阅读说明：本技术 苯并喹喔啉酮化合物及其合成方法和用途 (Benzoquinoxalinone compounds, and synthesis method and application thereof ) 是由 王恒山 陈碧炎 黄晓超 黄日镇 覃坚妹 杨金金 陈雪 贾强 褚长虎 胡琼莹 于 2020-06-16 设计创作，主要内容包括：本发明公开了一系列苯并喹喔啉酮化合物及其合成方法和应用,具体涉及式(I)的化合物及其合成方法和其在用于治疗癌症中的用途(The invention discloses a series of benzo-quinoxalinone compounds and a synthesis method and application thereof, in particular to a compound of a formula (I), a synthesis method and application thereof in treating cancers)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein

R is independently selected from hydrogen, halogen, hydroxyl, sulfhydryl and C₁～C₆Alkyl (alkenyl/alkynyl), halo C₁～C₆Alkyl (alkenyl/alkynyl), hydroxy-substituted C₁～C₆Alkyl (alkenyl/alkynyl), amino-substituted C₁～C₆Alkyl (alkenyl/alkynyl), amido substituted C₁～C₆Alkyl (alkenyl/alkynyl), carboxy-substituted C₁～C₆Alkyl (alkenyl/alkynyl), C₁～C₆Alkoxy, benzyl or substituted derivatives thereof, phenyl or substituted derivatives thereof, and five-or six-membered heterocyclic methyl or substituted derivatives thereof;

R₁is hydroxy or C₁～C₆An alkyl group;

R₂is hydrogen, C₂～C₆Acyl or C₅～C₁₀An arylformyl group;

each R is₃Independently selected from hydrogen, halogen, hydroxyl, carboxyl, sulfhydryl and C₁-C₆Mercapto group, C₁-C₆Alkyl (alkenyl/alkynyl), halo C₁～C₆Alkyl (alkenyl/alkynyl), hydroxy-substituted C₁～C₆Alkyl (alkenyl/alkynyl), amino-substituted C₁～C₆Alkyl (alkenyl/alkynyl), acylAmino-substituted C₁～C₆Alkyl (alkenyl/alkynyl), carboxy-substituted C₁～C₆Alkyl (alkenyl/alkynyl), and C₁～C₆An alkoxy group;

m is an integer selected from 1, 2, 3 or 4;

x is O or NH;

a is (CH)₂)_nN is an integer selected from 0, 1, 2, 3, 4, 5, 6 or 7;

b is O or CH₂；

And C is CH₂CH ═ CH or a group represented by the following formula (2I),

wherein

Each R is₄Independently selected from hydrogen, halogen, hydroxyl, carboxyl, sulfhydryl and C₁-C₆Mercapto group, C₁-C₆Alkyl (alkenyl/alkynyl), halo C₁～C₆Alkyl (alkenyl/alkynyl), hydroxy-substituted C₁～C₆Alkyl (alkenyl/alkynyl), amino-substituted C₁～C₆Alkyl (alkenyl/alkynyl), amido substituted C₁～C₆Alkyl (alkenyl/alkynyl), carboxy-substituted C₁～C₆Alkyl (alkenyl/alkynyl), and C₁～C₆An alkoxy group;

s is an integer selected from 1, 2, 3 or 4; t is an integer selected from 0, 1, 2 or 3; u is an integer selected from 0, 1 or 2; the bond of the dotted line may be present or absent, and if the dotted line is present, it represents a double bond, the configuration of (2I) is E formula or Z formula, and if the dotted line is absent, it represents that the bond at the dotted line is not present, and the benzene ring is directly linked to (CH)₂)_tAnd (4) connecting.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R is₃Are all hydrogen.

3. According to claimA compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein when R is₁When it is hydroxy, X is NH, R₂Is hydrogen; when R is₁Is C₁～C₆When alkyl, X is O, wherein C₁～C₆Alkyl is methyl or ethyl, R₂Is hydrogen or acetyl.

4. A compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 wherein R is isopropyl, benzyl or o-methylbenzyl.

5. A compound selected from the group consisting of:

ethyl 4- ((4-acetyl-2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) butyrate;

ethyl 5- ((4-acetyl-2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) pentanoate;

ethyl 6- ((4-acetyl-2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) hexanoate;

ethyl 8- ((4-acetyl-2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) octanoate;

ethyl 4- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) butyrate;

ethyl 5- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) pentanoate;

ethyl 6- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) hexanoate;

ethyl 7- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) heptanoate;

ethyl 8- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) octanoate;

4- ((4-acetyl-2- (2-methylbenzyl) -3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) butyric acid ethyl ester;

ethyl 5- ((4-acetyl-2- (2-methylbenzyl) -3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) pentanoate;

ethyl 7- ((4-acetyl-2- (2-methylbenzyl) -3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) heptanoate;

ethyl 4- (((4-acetyl-2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) methyl) benzoate;

(E) -ethyl 4- (((4-acetyl-2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -2-butenoate;

(E) -methyl 3- (4- (3- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) propoxy) phenyl) acrylate;

(E) -ethyl 4- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -2-butenoate;

ethyl 4- (((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) methyl) benzoate;

ethyl 5- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) pentanoate;

ethyl 6- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) hexanoate;

ethyl 8- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) octanoate;

4- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -N-hydroxybutyramide;

8- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -N-hydroxyoctanoyl amide;

n-hydroxy-4- ((2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) butanamide;

n-hydroxy-5- ((2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) pentanamide;

n-hydroxy-6- ((2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) hexanamide;

n-hydroxy-8- ((2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) octanoamide;

n-hydroxy- (E) -3- (4- (4- ((2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) butoxy) phenyl) acrylamide (Ib-7);

n-hydroxy-5- ((2- (2-methylbenzyl) -3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) pentanamide;

n-hydroxy-6- ((2- (2-methylbenzyl) -3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) hexanamide;

7- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -N-hydroxyheptanamide;

5- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -N-hydroxypentanamide;

6- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -N-hydroxyhexanamide;

4- (((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) methyl) -N-hydroxybenzamide;

n-hydroxy-7- ((2- (2-methylbenzyl) -3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) heptanamide.

6. A method for synthesizing a compound according to claims 1 to 5, said method comprising the steps of:

when R is₁Is C₁～C₆When X is O, the synthesis method comprises the following steps (a) to (d):

or when R is₁When it is hydroxy, X is NH, R₂' the remaining definitions with R, except for excluding hydrogen₂The synthesis method comprises the following steps (a) to (e):

(a) reacting an aminonaphthoquinone with a BOC-amino acid, wherein BOC is t-butyloxycarbonyl;

(b) cyclizing the product obtained in step (a);

(c) reacting the product obtained in step (b) with an acid anhydride R₂’-O-R₂' reaction;

(d) reacting the product obtained in the step (c) with halogenated ester (namely a compound (II)) to obtain a target product Ia, wherein Y in the compound (II) is Cl, Br or I;

(e) reacting the product obtained in step (e) with an alkali metal salt NH of hydroxylamine₂Obtaining a target product Ib by acidification after OM reaction, wherein M is Li, Na or K;

r, R therein₁、R₂、R₃A, B, C and m are as defined in claim 1;

steps (a) to (d) for synthesizing compound (Ia) and compound (Ib) are the same;

when the compound (Ia) is synthesized, if R2 is hydrogen, the target product Ia is obtained by directly reacting the product obtained in the step (b) with halogenated ester (namely the compound (II)) without the step (c);

when R2 is not hydrogen when compound (Ia) is synthesized, compound (Ia) is obtained according to the above steps (a) to (d).

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a compound synthesized according to the method of claim 6, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, excipients, or a combination thereof.

8. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, a compound synthesized by the method of claim 6 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, in the manufacture of a medicament for inhibiting HDAC.

9. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, a compound synthesized by the method of claim 6 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7 for the treatment of cancer.

10. The use according to claim 9, wherein the cancer is selected from the group consisting of colon cancer, rectal cancer, ovarian cancer, liver cancer, stomach cancer, bladder cancer, cervical cancer, lung cancer, kidney cancer, lymphoma, myeloma, breast cancer, prostate cancer, brain cancer and like malignancies.

Technical Field

The invention relates to the technical field of pharmaceutical compounds and medicaments, in particular to a benzoquinoxalinone compound and a synthesis method and application thereof.

Background

The quinoxalinone compounds are nitrogen-containing heterocyclic compounds formed by fusing aromatic ring benzene rings and pyrazine, are heterocyclic compounds with important application values, have various biological activities, and can be used as antitumor agents, HIV-1 reverse transcriptase inhibitors, N-methyl-D-aspartate receptor antagonists, anti (fungal) agents, anticoagulants, hypoglycemic agents and the like. In addition, derivatives of quinoxalinone compounds have also found wide application in dyes, fluorescent materials, semiconductors in Organic Photovoltaic (OPV) cells, pesticides, herbicides, and anthelmintics. Therefore, the compounds have great significance in the research of medicinal chemistry, but no published report on the introduction of long-chain acid ester or long-chain amide functional groups into the benzoquinoxalinone and the application of the compounds in the aspect of tumor resistance exists at present. Therefore, the deep research on the introduction of long-chain acid ester or long-chain amide functional groups into the p-quinoxalinone is beneficial to expanding the wider application of the compound in the field of drug research, and has very important significance for developing new therapeutic drugs.

At present, antitumor drugs based on epigenetic research are more and more favored and valued by researchers. The apparent genetic changes are closely related to the occurrence and development of tumors. By epigenetic modification is meant the realization of heritable regulatory mechanisms for gene expression independent of DNA sequence changes, the core of which is chromatin remodeling. Chromatin can be adapted to a relatively "open" or "closed" structure by modification of the nucleosome, the basic unit of chromatin. Nucleosomes are composed of DNA and histones, the amino acid residues of which can be modified by a variety of biological processes, such as acetylation, methylation, phosphorylation, ubiquitination, poly-ADP ribosylation, and the like. By specific modification, chromatin "turns on" or "turns off" the expression of genes, thereby silencing or activating tumor suppressor genes, resulting in the arrest of cell proliferation and induction of apoptosis.

Methylation and acetylation are 2 major directions for the study of epigenetic anti-tumor therapeutic strategies. Methylation is the silencing of downstream genes by the addition of a methyl group to a particular DNA sequence reading frame by the action of DNA methyltransferase. Acetylation is the addition or removal of acetyl groups to or from histones by the combined action of Histone Acetyltransferases (HATs) and Histone Deacetylases (HDACs). HATs can add acetyl groups, leading to "relaxation" of histone structure, to facilitate initiation of transcription; HDACs remove acetyl groups, resulting in a relatively "compact" structure of histones, thereby inhibiting the transcriptional activity of the associated genes.

It is generally accepted that a broad range of epigenetic interferences can be closely linked to tumor genetics by activating tumor genes, discarding southern blots, disrupting gene stability, and the like. It was found that malignant tumor tissues carry more aberrant epigenetic modifications than normal tissues. At the same time, as the degree of malignancy increases, the degree of abnormal epigenetic modification also increases. Many documents report that the acetylation state of histone is one of the important characteristics of tumor generation and evolution, and research finds that many tumor cells and tissues show a state of histone acetylation obviously lower than normal cells and tissues, and histone deacetylation does not show an obvious overexpression state. Recent studies have shown that histone deacetylase shows a very high potential as an effective drug target in therapeutic studies to try to restore epigenetic normative tumors. Researchers develop HDAC inhibitors, show excellent anti-tumor activity and tumor selectivity by up-regulating the acetylation degree of histone, prompt that the development of HDAC inhibitors has good application prospect, and open up a new idea for providing new markers for tumor diagnosis and prevention and treatment, developing new lead structures with high efficiency and low toxicity, and innovative drugs.

There are a total of 18 HDAC enzyme subtypes: class I HDACs (including HDAC1, HDAC2, HDAC3 and HDAC8), class II HDACs (including HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10), class III HDACs (including SIRT1-7), class IV HDACs (HDAC 11). The HDAC inhibitor can be hydroxamic acid, cyclic peptide, benzamide, short chain fatty acid, and other compounds. Among them, a representative compound of hydroxamic acid type HDAC inhibitors is SAHA (Vorinostat, trade name: Zolinza), which is the first HDAC inhibitor approved by FDA (2006). At present, an anti-tumor medicament taking benzoquinoxalinone long-chain acid ester or long-chain amide as an HDAC inhibitor does not exist clinically, so that the development of the benzoquinoxalinone long-chain acid ester or long-chain amide can expand the range of HDAC and open up a new medicament for tumor treatment.

Disclosure of Invention

According to one aspect of the present invention, there is provided a compound having the structure of formula (I):

wherein

R is independently selected from hydrogen, halogen, hydroxyl, sulfhydryl and C₁～C₆Alkyl (alkenyl/alkynyl), halo C₁～C₆Alkyl (alkenyl/alkynyl), substituted hydroxy C₁～C₆Alkyl (alkenyl/alkynyl), optionally substituted amino C₁～C₆Alkyl (alkenyl/alkynyl), substituted amido C₁～C₆Alkyl (alkenyl/alkynyl), substituted carboxy C₁～C₆Alkyl (alkenyl/alkynyl), C₁～C₆Alkoxy, benzyl or substituted derivatives thereof, phenyl or substituted groups thereof, and five-or six-membered heterocyclic methyl or substituted derivatives thereof;

R₁is hydroxy or C₁～C₆An alkyl group;

R₂is hydrogen, C₂～C₆Acyl or C₅～C₁₀An arylformyl group;

each R is₃Independently selected from hydrogen, halogen, hydroxyl, carboxyl, sulfhydryl and C₁-C₆Mercapto group, C₁-C₆Alkyl (alkenyl/alkynyl), halo C₁～C₆Alkyl (alkenyl/alkynyl), hydroxy-substituted C₁～C₆Alkyl (alkenyl/alkynyl), amino-substituted C₁～C₆Alkyl (alkenyl/alkynyl), amido substituted C₁～C₆Alkyl (alkenyl/alkynyl), carboxy-substituted C₁～C₆Alkyl (alkenyl/alkynyl), C₁～C₆An alkoxy group;

m is an integer selected from 1, 2, 3 or 4;

x is O or NH;

a is (CH)₂)_nN is an integer selected from 0, 1, 2, 3, 4, 5, 6 or 7;

b is O or CH₂；

And C is CH₂CH ═ CH or a group represented by the following formula (2I),

wherein

Each R is₄Independently selected from hydrogen, halogen, hydroxyl, carboxyl, sulfhydryl and C₁-C₆Mercapto group, C₁-C₆Alkyl (alkenyl/alkynyl), halo C₁～C₆Alkyl (alkenyl/alkynyl), hydroxy-substituted C₁～C₆Alkyl (alkenyl/alkynyl), amino-substituted C₁～C₆Alkyl (alkenyl/alkynyl), amido substituted C₁～C₆Alkyl (alkenyl/alkynyl), carboxy-substituted C₁～C₆Alkyl (alkenyl/alkynyl), and C₁～C₆An alkoxy group;

s is an integer selected from 1, 2, 3 or 4; t is an integer selected from 0, 1, 2 or 3; u is an integer selected from 0, 1 or 2; the bond of the dotted line may be present or absent, and if the dotted line is present, it represents a double bond, the configuration of (2I) is E formula or Z formula, and if the dotted line is absent, it represents the configuration at the dotted lineThe bond also being absent, the benzene ring being directly linked to (CH)₂) t are connected.

In one embodiment of the present invention, wherein each R is₃Are all hydrogen.

In one embodiment of the invention, when R is₁When it is hydroxy, X is NH, R₂Is hydrogen; when R is₁Is C₁～C₆When alkyl, X is O, wherein C₁～C₆Alkyl is methyl or ethyl, R₂Is hydrogen or acetyl.

In one embodiment of the invention, R is isopropyl, benzyl, o-methylbenzyl.

According to another aspect of the present invention there is provided a compound selected from:

ethyl 4- ((4-acetyl-2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) butyrate;

ethyl 5- ((4-acetyl-2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) pentanoate;

ethyl 6- ((4-acetyl-2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) hexanoate;

ethyl 8- ((4-acetyl-2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) octanoate;

ethyl 4- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) butyrate;

ethyl 5- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) pentanoate;

ethyl 6- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) hexanoate;

ethyl 7- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) heptanoate;

ethyl 8- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) octanoate;

4- ((4-acetyl-2- (2-methylbenzyl) -3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) butyric acid ethyl ester;

ethyl 5- ((4-acetyl-2- (2-methylbenzyl) -3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) pentanoate;

ethyl 7- ((4-acetyl-2- (2-methylbenzyl) -3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) heptanoate;

ethyl 4- (((4-acetyl-2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) methyl) benzoate;

(E) -ethyl 4- (((4-acetyl-2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -2-butenoate;

(E) -methyl 3- (4- (3- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) propoxy) phenyl) acrylate;

(E) -ethyl 4- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -2-butenoate;

ethyl 4- (((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) methyl) benzoate;

ethyl 5- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) pentanoate;

ethyl 6- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) hexanoate;

ethyl 8- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) octanoate;

4- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -N-hydroxybutyramide;

8- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -N-hydroxyoctanoyl amide;

n-hydroxy-4- ((2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) butanamide;

n-hydroxy-5- ((2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) pentanamide;

n-hydroxy-6- ((2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) hexanamide;

n-hydroxy-8- ((2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) octanoamide;

n-hydroxy- (E) -3- (4- (4- ((2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) butoxy) phenyl) acrylamide (Ib-7);

n-hydroxy-5- ((2- (2-methylbenzyl) -3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) pentanamide;

n-hydroxy-6- ((2- (2-methylbenzyl) -3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) hexanamide;

7- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -N-hydroxyheptanamide;

5- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -N-hydroxypentanamide;

6- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -N-hydroxyhexanamide;

4- (((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) methyl) -N-hydroxybenzamide;

n-hydroxy-7- ((2- (2-methylbenzyl) -3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) heptanamide.

"pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not destroy the biological activity and properties of the compound. The drug salts can be obtained by reacting the compounds with inorganic acids such as hydrohalic acids (e.g., hydrochloric or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxylic or sulfonic acid, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, for example, an ammonium salt, an alkali metal salt such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, a salt such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, C₁-C₇Alkylamine, cyclohexylamine, trisEthanolamine, organic base salts of ethylenediamine, and salts with amino acids such as arginine and lysine.

The compounds of the invention have geometric configurations (Z and E), and individual isomers and mixtures thereof are also encompassed by the invention.

Any of the compounds having a chiral carbon among the compounds of the present invention, and the respective optical isomers and racemates thereof are also included in the present invention. The optical isomers are obtained by optical fiber isolation from the racemic modification obtained above by using the basicity thereof and using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) by a known method, or are obtained by using an optically active compound prepared in advance as a raw material.

According to another aspect of the present invention there is provided a method of synthesizing a compound of formula (I), said method of synthesis comprising the steps of:

when R is₁Is C₁～C₆When X is O, the compound of formula (I) is a compound of formula (Ia), and the synthesis method comprises the following steps (a) to (e):

or when R is₁When it is hydroxy, X is NH, R₂' the remaining definitions with R, except for excluding hydrogen₂The compound of formula (I) is a compound of formula (Ib), and the synthesis method comprises the following steps (a) to (f):

(a) reacting an aminonaphthoquinone with a BOC-amino acid, wherein BOC-refers to t-butyloxycarbonyl;

(b) cyclizing the product obtained in step (a);

(c) reacting the product obtained in step (b) with an acid anhydride R₂’-O-R₂' reaction;

(d) reacting the product obtained in the step (c) with halogenated ester (namely a compound (II)) to obtain a target product Ia, wherein Y in the compound (II) is Cl, Br or I;

(e) reacting the product obtained in step (e) with an alkali metal salt NH of hydroxylamine₂Obtaining a target product Ib by acidification after OM reaction, wherein M is Li, Na or K;

r, R therein₁、R₂、R₃A, B, C and m are as described above;

steps (a) to (d) for synthesizing compound (Ia) and compound (Ib) are the same;

when compound (Ia) is synthesized, if R₂If the hydrogen is hydrogen, then the product obtained in the step (b) directly reacts with the halogenated ester (i.e. the compound (II)) to obtain a target product Ia without the step (c);

when compound (Ia) is synthesized, if R₂If not hydrogen, the compound (Ia) is obtained according to the above steps (a) to (d).

The method for synthesizing the compounds (Ia) and (Ib), wherein:

the reaction condition of the step (a) is that under the condition that a catalyst 1-hydroxybenzotriazole and a condensing agent 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride exist, the reaction is carried out for 12-24 hours, preferably 16-20 hours in aprotic polar solvents such as dichloromethane, acetonitrile, tetrahydrofuran, N-dimethylformamide and the like at-10-40 ℃, preferably-5-30 ℃;

the reaction condition of the step (b) is that cyclization reaction is carried out at 10-35 ℃ in the presence of trifluoroacetic acid;

the reaction condition of the step (c) is that organic alkali and inorganic alkali such as triethylamine, pyridine, N diisopropylethylamine, sodium methoxide, potassium methoxide, sodium ethoxide, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like react for 2-5 hours at 40-100 ℃, preferably 60-80 ℃ in the presence of catalyst alkali;

the reaction conditions of step (d) are in the presence of a base, including organic and inorganic bases;

and (e) acidifying after the reaction condition of the step (e) is at 20-30 ℃ for 20-2 hours, preferably 30-1 hour.

According to another aspect of the present invention there is provided a pharmaceutical composition comprising a compound having activity herein or a pharmaceutically acceptable salt thereof, or a compound obtained according to a process for the synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, excipients or a combination thereof.

The compounds of the invention having activity may be used as such or in the form of pharmaceutical compositions for use as medicaments. The pharmaceutical compositions contain 0.1 to 99%, preferably 0.5 to 90%, of the active compounds according to the invention, the remainder being pharmaceutically acceptable, non-toxic and inert pharmaceutically acceptable carriers for humans and animals.

Optionally, the pharmaceutical composition contains the active compound in a proportion of 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%.

Pharmaceutically acceptable carriers are one or more of solid, semi-solid and liquid diluents, fillers and pharmaceutical product excipients. The pharmaceutical composition of the present application is used in the form of an amount to be administered per unit body weight. The agents for use in the present application may take dosage forms customary in the art, for example: ointment, tablet, pill, suppository emulsion, infusion solution, injection, etc. These dosage forms are prepared according to well-known methods using conventional additives and excipients. The medicine thus prepared may be administered topically, parenterally, orally, etc. as required.

The amount of the compound having activity of the present invention to be administered may vary depending on the route of administration, age, body weight of the patient, type and severity of the disease to be treated, etc., and the daily dose may be 0.01 to 10mg/kg body weight, preferably 0.1 to 5mg/kg body weight. One or more administrations may be carried out.

According to another aspect of the present invention there is provided the use of a compound of the present application or a pharmaceutically acceptable salt thereof, a compound obtained according to a process for the synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for the inhibition of HDAC.

According to another aspect of the invention there is provided the use of a compound of the present application or a pharmaceutically acceptable salt thereof, a compound obtained according to a process for the synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the treatment of cancer.

The cancer is selected from malignant tumors such as colon cancer, rectal cancer, ovarian cancer, liver cancer, stomach cancer, bladder cancer, cervical cancer, lung cancer, kidney cancer, lymphoma, myeloma, breast cancer, prostate cancer, brain cancer and the like.

Drawings

FIG. 1 is a blank control chart of the apoptosis test.

FIG. 2 is an apoptosis test chart of SAHA (2. mu.M) as a positive control drug.

FIG. 3 is a graph showing an apoptosis test of Compound Ib-10 (2. mu.M) according to the present invention.

FIG. 4 is an apoptosis test chart of SAHA (4. mu.M) as a positive control drug.

FIG. 5 is a graph showing an apoptosis test of the compound Ib-10 (4. mu.M) of the present invention.

FIG. 6 is an apoptosis test chart of SAHA (8 μ M) as a positive control drug.

FIG. 7 is a graph showing an apoptosis test of the compound Ib-10 (8. mu.M) of the present invention.

Detailed Description

The present invention is further illustrated by the following specific examples, but the present invention is not limited to these examples.

The reagents used in the examples of the invention were as follows:

1, 4-naphthoquinone, benzyloxyamine hydrochloride, BOC-L-phenylalanine, BOC-L-valine, BOC-L-2-methylphenylalanine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, ethyl 4-bromobutyrate, ethyl 5-bromovalerate, ethyl 6-bromohexanoate, ethyl 7-bromohexanoate, ethyl 8-bromohexanoate, ethyl 4-bromobutenoate, ethyl 4- (bromomethyl) benzoate, methyl 4-hydroxycinnamate, 1, 3-dibromopropane, 1, 4-dibromobutane and hydroxylamine hydrochloride, wherein the methyl ferulate is analytically pure, and the reagents are purchased from Inoka technologies GmbH;

anhydrous acetonitrile, triethylamine, pyridine, acetic anhydride, trifluoroacetic acid, citric acid, sodium bicarbonate, potassium carbonate, sodium chloride, sodium hydroxide, anhydrous sodium sulfate, methanol, dichloromethane, anhydrous ethanol, petroleum ether, ethyl acetate and concentrated hydrochloric acid, all of which are analytically pure, and the reagents are purchased from Guangzhou Gangong chemical plant;

the apparatus and equipment used in the embodiment of the invention are as follows:

SHB-IIIA circulating water multi-purpose vacuum pump, rotary evaporator (Zhengzhou great wall science and trade Co., Ltd.); an electronic intelligent temperature controller, a 85-1A type magnetic stirrer (Chenghua instruments, Inc., of Chengyi city); AVANCE AV 400Hz superconducting NMR spectrometer (Bruker, Switzerland); EL104 electronic balance (mettler-toledo instruments ltd); KQ5200E ultrasonic cleaner (kunshan ultrasonic instruments ltd); DHG-9140A type electric heating constant temperature air blast drying oven (shanghai-chang scientific instruments ltd); rotary evaporator N-1300V-W (tokyo physical & chemical company, japan); agilent6545Q-TOF LS/MS LC-MS (Agilent technologies, Inc., USA).

Preparation example 1: synthesis of starting Material 2-amino-1, 4-naphthoquinone

4.79g of benzyloxyamine hydrochloride was weighed into a 500mL round-bottomed flask, 120mL of anhydrous ethanol and 3.03g of triethylamine were added thereto at 5 ℃ to stir the mixture sufficiently, and a 50mL anhydrous ethanol solution of 7.12g of 1, 4-naphthoquinone was added dropwise to the mixture. The mixture was left to react at room temperature for 2 to 5 hours with stirring, and the reaction was followed by thin layer chromatography. After the reaction is finished, the solvent is dried by spinning under reduced pressure, and is dissolved again by ethyl acetate, and the orange compound 2-amino-1, 4-naphthoquinone is obtained by silica gel column chromatography, wherein the yield is 92%.

Preparation example 2: synthesis of haloalkyl ester ((E) -methyl 3- (4- (3-bromopropoxy) -3-methoxyphenylacrylate), (E) -methyl 3- (4- (4-bromobutoxy) -3-methoxyphenylacrylate), (E) -methyl 3- (4- (3-bromopropoxy) phenyl) acrylate and (E) -methyl 3- (4- (4-bromobutoxy) phenyl) acrylate)

Adding omega-dihaloalkane, anhydrous acetonitrile and K into a round-bottom flask in sequence₂CO₃And esters, molar ratio: 1.5: 20-50: 21, stirring the mixture at 60-70 ℃ for 2-8 hours. The mixture was concentrated, water and ethyl acetate were added, extracted, the organic phase was separated, concentrated to collect the organic phase, and further purified by column chromatography to give the haloalkane ester as a colorless oil. The ester selected in the synthesis method is 4-hydroxy methyl cinnamate and ferulic acid methyl ester; omega-dihaloalkanes are 1, 3-dibromopropane, 1, 4-dibromobutane.

Preparation example 3: hydroxylamine potassium salt (NH)₂OK) Synthesis

Adding excessive potassium hydroxide into anhydrous methanol to prepare saturated solution, slowly dripping 14ml of the saturated solution into 24ml of anhydrous methanol solution containing 4.67g of hydroxylamine hydrochloride, controlling the temperature in the reaction solution to be lower than 40 ℃, controlling the dripping speed to be lower than 3 drops/second, reacting overnight after dripping is finished, and carrying out reduced pressure suction filtration on the compound for use.

Example 1 Synthesis of Compounds of formula (Ia) (Compounds Ia-1 to Ia-20)

(1) Synthesis of the intermediate obtained in step (a)

Adding BOC-amino acid (comprising BOC-L-phenylalanine, BOC-L-valine and BOC-L-2-methyl phenylalanine), dichloromethane, 1-hydroxybenzotriazole, triethylamine, 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride and 2-amino-1, 4-naphthoquinone into a flask at 0 ℃ while stirring, wherein the molar ratio of the two components is 1.3: 5: 1.3: 1, reacting at 0 ℃ for 1 hour after all the reactants are added, then reacting at room temperature for 16-20 hours, and tracking and monitoring the reaction by using thin layer chromatography. After the reaction is completed, washing the reaction solution with 0.1mol/L hydrochloric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution in sequence, wherein the volume ratio of the solution to the solvent is 1: 2, drying the solution with anhydrous sodium sulfate, and performing silica gel column chromatography (petroleum ether: ethyl acetate is 8: 1-6: 1, and the volume ratio) to obtain a yellow solid, namely the intermediate obtained in the step (a).

(2) Synthesis of the intermediate obtained in step (b)

The yellow solid product obtained in step (a): dichloromethane trifluoroacetic acid in a molar ratio of 1: 30: 8 was added to the reaction flask, and the mixture was stirred at room temperature for 12-24 hours, during which the reaction was monitored by thin layer chromatography. After the reaction is completed, the reaction liquid is decompressed and dried, ethyl acetate is added to dissolve the reaction liquid, a proper amount of water is added to extract the reaction liquid, an organic layer is separated out, an aqueous layer is extracted by ethyl acetate for three times, the organic layers are combined, drying the mixture by using anhydrous sodium sulfate, and purifying the mixture by using silica gel column chromatography (dichloromethane: methanol is 15: 1, volume ratio) to obtain a light yellow product which is substituted benzo [ f ] quinoxaline-3 (4H) -ketone, namely 2-benzyl-6-hydroxybenzo [ f ] quinoxaline-3 (4H) -ketone, 6-hydroxy-2-isopropylbenzo [ f ] quinoxaline-3 (4H) -ketone and 6-hydroxy-2- (2-methylphenyl) benzo [ f ] quinoxaline-3 (4H) -ketone, namely the intermediate obtained in the step (b).

(3) Synthesis of the intermediate obtained in step (c) (optionally, if R₂Is H, this step is not present)

Adding the substituted benzo [ f ] quinoxaline-3 (4H) -ketone obtained in the step (b), anhydrous acetonitrile, triethylamine and acetic anhydride into a flask, adding the materials according to the molar ratio of 1: 30: 1: 1.2, placing the materials at 80 ℃, stirring, refluxing and reacting for 2-5 hours, after the reaction is finished, carrying out suction filtration on reaction liquid, washing filter residues by using the anhydrous acetonitrile, carrying out reduced pressure spin-drying on filter residues, dissolving the filter residues by using ethyl acetate, adding water, extracting for 3 times by using ethyl acetate, drying an organic phase by using anhydrous sodium sulfate, combining the filter residues and the organic phase, and carrying out silica gel column chromatography (petroleum ether: ethyl acetate is 6: 1 in volume ratio) to obtain a light green solid product which is an acylation product and is an intermediate obtained in the step (c).

(4) Synthesis of Compound (Ia)

Adding the intermediate obtained in the step (c) or the intermediate obtained in the step (b) into a flask, adding potassium carbonate, acetone and alkyl halide according to the molar ratio of 1: 3.6: 3: 1.2, heating and refluxing the mixture for 5-8 hours, and monitoring the reaction by tracking with thin layer chromatography. After the reaction is completed, the reaction solution is filtered under reduced pressure, the filter residue is washed by dichloromethane, the filter residue is discarded, the filtrate is collected, the filtrate is dried under reduced pressure, and silica gel column chromatography (petroleum ether: ethyl acetate: 30: 1, volume ratio) is carried out to obtain white solid. The alkyl halide selected in this step is ethyl 4- (bromomethyl) benzoate, ethyl 4-bromobutyrate, ethyl 5-bromovalerate, ethyl 6-bromohexanoate, ethyl 7-bromoheptanoate, ethyl 8-bromooctanoate, ethyl 4-bromobutenoate, methyl (E) -3- (4- (2-bromoethoxy) phenyl) acrylate, methyl (E) -3- (4- (3-bromopropoxy) -3-methoxyphenyl) acrylate and methyl (E) -3- (4- (4-bromobutoxy) phenyl) acrylate.

The chemical names and parameters of the compounds of formula (Ia) are characterized as follows:

4- ((4-acetyl-2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) butyric acid ethyl ester (Ia-1)

Total yield of the route: 36.2 percent. A white solid.¹H NMR(400MHz，CDCl₃)δ9.17(d，J＝8.2Hz，1H)，7.94(d，J＝8.0Hz，1H)，7.77-7.72(m，1H)，7.69-7.64(m，1H)，7.55(s，1H)，7.37(d，J＝7.3Hz，2H)，7.30-7.25(m，2H)，7.19(t，J＝7.3Hz，1H)，4.50(t，J＝6.1Hz，2H)，4.39(s，2H)，4.15(q，J＝7.1Hz，2H)，2.50(s，3H)，2.38(t，J＝7.5Hz，2H)，2.19-2.09(m，2H)，1.27(t，J＝7.1Hz，3H)。¹³C NMR(101MHz，CDCl₃) δ 173.12, 169.10, 156.86, 147.82, 146.53, 138.68, 137.97, 133.87, 131.77, 129.24, 129.24, 128.38, 128.38, 127.79, 127.32, 126.44, 126.19, 124.22, 121.37, 116.91, 65.58, 60.48, 39.94, 30.87, 24.26, 21.10, 14.27. HR-MS (m/z): is calculated as C₂₇H₂₆N₂O₅Na[M+Na]⁺: 481.1739, respectively; measured value: 481.1740.

ethyl 5- ((4-acetyl-2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) pentanoate (Ia-2)

Total yield of the route: 37.5 percent. A white solid.¹H NMR(400MHz，CDCl₃)δ9.16(d，J＝8.2Hz，1H)，7.93(d，J＝8.1Hz，1H)，7.76-7.71(m，1H)，7.67-7.62(m，1H)，7.55(s，1H)，7.38(d，J＝7.4Hz，2H)，7.26(dd，J＝12.0，4.2Hz，2H)，7.18(t，J＝7.3Hz，1H)，4.46(t，J＝6.2Hz，2H)，4.38(s，2H)，4.15(q，J＝7.1Hz，2H)，2.49(s，3H)，2.36(t，J＝7.3Hz，2H)，1.89-1.80(m，2H)，1.78-1.70(m，2H)，1.26(t，J＝7.1Hz，3H)。¹³C NMR(101MHz，CDCl₃)δ173.49，169.19，157.09，147.86，146.73，138.80，138.13，133.92，131.92，129.38, 129.38, 128.42, 128.42, 127.84, 127.35, 126.47, 126.24, 124.28, 121.45, 117.03, 66.15, 60.44, 40.03, 34.03, 28.36, 21.73, 21.19, 14.40. HR-MS (m/z): is calculated as C₂₈H₂₈N₂O₅Na[M+Na]⁺: 495.1896, respectively; measured value: 495.1890.

ethyl 6- ((4-acetyl-2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) hexanoate (Ia-3)

Total yield of the route: 34.3 percent. A white solid.¹H NMR(400MHz，CDCl₃)δ9.13(d，J＝7.9Hz，1H)，7.90(d，J＝8.0Hz，1H)，7.74-7.68(m，1H)，7.65-7.60(m，1H)，7.52(s，1H)，7.34(d，J＝7.3Hz，2H)，7.27-7.21(m，2H)，7.16(t，J＝7.3Hz，1H)，4.42(t，J＝6.4Hz，2H)，4.35(s，2H)，4.11(q，J＝7.1Hz，2H)，2.47(s，3H)，2.27(t，J＝7.5Hz，2H)，1.84-1.75(m，2H)，1.66(dt，J＝15.3，7.6Hz，2H)，1.44-1.34(m，2H)，1.23(t，J＝7.1Hz，3H)。¹³C NMR(101MHz，CDCl₃) δ 173.76, 169.22, 157.20, 147.86, 146.77, 138.85, 138.19, 133.89, 131.95, 129.38, 129.38, 128.43, 128.43, 127.84, 127.34, 126.49, 126.24, 124.29, 121.46, 117.07, 66.45, 60.40, 40.06, 34.39, 28.63, 25.80, 24.83, 21.21, 14.42. HR-MS (m/z): is calculated as C₂₉H₃₀N₂O₅Na[M+Na]⁺: 509.2052, respectively; measured value: 509.2048.

ethyl 8- ((4-acetyl-2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) octanoate (Ia-4)

Total yield of the route: 38.7 percent. A white solid.¹H NMR(400MHz，CDCl₃)δ9.15(d，J＝8.0Hz，1H)，7.92(d，J＝8.1Hz，1H)，7.76-7.71(m，1H)，7.67-7.62(m，1H)，7.55(s，1H)，7.38(d，J＝7.3Hz，2H)，7.28-7.24(m，2H)，7.18(t，J＝7.3Hz，1H)，4.44(t，J＝6.5Hz，2H)，4.37(s，2H)，4.12(q，J＝7.1Hz，2H)，2.49(s，3H)，2.30(t，J＝7.5Hz，2H)，1.83-1.75(m，2H)，1.64(dd，J＝14.5，7.2Hz，2H)，1.41-1.31(m，6H)，1.25(t，J＝7.1Hz，3H)。¹³C NMR(101MHz，CDCl₃) δ 173.64, 168.91, 156.96, 147.51, 146.50, 138.55, 137.88, 133.53, 131.64, 129.08, 129.08, 128.09, 128.09, 127.50, 126.99, 126.16, 125.90, 123.96, 121.13, 116.77, 66.39, 60.00, 39.71, 34.18, 28.88, 28.81, 28.55, 25.72, 24.74, 20.88, 14.09. HR-MS (m/z): is calculated as C₃₁H₃₄N₂O₅Na[M+Na]⁺: 537.2365, respectively; measured value: 537.2359.

4- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) butyric acid ethyl ester (Ia-5)

Total yield of the route: 32.7 percent. A white solid.¹H NMR(400MHz，CDCl₃)δ9.18(d，J＝8.2Hz，1H)，7.92(d，J＝8.2Hz，1H)，7.73(t，J＝7.6Hz，1H)，7.64(t，J＝7.5Hz，1H)，7.56(s，1H)，4.55(t，J＝6.2Hz，2H)，4.17(q，J＝7.1Hz，2H)，3.61-3.49(m，1H)，2.56(t，J＝7.4Hz，2H)，2.50(s，3H)，2.27-2.19(m，2H)，1.43(d，J＝6.8Hz，6H)，1.26(t，J＝7.1Hz，3H)。¹³C NMR(101MHz，CDCl₃) δ 173.13, 169.17, 156.31, 152.44, 147.45, 137.92, 133.71, 131.90, 127.60, 127.14, 126.11, 124.21, 121.29, 116.92, 65.44, 60.54, 31.15, 30.59, 24.37, 21.10, 20.73, 20.73, 14.26. HR-MS (m/z): is calculated as C₂₃H₂₆N₂O₅Na[M+Na]⁺: 433.1739, respectively; measured value: 433.1732.

ethyl 5- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) pentanoate (Ia-6)

Total yield of the route: 31.1 percent. A white solid.¹H NMR(400MHz，CDCl₃)δ9.18(d，J＝7.9Hz，1H)，7.92(d，J＝7.9Hz，1H)，7.75-7.70(m，1H)，7.64(ddd，J＝8.2，7.0，1.2Hz，1H)，7.56(s，1H)，4.52(t，J＝6.0Hz，2H)，4.15(q，J＝7.1Hz，2H)，3.56(hept，J＝6.8Hz，1H)，2.49(s，3H)，2.43(t，J＝7.1Hz，2H)，1.97-1.83(m，4H)，1.43(d，J＝6.8Hz，6H)，1.26(t，J＝7.1Hz，3H)。¹³C NM[R(101MHz，CDCl₃)δ173.45，169.17，156.46,152.52, 147.42, 137.97, 133.61, 131.93, 127.57, 127.09, 126.08, 124.19, 121.29, 116.96, 65.90, 60.36, 33.98, 30.63, 28.36, 21.82, 21.09, 20.72, 20.72, 14.28. HR-MS (m/z): is calculated as C₂₄H₂₈N₂O₅Na[M+Na]⁺: 447.1896, respectively; measured value: 447.1892.

ethyl 6- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) hexanoate (Ia-7)

Total yield of the route: 28.9 percent. A white solid.¹H NMR(400MHz，CDCl₃)δ9.18(d，J＝8.2Hz，1H)，7.91(d，J＝8.1Hz，1H)，7.74-7.69(m，1H)，7.65-7.60(m，1H)，7.56(s，1H)，4.49(t，J＝6.5Hz，2H)，4.13(q，J＝7.1Hz，2H)，3.55(hept，J＝6.8Hz，1H)，2.48(s，3H)，2.35(t，J＝7.5Hz，2H)，1.93-1.85(m，2H)，1.75(dt，J＝15.2，7.5Hz，2H)，1.58-1.51(m，2H)，1.43(d，J＝6.8Hz，6H)，1.25(t，J＝7.1Hz，3H)。¹³C NMR(101MHz，CDCl₃) δ 173.62, 169.16, 156.53, 152.51, 147.41, 138.01, 133.55, 131.93, 127.55, 127.06, 126.06, 124.17, 121.29, 116.97, 66.19, 60.28, 34.31, 30.66, 28.58, 25.86, 24.75, 21.07, 20.70, 20.70, 14.29. HR-MS (m/z): is calculated as C₂₅H₃₀N₂O₅Na[M+Na]⁺: 461.2052, respectively; measured value: 461.2048.

ethyl 7- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) heptanoate (Ia-8)

Total yield of the route: 29.7 percent. A white solid.¹H NMR(400MHz，CDCl₃)δ9.18(d，J＝7.9Hz，1H)，7.92(d，J＝8.1Hz，1H)，7.71(dd，J＝11.2，4.0Hz，1H)，7.63(t，J＝7.6Hz，1H)，7.57(s，1H)，4.49(t，J＝6.5Hz，2H)，4.13(q，J＝7.1Hz，2H)，3.56(hept，J＝6.8Hz，1H)，2.49(s，3H)，2.32(t，J＝7.5Hz，2H)，1.92-1.83(m，2H)，1.73-1.64(m，2H)，1.54(dt，J＝14.5，7.1Hz，2H)，1.47-1.39(m，8H)，1.25(t，J＝7.1Hz，3H)。¹³C NMR(101MHz，CDCl3)δ173.76，169.16，156.57，152.54，147.37, 138.01, 133.52, 131.93, 127.53, 127.03, 126.03, 124.15, 121.27, 116.97, 66.33, 60.24, 34.30, 30.67, 28.87, 28.69, 25.94, 24.93, 21.08, 20.70, 20.70, 14.29. HR-MS (m/z): is calculated as C₂₆H₃₂N₂O₅Na[M+Na]⁺: 475.2209, respectively; measured value: 475.2204.

ethyl 8- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) octanoate (Ia-9)

Total yield of the route: 30.6 percent. A white solid.¹H NMR(400MHz，CDCl₃)δ9.18(d，J＝8.2Hz，1H)，7.92(d，J＝8.1Hz，1H)，7.73(dd，J＝11.1，4.0Hz，1H)，7.66-7.61(m，1H)，7.57(s，1H)，4.50(t，J＝6.5Hz，2H)，4.13(q，J＝7.1Hz，2H)，3.56(hept，J＝6.8Hz，1H)，2.50(s，3H)，2.31(t，J＝7.5Hz，2H)，1.91-1.83(m，2H)，1.66(dt，J＝14.7，7.5Hz，2H)，1.57-1.48(m，2H)，1.45-1.36(m，10H)，1.25(t，J＝7.1Hz，3H)。¹³C NMR(101MHz，CDCl₃) δ 173.85, 169.18, 156.60, 152.59, 147.35, 138.00, 133.50, 131.94, 127.53, 127.02, 126.02, 124.16, 121.26, 116.97, 66.43, 60.21, 34.37, 30.66, 29.10, 29.03, 28.80, 26.07, 24.94, 21.10, 20.68, 20.68, 14.29. HR-MS (m/z): is calculated as C₂₇H₃₄N₂O₅Na[M+Na]⁺: 489.2365, respectively; measured value: 489.2361.

4- ((4-acetyl-2- (2-methylbenzyl) -3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) butyric acid ethyl ester (Ia-10)

Total yield of the route: 39.1 percent. A white solid.¹H NMR(400MHz，CDCl₃)δ9.06-9.02(m，1H)，7.93(d，J＝7.7Hz，1H)，7.73-7.69(m，1H)，7.67-7.62(m，1H)，7.56(s，1H)，7.23-7.17(m，2H)，7.16-7.07(m，2H)，4.52(t，J＝6.2Hz，2H)，4.38(s，2H)，4.15(q，J＝7.1Hz，2H)，2.50(s，3H)，2.48(s，3H)，2.38(t，J＝7.5Hz，2H)，2.20-2.12(m，2H)，1.27(t，J＝7.1Hz，3H)。¹³C NMR(101MHz，CDCl₃)δ173.10，169.12，156.89，147.78，146.30，138.48，137.02,136.36, 133.82, 131.79, 130.27, 129.85, 127.80, 127.28, 126.60, 126.16, 125.79, 124.15, 121.33, 116.90, 65.62, 60.48, 37.21, 30.87, 24.26, 21.10, 20.06, 14.27. HR-MS (m/z): is calculated as C₂₈H₂₈N₂O₅Na[M+Na]⁺: 495.1896, respectively; measured value: 495.1890.

ethyl 5- ((4-acetyl-2- (2-methylbenzyl) -3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) pentanoate (Ia-11)

Total yield of the route: 34.8 percent. A white solid.¹H NMR(400MHz，CDCl₃)δ9.03(d，J＝8.2Hz，1H)，7.92(d，J＝8.0Hz，1H)，7.73-7.68(m，1H)，7.66-7.61(m，1H)，7.56(s，1H)，7.24-7.21(m，1H)，7.18(d，J＝6.8Hz，1H)，7.15-7.07(m，2H)，4.49(t，J＝6.3Hz，2H)，4.38(s，2H)，4.14(q，J＝7.1Hz，2H)，2.50(s，3H)，2.48(s，3H)，2.36(t，J＝7.4Hz，2H)，1.91-1.83(m，2H)，1.78-1.70(m，2H)，1.26(t，J＝7.1Hz，3H)。¹³C NMR(101MHz，CDCl₃) δ 173.40, 169.14, 157.03, 147.74, 146.38, 138.52, 137.05, 136.43, 133.75, 131.82, 130.22, 129.91, 127.78, 127.23, 126.55, 126.12, 125.76, 124.14, 121.32, 116.92, 66.13, 60.36, 37.17, 33.94, 28.26, 21.63, 21.10, 20.06, 14.30. HR-MS (m/z): is calculated as C₂₉H₃₀N₂O₅Na[M+Na]⁺: 509.2052, respectively; measured value: 509.2049.

ethyl 7- ((4-acetyl-2- (2-methylbenzyl) -3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) heptanoate (Ia-12)

Total yield of the route: 32.3 percent. A white solid.¹H NMR(400MHz，CDCl₃)δ9.04(d，J＝8.1Hz，1H)，7.92(d，J＝8.1Hz，1H)，7.71(t，J＝7.1Hz，1H)，7.66-7.61(m，1H)，7.56(s，1H)，7.24-7.21(m，1H)，7.18(d，J＝7.0Hz，1H)，7.15-7.07(m，2H)，4.46(t，J＝6.5Hz，2H)，4.37(s，2H)，4.13(q，J＝7.1Hz，2H)，2.50(s，3H)，2.49(s，3H)，2.30(t，J＝7.5Hz，2H)，1.87-1.78(m，2H)，1.68-1.60(m，2H)，1.41-1.37(m，4H)，1.26(t，J＝7.1Hz，3H)。¹³C NMR(101MHz，CDCl₃) δ 173.80, 169.16, 157.16, 147.71, 146.45, 138.57, 137.04, 136.46, 133.67, 131.83, 130.22, 129.88, 127.76, 127.20, 126.55, 126.09, 125.74, 124.12, 121.32, 116.96, 66.59, 60.25, 37.13, 34.32, 28.89, 28.65, 25.78, 24.91, 21.11, 20.08, 14.31. HR-MS (m/z): is calculated as C₃₁H₃₄N₂O₅Na[M+Na]⁺: 537.2365, respectively; measured value: 537.2362.

ethyl 4- (((4-acetyl-2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) methyl) benzoate (Ia-13)

Total yield of the route: 37.9 percent. A white solid.¹H NMR(400MHz，CDCl₃)δ9.14(d，J＝7.8Hz，1H)，7.98(d，J＝8.3Hz，2H)，7.91(d，J＝7.9Hz，1H)，7.75-7.70(m，1H)，7.63(ddd，J＝8.2，7.0，1.3Hz，1H)，7.53(s，1H)，7.35-7.30(m，4H)，7.25-7.21(m，2H)，7.18(ddd，J＝7.2，3.5，1.3Hz，1H)，5.52(s，2H)，4.40(s，2H)，4.35(q，J＝7.1Hz，2H)，2.47(s，3H)，1.36(t，J＝7.1Hz，3H)。¹³C NMR(101MHz，CDCl₃) δ 169.21, 166.51, 156.53, 148.04, 146.56, 141.74, 138.67, 137.96, 134.32, 131.87, 130.15, 129.82, 129.82, 129.41, 129.41, 128.54, 128.54, 127.97, 127.66, 127.66, 127.57, 126.63, 126.41, 124.38, 121.51, 116.94, 67.63, 61.14, 40.14, 21.22, 14.48. HR-MS (m/z): is calculated as C₃₁H₂₆N₂O₅Na[M+Na]⁺: 529.1739, respectively; measured value: 529.1735.

(E) -ethyl 4- (((4-acetyl-2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -2-butenoate (Ia-14)

Total yield of the route: 28.7 percent. A white solid.¹H NMR(400MHz，CDCl₃)δ9.17(d，J＝8.2Hz，1H)，7.95(d，J＝8.1Hz，1H)，7.76(t，J＝7.3Hz，1H)，7.68(t，J＝7.2Hz，1H)，7.56(s，1H)，7.40(d，J＝7.4Hz，2H)，7.30(t，J＝7.5Hz，2H)，7.22(t，J＝7.3Hz，1H)，7.11(dt，J＝15.8，4.3Hz，1H)，6.01(d，J＝15.8Hz，1H)，5.18(dd，J＝4.2，1.9Hz，2H)，4.45(s，2H)，4.23(q，J＝7.1Hz，2H)，2.51(s，3H)，1.32(t，J＝7.1Hz，3H)。¹³C NMR(101MHz，CDCl₃) δ 169.50, 166.49, 156.33, 148.41, 146.72, 142.28, 138.86, 138.16, 134.76, 132.14, 129.67, 129.67, 128.90, 128.90, 128.31, 127.94, 126.99, 126.76, 124.72, 122.49, 121.83, 117.22, 65.00, 60.99, 40.22, 21.52, 14.69. HR-MS (m/z): is calculated as C₂₇H₂₄N₂O₅Na[M+Na]⁺: 479.1583, respectively; measured value: 479.1579.

(E) -methyl 3- (4- (3- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) propoxy) phenyl) acrylate (Ia-15)

Total yield of the route: 33.5 percent. A white solid.¹H NMR(400MHz，CDCl₃)δ9.18(d，J＝8.0Hz，1H)，7.93(d，J＝8.0Hz，1H)，7.76-7.71(m，1H)，7.68-7.62(m，2H)，7.55(s，1H)，7.47(d，J＝8.7Hz，2H)，6.93(d，J＝8.7Hz，2H)，6.30(d，J＝16.0Hz，1H)，4.72(t，J＝6.1Hz，2H)，4.24(t，J＝6.2Hz，2H)，3.79(s，3H)，3.61-3.48(m，1H)，2.51(s，3H)，2.39(p，J＝6.1Hz，2H)，1.42(d，J＝6.8Hz，6H)。¹³C NMR(101MHz，CDCl₃) δ 169.17, 167.80, 160.71, 156.27, 152.35, 147.48, 144.54, 137.92, 133.75, 131.89, 129.78, 129.78, 127.62, 127.19, 126.13, 124.21, 121.30, 116.90, 115.29, 114.85, 114.85, 64.87, 63.06, 51.61, 30.65, 28.87, 21.11, 20.71, 20.71. HR-MS (m/z): is calculated as C₃₀H₃₀N₂O₆Na[M+Na]⁺: 537.2002, respectively; measured value: 527.1994.

(E) -4- ((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -2-butenoic acid ethyl ester (Ia-16)

Total yield of the route: 28.6 percent. A white solid.¹H NMR(400MHz，CDCl₃)δ9.20(d，J＝8.2Hz，1H)，7.94(d，J＝8.1Hz，1H)，7.75(t，J＝7.2Hz，1H)，7.67(dd，J＝11.2，4.0Hz，1H)，7.57(s，1H)，7.19(dt，J＝15.8，4.3Hz，1H)，6.20(dt，J＝15.7，1.8Hz，1H)，5.22(dd，J＝4.3，1.9Hz，2H)，4.24(q，J＝7.1Hz，2H)，3.62(hept，J＝6.8Hz，1H)，2.51(s，3H)，1.46(d，J＝6.8Hz，6H)，1.32(t，J＝7.1Hz，3H)。¹³C NMR(101MHz，CDCl₃) δ 169.24, 166.23, 155.48, 152.35, 147.74, 142.30, 137.85, 134.26, 131.95, 127.82, 127.47, 126.39, 124.41, 122.11, 121.45, 116.93, 64.67, 60.76, 30.72, 21.23, 20.90, 20.90, 14.40. HR-MS (m/z): is calculated as C₂₃H₂₄N₂O₅Na[M+Na]⁺: 431.1583, respectively; measured value: 431.1580.

ethyl 4- (((4-acetyl-2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) methyl) benzoate (Ia-17)

Total yield of the route: 38.1 percent. A white solid.¹H NMR(400MHz，CDCl₃)δ9.21-9.17(m，1H)，8.09(d，J＝8.3Hz，2H)，7.94(d，J＝7.9Hz，1H)，7.74(ddd，J＝8.2，7.0，1.2Hz，1H)，7.66(ddd，J＝8.2，7.0，1.3Hz，1H)，7.59(t，J＝4.2Hz，3H)，5.63(s，2H)，4.44-4.33(m，2H)，3.63(hept，J＝6.8Hz，1H)，2.52(s，3H)，1.45(d，J＝6.8Hz，6H)，1.40(t，J＝7.1Hz，3H).13C NMR(101MHz，CDCl3)δ169.04，166.27，155.77，152.28，147.50，141.84，137.72，133.94，131.78，130.00，129.74，129.74，127.58，127.44，127.44，127.19，126.14，124.18，121.24，116.75，67.29，60.93，30.60，21.02，20.65，20.65，14.27.HR-MS(m/z)：calcd for C27H26N2O5[M+Na]+：481.1739；found：481.1742.

Ethyl 5- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) pentanoate (Ia-18)

Total yield of the route: 29.8 percent. A white solid.¹H NMR(400MHz，DMSO-d₆)δ10.95(s，1H)，8.92(d，J＝8.2Hz，1H)，8.25(d，J＝8.0Hz，1H)，7.77-7.71(m，1H)，7.66(t，J＝7.3Hz，1H)，7.33(d，J＝7.3Hz，2H)，7.26(t，J＝6.0Hz，2H)，7.17(t，J＝6.1Hz，1H)，7.03(d，J＝4.2Hz，1H)，4.39(d，J＝3.7Hz，2H)，4.25(s，2H)，4.05(q，J＝7.0Hz，2H)，2.32(t，J＝7.0Hz，2H)，1.76(s，2H)，1.64(d，J＝6.2Hz，2H)，1.16(t，J＝7.0Hz，3H)。¹³C NMR(101MHz，DMSO-d₆) δ 172.66, 156.42, 155.06, 142.36, 140.23, 138.32, 130.93, 129.80, 128.88, 128.88, 128.88, 128.26, 128.26, 127.67, 126.56, 126.18, 125.36, 123.03, 122.33, 103.93, 65.60, 59.69, 33.15, 27.70, 21.20, 14.10. HR-MS (m/z): is calculated as C₂₆H₂₇N₂O₄[M+H]⁺: 431.1971, respectively; measured value: 431.1968.

ethyl 6- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) hexanoate (Ia-19)

Total yield of the route: 36.0 percent. A white solid.¹H NMR(400MHz，DMSO-d₆)δ10.96(s，1H)，8.93(d，J＝8.1Hz，1H)，8.26(d，J＝8.0Hz，1H)，7.76(t，J＝7.4Hz，1H)，7.68(t，J＝7.2Hz，1H)，7.34(d，J＝7.3Hz，2H)，7.29(t，J＝7.5Hz，2H)，7.20(t，J＝7.1Hz，1H)，7.04(s，1H)，4.40(d，J＝4.5Hz，2H)，4.27(s，2H)，4.05(q，J＝7.1Hz，2H)，2.28(t，J＝7.2Hz，2H)，1.79-1.71(m，2H)，1.62-1.53(m，2H)，1.41-1.32(m，2H)，1.17(t，J＝7.1Hz，3H)。¹³C NMR(101MHz，DMSO-d₆) δ 172.36, 156.08, 154.63, 141.99, 139.83, 137.94, 130.51, 129.35, 128.43, 128.43, 128.43, 127.85, 127.85, 127.29, 126.16, 125.77, 124.92, 122.60, 121.91, 103.51, 65.38, 59.23, 33.02, 27.53, 24.63, 23.75, 13.68. HR-MS (m/z): is calculated as C₂₇H₂₉N₂O₄[M+H]⁺: 445.2127, respectively; measured value: 445.2123.

ethyl 8- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) octanoate (Ia-20)

Total yield of the route: 37.4 percent. A white solid.¹H NMR(400MHz，DMSO-d₆)δ11.01(s，1H)，8.94(d，J＝8.0Hz，1H)，8.26(d，J＝8.0Hz，1H)，7.76(t，J＝7.4Hz，1H)，7.68(t，J＝7.5Hz，1H)，7.33(d，J＝7.2Hz，2H)，7.28(t，J＝7.5Hz，2H)，7.19(t，J＝7.1Hz，1H)，7.06(s，1H)，4.39(t，J＝6.1Hz，2H)，4.27(s，2H)，4.04(q，J＝7.1Hz，2H)，2.27(t，J＝7.3Hz，2H)，1.77-1.68(m，2H)，1.56-1.47(m，2H)，1.37-1.23(m，6H)，1.17(t，J＝7.1Hz，3H)。¹³C NMR(101MHz，DMSO-d₆) δ 172.84, 156.54, 155.08, 142.36, 140.28, 138.37, 130.93, 129.74, 128.81, 128.81, 128.81, 128.26, 128.26, 127.69, 126.56, 126.18, 125.35, 123.01, 122.32, 103.95, 65.94, 59.60, 33.49, 28.36, 28.36, 28.23, 25.35, 24.37, 14.10. HR-MS (m/z): is calculated as C₂₉H₃₂N₂O₄Na[M+Na]⁺: 495.2260, respectively; measured value: 495.2256.

example 2 Synthesis of Compounds of formula (Ib) (Compounds Ib-1 to Ib-14)

Adding 1g of benzoquinoxalinone ester synthesized according to the method in example 1 and an anhydrous methanol solution of hydroxylamine potassium into a flask, wherein the molar ratio of the benzoquinoxalinone ester to the hydroxylamine potassium is 1: 24, placing the flask in an ultrasonic cleaner for 30 minutes at 20-30 ℃, carrying out ultrasonic treatment, evaporating the solvent under reduced pressure, acidifying the residue by using a saturated citric acid solution with twice volume, adding ethyl acetate with the same volume, extracting for 3 times, combining organic phases, adding 20ml of brine, and extracting for 3 times. The organic phase was dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel (dichloromethane: methanol 10: 1) to give a solid.

The chemical names and parameters of the compounds of formula (Ib) are characterized as follows:

4- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -N-hydroxybutyramide (Ib-1)

Yield: 95.1 percent. A white solid.¹H NMR(400MHz，DMSO-d₆)δ10.98(s，1H)，10.47(s，1H)，8.90(d，J＝8.0Hz，1H)，8.76(s，1H)，8.24(d，J＝8.1Hz，1H)，7.74(t，J＝7.5Hz，1H)，7.66(t，J＝7.4Hz，1H)，7.36(d，J＝7.3Hz，2H)，7.28(t，J＝7.5Hz，2H)，7.18(t，J＝7.3Hz，1H)，7.02(s，1H)，4.39(t，J＝6.3Hz，2H)，4.28(s，2H)，2.16(t，J＝7.3Hz，2H)，2.02(dd，J＝13.4，6.5Hz，2H)。¹³C NMR(101MHz，DMSO-d₆)δ168.75，156.44，155.11，142.58，140.22，138.38，130.96，129.87，129.09，129.09，128.36，128.36，127.79，126.68，126.27，125.40，123.07，122.39，103.94，65.61，29.02，29.02，24.62。

HR-MS (m/z): is calculated as C₂₃H₂₂N₃O₄[M+H]⁺: 404.1610, respectively; measured value: 404.1612.

8- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -N-hydroxyoctanoyl amide (Ib-2)

Yield: 92.3 percent. A white solid.¹H NMR(400MHz，DMSO-d₆)δ11.00(s，1H)，10.40(s，1H)，8.97(d，J＝8.1Hz，1H)，8.73(s，1H)，8.29(d，J＝8.0Hz，1H)，7.80(t，J＝7.4Hz，1H)，7.72(t，J＝7.5Hz，1H)，7.34(dt，J＝14.9，7.4Hz，4H)，7.24(t，J＝7.0Hz，1H)，7.07(s，1H)，4.43(t，J＝5.8Hz，2H)，4.31(s，2H)，2.01(t，J＝7.3Hz，2H)，1.80-1.73(m，2H)，1.58-1.49(m，2H)，1.35-1.26(m，6H)。¹³C NMR(101MHz，DMSO-d₆) δ 169.16, 156.58, 155.08, 142.46, 140.29, 138.38, 130.96, 129.77, 128.85, 128.85, 128.85, 128.34, 128.34, 127.76, 126.62, 126.27, 125.36, 123.06, 122.37, 103.95, 66.01, 32.30, 28.58, 28.53, 28.32, 25.47, 25.11. HR-MS (m/z): calculated as C27H30N3O4[ M + H ]]⁺: 460.2236, respectively; measured value: 460.2238.

n-hydroxy-4- ((2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) butanamide (Ib-3)

Yield: 93.6 percent. A white solid.¹H NMR(400MHz，DMSO-d₆)δ10.89(s，1H)，10.47(s，1H)，8.96(d，J＝8.1Hz，1H)，8.74(s，1H)，8.24(d，J＝8.1Hz，1H)，7.75(t，J＝7.6Hz，1H)，7.66(t，J＝7.5Hz，1H)，7.03(s，1H)，4.44(t，J＝6.2Hz，2H)，3.48(dq，J＝13.5，6.8Hz，1H)，2.21(t，J＝7.3Hz，2H)，2.09-2.01(m，2H)，1.36(d，J＝6.8Hz，6H)。¹³C NMR(101MHz，DMSO-d₆)δ169.09，156.36，155.20，148.42，140.05，131.50，130.00，128.10，126.96，125.76，123.51，122.79，104.41，65.83，30.18，29.44，25.07，21.20，21.20。

HR-MS(m/z)：Is calculated as C₁₉H₂₂N₃O₄[M+H]⁺: 356.1610, respectively; measured value: 356.1616.

n-hydroxy-5- ((2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) pentanamide (Ib-4)

Yield: 90.8 percent. A white solid.¹H NMR(400MHz，DMSO-d₆)δ10.89(s，1H)，10.41(s，1H)，8.97(d，J＝8.1Hz，1H)，8.72(s，1H)，8.25(d，J＝8.1Hz，1H)，7.76(t，J＝7.5Hz，1H)，7.67(t，J＝7.5Hz，1H)，7.04(s，1H)，4.46(t，J＝5.9Hz，2H)，3.47(dt，J＝13.6，6.8Hz，1H)，2.07(t，J＝7.0Hz，2H)，1.81(dd，J＝13.4，6.4Hz，2H)，1.74(dd，J＝14.2，7.0Hz，2H)，1.37(d，J＝6.8Hz，6H)。¹³C NMR(101MHz，DMSO-d₆)δ168.94，155.97，154.73，147.93，139.63，131.05，129.51，127.64，126.49，125.29，123.06，122.33，103.97，65.55，31.93，29.83，27.96，21.97，20.68，20.68。

HR-MS (m/z): is calculated as C₂₀H₂₄N₃O₄[M+H]⁺: 370.1767, respectively; measured value: 367.1765.

n-hydroxy-6- ((2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) hexanamide (Ib-5)

Yield: 92.7 percent. A white solid.¹H NMR(400MHz，DMSO-d₆)δ10.88(s，1H)，10.38(s，1H)，8.97(d，J＝8.0Hz，1H)，8.69(s，1H)，8.24(d，J＝8.0Hz，1H)，7.75(t，J＝7.5Hz，1H)，7.67(t，J＝7.5Hz，1H)，7.04(s，1H)，4.44(t，J＝6.3Hz，2H)，3.46(dt，J＝13.7，6.8Hz，1H)，2.00(t，J＝7.3Hz，2H)，1.86-1.78(m，2H)，1.61(dt，J＝14.9，7.3Hz，2H)，1.51-1.42(m，2H)，1.36(d，J＝6.8Hz，6H).¹³C NMR(101MHz，DMSO-d₆)δ169.48，156.43，155.16，148.37，140.08，131.50，129.93，128.06，126.91，125.73，123.49，122.77，104.43，66.25，32.70，30.26，28.53，25.80，25.35，21.13，21.13。

HR-MS (m/z): is calculated as C₂₁H₂₆N₃O₄[M+H]+: 384.1923, respectively; measured value: 384.1926.

n-hydroxy-8- ((2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) octanoyl amide (Ib-6)

Yield: 93.6 percent. A white solid.¹H NMR(400MHz，DMSO-d₆)δ10.88(s，1H)，10.35(s，1H)，8.96(d，J＝8.2Hz，1H)，8.68(s，1H)，8.24(d，J＝8.1Hz，1H)，7.75(t，J＝7.5Hz，1H)，7.66(t，J＝7.5Hz，1H)，7.03(s，1H)，4.44(s，2H)，3.45(dt，J＝13.5，6.8Hz，1H)，1.95(t，J＝7.3Hz，2H)，1.80(s，2H)，1.51(dt，J＝15.5，7.7Hz，4H)，1.32(dd，J＝31.7，6.7Hz，10H)。¹³C NMR(101MHz，DMSO-d₆)δ169.58，156.44，155.16，148.35，140.09，131.50，129.91，128.07，126.91，125.72，123.49，122.77，104.41，66.35，32.71，30.30，29.02，28.95，28.77，26.07，25.55，21.10，21.10。

HR-MS (m/z): is calculated as C₂₃H₃₀N₃O₄[M+H]⁺: 412.2236: measured value: 412.2238.

n-hydroxy- (E) -3- (4- (4- ((2-isopropyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) butoxy) phenyl) acrylamide (Ib-7)

Yield: 94.7 percent. A white solid.¹H NMR(400MHz，DMSO-d₆)δ10.89(s，1H)，10.68(s，1H)，8.97(d，J＝8.1Hz，2H)，8.25(d，J＝8.0Hz，1H)，7.76(t，J＝7.5Hz，1H)，7.68(t，J＝7.6Hz，1H)，7.46(dd，J＝32.7，12.1Hz，3H)，7.05(s，1H)，6.98(d，J＝8.6Hz，2H)，4.53(d，J＝5.7Hz，2H)，4.13(d，J＝5.4Hz，2H)，3.45(dt，J＝13.5，6.7Hz，2H)，1.98(s，4H)，1.35(d，J＝6.8Hz，6H)。¹³C NMR(101MHz，DMSO-d₆)δ163.66，160.12，156.39，155.19，148.34，140.07，138.55，131.50，129.97，129.50，129.50，128.09，127.78，126.94，125.74，123.50，122.78，116.89，115.32，115.32，104.42，67.76，66.13，30.25，26.03，25.62，21.12，21.12。

HR-MS (m/z): calculated value C₂₈H₃₀N₃O₅[M+H]+: 488.2185, respectively; measured value: 488.2193.

n-hydroxy-5- ((2- (2-methylbenzyl) -3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) pentanamide (Ib-8)

Yield: 96.1 percent. A white solid.¹H NMR(400MHz，DMSO-d₆)δ10.95(s，1H)，10.40(s，1H)，8.80(d，J＝8.1Hz，1H)，8.72(s，1H)，8.24(d，J＝7.9Hz，1H)，7.73(t，J＝7.1Hz，1H)，7.66(t，J＝7.0Hz，1H)，7.24-7.17(m，2H)，7.14-7.10(m，2H)，7.03(s，1H)，4.43(t，J＝6.2Hz，2H)，4.27(s，2H)，2.43(s，3H)，2.04(t，J＝7.2Hz，2H)，1.80-1.74(m，2H)，1.70-1.63(m，2H)。¹³C NMR(101MHz，DMSO-d₆) δ 168.88, 156.54, 155.04, 142.18, 140.06, 136.72, 136.51, 130.93, 130.02, 129.69, 129.69, 127.79, 126.62, 126.38, 125.73, 125.34, 122.88, 122.37, 103.93, 65.78, 36.06, 31.89, 27.87, 21.80, 19.59. HR-MS (m/z): is calculated as C₂₅H₂₆N₃O₄[M+H]⁺: 432.1923, respectively; measured value: 432.1925.

n-hydroxy-6- ((2- (2-methylbenzyl) -3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) hexanamide (Ib-9)

Yield: 92.8 percent. A white solid.¹H NMR(400MHz，DMSO-d₆)δ10.95(s，1H)，10.37(s，1H)，8.81(d，J＝7.9Hz，1H)，8.69(s，1H)，8.24(d，J＝7.7Hz，1H)，7.76-7.71(m，1H)，7.70-7.64(m，1H)，7.19(dd，J＝5.6，2.9Hz，2H)，7.15-7.08(m，2H)，7.03(s，1H)，4.42(t，J＝6.3Hz，2H)，4.27(s，2H)，2.43(s，3H)，1.97(t，J＝7.4Hz，2H)，1.82-1.73(m，2H)，1.56(dt，J＝15.1，7.5Hz，2H)，1.36(dt，J＝15.0，7.6Hz，2H)。¹³C NMR(101MHz，DMSO-d₆)δ169.04，156.56，155.04，142.20，140.09，136.75，136.48，130.93，130.01，129.68，129.58，127.78，126.61，126.37，125.71，125.34，122.88，122.37，103.94，65.99，36.10，32.23，28.05，25.23，24.92，19.59。

HR-MS (m/z): is calculated as C₂₆H₂₈N₃O₄[M+H]⁺: 446.2080, respectively; measured value: 446.2083.

7- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -N-hydroxyheptanamide (Ib-10)

Yield: 93.5 percent. A white solid.¹H NMR(400MHz，DMSO-d₆) δ 10.36(s, 1H), 8.69(s, 1H), 8.63(d, J ═ 8.3Hz, 1H), 8.16(dd, J ═ 8.2, 2.9Hz, 1H), 7.70(dd, J ═ 10.9, 4.3Hz, 1H), 7.58-7.52(m, 1H), 7.40(d, J ═ 7.2Hz, 2H), 7.31(t, J ═ 7.5Hz, 2H), 7.21(t, J ═ 7.3Hz, 1H), 6.80(d, J ═ 4.5Hz, 1H), 4.17(s, 4H), 1.98(dd, J ═ 9.6, 4.8Hz, 2H), 1.88(d, J ═ 6.2, 2H), 1.60 (s, 1H), 1.37.6, 7.8 Hz, 14H), 1.88(d, J ═ 6.2, 1H), 1.6, 1.8 Hz, 7.6, 7.8 Hz, 14H). HR-MS (m/z): is calculated as C₂₆H₂₈N₃O₄[M+H]⁺: 446.2080, respectively; measured value: 446.2087.

5- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -N-hydroxypentanamide (Ib-11)

Yield: 91.2 percent. A white solid.¹H NMR(400MHz，DMSO-d₆) δ 10.97(s, 1H), 10.41(s, 1H), 8.92(d, J ═ 7.9Hz, 1H), 8.74(s, 1H), 8.24(d, J ═ 7.9Hz, 1H), 7.78-7.73(m, 1H), 7.70-7.65(m, 1H), 7.36(d, J ═ 7.0Hz, 2H), 7.29(t, J ═ 7.2Hz, 2H), 7.20(d, J ═ 7.1Hz, 1H), 7.02(s, 1H), 4.41(s, 2H), 4.27(s, 2H), 2.02(d, J ═ 6.6Hz, 2H), 1.76(s, 2H), 1.66(d, J ═ 6.6, 2H). HR-MS (m/z): the calculation is as follows: c₂₄H₂₄N₃O₄[M+H]⁺: 418.1767, respectively; measured value: 418.1766.

6- ((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) -N-hydroxyhexanamide (Ib-12)

Yield: 90.4 percent. A white solid.¹H NMR(400MHz，DMSO-d₆)δ10.97(s，1H)，10.38(s，1H)，8.92(d，J＝7.9Hz，1H)，8.70(s，1H)，8.23(d，J＝7.6Hz，1H)，7.74(d，J＝7.1Hz，1H)，7.68(d，J＝7.4Hz，1H)，7.36-7.26(m，4H)，7.20(d，J＝6.2Hz，1H)，7.02(s，1H)，4.39(s，2H)，4.27(s, 2H), 1.95(d, J ═ 6.5Hz, 2H), 1.75(s, 2H), 1.53(d, J ═ 6.7Hz, 2H), 1.35(s, 2H). HR-MS (m/z): is calculated as C₂₅H₂₆N₃O₄[M+H]⁺: 432.1923, respectively; measured value: 432.1929.

4- (((2-benzyl-3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) methyl) -N-hydroxybenzamide (Ib-13)

Yield: 90.9 percent. A white solid.¹H NMR(400MHz，DMSO)δ11.25(s，1H)，11.06(s，1H)，9.08(s，1H)，8.93(d，J＝8.1Hz，1H)，8.25(d，J＝8.1Hz，1H)，7.77(d，J＝7.3Hz，1H)，7.74(d，J＝7.0Hz，2H)，7.71-7.66(m，1H)，7.44(d，J＝8.2Hz，2H)，7.33-7.27(m，4H)，7.24-7.19(m，1H)，7.05(s，1H)，5.56(s，2H)，4.34(s，2H).¹³C NMR (101MHz, DMSO) δ 175.07, 171.76, 171.76, 156.46, 155.70, 142.80, 140.57, 138.72, 131.32, 130.59, 129.39, 129.39, 129.39, 128.85, 128.85, 128.85, 128.34, 127.89, 127.89127.39, 126.78, 125.92, 123.57, 122.85, 104.25, 72.88, 43.21. HR-MS (m/z): is calculated as C₂₇H₂₂N₃O₄[M+H]⁺: 452.1610, respectively; measured value: 452.1614.

n-hydroxy-7- ((2- (2-methylbenzyl) -3-oxo-3, 4-dihydrobenzo [ f ] quinoxalin-6-yl) oxy) heptanamide (Ib-14)

Yield: 93.7 percent. A white solid.¹H NMR (600MHz, MeOD) δ 8.88(d, J ═ 7.7Hz, 1H), 8.26(d, J ═ 8.2Hz, 1H), 7.65-7.62(m, 1H), 7.60-7.57(m, 1H), 7.15(d, J ═ 7.2Hz, 1H), 7.11(d, J ═ 7.3Hz, 1H), 7.08-7.06(m, 1H), 7.03(dd, J ═ 9.3, 4.6Hz, 1H), 6.99(s, 1H), 4.42(t, J ═ 6.3Hz, 2H), 4.29(s, 2H), 2.44(s, 3H), 2.06(t, J ═ 7.4Hz, 2H), 1.77(dd, J ═ 6, 1H), 1.35 (m, 1H), 1.31.35-1H, 1H). HR-MS (m/z): is calculated as C₂₇H₃₀N₃O₄[M+H]⁺：460.2236；found：460.2239。

Example 3: in vitro antitumor Activity test

Clinical tumor treatment drug regorafenib is used as a positive control drug, a corresponding solvent is used as a negative control drug, T24 (transitional cell carcinoma cells of bladder) and HCV-29 (epithelial cells of human bladder) are used as test cell strains: MTT method is used for in vitro antitumor activity test of the compound.

The drug and cells were co-cultured for 48 hours, and 190. mu.l of cells were seeded in 96-well plates (about 5X 10) at a density based on the results of the growth rate of the pre-experimental cells⁴-1x10⁵One/hole)

After culturing for 24 hours and cell adherence, 10 mul of samples with series concentration are respectively added, each sample is provided with 3 multiple wells, 4 negative control wells are additionally arranged, and blank substrates are added.

The cells were incubated at 37 ℃ for 48 hours under saturated humidity with 5% carbon dioxide, 10. mu.l of MTT (5mg/L) was added to each well, and the incubation was continued for 4 hours.

The supernatant was aspirated, and 150. mu.L/well of dimethyl sulfoxide was added thereto, and after sufficient dissolution, OD values were measured at measurement wavelengths of 570nm and 630nm with a microplate reader, and the cell proliferation inhibition ratio of each well was calculated, and the results are shown in Table 1 below.

TABLE 1 inhibitory Activity of the Compounds of the invention on different cell lines

The structural formula of regorafenib is as follows:

SAHA structural formula as follows:

as can be seen from the table, for the transitional cell carcinoma cell T24 of bladder, a considerable part of the benzoquinoxalinone compounds show better antitumor activity, and the compounds Ia-14, Ia-16, Ib-1 to Ib-6, Ib-9 and Ib-10 have better inhibitory activity on T24 cells than the clinical antitumor drug regorafenib; the inhibitory activity of Ib-3 to Ib-6 and Ib-10 on T24 cancer cells is better than that of clinical antitumor drug SAHA.

In order to verify the cytotoxicity of the compounds on human normal cells, the MTT method is utilized to carry out activity screening on human bladder epithelial cells HCV-29, and the result shows that most of the benzoquinoxalinone compounds have low toxicity on the human bladder epithelial normal cells.

The in vitro anti-tumor activity test shows that the benzoquinoxalinone compound provided by the invention can be expected to be used for preparing anti-tumor drugs.

Example 4: HDAC1, HDAC6 and HDAC8 enzyme Activity assays

Human HDAC1, HDAC6 and HDAC8 enzyme activity tests were performed, respectively, according to the instructions provided by the reagent vendor (shanghai fusheng industries ltd). HDAC inhibitor SAHA was used as a positive control. The method comprises the following steps:

(1) diluting a standard product: diluting the standard substance according to a reagent manufacturer;

(2) sample adding: blank holes (blank reference holes are not added with samples and enzyme labeling reagents, and other operations are the same), standard holes and sample holes to be detected are respectively arranged. The standard sample is accurately loaded with 50 mul on the enzyme-labeled coating plate, 40 mul of sample diluent is loaded in the sample hole to be detected, and then 10 mul of sample to be detected is loaded (the final dilution of the sample is 5 times). Adding a sample to the bottom of the hole of the enzyme label plate, keeping the sample from touching the hole wall as much as possible, and slightly shaking and uniformly mixing the sample and the hole wall;

(3) and (3) incubation: using a sealing plate film to seal the plate, and incubating for 30 minutes at 37 ℃;

(4) preparing liquid: diluting 20 times of the concentrated washing liquid with 20 times of distilled water for later use;

(5) washing: carefully uncovering the sealing plate film, discarding liquid, spin-drying, filling washing liquid into each hole, standing for 30 seconds, then discarding, repeating the steps for 5 times, and patting dry;

(6) adding an enzyme: adding 50 mul of enzyme-labeled reagent into each hole except for blank holes;

(7) and (3) incubation: the operation is the same as that in (3);

(8) washing: the operation is the same as (5);

(9) color development: adding 50 mul of color developing agent A into each hole, then adding 50 mul of color developing agent B, lightly shaking and uniformly mixing, and developing for 10 minutes at 37 ℃ in a dark place;

(10) and (4) terminating: stop the reaction by adding 50. mu.l of stop solution to each well (blue color immediately turns yellow);

(11) and (3) determination: the absorbance (OD value) of each well was measured sequentially at a wavelength of 450nm with the blank well being zeroed.

The results of the experiments are shown in table 2 below.

TABLE 2 inhibitory Activity of compounds of the present application on HDAC1, HDAC6 and HDAC8

By evaluating the inhibition activity of the above benzo-quinoxalinone compounds on HDAC subtypes, the inhibition activity of most of the compounds of the present invention on three subtypes, namely HDAC1, HDAC8 and HDAC6, is better or equivalent to that of SAHA, especially the inhibition activity of compound Ib-10 on three subtypes, namely HDAC1, HDAC8 and HDAC6, is better than that of SAHA of a positive control drug, the IC50 value reaches a low nanomolar level, the compound has a broad-spectrum HDAC inhibition activity, and the compound is expected to become a broad-spectrum HDAC inhibitor, thereby providing a reference for developing an antitumor lead compound.

EXAMPLE 5 Compound Ib-10 apoptosis assay

The apoptosis test procedure for compound Ib-10 is as follows:

(1) and (3) culturing the cells: a100 ml culture flask was taken, a certain amount of 1% double antibody and 10% fetal bovine serum in DMEM medium were added, and human bladder cancer cells T24 were placed in the medium and cultured in a constant temperature incubator containing 5% carbon dioxide and 95% air at 37 ℃.

(2) Digestion of cells and plating: after the non-small cell lung cancer A549 cells in logarithmic growth phase are cleaned by 3mL of PBS buffer solution (generally washed for 2-3 times), the cells are digested by 1mL of trypsin, after the cells are completely digested, 10% of fetal bovine serum DMEM culture medium is added to stop the digestion, the cells are blown down carefully and repeatedly to obtain single cell suspension, the single cell suspension is diluted by 10% of fetal bovine serum DMEM culture medium until the density is 20000 to 30000 cells/mL, and the diluted cell suspension is planted in a 6-well plate in a single-well 3mL manner.

(3) Adding medicine: and (3) culturing the cells in the step (2) in a constant-temperature incubator containing 5% of carbon dioxide at 37 ℃ until the adherent growth area of the cells is about 70% of the hole area. And adding a compound Ib-10 to be screened (the DMSO content of the compound is lower than 1%) into a single hole of the 6-hole plate, setting the drug concentration to be 2 mu M, 4 mu M and 8 mu M, setting the dosing concentration of the positive control group and the positive control group to be the same as that of the group to be tested, and setting a blank control group at the same time. The cells of the experimental and blank control groups were incubated at 37 ℃ for 24 hours in an incubator containing 5% carbon dioxide.

(4) Collecting cells: collecting the cells in the step (3), placing the collected cells in a centrifuge (1500r/min) for centrifugation, discarding the supernatant, washing the cells with 3ml of PBS solution, centrifuging and discarding the supernatant.

(5) Dyeing: to this tube was added 200. mu.L of 1 Xthe tube plus cells, centrifuged and the supernatant cell suspension was discarded, and transferred to a 1.5ml centrifuge tube, and 5. mu.L of FITC-labeled Annexin V was added, and incubated in a 37 ℃ incubator for 20 minutes. Then adding 300 mu L of 1 × Binding Buffer and 5 Binding i into a 1.5ml centrifuge tube, mixing uniformly, filtering, and keeping an ice layer away from light for later use.

(6) And (3) computer detection: and (5) putting the centrifuge tube in the step (5) on a machine, and completing all sample detection within 1 hour.

The results are shown in FIGS. 1 to 7, in which the cell numbers in the regions Q2 and Q3 indicate the cell numbers of apoptosis, and the cell numbers in the region Q4 indicate the number of living cells. In fig. 1, the blank control group had 1.1% of the total number of cells in the apoptotic number of cancer cells in the Q2 and Q3 regions after 24 hours. The positive control group had cancer cell apoptosis numbers of 9.3%, 32.0%, 43.3% of the total number of cells in the Q2 and Q3 regions at 3 concentrations (2. mu.M, 4. mu.M, and 8. mu.M) at 24 hours after SAHA addition, as shown in FIG. 2, FIG. 4, and FIG. 6, respectively. And the experimental group had 3 concentrations (2. mu.M, 4. mu.M and 8. mu.M) at 24 hours after the addition of compound Ib-10, as shown in FIG. 3, FIG. 5 and FIG. 7, the apoptotic numbers of the cancer cells in the Q2 and Q3 regions were 13.4%, 55.9% and 72.3% of the total number of the cells, respectively, and the apoptotic rates were 12.3%, 54.8% and 71.2% higher than those of the blank control group and 4.1%, 23.9% and 29.0% higher than those of the positive control group, respectively. The experimental results show that the compound Ib-10 can promote apoptosis well and has better effect than SAHA in promoting apoptosis at each tested concentration.