 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.18 (3H, t, OCH2CH 3, J= 7.1Hz), 1.42-1.48 (4H, m, CH2), 2.81 (3H d, NHCH3, J=4.2Hz), 4.01~4.16 (2H, m, OCH 2CH3), 6.72 (1H, s, ArH), 7.35 (1H, s, NH), 8.32 (1H, s, ArH).
Embodiment 30
2- methyl -2- [6- (methylamino) pyrimidine-4-yl] ethyl propionate (II-d-2)
II-c-2 2.0g (8.7mmol) and methylamine alcohol solution 6mL (43.5mmol) be raw material, the same II-d-1 of preparation method, Obtain yellow solid II-d-11 1.8g, yield 93.5%.MS (LR-ESI): m/z:224.1 [M+H]+。
Embodiment 31
1- [6- (2- hydroxyethylamino) pyrimidine-4-yl] cyclopropane -1- ethyl acetate (II-d-3)
II-c-1 5.3g (24mmol), ethanol amine 1.74mL (29mmol), carbonic acid are sequentially added in 250mL eggplant-shape bottle Caesium 15.6g (48mmol), 2 drop dehydrated alcohols and anhydrous DMF 60mL, 60 DEG C are flowed back 3 hours.Add water 30mL into reaction solution, It is extracted with dichloromethane (40mL × 3), merges organic layer, saturated salt solution 30mL washing, anhydrous sodium sulfate drying.It is chromatographed through column Isolate and purify to obtain white solid II-d-3 5.5g, yield 87.3%, MS (LR-ESI): m/z:252 [M+H]+。
Embodiment 32
1- [6- (2- methoxyethylamino) pyrimidine-4-yl] cyclopropane -1- ethyl acetate (II-d-4)
With II-c-1 5.5g (24mmol) and 2- methoxyethyl amine 1.8g (24mmol) for raw material, the same II-d- of preparation method 3, obtain white solid II-d-4 5.4g, yield 85.2%.MS (LR-ESI): m/z:266.3 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.11 (3H, t, OCH2CH 3, J=7.1Hz), 1.25~1.27 (4H, m, CH2CH2), 3.20 (3H, s, OCH3), 3.38~3.42 (4H, m, OCH2CH2NH), 4.00-4.072 (2H, m, OCH 2CH3), 6.68 (1H, m, NH), 7.45 (1H, s, ArH), 8.25 (1H, s, ArH).
Embodiment 33
1- [6- (3- dimethylaminopropylamino) pyrimidine-4-yl] cyclopropane -1- ethyl acetate (II-d-5)
Using II-c-1 5.5g (24mmol) and 3- dimethylaminopropylamine as raw material, the same II-d-3 of preparation method is obtained white solid Body II-d-5 5.9g, yield 84.6%.MS (LR-ESI): m/z:293.2 [M+H]+。
Embodiment 34
1- [6- [1- (methyl piperidine -4- base) methylamino] pyrimidine-4-yl] cyclopropane -1- ethyl acetate (II-d-6)
With II-c-1 2.0g (8.8mmol), 1- methyl -4- piperidines methylamine 5mL (35.2mmol) and diisopropyl ethyl amine Solution 7.3mL (44.1mmol) is raw material, and the same II-d-3 of preparation method obtains yellow solid II-d-6 2.3g, yield 82.3%. MS (LR-ESI): m/z:319 [M+H]+。
Embodiment 35
1- [6- [2- (nafoxidine -1- base) ethylamino] pyrimidine-4-yl] cyclopropane -1- ethyl acetate (II-d-7)
With II-c-1 2.0g (8.8mmol), 2- (nafoxidine -1- base) ethamine 4.0g (35.2mmol) and diisopropyl Ethyl amine aqueous solution 7.3mL (44.1mmol) is raw material, and the same II-d-3 of preparation method obtains yellow solid II-d-7 2.24g, yield 83.6%.MS (LR-ESI): m/z:305 [M+H]+。
Embodiment 36
1- [6- [2- (piperidin-1-yl) ethylamino]-pyrimidine-4-yl] cyclopropane -1- ethyl acetate (II-d-8)
With II-c-1 2.0g (8.8mmol), 2- (piperidin-1-yl) ethamine 4.5g (35.2mmol) and diisopropyl ethyl Amine aqueous solution 7.3mL (44.1mmol) is raw material, and the same II-d-3 of preparation method obtains yellow solid II-d-8 2.44g, yield 87%.MS (LR-ESI): m/z:319.2 [M+H]+。
Embodiment 37
1- [6- (the third amino of morpholinyl) pyrimidine-4-yl] cyclopropane -1- ethyl acetate (II-d-9)
With II-c-4 2.0g (8.8mmol), morpholinyl propylamine 4.3mL (35.2mmol) and diisopropyl ethyl amine are molten Liquid 7.3mL (44.1mmol) is raw material, and the same II-d-3 of preparation method obtains yellow solid II-d-9 2.44g, yield 87%.MS (LR-ESI): m/z:319.2 [M+H]+。
Embodiment 38
1- [6- (1- methyl piperidine -4- base amino) pyrimidine-4-yl] cyclopropane -1- ethyl acetate (II-d-10)
With II-c-1 2.0g (8.8mmol), 1- methyl piperidine -4- amine 4.4mL (35.2mmol) and diisopropyl ethyl amine Solution 7.3mL (44.1mmol) is raw material, and the same II-d-3 of preparation method obtains yellow solid II-d-10 2.1g, yield 80.2%.MS (LR-ESI): m/z:305 [M+H]+。
Embodiment 39
1- [6- [2- (4- methylpiperazine-1-yl) ethylamino] pyrimidine-4-yl] cyclopropane -1- ethyl acetate (II-d-11)
With II-c-1 2.0g (8.8mmol), 4- methyl-1-piperazine ethanamine 5.3mL (35.2mmol) and diisopropyl ethyl Amine aqueous solution 7.3mL (44.1mmol) is raw material, and the same II-d-3 of preparation method obtains yellow solid II-d-11 2.2g, yield 81.6%.MS (LR-ESI): m/z:334 [M+H]+。
Embodiment 40
1- [(2- methylamino) pyrimidine-4-yl] cyclopropane -1- ethyl acetate (II-d-12)
II-c-3 5.7g (28mmol) is raw material, and the same II-d-1 of preparation method obtains yellow solid II-d-12 5.5g, is received Rate 84.6%.MS (LR-ESI): m/z:222.1 [M+H]+。
Embodiment 41
1- [2- [the third amino of 3- (dimethylamino)] pyrimidine-4-yl] cyclopropane -1- ethyl acetate (II-d-13)
With II-c-3 2g (8.8mmol), N, N- dimethylaminopropylamine solution 5.6mL (44.1mmol) and diisopropyl second Base amine aqueous solution 7.3ml (44.1mmol) is raw material, and the same II-d-3 of preparation method obtains yellow solid II-d-13 2.1g, yield 86.4%.MS (LR-ESI): m/z:279.2 [M+H]+。
Embodiment 42
1- [2- [the third amino of 3- (morpholinyl)]-pyrimidine-4-yl] cyclopropane -1- ethyl acetate (II-d-14)
With II-c-3 2.0g (8.8mmol), morpholinyl propylamine 4.3mL (35.2mmol) and diisopropyl ethyl amine are molten Liquid 7.3mL (44.1mmol) is raw material, and the same II-d-3 of preparation method obtains yellow solid II-d-14 2.44g, yield 87%.MS (LR-ESI): m/z:319.2 [M+H]+。
Embodiment 43
1- [(6- methylamino) pyrimidine-4-yl] pentamethylene -1- ethyl acetate (II-d-15)
II-c-4 2.0g (7.9mmol) and methylamine alcohol solution 6mL (39.3mmol) be raw material, the same II-d-1 of preparation method, Obtain yellow solid II-d-15 1.71g, yield 87%.MS (LR-ESI): m/z:250 [M+H]+。
Embodiment 44
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (6- methylaminopyrimidin -4- base) cyclopropane -1- first Acylamino-] benzamide (II-1)
With II-d-1 0.11g (0.5mmol) and N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- aminobenzoic Amide (V-c-1,158mg, 0.48mmol) is raw material, and the same I-e-1 of preparation method obtains white solid II-1 0.2g, yield 82.7%.MS (LR-ESI): m/z:504 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.32 (2H, m, CH2), 1.58 (2H, m, CH2), 2.36 (3H, s, ArCH3), 2.81 (3H, s, NHCH3), 6.38 (1H, s, NH), 7.40~7.43 (2H, m, ArH), 7.68~7.73 (2H, m, ArH), 8.13 (1H, dd, ArH, J=2.2Hz, J=8.7Hz), 8.35~8.36 (2H, m, ArH), 8.47 (1H, s, ArH), 10.60 (1H, s, CONH), 11.20 (1H, s, CONH).
Embodiment 45
N- [3- [1- [6- (methylamino) pyrimidine-4-yl] cyclopropane -1- formamido group] -4- aminomethyl phenyl] chloro- 3- of -4- (trifluoromethyl) benzamide (II -2)
With II-d-1 (22.1mg, 0.1mmol) and N- (4- methyl -3- aminophenyl) -4- chloro- 3- (trifluoromethyl) benzene Formamide (VI-c 33mg, 0.1mmol) is raw material, and the same II-1 of preparation method obtains white solid II-2 42.4mg, yield 84.2%.ESI-MS m/z:504 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.2 (2H, m, CH2), 1.3 (2H, m, CH2), 2.26 (3H, s, ArCH3), 2.81 (3H, s, NHCH3), 6.35 (1H, s, NH), 7.21 (1H, d, ArH, J= 8.40Hz), 7.42 (1H, q, ArH, J=4.7Hz), 7.56 (1H, dd, ArH, J=1.95Hz, J=8.22Hz), 7.90 (1H, D, ArH, J=8.40Hz), 8.19 (1H, s, ArH), 8.27 (1H, dd, ArH, J=1.65Hz, J=8.4Hz), 8.40 (1H, D, ArH, J=1.5Hz), 8.46 (1H, s, ArH), 10.50 (1H, s, CONH), 11.50 (1H, s, CONH).
Embodiment 46
N- [5- [3- [4- chloro- 3- (trifluoromethyl) phenyl] urea groups] -2- aminomethyl phenyl] -1- [6- (methylamino) pyrimidine -4- Base] cyclopropane -1- formamide (II-3)
With II-d-1 (22.1mg, 0.1mmol), N- (3- amino -4- aminomethyl phenyl)-N '-(chloro- 3- trifluoromethylbenzene of 4- Base) urea (VII-b 34mg, 0.1mmol) is raw material, the same II-1 of preparation method obtains white solid II-3 45.6mg, yield 87.9%.ESI-MS m/z:519 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.3 (2H, m, CH2), 1.6 (2H, m, CH2), 2.2 (3H, s, ArCH3), 2.8 (3H, d, NHCH3, J=3.6Hz), 6.34 (1H, s, NH), 7.10~7.13 (1H, m, ArH), 7.20 (1H, dd, ArH, J=2Hz, J=8.2Hz), 7.41~7.43 (1H, m, ArH), 7.60 (2H, m, ArH), 7.95 (1H, s, ArH), 8.12 (1H, s, ArH), 8.45 (1H, s, ArH), 8.82 (1H, s, CONH), 9.01 (1H, s, CONH), 11.11 (1H, s, CONH).
Embodiment 47
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [2- methyl -2- [6- (methylamino) pyrimidine-4-yl] third Acylamino-] benzamide (II -4)
With II-d-2 0.11g (0.5mmol) and N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- aminobenzoic Amide (V-c-1,165mg, 0.5mmol) is raw material, and the same II-1 of operating method obtains white solid II-4 0.22g, yield 86.9%.ESI-MS m/z:506 [M+H]+。1H-NMR (300MHz, DMSO-d6): (6H, s, 2 × CH of δ 1.533), 2.12 (3H, s, CH3, ArCH3), 2.82 (3H, d, NHCH3, J=4.4Hz), 6.52 (1H, m, NH), 7.17 (1H, d, ArH, J= 8.2Hz), 7.43~7.44 (1H, m, ArH), 7.58 (1H, dd, ArH, J=1.8Hz, J=8.2Hz), 7.85 (1H, d, ArH, J=1.7Hz), 7.91 (1H, d, ArH, J=8.4Hz), 8.27 (1H, d, ArH, J=8.4Hz), 8.39 (1H, s, ArH), 8.47 (1H, s, ArH), 9.34 (1H, s, CONH), 10.48 (1H, s, CONH).
Embodiment 48
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (2- hydroxyethylamino) pyrimidine-4-yl] cyclopropyl Alkane -1- formamido group] benzamide (II-5)
With II-d-3 0.13g (0.5mmol) and N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- aminobenzoic Amide (V-c-1,165mg, 0.5mmol) is raw material, and the same II-1 of preparation method obtains white solid II-5 0.21g, yield 78.4%.MS (LR-ESI): m/z:534 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.31 (2H, m, CH2), 1.57 (2H, m, CH2), 2.30~2.36 (3H, m), 4.34 (4H, t, CH2, HOCH2CH2NH, J=5.0Hz), 4.76 (1H, s, OH), 6.45 (1H, s, NH), 7.39~7.47 (2H, m, ArH), 7.68~7.72 (2H, m, ArH), 8.11~8.14 (1H, m, ArH), 8.35 (2H, m, ArH), 8.44 (1H, s, ArH), 10.57 (1H, s, CONH), 11.26 (1H, s, CONH).
Embodiment 49
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- [2- (methoxyethylamino) pyrimidine-4-yl] Cyclopropane -1- formamido group] benzamide (II-6)
With II-d-4 0.13g (0.5mmol) and N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- aminobenzoic Amide (V-c-1,160mg, 0.5mmol) is raw material, and the same II-1 of preparation method obtains white solid II-6 0.21g, yield 78.4%.MS (LR-ESI): m/z:548 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.17~1.20 (2H, m, CH2), 1.31 (2H, m, CH2), 2.28 (3H, s, ArCH3), 3.26 (3H, s, OCH3), 3.45~3.46 (4H, m, OCH2CH2NH), 6.47 (1H, s, NH), 7.41 (1H, d, ArH, J=8.0Hz), 7.56 (1H, s, ArH), 7.68~7.73 (2H, m, ArH), 8.13 (1H, d, ArH, J=8.7Hz), 8.32~8.36 (2H, m, ArH), 8.46 (1H, s, ArH), 10.60 (1H, s, CONH), 11.20 (1H, s, CONH).
Embodiment 50
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- [3- (dimethylaminopropylamino) pyrimidine -4- Base] cyclopropane -1- formamido group] benzamide (II-7)
With II-d-5 (29.2mg, 0.1mmol) and N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- aminobenzoic Amide (V-c-1,33mg, 0.1mmol) is raw material, and the same II-1 of preparation method obtains white solid II-7 47.5mg, yield 82.7%.ESI-MS:m/z:575 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.34 (2H, m, CH2), 1.57 (2H, m, CH2), 1.88~1.93 (2H, m, NHCH2CH 2CH2N), 2.35 (3H, s, ArCH3), 2.73 (6H, s, 2 × NCH3), 3.06~ 3.11 (4H, m, NHCH 2CH2CH 2N), 6.52 (1H, s, NH), 7.41 (1H, d, ArH, J=8.0Hz), 7.70~7.73 (3H, M, ArH), 8.15~8.18 (1H, m, ArH), 8.34~8.47 (3H, m, ArH), 8.47 (1H, s, ArH), 10.70 (1H, s, CONH), 10.99 (1H, s, CONH).
Embodiment 51
N- [4- chloro- 3- (trifluoromethyl) phenyl] fluoro- 3- of -4- [1- [6- [1- (methyl piperidine -4- base) methylamino] pyrimidine - 4- yl] cyclopropane -1- formamido group] benzamide (II-8)
With II-d-6 (0.32g, 1mmol) and N- [4- chloro- 3- (trifluoromethyl) phenyl] fluoro- 3-AB of -4- (V-c-2,333mg, 1mmol) is raw material, and the same II-1 of preparation method obtains white solid II-8 0.45g, yield 74.2%. ESI-MS:m/z:627 [M+Na]+。1H-NMR (300MHz, DMSO-d6): 1.34~1.48 (3H, m, CH2- Cyclopropane, NHCH2CH), 1.61~1.65 (4H, m, CH2- cyclopropane, CH 2CH2), 1.75~1.82 (2H, T, CH2, J=11Hz), 2.12 (3H, s, NCH3), 2.71~2.74 (2H, m, CH2), 3.19~3.21 (2H, m, CH2), 3.44 (2H, m, NHCH2), 6.37 (1H, s, NH), 7.45~7.54 (2H, m, CH2, ArH), 7.71 (1H, d, ArH, J=8.8Hz), 7.77~7.82 (1H, m, ArH), 8.11 (1H, dd, ArH, J=2.2Hz, J=8.8Hz), 8.34 (1H, d, ArH, J= 2.3Hz), 8.43 (1H, s, ArH), 8.63 (1H, dd, ArH, J=1.9Hz, J=7.3Hz), 10.67 (1H, s, CONH), 11.95 (1H, s, CONH).
Embodiment 52
[[6- [2- (nafoxidine -1- base) ethylamino] is phonetic by 1- by N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- Pyridine -4- base] cyclopropane -1- formamido group] benzamide (II-9)
With II-d-5 (0.3g, 1mmol) and N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3-AB (V-c-1,328mg, 1mmol) is raw material, and the same II-1 of preparation method obtains white solid II-9 0.44g, yield 74.2%.1H- NMR (300MHz, DMSO-d6): 1.32 (2H, m, CH2- cyclopropane), 1.57 (2H, m, CH2- cyclopropane), 1.70 (4H, m, CH2CH 2CH 2CH2), 2.35 (3H, s, ArCH3), 2.63~2.73 (6H, m, NCH2), 3.42~3.44 (2H, m, NHCH2), 6.46 (1H, s, NH), 7.39~7.42 (2H, m, ArH), 7.68~7.73 (2H, m, ArH), 8.11~8.15 (1H, M, ArH), 8.34~8.36 (2H, m, ArH), 8.45 (1H, s, ArH), 10.59 (1H, s, CONH), 11.20 (1H, s, CONH).
Embodiment 53
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- [2- (piperidin-1-yl) ethylamino] pyrimidine -4- Base] cyclopropane -1- formamido group] benzamide (II-10)
With II-d-8 (31.8mg, 0.1mmol) and N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- aminobenzoic Amide (V-c-1,33mg, 0.1mmol) is raw material, and the same II-1 of preparation method obtains white solid II-10 49.5mg, yield 82.5%.ESI-MS m/z:601 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.34 (2H, m, CH2- Cyclopropane), 1.41 (2H, m, CH2- cyclopropane), 1.58 (6H, m, CH2CH2CH2), 2.35 (4H, m, CH2NCH2), 2.54~2.73 (2H, m, NCH2), 3.34 (3H, s, ArCH3), 3.43~3.46 (2H, m, NHCH2), 6.47 (1H, s, NH), 7.41 (2H, d, ArH, J=8.1Hz), 7.69~7.73 (2H, m, ArH), 8.13 (1H, dd, ArH, J= 2.2Hz, J=8.8Hz), 8.32 (1H, s, ArH), 8.36 (1H, d, ArH, J=2.2Hz), 8.50 (1H, s, ArH), 10.60 (1H, s, CONH), 11.10 (1H, s, CONH).
Embodiment 54
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (the third amino of morpholinyl) pyrimidine-4-yl] ring Propane -1- formamido group] benzamide (II-11)
With II-d-9 (0.33g, 1mmol) and N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- aminobenzoyl Amine (V-c-1,328mg, 1mmol) is raw material, and the same II-1 of preparation method obtains white solid II-8 0.44g, yield 70.8%. ESI-MS m/z:639 [M+Na]+。1H-NMR (300MHz, DMSO-d6): δ 1.20 (2H, m, CH2- cyclopropane), 1.59 (2H, m, CH2- cyclopropane), 1.65~1.72 (2H, m, NHCH2CH 2CH2N), 1.92 (3H, s, ArCH3), 2.30~2.37 (8H, m, NHCH 2CH2CH 2N(CH 2)2), 3.55~3.58 (4H, m, CH2OCH2), 6.39 (1H, s, NH), 7.41 (1H, d, ArH, J=8Hz), 7.48 (1H, t, ArH, J=5.3Hz), 7.69~7.72 (2H, m, ArH), 8.14 (1H, Dd, ArH, J=2.2Hz, J=8.8Hz), 8.36~8.37 (2H, m, ArH), 8.45 (1H, s, ArH), 10.58 (1H, s, CONH), 11.26 (1H, s, CONH).
Embodiment 55
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (1- methyl piperidine -4- base amino) pyrimidine -4- Base] cyclopropane -1- formamido group] benzamide (II-12)
With II-d-10 (30mg, 0.1mmol) and N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- aminobenzoic Amide (V-c-1,33mg, 0.1mmol) is raw material, and the same II-1 of preparation method obtains white solid II-12 50mg, yield 84.6%.ESI-MS:m/z:587 [M+H]+, 609 [M+Na]+。1H-NMR (300MHz, DMSO-d6): δ 1.32 (2H, m, CH2- Cyclopropane), 1.40~1.51 (2H, m, CH2- cyclopropane), 1.59~1.60 (2H, m, CH 2), 1.82 CH~ 1.86 (2H, m, CH 2CH), 1.95~2.02 (2H, m, NCH2), 2.15 (3H, s, ArCH3), 2.37 (3H, s, NCH3), 2.70 ~2.73 (2H, m, NCH2), 3.81 (1H, m, NHCH), 6.67 (1H, s, NH), 7.40~7.42 (2H, m, ArH), 7.69~ 7.72 (2H, m, ArH), 8.14 (1H, dd, ArH, J=2.1Hz, J=8.8Hz), 8.37~8.53 (3H, m, ArH), 10.60 (1H, s, CONH), 11.27 (1H, s, CONH).
Embodiment 56
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- [(1- methyl piperidine base -4- base) methylamino] Pyrimidine-4-yl] cyclopropane -1- formamido group] benzamide (II-13)
With II-d-6 (0.32g, 1mmol) and N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- aminobenzoyl Amine (V-c-1,33mg, 1mmol) is raw material, and the same II-1 of preparation method obtains white solid II-13 0.47g, yield 78.2%. ESI-MS:m/z:623 [M+Na]+。1H-NMR (300MHz, DMSO-d6): δ 1.19~1.24 (2H, m, CH2- Cyclopropane), 1.31 (2H, m, CH2- cyclopropane), 1.44~1.49 (1H, m, CH), 1.57~1.66 (4H, M, CH 2CHCH 2), 1.79~1.90 (2H, m, NCH2), 2.15 (3H, s, ArCH3), 2.36 (3H, s, NCH3), 2.74~2.77 (2H, m, NCH2), 3.21 (2H, m, NHCH2), 6.43 (1H, s, NH), 7.41 (1H, d, ArH, J=8.1Hz), 7.53 (1H, t, ArH, J=5.6Hz), 7.68~7.72 (2H, m, ArH), 8.14 (1H, dd, ArH, J=2.2Hz, J=8.8Hz), 8.35~ 8.37 (3H, m, ArH), 10.60 (1H, s, CONH), 11.18 (1H, s, CONH).
Embodiment 57
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- [2- (4- methylpiperazine-1-yl) ethylamino] Pyrimidine-4-yl] cyclopropane -1- formamido group] benzamide (II-14)
With II-d-11 (0.33g, 1mmol) and N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- aminobenzoyl Amine (V-c-1,33mg, 1mmol) is raw material, and the same II-1 of preparation method obtains white solid II-14 0.45g, yield 73.1%. ESI-MS:m/z:638 [M+Na]+。1H-NMR (300MHz, DMSO-d6): δ 1.34 (2H, m, CH2- cyclopropane), 1.60 (2H, m, CH2- cyclopropane), 2.13 (3H, s, ArCH3), 2.31 (3H, s, NCH3), 2.37~2.58 (10H, M, NCH2), 3.40 (2H, m, NHCH2), 6.46 (1H, s, NH), 7.34 (1H, s, ArH), 7.41 (1H, d, ArH, J=8Hz), 7.70 (2H, m, ArH), 8.14 (1H, dd, ArH, J=2Hz, J=8.8Hz), 8.37~8.46 (3H, m, ArH), 10.59 (1H, s, CONH), 11.31 (1H, s, CONH).
Embodiment 58
N- [4- [1- (methyl piperidine -4- base) oxygroup] -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (first ammonia Base) pyrimidine-4-yl] cyclopropane -1- formamido group] benzamide (II-15)
With II-d-1 (22.1mg, 0.1mmol) and N- [4- (1- methyl piperidine -4- base oxygroup) -3- (trifluoromethyl) benzene Base] -4- methyl -3- aminobenzamide (VIII-h-1,41mg, 0.1mmol) is raw material, the same II-1 of preparation method obtains white Solid II-15 50.8mg, yield 87.2%.ESI-MS:m/z:583 [M+H]+。1H-NMR (300MHz, DMSO-d6]): δ 1.64 ~1.82 (4H, m, CH2- cyclopropane), 1.95 (3H, s, ArCH3), 2.19 (4H, m, CH 2CHCH 2), 2.24~2.26 (2H, m, NCH2), 2.39 (3H, s, NCH3), 2.54-2.55 (2H, m, NCH2), 2.88 (3H, d, NHCH3, J=3.3Hz), 4.58 (1H, m, OCH), 6.42 (1H, s, NH), 7.27-7.30 (1H, m, ArH), 7.33-7.39 (1H, m, ArH), 7.42- 7.48 (1H, m, ArH), 7.72 (1H, dd, ArH, J=1.5Hz, J=7.9Hz), 7.90~8.07 (1H, m, ArH), 8.14~ 8.15 (1H, d, ArH, J=2.5Hz), 8.41 (1H, s, pyrimidine-H), 8.50 (1H, s, pyrimidine-H), 10.35 (1H, s, CONH), 11.34 (1H, s, CONH).
Embodiment 59
N- [4- [(1- methyl piperidine -4- base) methoxyl group] -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (first ammonia Base) pyrimidine-4-yl] cyclopropane -1- formamido group] benzamide (II-16)
With II-d-1 (22.1mg, 0.1mmol) and N- [4- [and (1- methyl piperidine -4- base) methoxyl group) -3- (trifluoromethyl) Phenyl] -4- methyl -3-AB (VIII-c-2,42mg, 0.1mmol) is raw material, the same II-1 of preparation method obtains white Color solid II-15 49.2mg, yield 82.5%.ESI-MS:m/z:597 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.33~1.40 (4H, m, CH2- cyclopropane), 1.58 (2H, m, CH2), 1.69~1.73 (3H, m, CH3), 1.87 (2H, t, CH2, J=10.9Hz), 2.16 (3H, s, ArCH3), 2.35 (3H, s, NCH3), 2.77~2.89 (5H, m, CH2NCH2, CH), 3.93~3.95 (2H, m, OCH2), 6.38 (1H, s, NH), 7.24 (1H, d, ArH, J=9.1Hz), 7.37~7.43 (2H, m, ArH), 7.68 (1H, d, ArH, J=7.8Hz), 8.0 (1H, d, ArH, J=9.0Hz), 8.08 (1H, d, ArH, J= 2.2Hz), 8.33 (1H, s, ArH), 8.46 (1H, s, ArH), 10.28 (1H, s, CONH), 11.15 (1H, s, CONH).
Embodiment 60
N- [4- (morpholinyl propoxyl group) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (methylamino) pyrimidine - 4- yl] cyclopropane -1- formamido group] benzamide (II-17)
With II-d-1 (22.1mg, 0.1mmol) and N- [4- (morpholinyl propoxyl group) -3- (trifluoromethyl) phenyl] -4- Methyl -3-AB (VIII-h-3,61.3mg, 0.1mmol) is raw material, and the same II-1 of preparation method obtains white solid II-17 49.8mg, yield 88.3%.ESI-MS:m/z:613 [M+H]+。1H-NMR (300MHz, DMSO-d6]): δ 1.34~ 1.46 (2H, m, CH2- cyclopropane), 1.61~1.69 (2H, m, CH2- cyclopropane), 1.84~1.92 (2H, M, CH2), 2.36~2.46 (2H, m, CH2), 2.12~2.26 (8H, m, CH2), 2.84~2.90 (3H, m, NHCH3), 3.45 (3H, s, ArCH3), 4.11~4.14 (2H, t, OCH2, J=6.0Hz), 6.40 (1H, s, NH), 7.26 (1H, d, ArH, J= 9.1Hz), 7.38~7.45 (2H, m, ArH), 7.65~7.75 (1H, m, ArH), 8.00~8.04 (1H, m, ArH), 8.10~ 8.11 (1H, d, ArH, J=2.4Hz), 8.37 (1H, s, pyrimidine-H), 8.48 (1H, s, pyrimidine-H), 10.32 (1H, s, CONH), 11.24 (1H, s, CONH).
Embodiment 61
N- [4- (morpholinyl methyl) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (methylamino) pyrimidine-4-yl] Cyclopropane -1- formamido group] benzamide (II-18)
With II-d-1 (22.1mg, 0.1mmol) and N- [4- (morpholinyl methyl) -3- (trifluoromethyl) phenyl] -4- methyl - 3-AB (VIII-i, 39.3mg, 0.1mmol) is raw material, and the same II-1 of preparation method obtains white solid II-18 47.9mg, yield 84.2%.ESI-MS:m/z:613 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.33 (2H, m, CH2- Cyclopropane), 1.58 (2H, m, CH2- cyclopropane), 2.36~2.38 (7H, m, 2 × NCH2, ArCH3), 2.82 (3H, s, NHCH3), 3.58~3.59 (6H, m, CH2), 6.39 (1H, m, NH), 7.39~7.44 (2H, m, ArH), 7.68~ 7.74 (2H, m, ArH), 8.06 (1H, d, ArH, J=8.4Hz), 8.21 (1H, s, ArH), 8.34 (1H, s, ArH), 8.47 (1H, S, ArH), 10.47 (1H, s, CONH), 11.16 (1H, s, CONH).
Embodiment 62
N- [4- [(1- methyl piperidine -4- base) methoxyl group] -3- (trifluoromethyl) phenyl] -4- methyl -3- [2- methyl -2- [6- (methylamino) pyrimidine-4-yl] propionamido] benzamide (II-19)
With II-d-2 (22mg, 0.1mmol) and N- [4- [and (1- methyl piperidine -4- base) methoxyl group) -3- (trifluoromethyl) benzene Base] -4- methyl -3-AB (VIII-h-2,42.1mg, 0.1mmol) is raw material, the same II-1 of preparation method obtains white Color solid II-19 51.7mg, yield 86.4%.ESI-MS:m/z:599 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.29~1.41 (2H, m, CH2), 1.55 (6H, s, 2 × CH3), 1.69~1.73 (3H, m, CH2, CH), 1.83~1.90 (2H, M, NCH2), 2.16 (3H, m, NCH3), 2.21 (3H, s, ArCH3), 2.77~2.83 (5H, m, NCH2, NHCH3), 3.94 (2H, D, OCH2, J=5.4Hz), 6.53 (1H, m, NH), 7.25 (1H, d, ArH, J=9.1Hz), 7.34~7.36 (1H, d, ArH, J =8.1Hz), 7.42 (1H, d, ArH, J=4.3Hz), 7.70 (1H, dd, ArH, J=1.6Hz, J=7.9Hz), 7.97~ 8.00 (2H, m, ArH), 8.07 (1H, d, ArH, J=2.4Hz), 8.47 (1H, s, ArH), 9.42 (1H, s, CONH), 10.29 (1H, s, CONH).
Embodiment 63
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [2- (methylamino) pyrimidine-4-yl] cyclopropane -1- Formamido group] benzamide (II-20)
With II-d-12 (22mg, 0.1mmol) and N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- aminobenzoic Amide (V-c-1,33mg, 0.1mmol) is raw material, and the same II-1 of preparation method obtains white solid II-20 44.1mg, yield 87.5%.ESI-MS:m/z:504 [M+H]+, 526 [M+Na]+。1H-NMR (300MHz, DMSO-d6]: 1.41 (2H, m, CH2), 1.56 (2H, m, CH2), 2.28 (3H, s, ArCH3), 2.79-2.82 (3H, m, NHCH3), 6.56 (1H, s, NH), 7.28 (1H, S, ArH), 7.40~7.43 (1H, d, ArH, J=7.9Hz), 7.71~7.76 (2H, m, ArH), 8.07 (1H, s, ArH), 8.11 (1H, d, ArH, J=2.0Hz), 8.23 (1H, d, pyrimidine-H, J=2.5Hz), 8.35 (1H, d, Pyrimidine-H, J=2.3Hz), 10.60 (1H, s, CONH), 10.74 (1H, s, CONH).
Embodiment 64
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [2- [the third amino of 3- (dimethylamino)] pyrimidine -4- Base] cyclopropane -1- formamido group] benzamide (II-21)
With II-d-13 (29mg, 0.1mmol) and N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- aminobenzoic Amide (V-c-1,33mg, 0.1mmol) is raw material, and the same II-1 of preparation method obtains white solid II-21 50.1mg, yield 87.2%.ESI-MS:m/z:575 [M+H]+, 597 [M+Na]+。1H-NMR (300MHz, DMSO-d6]: δ 1.39 (2H, s, CH2- Cyclopropane), 1.53 (2H, s, CH2- cyclopropane), 1.62~1.72 (2H, m, NHCH2CH 2CH2), 2.17~ 2.19 (9H, m, ArCH3, N (CH3)2), 2.30~2.32 (2H, m, NCH2), 3.26~3.36 (2H, m, NHCH2), 6.52 (1H, M, NH), 7.22~7.28 (2H, m, ArH), 7.56~7.58 (1H, m, ArH), 7.90~7.93 (2H, m, ArH), 8.21~ 8.29 (2H, m, ArH), 8.40 (1H, s, ArH), 10.51 (1H, s, CONH), 10.70 (1H, s, CONH).
Embodiment 65
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [2- [the third amino of 3- (morpholinyl)] pyrimidine-4-yl] Cyclopropane -1- formamido group] benzamide (II-22)
With II-d-14 (33.4mg, 0.1mmol) and N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- aminobenzene Formamide (V-c-1,33mg, 0.1mmol) is raw material, and the same II-1 of preparation method obtains white solid II-22 50.3mg, yield 81.6%.ESI-MS m/z:617 [M+H]+, 639 [M+Na]+。1H-NMR (300MHz, DMSO-d6): δ 1.40~1.41 (2H, m, CH2- cyclopropane), 1.57 (2H, m, CH2- cyclopropane), 1.63~1.72 (2H, m, NHCH2CH 2CH2), 2.29 (9H, m, 3 × NCH2, ArCH3), 3.27~3.34 (2H, m, NHCH2), 3.53 (4H, m, CH2OCH2), 6.53~6.55 (1H, m, NH), 7.31 (1H, s, ArH), 7.41 (1H, d, ArH, J=8Hz), 7.70~7.78 (2H, m, ArH), 8.12~8.16 (2H, m, ArH), 8.22 (1H, d, ArH, J=5Hz), 8.40 (1H, d, ArH, J= 2.3Hz), 10.60 (1H, s, CONH), 10.80 (1H, s, CONH).
Embodiment 66
N- [4- (morpholinyl propoxyl group) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [2- (methylamino) pyrimidine - 4- yl] cyclopropane -1- formamido group] benzamide (II-23)
With II-d-12 (22.1mg, 0.1mmol) and N- [4- (morpholinyl propoxyl group) -3- (trifluoromethyl) phenyl] -4- Methyl -3-AB (V-c-6,32.8mg, 0.1mmol) is raw material, and the same II-1 of preparation method obtains white solid II- 23 48.8mg, yield 86.5%.ESI-MS:m/z:613 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.41 (2H, m, CH2- cyclopropane), 1.56 (2H, m, CH2- cyclopropane), 1.86-1.90 (2H, m, NCH2CH 2CH2O), 2.28 (3H, s, ArCH3), 2.35~2.45 (6H, m, 3 × NCH2), 2.81 (3H, d, NHCH3, J=4.0Hz), 3.57 (4H, s, CH2OCH2), 4.11-4.13 (2H, m, OCH2), 6.55 (1H, m, NH), 7.26 (1H, s, ArH), 7.28 (1H, d, ArH, J= 9.0Hz), 7.40 (1H, d, ArH, J=7.8Hz), 7.72 (1H, m, ArH), 7.98~8.08 (3H, m, ArH), 8.22~ 8.28 (1H, m, ArH), 10.30 (1H, s, CONH), 10.70 (1H, s, CONH).
Embodiment 67
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (methylamino) pyrimidine-4-yl] pentamethylene - 1- formamido group] benzamide (II-24)
With II-d-15 (25mg, 0.1mmol) and N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- aminobenzoic Amide (V-c-1,33mg, 0.1mmol) is raw material, and the same II-1 of preparation method obtains white solid II-24 44.8mg, yield 84.2%.ESI-MS:m/z:532 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.68 (4H, m, CH2- Cyclopentane), 2.21 (3H, s, ArCH3), 2.34 (3H, s, NHCH3), 2.72 (4H, m, CH2- cyclopentane), 6.61 (1H, m, NH), 7.08~7.14 (1H, m, ArH), 7.41~7.47 (1H, m, ArH), 7.71~7.74 (1H, m, ArH), 7.78~7.86 (1H, m, ArH), 8.10 (1H, dd, ArH, J=2.3Hz, J=8.8Hz), 8.24~8.26 (2H, m, ArH), 8.32~8.33 (1H, d, ArH, J=2.3Hz), 9.45 (1H, s, CONH), 10.67 (1H, s, CONH).
Embodiment 68
The chloro- 9- of 6- (tetrahydro -2H- pyrans -2- base) -9H- purine (III-a)
6-chloropurine 1.0g (6.5mmol) is added in 100mL eggplant-shape bottle, 3,4- dihydro -2H- pyrans 1.8mL (19mmol), p-methyl benzenesulfonic acid 0.033g (0.2mmol), analysis pure ethyl acetate 20mL dissolution.3h is stirred after being warming up to 75 DEG C, Reaction solution is cooled to room temperature, evaporating solvent under reduced pressure, column chromatographic isolation and purification obtains white solid III-a 1.35g, yield 87.6%, ESI-MS:m/z:239 [M+H]+。
Embodiment 69
2- [9- [tetrahydro -2H- pyrans -2- base] -9H- purine -6- base] diethyl malonate (III-b)
With III-a (20g, 83.6mmol) for raw material, the same I-b of preparation method obtains white solid III-b 17g, yield 56.2%, ESI-MS:m/z:363.1 [M+H]+。。
Embodiment 70
2- [9- [tetrahydro -2H- pyrans -2- base] -9H- purine -6- base] ethyl acetate (III-c)
With III-b (9.0g, 25mmol) for raw material, the same I-c of preparation method obtains faint yellow solid III-c 6.7g, yield 92.4%.ESI-MS:m/z:291.1 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.18 (3H, t, CH2CH 3, J= 7.1Hz), 1.58~1.65 (2H, m, pyran-H), 1.73~1.79 (1H, m, pyran-H), 1.98~2.03 (2H, m, Pyran-H), 2.34~2.40 (1H, m, pyran-H), 3.68~3.77 (1H, m, pyran-H), 4.03 (1H, d, pyran- H, J=11.3Hz), 4.12 (2H, q, CH 2CH3, J=7.0Hz), 4.18 (2H, s, CH2CO), 5.80 (1H, dd, pyran-H, J =2.1Hz, J=10.9Hz), 8.78 (1H, s, purine-H), 8.88 (1H, s, purine-H).
Embodiment 71
1- [9- (tetrahydro -2H- pyrans -2- base) -9H- purine -6- base] cyclopropane -1- ethyl acetate (III-d-1)
With III-c (6.7g, 23mmol) for raw material, the same I-d of preparation method obtains compound III-d-1 6.6g, yield 90.2%.ESI-MS:m/z:317.2 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.05 (3H, t, CH2CH 3, J= 14.2Hz), 1.60~1.63 (6H, m, CH2-pyran and CH2CH2- cyclopropane), 1.72~1.78 (1H, m, Pyran-H), 1.98~2.01 (2H, m, pyran-H), 2.33~2.37 (1H, m, pyran-H), 3.70~3.75 (1H, m, Pyran-H), 4.01 (1H, d, pyran-H, J=5.8Hz), 4.07 (2H, q, CH 2CH3, J=7.1Hz), 5.77 (1H, dd, Pyran-H), 8.73 (1H, s, purine-H), 8.83 (1H, s, purine-H).
Embodiment 72
2- methyl -2- [9- (tetrahydro -2H- pyrans -2- base) -9H- purine -6- base] ethyl propionate (III-d-2)
With III-c (3.0g, 10.3mmol) and iodomethane (5.87g, 41.3mmol) for raw material, the same I-d of preparation method is obtained Compound III-d-2 3.1g, yield 94.3%.ESI-MS:m/z:319.2 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.05 (3H, t, CH2CH 3, J=7Hz), 1.60~1.64 (2H, m, pyran-H), 1.68 (6H, s, 2 × CH3), 1.98~ 2.01 (4H, m, pyran-H), 3.72~3.73 (1H, m, pyran-H), 3.99~4.04 (1H, m, pyran-H), 4.06~ 4.10 (2H, q, CH 2CH3, J=7.0Hz), 5.82 (1H, s, pyran-H), 8.5 (1H, s, pyrine-H), 8.82 (1H, s, pyrine-H)。
Embodiment 73
1- [9- (tetrahydro -2H- pyrans -2- base) -9H- purine -6- base] pentamethylene -1- ethyl acetate (III-d-3)
With III-c (5.0g, 17.2mmol) and Isosorbide-5-Nitrae-dibromobutane (14.9g, 68.8mmol) for raw material, preparation method is same I-d obtains compound III-d-3 5.35g, yield 90.2%.ESI-MS:m/z:345 [M+H]+。1H-NMR (300MHz, DMSO- d6): δ 1.12 (3H, t, CH2CH 3, J=10.0Hz), 1.59~1.75 (7H, m, pyran-H and cyclopentane-H), 1.97~2.01 (6H, m, pyran-H and cyclopentane-H), 2.3~2.42 (1H, m, pyran-H), 3.68~ 3.74 (1H, m, pyran-H), 3.95~4.12 (1H, d, pyran-H), 4.09 (2H, q, CH 2CH3, J=10.0Hz), 5.79 ~5.81 (1H, d, pyran-H), 8.77 (1H, s, pyrine-H), 8.82 (1H, s, pyrine-H).
Embodiment 74
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [9- (tetrahydro -2H- pyrans -2- base) -9H- purine - 6- yl] cyclopropane -1- formamido group] benzamide (III-e-1)
With III-d-1 (0.2g, 0.63mmol) and V-c-1 (0.23g, 0.69mmol) for raw material, the same I-e- of preparation method 1, obtain light yellow solid III-e-1 0.32g, yield 83.6%.ESI-MS:m/z:599 [M+H]+。
Embodiment 75
N- (3- isopropyl phenyl) -4- methyl -3- [1- [9- (tetrahydro -2H- pyrans -2- base) -9H- purine -6- base] cyclopropyl Alkane -1- formamido group] benzamide (III-e-2)
With III-d-1 (0.2g, 0.63mmol) and N- (3- isopropyl phenyl) -4- methyl -3-AB (V-c- 3,0.19g, 0.69mmol) it is raw material, the same I-e-1 of preparation method obtains light yellow solid III-e-2 0.29g, yield 85.2%.ESI-MS:m/z:539.3 [M+H]+。
Embodiment 76
N- [4- chloro- 3- (trifluoromethyl) phenyl] fluoro- 3- of -4- [1- [9- (tetrahydro -2H- pyrans -2- base) -9H- purine -6- Base] cyclopropanecarbonyl amino] benzamide (III-e-3)
With III-d-1 (0.2g, 0.63mmol) and V-c-2 (0.23g, 0.69mmol) for raw material, the same I-e- of preparation method 1, obtain light yellow solid III-e-3 0.31g, yield 8.4%.ESI-MS:m/z:603 [M+H]+。
Embodiment 77
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [2- methyl -2- [9- (tetrahydro -2H- pyrans -2- base) - 9H- purine -6- base] propionamido] benzamide (III-e-4)
With III-d-2 (0.2g, 0.69mmol) and V-c-1 (0.25g, 0.76mmol) for raw material, the same I-e- of preparation method 1, obtain light yellow solid III-e-4 0.35g, yield 83.7%.ESI-MS m/z:601 [M+H]+。
Embodiment 78
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [9- (tetrahydro -2H- pyrans -2- base) -9H- purine - 6- yl] pentamethylene -1- formamido group] benzamide (III-e-5)
With III-d-3 (0.2g, 0.58mmol) and V-c-1 (0.21g, 0.64mmol) for raw material, the same I-e- of preparation method 1, obtain light yellow solid III-e-5 0.32g, yield 87.4%.ESI-MS:m/z:627.2 [M+H]+。
Embodiment 79
N- [4- (morpholinyl methyl) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [9- (tetrahydro -2H- pyrans -2- Base) -9H- purine -6- base] cyclopropane -1- formamido group] benzamide (III-e-6)
With III-d-1 (0.18g, 0.58mmol) and VIII-i (0.25g, 0.64mmol) for raw material, the same I- of preparation method E-1 obtains light yellow solid III-e-6 0.34g, yield 87.4%.ESI-MS:m/z:664 [M+H]+。
Embodiment 80
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (9H- purine -6- base) cyclopropane -1- formyl ammonia Base] benzamide (III-1)
III-e-1 0.30g is added in 50ml eggplant-shape bottle, using methanol as solvent, concentrated hydrochloric acid is added dropwise to dissolving, stirs 2h After filter, obtain white solid III-1 0.24g, yield 94.2%.ESI-MS:m/z:515.1 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.86~1.87 (2H, m, CH2- cyclopropane), 2.12~2.17 (2H, m, CH2- Cyclopropane), 2.41 (3H, s, ArCH3), 6.96 (1H, s, ArH), 7.22 (1H, t, ArH, J=8.2Hz), 7.34~ 7.41 (2H, m, ArH), 7.55~7.63 (2H, m, ArH), 8.61 (1H, s, purine-H), 8.93 (1H, s, purine-H), 10.13 (1H, s, NHCO), 11.15 (1H, s, NHCO), 13.51 (1H, s, purine-NH).
Embodiment 81
N- (3- isopropyl phenyl) -4- methyl -3- [1- (9H- purine -6- base) cyclopropane -1- formamido group] benzamide (III-2)
Using III-e-2 0.30g as raw material, the same III-1 of preparation method obtains white solid III-2 0.24g, yield 93.6%.ESI-MS:m/z:477.2 [M+H]+。1H-NMR (300MHz, DMSO-d6): (6H, d, the CH (C of δ 1.21H 3)2, J= 6.9Hz), 1.82 (2H, m, CH2- cyclopropane), 2.12 (2H, m, CH2- cyclopropane), 2.42 (3H, s, ArCH3), 2.82~2.91 (1H, m, CH(CH3)2), 6.97 (1H, d, ArH, J=6.8Hz), 7.27 (1H, t, ArH, J= 8.1Hz), 7.37 (1H, d, ArH, J=8.0Hz), 7.63~7.69 (3H, m, ArH), 8.28 (1H, s, ArH), 8.55 (1H, S, purine-H), 8.91 (1H, s, purine-H), 10.10 (1H, s, NHCO), 11.37 (1H, s, NHCO), 13.68 (1H, S, purine-NH).
Embodiment 82
N- [4- chloro- 3- (trifluoromethyl) phenyl] fluoro- 3- of -4- [1- (9H- purine -6- base) cyclopropane -1- formamido group] Benzamide (III-3)
Using III-e-3 0.30g as raw material, the same III-1 of preparation method obtains white solid III-3 0.26g, yield 94.3%.ESI-MS:m/z:519.1 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.87 (2H, m, CH2- Cyclopropane), 2.35 (2H, m, CH2- cyclopropane), 7.41~7.48 (3H, m, ArH), 7.88 (1H, d, ArH, J=7.4Hz), 7.91~7.94 (1H, m, ArH), 8.13 (1H, s, ArH), 8.58 (1H, s, purine-H), 8.97 (1H, s, Purine-H), 10.23 (1H, s, NHCO), 11.52 (1H, s, NHCO), 13.83 (1H, s, purine-NH).
Embodiment 83
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [2- methyl -2- (9H- purine -6- base) propionamido] Benzamide (III-4)
Using III-e-4 0.30g as raw material, the same III-1 of preparation method obtains white solid III-4 0.24g, yield 93.7%.ESI-MS:m/z:517.1 [M+H]+。1H-NMR (300MHz, DMSO-d6): 1.86 (6H, s, 2 × CH3), 2.17 (3H, s, ArCH3), 7.37 (1H, d, ArH .J=8.0Hz), 7.72 (1H, d, ArH, J=8.8Hz), 7.79 (1H, d, ArH, J=8.0Hz), 7.87 (1H, s, ArH), 8.16 (1H, dd, ArH, J=2.0Hz, J=8.0Hz), 8.40 (1H, d, ArH, J= 2.0Hz), 8.74 (1H, s, NHCO), 8.97 (1H, s, purine-H), 9.15 (1H, s, purine-H), 10.67 (1H, s, NHCO)。
Embodiment 84
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (9H- purine -6- base) pentamethylene -1- formyl ammonia Base] benzamide (III-5)
Using III-e-5 0.30g as raw material, the same III-1 of preparation method obtains white solid III-5 0.24g, yield 91.6%.ESI-MS m/z:543.1 [M+H]+。1H-NMR (300MHz, DMSO-d6): 1.73~1.77 (4H, m, Cyclopentane-H), 2.09 (3H, s, ArCH3), 2.51-2.68 (4H, m, cyclopentane-H), 7.34 (1H, d, ArH, J=8.0Hz), 7.70~7.77 (2H, m, ArH), 7.86 (1H, s, ArH), 8.14 (1H, d, ArH, J=8.0Hz), 8.38 (1H, s, ArH), 8.75 (1H, s, NHCO), 8.97 (1H, s, purine-H), 9.10 (1H, s, purine-H), 10.67 (1H, s, NHCO), 13.23 (1H, s, purine-NH).
Embodiment 85
N- [4- (morpholinyl methyl) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (9H- purine -6- base) cyclopropane - 1- formamido group] benzamide (III-6)
Using III-e-6 0.30g as raw material, the same III-1 of preparation method obtains white solid III-6 0.24g, yield 91.6%.ESI-MS:m/z:580 [M+H]+。1H-NMR (300MHz, DMSO-d6): 1.82~1.84 (2H, m, CH2- Cyclopropane), 2.11 (2H, m, CH2- cyclopropane), 2.38 (7H, s, CH2NCH2, ArCH3), 3.58~3.60 (6H, m, ArCH2N, CH2OCH2), 7.39 (1H, d, ArH, J=7.95Hz), 7.69~7.74 (2H, m, ArH), 8.06 (1H, D, ArH, J=8.34Hz), 8.20 (1H, s, ArH), 8.32 (1H, s, ArH), 8.56 (1H, s, purine-H), 8.91 (1H, S, purine-H), 10.47 (1H, s, NHCO), 11.38 (1H, s, NHCO), 13.65 (1H, s, purine-NH).
Embodiment 86
2- (2- bromopyridine -4- base) ethyl acetate (IV-a)
The bromo- 4- picoline (3.44g, 20mmol) of 2- and lithium diisopropylamine 2M/L are added in 250mL eggplant-shape bottle Tetrahydrofuran solution (20mL, 40mmol) adds anhydrous tetrahydro furan 100mL to dissolve, and diethyl carbonate is added after stirring 2h (2.84g, 24 mmol), are stirred at room temperature 10h, and TLC detects raw material point and disappears.Reaction solution is poured into saturated ammonium chloride solution 50mL, Ethyl acetate extracts (200mL × 3), merges organic layer, and saturated sodium chloride solution washs (100mL × 3), and anhydrous magnesium sulfate is dry Overnight.Excess of solvent is removed under reduced pressure, column chromatographic purifying obtains white solid IV-a 3.4g, yield 70.1%.ESI-MS:m/z: 266[M+Na]+。
Embodiment 87
1- (2- bromopyridine -4- base) cyclopropane -1- ethyl acetate (IV-b)
IV-a (3.40g, 14mmol) is added in 250mL eggplant-shape bottle, with anhydrous DMF 50mL dissolution, slowly adds under ice bath Enter sodium hydroxide (1.68g, 42mmol), stirs 30min, 1,2- Bromofume (3.20g, 16.8mmol) is slowly added to react In bottle, normal-temperature reaction 1h, TLC detect raw material point and disappear.Reaction solution is poured into saturated ammonium chloride solution 100mL, ethyl acetate extraction It takes (200mL × 3), merges organic layer, saturated sodium chloride solution washs (50mL × 3), and anhydrous magnesium sulfate is dried overnight.Decompression removes Excess of solvent is removed, column chromatographic purifying obtains transparent oil IV-b 2.5g, yield 65%.ESI-MS:m/z:292 [M+Na]+。
Embodiment 88
1- (2- cyanopyridine -4- base) cyclopropane -1- ethyl acetate (IV-c)
IV-b (2.5g, 9mmol), zinc cyanide (1.6g, 9mmol) and tetra-triphenylphosphine palladium are added in two neck bottle of 100mL (0.52g, 0.45mmol), anhydrous DMF 40mL dissolution, nitrogen protection, 90 DEG C are heated to reflux 2h, and TLC detects raw material point and disappears. It is poured into 50mL water dilute reaction solution.Gained liquid is poured into saturated ammonium chloride solution 100mL, ethyl acetate extraction (200mL × 3), merge organic layer, saturated sodium chloride solution washs (50mL × 3), and anhydrous magnesium sulfate is dried overnight.It is removed under reduced pressure extra molten Agent, column chromatographic purifying obtain IV-c 1.7g, yield 88%.ESI-MS:m/z:239 [M+Na]+。
Embodiment 89
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (2- cyano) pyridin-4-yl] cyclopropane -1- Formamido group] benzamide (IV-d-1)
IV-c (1.7g, 7.86mmol) is added in 250mL three-necked bottle, VII-b-2 (3.23g, 9.4mmol), with 80mL Dry toluene dissolves, nitrogen protection, and the toluene solution (2M, 11.8mL, 23.6mmol) of trimethyl aluminium is slowly added under ice bath, is removed Ice bath is removed, 80 DEG C of stirrings 5h, TLC is to slowly warm up to and detects raw material point disappearance.Extract reaction of going out, ethyl acetate extraction with 1M dilute hydrochloric acid (200 mL × 3), saturated sodium bicarbonate solution wash (100mL × 3), and anhydrous magnesium sulfate is dry.Excess of solvent is removed under reduced pressure, obtains Yellow solid IV-d-1 2.42g, yield 60%, ESI-MS m/z:536 [M+Na]+。
Embodiment 90
1- [- 4 base of 2- (carbamoyl) pyrimidine] cyclopropyl -1- ethyl acetate (IV-d-2)
IV-c (1.7g, 7.9mmol) is dissolved in anhydrous DMF 40mL, be slowly added under ice bath ammonium hydroxide (1.38g, 39.5mmol), hydrogen peroxide (30%, 2.3g, 20mmol) is added dropwise after stirring 30min, 2h is stirred at room temperature, TLC detection raw material point disappears It loses.Reaction solution is filtered, solid-like crude product is obtained, column chromatographic isolation and purification obtains solid IV-d-2 1.6g, yield 85%.ESI- MS:m/z:235 [M+H]+。
Embodiment 91
1- [2- (methylamino formamide) pyridin-4-yl] cyclopropane -1- ethyl acetate (IV-e)
It is that raw material is dissolved in anhydrous DMF 20ml with IV-d-2 (1.6g, 6.8mmol), adds NaH (60%, 7.5mmol), Iodomethane (0.97g, 6.8mmol) is added under conditions of ice bath after stirring 30min, water quenching reaction is added after reacting 30min. It washes (50mL × 2), ethyl acetate extracts (100mL × 2).Column chromatographic isolation and purification obtains IV-e 1.57g, yield 93%, ESI- MS:m/z:249 [M+H]+。
Embodiment 92
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (2- carbamyl) pyridin-4-yl] cyclopropyl Alkane -1- formamido group] benzamide (IV-1)
With IV-d-1 (2.42,4.7mmol) and N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- aminobenzoyl Amine (V-c-1,1.55g, 4.7mmol) is raw material, and the same II-1 of preparation method obtains IV-1 2.0g, yield 82%.ESI-MS:m/ Z:532 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.24~1.26 (2H, m, CH2), 1.51~1.56 (2H, m, CH2), 2.17 (3H, s, ArCH3), 7.42 (1H, d, ArH, J=7.8Hz), 7.55 (1H, dd, ArH, J=1.7Hz, J= 5.0Hz), 7.59~7.62 (1H, m, ArH), 7.68 (1H, s, NH 2), 7.71~7.73 (1H, m, ArH), 7.97 (1H, d, ArH, J=1.0Hz), 8.13 (1H, s, NH 2), 8.37 (1H, d, ArH, J=1.7Hz), 8.56 (1H, d, ArH, J= 5.0Hz), 8.64 (1H, d, ArH, J=7.8Hz), 8.82~8.85 (1H, m, ArH), 9.08 (1H, s, CONH), 10.54 (1H, s, CONH).
Embodiment 93
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (2- methyl-carbamoyl) pyridin-4-yl] ring Propane -1- formamido group] benzamide (IV-2)
With IV-e (1.57g, 6.3mmol) and N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- aminobenzoyl Amine (V-c-1,2.06g, 6.3mmol) is raw material, and the same II-1 of preparation method obtains IV-2 2g, yield 60%.ESI-MS:m/z: 546[M+H]+。1H-NMR (300MHz, DMSO-d6): δ 1.26~1.28 (2H, m, CH2), 1.52~1.58 (2H, m, CH2), 2.18 (3H, s, ArCH3), 2.82~2.83 (3H, d, NHCH 3), 7.39 (1H, d, ArH, J=8.0Hz), 7.61~7.62 (1H, m, ArH), 7.71 (1H, d, ArH, J=8.9Hz), 7.76~7.79 (1H, m, ArH), 7.82 (1H, s, ArH), 8.07 (1H, s, NH), 8.13 (1H, dd, ArH, J=2.1Hz, J=8.9Hz), 8.35 (1H, d, ArH, J=2.1Hz), 8.61 (1H, D, NH, J=4.8Hz), 8.81~8.83 (1H, m, ArH), 9.04 (1H, s, CONH), 10.58 (1H, s, CONH).
Embodiment 94
4- methyl-3-nitro chlorobenzoyl chloride (V-a-1)
4- methyl-3-nitro benzoic acid (1.81g, 10.0mmol) and 50mL thionyl chloride are added in 100mL eggplant-shape bottle, After back flow reaction 3h, vacuum distillation removes extra thionyl chloride, obtains yellow oil V-a-1 1.90g, yield 95.0%, directly Connect investment in next step.
Embodiment 95
The fluoro- 3- nitrobenzoyl chloride (V-a-2) of 4-
With the fluoro- 3- nitrobenzoic acid (1.85g, 10.0mmol) of 4- for raw material, the same V-a-1 of preparation method obtains yellow oily Object V-a-2 1.93g, yield 89.6%.
Embodiment 96
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl-3-nitro benzamide (V-b-1)
The chloro- 3- of 4- (trifluoromethyl) aniline (0.78g, 4mmol) and anhydrous triethylamine are added in 100mL eggplant-shape bottle (2.67g, 26.7mmol), anhydrous CH2Cl220mL dissolves, and stirs in ice bath.By V-a-1 (1.90g, 9.5mmol) with anhydrous CH2Cl250 mL dissolution, and instill wherein, 3h is stirred at room temperature, is disappeared through TLC detection raw material.Remove excess of solvent, column under reduced pressure (eluant, eluent is ethyl acetate: petroleum ether=50: 1), obtaining off-white powder V-b-1 1.10g, yield for chromatography purifying 76.9%.Mp:174~175 DEG C.ESI-MS:m/z:359.0 [M+H]+。1H-NMR (300MHz, CDCl3): δ 2.48 (3H, s, ArCH3), 7.52 (1H, d, ArH, J=8.7Hz), 7.69 (1H, dd, ArH, J=2.4Hz, J=9.0Hz), 8.00 (1H, d, ArH, J=8.7Hz), 8.24~8.30 (2H, m, ArH), 8.64 (1H, d, ArH, J=8.1Hz), 10.83 (1H, s, NHCO).
Embodiment 97
N- [4- chloro- 3- (trifluoromethyl) phenyl] fluoro- 3- nitrobenzamide (V-b-2) of -4-
With the chloro- 3- 5-trifluoromethylaniline (0.44g, 4mmol) of V-a-2 (1.93g, 9.0mmol) and 4- for raw material, preparation side The same V-b-1 of method obtains white solid V-b-2 1.19g, yield 81.2%.Mp:181~182 DEG C.ESI-MS:m/z:363.0 [M+ H]+。1H-NMR (300MHz, DMSO-d6): δ 7.68~7.75 (2H, m, ArH), 7.92 (1H, d, ArH, J=2.1Hz), 8.08 (1H, d, ArH, J=8.1Hz), 8.51~8.56 (2H, m, ArH), 10.82 (1H, s, NHCO).
Embodiment 98
N- (3- isopropyl phenyl) -4- methyl-3-nitro benzamide (V-b-3)
With V-a-1 (1.90g, 9.5mmol) and 3- isopropyl aniline (0.54g, 4mmol) for raw material, the same V- of preparation method B-1 obtains light yellow solid V-b-3 0.893g, yield 74.8%.Mp:102~104 DEG C.ESI-MS:m/z:299.1 [M+H]+。1H-NMR (300MHz, DMSO-d6): 1.22 (6H, d, CH (CH3)2, J=6.9Hz), 2.48 (3H, s, ArCH3), 2.82~ 2.93 (1H, m, CH (CH3)2), 7.03 (1H, d, ArH, J=7.5Hz), 7.29 (1H, t, ArH, J=8.4Hz), 7.62 (2H, d, ArH, J=1.8Hz), 7.98 (1H, d, ArH, J=8.4Hz), 8.27 (1H, dd, ArH, J=2.1Hz, J=8.4Hz), 8.64 (1H, d, ArH, J=2.1Hz), 10.49 (1H, s, NHCO).
Embodiment 99
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3-AB (V-c-1)
V-b-1 (0.97g, 3mmol), iron powder (0.54g, 9.6mmol), NH are added in 100mL eggplant-shape bottle4Cl (0.39g, 7.2mmol) and 75% ethyl alcohol 50mL is warming up to reflux 0.5h.Reaction solution is cooled to room temperature, filters and removes de-iron Powder, removes excess of solvent under reduced pressure, and column chromatographic isolation and purification obtains white solid V-c-1 0.654g, yield 66.3%.Mp:154~ 156℃.ESI-MS:m/z:329.0 [M+H]+。1H-NMR (300MHz, CDCl3): δ 2.24 (3H, s, ArCH3), 3.80 (2H, S, ArNH2), 7.13~7.18 (2H, m, ArH), 7.21 (1H, s, ArH), 7.48 (1H, d, ArH, J=8.7Hz), 7.88 (1H, d, ArH, J=8.7Hz), 7.94 (1H, s, ArH), 7.95 (1H, s, CONH).
Embodiment 100
N- [4- chloro- 3- (trifluoromethyl) phenyl] fluoro- 3-AB of -4- (V-c-2)
With V-b-2 (1.09g, 3mmol) for raw material, the same V-c-1 of preparation method obtains off-white powder V-c-2 0.722g, Yield 72.3%.Mp:174~175 DEG C.ESI-MS:m/z:333.0 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 5.43 (2H, s, ArNH2), 7.15 (2H, d, ArH, J=8.7Hz), 7.35 (1H, d, ArH, J=8.1Hz), 8.51~8.56 (2H, m, ArH), 10.82 (1H, s, NHCO).
Embodiment 101
N- (3- isopropyl phenyl) -4- methyl -3-AB (V-c-3)
With V-b-3 (0.84g, 3mmol) for raw material, the same V-c-1 of preparation method obtains off-white powder V-c-2 0.534g, Yield 66.2%.Mp:152~154 DEG C.ESI-MS m/z:269.1 [M+H]+。1H-NMR (300MHz, CDCl3): δ 1.26 (6H, d, (CH3)2CH, J=6.9Hz), 2.20 (3H, s, ArCH3), 2.90~2.93 (1H, m, (CH3)2CH), 3.77 (2H, s, ArNH2), 7.00 (1H, d, ArH, J=7.8Hz), 7.09~7.15 (2H, m, ArH), 7.22-7.29 (2H, m, ArH), 7.46 (1H, d, ArH, J=8.1Hz), 7.50 (1H, s, ArH), 7.82 (1H, s, CONH).
Embodiment 102
The chloro- 3- trifluoromethyl benzoyl chloride (VI-a) of 4-
Using the chloro- 3- trifluoromethylbenzoic acid of 4- as raw material, the same V-a-1 of preparation method obtains yellow oil VI-a, yield 92.8%.
Embodiment 103
N- (4- methyl-3-nitro phenyl)-[the chloro- 3- of 4- (trifluoromethyl)] benzamide (VI-b)
With VI-a-1 and 4- methyl-3-nitro aniline (0.61g, 4mmol) for raw material, the same V-b-1 of preparation method is obtained white Solid VI-b-1 1.07g, yield 82.6%.Mp:165~167 DEG C.ESI-MS:m/z:324.0 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 2.45 (3H, s, ArCH3), 7.51 (1H, d, ArH, J=7.8Hz), 7.76 (1H, t, ArH, J= 7.9Hz), 8.01 (1H, d, ArH, J=8.5Hz), 8.05 (1H, d, ArH, J=8.4Hz), 8.21 (1H, s, ArH), 8.29 (1H, dd, ArH, J=2.1Hz, J=8.4Hz), 8.67 (1H, d, ArH, J=2.1Hz), 10.80 (1H, s, NHCO).
Embodiment 104
N- (3- amino -4- aminomethyl phenyl) -4- chloro- 3- (trifluoromethyl) benzamide (VI-c)
Using VI-b as raw material, the same V-c-1 of preparation method obtains off-white powder VI-c 0.736g, yield 83.4%.Mp: 157~159 DEG C.ESI-MS:m/z:294.1 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 2.03 (3H, s, ArCH3), 4.87 (2H, s, ArNH2), 6.80~6.89 (2H, m, ArH), 7.11 (1H, d, ArH, J=2.1Hz), 7.76 (1H, t, ArH, J =7.8Hz), 7.94 (1H, d, ArH, J=7.8Hz), 8.21~8.25 (2H, m, ArH), 10.13 (1H, s, CONH).
Embodiment 105
N- [4- chloro- 3- (trifluoromethyl) phenyl]-N '-(4- methyl-3-nitro phenyl) urea (VII-a)
Be added in 100mL eggplant-shape bottle the chloro- 3- 5-trifluoromethylaniline (2g, 10.2mmol) of 4- and CDI (1.76g, 10.9mmol), anhydrous methylene chloride 30mL dissolves.Stir 16h at room temperature, be added 4- methyl-3-nitro aniline (1.55g, 10.2mmol), 18h is stirred.TLC detects reaction raw materials and disappears, and filters, is washed with a small amount of methylene chloride, light yellow admittedly dry Body VII-a 3.35g, yield 95.6%.Mp:219~220 DEG C.ESI-MS:m/z:373.0 [M+H]+。1H-NMR (300MHz, DMSO-d6): δ 2.46 (3H, s, ArCH3), 7.42 (1H, d, ArH, J=8.4Hz), 7.58~7.69 (3H, m, ArH), 8.10 ~8.11 (1H, m, ArH), 8.28 (1H, d, ArH, J=7.6Hz), 9.26 (1H, s, NHCONH), 9.31 (1H, s, NHCONH)。
Embodiment 106
N- [4- chloro- 3- (trifluoromethyl) phenyl]-N '-(4- methyl -3- aminophenyl) urea (VII-b)
VI-a-2 (1.12g, 3mmol) is added in 100mL eggplant-shape bottle, the same V-c-1 of preparation method obtains white solid VII- B 0.720g, yield 69.8%.Mp:199~201 DEG C.ESI-MS:m/z:344.0 [M+H]+。1H-NMR (300MHz, DMSO- d6): δ 1.98 (3H, s, ArCH3), 4.76 (2H, s, ArNH2), 6.55 (1H, d, ArH, J=8.1Hz), 6.78 (1H, d, ArH, J=8.4Hz), 6.87 (1H, d, ArH, J=2.1Hz), 7.54~7.63 (2H, m, ArH), 8.18 (1H, d, ArH, J= 2.1Hz), 9.18 (1H, s, NHCONH), 9.82 (1H, s, NHCONH)。
Embodiment 107
4- [4- nitro -2- (trifluoromethyl) phenyl] morpholine (VIII-a-1)
With the fluoro- 3- trifluoromethyl nitrobenzene 0.42g (2mmol) of 4- and morpholine 0.9mL (10mmol) for raw material, dimethyl is sub- Sulfone 5mL dissolution, 100 DEG C are heated 5 hours.It is cooling, evaporating solvent under reduced pressure, give light yellow oil VIII-a-1, without further purification directly Connect throwing in next step.
Embodiment 108
1- methyl -4- [4- nitro -2- (trifluoromethyl) phenyl] piperazine (VIII-a-2)
With the fluoro- 3- trifluoromethyl nitrobenzene 0.42g (2mmol) of 4- and N methyl piperazine 1.1mL (10mmol) for raw material, system The same VIII-a-1 of Preparation Method, give light yellow oil VIII-a-2 0.45g are directly thrown in next step without further purification.
Embodiment 109
4- [4- amino -2- (trifluoromethyl) phenyl] morpholine (VIII-b-1)
With VIII-a-1 2.8g (10mmol) for raw material, the same V-c-1 of preparation method obtains light yellow solid VIII-b-1 2.3g, yield 92.4%.
Embodiment 110
1- methyl -4- [4- amino -2- (trifluoromethyl) phenyl] piperazine (VIII-b-2)
With VIII-a-2 2.9g (10mmol) for raw material, the same V-c-1 of preparation method obtains light yellow solid VIII-b-2 2.3g, yield 87.8%.
Embodiment 111
N- [4- morpholinyl -3- (trifluoromethyl) phenyl] -4- methyl-3-nitro benzamide (VIII-c-1)
With VIII-b-1 2.5g (10mmol) for raw material, the same V-b-1 of preparation method obtains light yellow solid VIII-c-1 3.8g, yield 91.8%.
Embodiment 112
N- [4- (4- methylpiperazine-1-yl) -3- (trifluoromethyl) phenyl] -4- methyl-3-nitro benzamide (VIII- c-2)
With VIII-b-2 2.6g (10mmol) for raw material, the same V-b-1 of preparation method obtains light yellow solid VIII-c-2 3.9g, yield 93.5%.
Embodiment 113
N- [4- morpholinyl -3- (trifluoromethyl) phenyl] -4- methyl -3-AB (VIII-d-1)
With VIII-c-1 4.1g (10mmol) for raw material, the same V-c-1 of preparation method obtains light yellow solid VIII-d-1 3.2g, yield 84.8%, ESI-MS:m/z:380 [M+H]+。
Embodiment 114
N- [4- (4- methylpiperazine-1-yl) -3- (trifluoromethyl) phenyl] -4- methyl -3-AB (VIII- d-2)
With VIII-c-2 4.2g (10mmol) for raw material, the same V-c-1 of preparation method obtains light yellow solid VIII-d-2 3.3g, yield 83.5%, ESI-MS:m/z:393 [M+H]+。
Embodiment 115
1- methyl -4- [4- nitro -2- (trifluoromethyl) phenoxy group] piperidines (VIII-e-1)
1- methyl -4- piperidine alcohols 1.15g (10mmol) is dissolved in DMF10mL, is added sodium hydrogen 0.48g (12mmol), The fluoro- 3- trifluoromethyl nitrobenzene 0.42g (2mmol) of 4-, 100 DEG C of heating 5h are added after 0.5h.It is cooled to room temperature, washes (50mL × 2), ethyl acetate extracts (100mL × 2), evaporating solvent under reduced pressure, give light yellow oil VIII-e-1, without further purification directly It throws in next step.
Embodiment 116
1- methyl -4- [4- nitro -2- (trifluoromethyl) Phenoxymethyl] piperidines (VIII-e-2)
With 1- methyl -4- piperidine carbinols 1.29g (10mmol) for raw material, the same VIII-e-1 of preparation method obtains light yellow oil Shape object VIII-e-2 is directly thrown in next step without further purification.
Embodiment 117
4- [3- [4- nitro -2- (trifluoromethyl) phenoxy group] propyl] morpholine (VIII-e-3)
With 3- (4- morpholinyl) -1- propyl alcohol 1.45g (10mmol) for raw material, the same VIII-e-1 of preparation method is obtained light yellow Grease VIII-e-3 is directly thrown in next step without further purification.
Embodiment 118
1- methyl -4- [4- amino -2- (trifluoromethyl) phenoxy group] piperidines (VIII-f-1)
With VIII-e-1 2.8g (10mmol) for raw material, the same V-c-1 of preparation method obtains light yellow solid VIII-f-1 2.45g, yield 89.4%.
Embodiment 119
1- methyl -4- [4- amino -2- (trifluoromethyl) Phenoxymethyl] piperidines (VIII-f-2)
With VIII-e-2 3.18g (10mmol) for raw material, the same V-c-1 of preparation method obtains light yellow solid VIII-f-2 2.49g, yield 86.4%.
Embodiment 120
4- [3- [4- amino -2- (trifluoromethyl) phenoxy group] propyl] morpholine (VIII-f-3)
With VIII-e-3 2.9g (10mmol) for raw material, the same V-c-1 of preparation method obtains light yellow solid VIII-f-3 2.6g, yield 85.2%.
Embodiment 121
N- [4- [1- (methyl piperidine -4- base) oxygroup] -3- (trifluoromethyl) phenyl] -4- methyl-3-nitro benzamide (VIII-g-1)
With VIII-f-1 2.74g (10mmol) for raw material, the same V-b-1 of preparation method obtains light yellow solid VIII-g-1 3.74g, yield 85.6%.
Embodiment 122
N- [4- [(1- methyl piperidine -4- base) methoxyl group] -3- (trifluoromethyl) phenyl] -4- methyl-3-nitro benzoyl Amine (VIII-g-2)
With VIII-f-2 2.88g (10mmol) for raw material, the same V-b-1 of preparation method obtains light yellow solid VIII-g-1 3.95g, yield 87.6%.
Embodiment 123
N- [4- (morpholinyl propoxyl group) -3- (trifluoromethyl) phenyl] -4- methyl-3-nitro benzamide (VIII-g- 3)
With VIII-f-3 3.04g (10mmol) for raw material, the same V-b-1 of preparation method obtains light yellow solid VIII-g-3 4.08g, yield 87.2%.
Embodiment 124
N- [4- [1- (methyl piperidine -4- base) oxygroup] -3- (trifluoromethyl) phenyl] -4- methyl -3-AB (VIII-h-1)
With VIII-g-1 4.37g (10mmol) for raw material, the same V-c-1 of preparation method obtains light yellow solid VIII-h-1 3.52g, yield 86.4%, ESI-MS:m/z:408 [M+H]+。
Embodiment 125
N- [4- [(1- methyl piperidine -4- base) methoxyl group] -3- (trifluoromethyl) phenyl] -4- methyl -3- aminobenzoyl Amine (VIII-h-2)
With VIII-g-2 4.51g (10mmol) for raw material, the same V-c-1 of preparation method obtains light yellow solid VIII-h-2 3.61g, yield 85.7%, ESI-MS m/z:422 [M+H]+。
Embodiment 126
N- [4- (morpholinyl propoxyl group) -3- (trifluoromethyl) phenyl] -4- methyl -3-AB (VIII-h- 3)
With VIII-g-3 4.67g (10mmol) for raw material, the same V-c-1 of preparation method obtains light yellow solid VIII-h-3 3.81g, yield 87.2%, ESI-MS:m/z:438 [M+H]+。
Embodiment 127
1- bromomethyl -4- nitro -2- (trifluoromethyl) benzene (VIII-i)
By 1- methyl -4- nitro -2- (trifluoromethyl) benzene 2.05g (10mmol) and N-bromosuccinimide 2.14g (12mmol) is dissolved in 1,2- dichloroethanes 30mL, back flow reaction 5h.It is cooled to room temperature, evaporating solvent under reduced pressure, washes (100mL × 2), ethyl acetate extract (200mL × 2).Evaporating solvent under reduced pressure, column chromatographic isolation and purification obtain light yellow solid VIII-i 2.45g, yield 86.4%, ESI-MS:m/z:284 [M+H]+。
Embodiment 128
4- [4- nitro -2- (trifluoromethyl) benzyl] morpholine (VIII-g)
VIII-i 1.14g (4mmol) and morpholine 0.5mL (6mmol) are dissolved in THF20mL, with triethylamine 0.9mL (6mmol) is acid binding agent, and flow back 2h.It is cooled to room temperature, evaporating solvent under reduced pressure, washes (100mL × 2), ethyl acetate extracts (200mL × 2), evaporating solvent under reduced pressure, give light yellow oil VIII-j are directly thrown in next step without further purification.
Embodiment 129
4- (morpholine -4- ylmethyl) -3- (trifluoromethyl) aniline (VIII-k)
With VIII-g 1.16g (4mmol) for raw material, the same V-c-1 of preparation method obtains yellow solid VIII-k 0.96g, receives Rate 92.3%, ESI-MS:m/z:261 [M+H]+。
Embodiment 130
N- [4- (morpholine -4- ylmethyl) -3- (trifluoromethyl) phenyl] -4- methyl-3-nitro benzamide (VIII-l)
With VIII-k 1g (4mmol) for raw material, the same V-b-1 of preparation method obtains light yellow solid VIII-l 1.43g, receives Rate 84.3%.
Embodiment 131
N- [4- (morpholine -4- ylmethyl) -3- (trifluoromethyl) phenyl] -4- methyl -3-AB (VIII-m)
With VIII-l 1.7g (4mmol) for raw material, the same V-c-1 of preparation method obtains light yellow solid VIII-m 1.36g, Yield 86.4%, ESI-MS:m/z:394 [M+H]+。

Claims (8)

1. the compound of logical formula (I) or its pharmaceutically acceptable salt:
Wherein Q is phonetic selected from replacing for 7H- pyrrolo- [2,3-d] pyrimidine-4-yl shown in above formula, 6- substituted pyrimidines -4- base, 2- Pyridine -4- base, 9H- purine -6- base and 2- substituted pyridines -4- base；
Wherein R1、R2Connection forms the carbocyclic ring of 3-6 carbon atom；
R3Selected from hydrogen, alkyl, halogen, cyano, alkoxy, alkylthio group；
R4、R5It is each independently selected from hydrogen, halogen, cyano, alkyl, phenyl, naphthalene, acenaphthenyl, tetralyl or Het1Substituent group, Wherein the alkyl can be further replaced one or more halogens, cyano, the Het1Substituent group is selected from pyrazolyl, furans Base, thienyl, pyridyl group, pyrazinyl, pyrimidine radicals；Or following aliphatic heterocycle: nafoxidine base, morpholinyl, piperazinyl, piperazine Piperidinyl；Or following substituent group: morpholinyl alkyl, morpholinylalkoxy groups, morpholinyl alkyl amino, piperazinyl alkyl, piperazinyl Alkyl amino, piperazinyl alkoxy, piperidinylalkyl group, piperidyl alkoxy, piperidinylalkyl group amino；The phenyl, naphthalene, acenaphthene Base or tetralyl are respectively optionally replaced by 1,2 or 3 substituent group, each substituent group independently selected from hydrogen, alkyl, cyano, halogen, Hydroxyl, sulfydryl, alkoxy, alkylthio group, alkyl amino, alkoxyalkyl, phenyl, naphthalene, acenaphthenyl, tetralyl, phenylalkyl, Naphthylalkyl, acenaphthenyl alkyl, tetralyl alkyl；
R6Selected from H ,-NHR ,-NH (CH2)1-6OR、-NH(CH2)1-6SR、-NH(CH2)1-6NHR、-NH(CH2)1-6NR2、- NHCONHR、-CONHR、-NH(CH2)1-6CO2H、-NH(CH2)1-6Het2With-O (CH2)1-6OR, the R are selected from hydrogen or alkyl, institute State Het2Selected from piperidyl, pyrrole radicals, pyrazolyl, imidazole radicals, furyl, morpholinyl, thienyl, oxazolyl, isoxazolyl, thiophene Oxazolyl, isothiazolyl, pyridyl group, pyrimidine radicals, piperazinyl, substituted piperazinyl, pyrazinyl or pyridazinyl monocyclic heterocycles；Or it is selected from Quinolyl, quinoxalinyl, indyl, benzimidazolyl, benzoxazolyl, benzo isoxazolyl, benzothiazolyl, benzisothia Oxazolyl, benzofuranyl, benzothienyl, 2,3- dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxane or benzo [d] [1,3] dioxy penta The bicyclic heterocycle of ring group；Each monocycle or bicyclic heterocycle are optionally replaced by 1,2 or 3 substituent group, each substituent group be independently selected from halogen, Hydroxyl, alkyl or alkoxy, or it is selected from C3-C8Aliphatic carbocyclic ring, or selected from following substituent group: nafoxidine base, morpholine Base, alkoxy morpholinyl, piperazinyl, piperidyl, alkylaminopiperidine base；
L each independently represents CONH, NHCO, NHCONH, NHSO2Or SO2NH；
Abovementioned alkyl is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom；It or is full with the ring-type of 3-6 carbon atom And alkyl；Or the cyclic annular saturation with 3-6 carbon atom for linear chain or branched chain saturated hydrocarbyl of the connection with 1-6 carbon atom Alkyl；
Alkoxy is the linear chain or branched chain saturation oxyl with 1-6 carbon atom, or is full with the ring-type of 3-6 carbon atom And oxyl, or it is full to connect the ring-type with 3-6 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom And oxyl；
Alkylthio group is the linear chain or branched chain saturation sulfenyl with 1-6 carbon atom, or is full with the ring-type of 3-6 carbon atom And sulfenyl；Or it is full to connect the ring-type with 3-6 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom And sulfenyl.
2. logical formula (I) compound according to claim 1 or its pharmaceutically acceptable salt, wherein R1、R2Connection forms 3-6 The carbocyclic ring of carbon atom；
R3Indicate alkyl or halogen；
R4、R5Each independently represent hydrogen, halogen, cyano, alkyl, phenyl, naphthalene, acenaphthenyl, tetralyl or Het1Substituent group, Wherein the alkyl can be further replaced one or more halogens, cyano, Het1Selected from aliphatic heterocycle: morpholinyl, piperazine Piperazine base, piperidyl；Or following substituent group: morpholinyl alkyl, morpholinylalkoxy groups, morpholinyl alkyl amino, piperazinyl alkyl, Piperazinyl alkyl amino, piperazinyl alkoxy, piperidinylalkyl group, piperidyl alkoxy, piperidinylalkyl group amino；
R6Selected from H ,-NHR ,-NH (CH2)1-6OR、-NH(CH2)1-6NHR、-NH(CH2)1-6NR2、-NHCONHR、-CONHR、-NH (CH2)1-6CO2H、-NH(CH2)1-6Het2Or-O (CH2)1-6OR, the R are selected from hydrogen or alkyl；The Het2Selected from nafoxidine Base, morpholinyl, alkoxy morpholinyl, piperazinyl, piperidyl, alkylaminopiperidine base；
L is selected from CONH, NHCO, NHCONH, NHSO2Or SO2NH。
3. logical formula (I) compound according to claim 1 or its pharmaceutically acceptable salt, wherein R1、R2Connection forms 3 yuan or 5 The carbocyclic ring of member；
R3Indicate methyl or halogen；
R4、R5Be each independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, morpholinyl, morpholine methyl, 2- (morpholine -1- base) ethyoxyl, 3- (morpholine -1- base) propoxyl group, piperidyl, piperidin-4-ylmethyl, piperazinyl；
R6Indicate methylamino, methoxyethylamino, dimethylaminopropylamino, hydroxyethylamino, 2- (nafoxidine -1- base) ethyl Amino, 2- (nafoxidine -1- base) propylcarbamic, 2- (piperidin-1-yl) ethylamino, 1- methyl piperidine -4- base amino, 1- first Phenylpiperidines -4- base methylamino, 2- (4- methylpiperazine-1-yl) ethylamino, 3- (morpholinyl -1- base) propylcarbamic, amino first Acyl group or methyl-carbamoyl；
L indicates CONH, NHCO or NHCONH.
4. following any compound or its pharmaceutically acceptable salt:
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) cyclopropane - 1- formamido group] benzamide (I-1),
N- [3- [1- (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) cyclopropane -1- formamido group] -4- aminomethyl phenyl] chloro- 3- of -4- (trifluoromethyl) benzamide (I-2),
N- [5- [4- chloro- 3- (trifluoromethyl) phenyl urea groups] -2- aminomethyl phenyl] -1- (7H- pyrrolo- [2,3-d] pyrimidine -4- Base) -1- cyclopropane carboxamide (I-3),
N- [4- morpholinyl -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) cyclopropyl Alkane -1- formamido group] benzamide (I-4),
[(7H- pyrrolo- [2,3-d] is phonetic by 1- by -4- methyl -3- by N- [4- (4- methylpiperazine-1-yl) -3- (trifluoromethyl) phenyl] Pyridine -4- base) cyclopropane -1- formamido group] benzamide (I-5),
N- [4- (1- methyl piperidine -4- base oxygroup) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (7H- pyrrolo- [2,3- D] pyrimidine-4-yl) cyclopropane -1- formamido group] benzamide (I-6),
N- [4- [(1- methyl piperidine -4- base) methoxyl group] -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) cyclopropane -1- formamido group] benzamide (I-7),
[(7H- pyrrolo- [2,3-d] is phonetic by 1- by -4- methyl -3- by N- [4- (morpholinyl propoxyl group) -3- (trifluoromethyl) phenyl] Pyridine -4- base) cyclopropane -1- formamido group] benzamide (I-8),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (6- methylaminopyrimidin -4- base) cyclopropane -1- formyl ammonia Base] benzamide (II-1),
N- [3- [1- [6- (methylamino) pyrimidine-4-yl] cyclopropane -1- formamido group] -4- aminomethyl phenyl] chloro- 3- (trifluoro of -4- Methyl) benzamide (II-2),
N- [5- [3- [4- chloro- 3- (trifluoromethyl) phenyl] urea groups] -2- aminomethyl phenyl] -1- [6- (methylamino) pyrimidine-4-yl] Cyclopropane -1- formamide (II-3),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (2- hydroxyethylamino) pyrimidine-4-yl] cyclopropane - 1- formamido group] benzamide (II-5),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- [2- (methoxyethylamino) pyrimidine-4-yl] cyclopropyl Alkane -1- formamido group] benzamide (II-6),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- [3- (dimethylaminopropylamino) pyrimidine-4-yl] ring Propane -1- formamido group] benzamide (II-7),
N- [4- chloro- 3- (trifluoromethyl) phenyl] fluoro- 3- of -4- [1- [6- [1- (methyl piperidine -4- base) methylamino] pyrimidine -4- Base] cyclopropane -1- formamido group] benzamide (II-8),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- [2- (nafoxidine -1- base) ethylamino] pyrimidine -4- Base] cyclopropane -1- formamido group] benzamide (II-9),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- [2- (piperidin-1-yl) ethylamino] pyrimidine-4-yl] Cyclopropane -1- formamido group] benzamide (II-10),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (the third amino of morpholinyl) pyrimidine-4-yl] cyclopropyl Alkane -1- formamido group] benzamide (II-11),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (1- methyl piperidine -4- base amino) pyrimidine-4-yl] Cyclopropane -1- formamido group] benzamide (II-12),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- [(1- methyl piperidine base -4- base) methylamino] pyrimidine - 4- yl] cyclopropane -1- formamido group] benzamide (II-13),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- [2- (4- methylpiperazine-1-yl) ethylamino] pyrimidine - 4- yl] cyclopropane -1- formamido group] benzamide (II-14),
[[6- (methylamino) is phonetic by 1- by -4- methyl -3- by N- [4- [1- (methyl piperidine -4- base) oxygroup] -3- (trifluoromethyl) phenyl] Pyridine -4- base] cyclopropane -1- formamido group] benzamide (II-15),
N- [4- [(1- methyl piperidine -4- base) methoxyl group] -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (methylamino) Pyrimidine-4-yl] cyclopropane -1- formamido group] benzamide (II-16),
N- [4- (morpholinyl propoxyl group) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (methylamino) pyrimidine-4-yl] Cyclopropane -1- formamido group] benzamide (II-17),
N- [4- (morpholinyl methyl) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (methylamino) pyrimidine-4-yl] cyclopropyl Alkane -1- formamido group] benzamide (II-18),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [2- (methylamino) pyrimidine-4-yl] cyclopropane -1- formyl Amino] benzamide (II-20),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [2- [the third amino of 3- (dimethylamino)] pyrimidine-4-yl] ring Propane -1- formamido group] benzamide (II-21),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [2- [the third amino of 3- (morpholinyl)] pyrimidine-4-yl] cyclopropyl Alkane -1- formamido group] benzamide (II-22),
N- [4- (morpholinyl propoxyl group) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [2- (methylamino) pyrimidine-4-yl] Cyclopropane -1- formamido group] benzamide (II-23),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (methylamino) pyrimidine-4-yl] pentamethylene -1- first Acylamino-] benzamide (II-24),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (9H- purine -6- base) cyclopropane -1- formamido group] benzene Formamide (III-1),
N- (3- isopropyl phenyl) -4- methyl -3- [1- (9H- purine -6- base) cyclopropane -1- formamido group] benzamide (III-2),
N- [4- chloro- 3- (trifluoromethyl) phenyl] fluoro- 3- of -4- [1- (9H- purine -6- base) cyclopropane -1- formamido group] benzene first Amide (III-3),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (9H- purine -6- base) pentamethylene -1- formamido group] benzene Formamide (III-5),
N- [4- (morpholinyl methyl) -3- (trifluoromethyl) phenyl] -4- methyl -3- [1- (9H- purine -6- base) cyclopropane -1- first Acylamino-] benzamide (III-6),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (2- carbamyl) pyrimidine-4-yl] cyclopropane -1- Formamido group] benzamide (IV-1),
N- [4- chloro- 3- (trifluoromethyl) phenyl] -4- methyl -3- [1- [6- (2- methyl-carbamoyl) pyrimidine-4-yl] cyclopropyl Alkane -1- formamido group] benzamide (IV-2).
5. logical formula (I) compound according to claim 1 or its pharmaceutically acceptable salt and according to claim 4ization Object or its pharmaceutically acceptable salt are closed, wherein the pharmaceutically acceptable salt is the acid that the compound and following acid are formed Addition salts: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, naphthalene sulfonic acids, citric acid, tartaric acid, lactic acid, acetone Acid, acetic acid, maleic acid, benzene sulfonic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or tussol；Or described pharmaceutically may be used The salt of receiving is the salt that the compound and following inorganic base are formed: alkali metal cations, alkaline earth metal cation or ammonium sun Ion.
6. a kind of pharmaceutical composition, wherein logical formula (I) compound or its pharmaceutically acceptable salt and medicine containing claim 1 Acceptable carrier on, or the compound containing claim 4 or its pharmaceutically acceptable salt and pharmaceutically acceptable Carrier.
7. the compound of logical formula (I) according to claim 1 or the compound of its pharmaceutically acceptable salt and claim 4 Or its pharmaceutically acceptable salt is preparing the use in the drug for preventing or treating disease related with Raf kinase On the way.
8. purposes according to claim 7, wherein disease related with Raf kinase be melanoma, liver cancer, kidney, Acute leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, cutaneum carcinoma, colorectal cancer, cancer of pancreas, oophoroma, cream Gland cancer, myelodysplastic syndrome, the cancer of the esophagus, gastric cancer or celiothelioma.
CN201610158137.9A 2016-03-16 2016-03-16 Novel aryl amide Raf kinase and its preparation method and application Active CN105801584B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610158137.9A CN105801584B (en) 2016-03-16 2016-03-16 Novel aryl amide Raf kinase and its preparation method and application

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610158137.9A CN105801584B (en) 2016-03-16 2016-03-16 Novel aryl amide Raf kinase and its preparation method and application

Publications (2)

Publication Number Publication Date
CN105801584A CN105801584A (en) 2016-07-27
CN105801584B true CN105801584B (en) 2019-03-05

Family

ID=56454402

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610158137.9A Active CN105801584B (en) 2016-03-16 2016-03-16 Novel aryl amide Raf kinase and its preparation method and application

Country Status (1)

Country Link
CN (1) CN105801584B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7230041B2 (en) 2017-10-26 2023-02-28 ザイノミック・ファーマシューティカルズ・インコーポレイテッド Crystalline salt of B-RAF kinase inhibitor

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6432949B1 (en) * 1998-08-04 2002-08-13 Astrazeneca Ab Amide derivatives useful as inhibitors of the production of cytokines
US8183248B2 (en) * 2005-05-13 2012-05-22 Irm Llc Substituted pyrrolo[2,3-d]pyrimidines and compositions as protein kinase inhibitors
CN1321150C (en) * 2005-09-12 2007-06-13 上海汽车集团股份有限公司 Thermoplastic expanded NVH material and its production method
WO2008144253A1 (en) * 2007-05-14 2008-11-27 Irm Llc Protein kinase inhibitors and methods for using thereof
CN103550138B (en) * 2013-10-29 2015-11-25 中国药科大学 A kind of sorafenib organogel and preparation method thereof

Also Published As

Publication number Publication date
CN105801584A (en) 2016-07-27

Similar Documents

Publication Publication Date Title
JP6286472B2 (en) Novel 3,5-disubstituted-3H-imidazo [4,5-B] pyridine compounds and 3,5-disubstituted-3H- [1,2,3] triazolo [4,5-B as protein kinase modulators ] Pyridine compounds
JP2021121219A (en) Protein kinase conjugates and inhibitors
CN102099352B (en) STAT3 inhibitor containing quinolinecarboxamide derivative as active ingredient
CN105315285B (en) 2,4 2 substitution 7H pyrrolo-es [2,3 d] pyrimidine derivatives, its preparation method and purposes pharmaceutically
KR102260403B1 (en) Heterocyclic derivatives and use thereof
CN107231802B (en) Heterocyclic derivatives and use thereof
CN101568529A (en) Heteroaryl-heteroaryl compounds as cdk inhibitors for the treatment of cancer, inflammation and viral infections
US20120101079A1 (en) Substituted 6-amino-nicotinamides as kcnq2/3 modulators
CN101568530A (en) Indol-4-yl-pyrimidinyl-2-yl-amine derivatives and use thereof as cyclin dependant kinase inhibitors
JP2015524448A (en) Alkynyl heteroaromatic compounds and their applications
CA2802130C (en) Cyanoquinoline derivatives
TWI748996B (en) Pyrimidine seven-membered ring compound, preparation method thereof, medicinal composition and application thereof
CN102725287A (en) 1,3,4-oxadiazole-2-carboxamide compound
CN109810041A (en) Halogenated allyl amine SSAO/VAP-1 inhibitor and its application
KR20090061041A (en) Nicotinic acid derivatives as modulators of metabotropic glutamate receptors
CN103214481B (en) Novel imidazole also [1,2-a] pyridine compounds and their, its preparation method, comprise the medical composition and its use of this compounds
US9168259B2 (en) Substituted 6-amino-nicotinamides as KCNQ2/3 modulators
CN106565674A (en) Octahydrocyclopentano[c]pyrrole derivatives, and preparation methods and medicinal application thereof
CN104822658B (en) It is used as the fused tricyclic amides compound of a variety of kinase inhibitors
CN105801584B (en) Novel aryl amide Raf kinase and its preparation method and application
JP2020506226A (en) Amide compounds and uses thereof
CN109970717A (en) 4- (cycloaliphatic ring and pyrimidine/pyridine replaces) amino -1H-3- pyrazole carboxamides FLT3 inhibitor and application thereof
CN102174035B (en) Aromatic dihydrazide type PLK1 (Polo-like Kinase 1) inhibitor and applications thereof
CN102558172B (en) 5,8-bis-replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof, Preparation Method And The Use
CN109641909A (en) The mechanism target and its treatment use of rapamycin signal pathway inhibitor

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant