CN105859618B - (2H, the 4H) diketone of isoquinolin 1,3 and its preparation method and purposes of the nitrile group containing cycloalkyl - Google Patents

(2H, the 4H) diketone of isoquinolin 1,3 and its preparation method and purposes of the nitrile group containing cycloalkyl Download PDF

Info

Publication number
CN105859618B
CN105859618B CN201610244141.7A CN201610244141A CN105859618B CN 105859618 B CN105859618 B CN 105859618B CN 201610244141 A CN201610244141 A CN 201610244141A CN 105859618 B CN105859618 B CN 105859618B
Authority
CN
China
Prior art keywords
reaction
isoquinolin
preparation
nitrile group
compound
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.)
Expired - Fee Related
Application number
CN201610244141.7A
Other languages
Chinese (zh)
Other versions
CN105859618A (en
Inventor
唐石
邓佑林
李捷
李增增
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.)
Jishou University
Original Assignee
Jishou 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 Jishou University filed Critical Jishou University
Priority to CN201610244141.7A priority Critical patent/CN105859618B/en
Publication of CN105859618A publication Critical patent/CN105859618A/en
Application granted granted Critical
Publication of CN105859618B publication Critical patent/CN105859618B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms

Landscapes

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

Abstract

The invention discloses a kind of isoquinolin 1,3 (2 of nitrile group containing cycloalkylH,4H) dione compounds and its preparation method and purposes.The compound has such as formula（I）Shown structure, preparation method be withNMethacrylylNAlkylbenzamide is start material, 1,1,The cyclohexanenitrile of azo two is free radical source matter, K3PO4As alkali, using DMF as solvent, react and carried out under air ambient, reaction temperature is 85 degree.After reaction 8 hours, purify to obtain through column chromatography or TLC separation.The very high inhibition of such compound on prostate cancer cell LNCap cells shows, particularly wherein one or two kind show as it is very promising, this for find treatment prostate cancer lead compound provide splendid opportunity；And synthetic reaction is simple to operate, without any metallic catalyst, reaction system is gentle, and condition is simple, and cost is low, and yield is high, has great application value.

Description

The isoquinolin -1,3 (2 of the nitrile group containing cycloalkylH,4H)-diketone and its preparation method and purposes
Technical field
The present invention relates to isoquinolin -1,3 (2H, the 4H)-diketone and its preparation method and purposes of one kind nitrile group containing cycloalkyl.
Background technology
In numerous heterocyclic compounds, isoquinolines and its derivative are because its significant pharmacology and bioactivity are by people Extensive concern, they show important physiologically actives, such as eased pain, antitumor, HIV-I RT inhibitor, 5-HT3Acceptor by Body antagonist etc..Therefore the isoquinolin -1,3 (2 of development itrile group substitutionH,4H)-dione compounds synthetic method has important practice And theory value.
So far, isoquinolin -1,3 (2 of the substitution containing cyclohexane carbonitrileH,4HThere is not been reported for)-diketone synthetic method, We have found that benzamide compound can be under without metal catalyzed conditions, with 1,1,The cyclohexanenitrile of-azo two is in gentle reaction Under the conditions of occur series connection addition/cyclization, effectively by cyclohexane carbonitrile group introduce isoquinolin -1,3 (2H,4H)-diketone. This synthetic method is simple and convenient, and yield is high, the one step to form the loop in the presence of without any transition-metal catalyst.Main By product is nothing Evil nitrogen gas, show " green " and " Atom economy " characteristic, therefore have high practical reference value.And by swollen Knurl suppresses experiment, the very high inhibitory activity of this compound on prostate cancer LNCap cells shows, to find anti-prostate tumor Isobioquin group lead compound provide important opportunity.
The content of the invention
The present invention is exactly overcome the deficiencies in the prior art, there is provided a kind of brand-new with important biomolecule activity contains cycloalkyl The isoquinolin -1,3 (2 of nitrile group substitutionH,4H)-dione compounds and preparation method thereof.
In order to realize the object of the invention, the invention provides the isoquinolin -1 of the nitrile group containing cycloalkyl, 3 (2H,4H)-diketone The synthetic route of compound, its structural formula are shown below：
Wherein, R1Can be H, 4-Cl, 4-F, 4-Me, 4-CF, 4-OMe, 4-Br, 3-Cl, 2-OMe, 2-Me etc. In any one, R2Can ben-Bu, i-Pr, -Me, -CH2Ph, -CH2CO2Any one in Et etc..
The isoquinolin -1,3 (2 of the above-mentioned substitution of nitrile group containing cycloalkylH,4HThe preparation scheme of)-dione compounds is as follows：
WithN- iso-propionyl-N- alkylbenzamide（II）For substrate, K3PO4As alkali, with DMF (N,N- dimethyl methyl Acid amides) be used as solvent, react and carried out under air ambient, reaction temperature be 85 degree, reaction 8 hours after, by series connection oneself Synthesize to obtain product by base addition/C-H cyclization processes（I）, for yield between 60-80%, its reaction equation is as follows：
R in reaction expression1,R2Can be shown in following each group：
1: R1 = H, R2 = n-Bu
2: R1 = H, R2 = i-Pr
3: R1 = H, R2 = Me
4: R1 = 4-Cl, R2 = n-Bu
5: R1 = 4-Cl, R2 = i-Pr
6: R1 = 4-F, R2 = CH2CO2Et
7: R1 = 4-F, R2 = Me
8: R1 = 4-Me, R2 = n-Bu
9: R1 = 4-Me, R2 = CH2Ph
10: R1 = 2-Me, R2 = n-Bu
11: R1 = 2-Me, R2 = i-Pr
12: R1 = 4-Br, R2 = n-Bu
13: R1 = 4-OMe, R2 = i-Pr
14: R1 = 3-Cl, R2 = n-Bu
15: R1 = 3-Cl, R2 = Me
16: R1 = 4-CF3, R2 = n-Bu
17: R1 = 4-CF3, R2 = Me
In above-mentioned reaction：With K3PO4As alkali, with DMF (N,N- dimethylformamide) solvent is used as, in the ring of air Carried out under border, reaction temperature is 85 degree, and after reaction terminates plus ethyl acetate extracts, and is then washed, collected organic with saturated common salt Layer, through drying, concentration, column chromatography（Or thin-layer chromatography）Obtain reaction product.
The isoquinolin -1,3 (2 for the substitution of nitrile group containing cycloalkyl that the present invention obtainsH,4H)-dione compounds are to prostate Cancer LNCap cells also have certain inhibitory activity, and new selection is provided for the development and application of drugs for prostate cancer, And preparation method has operation simple, reaction system is gentle, and condition is simple, and cost is low, and yield is high, has and greatly promotes Application value.
Embodiment
Below in conjunction with instantiation, the present invention is further illustrated
Material synthesis
Reaction raw materialsN- isobutyryl-N- butyl benzamide compound（B）Preparation, can be passed through by chlorobenzoyl chloride such as chemical Two simple synthesis steps shown in formula 1 obtain, and also can directly buy.
Chemical formula 1
Step 1：
Chlorobenzoyl chloride is added in 100 mL round-bottomed flasks（10 mmol）With the mL of dry methylene chloride 10, then this is mixed Compound adds the triethylamine for being dissolved in a small amount of dry methylene chloride under condition of ice bath（18 mmol, 1.8 eq）Equally it is dissolved in few Measure a n-butylamine of dry methylene chloride（10 mmol, 1 eq）5 min are stirred, ice bath is removed and then reacts 2-6 at room temperature h.Mixture is washed through saturated common salt, filtering, and crude product is obtained after filtrate is distilled off.With ethyl acetate and petroleum ether（v:v = 1:10）For eluent, middle benzoyl butylamine C is separated to obtain using column chromatography.
Step 2：
Then α-methacrylic acid is added in another 100 mL round-bottomed flask（10 mmol）With dry methylene chloride 10 ML, then it is slowly added into and is dissolved in 5-8 mL dry methylene chloride equivalents of oxalyl chloride（12.5 mmol, 1.25 eq）, add 3-5 drops DMF, then in unlimited system normal-temperature reaction 1-2 h.After having reacted, under condition of ice bath toward reaction obtained by mixture in plus Enter the triethylamine for being dissolved in a small amount of dry methylene chloride（18 mmol, 1.8 eq）, then add intermediate benzoyl obtained by previous step Butylamine C, rise temperature to room temperature continue to react 3-8 h.After reaction terminates, ethyl acetate is added, is then washed using salt, water Mutually it is extracted with ethyl acetate again.Organic phase is collected, is dried, concentration, product is separated to obtain using column chromatographyN- butyl-N- diformazan The propylene benzamide of base -4, weak yellow liquid, yield 78%.
The structure of wherein product be according to the nuclear-magnetism of product (1H NMR and13C NMR) data determine compared to relatively.
Compound A structure characterizes：1H NMR (400 MHz, CDCl3) δ: 8.05 (d, J = 7.9 Hz, 2H), 7.70 (t,J = 7.5 Hz, 1H), 7.66 (t, J = 7.6 Hz, 2H),5.79 (s, 1H), 5.70 (s, 1H), 4.12 (m,2H), 1.98 (s, 3H), 1.56 (s, 2H), 1.31 (m, 2H), 0.90 (t, J = 7.3Hz, 3H), 13C NMR (101 MHz, CDCl3) δ: 172.4, 164.5, 141.4, 134.2, 131.3, 128.8, 127.5,124.8,118.1,41.8,29.5,19.8,19.5,13.8;; HRMSm/z (EI) calcd forC15H20NO2 [M]+ 246.1489, found: 246.1492.
According to the preparation method in above-described embodiment, can also equally prepare followingN- iso-propionyl-N- alkyl benzoyl Amine derivative（II）, reaction expression is as follows：
R in reaction expression1,R2Can be shown in following each group：
1: R1 = H, R2 = n-Bu
2: R1 = H, R2 = i-Pr
3: R1 = H, R2 = Me
4: R1 = 4-Cl, R2 = n-Bu
5: R1 = 4-Cl, R2 = i-Pr
6: R1 = 4-F, R2 = CH2CO2Et
7: R1 = 4-F, R2 = Me
8: R1 = 4-Me, R2 = n-Bu
9: R1 = 4-Me, R2 = CH2Ph
10: R1 = 2-Me, R2 = n-Bu
11: R1 = 2-Me, R2 = i-Pr
12: R1 = 4-Br, R2 = n-Bu
13: R1 = 4-OMe, R2 = i-Pr
14: R1 = 3-Cl, R2 = n-Bu
15: R1 = 3-Cl, R2 = Me
16: R1 = 4-CF3, R2 = n-Bu
17: R1 = 4-CF3, R2 = Me
Target product（I）Preparation
The isoquinolin -1,3 (2 of target product nitrile group containing cycloalkyl provided by the inventionH,4H)-dione compounds（I）System Preparation Method, with the system of 1- (2- butyl -4- methyl-1,3-dioxy -1,2,3,4- tetrahydro isoquinolyls)-cyclohexane carbonitrile (A) Exemplified by standby
Sequentially added in reaction tubeN- iso-propionyl-N- alkylbenzamide benzamide (1 mmol), 1,1,- azo Two cyclohexanenitriles（4.0 mmol, 4 equiv）, K3PO4 (2.0 mmol, 2 equiv), DMF (5.0 mL) is added to be used as solvent, It is put into 70 degree of oil bath pan and reacts in air, after reaction terminates after (usual 6-8 h), adds ethyl acetate, then utilize Salt is washed, and aqueous phase is extracted with ethyl acetate again.Organic phase is collected, is dried, concentration, product 1- is separated to obtain using column chromatography （2- butyl -4- methyl isophthalic acids, 3- dioxies -1,2,3,4- tetrahydro isoquinolyls）- cyclohexane carbonitrile（A）, weak yellow liquid, yield 85%。
The structure of wherein product be according to the nuclear-magnetism of product (1H NMR and13C NMR) data determine compared to relatively.
Product A structural characterizations：1H NMR (400 MHz, CDCl3) δ: 8.30 (d, J = 7.9 Hz, 1H), 7.73 – 7.60 (m, 1H), 7.58 – 7.44 (m, 2H), 4.10 – 3.95 (m, 2H), 2.75 (d, J = 14.6 Hz, 1H), 2.35 (d, J = 14.6 Hz, 1H), 1.63 – 1.54 (m, 5H), 1.55 – 1.34 (m, 7H), 1.30 – 0.99 (m, 5H), 0.96 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 175.6, 163.7, 141.3, 133.7, 129.4, 128.1, 126.7, 124.7, 121.5, 49.8, 45.7, 40.6, 38.2, 37.0, 35.8, 33.9, 29.6, 24.8, 23.1, 22.5, 20.4, 13.8; HRMS m/z (ESI) calcd for C22H29N2O2 [M+H]+ 353.2224, found: 353.2221.
According to the preparation method in above-described embodiment, can also equally prepare the isoquinolin of the nitrile group containing cycloalkyl below- 1,3(2H,4H)-dione compounds（I）, the formula of reaction is as follows：
R in reaction expression1, R2Can be shown in following each group：
1: R1 = H, R2 = n-Bu
2: R1 = H, R2 = i-Pr
3: R1 = H, R2 = Me
4: R1 = 4-Cl, R2 = n-Bu
5: R1 = 4-Cl, R2 = i-Pr
6: R1 = 4-F, R2 = CH2CO2Et
7: R1 = 4-F, R2 = Me
8: R1 = 4-Me, R2 = n-Bu
9: R1 = 4-Me, R2 = CH2Ph
10: R1 = 2-Me, R2 = n-Bu
11: R1 = 2-Me, R2 = i-Pr
12: R1 = 4-Br, R2 = n-Bu
13: R1 = 4-OMe, R2 = i-Pr
14: R1 = 3-Cl, R2 = n-Bu
15: R1 = 3-Cl, R2 = Me
16: R1 = 4-CF3, R2 = n-Bu
17: R1 = 4-CF3, R2 = Me
From above embodiment as can be seen that the present invention the nitrile group containing cycloalkyl isoquinolin -1,3 (2H, 4H)-dione compounds（I）Preparation method has that operation is simple, and without any metallic catalyst, reaction system is gentle, bar Part is simple, and cost is low, and yield is high, can prepare isoquinolin -1,3 (2 of a variety of substitutions of nitrile group containing cycloalkylH,4H)-diketone spreads out Biology, there is great application value.
Comparative example 1
Sequentially added in reaction tubeN- butyl-N- dimethyl allene benzamide (1.0 mmol), trifluoromethane sulfonic acid （1.0 equiv）, using dichloromethane (5.0 mL) as solvent, 10 h are reacted under 50 degree of temperature conditionss.After reaction terminates, Ethyl acetate is added, is then washed using salt, aqueous phase is extracted with ethyl acetate again.Organic phase is collected, is dried, is concentrated, is utilized Column chromatography separates to obtain product 2- butyl -4,4- dimethyl-isoquinolin -1,3 (2H,4H)-diketone (D), white solid, production Rate 49%.
Compound D structural characterizations, white solid thing:1H NMR (400 MHz, CDCl3) δ: 8.30 (dd, J = 7.9, 1.2 Hz, 1H), 7.68 (m, 1H), 7.50 (td, J = 8.0, 1.1 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 4.11 – 3.94 (m, 2H), 1.69 （s, 3H）, 1.67 (s, 3H), 1.61 (m, 2H), 1.41 (dq, J = 14.8, 7.4 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H); HRMS m/z (ESI) calcd for C16H19F3NO2 [M+H]+ 245.1411, found: 245.1413.
Tumor suppression is tested：
From the adherent prostate cancer LNCap cells and liver cancer Hep3B cells of exponential phase, after being digested with pancreatin, use Contain
The RPMIl640 culture mediums of 10% calf serum are made into 5000/ml cell suspension, are seeded in the training of 96 holes Support in plate, the μ l of inoculation 100 per hole, 37 degree, 5% CO2Culture to cell monolayer is paved with bottom hole.
The culture medium for the embodiment sample containing various concentrations that experimental group renews, control group then change the culture containing isometric solvent
Base, every group sets 3~5 parallel holes, 37 degree, 5% CO2Cultivate 4~5d.
Abandoning supernatant, the MTT containing 0.2mg/ml of 100 μ l Fresh serum free medium is added per hole.37 degree
Continue to cultivate 4h.It is careful to abandon supernatant, and 100 μ l DMSO are added, after being mixed with miniature ultrasonic oscillator, in enzyme mark Using tested wavelength as 570nm on instrument, reference wavelength is that 450nm determines OD value.
Inhibiting rate of the medicine to growth of tumour cell is calculated as follows：
Growth of tumour cell inhibiting rate %=(1-OD experiments/OD controls) × 100%
Dose-effect curve, Cong Zhongqiu can obtain to the mapping of growth of tumour cell inhibiting rate with the various concentrations of same sample
Go out the half casualty-producing concentrations IC of sample50。
Table 1 is the IC of some compound on prostate cancer LNCap cells of the invention50Value：
Table 1
Compound IC50(μg/ml)
1 15.3
6 2.7
10 7.1
14 11.2
Comparative example 1 102
Table 2 is IC of some compounds of the invention to liver cancer Hep3B cells50Value：
Table 2
Compound IC50(μg/ml)
1 13.5
6 12.4
10 21.1
14 18.8
Comparative example 1 113.2
The compound 6 that can be seen that the present invention from above biological activity test data has to prostate cancer LNCap cells Significant inhibition.
Above-mentioned simply presently preferred embodiments of the present invention, not makees any formal limitation to the present invention.It is any to be familiar with sheet The technical staff in field, in the case where not departing from technical solution of the present invention scope, all using the technology contents of the disclosure above Many possible changes and modifications are made to technical solution of the present invention, or are revised as the equivalent embodiment of equivalent variations.Therefore, it is all It is the content without departing from technical solution of the present invention, any is simply repaiied to made for any of the above embodiments according to the technology of the present invention essence Change, equivalent variations and modification, all should fall in the range of technical solution of the present invention protection.

Claims (1)

1. a kind of isoquinolin -1 of nitrile group containing cycloalkyl, the preparation method of 3 (2H, 4H)-dione compounds, it is characterised in that： Using N- methacrylyl-N- alkylbenzamides as substrate, 1,1,The cyclohexanenitrile of-azo two is radical source, K3PO4 as alkali, with DMF reacts and carried out under air ambient, reaction temperature is 85 degree, after reacting 8 hours, is extracted with ethyl acetate, so as solvent Washed afterwards with saturated common salt, collected organic layer, through drying, concentration, column chromatography or thin-layer chromatography obtain target product, i.e., containing cycloalkanes Isoquinolin -1,3 (2H, 4H) of base nitrile group-cyclohexadione compounds (I), for yield between 60-85%, its reaction expression is as follows：
Wherein, R1For H, 4-Cl, 4-F, 4-Me, 4-OMe, 4-Br, 3-Cl, any one in 2-OMe, 2-Me, R2Forn-Bu, i-Pr, -Me, -CH2Ph, -CH2CO2Any one in Et.
CN201610244141.7A 2016-04-19 2016-04-19 (2H, the 4H) diketone of isoquinolin 1,3 and its preparation method and purposes of the nitrile group containing cycloalkyl Expired - Fee Related CN105859618B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610244141.7A CN105859618B (en) 2016-04-19 2016-04-19 (2H, the 4H) diketone of isoquinolin 1,3 and its preparation method and purposes of the nitrile group containing cycloalkyl

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610244141.7A CN105859618B (en) 2016-04-19 2016-04-19 (2H, the 4H) diketone of isoquinolin 1,3 and its preparation method and purposes of the nitrile group containing cycloalkyl

Publications (2)

Publication Number Publication Date
CN105859618A CN105859618A (en) 2016-08-17
CN105859618B true CN105859618B (en) 2018-01-02

Family

ID=56633348

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610244141.7A Expired - Fee Related CN105859618B (en) 2016-04-19 2016-04-19 (2H, the 4H) diketone of isoquinolin 1,3 and its preparation method and purposes of the nitrile group containing cycloalkyl

Country Status (1)

Country Link
CN (1) CN105859618B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108017582B (en) * 2018-01-29 2020-08-11 西北师范大学 Synthetic method of bromine-containing 1, 3-isoquinolinedione derivative

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105153030A (en) * 2015-10-14 2015-12-16 吉首大学 Perfluoro group substituted isoquinoline-1,3(2H,4H)-diketone as well as preparation method and application thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105153030A (en) * 2015-10-14 2015-12-16 吉首大学 Perfluoro group substituted isoquinoline-1,3(2H,4H)-diketone as well as preparation method and application thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
2-芳基-1,3-异喹啉二酮类抗肿瘤化合物的设计、合成和抗肿瘤活性;康博瑞,等.;《2011年全国药物化学学术会议——药物的源头创新论文摘要集》;20111119;第349页 *
Aerobic oxidative cyclization of benzamides via meta-selective C-H tert-alkylation: rapid entry to 7-alkylated isoquinolinediones;Shi Tang, et al.;《Chem.Commun.》;20160210;第52卷;第4470-4473页 *
连续的Ugi多组分/成环反应合成异喹啉-1,3（2H,4H）-二酮;袁玎,等.;《中国化学会第九届全国有机化学学术会议》;20150728;第292页 *
铱（Ⅲ）和碘单质催化的异喹啉、异吲哚啉酮类化合物合成方法研究;陈丹.;《中国优秀硕士学位论文全文数据库·工程科技I辑》;20120715(第07期);全文 *

Also Published As

Publication number Publication date
CN105859618A (en) 2016-08-17

Similar Documents

Publication Publication Date Title
Rai et al. Synthesis and in vitro biological evaluation of new pyrazole chalcones and heterocyclic diamides as potential anticancer agents
CN105017259A (en) Trifluoromethyl containing quinazoline derivative and preparation method and application thereof
CN108117507A (en) A kind of preparation method and use of azaspiro cyclohexadienone
CN111925381A (en) Synthesis method of baroxavir key intermediate
CN110128343A (en) A kind of hydrazide kind compound
CN104072493A (en) Naphthalimide compound containing 2-mercaptobenzothiazole and triazole heterocycle, preparation method and application thereof
CN105153030B (en) (2H, the 4H) diketone of isoquinolin 1,3 and its preparation method and purposes of full-fluorine group substitution
CN106946972B (en) A kind of ursolic acid derivative with anti-tumor activity and preparation method thereof
CN104151391B (en) A kind of oleanolic acid derivate with antitumor action and its production and use
CN106366151B (en) Oleanolic acid -3- ketone derivatives with antitumor action and its preparation method and application
CN105859618B (en) (2H, the 4H) diketone of isoquinolin 1,3 and its preparation method and purposes of the nitrile group containing cycloalkyl
CN104761482B (en) 3 (2,2 dimethyl) third cyano group 3 alkane (virtue) base indolones and preparation method thereof
MX2010012297A (en) Novel n-(2-amino-phenyl)-acrylamides.
CN105418610A (en) 10-hydroxyevodiamine type anti-tumor compounds as well as preparation method and application thereof
CN105622507B (en) A kind of naphthalimide derivative and its preparation method and application
CN104592114B (en) Substd quinolines histone deacetylases inhibitor and preparation method and application
CN106220558B (en) N-4- pyridine acyl-dehydroabietylamine derivatives and its preparation method and application
CN105503977A (en) 1,3,4-oxadiazole derivative containing glucosamine molecules and preparation method and application thereof
CN113045567B (en) Phosphatase recruitment chimera (PHORCs) compound based on protein phosphatase 5, preparation method and medical application thereof
CN105777635B (en) Isoquinolin -1,3- (2H, the 4H)-diketone and its preparation method and purposes of the substitution of group containing methyl isobutyrate
CN107163028A (en) A kind of benzamides Hedgehog inhibitor and its preparation method and application
CN103172575A (en) Preparation method of one-class 1,3-dipole quinazoline compound
CN107353287B (en) A kind of quinoxaline and heterocyclic fourth ketone compounds and its application in antitumor
CN106946974B (en) Ursolic amide derivative containing pyrazole heterocycle and synthesis and application thereof
CN105566270B (en) 3 aryl-coumarin derivatives and preparation method thereof

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
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20180102

Termination date: 20190419