CN105732624B

CN105732624B - The preparation method and its usage of pyrroles [4,3,2-de] quinoline -2 (1H) -one class BRD4 protein inhibitor

Info

Publication number: CN105732624B
Application number: CN201610064215.9A
Authority: CN
Inventors: 陆涛; 陈亚东; 张智敏; 冉挺; 姜飞; 陈红丽; 卞媛媛; 张德伟
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2016-01-28
Filing date: 2016-01-28
Publication date: 2019-08-02
Anticipated expiration: 2036-01-28
Also published as: CN105732624A

Abstract

The present invention relates to field of medicinal chemistry, more particularly to pyrroles [4,3,2-de] (1H) -one of quinoline -2 analog derivative, their preparation method, the Pharmaceutical composition containing these compounds and their medical application, especially as the anticancer usage of BRD4 protein inhibitor.

Description

The preparation side of pyrroles [4,3,2-de] quinoline -2 (1H) -one class BRD4 protein inhibitor Method and application thereof

Technical field

The present invention relates to field of medicinal chemistry, and in particular to pyrroles [4,3,2-de] (1H) -one of quinoline -2 analog derivative, it Preparation method, the Pharmaceutical composition containing these compounds and their medical application, especially as BRD4 albumen The purposes of inhibitor.

Background technique

In recent years, tumour becomes one of the main reason for leading to human death in global range.Tumour generally has totality The features such as cure rate is low and high recurrence rate, therefore prevent, treat and inhibit tumor recurrence that there is important scientific research value, it realizes The prevention and healing of tumour have comparable urgent and challenge.

The exception of epigenetic regulation is to lead to one of tumorigenic key factor.Current research discovery, BRD4 albumen The epigenetic of mediation is abnormal closely related with the overexpression of oncogene and in close relations with the growing multiplication of cancer cell.BRD4 It is a member of Bromo and extra C-terminal domain (BET) protein family, due in the potential of anti-tumor aspect Value, causes the very big concern of major drugmaker and scientific research institution.BET albumen is also referred to as epigenetic identification albumen, can To identify the epigenetics information change in cellular histone, and transmit activated cell division etc. signal.It is with leukaemia , the gene mutation of BET albumen can interfere this signal to transmit in haemocyte, and cause sick cell uncontrollably to divide, from And insulting histoorgan.The code area Bromodomain of BRD3/BRD4 and NUT (nucleoprotein in testis) gene contaminate Chromaticness transposition is formed where the pathogenesis that BRD-NUT pattern of fusion proto-oncogene is center line cancer, and BRD4 albumen participates at present The positive evidence of tumor invasion process.Research simultaneously is, it was also found that include AML in haematopoietic cancer, Burkitt lymthoma, In the model of Huppert's disease and B cell acute lymphatic leukemia, pass through combination of the interference BRD4 on the site MYC Directly by MYC silencing.Since the isomers of known various MYC is the important regulatory factor of cell Proliferation and survival, and MYC is A possible oncogene of overexpression in many cancers, therefore Bromodomain Antagonism is also for the first time for for MYC drive Dynamic tumour generation provides an effect chance.These results of study illustrate that BRD4 and kinds of tumors have close ties, especially It plays a significant role in some tumours for being difficult to cure or there is no effective treatment means so far, with grinding for relation between tumor Study carefully and provides new strategy for oncotherapy.By acting on the small molecule compound of BRD4 protein B romodomain structural domain, The specific binding for interfering Bromodomain structural domain and acetylated lysine influences transcriptional regulatory in tumour cell and its The targeted therapy to tumour may be implemented in its cell processes.Therefore, BRD4 albumen is that a very promising epigenetic is new Target spot, and the micromolecular inhibitor for acting on BRD4 protein B romodomain structural domain also have in tumor research it is wide Application prospect, and be possible to therefrom develop new type antineoplastic medicine.

The selective depressant JQ1 and IBET151 of reported BRD4 albumen, crystal complex show this micromolecular Inhibitor is just being incorporated in the acetylated lysine identification pocket of Bromodomain structural domain, to block The acetylation regulation that Bromodomain structural domain mediates, therapeutic effect of these inhibitor in several cancers have been obtained It confirms.Currently, the micromolecular inhibitor structure type of BRD4 albumen is few and selectivity is prominent not enough, people are limited to containing The biological function of Bromodomain domain protein and its carry out in-depth study in terms of antitumor potentiality.In addition, existing BRD4 protein inhibitor function and effect wait raising, mechanism needs to be furtherd elucidate.Therefore, it finds efficient, highly selective new Type small molecule BRD4 protein inhibitor is a hot spot of the antitumor research of epigenetic.

Summary of the invention

The present invention by research BRD4 albumen crystal structure model, designed and synthesized it is a series of containing pyrroles [4,3, 2-de] quinoline -2 (1H) -one parent nucleus brand new compound, pharmacological tests show: the compound of the present invention has Good BRD4 protein inhibiting activity.

Technical scheme is as follows:

1, lead to the compound or its pharmaceutically acceptable salt of formula (I):

Wherein, in formula (I) compound represented:

R¹Indicate hydrogen, alkyl；

R²Indicate hydrogen, halogen, hydroxyl, cyano, Het ,-NHR ,-OR ,-NH (CH₂)_1-10Het、-O(CH₂)_1-10Het、-NH (CH₂)_1-10OR、-O(CH₂)_1-10OR、-NH(CH₂)_1-10NHR、-O(CH₂)_1-10NHR、-NH(CH₂)_1-10NR₂、-O(CH₂)_1- ₁₀NR₂,-CONHR ,-CONHHet ,-COOR ,-COOHet ,-NHCOOR ,-NHCOOHet ,-NHCONHR or-NHCONHHet.R table Show that hydrogen or alkyl, Het are selected from piperidyl, pyrrole radicals, pyrazolyl, piperidyl, imidazole radicals, furyl, morpholinyl, thienyl, evil Oxazolyl, isoxazolyl, thiazolyl, 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, benzene Benzothiazolyl, benzisothia oxazolyl, benzofuranyl, benzothienyl, 2,3- dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxane or The bicyclic heterocycle of benzo [d] [1,3] dioxolanyl；Each monocycle or bicyclic heterocycle are optionally replaced by 1,2 or 3 substituent group, respectively Substituent group is independently selected from halogen, halogenated alkyl, hydroxyl, alkyl or alkoxy, or is selected from C₃-C₈Aliphatic carbocyclic ring or following Aliphatic heterocycle: nafoxidine base, morpholinyl, alkoxy morpholinyl, piperazinyl, piperidyl, alkylamino piperidyl；

L each independently represents NHCONH, SO₂NH、NHCO、NHCH₂、NHCH(CH₃)、NR⁴SO₂Equal connexons, Wherein R⁴It can be hydrogen, alkyl, alkoxy acyl, alkoxy acyl alkyl, alkoxyalkyl, aralkyl, alkylcarbamoyl alkyl；

R³It is arbitrarily selected from alkyl, phenyl, naphthalene or Het, phenyl and naphthalene can optionally be replaced by following group: halogen, Cyano, hydroxyl, amino, sulfydryl, alkyl, alkoxy, alkylamino, halogenated alkoxy, alkylamino sulfonyl, alkoxy formoxyl, Fragrant amino, carbanilino；

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 saturated hydrocarbyl with 1-6 carbon atom；It or is the ring-type with 3-6 carbon atom Saturated hydrocarbyl；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 alkyl；Wherein each carbon atom is optionally substituted with an oxygen；

Alkylamino is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom；It or is the ring-type with 3-6 carbon atom Saturated hydrocarbyl；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 alkyl；Wherein each carbon atom is optionally replaced by nitrogen；

Aryl is the carbocyclic ring selected from phenyl, naphthalene, acenaphthenyl or tetralyl, is respectively optionally taken by 1,2 or 3 substituent group In generation, each substituent group is independently selected from hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alcoxyl Base alkyl, aralkyl, alkyl diaryl, aryl or Het；

Halogen be selected from fluorine, chlorine, bromine or iodine substituent group；

2, preferred embodiment of the invention is:

R¹Indicate hydrogen, methyl, ethyl；

R²Indicate hydrogen, chlorine, hydroxyl, cyano, methoxyl group, ethyoxyl, tert-butoxy, tertiary fourth amino, ethoxy carbonyl, tertiary fourth Epoxide carbonyl, B aminocarbonyl, tert-butylamine carbonyl, ethoxycarboxamido, ethylamino formamido group, ethylamino -2- oxo second Amino, 4- methylpiperazine-1-yl, 2- morpholinyl, penta amino of ring, cyclopropylamino, 2- (piperidin-1-yl)-ethylamino, 4- (tertiary fourth Oxygen carbonyl) piperazine -1- base, (1- methyl piperidine -4- base) methylamino, (1- methyl piperidine -4- base) ethylamino, 2- (4- methyl piperazine Piperazine -1- base) ethylamino, cyclopentyloxy, carbanilino, 2- morpholine base oxethyl, 2- (4- methylpiperazine-1-yl) ethoxy Base, ((4- luorobenzyl) oxygroup) formamido group, cyclopenta, phenylamino, ((4- luorobenzyl) oxygen) carbonyl -2- oxoethyl, 2- (6- Oxa- -3- aza-bicyclo [3,1,1] heptane -3- base) -2- oxoethyl, ((1- methyl piperidine -4- base) methylamino) -2- oxo Ethyl；

R³Indicate 2- amyl, phenyl, 2- thienyl, 2- pyridyl group, morpholinyl, 2- methoxy oxygen phenyl, 4- chlorphenyl, 2- chlorine Phenyl, 4- aminomethyl phenyl, 4- methoxyphenyl, 4- isopropyl phenyl, 3- trifluoromethylphenyl, 2- ethoxyl phenenyl, 2- (tertiary fourth oxygen Base carbonyl) phenyl, 2- (methoxycarbonyl) phenyl, 2- cyano-phenyl, 2- Trifluoromethoxyphen-l, 2- (dimethylamino) benzene Base, 2- aminosulfonyl phenyl, 4- (phenylamino) phenyl, 4- (phenyl amino carbonyl) phenyl, 1,1 '-xenyl, 2,5- bis- The chloro- 4- fluorophenyl of tolyl, 2,4- 3,5-dimethylphenyl, 2,5- dichlorophenyl, 2,4- dichlorophenyl, 2,5- difluorophenyl, 2-, 3- The chloro- 2- methoxyphenyl of chloro- 2- fluorophenyl, 2,4- Dimethoxyphenyl, 4-, 8- quinolyl, 1- naphthalene, 2- naphthalene；

L can independently indicate NHCO, NHCH₂、NHCH(CH₃)、SO₂NH、NHCOC(CH₂)₂、NR⁴SO₂Deng link, wherein R⁴ It can be hydrogen, methyl, ethyl, butyl, methylamino -2- oxoethyl, dimethylamino -2- oxoethyl, ethyloxycarbonyl, second Oxygroup -2- oxoethyl, tert-butoxy -2- oxoethyl

3, the preferably following structural compounds of compounds of formula I:

1- methyl -2- oxo-N-phenyl -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- sulfonamide (I-1)

N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-2)

6- (1- phenethyl) amino -1- methylpyrrole simultaneously [4,3,2-de] quinoline -2 (1H) -one (I-3)

N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) -1- phenycyclopropyl -1- first Amide (I-4)

1- methyl -6- ((1- phenethyl) amino) pyrrolo- [4,3,2-de] quinoline -2 (1H) -one (I-5)

N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzamide (I-6)

4- methyl-N- (2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-7)

The chloro- N- of 4- (1- ethyl-2-oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-8)

The chloro- N- of 4- (2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-9)

The chloro- N- ethyl-N- of 4- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzene sulfonyl Amine (I-10)

The chloro- N- of N- normal-butyl -4- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzene sulphur Amide (I-11)

Ethyl ((4- chlorphenyl) sulfonic group) (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- Base) carbamate (I-12)

4- methyl-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I- 13)

4- isopropyl-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-14)

2,5- dimethyl-N -s (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzene sulfonyl Amine (I-15)

The chloro- N- of 4- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I- 16)

2,6- bis- chloro- N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-17)

The fluoro- N- of the chloro- 2- of 3- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-18)

2- methoxyl group-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-19)

4- methoxyl group-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-20)

The chloro- N- of the fluoro- 2- of 4- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-21)

The chloro- N- of 2- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I- 22)

2,6- bis- fluoro- N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-23)

N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) -3- (trifluoromethyl) benzene sulphur Amide (I-24)

N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) pyridine -3- sulfonamide (I- 25)

N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) thiophene -2- sulfonamide (I- 26)

N- (chloro- 1- methyl -2- oxo -1, the 2- pyrrolin of 4- simultaneously [4,3,2-de] quinoline -6- base) -4- Methyl benzenesulfonyl Amine (I-27)

The chloro- N- of 4- (chloro- 1- methyl -2- oxo -1, the 2- pyrrolin of 4- simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-28)

The chloro- N- of 2- (chloro- 1- methyl -2- oxo -1, the 2- pyrrolin of 4- simultaneously [4,3,2-de] quinoline -6- base)-benzene sulfonyl Amine (I-29)

Ethyl n-((4- chlorphenyl) sulfonyl)-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline Quinoline -6- base) acetic acid esters (I-30)

The chloro- N- of 3- (chloro- 1- methyl -2- oxo -1, the 2- pyrrolin of 4- simultaneously [4,3,2-de] quinoline -6- base) -2- fluorobenzene Sulfonamide (I-31)

The chloro- N- of 4- (1- methyl -2- oxo -4- (4- methylpiperazine-1-yl) -1,2- pyrrolin simultaneously [4,3,2-de] quinoline Quinoline -6- base) benzsulfamide (I-32)

The chloro- N- of 4- (1- methyl -2- oxo -4- (morpholine -1- base) -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- Base) benzsulfamide (I-33)

The chloro- N- of 4- (tertiary fourth amino -1, the 2- pyrrolin of 1- methyl -2- oxo -4- simultaneously [4,3,2-de] quinoline -6- base) benzene Sulfonamide (I-34)

The chloro- N- of 4- (1- methyl -2- oxo -4- hydroxyl -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzene sulfonyl Amine (I-35)

N- (the tertiary fourth amino -1- methyl -2- oxo of 4- -- 1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) -4- first Base benzsulfamide (I-36)

2- ((the chloro- N- of 4- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) phenyl) sulphonyl Amido)-N- methylacetamide (I-37)

2- ((the chloro- N- of 4- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base)) phenyl) sulphur Amide groups)-N, N- dimethyl acetamide (I-38)

(1- methyl -2- oxo -1,2- pyrrolin is simultaneously [4,3,2-de] by tert-butyl-n-((4- chlorphenyl) sulfonic group)-N- Quinoline -6- base) acetic acid esters (I-39)

2- methoxyl group-N- (tertiary fourth amino -1, the 2- pyrrolin of 1- methyl -2- oxo -4- simultaneously [4,3,2-de] quinoline -6- Base) benzsulfamide (I-40)

2- methoxyl group-N- (1- methyl -2- oxo -4- (morpholine -1- base) -1,2- pyrrolin simultaneously [4,3,2-de] quinoline - 6- yl) benzsulfamide (I-41)

2- methoxyl group-N- (1- methyl -2- oxo -4- (4- methylpiperazine-1-yl) -1,2- pyrrolin simultaneously [4,3,2- De] quinoline -6- base) benzsulfamide (I-42)

2- methoxyl group-N- (penta amino -1,2- pyrrolin of 1- methyl -2- oxo -4- ring simultaneously [4,3,2-de] quinoline -6- Base) benzsulfamide (I-43)

2- methoxyl group-N- (1- methyl -2- oxo -4- cyclopropylamino -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- Base) benzsulfamide (I-44)

2- methoxy-. N-methyl-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base)) Benzsulfamide (I-45)

2- ethyoxyl-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-46)

N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) quinoline -8- sulfonamide (I- 47)

N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) naphthalene -2- sulfonamide (I-48)

N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) naphthalene -1- sulfonamide (I-49)

N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base)-[1,1 '-xenyl] -4- Sulfonamide (I-50)

(- 1,2- pyrrolin is simultaneously by 1- methyl -2- oxo -4- ((2- (piperidin-1-yl) ethyl) amino) by 2- methoxyl group-N- [4,3,2-de] quinoline -6- base) benzsulfamide (I-51)

2- methoxyl group-N- (1- methyl -4- (((1- methyl piperidine -4- base) methyl) amino) -2- oxo -1,2- dihydro pyrrole Cough up simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-52)

2- methoxyl group-N- (1- methyl -4- ((2- (4- methylpiperazine-1-yl) ethyl) amino) -2- oxo -1,2- dihydro Pyrrolo- [4,3,2-de] quinoline -6- base) benzsulfamide (I-53)

The chloro- 2- methoxyl group-N- of 4- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzene sulphur Amide (I-54)

2- methoxyl group-N- (1- methyl -4- (((1- methyl piperidine -4- base) ethyl) amino) -2- oxo -1,2- dihydro pyrrole Cough up simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-55)

Tert-butyl -4- (6- ((2- methoxyphenyl) sulfoamido) -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4, 3,2-de] quinolyl-4) piperazine -1- formic acid esters (I-56)

Tert-butyl 2- (N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) sulfoamido) Benzoic ether (I-57)

Methyl 2- (N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) sulfoamido) benzene Formic acid esters (I-58)

2,4- bis- chloro- N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-59)

2,4- dimethoxy-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzene sulphur Amide (I-60)

2,4- dimethyl-N -s (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzene sulfonyl Amine (I-61)

2- trifluoromethoxy-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzene sulphur Amide (I-62)

The chloro- 2- methoxyl group-N- of 4- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base)) benzene Sulfonamide (I-63)

2- cyano-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I- 64)

2- methoxyl group-N- (4- methoxyl group -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) Benzsulfamide (I-65)

2- methoxyl group-N- (4- ethyoxyl -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) Benzsulfamide (I-66)

2- methoxyl group-N- (4- tert-butoxy -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- Base) benzsulfamide (I-67)

2- methoxyl group-N- (4- cyclopentyloxy -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- Base) benzsulfamide (I-68)

(1- methyl -4- (2- morpholine base oxethyl) -2- oxo -1,2- pyrrolin is simultaneously [4,3,2-de] by 2- methoxyl group-N- Quinoline -6- base) benzsulfamide (I-69)

2- methoxyl group-N- (1- methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) -2- oxo -1,2- pyrrolin And [4,3,2-de] quinoline -6- base) benzsulfamide (I-70)

Methyl -6- ((2- methoxyphenyl) sulfoamido) -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2- De] quinoline -4- formic acid esters (I-71)

Tert-butyl -6- ((2- methoxyphenyl) sulfoamido) -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2- De] quinoline -4- formic acid esters (I-72)

N- ethyl -6- ((2- methoxyphenyl) sulfoamido) -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2- De] quinoline -4- formamide (I-73)

N- tert-butylamine -6- ((2- methoxyphenyl) sulfoamido) -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3, 2-de] quinoline -4- formamide (I-74)

6- ((2- methoxyphenyl) sulfoamido) -1- methyl -2- oxo-N-phenyl -1,2- pyrrolin simultaneously [4,3,2- De] quinoline -4- formamide (I-75)

4- (N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) sulfonyl)-N- (pyrrole Pyridine -3- base) benzamide (I-76)

N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) -4- (anilino-) benzene sulfonyl Amine (I-77)

2- (dimethylamino)-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzene sulphur Amide (I-78)

N¹Methyl-N³(1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) phenyl -1,3- Disulfonic acid amide (I-79)

N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) oxinane -4- sulfonamide (I-80)

N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) amyl -2- sulfonamide (I- 81)

N- (4- cyano -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) -2- methoxybenzene Sulfonamide (I-82)

4- fluorophenyl (6- ((2- methoxyphenyl) sulfonamido) -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3, 2-de] quinolyl-4) carbamate (I-83)

Ethyl (6- ((2- methoxyphenyl) sulfonamido) -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2- De] quinolyl-4) carbamate (I-84)

N- (4- (3- second carbamyl ammonia) -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) - 2- methoxybenzenesulphoismide (I-85)

Specific structure is shown in Table:

According to the present invention, pharmaceutically acceptable salt includes the acid-addition salts that logical formula (I) compound and following acid are formed: salt Acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, naphthalene sulfonic acids, citric acid, tartaric acid, lactic acid, acetone Acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, tussol.It additionally include the acid of inorganic base Salt, such as: containing alkali metal cations, alkaline earth metal cation, ammonium cation salt.The invention further relates to a kind of medicine groups Object is closed, the present invention containing therapeutically effective amount leads to formula (I) compound represented or its officinal salt and one or more medicines Acceptable carrier or excipient on.

Exist the invention further relates to logical formula (I) compound represented or its officinal salt or comprising its pharmaceutical composition Purposes in the drug of preparation treatment Bromodomain dependence disease.

Exist the invention further relates to logical formula (I) compound represented or its officinal salt or comprising its pharmaceutical composition Preparation inhibits the purposes in the drug of BRD4.

The invention further relates to logical formula (I) compound represented or its must exist with salt or comprising its pharmaceutical composition The purposes in the drug for the treatment of cancer or hyperblastosis class disease is prepared, wherein the cancer is selected from melanoma, mamillary Thyroid tumors, cholangiocarcinoma, colon cancer, oophoroma, center line cancer, non-small cell lung cancer, malignant lymphatic tumor, liver, kidney, bladder, Prostate, mammary gland, the cancer of pancreas and sarcoma and skin, colon, thyroid gland, lung and ovary primary and recurrent solid tumor Or leukaemia.

Specific embodiment

In order to complete synthesis purpose of the invention, the present invention uses following synthetic technology scheme:

A kind of synthetic method of the logical formula (I) of the present invention, comprises the following steps that

Method 1-1:

Method 1-2:

Method 1-3:

Method 1-4:

Method 1-5:

Method 1-6:

Method 1-7:

Method 1-8:

a)H₂SO₄, HNO₃；B) Isosorbide-5-Nitrae-dioxane, tert-Butylamine；C) NaH, CH₃I, DMF；D) TFA, CH₂Cl₂E) tert-Butyl (triphenylphosphoranylidene) acetate, CH₂Cl₂；f)TFA；g)POCl₃；h) Pd/C, H₂；I) 4-Chlorobenzenesulfonylchloride, CH₂Cl₂, Py；j)tert-Butylamine；k)NH₄Cl, Fe, 75%C₂H₅OH；1) 4-Chlorobenzenesulfonyl chloride, CH₂Cl₂, pyridine；M) Pd/C, H₂, NaHCO₃, 15h；N) CuCN, DMF；O) NaOH (aq), reflux；P) EDCl, HOBT, EthylaMine；q)BrCH₂CON (CH₃)₂, K₂CO₃；R) HCl, NaNO₂, H₃PO₄；s)ClSO₂OH；T) DMF, PhCH₂Br, K₂CO₃；u)1- Phenylcyclopropane-1-carbonyl chloride, DMF.

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.

Experimental study of the part of compounds to BRD4 protein binding capacity

The test of BRD4 protein binding capacity

One: DSF method of method

1) experimental material and equipment: BRD4 albumen, HEPES, NaCl, fluorescence probe SYPRO Orange, 96 orifice plates, Mx3005p Real Time PCR machine(Stratagene)。

2) experimental principle: obtained compound takes Differential Scanning Fluorimetry method (DSF, also referred to as Thermal ShiftAssay method) is measured the binding ability activity of BRD4 albumen, and and positive control drug Compare, filters out the relatively good compound of activity.DSF method be based on receptor before and after binding partner thermodynamic quantity variation come The binding ability of ligand is assessed, is a kind of molecule screening technique of sxemiquantitative.This method has quick, simple, efficient, spirit Quick, the advantages that technology path is reliable and pollution-free, the extensive application in terms of fragment and small molecule compound screening, is ratio Appropriate BRD4 inhibitor activity test method.

3) experimental procedure: DSF method carries out in Mx3005p Real Time PCR machine (Stratagene) equipment Test.By BRD4 albumen be added containing 10nM HEPES, 500nM NaCl, pH value be 7.5 buffer solution in, in 96 orifice plates Finally it is made into the solution of 2 μM/20 μ L.Untested compound is added in solution with 10 μM of concentration, while being added with 1: 1000 ratio Enter fluorescence probe SYPRO Orange.The exciting light and wavelength of transmitted light of SYPRO Orange is separately positioned on 465nm and 590nm Place.Temperature DEG C 3 DEG C of raising per minute from 25 DEG C to 96, and fluorescence reading is read at each interval.Then according to fluorescence intensity and Theoretical reduction formula between temperature change obtains temperature of the albumen before and after binding partner by Statistics Method the Fitting Calculation Difference, the method as assessment binding ability.

Two: FRET method of method

1) material: BRD4 albumen；HTRF KinEASE (Cisbio, France)；MgCl₂、MnCl₂,DTT；384 low volumes Blank (Corning, USA)；Pipette tips (Axygen, USA)；DMSO (Sigma, USA)

2) method: the albumen reaction buffer and peptide substrates of 5 μ L is added in every hole, and 10 μ L of compound is incubated for 30 minutes.Mixing Object is further incubated at room temperature 2 hours.The stop bath that 5 μ L are added terminates reaction.It is detected using EnVision multiple labeling reader Fluorescence signal ratio.Data are analyzed using Graphpad Prism 5.

Part preferred compound experimental result

The in vitro antitumor activity assay of target compound

With mtt assay measurement to the inhibiting effect of leukemia cell line MV4-11, AML-2, HL60 tumor cell line.

Mtt assay can make exogenous MTT be reduced into difficulty using in living cells mitochondria in the presence of dehydrogenase relevant to NADP The bluish violet crystal (Formazan) of dissolubility, and be deposited in cell, and dead cell is without this function.Dimethyl sulfoxide is used again (DMSO) or the purple crystal thing in three liquid (10%SDS-5% isobutanol -0.01mol/L HCL) dissolution cell, use are enzyme-linked Immune detector measures its amount of viable cell of its OD value indirect reaction at 570nm wavelength.

Specific method: the tumour cell to test in cell log growth period is inoculated with by certain cell concentration In in 96 well culture plates, sieved sample (can directly add after suspension cell fishplate bar) is added in culture afterwards for 24 hours, and cell is in 37 DEG C, 5% CO₂Under the conditions of continue culture 48 hours after, be added MTT continue culture 4 hours, it is dissolving crystallized with DMSO, carried out under microplate reader Detection.

Partial target compound to knot leukaemia cell MV4-11, AML-2, HL60 anti tumor activity in vitro result such as Under:

Compound numbers	MV4-11(IC₅₀/μM)	AML-2(IC₅₀/μM)	HL60(IC₅₀/μM)
				I-14	0.46	0.50	3.30
I-19	0.25	0.37	4.17
				I-22	0.87	2.44	8.97
I-28	0.29	0.82	7.66
				I-39	1.45	18.09	10.31
I-45	0.26	0.79	3.84

Biological activity test the result shows that, compound provided by the present invention have BRD4 inhibitory effect.The compounds of this invention Can be used for treating various parenchymatous organ's cancers, including melanoma, liver cancer, kidney, lung cancer, prostate cancer, thyroid cancer, Cutaneum carcinoma, colorectal cancer, cancer of pancreas, oophoroma, breast cancer, carcinoma of testis, osteocarcinoma, the cancer of the brain, the cancer of the esophagus, gastrointestinal cancer, soft group Tumor, leukemia, lymph cancer etc. are knitted, wherein can be the cancer mediated by BRD4, is also possible to the cancer independent of above-mentioned mechanism. Therefore, the present invention proposes, the compounds of this invention can be used for the preparation of anticancer drug.

BRD4 albumen external activity test shows that compound provided by the present invention has significant BRD4 protein binding energy Power.Since BRD4 has key effect in growth of tumour cell proliferation, and there is external protein inhibiting activity experiment to support, this Compound provided by inventing can be used for preventing or treating in the drug of disease related with BRD4 inhibitor, especially tumour Drug in.

Specific embodiment

Fusing point is measured with b shape melting point tube, and medium is methyl-silicone oil, and thermometer does not correct；¹HNMR is with JEOL FX90Q type Fu Vertical leaf transformation Nuclear Magnetic Resonance, BRUKER ACF-300 type Nuclear Magnetic Resonance and BRUKER AM-500 type Nuclear Magnetic Resonance are completed (TMS internal standard)；MS 2000 type Fourier transform mass spectrometer of Nicolet and the measurement of MAT-212 type mass spectrograph.

Embodiment 1

5- nitro -4--bromo indole quinoline -2,3- diketone (I-a)

HNO is added in 250mL three-necked bottle₃70mL and H₂SO₄18mL is placed under the conditions of ice salt bath and stirs, and maintains temperature 0 DEG C, the H dissolved with 4--bromo indole quinoline -2,3- diketone 5g (27.5mmol) is added dropwise by constant pressure funnel₂SO₄Then 18mL is tieed up 0 DEG C of temperature reaction about 2h is held, TLC detects fully reacting, reaction solution poured into 300mL mixture of ice and water, stirring while adding, ice There is solid precipitation after thawing, filter, filter cake vacuum drying obtains solid 4.04g, yield 64.8%.¹H-NMR [300MHz, DMSO- d₆]: δ 7.98 (H, d, J=7.5Hz, ArH), 8.49 (H, d, J=7.5Hz, ArH), 11.09 (H, s ,-NH-) .ESI-MS m/ Z:227.0 [M+H]⁺.

Embodiment 2

Tertiary fourth amino -5- nitroindoline quinoline -2, the 3- diketone (I-b) of 4-

I-a 4.04g (17.8mmol) and Isosorbide-5-Nitrae-dioxane 60mL are added in 200mL pressure pipe, then tert-butylamine is added dropwise 4.07mL (44.5mmol), 100 DEG C of oil bath heatings react 2h, and TLC detects fully reacting, and reaction solution is added in appropriate salt water, with Ethyl acetate (100mL × 3) extraction, extract liquor are concentrated and dried, and obtain solid 4.15g, yield 88.6%.¹H-NMR [300MHz, DMSO-d₆]: δ 1.38 (9H, s ,-CH₃), 6.20 (H, s ,-NH-), 7.52 (H, d, J=7.5Hz, ArH), 8.47 (H, d, J= 7.5Hz, ArH), 11.09 (H, s ,-NH-) .ESI-MS m/z:264.0 [M+H]⁺.

Embodiment 3

Tertiary fourth amino -5- nitroindoline quinoline -2, the 3- diketone (I-c) of 1- methyl -4-

I-b 4.15g (15.8mmol) and DMF 80mL are added in the mono- neck bottle of 200mL, is placed in ice salt bath and stirs, add Enter 60%NaH 758mg (19.0mmol), iodomethane 2.68g (19.0mmol) is added after 15m In, and the reaction was continued under room temperature 0.5h, TLC detect fully reacting, and reaction solution is slowly poured into ammonium chloride saturated solution (200mL), filter, and filter cake vacuum drying obtains Solid 4.03g, yield 92.1%.¹H-NMR [300MHz, DMSO-d₆]: δ 1.38 (9H, s ,-CH₃), 3.46 (3H, s ,-CH₃), 6.20 (H, s ,-NH-), 7.52 (H, d, J=7.5Hz, ArH), 8.47 (H, d, J=7.5Hz, ArH) .ESI-MS m/z:277.1 [M+H]⁺.

Embodiment 4

1- methyl -4- amino -5- nitroindoline quinoline -2,3- diketone (I-d)

I-c 4.03 (14.5mmol) and methylene chloride 35mL is added in the mono- neck bottle of 200mL, TFA is then slowly added dropwise 28mL reacts at room temperature 1h, and TLC detects fully reacting, and reaction solution is concentrated, silica gel column chromatogram separating purification (DCM: PE=4: 1, 500mL+1mL triethylamine), it is concentrated and dried, obtains solid 2.58g, yield 80.6%.¹H-NMR [300MHz, DMSO-d₆]: δ 3.46 (3H, s ,-CH₃), 7.62 (2H, s ,-NH₂), 7.56 (H, d, J=7.5Hz, ArH), 8.42 (H, d, J=7.5Hz, ArH) .ESI- MS m/z:222.0 [M+H]⁺.

Embodiment 5

Tert-butyl -2- (1- methyl -4- amino -5- nitro -2--oxindole quinoline -3- subunit) acetic acid esters (I-e)

I-d 2.58g (11.7mmol) and methylene chloride 100mL are added in the mono- neck bottle of 250mL, by triphenyl phosphorus acetic acid Tert-butyl ester 4.43g (11.7mmol), which is dissolved in after methylene chloride 30mL, to be slowly added dropwise with the low liquid funnel of constant pressure to the methylene chloride of 2-4 In solution, the reaction was continued 0.5h after being added dropwise to complete, TLC detect fully reacting, reaction solution concentration, silica gel column chromatogram separating purification (DCM: PE=1: 1,500mL) is concentrated and dried, obtains solid 2.61g, yield 69.3%.¹H-NMR [300MHz, DMSO-d₆]: δ 1.42 (9H, s ,-CH₃), 3.24 (3H, s ,-CH₃), 7.10 (H, s ,-CH), 7.32 (H, d, J=7.5Hz, ArH), 7.62 (2H, S ,-NH₂), 8.02 (H, d, J=7.5Hz, ArH) .ESI-MS m/z:320.1 [M+H]⁺.

Embodiment 6

1- methyl -6- nitro-pyrrole simultaneously [2,3,4-de] quinoline -2,4 (1H, 5H)-diketone (I-f)

I-e 2.61g (8.1mmol) and TFA 60mL, 80 DEG C of heating reflux reaction 2h are added in the mono- neck bottle of 200mL, TLC detects fully reacting, and reaction solution is concentrated and dried, and obtains solid 1.84g, yield 92.8%.¹H-NMR [300MHz, DMSO-d₆]: δ 3.24 (3H, s ,-CH₃), 7.57 (H, s, ArH), 7.70 (H, d, J=7.5Hz, ArH), 8.27 (H, d, J=7.5Hz, ArH), 11.66 (H, s ,-NH-) .ESI-MS m/z:246.0 [M+H]⁺.

Embodiment 7

1- methyl -6- nitro -4- chlorine pyrrolo- [2,3,4-de] quinoline -2 (1H) -one (I-g)

I-f1.84g (7.52mmol) and POCl3 40mL, 100 DEG C of heating reflux reactions are added in the mono- neck bottle of 100mL 1h, TLC detect fully reacting, and reaction solution is slowly added dropwise to mixture of ice and water (300mL), stirring while adding, with ethyl acetate (150mL × 3) extraction, the dry concentration of organic phase, column chromatography separating purification (DCM: PE=2: 1) are concentrated and dried, obtain solid 1.02g, yield 51.5%.¹H-NMR [300MHz, DMSO-d₆]: δ 3.89 (3H, s ,-CH₃), 7.68 (H, s, ArH), 7.73 (H, D, J=7.5Hz, ArH), 8.54 (H, d, J=7.5Hz, ArH) .ESI-MS m/z:264.0 [M+H]⁺.

Embodiment 8

1- methyl -6- amino -4- chlorine pyrrolo- [2,3,4-de] quinoline -2 (1H) -one (I-h)

I-g 1.02g (3.87mmol) and THF30mL, methanol 10mL, H are added in the mono- neck bottle of 100mL₂Room temperature is also under atmosphere Former 4h, TLC detect fully reacting, and aubergine is presented in reaction solution, filter, and with THF washing 3 times, filtrate is concentrated and dried filter residue, obtain purple Black solid 824mg, yield 91.0%.¹H-NMR [300MHz, DMSO-d₆]: δ 3.89 (3H, s ,-CH₃), 4.82 (2H, s ,- NH₂), 7.49 (H, d, J=7.5Hz, ArH), 7.58 (H, d, J=7.5Hz, ArH), 8.59 (H, s, ArH) .ESI-MS m/z: 234.0[M+H]⁺.

Embodiment 9

The tertiary fourth amino 6- nitro-pyrrole of 1- methyl -4- simultaneously [2,3,4-de] quinoline -2 (1H) -one (I-i)

I-g 165mg (0.63mmol) and tert-butylamine 10mL are added in 50mL pressure pipe, 2h, TLC are reacted in 100 DEG C of oil baths Fully reacting is detected, reaction solution is directly concentrated and dried, and obtains solid 181mg, yield 95.2%.¹H-NMR [300MHz, DMSO-d₆]: δ 1.36 (9H, s ,-CH₃), 3.89 (3H, s ,-CH₃), 5.12 (H, s ,-NH-), 7.59 (H, d, J=7.5Hz, ArH), 7.68 (H, S, ArH), 8.30 (H, d, J=7.5Hz, ArH) .ESI-MS m/z:323.I [M+Na]⁺.

Embodiment 10

The tertiary fourth amino-pyrroles of 1- methyl -6- amino -4- simultaneously [2,3,4-de] quinoline -2 (1H) -one (I-j)

I-i 360mg (1.20mmol), ammonium chloride 193mg (3.60mmol), iron powder 268mg are added in the mono- neck of 100mL (4.80mmol) and 75% ethyl alcohol 20mL, 80 DEG C of back flow reactions 3h, TLC detect fully reacting, and atropurpureus is presented in reaction solution, takes out Filter, filter residue obtain solid 290mg yield with THF washing 3 times, filtrate with EA (200mL × 2) extraction, the dry concentration of extract liquor 89.2%.¹H-NMR [300MHz, DMSO-d₆]: δ 1.36 (9H, s ,-CH₃), 3.89 (3H, s ,-CH₃), 4.82 (2H, s ,-NH₂), 5.12 (H, s ,-NH-), 7.34 (H, d, J=7.5Hz, ArH), 7.35 (H, d, J=7.5Hz, ArH), 7.59 (H, s, ArH) .ESI-MS m/z:271.1 [M+H]⁺.

Embodiment 11

1- methyl -6- amino-pyrroles simultaneously [2,3,4-de] quinoline -2 (1H) -one (I-k)

I-g 2.6g and THF30mL, methanol 10mL, NaHCO are added in the mono- neck bottle of 100mL₃Room temperature under 0.8g nitrogen atmosphere 15h is reacted, TLC detects fully reacting, filters, and with THF washing 3 times, filtrate is concentrated and dried filter residue, and column chromatography for separation obtains red Solid 1.7g, yield 85%.¹H NMR (300MHz, DMSO) δ 8.61 (d, J=7.6Hz, 1H), 7.61 (d, J=7.6Hz, 1H), 7.54 (d, J=7.6Hz, 1H), 7.37 (d, J=7.6Hz, 1H), 4.82 (s, 2H), 3.89 (s, 3H), ESI-MS m/z: 200.1[M+H]⁺.

Embodiment 12

1- methyl -6- nitro -4- cyanopyrrole simultaneously [2,3,4-de] quinoline -2 (1H) -one (I-q)

I-g 0.26g is dissolved in DMF 10mL, CuCN 0.13g is added, 120 degrees Celsius is heated to and reacts 3 hours, to After reaction, reaction solution is poured into weak aqua ammonia, is extracted with dichloromethane, be associated with several layers of, column chromatography for separation, obtained white solid Body 0.117g, yield 46%.¹H NMR (300MHz, DMSO) δ 8.76 (d, J=7.6Hz, 1H), 7.84 (d, J=7.6Hz, 1H), 7.68 (s, 1H), 3.86 (s, 3H), ESI-MS m/z:277.0 [M+Na]⁺.

Embodiment 13

1- methyl -6- nitro -2- oxo -1,2- pyrrolin [4,3,2-de] Cinchonic Acid (I-m)

I-l0.25g is added in the NaOH solution of 10mL 3M, is heated to reflux 8 hours, reaction solution is poured into 200mL ice water In, PH is adjusted to there is no solid precipitations with 1M hydrochloric acid, is filtered, filter cake drying obtains 2-m 1.74g, yield 64%.¹H NMR (300MHz, DMSO) δ 12.17 (s, 1H), 8.77 (d, J=7.6Hz, 1H), 8.22 (s, 1H), 7.97 (d, J=7.6Hz, 1H), 3.88 (s, 3H), ESI-MS m/z:274.0 [M+H]⁺.

Embodiment 14

N- ethyl -1- methyl -6- nitro -2- oxo -1,2- pyrrolin [4,3,2-de] quinoline -4- formamide (I-n)

I-m 0.27g is added in 25mL eggplant type bottle, EDCI 0.16g, HOBT 0.20g adds methylene chloride 10mL Be stirred at room temperature, after 30 minutes be added 0.5mL ethylamine solution, continue room temperature reaction 3 hours, after 20m is added in reaction solution Water, methylene chloride extraction, is associated with several layers of, column chromatography for separation, obtains faint yellow solid 0.27g, yield 89%.¹H NMR (300MHz, DMSO) δ 8.98 (m, 1H), 8.71 (d, J=7.6Hz, 1H), 8.25 (s, 1H), 7.81 (d, J=7.6Hz, 1H), 3.40 (s, 3H), 3.04 (m, 2H), 1.04 (m, 3H), ESI-MS m/z:323.1 [M+Na]⁺.

Embodiment 15

1- methylpyrrole [4,3,2-de] quinoline -2 (1H) -one (I-o)

I-k 2.0g is added in 100mL eggplant type bottle, adds the dilute hydrochloric acid 30mL of 0.5M, is stirred under ice bath, 30 minutes The NaNO of 0.5M is added dropwise afterwards₂Aqueous solution 5mL, continuation are reacted 1 hour under ice bath, after reaction solution is added to the H of 1M₃PO₄ In aqueous solution, 65 degrees Celsius are heated to, is reacted 3 hours, rear that ethyl acetate extraction is added, column chromatography for separation obtains white solid I-o 0.82g, yield 45%.¹H NMR (300MHz, DMSO) δ 8.69 (d, J=7.6Hz, 1H), 7.76 (d, J=7.6Hz, 1H), 7.70 (d, J=7.6Hz, 1H), 7.46 (d, J=7.6Hz, 1H), 7.42 (d, J=7.6Hz, 1H), 3.89 (s, 3H), ESI-MS M/z:185.1 [M+H]⁺.

Embodiment 16

1- methyl -2- oxo -1,2- pyrrolin [4,3,2-de] quinoline -6- sulfonic acid chloride (I-P)

In the chlorosulfonic acid that I-o 0.18g is added to 2mL under ice bath, reacted 30 minutes under ice bath, reaction solution is slow It is poured into ice-water bath, white solid is precipitated, filters to obtain 1-p 1.81g, yield 64%.¹H NMR (300MHz, DMSO) δ 8.71 (d, J=7.6Hz, 1H), 8.13 (d, J=7.6Hz, 1H), 7.99 (d, J=7.6Hz, 1H), 7.42 (d, J=7.6Hz, 1H), 7.42 (d, J=7.6Hz, 1H), 3.91 (s, 3H), ESI-MS m/z:283.0 [M+H]

Embodiment 17

I-p 0.20g, aniline 0.079g and methylene chloride 20mL is added in the mono- neck bottle of 50mL, a small amount of pyridine 2 is added dropwise and drips, room Temperature reaction 12h, TLC detect fully reacting, reaction solution concentration, and column chromatography separating purification (PE: EA=8: 1) is concentrated and dried pure again Change, obtains high-purity solid 0.172g, yield 72%.¹H NMR (300MHz, DMSO) δ 9.88 (s, 1H), 8.69 (d, J= 7.6Hz, 1H), 8.13 (d, J=7.6Hz, 1H), 8.01 (d, J=7.6Hz, 1H), 7.42 (d, J=7.6Hz, 1H), 7.14 (t, J=4.4Hz, 2H), 6.80 (t, J=4.4Hz, 1H), 6.78 (d, J=4.4Hz, 2H), 3.86 (s, 3H), ESI-MS m/z: 340.1[M+H]⁺.

Embodiment 18

I-k 0.29g, benzene sulfonyl chloride 0.2g and methylene chloride 20mL is added in the mono- neck bottle of 50mL, a small amount of pyridine 2 is added dropwise and drips, 12h is reacted at room temperature, TLC detects fully reacting, reaction solution concentration, and column chromatography separating purification (PE: EA=7: 1) is concentrated and dried again Purifying, obtains high-purity solid 0.35g, yield 78%.¹H NMR (300MHz, DMSO) δ 10.01 (s, 1H), 8.61 (d, J= 7.6Hz, 1H), 7.67 (d, J=4.4Hz, 2H), 7.63 (t, J=4.4Hz, 1H), 7.61 (d, J=7.6Hz, 1H), 7.55 (t, J=4.4Hz, 2H), 7.54 (d, J=7.6Hz, 1H), 7.37 (d, J=7.6Hz, 1H), 3.85 (s, 3H), ESI-MS m/z: 340.1[M+H]⁺.

Embodiment 19

I-k 0.20g, K is added in the mono- neck bottle of 50mL₂CO₃0.164g adds MDF 20mL to dissolve, and 20m In is stirred at room temperature, adds Bromobenzyl 0.20g reacts at room temperature 5h, and TLC detects fully reacting, and reaction solution is concentrated, and column chromatography separating purification (PE: EA=9: 1) is dense The dry repurity of contracting, obtains high-purity solid 0.18g, yield 62%.¹H NMR (300MHz, DMSO) δ 8.61 (d, J=7.6Hz, 1H), 7.61 (d, J=7.6Hz, 1H), 7.54 (t, J=7.6Hz, 1H), 7.37 (d, J=7.6Hz, 1H), 7.31 (m, 4H), 7.29 (t, J=4.4Hz, 1H), 6.78 (s, 1H), 4.33 (m, 2H), 3.88 (s, 3H), ESI-MS m/z:290.1 [M+H]⁺.

Embodiment 20

I-k 0.4g is added in 50mL eggplant type bottle, EDC I 0.30g, HOBT 0.38g adds methylene chloride 20mL Be stirred at room temperature, after 30 minutes be added 1- cyclo-propane -1- carboxylic acid 0.32g, continue room temperature reaction 3 hours, after in reaction solution 40mL water is added, methylene chloride extraction is associated with several layers of, column chromatography for separation, obtains faint yellow solid I-4 0.61g, yield 90%.¹H NMR (300MHz, DMSO) δ 10.08 (s, 1H), 8.77 (d, J=7.6Hz, 1H), 8.61 (d, J=7.6Hz, 1H), 7.77 (d, J =7.6Hz, 1H), 7.46 (d, J=7.6Hz, 1H), 7.42 (d, J=7.6Hz, 2H), 7.30 (t, J=4.4Hz, 1H), 7.28 (t, J=4.4Hz, 2H), 3.89 (s, 3H), 1.52-1.27 (m, 4H), ESI-MS m/z:344.1 [M+H]⁺.

Embodiment 21

The same I-3 of synthetic method,¹H NMR (300MHz, DMSO) δ 8.61 (d, J=7.6Hz, 1H), 7.61 (d, J= 7.6Hz, 1H), 7.54 (d, J=4.4Hz, 1H), 7.47 (s, 1H), 7.37 (d, J=4.4Hz, 1H), 7.36 (d, J=4.4Hz, 2H), 7.32 (t, J=7.6Hz, 2H), 7.27 (t, J=7.6Hz, 1H), 4.01 (m, 1H), 3.88 (s, 3H), 1.43 (d, J= 4.4Hz, 3H), ESI-MS m/z:326.1 [M+Na]⁺.

Embodiment 22

The same I-4 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.31 (s, 1H), 8.61 (d, J=7.6Hz, 1H), 7.97 (d, J=7.6Hz, 2H), 7.62 (t, J=4.4Hz, 1H), 7.61 (d, J=7.6Hz, 1H), 7.54 (t, J=7.6Hz, 2H), 7.52 (d, J=7.6Hz, 1H), 7.37 (d, J=7.6Hz, 1H), 3.89 (s, 3H), ESI-MS m/z:304.1 [M+H]⁺.

Embodiment 23

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.62 (s, 1H), 10.03 (s, 1H), 8.61 (d, J= 7.6Hz, 1H), 7.69 (d, J=7.6Hz, 2H), 7.62 (d, J=7.6Hz, 1H), 7.54 (d, J=7.6Hz, 1H), 7.37 (d, J=7.6Hz, 1H), 7.36 (d, J=7.6Hz, 2H), 2.45 (s, 3H), ESI-MS m/z:340.1 [M+H]⁺.

Embodiment 24

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.01 (s, 1H), 8.61 (d, J=7.6Hz, 1H), 7.69 (d, J=4.4Hz, 2H), 7.61 (d, J=4.4Hz, 2H), 7.59 (d, J=7.6Hz, 1H), 7.54 (d, J=7.6Hz, 1H), 7.37 (d, J=7.6Hz, 1H), 4.38 (q, J=4.4Hz, 2H), 1.13 (t, J=4.4Hz, 3H), ESI-MS m/z: 388.0[M+H]⁺.

Embodiment 25

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.62 (s, 1H), 10.01 (s, 1H), 8.61 (d, J= 7.6Hz, 1H), 7.68 (d, J=4.4Hz, 2H), 7.63 (d, J=4.4Hz, 2H), 7.61 (d, J=7.6Hz, 1H), 7.54 (d, J=7.6Hz, 1H), 7.37 (d, J=7.6Hz, 1H), ESI-MS m/z:360.0 [M+H]⁺.

Embodiment 26

In the eggplant type bottle of 50mL, I-16 0.2g, K is added₂CO₃0.07g adds anhydrous DMF 20mL, stirs at room temperature After mixing 30 minutes, bromoethane 0.17g continues room temperature reaction 6 hours.After complete reaction, reaction solution is poured into 50mL water, It is extracted with ethyl acetate three times, merges organic layer, vacuum distillation removes solvent, obtains light yellow solid I-10 through column chromatography for separation 0.15g, yield 72%.¹H NMR (300MHz, DMSO) δ 8.61 (d, J=7.6Hz, 1H), 7.78 (d, J=4.4Hz, 2H), 7.67 (d, J=4.4Hz, 2H), 7.60 (d, J=7.6Hz, 1H), 7.54 (d, J=7.6Hz, 1H), 7.37 (d, J=7.6Hz, 1H), 3.85 (s, 3H), 3.27 (q, J=4.4Hz, 2H), 1.18 (t, J=4.4Hz, 3H), ESI-MS m/z:424.1 [M+Na]⁺.

Embodiment 27

The same I-10 of synthetic method,¹H NMR (300MHz, DMSO) δ 8.63 (d, J=7.6Hz, 1H), 7.76 (d, J= 4.4Hz, 2H), 7.65 (d, J=4.4Hz, 2H), 7.62 (d, J=7.6Hz, 1H), 7.50 (d, J=7.6Hz, 1H), 7.31 (d, J=7.6Hz, 1H), 3.82 (s, 3H), 3.16 (t, J=4.4Hz, 2H), 1.41 (m, 2H), 1.34 (m, 2H), 0.83 (m, 3H), ESI-MS m/z:430.1 [M+H]⁺.

Embodiment 28

The same I-10 of synthetic method,¹H NMR (300MHz, DMSO) δ 8.65 (d, J=7.6Hz, 1H), 7.72 (d, J= 7.6Hz, 2H), 7.62 (d, J=7.6Hz, 2H), 7.58 (d, J=7.6Hz, 1H), 7.51 (d, J=7.6Hz, 1H), 7.33 (d, J=4.4Hz, 1H), 4.18 (m, 2H), 3.91 (s, 3H), 1.22 (t, J=4.4Hz, 3H), ESI-MS m/z:468.1 [M+Na]⁺.

Embodiment 29

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.42 (s, 1H), 9.12 (d, J=4.4Hz, 1H), 7.96 (d, J=4.4Hz, 1H), 7.70 (d, J=8.2Hz, 2H), 7.52 (d, J=7.7Hz, 1H), 7.26 (d, J=8.1Hz, 2H), 7.12 (d, J=7.7Hz, 1H), 3.31 (s, 3H), 2.28 (s, 3H), ESI-MS m/z:376.1 [M+Na]⁺.

Embodiment 30

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.07 (s, 1H), 8.65 (d, J=7.6Hz, 1H), 7.75 (d, J=7.6Hz, 2H), 7.63 (d, J=7.6Hz, 1H), 7.53 (d, J=7.6Hz, 2H), 7.49 (d, J=4.4Hz, 1H), 7.34 (d, J=4.4Hz, 1H), 3.82 (s, 3H), 2.85 (m, 1H), 1.24 (d, J=4.4Hz, 6H), ESI-MS m/z: 382.1[M+H] ⁺.

Embodiment 31

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.99 (s, 1H), 8.67 (d, J=7.6Hz, 1H), 7.68 (s, 1H), 7.60 (d, J=7.6Hz, 1H), 7.52 (d, J=7.6Hz, 1H), 7.39 (d, J=7.6Hz, 1H), 7.32 (d, J= 7.6Hz, 2H), 3.91 (s, 3H), 2.61 (s, 3H), 2.39 (s, 3H), ESI-MS m/z:390.1 [M+Na]+

Embodiment 32

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.02 (s, 1H), 8.61 (d, J=4.4Hz, 1H), 7.69 (d, J=4.4Hz, 2H), 7.61 (d, J=8.2Hz, 1H), 7.54 (d, J=7.7Hz, 1H), 7.37 (d, J=8.1Hz, 2H), 7.12 (d, J=7.7Hz, 1H), 3.87 (s, 3H), ESI-MS m/z:374.0 [M+Na]⁺.

Embodiment 33

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.52 (s, 1H), 8.74 (d, J=7.6Hz, 1H), 8.65 (d, J=7.5Hz, 1H), 8.56 (d, J=7.6Hz, 1H), 7.65-7.64 (t, J=4.4Hz, 3H), 7.45 (d, J=7.6Hz, 1H), 3.43 (s, 3H), ESI-MS m/z:430.0 [M+Na]⁺.

Embodiment 34

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.51 (s, 1H), 8.73 (d, J=7.5Hz, 1H), 8.64 (d, J=7.6Hz, 1H), 8.57 (d, J=7.7Hz, 1H), 7.72 (m, 1H), 7.47-7.44 (m, 3H), 7.46 (d, J= 7.7Hz, 1H), 3.45 (s, 3H), ESI-MS m/z:392.0 [M+H]⁺.

Embodiment 35

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.50 (s, 1H), 9.17 (d, J=4.4Hz, 1H), 7.99 (d, J=4.4Hz, 1H), 7.71 (dd, J=7.8,1.6Hz, 1H), 7.58-7.44 (m, 2H), 7.09 (dd, J=7.7, 6.2Hz, 2H), 6.96 (t, J=7.6Hz, 1H), 3.74 (d, J=12.6Hz, 3H), 3.31 (d, J=6.4Hz, 3H), ESI-MS M/z:370.1 [M+H]⁺.

Embodiment 36

4- methoxyl group-N- (J- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-20)

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.53 (s, 1H), 8.75 (d, J=7.6Hz, 1H), 8.65 (d, J=7.5Hz, 1H), 8.56 (d, J=7.7Hz, 1H), 7.64 (d, J=4.4Hz, 2H), 7.45 (d, J=7.7Hz, 1H), 7.12 (d, J=4.5Hz, 2H), 3.84 (s, 3H), 3.43 (s, 3H), ESI-MS m/z:370.1 [M+H]⁺.

Embodiment 37

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.56 (s, 1H), 9.10 (d, J=4.4Hz, 1H), 8.07-7.93 (m, 2H), 7.71-7.63 (m, 1H), 7.52 (dd, J=15.8,7.6Hz, 1H), 7.33-7.24 (m, 1H), 7.16 (dd, J=13.6,7.6Hz, 1H), 3.32 (d, J=2.8Hz, 3H), ESI-MS m/z:392.0 [M+H]⁺.

Embodiment 38

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.55 (s, 1H), 8.76 (d, J=7.6Hz, 1H), 8.65 (d, J=7.7Hz, 1H), 8.57 (d, J=7.6Hz, 1H), 7.80-7.77 (m, 2H), 7.50-7.39 (m, 3H), 3.45 (s, 3H), ESI-MS m/z:396.0 [M+Na]⁺.

Embodiment 39

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.55 (s, 1H), 8.76 (d, J=7.6Hz, 1H), 8.68 (d, J=7.5Hz, 1H), 8.57 (d, J=7.6Hz, 1H), 7.45 (d, J=7.8Hz, 1H), 7.29-7.28 (m, 3H), 3.45 (s, 3H), ESI-MS m/z:398.1 [M+Na]⁺.

Embodiment 40

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.52 (s, 1H), 8.74 (d, J=7.6Hz, 1H), 8.65 (d, J=7.5Hz, 1H), 8.56 (d, J=7.6Hz, 1H), 8.16 (t, J=4.4Hz, 1H), 7.86 (m, 1H), 7.66-7.62 (m, 2H), 7.45 (d, J=7.6Hz, 1H), 3.44 (s, 3H), ESI-MS m/z:430.1 [M+Na]⁺.

Embodiment 41

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.57 (s, 1H), 8.91 (d, J=4.4Hz, 1H), 8.74 (d, J=7.6Hz, 1H), 8.65 (d, J=7.5Hz, 1H), 8.56 (d, J=7.6Hz, 1H), 8.45-8.42 (m, 2H), 7.62 (m, 1H), 7.45 (d, J=7.6Hz, 1H), 3.46 (s, 3H), ESI-MS m/z:363.1 [M+Na]⁺.

Embodiment 42

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.58 (s, 1H), 8.74 (d, J=7.6Hz, 1H), 8.65 (d, J=7.5Hz, 1H), 8.56 (d, J=7.6Hz, 1H), 7.69 (dd, J=4.8Hz, 1H), 7.45 (d, J=7.6Hz, 1H), 7.25-7.17 (m, 2H), 3.43 (s, 3H), ESI-MS m/z:368.0 [M+Na]⁺.

Embodiment 43

I-h 0.20g, p-methyl benzene sulfonic chloride 0.19g and methylene chloride 20mL is added in the mono- neck bottle of 50mL, is added dropwise a small amount of Pyridine 4 drips, and reacts at room temperature 10h, and TLC detects fully reacting, and reaction solution is concentrated, and column chromatography separating purification (PE: EA=8: 1) is dense The dry repurity of contracting, obtains high-purity solid 0.22g, yield 67%.¹H NMR (300MHz, DMSO) δ 9.56 (s, 1H), 8.65 (d, J=7.5Hz, 1H), 8.56 (d, J=7.6Hz, 1H), 7.99 (s, 1H), 7.74 (d, J=4.4Hz, 2H), 7.40 (d, J= 4.5Hz, 2H), 3.43 (s, 3H), 2.34 (s, 3H), ESI-MS m/z:388.0 [M+H]⁺.

Embodiment 44

The same I-27 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.59 (s, 1H), 8.65 (d, J=7.5Hz, 1H), 8.56 (d, J=7.6Hz, 1H), 7.99 (s, 1H), 7.80 (d, J=4.4Hz, 2H), 7.62 (d, J=4.5Hz, 2H), 3.44 (s, 3H), ESI-MS m/z:430.0 [M+Na]⁺.

Embodiment 45

The same I-27 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.58 (s, 1H), 8.65 (d, J=7.5Hz, 1H), 8.56 (d, J=7.6Hz, 1H), 7.99 (s, 1H), 7.80-7.77 (m, 2H), 7.50 (m, 1H), 7.39 (m, 1H), 3.44 (s, 3H), ESI-MS m/z:430.0 [M+Na]⁺.

Embodiment 46

The same I-10 of synthetic method,¹H NMR (300MHz, DMSO) δ 8.63 (d, J=7.6Hz, 1H), 7.73 (d, J= 7.6Hz, 2H), 7.64 (d, J=7.6Hz, 2H), 7.59 (d, J=7.6Hz, 1H), 7.52 (d, J=7.6Hz, 1H), 7.36 (d, J=4.4Hz, 1H), 4.78 (s, 2H), 3.91 (s, 3H), 1.40 (s, 9H), ESI-MS m/z:460.1 [M+H]⁺.

Embodiment 47

The same I-27 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.51 (s, 1H), 8.65 (d, J=7.5Hz, 1H), 8.56 (d, J=7.6Hz, 1H), 7.99 (s, 1H), 7.72 (m, 1H), 7.47-7.44 (m, 2H), 3.46 (s, 3H), ESI-MS M/z:448.0 [M+Na]⁺.

Embodiment 48

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.02 (s, 1H), 8.57 (d, J=7.6Hz, 1H), 8.33 (d, J=7.6Hz, 1H), 7.80 (d, J=7.6Hz, 2H), 7.62 (d, J=7.6Hz, 2H), 7.34 (s, J=7.6Hz, 1H), 3.62 (t, 4H), 3.44 (s, 3H), 2.36 (t, 4H), 2.26 (s, 3H), ESI-MS m/z:494.1 [M+Na]⁺.

Embodiment 49

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.07 (s, 1H), 8.58 (d, J=7.6Hz, 1H), 8.41 (d, J=7.6Hz, 1H), 7.83 (d, J=7.6Hz, 2H), 7.69 (d, J=7.6Hz, 2H), 7.37 (s, J=7.6Hz, 1H), 3.65 (t, 4H), 3.57 (t, 4H), 3.47 (s, 3H), ESI-MS m/z:459.1 [M+H]⁺.

Embodiment 50

I-j 0.20g, p-methyl benzene sulfonic chloride 0.18g and methylene chloride 20mL is added in the mono- neck bottle of 50mL, is added dropwise a small amount of Pyridine 4 drips, and reacts at room temperature 10h, and TLC detects fully reacting, and reaction solution is concentrated, and column chromatography separating purification (PE: EA=6: 1) is dense The dry repurity of contracting, obtains high-purity solid 0.25g, yield 78%.¹H NMR (300MHz, DMSO) δ 9.99 (s, 1H), 8.56 (d, J=7.6Hz, 1H), 8.27 (d, J=7.6Hz, 1H), 7.80 (d, J=7.6Hz, 2H), 7.62 (d, J=7.6Hz, 2H), 7.41 (s, J=7.6Hz, 1H), 4.0 (s, 1H), 3.52 (s, 3H), 1.27 (s, 9H), ESI-MS m/z:467.1 [M+Na]⁺.

Embodiment 51

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 11.53 (s, 1H), 10.02 (s, 1H), 8.63 (d, J= 7.6Hz, 1H), 8.45 (d, J=7.6Hz, 1H), 7.80 (d, J=7.6Hz, 2H), 7.62 (d, J=7.6Hz, 2H), 7.32 (s, J=7.6Hz, 1H), 3.67 (s, 3H), ESI-MS m/z:390.0 [M+H]⁺.

Embodiment 52

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.86 (s, 1H), 8.56 (d, J=7.6Hz, 1H), 8.27 (d, J=7.6Hz, 1H), 7.80 (d, J=7.6Hz, 2H), 7.62 (d, J=7.6Hz, 2H), 7.34 (s, J=7.6Hz, 1H), 4.0 (s, 1H), 3.44 (s, 3H), 2.34 (s, 3H), 1.27 (s, 9H), ESI-MS m/z:447.2 [M+Na]⁺.

Embodiment 53

The same I-10 of synthetic method,¹H NMR (300MHz, DMSO) δ 8.64 (d, J=7.6Hz, 1H), 7.78 (d, J= 7.6Hz, 2H), 7.65 (d, J=7.6Hz, 2H), 7.62 (d, J=4.4Hz, 1H), 7.57 (d, J=4.4Hz, 1H), 7.5 (s, 1H), 7.37 (d, J=7.6Hz, 1H), 4.15 (s, 2H), 3.91 (s, 3H), 2.83 (m, 3H), ESI-MS m/z:467.1 [M+ Na]⁺.

Embodiment 54

The same I-10 of synthetic method,¹H NMR (300MHz, DMSO) δ 8.61 (d, J=7.6Hz, 1H), 7.78 (d, J= 7.6Hz, 2H), 7.63 (d, J=7.6Hz, 2H), 7.61 (d, J=7.6Hz, 1H), 7.55 (d, J=7.6Hz, 1H), 7.39 (d, J=4.4Hz, 1H), 4.28 (s, 2H), 3.92 (s, 3H), 2.96 (s, 6H), ESI-MS m/z:459.1 [M+H]⁺.

Embodiment 55

The same I-10 of synthetic method,¹H NMR (300MHz, DMSO) δ 8.61 (d, J=7.6Hz, 1H), 7.76 (d, J= 7.6Hz, 2H), 7.65 (d, J=7.6Hz, 2H), 7.62 (d, J=7.6Hz, 1H), 7.55 (d, J=7.6Hz, 1H), 7.33 (d, J=4.4Hz, 1H), 4.82 (s, 2H), 4.19 (m, 2H), 3.95 (s, 3H), 1.26 (t, J=4.4Hz, 3H), ESI-MS m/z: 510.1[M+Na]⁺.

Embodiment 56

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 8.40 (s, 1H), 7.87 (dd, J=7.8,1.6Hz, 1H), 7.62-7.52 (m, 1H), 7.43 (s, 1H), 7.21 (t, J=3.8Hz, 2H), 7.15 (d, J=8.2Hz, 1H), 7.07 (t, J=7.3Hz, 1H), 6.59 (d, J=7.8Hz, 1H), 3.67 (s, 3H), 3.56-3.21 (m, 3H), 3.21 (d, J= 8.9Hz, 3H), 2.57-2.44 (m, 3H), ESI-MS m/z:463.2 [M+Na]⁺.

Embodiment 57

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.01 (s, 1H), 7.80 (d, J=4.4Hz, 1H), 7.74 (d, J=4.4Hz, 1H), 7.59 (s, 1H), 7.26 (t, J=4.4Hz, 1H), 7.25 (d, J=7.6Hz, 1H), 7.22 (d, J=7.6Hz, 1H), 7.21 (d, J=4.4Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.70 (m, 8H), ESI-MS M/z:477.1 [M+Na]⁺.

Embodiment 58

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.02 (s, 1H), 7.81 (dt, J=8.9,4.4Hz, 1H), 7.68 (s, 1H), 7.56 (dd, J=11.4,4.3Hz, 1H), 7.44 (d, J=7.7Hz, 1H), 7.15 (d, J=8.3Hz, 1H), 7.04 (t, J=7.5Hz, 1H), 6.73 (d, J=7.7Hz, 1H), 3.81 (s, 4H), 3.76 (s, 3H), 3.28 (d, J= 7.3Hz, 3H), 2.58-2.50 (m, 4H), 2.29 (s, 3H) .ESI-MS m/z:490.1 [M+Na]⁺.

Embodiment 59

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.03 (s, 1H), 9.30 (m, 1H), 7.83 (d, J= 4.4Hz, 1H), 7.76 (t, J=4.4Hz, 1H), 7.57 (s, 1H), 7.35 (d, J=7.6Hz, 1H), 7.34 (d, J=7.6Hz, 1H), 7.26 (t, J=4.4Hz, 1H), 7.21 (d, J=4.4Hz, 1H), 3.94 (s, 3H), 3.82 (s, 3H), 2.64 (m, 1H), 1.83-1.58 (m, 4H), 1.73-1.63 (m, 4H), ESI-MS m/z:475.1 [M+Na]⁺.

Embodiment 60

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.07 (s, 1H), 9.33 (m, 1H), 7.80 (d, J= 4.4Hz, 1H), 7.74 (t, J=4.4Hz, 1H), 7.59 (s, 1H), 7.36 (d, J=7.6Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 7.28 (t, J=4.4Hz, 1H), 7.22 (d, J=4.4Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 2.25 (m, 1H), 0.83-0.58 (m, 4H), ESI-MS m/z:447.1 [M+Na]⁺.

Embodiment 61

The same I-10 of synthetic method,¹H NMR (300MHz, DMSO) δ 8.65 (d, J=7.6Hz, 1H), 7.82 (d, J= 7.6Hz, 1H), 7.74 (t, J=7.6Hz, 1H), 7.62 (d, J=7.6Hz, 1H), 7.55 (d, J=7.6Hz, 1H), 7.37 (d, J=4.4Hz, 1H), 7.26 (t, J=4.4Hz, 1H), 7.21 (d, J=4.4Hz, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 3.20 (s, 3H), ESI-MS m/z:384.1 [M+H]⁺.

Embodiment 62

Synthetic method same I-2,1H NMR (300MHz, DMSO) δ 9.56 (s, 1H), 8.74 (d, J=7.6Hz, 1H), 8.65 (d, J=7.5Hz, 1H), 8.56 (d, J=7.6Hz, 1H), 7.75 (m, 1H), 7.45 (d, J=7.6Hz, 1H), 7.34-7.18 (m, 3H), 3.45 (s, 3H), ESI-MS m/z:384.1 [M+H]⁺.

Embodiment 63

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.02 (s, 1H), 8.94 (d, J=7.6Hz, 1H), 8.61 (d, J=4.4Hz, 1H), 8.50 (d, J=4.4Hz, 1H), 8.46 (d, J=4.4Hz, 1H), 8.29 (d, J=4.4Hz, 1H), 7.93 (t, J=4.4Hz, 1H), 7.62 (t, J=7.6Hz, 1H), 7.61 (d, J=7.6Hz, 1H), 7.54 (d, J= 7.6Hz, 1H), 7.37 (d, J=7.6Hz, 1H), 3.89 (s, 3H), ESI-MS m/z:391.1 [M+H]⁺.

Embodiment 64

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.03 (s, 1H), 8.80 (s, 1H), 8.61 (d, J= 7.6Hz, 1H), 8.30 (d, J=4.4Hz, 1H), 8.13 (d, J=4.4Hz, 1H), 8.02 (d, J=7.6Hz, 1H), 8.01 (d, J=7.6Hz, 1H), 7.61 (d, J=7.6Hz, 1H), 7.59 (m, 2H), 7.54 (d, J=7.6Hz, 1H), 7.37 (d, J= 7.6Hz, 1H), 3.89 (s, 3H), ESI-MS m/z:390.1 [M+H]⁺.

Embodiment 65

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.01 (s, 1H), 8.81 (d, J=7.6Hz, 1H), 8.63 (t, J=7.6Hz, 1H), 8.50 (d, J=4.4Hz, 1H), 8.33 (d, J=4.4Hz, 1H), 8.15 (d, J=7.6Hz, 1H), 7.96 (t, J=7.6Hz, 1H), 7.61 (d, J=7.6Hz, 1H), 7.54 (d, J=7.6Hz, 1H), 7.52 (t, J= 4.4Hz, 1H), 7.41 (d, J=7.6Hz, 1H), 7.37 (d, J=7.6Hz, 1H), 3.86 (s, 3H), ESI-MS m/z:390.1 [M+H]⁺.

Embodiment 66

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.05 (s, 1H), 8.61 (d, J=7.6Hz, 1H), 7.88 (m, 4H), 7.75 (d, J=4.4Hz, 2H), 7.61 (d, J=7.6Hz, 1H), 7.54 (d, J=7.6Hz, 1H), 7.49 (t, J=7.6Hz, 2H), 7.41 (t, J=7.6Hz, 1H), 7.37 (d, J=7.6Hz, 1H), 3.88 (s, 3H), ESI-MS m/ Z:438.1 [M+Na]⁺.

Embodiment 67

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.02 (s, 1H), 7.83 (d, J=4.4Hz, 1H), 7.76 (m, 1H), 7.74 (t, J=4.4Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.6Hz, 1H), 7.34 (d, J= 7.6Hz, 1H), 7.28 (t, J=4.4Hz, 1H), 7.21 (d, J=7.6Hz, 1H), 3.87 (s, 3H), 3.34 (m, 2H), 2.50 (m, 2H), 2.42 (m, 4H), 1.49 (m, 4H), 1.37 (m, 2H), ESI-MS m/z:496.2 [M+H]⁺.

Embodiment 68

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.05 (s, 1H), 7.81 (d, J=4.4Hz, 1H), 7.78 (m, 1H), 7.76 (t, J=4.4Hz, 1H), 7.61 (s, 1H), 7.37 (d, J=7.6Hz, 1H), 7.31 (d, J= 7.6Hz, 1H), 7.26 (t, J=4.4Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 3.91 (s, 3H), 3.83 (s, 3H), 2.98 (m, 2H), 2.50-2.41 (m, 4H), 2.18 (s, 3H), 1.56-1.31 (m, 4H), 1.42 (m, 1H), ESI-MS m/z:496.2 [M+H]⁺.

Embodiment 69

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.02 (s, 1H), 7.80 (d, J=4.4Hz, 1H), 7.76 (m, 1H), 7.74 (t, J=4.4Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.6Hz, 1H), 7.34 (d, J= 7.6Hz, 1H), 7.26 (t, J=4.4Hz, 1H), 7.21 (d, J=7.6Hz, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 3.34 (m, 2H), 2.50 (m, 2H), 2.29 (m, 8H), 2.14 (s, 3H), ESI-MS m/z:533.2 [M+Na]⁺.

Embodiment 70

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.52 (s, 1H), 9.15 (d, J=4.4Hz, 1H), 7.94 (d, J=4.4Hz, 1H), 7.73 (dd, J=7.8,1.6Hz, 1H), 7.56-7.42 (m, 2H), 7.07 (dd, J=7.7, 6.2Hz, 2H), 3.78 (d, J=12.6Hz, 3H), 3.34 (d, J=6.4Hz, 3H), ESI-MS m/z:426.0 [M+Na]⁺.

Embodiment 71

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.00 (s, 1H), 8.66 (m, 1H), 7.80 (d, J= 4.4Hz, 1H), 7.74 (t, J=4.4Hz, 1H), 7.59 (s, 1H), 7.35 (d, J=7.6Hz, 1H), 7.34 (d, J=7.6Hz, 1H), 7.26 (d, J=7.6Hz, 1H), 7.21 (d, J=7.6Hz, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.51 (m, 2H), 2.51-2.41 (m, 4H), 2.21 (s, 3H), 1.56-1.31 (m, 4H), 1.50 (m, 2H), 1.40 (m, 1H), ESI-MS m/z: 510.2 [M+H]⁺.

Embodiment 72

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.53 (s, 1H), 9.16 (d, J=4.4Hz, 1H), 7.96 (d, J=4.4Hz, 1H), 7.70 (d, J=7.8,1.6Hz, 1H), 7.44 (s, 1H), 7.09 (dd, J=7.7,6.2Hz, 2H), 6.96 (t, J=7.6Hz, 1H), 3.89 (d, J=12.6Hz, 3H), 3.83 (d, J=6.4Hz, 3H), 3.73-3.70 (m, 4H), 3.32-3.30 (m, 4H), 1.42-1.39 (m, 9H) .ESI-MS m/z:577.2 [M+Na]⁺.

Embodiment 73

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.57 (s, 1H), 8.74 (d, J=7.6Hz, 1H), 8.65 (d, J=7.5Hz, 1H), 8.56 (d, J=7.6Hz, 1H), 8.35 (m, 1H), 7.97 (m, 1H), 7.82 (m, 1H), 7.56 (m, 1H), 7.45 (d, J=7.6Hz, 1H), 3.45 (s, 3H), 1.38 (s, 9H), ESI-MS m/z:440.1 [M+H]⁺.

Embodiment 74

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.54 (s, 1H), 8.74 (d, J=7.6Hz, 1H), 8.65 (d, J=7.5Hz, 1H), 8.56 (d, J=7.6Hz, 1H), 8.33 (m, 1H), 7.97 (m, 1H), 7.83 (m, 1H), 7.56 (m, 1H), 7.45 (d, J=7.6Hz, 1H), 3.89 (s, 3H), 3.44 (s, 3H), ESI-MS m/z:398.1 [M+Na]⁺.

Embodiment 75

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.58 (s, 1H), 8.74 (d, J=7.6Hz, 1H), 8.65 (d, J=7.5Hz, 1H), 8.56 (d, J=7.6Hz, 1H), 7.97 (d, J=4.5Hz, 1H), 7.74 (d, J=4.9Hz, 1H), 7.50-7.45 (m, 2H), 3.46 (s, 3H), ESI-MS m/z:430.0 [M+Na]⁺.

Embodiment 76

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.57 (s, 1H), 8.74 (d, J=7.6Hz, 1H), 8.65 (d, J=7.5Hz, 1H), 8.56 (d, J=7.6Hz, 1H), 7.64 (d, J=4.5Hz, 1H), 7.45 (d, J=7.5Hz, 1H), 6.86 (d, J=4.5Hz, 1H), 6.68 (dd, J=4.4Hz, 1H), 3.83 (s, 6H), 3.46 (s, 3H), ESI-MS m/z: 400.1[M+H] ⁺.

Embodiment 77

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.55 (s, 1H), 8.74 (d, J=7.6Hz, 1H), 8.65 (d, J=7.5Hz, 1H), 8.56 (d, J=7.6Hz, 1H), 7.62 (d, J=4.5Hz, 1H), 7.45 (d, J=7.6Hz, 1H), 7.38 (d, J=4.5Hz, 1H), 7.21 (dd, J=4.4Hz, 1H), 3.44 (s, 3H), 2.34 (s, 6H), ESI-MS m/z: 390.1[M+Na] ⁺.

Embodiment 78

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.57 (s, 1H), 8.74 (d, J=7.6Hz, 1H), 8.65 (d, J=7.5Hz, 1H), 8.56 (d, J=7.6Hz, 1H), 7.75 (m, 1H), 7.45 (d, J=4.6Hz, 1H), 7.34-7.18 (m, 3H), 3.47 (s, 3H), ESI-MS m/z:446.1 [M+Na]⁺.

Embodiment 79

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.59 (s, 1H), 8.74 (d, J=7.6Hz, 1H), 8.65 (d, J=7.5Hz, 1H), 8.56 (d, J=7.6Hz, 1H), 7.69 (d, J=4.5Hz, 1H), 7.47-7.45 (m, 2H), 7.18 (m, 1H), 3.84 (s, 3H), 3.45 (s, 3H), ESI-MS m/z:426.0 [M+Na]⁺.

Embodiment 80

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.57 (s, 1H), 8.74 (d, J=7.6Hz, 1H), 8.65 (d, J=7.5Hz, 1H), 8.56 (d, J=7.6Hz, 1H), 8.04 (m, 1H), 7.92-7.90 (m, 2H), 7.63 (m, 1H), 7.45 (d, J=4.6Hz, 1H), 3.46 (s, 3H), ESI-MS m/z:387.1 [M+Na]⁺.

Embodiment 81

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.07 (s, 1H), 8.65 (d, J=7.6Hz, 1H), 8.45 (d, J=7.6Hz, 1H), 7.78 (d, J=7.6Hz, 1H), 7.39 (s, J=7.6Hz, 1H), 7.32 (t, J=7.6Hz, 1H), 7.28 (d, J=7.6Hz, 1H), 7.15 (t, J=7.6Hz, 1H), 3.94 (s, 3H), 3.80 (s, 3H), 3.41 (s, 3H), ESI-MS m/z:400.1 [M+H]⁺.

Embodiment 82

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.02 (s, 1H), 7.85 (d, J=7.6Hz, 1H), 7.79 (t, J=4.4Hz, 1H), 7.65 (s, 1H), 7.49 (d, J=7.6Hz, 1H), 7.47 (d, J=4.4Hz, 1H), 7.28- 7.20 (m, 2H), 4.41 (q, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 1.36 (t, J=4.4Hz, 3H) .ESI-MS m/z: 414.1[M+H] ⁺.

Embodiment 83

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.08 (s, 1H), 7.87 (d, J=7.6Hz, 1H), 7.73 (t, J=4.4Hz, 1H), 7.62 (s, 1H), 7.57 (d, J=7.6Hz, 1H), 7.49 (d, J=4.4Hz, 1H), 7.29- 7.19 (m, 2H), 3.79 (s, 3H), 3.63 (s, 3H), 1.45 (s, 9H) .ESI-MS m/z:464.1 [M+Na]⁺.

Embodiment 84

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.92 (s, 1H), 8.69 (d, J=7.6Hz, 1H), 8.41 (d, J=7.6Hz, 1H), 7.72 (d, J=7.6Hz, 1H), 7.39 (s, J=7.6Hz, 1H), 7.33 (t, J=7.6Hz, 1H), 7.25 (d, J=7.6Hz, 1H), 7.09 (t, J=7.6Hz, 1H), 3.86 (s, 3H), 3.71 (m, 1H), 3.54 (s, 3H), (2.01 q, 4H), 1.56 (m, 4H), ESI-MS m/z:476.1 [M+Na]⁺.

Embodiment 85

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.09 (s, 1H), 7.81 (d, J=7.6Hz, 1H), 7.73 (t, J=4.4Hz, 1H), 7.57 (s, 1H), 7.49 (d, J=7.6Hz, 1H), 7.42 (d, J=4.4Hz, 1H), 7.23- 7.17 (m, 2H), 4.11 (t, J=4.4Hz, 2H), 3.82 (s, 3H), 3.57 (t, J=4.4Hz, 4H), 2.66 (t, J= 4.4Hz, 2H), 2.50 (t, J=4.4Hz, 4H) .ESI-MS m/z:499.2 [M+H]⁺.

Embodiment 86

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.98 (s, 1H), 7.83 (d, J=7.6Hz, 1H), 7.76 (t, J=4.4Hz, 1H), 7.61 (s, 1H), 7.51 (d, J=7.6Hz, 1H), 7.49 (d, J=4.4Hz, 1H), 7.29- 7.23 (m, 2H), 4.15 (t, J=4.4Hz, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 2.69 (t, J=4.4Hz, 2H), 2.29 (t, J=4.4Hz, 8H), 2.14 (s, 3H) .ESI-MS m/z:512.2 [M+H]⁺.

Embodiment 87

The same I-74 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.21 (s, 1H), 8.77 (d, J=7.6Hz, 1H), 8.71 (d, J=7.6Hz, 1H), 7.91 (d, J=7.6Hz, 1H), 7.48 (s, J=7.6Hz, 1H), 7.36 (t, J=7.6Hz, 1H), 7.29 (d, J=7.6Hz, 1H), 7.16 (t, J=7.6Hz, 1H), 4.30 (p, 2H), 3.81 (s, 3H), 3.43 (s, 3H), 1.29 (t, 3H), ESI-MS m/z:463.1 [M+Na]⁺.

Embodiment 88

The same I-74 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.01 (s, 1H), 8.13 (s, 1H), 7.80 (d, J= 7.6Hz, 1H), 7.74 (t, J=4.4Hz, 1H), 7.60 (d, J=7.6Hz, 1H), 7.47 (d, J=4.4Hz, 1H), 7.25- 7.20 (m, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 3.79 (s, 3H) .ESI-MS m/z:470.1 [M+H]⁺.

Embodiment 89

By the I-n same I-h of 0.25g reducing preparation method, reduction yield is 0.20g, yield 89%.In the mono- neck bottle of 50mL Reduzate 0.20g, O-methoxy benzene sulfonyl chloride 0.18g and the methylene chloride 20mL of I-n is added, a small amount of pyridine 4 is added dropwise and drips, room Temperature reaction 12h, TLC detect fully reacting, reaction solution concentration, and column chromatography separating purification (PE: EA=6: 1) is concentrated and dried pure again Change, obtains high-purity solid 0.25g, yield 77%.¹H NMR (300MHz, DMSO) δ 9.86 (s, 1H), 8.68 (d, J=7.6Hz, 1H), 8.59 (d, J=7.6Hz, 1H), 8.03 (s, 1H), 7.82 (s, J=7.6Hz, 1H), 7.76 (d, J=7.6Hz, 1H), 7.34 (t, J=7.6Hz, 1H), 7.25 (d, J=7.6Hz, 1H), 7.17 (t, J=7.6Hz, 1H), 3.78 (s, 3H), 3.53 (s, 3H), 3.04 (p, 2H), 1.04 (t, 3H), ESI-MS m/z:463.1 [M+Na]⁺.

Embodiment 90

The same I-73 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.04 (s, 1H), 8.37 (s, 1H), 8.16 (s, 1H), 7.83 (d, J=7.6Hz, 1H), 7.77 (t, J=4.4Hz, 1H), 7.75 (d, J=7.6Hz, 1H), 7.57 (d, J=4.4Hz, 1H), 7.27-7.23 (m, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 1.51 (s, 3H) .ESI-MS m/z:469.1 [M+H]⁺.

Embodiment 91

The same I-73 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.02 (s, 1H), 9.86 (s, 1H), 8.14 (s, 1H), 7.81 (d, J=7.6Hz, 1H), 7.76 (d, J=7.6Hz, 2H), 7.75 (d, J=7.6Hz, 1H), 7.74 (t, J=4.4Hz, 1H), 7.57 (d, J=4.4Hz, 1H), 7.32 (t, J=7.6Hz, 2H), 7.27-7.21 (m, 2H), 7.07 (t, J=7.6Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H) .ESI-MS m/z:489.1 [M+H]⁺.

Embodiment 92

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.54 (s, 1H), 10.01 (s, 1H), 8.93 (s, 1H), 8.61 (d, J=7.6Hz, 1H), 8.33 (d, J=7.6Hz, 1H), 8.30 (d, J=4.4Hz, 2H), 8.17 (d, J=7.6Hz, 1H), 7.91 (d, J=4.4Hz, 2H), 7.61 (d, J=7.6Hz, 1H), 7.54 (d, J=7.6Hz, 1H), 7.40 (t, J= 7.6Hz, 1H), 7.37 (d, J=7.6Hz, 1H), 3.86 (s, 3H) .ESI-MS m/z:460.1 [M+H]⁺.

Embodiment 93

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.67 (s, 1H), 8.61 (d, J=7.6Hz, 1H), 8.36 (s, 1H), 7.66 (d, J=4.4Hz, 2H), 7.61 (d, J=7.6Hz, 1H), 7.54 (d, J=7.6Hz, 1H), 7.40 (t, J= 4.4Hz, 2H), 7.37 (d, J=7.6Hz, 1H), 7.21 (d, J=4.4Hz, 2H), 7.06 (d, J=4.4Hz, 2H), 7.02 (t, J=4.4Hz, 1H), 3.89 (s, 3H) .ESI-MS m/z:431.1 [M+H]⁺.

Embodiment 94

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.03 (s, 1H), 8.65 (d, J=7.6Hz, 1H), 7.66 (d, J=4.4Hz, 1H), 7.60 (d, J=7.6Hz, 1H), 7.56 (d, J=7.6Hz, 1H), 7.50 (t, J=4.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 6.98 (d, J=4.4Hz, 1H), 6.92 (t, J=4.4Hz, 1H), 3.95 (s, 3H), 3.01 (s, 6H) .ESI-MS m/z:405.1 [M+Na]⁺.

Embodiment 95

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.10 (s, 1H), 8.60 (d, J=7.6Hz, 1H), 8.50 (d, J=4.4Hz, 1H), 8.18 (d, J=4.4Hz, 2H), 7.93 (t, J=4.4Hz, 1H), 7.74 (s, 1H), 7.61 (d, J=7.6Hz, 1H), 7.54 (d, J=7.6Hz, 1H), 7.37 (d, J=7.6Hz, 1H), 3.91 (s, 3H), 2.47 (s, 3H) .ESI-MS m/z:433.0 [M+H]⁺.

Embodiment 96

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.58 (s, 1H), 8.63 (d, J=7.6Hz, 1H), 7.61 (d, J=7.6Hz, 1H), 7.54 (d, J=7.6Hz, 1H), 7.37 (d, J=7.6Hz, 1H), 3.93 (s, 3H), 3.67- 3.57 (m, 4H), 3.10 (m, 1H), 2.25-2.00 (m, 4H) .ESI-MS m/z:380.4 [M+Na]⁺.

Embodiment 97

The same I-2 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.65 (s, 1H), 8.67 (d, J=7.6Hz, 1H), 7.66 (d, J=7.6Hz, 1H), 7.59 (d, J=7.6Hz, 1H), 7.42 (d, J=7.6Hz, 1H), 3.97 (s, 3H), 3.00 (m, 1H), 1.77 (m, 2H), 1.38 (m, 3H), 1.31 (m, 2H), 0.89 (t, J=4.4Hz, 3H) .ESI-MS m/z:334.1 [M+H]⁺.

Embodiment 98

The same I-73 of synthetic method,¹H NMR (300MHz, DMSO) δ 10.13 (s, 1H), 8.73 (d, J=7.6Hz, 1H), 8.63 (d, J=7.6Hz, 1H), 8.57 (s, J=7.6Hz, 1H), 7.79 (d, J=7.6Hz, 1H), 7.38 (t, J=7.6Hz, 1H), 7.31 (d, J=7.6Hz, 1H), 7.21 (t, J=7.6Hz, 1H), 3.85 (s, 3H), 3.42 (s, 3H), ESI-MS m/z: 395.1[M+H]⁺.

Embodiment 99

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.88 (s, 1H), 9.15 (s, 1H), 8.58 (d, J= 7.6Hz, 1H), 8.37 (d, J=7.6Hz, 1H), 7.87 (d, J=7.6Hz, 1H), 7.52 (t, J=7.6Hz, 1H), 7.39 (d, J=7.6Hz, 2H), 7.32 (d, J=7.6Hz, 1H), 7.21 (t, J=7.6Hz, 1H), 7.19 (d, J=7.6Hz, 2H), 7.10 (s, J=7.6Hz, 1H), 4.65 (s, 2H), 3.81 (s, 3H), 3.47 (s, 3H), ESI-MS m/z:559.1 [M+Na]⁺.

Embodiment 100

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 9.93 (s, 1H), 9.15 (s, 1H), 8.61 (d, J= 7.6Hz, 1H), 8.39 (d, J=7.6Hz, 1H), 7.76 (d, J=7.6Hz, 1H), 7.34 (t, J=7.6Hz, 1H), 7.29 (d, J=7.6Hz, 1H), 7.21 (t, J=7.6Hz, 1H), 7.12 (s, J=7.6Hz, 1H), 4.13 (p, 2H), 3.69 (s, 3H), 3.36 (s, 3H), 1.29 (t, 3H), ESI-MS m/z:479.1 [M+Na]⁺.

Embodiment 101

The same I-34 of synthetic method,¹H NMR (300MHz, DMSO) δ 11.26 (s, 1H), 10.53 (s, 1H), 8.59 (d, J= 7.6Hz, 1H), 8.41 (d, J=7.6Hz, 1H), 7.71 (d, J=7.6Hz, 1H), 7.37 (t, J=7.6Hz, 1H), 7.28 (d, J=7.6Hz, 1H), 7.19 (t, J=7.6Hz, 1H), 7.13 (s, J=7.6Hz, 1H), 5.12 (s, 1H), 3.79 (s, 3H), 3.37 (s, 3H), 3.24 (p, 2H), 1.04 (t, 3H), ESI-MS m/z:478.1 [M+Na]⁺。

Claims

1. the compound of logical formula (I) or its pharmaceutically acceptable salt:

Wherein, in formula (I) compound represented:

R¹Indicate hydrogen, alkyl；

R²Indicate hydrogen, halogen, cyano, Het ,-NHR ,-OR ,-NH (CH₂)_1-10Het、-O(CH₂)_1-10Het、-NH(CH₂)_1-10OR、- O(CH₂)_1-10OR、-NH(CH₂)_1-10NHR、-CONHR、-NH(CH₂)_1-10NR₂、-O(CH₂)_1-10NR₂、-CONHHet、-COOR、- COOHet ,-NHCOOR ,-NHCOOHet ,-NHCONHR or-NHCONHHet, R indicate hydrogen or alkyl；

L each independently represents SO₂NH、NR⁴SO₂Connexon, wherein R⁴It can be hydrogen, alkyl, alkoxy acyl, alkoxy acyl alkane Base, alkoxyalkyl or alkane carbamyl alkyl；

R³Arbitrarily be selected from alkyl, phenyl, naphthalene or Het, phenyl and naphthalene can optionally replace by following group: halogen, cyano, Hydroxyl, amino, sulfydryl, alkyl, alkoxy, alkylamino, halogenated alkoxy, alkylamino sulfonyl, alkoxy formoxyl, fragrant ammonia Base, carbanilino；

The aryl is selected from the carbocyclic ring of phenyl, naphthalene, acenaphthenyl or tetralyl, is respectively optionally taken by 1,2 or 3 substituent group In generation, each substituent group is independently selected from hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alcoxyl Base alkyl, aralkyl, alkyl diaryl, aryl or Het, wherein aryl is the carbon selected from phenyl, naphthalene, acenaphthenyl or tetralyl Ring；

The Het is selected from piperidyl, pyrrole radicals, pyrazolyl, imidazole radicals, furyl, morpholinyl, thienyl, oxazolyl, different evil Oxazolyl, thiazolyl, isothiazolyl, pyridyl group, pyrimidine radicals, piperazinyl, pyrazinyl or pyridazinyl monocyclic heterocycles；Or it is selected from quinoline Base, quinoxalinyl, indyl, benzimidazolyl, benzoxazolyl, benzo isoxazolyl, benzothiazolyl, benzisothiazole Base, benzofuranyl, benzothienyl, 2,3- dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxane or benzo [d] [1,3] dioxolanes The bicyclic heterocycle of base；Each monocycle or bicyclic heterocycle are optionally replaced by 1,2 or 3 substituent group, and each substituent group is independently selected from halogen, halogen Substituted alkyl, hydroxyl, alkyl or alkoxy, or it is selected from C₃-C₈Aliphatic carbocyclic ring or following aliphatic heterocycle: nafoxidine Base, morpholinyl, alkoxy morpholinyl, piperazinyl, piperidyl, alkylamino piperidyl；

The 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；

The alkoxy is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom；It or is the ring-type with 3-6 carbon atom Saturated hydrocarbyl；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 alkyl；Wherein each carbon atom is optionally substituted with an oxygen, and does not include the case where not being substituted with an oxygen；

The alkylamino is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom；It or is the ring-type with 3-6 carbon atom Saturated hydrocarbyl；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 alkyl；Wherein each carbon atom is optionally replaced by nitrogen, does not include the case where not replaced by nitrogen；

The halogen be selected from fluorine, chlorine, bromine or iodine substituent group.

2. the compound of claim 1 or its pharmaceutically acceptable salt, it is characterised in that:

R¹Indicate hydrogen, methyl, ethyl；

R²Indicate hydrogen, chlorine, hydroxyl, cyano, methoxyl group, ethyoxyl, tert-butoxy, tertiary fourth amino, ethoxy carbonyl, tert-butoxy Carbonyl, B aminocarbonyl, tert-butylamine carbonyl, ethoxycarboxamido, ethylamino formamido group, 4- methylpiperazine-1-yl, 2- Quinoline base, penta amino of ring, cyclopropylamino, 2- (piperidin-1-yl)-ethylamino, (1- methyl piperidine -4- base) methylamino, (1- methyl piperazine Pyridine -4- base) ethylamino, 2- (4- methylpiperazine-1-yl) ethylamino, cyclopentyloxy, 2- morpholine base oxethyl, 2- (4- methyl piperazine Piperazine -1- base) ethyoxyl, cyclopenta；

R³Indicate 2- amyl, phenyl, 2- thienyl, 2- pyridyl group, morpholinyl, 2- methoxyphenyl, 4- chlorphenyl, 2- chlorphenyl, 4- aminomethyl phenyl, 4- methoxyphenyl, 4- isopropyl phenyl, 2- ethoxyl phenenyl, 2- (tert-butoxycarbonyl) phenyl, 2- (first Epoxide carbonyl) phenyl, 2- cyano-phenyl, 2- Trifluoromethoxyphen-l, 2- (dimethylamino) phenyl, 2- aminosulfonyl benzene Base, 4- (phenylamino) phenyl, 4- (phenyl amino carbonyl) phenyl, 2,5- 3,5-dimethylphenyl, 2,4- 3,5-dimethylphenyl, 2,5- dichloro The chloro- 4- fluorophenyl of phenyl, 2,4- dichlorophenyl, 2,5- difluorophenyl, 2-, the chloro- 2- fluorophenyl of 3-, 2,4- Dimethoxyphenyl, The chloro- 2- methoxyphenyl of 4-, 8- quinolyl, 1- naphthalene, 2- naphthalene；

L can independently indicate SO₂NH、NR⁴SO₂Connexon, wherein R⁴It can be hydrogen, methyl, ethyl, butyl, methylamino -2- oxo second Base, dimethylamino -2- oxoethyl, ethyloxycarbonyl, ethyoxyl -2- oxoethyl, tert-butoxy -2- oxoethyl.

3. the compound of claim 2 or its pharmaceutically acceptable salt it is characterized by:

The chloro- N- ethyl-N- of 4- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-10)

The chloro- N- of N- normal-butyl -4- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-11)

Ethyl ((4- chlorphenyl) sulfonic group) (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) ammonia Carbamate (I-12)

4- methyl-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-13)

4- isopropyl-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I- 14)

2,5- dimethyl-N -s (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I- 15)

The chloro- N- of 4- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-16) 2, The chloro- N- of 6- bis- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-17)

The fluoro- N- of the chloro- 2- of 3- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I- 18)

2- methoxyl group-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I- 19)

4- methoxyl group-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I- 20)

The chloro- N- of the fluoro- 2- of 4- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I- 21)

The chloro- N- of 2- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-22)

2,6- bis- fluoro- N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I- 23)

N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) pyridine -3- sulfonamide (I-25)

N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) thiophene -2- sulfonamide (I-26)

N- (chloro- 1- methyl -2- oxo -1, the 2- pyrrolin of 4- simultaneously [4,3,2-de] quinoline -6- base) -4- methyl benzenesulfonamide (I-27)

The chloro- N- of 4- (chloro- 1- methyl -2- oxo -1, the 2- pyrrolin of 4- simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I- 28)

The chloro- N- of 2- (chloro- 1- methyl -2- oxo -1, the 2- pyrrolin of 4- simultaneously [4,3,2-de] quinoline -6- base)-benzsulfamide (I- 29)

Ethyl n-((4- chlorphenyl) sulfonyl)-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- Base) acetic acid esters (I-30)

The chloro- N- of 3- (chloro- 1- methyl -2- oxo -1, the 2- pyrrolin of 4- simultaneously [4,3,2-de] quinoline -6- base) -2- fluorobenzene sulphonyl Amine (I-31)

The chloro- N- of 4- (1- methyl -2- oxo -4- (4- methylpiperazine-1-yl) -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- Base) benzsulfamide (I-32)

The chloro- N- of 4- (tertiary fourth amino -1, the 2- pyrrolin of 1- methyl -2- oxo -4- simultaneously [4,3,2-de] quinoline -6- base) benzene sulfonyl Amine (I-34)

The chloro- N- of 4- (1- methyl -2- oxo -4- hydroxyl -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-35)

N- (the tertiary fourth amino -1- methyl -2- oxo of 4- -- 1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) -4- methylbenzene Sulfonamide (I-36)

2- ((the chloro- N- of 4- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) phenyl) sulfonamide Base)-N- methylacetamide (I-37)

2- ((the chloro- N- of 4- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base)) phenyl) sulfonamide Base)-N, N- dimethyl acetamide (I-38)

Tert-butyl-n-((4- chlorphenyl) sulfonic group)-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline Quinoline -6- base) acetic acid esters (I-39)

2- methoxyl group-N- (tertiary fourth amino -1, the 2- pyrrolin of 1- methyl -2- oxo -4- simultaneously [4,3,2-de] quinoline -6- base) benzene Sulfonamide (I-40)

2- methoxyl group-N- (1- methyl -2- oxo -4- (4- methylpiperazine-1-yl) -1,2- pyrrolin simultaneously [4,3,2-de] quinoline Quinoline -6- base) benzsulfamide (I-42)

2- methoxyl group-N- (penta amino -1,2- pyrrolin of 1- methyl -2- oxo -4- ring simultaneously [4,3,2-de] quinoline -6- base) benzene Sulfonamide (I-43)

2- methoxyl group-N- (1- methyl -2- oxo -4- cyclopropylamino -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzene Sulfonamide (I-44)

2- methoxy-. N-methyl-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base)) benzene sulphur Amide (I-45)

2- ethyoxyl-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I- 46)

N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) quinoline -8- sulfonamide (I-47)

2- methoxyl group-N- (1- methyl -2- oxo -4- ((2- (piperidin-1-yl) ethyl) amino) -1,2- pyrrolin simultaneously [4,3, 2-de] quinoline -6- base) benzsulfamide (I-51)

(- 2- oxo -1,2- pyrrolin is simultaneously by 1- methyl -4- (((1- methyl piperidine -4- base) methyl) amino) by 2- methoxyl group-N- [4,3,2-de] quinoline -6- base) benzsulfamide (I-52)

2- methoxyl group-N- (1- methyl -4- ((2- (4- methylpiperazine-1-yl) ethyl) amino) -2- oxo -1,2- pyrrolin And [4,3,2-de] quinoline -6- base) benzsulfamide (I-53)

The chloro- 2- methoxyl group-N- of 4- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-54)

(- 2- oxo -1,2- pyrrolin is simultaneously by 1- methyl -4- (((1- methyl piperidine -4- base) ethyl) amino) by 2- methoxyl group-N- [4,3,2-de] quinoline -6- base) benzsulfamide (I-55)

Tert-butyl 2- (N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) sulfoamido) benzene first Acid esters (I-57)

Methyl 2- (N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) sulfoamido) benzoic acid Ester (I-58)

2,4- bis- chloro- N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I- 59)

2,4- dimethoxy-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-60)

2,4- dimethyl-N -s (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I- 61)

2- trifluoromethoxy-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-62)

The chloro- 2- methoxyl group-N- of 4- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base)) benzene sulfonyl Amine (I-63)

2- cyano-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-64)

2- methoxyl group-N- (4- methoxyl group -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzene sulphur Amide (I-65)

2- methoxyl group-N- (4- ethyoxyl -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzene sulphur Amide (I-66)

2- methoxyl group-N- (4- tert-butoxy -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzene Sulfonamide (I-67)

2- methoxyl group-N- (4- cyclopentyloxy -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzene Sulfonamide (I-68)

2- methoxyl group-N- (1- methyl -4- (2- morpholine base oxethyl) -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline Quinoline -6- base) benzsulfamide (I-69)

2- methoxyl group-N- (1- methyl -4- (2- (4- methylpiperazine-1-yl) ethyoxyl) -2- oxo -1,2- pyrrolin simultaneously [4, 3,2-de] quinoline -6- base) benzsulfamide (I-70)

Methyl -6- ((2- methoxyphenyl) sulfoamido) -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline Quinoline -4- formic acid esters (I-71)

Tert-butyl -6- ((2- methoxyphenyl) sulfoamido) -1- methyl -2- oxo -1,2- pyrrolin is simultaneously [4,3,2-de] Quinoline -4- formic acid esters (I-72)

N- ethyl -6- ((2- methoxyphenyl) sulfoamido) -1- methyl -2- oxo -1,2- pyrrolin is simultaneously [4,3,2-de] Quinoline -4- formamide (I-73)

N- tert-butylamine -6- ((2- methoxyphenyl) sulfoamido) -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2- De] quinoline -4- formamide (I-74)

N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) -4- (anilino-) benzsulfamide (I- 77)

2- (dimethylamino)-N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) benzsulfamide (I-78)

N- (1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) amyl -2- sulfonamide (I-81)

N- (4- cyano -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) -2- methoxybenzene sulphonyl Amine (I-82)

Ethyl (6- ((2- methoxyphenyl) sulfonamido) -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline Quinoline -4- base) carbamate (I-84)

N- (4- (3- second carbamyl ammonia) -1- methyl -2- oxo -1,2- pyrrolin simultaneously [4,3,2-de] quinoline -6- base) -2- first Oxygroup benzsulfamide (I-85).

4. the compound of any one of claim 1-3 or its pharmaceutically acceptable salt, wherein pharmaceutically acceptable salt includes The acid-addition salts that logical formula (I) compound and following acid are formed: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene sulfonic acid, to first Benzene sulfonic acid, naphthalene sulfonic acids, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, benzene Guanidine-acetic acid, tussol, or containing alkali metal cations, alkaline earth metal cation, ammonium cation salt inorganic base acid Salt.

5. a kind of pharmaceutical composition, wherein containing the described in any item compounds of claim 1-4 or its pharmaceutically-acceptable salts And pharmaceutically acceptable carrier.

6. drug described in the described in any item compounds of claim 1-4 or its pharmaceutically acceptable salt or claim 5 It combines and is preparing the purposes in the drug for preventing or treating clinical disease related with BRD.

7. purposes as claimed in claim 6, wherein disease related with BRD be melanoma, liver cancer, kidney, acute leukemia, Huppert's disease, lymph cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, cutaneum carcinoma, cancer of pancreas, oophoroma, mammary gland Cancer, myelodysplastic syndrome, the cancer of the esophagus, gastrointestinal cancer or celiothelioma.